EXECUTIVE SUMMARY - environmentclearance.nic.inenvironmentclearance.nic.in/writereaddata/Online/... · Multiple Effect Evaporator (MEE) followed by RO Filtration. B Air pollution

M/s. R L FineChem Pvt. Ltd.,

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CHAPTER 1

EXECUTIVE SUMMARY

1.1 INTRODUCTION

1.1.1 Preamble

Amendment of the Environmental Impact Notification No. S.O. 60(E) dated 27.01.1994, issued by the MoEF, Govt. of India has made mandatory under Schedule-I of EIA notification for 30 different activities to obtain NOC (No Objection Certificate) from the State Pollution Control Board and Environmental Clearance from the Ministry of Environment & Forests, Govt. of India. This amendment to the EIA Notification is effective from 14.09.2006. It is in this context that all such activities need to prepare Rapid Environmental Impact Assessment (REIA) report. The proposed project comes within the interstate boundary of 5 KM due to which this industry falls under category A which necessitate the EC clearance from MOEF as per the above said notification. M/s. R L Finechem Pvt. Ltd., HIG;#2000, Ray House; Near Yelahanka New Town Police Station; Yelahanka; Bangalore-560 064, intends to establish an Active Pharmaceutical Ingredients (APIs) manufacturing industry with R & D activity at Plot No. 27-29, KIADB Industrial Area, Gouribidanoor, Karnataka. The APIs proposed to be manufactured are provided under section 1.1.2 (Project at Glance)

Sl. No.

APIs Production capacity (kg/month)

Nature/ Type of product

1 Amtriptyline hydrochloride 10,000

All products are API’s

2 Imipramine HCl/Desipramine HCl 1,150

3 Cyproheptadine HCl 700

4 Pitofenone HCl 700

5 Pyrimethamine 600

6 Cyclobenzaprine HCl 1,150

7 Clomipramine HCl 600

8 Chlorpromazine HCl 1,500

9 Doxylamine Succinate 1,400

10 Orphenadrine Citrate/ HCl 4,000

11 Trimipramine Maleate/ Mesylate 500

12 Flupentixol HCl 40

13 Melitracen HCl 300

14 Carbinoxamine Maleate 700

15 Opipramol HCl 400

16 Sulfadoxine 2,400


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17 Doxepin HCl 280

18 Nitrazepam 240

19 Dothiepin HCl 1,200

20 Bromazepam 60

21 Flunarazine HCl 430

22 Cinnarazine 2,500

23 Clonazepam 130

24 Lorazepam 130

25 Duloxetine HCl 300

26 Dapoxetine HCl 50

27 Desvenlafaxine HCl 400

28 Trihexyphenadyl HCl 300

29 Tramadol HCl 2,500

30 Sulfamethoxy Pyrazine HCl 500

31 Alimemazine Tartarate 200

32 Alprazolam 110

33 Diazepam 120

34 Buclazine HCl 400

35 Meclazine HCl 400

36 Carbamezapine 2,000

TOTAL 38,390

Sl.No. Details

1 Project Establishment of Active Pharmaceutical Ingredients (APIs) manufacturing industry with R & D activity – “M/s. R L Finechem Pvt. Ltd.,”

2 Project developers M/s. R L Finechem Pvt. Ltd., HIG;#2000, Ray House; Near Yelahanka New Town Police Station; Yelahanka; Bangalore-560 064

3 Location of the site

Plot No. 27-29, KIADB Industrial Area, Gouribidanoor, Karnataka.

4 Constitution of the Organization

Private Limited Company

5 Raw materials Details of the raw materials required by the industry is appended in Section 3.6.1, Chapter 3 of this report.

6 Product/s proposed to be manufactured with production capacities? #

The following APIs are proposed to be manufactured

Sl. No.

APIs Production capacity

(kg/month)

Production capacity

(kg/annum)

1 Amtriptyline 10,000 1,20,000

1.1.2 PROJECT AT GLANCE


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hydrochloride

2 Imipramine HCl/Desipramine HCl

1,150 13,800

3 Cyproheptadine HCl 700 8,400

4 Pitofenone HCl 700 8,400

5 Pyrimethamine 600 7,200

6 Cyclobenzaprine HCl 1,150 13,800

7 Clomipramine HCl 600 7,200

8 Chlorpromazine HCl 1,500 18,000

9 Doxylamine Succinate 1,400 16,800

10 Orphenadrine Citrate/ HCl

4,000 48,000

11 Trimipramine Maleate/ Mesylate

500 6,000

12 Flupentixol HCl 40 480

13 Melitracen HCl 300 3,600

14 Carbinoxamine Maleate 700 8,400

15 Opipramol HCl 400 4,800

16 Sulfadoxine 2,400 28,800

17 Doxepin HCl 280 3,360

18 Nitrazepam 240 2,880

19 Dothiepin HCl 1,200 14,400

20 Bromazepam 60 720

21 Flunarazine HCl 430 5,160

22 Cinnarazine 2,500 30,000

23 Clonazepam 130 1,560

24 Lorazepam 130 1,560

25 Duloxetine HCl 300 3,600

26 Dapoxetine HCl 50 600

27 Desvenlafaxine HCl 400 4,800

28 Trihexyphenadyl HCl 300 3,600

29 Tramadol HCl 2,500 30,000

30 Sulfamethoxy Pyrazine HCl

500 6,000

31 Alimemazine Tartarate 200 2,400

32 Alprazolam 110 1,320

33 Diazepam 120 1,440

34 Buclazine HCl 400 4,800

35 Meclazine HCl 400 4,800

36 Carbamezapine 2,000 24,000

Total 38,390 4,60,680

7 Project cost? Sl. no.

Cost of ` (Crores)


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1 Land 2.5

2 Construction 6.7

3 Proposed investment on Plant and machinery

21

4 Environment Management Budget 3

TOTAL 33.2

Rupees Thirty Three Crores & Two Lakhs Only

8 Total man power requirement during construction

phase occupancy

phase

Construction phase: 50 people during peak construction period. Occupancy/Operational phase: 110 employees.

9 Proposed trees to be planted?

Tress proposed to be planted – 300

10 Species of trees to be planted?

Araka, Silver Oak, Wild Badam, Mango, Neem trees, Michelia champaca, Butea monosperma, Pongamia pinnata, Bauhinia purpurea, Cassia fistula, Alstonia scholaris, and several native species

11 Rain water harvesting tank details?

114 KL capacity

12 Groundwater recharging pits details?

1.2 m dia x 2.5 m deep spaced at 10 m center to center all along the storm water drain.

13 Elevation of the project site with respect to MSL?

686 m above MSL; Latitude: 13°42'23.74"N; Longitude: 77°30'11.96"E

14 Total area of the project?

24,290 SQM (about 6 Acres)

15 Hydrology and hydrogeology?

Gollapuram Lake at a distance of about 3.5 km towards North East direction, Kudumaldkunta Lake at a distance of about 1 km towards South West direction, Yerrahalli Lake at a distance of about 2.5 km towards South direction, Yerrahalli Lake at a distance of about 2.5 km towards South direction, Gaudasandra Lake at a distance of about 4 km towards South East direction, Thumakunta Lake at a distance of about 2 km towards North direction, Penner River at a distance of about 2.5 km towards West direction, Melya Lake at a distance of about 5 km towards East direction.

16 Ground water quality?

Potabilty of water has to be tested.

17 Noise levels? Noise levels are to be tested.


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18 Facilities provided for the workers during construction phase at site?

1. Adequate potable drinking water supply 2. Septic tank and soak pit facility for treating wastewater generated from the workers.

1.1.3 Summary of water, wastewater, air & solid waste details

Sl. No.

Particulars Details

A Water, wastewater details

1 Water supply sources Bore well water supply

2 Total water requirement 186.050 KLD

3 Total wastewater generated

72.955 KLD

4 Treatment/Disposal details

Effluent Treatment Plant (ETP) with Multiple Effect Evaporator (MEE) followed by RO Filtration.

B Air pollution details

1 Sources of air pollution Process sections, Boiler, DG set

2 Air pollution control units provided

* Packed column scrubbers for process sections with Chimney height of 5 m above RL. * DG set stack height as per the stack height calculation for 500 KVA is 7 m above RL. * For agro based fuel boiler for 3 Tons stack height of 30.5 m above RL and with Mechanical dust collector. * Thermic Fluid Heater (TFH) of stack

Briquette Fired- 1 no with chimney height 30.5 m AGL

Furnace Oil Fired- 1 no with chimney height 13 m AGL



C Solid/Hazardous wastes

1 Source of solid waste Domestic sources and Manufacturing process.

2 Total quantity of solid waste generated

Domestic solid waste – 6,600 kg/annum


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Hazardous solid waste

Sl. no

Hazardous waste Quantity kg/annum

1 Residue from the manufacturing process – (solvent recovery)

55,200

2 Spent Carbon 25,464

3 Waste oil generation from DG set

200 L

4 Inorganic salt from MEE.

85,140

3 Treatment/Disposal of solid wastes

* The domestic wastes are segregated at source and collected in bins. The organic portion of the solid wastes will be composted and recyclable portion will be disposed to the recycler for scientific recycling. * The disposal optioclingns for various types of generated hazardous waste handling and management is detailed in Chapter 3, Section 3.9.5 of this report.

1.1.4 Water requirement and wastewater treatment and discharge details

i) QUANTITY OF WATER REQUIRED AND WASTEWATER GENERATED The total quantity of water requirement for the industry is about 186.050 KLD. The break-up of the consumption of water is as presented in table below.

Water consumption and discharge

Water consumed for Consumption (LPD)

Discharge (LPD)

(a) Domestic (toilet, canteen etc.) 4,950 4,455

(b) Gardening/Landscape development

5,000 -

(c) Industrial purpose 1,76,100 68,500

1 Process

DM plant and its rejects 20,400 or say 20,500+2,000=22,500

22,459 (from process) + 2,000

(DM reject)=24,459 or say 25,500

2 Washing/Cleaning 29,810 or say 30,000 30,000


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3 Softener/rejects 20,000 2,000 (blow-down) Boiler feed for 3 MT boiler 18,000

4 Cooling tower – 5 nos. 75,600 (make-up water)

1,000 (bleed off)

5 Scrubber – 4 no. 5,000 5,000

6 R&D 5,000 5,000

Total 1,86,050 LPD or say 186.050 KLD

72,955 LPD or say 72.955

KLD Note:

LPD = L/day; KLD = kilo liter/day The excess quantity of process effluent generated is due to the reactions taking

place during the manufacturing process. ii) WASTEWATER TREATMENT AND DISPOSAL DETAILS

The treatment methods and the final disposal of each type of wastewater generated is appended in the table below

Sewage/wastewater treatment and discharge

Sewage/effluent generated from

Treatment provided Final disposal point

(a) Domestic Sewage is mixed and treated along with Low strength Effluent treatment plant

Recycle and on land irrigation

(b) Industrial Full fledged ETP with collection tanks of 10 KL capacity (3 no.s) are proposed to be provided.

Industrial effluent is proposed to be treated in Effluent Treatment Plant (ETP) with Multiple Effective Evaporator (MEE) followed by RO fitration for treatment, reuse and disposal.

The raw materials required for the manufacture of APIs are appended in the table 1 below. Raw materials as listed will be procured as per the production requirement.

Table 1: Raw materials requirement

Sl. No.

Product Raw materials Quantity required Solvents required after recycling

kg/annum kg/batch kg/month kg/annum

1 Amtriptyline THF 40 1360 16320

1.1.5 RAW MATERIALS


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hydrochloride Dibenzo suberone 208 7072 84864

Toluene 2200 74800 897600 163200

Water 1600 54400 652800

Mg 24 816 9792

Dimethylamino propyl chloride

120 4080 48960

Con Hcl acid 110 3740 44880

N-Butanol 1000 34000 408000 40800

HCl gas 36 1224 14688

Acetone 1800 61200 734400 163200

NaOH 80 2720 32640

H2O2 (20%) 80 2720 32640

Carbon 20 680 8160

2 Imipramine HCl/Desipram

ine HCl

Imino Dibenzyl 195 780 9360

Dimethylamino Propyl Chloride

120 480 5760

Sodamide 39 156 1872

Toluene 1000 4000 48000 4800

Water 600 2400 28800

Methanol Hcl 110 440 5280

Acetone 800 3200 38400 4800

Carbon 10 40 480

3 Cyproheptadine HCl

THF 25 75 900

Dibenzo Suberenone

206 618 7416

N-Methylchloro Piperidine

133 399 4788

Toluene 2600 7800 93600 7200

Water 500 1500 18000

Methanol 600 1800 21600 3600

Con. HCl 110 330 3960

IPA 1500 4500 54000 9000

Carbon 15 45 540

Magnesium 24 72 864

4 Pitofenone HCl

Potassium bicarbonate

100 200 2400

Methyl ester intermediate

256 512 6144

Chloro ethyl piperidine

147 294 3528

Toluene 1000 2000 24000 2400

Water 600 1200 14400


Acetone 1000 2000 24000 3600


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Carbon 10 20 240

5 Pyrimethamine

PCBC 150 450 5400

Ester 116 348 4176

Toluene 750 2250 27000 3600

Water 1000 3000 36000

MEG 60 180 2160

Methanol 1200 3600 43200 4500

Guanidine 60 180 2160

Carbon 10 30 360

6 Cyclobenzaprine HCl


120 360 4320

Dibenzo Suberenone

206 618 7416

Toluene 2500 7500 90000 9000

Water 600 1800 21600

Con. Hcl 110 330 3960

Acetone 1000 3000 36000 6300

Mg 24 72 864

Carbon 10 30 360

7 Clomipramine HCl

3-Chlorolmino Dibenzyl

230 460 5520


120 240 2880

Sodamide 39 78 936

Toluene 1000 2000 24000 2400

Water 600 1200 14400


Acetone 800 1600 19200 2400

Carbon 10 20 240

8 Chlorpromazine HCl

KOH 59 295 3540

2-Chloro pheno thiazine

233 1165 13980

Toluene 1000 5000 60000 6000

Water 600 3000 36000


120 600 7200

Acetone 1000 5000 60000 12000


Carbon 10 50 600

9 Doxylamine Succinate

2-Acetyl pyridine 120 600 7200

Chloro Benzene 112 560 6720

Diethylamino ethyl chloride

107 535 6420

Water 1200 6000 72000

Toluene 1200 6000 72000 9000


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THF 30 150 1800

NaOH 40 200 2400

Carbon 15 75 900

Mg 24 120 1440

Succinic acid 110 550 6600

Acetone 1000 5000 60000 10500


2-methyl Benzo phenone

215 2150 25800

NaOH 40 400 4800

Dimethylamino Ehtanol

90 900 10800

Toluene 1000 10000 120000 12000

Citric acid 180 1800 21600

Water 600 6000 72000

Acetone 1500 15000 180000 30000

Carbon 10 100 1200


Sodamide 39 78 936


Toluene 1000 2000 24000 2400

Water 600 1200 14400

Dimethylamino Methylpropyl chloride

135 270 3240

Acetone/EA 800 1600 19200 2400

Maleic acid 110 220 2640

Carbon 10 20 240

12 Flupentixol HCl

THF 10 10 120

Trifluorothioxanthone

28 28 336

Mg 2.5 2.5 30

Toluene 700 700 8400 840

Water 200 200 2400

Acetone 300 300 3600 420

Carbon 5 5 60

Con Hcl acid 21 21 252

Piperizino ehtanol intermediate

20 20 240

13 Melitracen HCl

THF 30 30 360

Dimethyl anthrone

220 220 2640


120 120 1440

Toluene 2200 2200 26400 4200

Water 600 600 7200


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Mg 24 24 288

Acetone 1000 1000 12000 2100

Carbon 15 15 180


14 Carbinoxamine Maleate

Pyridine Benz Hydrol

220 440 5280

NaOH 40 80 960

Dimethylamino Ethyl chloride

107 214 2568

Toluene 1000 2000 24000 2400


Water 600 1200 14400

Acetone 1000 2000 24000 4200

Carbon 10 20 240

15 Opipramol HCl

Imino stilbene 96 96 1152

NaOH 40 40 480

Bromochloro Propane

78 78 936

Toluene 2000 2000 24000 2400

Piperizinoethanol 65 65 780

Water 1200 1200 14400

Acetone 1200 1200 14400 2400

Carbon 10 10 120

HCl 36 36 432

16 Sulfadoxine P-Amino sulfonamide

172 1376 16512

Methoxy dichloro pyrimidine

179 1432 17184

Water 2000 16000 192000

Toluene 1500 12000 144000 24000

NaOH 40 320 3840

Methanol 2000 16000 192000 19200

Sodium methoxide

54 432 5184

Carbon 15 120 1440

17 Doxepin HCl Mg 24 24 288


120 120 1440

Toluene 2500 2500 30000 3000

Doxiepinone 210 210 2520

THF 20 20 240

Water 600 600 7200

Con Hcl 110 110 1320

Acetone 1000 1000 12000 2100

Carbon 10 10 120


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18 Nitrazepam Chloroacetyl chloride

112 112 1344

2-amino 5-nitro benzophenone

242 242 2904

Toluene 1000 1000 12000 1800

Ammonia 51 51 612

Carbon 10 10 120

Methanol 1250 1250 15000 3000

19 Dothiepin HCl Mg 24 96 1152


120 480 5760

Toluene 2500 10000 120000 12000

Dothiepinone 226 904 10848

THF 20 80 960

Water 600 2400 28800

Con Hcl 110 440 5280

Acetone 1000 4000 48000 8400

Carbon 10 40 480

20 Bromazepam Chloroacetyl chloride

30 30 360

2-amino 5-bromo benzoyl pyridine

70 70 840

Toluene 600 600 7200 1200

Ammonia 14 14 168

Carbon 5 5 60

Methanol 800 800 9600 2400

21 Flunarazine HCl

Difluro Benzhydrol

220 220 2640

Piperizine 86 86 1032

Toluene 1500 1500 18000 2400

HCl 110 110 1320

NaOH 40 40 480

Water 1425 1425 17100

Cinnamyl alcohol 134 134 1608

Acetone/IPA 2000 2000 24000 4200

Carbon 15 15 180

Methanol 2000 2000 24000 3600

HCl Gas 73 73 876

22 Cinnarazine Benzhydrol 184 1288 15456


Toluene 1500 10500 126000 16800

HCl 110 770 9240

NaOH 40 280 3360

Water 1425 9975 119700



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Acetone/IPA 2000 14000 168000 29400

Carbon 15 105 1260

Methanol 2000 14000 168000 25200

23 Clonazepam Chloroacetyl chloride

56 56 672

2-amino 5-nitro chloro benzophenone

138 138 1656

Toluene 600 600 7200 1200

Ammonia 25 25 300

Carbon 5 5 60

Methanol 800 800 9600 2400

24 Lorazepam Chloroacetyl chloride

56 56 672

2-amino dichloro benzophenone

133 133 1596

Water 600 600 7200

Toluene 1200 1200 14400 2400

NaOH 60 60 720

Hydroxyl amine 16 16 192

Carbon 10 10 120

Methanol 1300 1300 15600 3000

Acetic anhydride 45 45 540

25 Duloxetine HCl

Formaldehyde 30 30 360

2-Acetyl thiophene

126 126 1512

Water 1800 1800 21600

Toluene 1800 1800 21600 3600

Dimethyl amine 45 45 540

Acetone 1000 1000 12000 2400

HCl 36 36 432

Carbon 10 10 120

H2 gas

Methanol 1000 1000 12000 2400

Ni cat 2 2 24

DMSO 600 600 7200 600

Fluro naphthalene

145 145 1740

KOH 112 112 1344

26 Dapoxetine HCl

3-Chloro propio phenone

34 34 408

Methanol 300 300 3600 600

Water 900 900 10800

Ni 1 1 12

Toluene 500 500 6000 600


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Alfa Napthol 30 30 360

Methane sulfonic acid

19 19 228

Carbon 10 10 120


HCl 7 7 84

KOH 11 11 132

Acetone 500 500 6000 1800

27 Desvenlafaxine HCl

Venalafaxine hydrochloride

313 313 3756

Toluene 2000 2000 24000 1800

NaOH 40 40 480

Acetone 1000 1000 12000 2400


Water 1018 1018 12216

Carbon 15 15 180

28 Trihexyphenadyl HCl

Acetophenone 120 120 1440


Piperidine 85 85 1020

Water 1200 1200 14400

Toluene 1100 1100 13200 1200

THF 30 30 360

Cyclohexyl chloride

118 118 1416

Carbon 15 15 180

Mg 24 24 288

HCL 36 36 432

Acetone 1000 1000 12000 2100

29 Tramadol HCl Cyclo hexanone 98 980 11760


Dimethylamine 45 450 5400

Toluene 1100 11000 132000 12000

THF 30 300 3600

Water 1200 12000 144000

Metabromo methoxy anisole

187 1870 22440

Mg 24 240 2880

Carbon 15 150 1800

Acetone 1000 10000 120000 21000

HCl 36 360 4320


P-amino sulfonamide

172 344 4128

DMF 1500 3000 36000 2400

Dichloro pyazine 148 296 3552

KHCO3 100 200 12000


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Potassium methoxide

70 140 1680

Water 1000 2000 24000

Carbon 15 30 360

Methanol 2000 4000 48000 8400

31 Alimemazine Tartarate

Phenothiazine 199 199 2388

Sodium methoxide

54 54 648

THF 800 800 9600 1200


135 135 1620

IPA 600 600 7200 1200

Carbon

L-Tartaric acid 50 50 600

Hydrogen peroxide20% solu

100 100 1200

HCl 11 11 132

Acetone 1600 1600 19200 4800

32 Alprazolam Chloroacetyl chloride

56 56 672

2-amino 5-chloro benzophenone

115 115 1380

Toluene 600 600 7200 1200

Ammonia 25 25 300

Carbon 5 5 60

Methanol 800 800 9600 2400

33 Diazepam Chloroacetyl chloride

56 56 672

2-methyklamino 5-chloro benzophenone

123 123 1476

Ammonia 25 25 300

Toluene 600 600 7200 1200

Methanol 800 800 9600 1800

Carbon 5 5 60

34 Buclazine HCl P-Chloro benzhydryl piperizine

286 286 3432

P-Tert butyl benzyl chloride

182 182 2184

Water 600 600 7200

Toluene 1000 1000 12000 1200

NaOH 40 40 480

Acetone 800 800 9600 1500

HCl 70 70 840


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Carbon 10 10 120

35 Meclazine HCl

P-Chloro benzhydryl piperizine

286 286 3432

Meta metyl benzyl chloride

140 140 1680

Water 600 600 7200

Toluene 1000 1000 12000 1200

NaOH 40 40 480

Acetone 800 800 9600 1500

HCl 70 70 840

Carbon 10 10 120

36 Carbamezapine

Ammonia 40 320 3840

IPA 2000 16000 192000 24000

Iminostibene Carconyl chloride

255 2040 24480

Water 700 5600 67200

1.1.6 Solvent recovery and recycling

Various solvents are proposed to be used during the manufacturing process. The solvents proposed to be recovered and recycled during the process of recovering the solvent of such product are detailed in table 1.1 below.

Table: 1.1 Solvent recovery

Sl.No

Product Raw materials Quantity (kg/annum)

Recovered and recycled

Lost

1 Amtriptyline hydrochloride Stage 1

Toluene 775200

122400

Acetone 326400 81600

Stage 2 Toulene 367200 40800

Acetone 244800 81600

N-Butanol 367200 40800

2 Imipramine

HCl/Desipramine HCl

Toluene 43200 4800

Acetone 33600 4800

3 Cyproheptadine HCl Toluene 86400 7200

Methanol 18000 3600

IPA 45000 9000

4 Pitofenone HCl Toluene 21600 2400

Acetone 20400 3600

5 Pyrimethamine Toluene 23400 3600


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Methanol 38700 4500

6 Cyclobenzaprine HCl Toluene 81000 9000

Acetone 29700 6300

7 Clomipramine HCl Toluene 21600 2400

Acetone 16800 2400

8 Chlorpromazine HCl Toluene 54000 6000

Acetone 48000 12000

9 Doxylamine Succinate Toluene 63000 9000

Acetone 49500 10500


Toluene 108000 12000

Acetone 150000 30000


Toluene 21600 2400

Acetone/EA 16800 2400

12 Flupentixol HCl Toluene 7560 840

Acetone 3180 420

13 Melitracen HCl Toluene 22200 4200

Acetone 9900 2100


Toluene 21600 2400

Acetone 19800 4200

15 Opipramol HCl Toluene 21600 2400

Acetone 12000 2400

16 Sulfadoxine Toluene 120000 24000

Methanol 172800 19200

17 Doxepin HCl Toluene 27000 3000

Acetone 9900 2100

18 Nitrazepam Toluene 10200 1800

Methanol 12000 3000

19 Dothiepin HCl Toluene 108000 12000

Acetone 39600 8400

20 Bromazepam Toluene 6000 1200

Methanol 7200 2400

21 Flunarazine HCl Toluene 15600 2400

Acetone/IPA 19800 4200

Methanol 20400 3600

22 Cinnarazine Toluene 109200 16800


Methanol 142800 25200

23 Clonazepam Toluene 6000 1200

Methanol 7200 2400

24 Lorazepam Toluene 12000 2400

Methanol 12600 3000

25 Duloxetine HCl Toluene 18000 3600

Acetone 9600 2400

Methanol 9600 2400


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DMSO 6600 600

26 Dapoxetine HCl Methanol 3000 600

Toluene 5400 600

Acetone 4200 1800

27 Desvenlafaxine HCl Toluene 22200 1800

Acetone 9600 2400

28 Trihexyphenadyl HCl Toluene 12000 1200

Acetone 9900 2100

29 Tramadol HCl Toluene 120000 12000

Acetone 99000 21000


DMF 33600 2400

Methanol 39600 8400


THF 8400 1200

IPA 6000 1200

Acetone 14400 4800

32 Alprazolam Toluene 6000 1200

Methanol 7200 2400

33 Diazepam Toluene 6000 1200

Methanol 7800 1800

34 Buclazine HCl Toluene 10800 1200

Acetone 8100 1500

35 Meclazine HCl Toluene 10800 1200

Acetone 8100 1500

36 Carbamezapine IPA 168000 24000

Note: * The solvent lost during the process of solvent distillation is mainly due to organic thermal disintegration and in form of residue left behind from the bottom un-distilled product. Evaporation loss is minimized by the passage of chilled brine solution and chilled water through the double condenser.

1.1.7 Air pollution details

The major air pollution sources from the industry are DG set, boiler and process sections. These sources are provided with stacks of adequate height so as to disperse the emanating flue gases containing SPM, oxides of sulfur and nitrogen without affecting the ground level concentrations and packed column scrubbers are proposed to the process sections with adequate stack height as per the regulatory requirements. The sources of air pollution, type of fuel used, fuel consumption and chimney heights for each of the air pollution sources of the proposed project are indicated in the following table 1.2.


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Table: 1.2 Air pollution sources, fuel consumption and chimney height details

SI. no.

Stack attached to

Fuel used Fuel consumption

Number of

stacks

Stack height

Air pollution control unit

Predicted emissions

1 Process section

- - 1 5 m ARL

Packed column scrubber – 1 no.

Acid mist/ VOCs

2 R&D - - 1 3 m ARL


-

3 Steam boiler – 3Ton capacity – 2 no.s

Briquette 300 L/hr 1 30.5 m AGL

Stack SO2, NOx, SPM

4 D.G. set – 500 kVA – 1 no.

HSD 117.5 L/hr 1 7 m AGL

Stack SOx, NOx, SPM

5 Thermic Fluid Heater

Briquette Fired- 1 no

75 Kgs/hr 1 30.5 m AGL

Stack SOx, NOx, SPM

Furnace Oil Fired- 1 no

25 L/Hr 1 13 m AGL

Stack SOx, NOx, SPM


13 L/Hr 1 13 m AGL

Stack SOx, NOx, SPM


6 L/Hr 13 m AGL

Stack SOx, NOx, SPM

* Stack height calculation for DGs Formula adopted for stack height calculation

H = 14(Q)0.3

Where, H is stack height Above Ground Level Q is sulfur content in exhaust in kg/hr (As per Handbook on Environmental Legislations and Technologies) Fuel consumption = 117.5 L/hr = 0.1175 m3/hr Sulfur content in HSD = 0.25% Density of sulfur = 2046 kg/m3 Therefore, Q = 0.1175 x (0.25/100) x 2046 = 0.0601 kg/hr


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Therefore, height of chimney = 14 (0.0601)0.3 = 6.02 m AGL Or say 7 m AGL Therefore it is proposed to provide 1 stack of height 7 m AGL for one diesel generator of 500 kVA capacity. ** Stack height calculation for boiler Formula adopted for stack height calculation

H = 74(Q)0.27

Where, H is stack height Above Ground Level Q is ash produced in tons/hr Type of fuel used – briquettes, husk, wood Capacity of boiler = 3 MT Fuel consumption = 0.3 tons/hr For agro based fuel ash produced per ton of fuel burnt = 6.5 kg (As per Handbook on Environmental Legislations and Technologies) Therefore, Q = 1.95 kg/hr = 0.00195 tons/hr Therefore, height of chimney = 74 (0.00195)0.27 = 13.72m AGL Or say 30.5 m AGL However it is proposed to install a stack of height 30.5 m AGL with Mechanical dust collector to collect the fly ash.

1.1.8 Noise pollution details

The major source of noise pollution in the industry is the DG set for which acoustic enclosure is proposed. Also ambient noise levels will be ensured within the ambient standards by inbuilt design of mechanical equipment and building apart from vegetation (tree plantations) along the periphery and at various locations within the industry premises.

1.1.9 Solid waste details

The quantity of solid waste generated from the proposed industry is detailed in the following table 1.3.


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Table: 1.3 Solid waste generation during the operation phase

Total no. of employees 110

Assuming per capita solid waste generation rate as 0.25 kg/capita/day

Quantity of solid waste generated 27.5 kg/day

Organic solid waste : 60 % of the total waste 16.5 kg/day

Inorganic solid waste : 40 % of the total waste 11 kg/day

Disposal of domestic solid waste The domestic wastes are segregated at source, collected in bins and composted.

1.1.10 Hazardous raw materials used in the manufacturing process

The following raw materials used during the process of manufacture of APIs are hazardous in nature according to Manufacture, Storage and Import of Hazardous Chemical (Amendment) Rules, 19th January 2000, Schedule I, Part II in the table 1.4

Table: 1.4 Hazardous raw materials

Hazardous raw material Sl. No. as per Manufacture, Storage and Import of Hazardous Chemical (Amendment) Rules, 19th January 2000, Schedule I, Part II

Hydrochloric acid 313

N- Butanol 412

Sodium Hydroxide 571

Magnesium 350

Potassium hydroxide 522

Methanol 377

Ammonia 31

Toulene 628

Iso Propyl Alcohol 334

Formaldehyde 295

Dimethyl Amine 215

Acetone 4

Chloroacetyl Chloride 124

Acetic anhydride 45

Cyclohexanone 161

Hydrogen peroxide 318


- 22 -

1.1.11 Hazardous waste generation and its management during the manufacturing process

The hazardous wastes generated during the process of manufacture of different APIs are stored at hazardous waste storage area and sent to cement industries for co-incineration (as an auxiliary fuel) during the manufacture of cement. The quantities of hazardous waste generated from various processes are shown in the following tables 1.5.

1) Organic process/solvent residue and spent carbon

Table: 1.5 Quantity of process residue generation from solvent recovery and spent carbon generation from manufacturing process

Sl. No.

APIs Quantity of hazardous waste generated, kg/annum

Quantity of spent carbon, kg/annum

1 Amtriptyline hydrochloride 1st stage

9,384 9,792

2nd stage 9,384

2 Imipramine hydrochloride

1,584 576

3 Cyproheptadiene HCl 1,908 720

4 Pitofenone HCl 864 288

5 Pyrimethamine 2,016 432

6 Cyclobenzaprine HCl 936 432

7 Clomipramine HCl 744 288

8 Chlorpromazine HCl 2,280 720


2,160 1,080


5,520 1,440


840 288


13 Melitracen HCl 360 216


1,128 288

15 Opipramol HCl 252 144

16 Sulfadoxine 576 1728

17 Doxepin HCl 408 144

18 Nitrazepam 516 144


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19 Dothiepin HCl 1,728 576


21 Flunarazine HCl 552 216

22 Cinnarizine 3,024 1512

23 Clonazepam 336 84

24 Lorazepam 396 144

25 Duloxetine HCl 396 144


27 Desvenlafaxine HCl 168 216

28 Trihexyphenadyl HCl 312 216

29 Tramadol HCl 3,480 2160


744 432

31 Alimemazine Tartarate 1st step A

348 288

2nd step B 132

32 Alprazolam 300 84

33 Diazepam 276 84

34 Buclazine HCl 624 144

35 Meclazine HCl 588 144

36 Carbamezapine 480 -

TOTAL 55,200 25,464

Spent carbon is used during the process of manufacture of different APIs. The spent carbon will be disposed for co-incineration in cement manufacturing.

2) Others : The various hazardous waste generated from the industry is presented in table 1.6

Table: 1.6 Miscellaneous types of hazardous waste generated

Sl. No.

Particulars Quantity of hazardous waste

generated kg/annum

Disposal Options Category


200 L Disposed through authorized recyclers

5.1

2 Residue from solvent recovery plant

55,200 Disposed through Cement industries for co incinerations

28.1

3 Used MS drums (either reused if it cannot scrapped)

120 Disposed through authorized recyclers

33.3


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4 Used poly bags 180 Disposed through authorized recyclers

33.3

5 Inorganic salt from MEE

85,140 Disposed to TSDF for scientific landfill.

34.3

6 Spent carbon 25,464 Disposed through Cement industries for co incinerations

28.2

7 Spent organic solvent fraction from MEE stripper

205 KL/Annum Disposed through authorized solvent recyclers

28.5

The project proponents will usually identify certain basic factors while selecting the site for the project. Such factors are usually related to the titles of the property, commercial viability, location of the site, availability of raw materials and resources required etc. In addition to this the environmental setting of the proposed location is also an important factor while deciding the site for a project. All these criteria are favorable for the establishment of M/s. R L Fine Chem Pvt. Ltd., Since the project site is located at KIADB Industrial Area. The project well connected by Hindupur Gouribidanoor road at about 0.5 km SH 9. Therefore the project site is well connected by roadways. Devarapalli Railway Station is at a distance of about 3.5 km towards North direction. Hence the raw materials and the other utilities required by the industry can be easily transported. From the view point of basic infrastructural facilities required for the industry Viz. power supply, water supply and sanitation facilities will not be a problem as the industry is coming up in a designated industrial area. As far as the environmental setting is concerned the proposed project site is located at KIADB industrial area, surroundings have villages, individual residential units, few commercial establishments. The general topographical features of the area reveal that the proposed project site and its surroundings is generally a plain land with slight undulations. This plot is located at an elevation of about 686 m above MSL, the climatic conditions is temperate (semi arid) with moderate annual rainfall varies from 500 mm to 850 mm. Site bearings The proposed project site is surrounded by vacant plots/industrial plot in all directions.

1.1.12 Project setting


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Sl.No. Particulars Direction w.r.t. project site

1 40' road West

2 Site no 26, belong to industry

North

3 Industrial Area second phase South

4 Small scale industrial area East


- 26 -

1.2. ENVIRONMENTAL IMPACTS AND MANAGEMENT PLAN

Sl. no.

Environmental components

Predicted impacts Probable source of impact Mitigation measures Remarks

1 Ambient air quality

Marginal negative impact inside the construction site premises. No negative impact outside.

Fugitive dust emissions generated during construction in the beginning followed by fabrication, erection of plant and machinery installations during later part of the project.

Carrying out the construction activities in closed manner.

Intermittent spraying of water.

Use of PPE.

Impacts are temporary (only during construction period) in nature. Also the proposed project does not involve extensive construction activities (total built-up area is 8,000 SQM); construction is more of fabrication and erection type except admin, R & D and Watch and ward buildings.

2 Noise Marginal negative impact near noise generation sources inside the premises. No significant impact on the ambient noise levels to the surrounding area.

Noise generation from construction activities and operation of construction equipments and also from the movement of vehicles carrying construction materials to and from the project site.

Use of well maintained construction equipments.

Use of PPE – ear plugs and muffs by the construction workers.

Temporary impact only during construction phase.

3 Water quality No significant impact

Discharge of sewage from housing facilities of construction workers

The sewage generated will be treated in septic tank and soak pit

Impact will be temporary. Local construction workers

will be employed.

4 Land No negative impact

Solid waste generated from housing facilities of construction workers

Wastes will be collected and composted on site. Non-compostable

-

1.2.1 Environmental management plan during construction phase


- 27 -

waste will be disposed scientifically.

5 Socio-economic

Overall positive impact

Employment opportunities - -

Sl. no.

Environmental components

Predicted impacts

Probable source of impact

Mitigation measures Remarks

1 Ambient air quality

Minor negative impact.

Process of manufacture of APIs

Particulate and gaseous emissions from DG set and boiler

Manufacturing process involves closed operations in various controlled reactors.

The process area will be provided with abundant natural light and ventilation and high roofs to disperse the fumes/gases to the outside atmosphere; preventing the increase of ground level concentrations (GLC’S) as it gets dispersed.

Packed column scrubbers are proposed to neutralize and control dust and fumes from the process section.

The treated waste gases and fumes will be let out through stacks of 5 m height ARL.

The emissions from DG & boiler

DG sets will be used only during power failure.

1.2.2 Environmental management plan during operation phase


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will be let out through stacks of heights 7 m AGL and 30.5 m AGL respectively.

2 Noise Minor negative impact near noise generation sources inside the premises.

Operation of machineries during the manufacturing process.

Handling and conveying of raw materials and semi-finished components to different areas of operations

Operation of DG set.

The conveying system shall be maintained by following routine and periodic maintenance to reduce noise generation in material handling.

DG set with prebuilt acoustic enclosure as per CPCB norms will be installed in dedicated utility area, where the access will be restricted. Also the use of PPE (ear plugs) will be mandatory in this area.

Green belt at the project boundary will further act as noise barrier and help in attenuation of noise.

-

3 Water quality No significant adverse impact

Discharge of domestic sewage and industrial effluent

Domestic sewage will be mixed with industrial effluent at aeration stage and treated.

The industrial effluent is proposed to be treated in a Effluent Treatment Plant (ETP) with Multiple Effect Evaporator (MEE) followed by RO Filtration for treatment, reuse and disposal.

Water conservation measures will be encouraged.

4 Land No negative impact

Discharge of wastewater.

Storage and disposal of solid

Domestic sewage will be mixed with industrial effluent at aeration stage and treated. The industrial effluent is proposed

-


- 29 -

wastes. to be treated in Effluent Treatment Plant (ETP) with Multiple Effect Evaporator followed by RO Filtration for treatment, reuse and disposal.

5 Socio-economic

Overall positive impact

Employment opportunities

Locally available man power will be utilized to the maximum possible extent.

-

3000M/s. R L Fine Chem Pvt. Ltd.,

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CHAPTER 2

INTRODUCTION OF THE PROJECT/ BACKGROUND INFORMATION

2.1 INTRODUCTION OF PROJECT PROPONENT

The M/s. R L Fine Chem Pvt. Ltd., having a registered office at M/s. R L Fine Chem Pvt. Ltd., HIG; #2000, Ray House; Near Yelahanka New Town Police Station; Yelahanka; Bangalore-560 064 proposed to establish an industry at Plot No. 27-29, KIADB Industrial Area, Gouribidanoor, Karnataka.

2.2 BRIEF DESCRIPTION ABOUT THE NATURE OF THE PROJECT

The proposed industry M/s. R L Finechem Pvt. Ltd., is a Private Limited company with Shri Anjan Kumar Roy as the Director. The industry is proposed to be established at Plot No. 27-29, KIADB Industrial Area, Gouribidanoor, Karnataka. The main activity of the company is to manufacture Active Pharmaceutical Ingredients (API’s).

An active ingredient (AI) is the substance of a pharmaceutical drug that is biologically active. Terms in similar use include: active pharmaceutical ingredient (API) and bulk active in medicine. Some medications may contain more than one active ingredient. The traditional word for the API is pharmacon or pharmakon which originally denoted a magical substance or drug. A dosage form of a drug is traditionally composed of two things: The API, which is the

drug itself; and an excipient, which is the substance of the tablet, or the liquid the

API is suspended in, or other material that is pharmaceutically inert. Drugs are chosen

primarily for their active ingredients.

Anjan Kumar Roy is the founder of M/s R L Finechem Pvt Ltd., With a M Sc. degree

and a Diploma in Business Management; he has worked in various capacities in

reputed multinational companies for 9 years. Apart from this he is having experience

of running the pharma industry for more than 25 years. Mr. Roy is also been

recognized as an approved expert chemist in the manufacture of basic drugs by the

Drugs Controller of Karnataka. By virtue of his rich experience both technically &

commercially in running the units for more than 25 years & also supported by well

qualified & highly experienced technical force, the group is confident of the success

of the new project.


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The company already has an Active Pharmaceutical Ingredients (API) manufacturing

facility (M/s. R L Finechem I) at No. 15, Yelahanka. Now the company proposes to

obtain Environmental Clearance from SEIAA for the Active Pharmaceutical Ingredients

(API) manufacturing industry at Plot No. 27-29, KIADB Industrial Area, Gouribidanoor,

Karnataka.

The M/s. R L Finechem Pvt. Ltd.HIG; # 2000, Ray house, near Yelahanka New Town

Police Station, Yelahanka, Bangalore – 560 064 proposes to establish an industry at

Plot No. 27-29, KIADB Industrial Area, Gouribidanoor, Karnataka.

2.3 NEED FOR THE PROJECT AND ITS IMPORTANCE TO THE COUNTRY AND/REGION

Bulk drugs have become a part of our life for sustaining many of our day-to-day activities, preventing and controlling diseases. Bulk drugs manufacturing sector in India is well established and has recorded a steady growth in the overall Indian industrial scenario. The bulk drugs and allied industries have been amongst the fastest growing segments of the Indian industry.

The Indian Pharmaceutical Industry today is in the front rank of India’s science-based industries with wide ranging capabilities in the complex field of drug manufacture and technology. It is expected to reach a level of Rs 3200 billion by 2012. It ranks very high in the third world, in terms of technology, quality and range of medicines manufactured. From simple headache pills to sophisticated antibiotics and complex cardiac compounds, almost every type of medicine is now made indigenously.

Playing a key role in promoting and sustaining development in the vital field of medicines, Indian Pharma Industry boasts of quality producers and many units approved by regulatory authorities in USA and UK. International companies associated with this sector have stimulated, assisted and spearheaded this dynamic development in the past years and helped to put India on the pharmaceutical map of the world.

India's pharmaceutical industry is the third largest in the world in terms of volume. Its rank is 14th in terms of value. India is also one of the top five active pharmaceutical ingredients (API)producers (with a share of about 6.5 per cent).

The pharmaceutical industry in India meets around 70% of the country's demand for bulk drugs, drug intermediates, chemicals, tablets, capsules, orals and injectibles. .Between September 2008 and September 2009, the total turnover of India's pharmaceuticals industry was US $21.04 billion. The domestic market was worth US $12.26 billion. This was reported by the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers. As per a report by IMS Health India, the Indian pharmaceutical market reached US $10.04 billion in size in July 2010. A highly organized sector, the Indian Pharma Industry is estimated to be worth $4.5 billion, growing at about 8 to 9 percent annually.


- 32 -

The pharmaceutical industry in Karnataka contributes Rs. 350 crore in revenue to the State exchequer and provides employment for 12,000 people. Its growth rate is between 10-12 per cent as against the national pharma growth of 12-14 percent. Pharma products worth Rs. 2,000 crore are produced annually, which is 10 per cent of the national production. The exports sales are Rs.850 crore which is 8 per cent of Indian exports. International pharma majors have preferred many companies from the State. When large companies offer their services on contractual basis to global MNCs, they want to outsource drug production for the domestic market from quality small-medium manufacturers in State. Here the small-medium units ideally fit into slot as third party manufacturers and serve as major hubs for pharmaceutical outsourcing. In fact, two of Indian pharma sectors top five brands, are already outsourced from Karnataka. The units have been recognised for stringent regulatory enforcement and known to manufacture quality products. Another added advantage favoring the State is that it is emerging as an investment destination. Hence the proponents have proposed setting-up of the new pharmaceutical industry - M/s. R L Fine Chem Pvt. Ltd., at Plot no: 27-29, KIADB industrial area, Gouribidanoor, Karnataka.

2.4 DEMAND SUPPLY GAP, IMPORTS vs INDIGENOUS PRODUCTION

Indian pharmaceutical companies supply almost all the country's demand for API and nearly 70 per cent of demand for bulk drugs. The imports of pharmaceuticals are estimated at 10 to 12 percent of the total market. The major suppliers are Switzerland, China, USA, Germany, Italy, Denmark, France, and UK. Imports include raw materials and finished products. Some major pharmaceuticals which are imported include Provitamins and Vitamins, Cortisones, Hydrocortisone, Insulin, Penicillin, Osetrogen, Progesterone and other hormones, Erythromycin and other ANTIBIOTICS, Antisera & other blood fraction, and Glycosides. The imports are from Switzerland, US and Germany primarily consist of finished medicament in dosage forms for retail sales.

2.5 EXPORT POSSIBILITY

The size of the domestic pharmaceutical market is larger than export market. However, owing to the growth of global generics market, stringent price controls in the domestic market, and better margins, the export market is growing much faster than the domestic market.


- 33 -

India exports pharmaceuticals to numerous countries around the world, including to the U.S., Germany, France, Russia and UK. The Indian pharmaceutical industry ranks 17th with respect to exports value of bulk actives and dosage. Exports constitute nearly 40 per cent of the production, with bulk drugs 45 per cent. According to the Pharmaceutical Export Promotion Council (Pharmexcil), the pharmaceutical exports in 2007-08 stood at US $6.68 billion against US $5.73 billion in 2006-07, recording a growth rate of 16 per cent. The industry has been clocking export growth rate, recording 18 per cent, 23 per cent and 17 per cent growth rates during 2006-07, 2005-06, and 2004-05, respectively. The overall pharmaceutical exports are estimated to increase at a CAGR of 30-32 percent and reach US $ 18.3 billion in 2010 - 11.

2.6 EMPLOYMENT GENERATION DUE TO THE PROJECT

The total direct employment potential of the proposed industry is about 110 people. However, there are indirect employment generation due to the project during the transportations, marketing & distribution etc.


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CHAPTER 3

PROJECT DESCRIPTION

3.1 TYPE OF PROJECT

The main activity of the proposed industry is manufacturing of Active Pharmaceutical Ingredients (APIs). The total production capacity 38,390 kg/month.

3.2 LOCATION OF THE PROPOSED INDUSTRY

The industry is proposed to be established at Plot No. 27-29, KIADB Industrial Area, Gouribidanoor, Karnataka. Google map is appended as fig 3.1.

fig 3.1: Google map showing project site Note: Latitude: 13°42'23.74"N; Longitude: 77°30'11.96"E 686 m above MSL;


- 35 -

GOWRIBIDANOOR DISTRICT


- 36 -

Fig 3.1: Maps showing project boundary & project site location

3.3 BASIS OF SELECTING THE PROPOSED SITE

The efficient functioning of any industry mainly depends on the availability of its basic requirements viz. raw materials, fuel, power, water, manpower etc. The industry is proposed to be established in KIADB Industrial Area, Gouribidanoor. The choice of the land confers several advantages, which are summarized below.

1. The site is well connected by roadways. 2. Water will be supplied from Borewell. 3. Power will be supplied from BESCOM. 4. Housing colonies, educational facilities, hospitals and other amenities are expected to

be developed due to proposed industrial area development. 5. No incidence of cyclones, earthquake, floods or landslides in the region.

3.3.1 Proposed environmental safeguards

1.Industrial effluent is proposed to be treated in Effluent Treatment Plant with Multiple Effective Evaporator followed by RO Filtration for treatment, reuse and disposal.


- 37 -

The domestic sewage will be mixed with industrial effluent at aeration stage and treated.

Adequate measures are adopted for collection and storage of effluents generated in the Industry and also to prevent spillages and overflows. Therefore pollution in the surrounding areas is not anticipated.

2.Well-designed stacks of adequate heights are proposed for the boiler and generator for dispersion of gaseous emissions at levels as per the guidelines.

Well designed scrubbers (column – 4 no.s – one each for production and R&D) will be proposed for scrubbing the fumes emanating from the process area so that the neutralized fumes are let out into the atmosphere at a height so as to not affect GLC’s.

3.The proposed APIs manufacturing industry is coming up in a designated industrial area & and it is not an ecologically sensitive area. Therefore no adverse effects on the fragile ecosystem are anticipated.

3.4 SIZE/MAGNITUDE OF OPERATION

The industry “M/s. R L Fine Chem Pvt. Ltd.,” is a large scale industrial unit with a total capital investment of Thirty Three Crores Two Lakhs only. The total production capacity proposed is 38,390 kg/month.

3.5 MANUFACTURING PROCESS DESCRIPTION

3.5.1 Products manufactured

The following APIs are proposed to be manufactured.

Table 3.1: APIs are proposed to be manufactured

Sl. no. APIs Production capacity

kg/month kg/annum

1 Amtriptyline hydrochloride 10,000 1,20,000

2 Imipramine HCl/Desipramine HCl

1,150 13,800

3 Cyproheptadine HCl 700 8,400

4 Pitofenone HCl 700 8,400


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5 Pyrimethamine 600 7,200

6 Cyclobenzaprine HCl 1150 13,800

7 Clomipramine HCl 600 7,200

8 Chlorpromazine HCl 1500 18,000

9 Doxylamine Succinate 1400 16,800

10 Orphenadrine Citrate/ HCl 4000 48,000


500 6,000


13 Melitracen HCl 300 3,600

14 Carbinoxamine Maleate 700 8,400

15 Opipramol HCl 400 4,800

16 Sulfadoxine 2400 28,800

17 Doxepin HCl 280 3,360

18 Nitrazepam 240 2,880

19 Dothiepin HCl 1200 14,400


21 Flunarazine HCl 430 5,160

22 Cinnarazine 2500 30,000

23 Clonazepam 130 1,560

24 Lorazepam 130 1,560

25 Duloxetine HCl 300 3,600


27 Desvenlafaxine HCl 400 4,800

28 Trihexyphenadyl HCl 300 3,600

29 Tramadol HCl 2500 30,000

30 Sulfamethoxy Pyrazine HCl 500 6,000

31 Alimemazine Tartarate 200 2,400

32 Alprazolam 110 1,320

33 Diazepam 120 1,440

34 Buclazine HCl 400 4,800

35 Meclazine HCl 400 4,800

36 Carbamezapine 2,000 24,000

TOTAL 38,390 4,60,680

Note:

The total production capacity is 4,60,680 kg/annum.


- 39 -

3.5.2 Manufacturing process description

The manufacturing process for each product proposed to be produced is described with stoichiometric and gravimetric balances along with process description and material balance flow charts as under. 3.5.2.1 AMTRIPTYLINE HYDROCHLORIDE


- 40 -

N

OH

N .HCl

Amitriptyline Grignardbase

Amitriptyline HCl

Acetone

295

36.5

313.5

18

N

OH

Amitriptyline Grignardbase

295

O

Dibenzo suberoneDimethylamino propyl chloride

208121

THF/Toluene

Mg

MgCl

Reaction scheme

Cl N

5924

NH

263

H2O

299.5

HCL

36.5

18

NaOH

Nortrityline base

1st step

2nd step A

2nd step B

CH3OHNa

54NH

Nortrityline (DesAmitriptylne)Hydrochloride

.HCl

N butanol

Acetone

H2O

HCl

NaOH

40

H2O2

80(20%)=16

N

293

AmitriptylineN-oxide

O

NaCl H2O

8258.5

Salt A

Salt C

Salt B

Toluene

40

MANUFACTURING PROCESS (FOR SALTS OF AMITRIPTYLINE) 1st step: Dibenzo suberone is converted to Hydroxy Amitriptyline base by reacting with dimethylamino propylchloride in solvent THF and Toluene (Grignard reaction) at <35*C.in SS reactor over a period of 20 hrs. After the reaction solvent is removed by distillation in another SS reactor and the product Hydroxy Amitriptyline base is isolated with water. Solid is centrifuged and taken for next step.


- 41 -

The solvent is recovered and reused. 2nd step ( to make 3-salts/ derivative): 1) The Hydroxy Amitriptyline base (Grignard Base) is dissolved in Toluene by heating at 40-50 * C in SS reactor, charcoaled and filtered. The clear solution from above is added slowly to conc Hydrchloric acid in glass lined reactor and then refluxed for 12-14 hrs with simultaneous removal of water Azetrope. After the removal of water reaction is complete, cooled gradually over a period of 2-4 hrs to temp < 15*C to get Amitriptyline hydrochloride crystals (Salt A). These are centrifuged washed with Acetone and the solid is dried. The Mother liquor is sent for recovery. 2) The Amitriptyline hydrochlorideis Heated at temp 90*C in sodium hydroxide solution and cooled to 10*C. The mass is reacted with Hydrogen peroxide solution (20%) which is added slowly maintaining temp< 10*C to get Amitrityline N-Oxide (Salt B). 3) The Hydroxy Amitriptyline base (Grignard Base) is refluxed in N- butanol solvent is in presence of base Sodium hydroxide in SS reactor to get Des Amitriptyline Base (Nortriptyline base). Solvent is removed by Vacuum distillation and quenched with water to get 2 layers. Top organic layer is liquid Nortrityline base which is immediately dissolved in acetone. This solution in Acetone is charcoaled , filtered and clear filtrate is converted to Nortriptyline Hydrochloride (Des Amitrityline) Crystals (Salt C) are obtained by passing Hcl gas in GL reactor at temp <%*C; which is isolated by Centrifuging and the solid is dried . The mother liquor from the centrifuge is sent for solvent recovery and the recovered solvent is recycled.

AMTRIPTYLINE HYDROCHLORIDE (SALT A) MASS BALANCE SL NO PRODUCTION B Size 300kg No of batchs 34/Month

All inclusive

Raw material used

1 THF 40kg

2 Dibenzo suberone 208kg

3 Toluene 2200Lt For salt A)

4 Water 1600Lt(for salt AB &C)

5 Mg 24kg

6 Dimethylamino propyl chloride 120kg

7 Con Hcl acid 110kg

8 N-Butanol 1000L

9 HCl gas 36kg

8 Acetone 1800 Lt( for AB& C salt)

9 NaOH 80kg (for B&C salt)

10 H2O2 (20%) 80kg


- 42 -

11 Carbon 20Kg(for A& C)

Yield (Amitriptyline HCL (Salt A)) Des methyl Amitriptyline HCl(Salt C)

290kgs/280kg Only 1 batch for every 3 months of salt B is taken (260kg)

Batch size 300kgs --- Amtriptyline HCL (Salt A) given for salt A

Input Reactors Output

THF 40L SSR 3000L(for step 1 Grignard reaction)

Amtriptyline HCL (Salt A) Yield :: 290kg Oveall yield ::92.5%

Dibenzo suberone – 208KG

SSR 3000L (for step 1 reaction workup)

I.Product: stage-1 :96.5% Stage-2A:96%

Toluene -2200Lt SSR 3000L (for step 2 Dissolution)

Toluene: 1900L Loss: 340L Include THF(40L) Acetone: 800L Loss: 200L P. Water: 752 L Contns Mg Cl Cleaning water 1500L goes to CETP Hazardous waste: salt A 20-25kg Spent Carbon: 12kg

Water – 600Lt GLR 1500L(for step 2 reaction)

Mg – 24KG

Dimethylamino propyl chloride – 120KG

SSR 3000L (for solvent recovery)

Con Hcl acid – 110KG

Acetone – 1000Lt

Carbon – 10Kg

Time cycle 1st stage 2nd stage 3rd stage final

1) Reaction ………… 16-18hrs 12-14hrs - Drying

2) Isolation , cooling

& Centrifuge… 4-6hrs 2-4hrs -

Solvent recovery…… 10-14hrs (MLR-1) 10-14hrs (MLR-2) ----- Water used for washing/cleaning equipment, cleaning waste water 1500L goes to CETP along with process waste water 752kgs Batch size 300kgs ---

Nortriptyline HCL (Desmethyl amitriptyline Hcl: Salt C) Input Reactors Output

THF – 40L SSR 3000L(for step 1 Grignard reaction)

Des methylAmtriptyline HCL (Salt C) Yield :: 280kg Oveall yield ::92.5%

Dibenzo suberone – 208KG


I.Product: stage-1 :96.5%


- 43 -

Toluene -1000Lt SSR 3000L (for step 2 Reaction)

Toluene: 900L Loss: 140L Include THF(40L) Acetone: 800L Loss: 200L N butanol :900L loss 100L P. Water: Stage-1 ;660kg/L (Contns MgCl) stage-2 :672kg/L (Contns NaCl) Cleaning water 1500L goes to CETP Hazardous waste: salt A 16-18kg Spent Carbon: 12kg

Water – 1200Lt GLR 1500L(for step 2 reaction)

Mg – 24KG

Dimethylamino propyl chloride – 120KG


Con Hcl acid – 36.5KG

Acetone – 800Lt

Carbon – 10Kg

N-Butanol – 1000L

NaOH- 40kg




& Centrifuge … 4-6hrs 2-4hrs -

Solvent recovery…… 10-14 hrs (MLR-3) ------ Water used for washing/cleaning equipment, cleaning waste water 1500L goes to CETP along with process waste water 1332kgs


- 44 -

Process Waste Water-1,23&4 : 1975.5kgCleaning Waste Water : 1500L

FLOW CHART FOR AMTRIPTYLINE HYDRCHLORIDE

Total waste water to CETP is 3475.5L/kg

2nd stepproduct A&C

SS reactor-1cap 3000LToluene layer& MLR

SSreactor -1cap:3000L

Grignard

Toluene/THF1000L/40L

Dibenzo suberone208 kg

Dimethylaminopropyl chloride120kg

Water600L

Centrifuge

RecoveredToluene900L

Amitriptyline base 295kgwet(Conent 285kg)

Water-1includes660 kgs/MgCL

MLR TolueneSolvent Loss:140L

Residue-1haz waste10.0kg

1st step

Toluene 1200L SS reactor-2cap :3000LDissolution

Haz Waste 1,::22-25kgHaz wate -2&3:: 22-25kg

Amitritylinebase 285kgs

GL reactor

Solvent recovery

Toluene MLR-1loss 100.0L

Toluene 1000LLoss :100L

reaction

1500LConc HCL acid 110kgs(36.5+74)

Centrifuge

SSreactor 2noscap:3000/ 1500Lfor recovery Acetone 1600L

Loss :200Lfrom 1&3

Amitriptylinehydrochloride290.0kgs(Salt A)

Acetone wash1000L

Acetone MLR-2Loss ::100L

MLR-1MLR-2MLR-3

Nortriptyline (Salt C)Hydrochloride280Kg(desmethyl Amitriptyline)

Mg 24

SS reactor-2cap :3000LReaction

GL reactor

reaction

1500L

SS reactor-3cap :2000LDissolution

N-Butanol 1000L

NaOH 40 kg

HCl 36.5

Acetone800L

Water-3 672kg

Water-292kg

Water 600L

Amitritylinebase 285kgs

NButanol 900L Loss :100L

MLR-3

Acetone loss 100L

Centrifuge

Water 400L

NaOH 40kg

AMTN HCL290kg

CentrifugeAmtriptyline N-Oxide265kg (Salt B)

Water-4::548.5kg2nd stepProduct B

C- 10kg

C-12 kg

C-10 kg

Spent C -12kg

Spent carbon wet 24 kg

H2O2 80kg20%

12

10

11

10


- 45 -

3.5.2.2 IMIPRAMINE HCL/DESIPRAMINE HCL


121

Cl N

N

N

N

N

+ HCl

Imipramine Base

280

Hydrochloric acid

36.5

.HCl

Imipramine Hydrochloride

316.5

Acetone

N

N

Imipramine Base

280

NH

Imino dibenzyl

195

Toluene

NaCl NH3NaNH2

39

58 17

Reaction scheme

1st step

2nd step

COOH COOH

OH

HO

388

N

N .pamoate

Imipramine palmoate

668

Ethyl acetate


- 46 -

MANUFACTURING PROCESS

It involves 2 steps

1st step

Iminodibenzyl is dissolved in SS reactor in Solvent Toluene and to this was added

Sodamide base under nitrogen and Dimethylamino propyl chloride is added slowly.

The resultant mass is refluxed for 24 hrs to get Imipramine base. The product is

then worked up with water, after the reaction is complete by quenching in water,

and separating the organic layer.

The organic layer is distilled to recover the Toluene and concentrated liquid

Imipramine base is taken for the next step.

Recovered Toluene is recycled.

2nd step

Imipramine base is dissolved in solvent Acetone in SS reactor, charcoaled and

filtered. The clear filtrate is transferred to Glass lined reactor. This clear solution

is cooled < 15*C in Glass lined reactor and treated with methanolic solution of HCL

to get imipramine hydrochloride crude.

The resultant mixture is heated to reflux for 4hrs and cooled to <15* C to get pure

Imipramine hydrochloride in crystals which is centrifuged and dried.

The mother liquor is sent for recovering sovent which is recycled.

Imipramine base is also converted another salt as pamoate by dissolving in Ethyl

acetate and treating with Pamoic acid.

IMIPRAMINE HYDROCHLORIDE MASS BALANCE SL NO PRODUCTION B size 300kg No of batchs 4/Month

Raw material used

1 Imino Dibenzyl 195kg

2 Dimethylamino Propyl Chloride 120kg

3 Sodamide 39 kg

4 Toluene 1000Lt

5 Water 600Lt

6 Methanol Hcl 130kg

7 Acetone 800L


- 47 -

8 Carbon 10kg

Yield (Imipramine Hydrochloride) 285kgs

Batch size 300kgs --- Imipramine Hydrochloride


Imino Dibenzyl 195kg SSR 3000L(for step 1 Reaction)

Imipramine Hydrochloride Yield ::285kgs Overall yield:90%

Dimethylamino Propyl Chloride 120 kg

SSR 3000L (for step 1 workup)

I.Product: 1st stage::95% 2nd stage:95%

Sodamide 39kg SSR 2000L (for step 2 dissolution)

Toluene: 900L Loss: 100L Acetone: 700L Loss: 200L Methanol loss : 70kg(100L) NH3 :17kg P.Water: 660 L stage-1 (Cont NaCl ) Cleaning water::500L goes to CETP Hazardous waste: 30-35kg Spent carbon: 12Kg

Toluene 1000L GLR 2000L (for step2 reaction)

Water 600 L SSR 2000L (for solvent recovery)

Methanol Hcl 110kg

Acetone 800 L

Carbon 10kg


1) Reaction ………… 22-24hrs 12-14hrs ----

Drying


& Centrifuge… 4-6hrs 2-4hrs ---

3) Solvent recovery…… 8-10hrs (MLR-1) -----

Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP along with process waste water 660kgs


- 48 -

Process Waste Water ::660 kgCleaning waste Water :500L

Imipramine base265 kgs

Acetone 800L

SS reactor-22000L

GLreactor2000L

SSreactor 2000Lfor solvent recovery

FLOW CHART FOR IMIPRAMINE HYDROCHLORIDE

MLR Acetonemixfor recycle

acetone

dissolution

Reaction

Total waste water to CETP is 1160kg

centrifuge +

Acetone Pure 700Lloss 100L

Haz Waste kgs 30-35kg

MLRAcetone

Methanol hcl110.0 kgs(120L)

Imipramine hydrochloride285.0kgs

2nd Step

(74kg+35.0kg)

Solvent lossAceton100.0L

SS reactor-1 cap:3000LRection

SS Reactor-1cap:3000LWork-up

IminoDibenzyl 195kg

DimethylaminoPropyl chloride120kg

Sodamide39kg

Toluene1000L

NH3 17kg

Water 600L

Water +NaCl660kg

Recov Toluene900L Loss:100L

Imipramine Base280kg(cont 265kg)

1st step

Imipramine pamoate(Base-56:&P acid-67)gives110kg final

Carbon 10kg Spent C12 kg wet

Spentcarbon 12 kg wet

15

15

100L methanol


- 49 -

3.5.2.3 CYPROHEPTADINE HCL

N

OH

N .HCl

+ HCl + H2O

Cyproheptadine Grignardbase

Hydrochloric acid Cyproheptadine HCl Water

Toluene

30536.5 323.5 18

N

OH

Cyproheptadine Grignardbase

305

N

Cl

O

206

Dibenzosuberenone N-methyl chloropiperidine

133.5

Mg

24

Toluene/ THF

MgCl

59.5

Reaction scheme

IPA

MANUFACTURING PROCESS This involves 2 steps 1st step Dibenzosuberenone is converted to Hydroxy cyproheptadiene baseby Grignard reaction in SS reactor with N-methyl chloro piperidine in suitable solvent THF and Toluene mixture using Magnessium filings at temperature 80-85*C for 16 hrs. After the reaction is complete, reaction mass is quenched with water at temperature <35*C to get 2-layers which is separated. Organic layer is concentrated to recover Toluene and solid Grignard baseis obtained by adding Methanol. Solid is centrifuged and taken for 2nd step.


- 50 -

Mother liquor is sent for recovery of methanol by distillation. Both recovered solvents are then recycled after purification in SRP. 2nd step The Hydroxy cyproheptadiene base is dissolved in Toluene by heating at 40-50 * C in SS reactor. The clear solution from above is added slowly to conc Hydrchloric acid in glass lined reactor and then refluxed for 12-14 hrs with simultaneous removal of water Azetrope. After the removal of water reaction is complete, cooled gradually over a period of 2-4 hrs to temp < 15*C to get cyproheptadiene hydrochloride crystals. These are centrifuged and the solid is dried. The product is crystallized in IPA BY Heating and cooling. The mother liquor from the centrifuge is sent for solvent recovery and the recovered solvent is recycled.

CYPROHEPTADIENE Gravimetric/MASS BALANCE SL NO PRODUCTION B size 300kgs No of batchs:3/month

Raw material used

1 THF 25L

2 Dibenzo Suberenone 206kg

3 N-Methylchloro Piperidine 133 kg

4 Toluene 2600Lt(1st &2nd stage)

5 Water 500Lt (1st stage)

6 Methanol 600Lt (1st stage)

7 Con. HCl 110Kg

8 IPA 1500Lt(2nd stage)

9 Carbon 15kg

10 Magnessium 24kg

Yield (Cyproheptadiene) 270kgs


THF 25L(20kg) SSR 3000L(Griganard Reaction)

Cyproheptadiene::270kg (Theo::323kg)overall yield84%

Dibenzo Suberenone 206kg

SSR 3000L (for workup) Product: 1st stage 95% 2nd stage 88%

N-Methylchloro Piperidine 133kg

SSR 3000L (for Dissolution) Toluene: 2400L Loss: 200L Methanol: 500L Loss: 100L IPA: 1250L Loss:250L P Water-1 : 575L/kg step-1

Toluene 2600L GLR 3000L (for reaction)

Magnessium 24kg SSR 3000L (for dissolution


- 51 -

crystallisation) (includes MgCl/THF) P Water-2 :90 L step-2 Total P water 665L Cleaning water::1500L goes to CETP Hazardous waste: 50-55kg Spent Carbon: 20kg

Water 500L SSR 3000L/2000L (for solvent recovery) Methanol 600L

Con. HCl 110Kg

IPA 1500 L

Carbon 15Kg


1) Reaction ………… 16-18hrs 12-14hrs -

Drying



3) Solvent recovery…… 8-10hrs (MLR-1) 10-12hrs(MLR-2) 12-16hrs(MLR-3)



- 52 -

Toluene1800LSS reactor-23000LDissolution

Haz Waste 1, 2 & 3 50-55kgsCarbon :20 kgs

Process Waste Water-1&2: 675kgCleaning Waste Water : 1500LTotal water 2175kg/L

FLOW CHART FOR CYPROHEPTADIENE

Hydroxycyproheptadiene290kgs

GL reactor

2nd step

MLR-1 MethanolMLR-2 TolueneMLR-3 IPA

Tol Solvent loss 75.0L

Toluene recov 1650LLoss Tol :75L

reaction

3000L

Conc HCL acid 110.0kgs(36+74watr)

Centrifuge

Solvent recoverycap3000/2000LMLR SSReactor

Cyproheptadiene320.0 kgs Crude +

TolueneMLR-2

Water-292.0kgs

SS REactor-33000L dissolutionCrystallisation

Pure Cyproheptadiene 270 kgs

Isolation

Iso propyl alcohol 1500L

Carbon 15 kgs

IPA recov 1250LLoss :150L

Centrifuge IPA Loss 100LMLR-3

Carbon 20 kg wet

Toluene/THF: 800/25L

SS reactor-1 cap :3000LGrignard ReactionDibenzo

suberenone 206kg

1st step

Methanol Recov 500L Loss 50L

SS REactor-1cap 3000Lwork /up

Hydroxy CyproheptadieneBase 305kg wet(content::290 kgs)

Water 500L

Methanol600L

Centrifuge

N-methylchloro pipridine133.0kg Aqueous water-1

Layer 575 Kg

Recov Toluene 750 LLoss 50L

Solvent Loss50L MLR-1

Mg 24kg

Solvent recovery

15

37


- 53 -

3.5.2.4 PITOFENONE HCL

Reaction scheme

CO2CH3

O

N

O

CO2CH3

O

N

O

.HCl

+ HCl

Pitofenone Base Hydrochloric acid Pitofenone hydrochloride

Acetone

367 36.5 403.5

CO2CH3

O

N

O

Pitofenone Base

367

N

CO2CH3

OH

OCl


256

Chloroethyl piperidine

147

toluene

BaseKHCO3

100

KCl CO2

74 44

H2O

18


It involves 2 steps

1st step

Ester intermediate is dissolved in solvent toluene and reacted with chloroethyl

piperidine in presence of base (potassium carbonate) and the reaction mass is


- 54 -

refluxed and after the reaction the reaction mass is quenched with water and

separated the organic layer which contains Pitophenone base.

The organic layer is having pitofenone base which is isolated by solvent distillation

and the thick organic mass (residue) is taken for the next step.

Solvent is reused after recovery.

2nd step

Pitofenone base is dissolved in Acetone in SS reactor, treated with carbon, filtered

and transferred the clear filtrate to Glass lined reactor.

The above solution is cooled to<10*C and hydrogen chloride gas is passed slowly over a

period of 4 hrs by maintaining temperature below 20* C till Ph 2 is achieved.

The above reaction mixture is stirred at temp <25*C for 4hrs and cooled to temp < 10

*C to get pitofenone hydrochloride crystals which is separated by centrifuging to

isolate the product and dried.

The mother liquor from the above centrifuge is sent for recovery of Acetone solvent

which is recycled.

PITOFENONE HYDROCHLORIDE MASS BALANCE SL NO PRODUCTION B Size 350kg No of batchs 2/month

Raw material used

1 Potassium bicarbonate 100kg

2 Methyl ester intermediate 256kg

3 Chloro ethyl piperidine 147kg

4 Toluene 1000Lt

5 Water 600Lt


7 Acetone 1000L

8 Carbon 10kg

Yield (Pitofenone Hydrochloride) 365kgs

Batch size 350kg --- Pitofenone Hydrochloride


Potassium bicarbonate – 100kg

SSR 3000L(for step 1 Reaction)

Pitofenone Hydrochloride Yield 365kg Overall yield 90%


- 55 -

Methyl ester intermediate – 256kg

SSR 3000L (for step 1 workup) I.Product stage-1 ::95% Stage-2 ::95%

Chloro ethyl piperidine – 147kg

SSR 2000L (for step 2 dissolution)

Toluene: 900L Loss: 100L Acetone: 850L Acetone mix Loss: 250L (conts 70kgMethanol) CO2 ::44kg P. Water: stage-1 :: 695kg/ L Contns NaCl Cleaning water :::500L goes to CETP Hazardous waste: 34-38kg Spent carbon: 12Kg

Toluene – 1000L GLR 2000L (for step2 reaction)

Water – 600L SSR 2000L (for solvent recovery)

Methanol Hcl – 110kg

Acetone – 1000L

Carbon – 10kg


1) Reaction ………… 22-24hrs 12-14hrs ----

Drying


& Centrifuge … 4-6hrs 2-4hrs ---




- 56 -

FLOW CHART FOR PITOFENONE HYDROCHLORIDE

Process Waste Water ::695.0 kgCleaning waste Water :500L

Pitofenone base350 kgs

Acetone 1000L

SS reactor-2cap 2000LDissolution

GLreactor2000L

SSreactorcap 2000Lsolvent recovery

MLR AcetoneLoss :;150L

Reaction

Total waste water to CETP is 1195 L/kg

centrifuge

Acetone Pure 850Lloss ::100L

Haz Waste 34-38kgkgs

MLRAcetone


Pitofenone hydrochloride365.0kgs

2nd Step

(74kg+36.0kg100L methanol)


SS Reactor-1cap:3000LWork-up/Org layer

Chloro ethylPiperidine 147kg

Methyl esterintermediate 256kg

Toluene1000L

Water 600L

Water +NaCl695kg


Pitofenone BaseLiquid 365 crude(content 350kg)

1st step



Potassium bi carbonate 100kg

CO2 44kg

Solvent recovery

17

20


- 57 -

3.5.2.5 PYRIMETHAMINE

Reaction scheme

Cl

CNOO

+H2N NH2

NH

Cl

NN

NH2

NH2

Cyano Ketal Compound

GuanidinePyremethamine

Methanol

248.559251.5

+ CH2OHCH2OH

Ethylene Glycol

62

Cl

CNOO

Cyano Ketal Compound

251.5

OHHO

Cl

CN

O

Cation resin

Toluene

Keto nitrile

207.5

MEG

62

H2O

18

2nd step

3rd step

Cl

CN

O

Keto nitrile

207.5

Cl

CN

151.5

p-Chloro benzyl cyanide

O

O

IsopropylPropionate

116

OH

Iso propanol

60

base

Toluene

1st Step


- 58 -


This involves 3 steps

1st step

P-chloro benzyl cyanide is reacted with Iso propyl propionate ester (ester) in SS

reactor by refluxing for 16hrs in Toluene solvent using anion resin to get Keto nitrile.

After the reaction is complete the mass is filtered to remove resin and the filtrate is

worked with water to get 2 layers. The water layer is separated and organic layer is

taken for the next step. Resin is reused.

2nd step

Keto nitrile in toluene media is reacted with Monoethylene glycol to get Cyano ketal

compound by refluxing for 14hrs using cation resin simultaneously removing water

azeotropically.After the reaction is complete the reaction mass is filtered to remove

the resin . The filtered mass is quenched in water and top organic layer is

concentrated by distilling the solvent to get syrupy liquid mass. This is Cyano ketal

compound which is taken for the next step Resin is recycled.

3rd step

Cyano ketal compound is dissolved in SS reactor in Methanol solvent charcoaled with

carbon and filtered to get clear solution. The above solution is treated with guanidine

and the reaction mass is refluxed for 16 hrs at 65-70*C and the the mass is stirred at

temp <25*C for 2-4hrs and cooled to temp < 10 *C to get Pyrimethamine crystals

which is separated by centrifuging to isolate the product and dried.

The mother liquor from the above centrifuge is sent for recovery of Methanol solvent

at 75*C, which is recycled. The ethylene glycol is distilled later at higher temp > 110*

C under vacuum which is used in the chilling brine solution.

PYRIMETHAMINE Gravimtric/MASS BALANCE

SL NO PRODUCTION (B size) No of batchs 3/Month

Raw material used

1 PCBC 150kg

2 Ester 116kg

3 Toluene 750Lt

4 Water 1000Lt

5 MEG 60kg

6 Methanol 1200L

7 Guanidine 60kg

8 Carbon 10Kg


- 59 -

Yield (Pyrimethamine) 200kgs

Batch size 200 kgs --- Pyrimethamine


PCBC 150kgs SSR 2000L(for step 1 reaction)

Pyrimethamine

Ester 116 kgs SSR 2000L (for step 2 reaction workup)

Product: 200kgs Yeild:81% (Theo::248kg)

Toluene 750L SSR 2000L (for step 3 condensation)

Toluene: 650L Loss: 100L Methanol: 1075L Loss: 125L P Water: 1st step ::560 kg/L 2nd step::520kg/L Total P.Wwater; ::1080 L Cleaning water :500L Totalwaste ::1580 goes to CETP By product: 50kg (Ethylene glycol) Hazardous waste: 55-58 Spent Carbon: 12kg

MEG 60 kg SSR 2500L (for solvent recovery)

Water 1000L

Methanol 1200L

Guanidine 60kg

Carbon 10kg


1) Reaction ………… 16-18hrs 12-14hrs 16-18hrs Drying


& Centrifuge… 4-6hrs 2-4hrs 6-8hrs

3) Solvent recovery… 2hrs 10-12hrs 12-16hrs



- 60 -

Cyano ketal intermediate250kgs

Guanidine 60.0 kgs

SS reactor-22000LCondensation


Solv Loss DistillationMethanol 75.0L

By product ::Ethylene glycol 50.0 kgs

Process Waste Water 1&2:1080kgCleaning waste Water :500 L

FLOW CHART FOR PYRIMETHAMINE

MLR

Total waste water to CETP is 1580L

centrifuge

Solvent loss 50.0 L Methanol

Methanol recovered1075 L recycle

Haz Waste 55-58 kgs

Solvent recoveryMLR

Methanol 1200L

Pyrimethamine200.0kgs

SS Reactor-2

2000L Reaction workup

MLR

Ethylene glycol50.0kgs

Condensation and reaction

3rd step

MEG 60 kg

SSReactor-1cap 2000L

Reaction

Water500L

Cyano ketal Intermediate::280 kgsSS reactor concentratecontains250kg purepd.

Water-2520Kg

Toluene recov:650LLoss:50L

Resin cat

2nd step

PCBC150Kg

Ester116kg

Toluene750 L Water

500L

Organic layerKeto NitrileMass:205Kg/700LToluene

W/up

W/up

Water -1IPA mix :560L

Solv. Toluene loss :: 50L

Transfer

!st step

Carbon 10kg

Spent carbon 12kg

Spent carbon 12kg

48

10


- 61 -

3.5.2.6 CYCLOBENZAPRINE HCL

Reaction scheme

N

OH

N .HCl

+ HCl + H2O

Cyclobenzaprine Grignardbase

Hydrochloric acid Cyclobenzaprine HCl Water

Acetone

29336.5 311.5 18

N

OH

Cyclobenzaprine Grignardbase

293

O

Dibenzo suberenone

206

Cl N

Dimethylamino propyl chlooride

121

THF/Toluene

Mg

MgCl

24 59

MANUFACTURING PROCESS 1st step Dibenzo suberonone is converted to Cyclobenzaprine Grignard base by reacting with dimethylamino propylchloride in solvent THF and Toluene (Grignard reaction) at <35*C.in SS reactor over a period of 20 hrs. After the reaction the mass is quenched in water and layers were separated. Top organic layer is transferred to other SS reactor and 50% Solvent is removed by distillation and the product Cyclobenzaprine Grignard base is isolated by cooling to < 5*C and centrifuging. The solid is taken for next step.


- 62 -

The solvent is recovered and reused. 2nd step The Cyclobenzaprine Grignard base is dissolved in Toluene by heating at 40-50 * C in SS reactor Charcoaled and filtered. The clear filtrate is transferred to GL reactor To the clear solution from above is added slowly to conc Hydrchloric acid in glass lined reactor and then refluxed for 12-14 hrs with simultaneous removal of water Azetrope. After the removal of water reaction is complete, cooled gradually over a period of 2-4 hrs to temp < 15*C to get Cyclbenzaprine hydrochloride crystals. These are centrifuged, washed with acetone and the solid is dried. The mother liquor from the centrifuge is sent for solvent recovery and both the recovered solvent is recycled. CYCLOBENZAPRIN HYDROCHLORIDE MASS BALANCE

SL NO PRODUCTION B Size 300kg No of batchs 3/Month

Raw material used


2 Dibenzo Suberenone 206kg

3 Toluene 2500Lt(1st &2nd stage


5 Con. Hcl 110kg

6 Acetone 1000L(final)

7 Mg 24kg

8 Carbon 10Kg

Yield (Cyclobenzaprin Hydrochloride) 285kgs

Batch size 300kgs --- Cyclobenzaprin Hydrochloride


Dimethylamino Propyl Chloride 120kgs

SSR 3000L(for step 1 Grignard)

Cyclobenzaprin Hydrochloride Yield:285Kg(Theo:311kg) Overall yield:91%

Dibenzo Suberenone 206kgs SSR 3000L (for step 1 Toluene layer)

Stage-1yield 97% Stage -2 yield 94%

Toluene 2500 L SSR 3000L (for step 2 dissolution)

Toluene: 2250 loss ::250L Acetone: 825L Loss: 175L P Water : stage-1 660kg/L (cont MgCl) P water : Stage-2 ::90kg Total P.water ::750kg/L Cleaning water :::500L

Water 600L GLR 3000L (for step2 reaction)

Con. Hcl 110 Kgs SSR 2000L (for solvent recovery)

Acetone 1000L

Mg 24Kg


- 63 -

Carbon 10Kg goes to CETP Hazardous waste: 25-28kg Spent Carbon: 12kg


1) Reaction ………… 16-18hrs 12-14hrs ---- Drying



3) Solvent recovery… 8-10hrs (MLR-1) 10-12hrs(MLR-2)

Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP


- 64 -

Toluene1500L SS reactor-2cap 3000L

Haz Waste 1& 2 25-28kg

Process Waste Water-1&2 :750kgCleaning Waste Water : 500L

CyclobenzprineGrignard base290.0 kgswet


dissolution

2nd step

MLR -1MLR-2

MLR-1 TolueneSolvent loss:75L

Recovered Toluene1350L Loss:75L

Conc HCL acid 110.0kgs(36+70)

Centrifuge

Solvent recovery MLRCap:;SSreactor 2000L Recovered Acetone

825L Loss :75L

Cyclobenzaprinehydrochloride285.0 kgs

Water-290.0kgs

MLR -2 AcetoneSolvent Loss :100L

Acetone 1000L(Top wash)


GLreactorcap 3000LReaction


Grignard

Toluene1000L

Dibenzo suberenone206 kg


Water600L

Centrifuge


Cyclo benzaprine Grignard base 290wet(content 285 Kg )

MLR


Solvent Loss:100L


1st step Grignard reaction

Mg 24

Carbon 10 kg

Spent carbon 12kg wet


8

17


- 65 -

3.5.2.7 CLOMIPRAMINE HCL

Reaction scheme


121

Cl N

N

N

N

N

+ HCl

CIomipramine Base

314

Hydrochloric acid

36.5

.HCl

CIomipramine Hydrochloride

350.5

Acetone

N

N

CIomipramine Base

314

NH

3-ChloroImino dibenzyl

229

Toluene

NaCl NH3NaNH2

39

58 17Cl

Cl

Cl Cl


It involves 2 steps

1st step

3-Cloro Iminodibenzyl is dissolved in SS reactor in Solvent Toluene and to this was

added Sodamide base under nitrogen and the mass is refluxed for 24 hrs to get

clomipramine base. The product is then worked up, after the reaction is complete

by quenching in water, and separating the organic layer.


- 66 -


CIomipramine base is taken for the next step.


2nd step

Clomipramine base is dissolved in solvent Acetone in SS reactor, charcoaled and

filtered. The clear filtrate is transferred to Glass lined reactor. This CIomipramine

base is dissolved in glass lined reactor is cooled < 15*C and treated with

methanolic solution of HCL to get Clomipramine hydrochloride crude.


Clomipramine hydrochloride in crystals which is centrifuged and dried.

The mother liquor is sent for recovering solvent which is recycled.

CLOMIPRAMINE HYDROCHLORIDE MASS BALANCE SL NO PRODUCTION B size 300kg No of batchs 2/Month

Raw material used

1 3-Chlorolmino Dibenzyl 230kg


3 Sodamide 39 kg

4 Toluene 1000Lt (1st step)

5 Water 600Lt


7 Acetone 800L(final)

8 Carbon 10kg

Yield (Clomipramine Hydrochloride) 320kgs

Batch size 300kgs --- Clomipramine Hydrochloride


3-Chlorolmino Dibenzyl 230kg


ClomipramineHydrochloride Yield 320kg (Theo:350kg) Overall yield 91%

Dimethylamino Propyl Chloride 120 kg


Product: 1st stage 98% 2nd stage 93%

Sodamide 39kg SSR 2000L (for step 2 dissolution)

Toluene: 900L Loss: 100L Acetone: 700L Loss: 100L Methanol loss : 74kg(100L) NH3 :17kg P.Water: 660 L stage-1 (Cont NaCl )

Toluene 1000L GLR 2000L (for step2 reaction)

Water 600 L SSR 2000L (for solvent recovery)


- 67 -

Methanol Hcl 110kg Methanol 74kg Hcl 36kg

Cleaning water :500L goes to CETP Hazardous waste: 28-30kg Spent Carbon: 12kg

Acetone 800 L

Carbon 10kg








- 68 -

Clomipramine base310 kgs

Acetone 800L

SS reactor-22000L

GLreactor2000L



FLOW CHART FOR CLOMIPRAMINE HYDROCHLORIDE


acetone

dissolution

Reaction


centrifuge

+

Acetone Pure 700LLoss 100L

Haz Waste 30-32kgs

MLRAcetone


Clomipramine hydrochloride320.0kgs

2nd Step

(74kg+36.0kg)




3--chloroIminoDibenzyl 230kg


Sodamide39kg

Toluene1000L

NH3 17kg

Water 600L

Water +NaCl660kg


Clomipramine Base320 (content 310kg)

1st step

Carbon10kg Spent carbon12 kg wet

spent caron 12 kg

4

Cont 100L methanol)

25


- 69 -

3.5.2.8 CHLORPROMAZINE HCL

Reaction scheme

N

S

Cl

N .HCl

N

S

Cl

N

.HCl+

Chlorpromazine Base Hydrochloric acid

Acetone

Chlorpromazine Hydrochloride

318.5 36.5 355

N

S

Cl

N

Chlorpromazine Base

318.5

NH

S

Cl

233.5


N

Cl


121

KOH

Toluene

56

KCl

74

H2O

18

MANUFACTURING PROCESS INVOLVES 2- STEPS

1st step

3-chloro phenothiazine is converted to Chlopromazine base by reacting with

Dimethylamino propyl chloride in SS reactor in Solvent Toluene in presence of KOH

base at temperature 85-100*C for 15-17 hrs. After the reaction is complete, the

mass is quenched in water to get 2- layers. Top organic layer containing the

product Chlopromazine base.


- 70 -

The Chlopromazine base is isolated as thick mass by concentration of Toluene

layer by distillation.

The recovered Toluene after purification in Solvent recovery plant is recycled.

2nd step

Chlopromazine base is disoolved in solvent Acetone in SS reactor charcoaled with

carbon, filtered to get clear solution. This clear solution is transferred to glass

lined reactor. The solution is then cooled < 15*C in Glass lined reactor and treated

with methanolic solution of HCL to get Chlopromazine hydrochloride crude.


Chlopromazine hydrochloride in crystals which is centrifuged and dried.

The mother liquor is sent for recovering solvent acetone which is recycled.

CHLORPROMAZINE HYDROCHLORIDE MASS BALANCE SL NO PRODUCTION B Size 300kg No of batchs::5/month

Raw material used

1 KOH 59kg

2 2-Chloro pheno thiazine 233kg

3 Toluene 1000Lt(1st stage)



6 Acetone 1000Lt(final)


8 Carbon 10kg

Yield (Chlorpromazine Hydrochloride) 315kgs

Batch size 300kgs --- Chlorpromazine Hydrochloride


KOH – 59kg SSR 3000L(for step 1 reaction)

ChlorpromazineHydrochloride Yield :315.0kg Overall yield : 88.5%

2-Chloro pheno thiazine – 233kg


I.Product:stage-1::94% Stage-2::94%

Toluene – 1000L SSR 1000L (for step 2 dissolution)

Toluene: 900L Loss: 100L Acetone 850L Loss:225L (Contns 65kgMeOH) P.Water: stage-1 ::692 kg/L Cleaning water ::500L goes to CETP

Water- 600L GLR 1000Lfor reaction)

Dimethylamino Propyl Chloride – 120kg

GLR 2500L (for solvent recovery)


- 71 -

Acetone – 1000L Hazardous waste: 35-40kg Spent Carbon: 12kg Methanol Hcl – 100kg

Carbon – 10kg








- 72 -

Chlorpromazinebase 300.0 kgs

Acetone 1000LSS reactor-21000L

GLreactor1000L

SS reactor cap 3000LMLR solv recovery

Process Waste Water 692kgCleaning waste Water :500L

FLOW CHART FOR CHLORPROMAZINE HYDROCHLORIDE


dissolution

Reaction

Total waste water 1192kg/L

centrifuge

Acetone 850L Loss mix :100L

Haz Waste 35-40 kgs

Solvent recoveryMLR

Methanol hcl100 kg (110L)35.5kg +75L

Chlorpromazine hydrochloride315.0kgs

1st Step

2nd Step

Solvent Acetone Loss(mix)125.0L



2-chloro phenothiazine 233kg


KOH 59kg

Toluene 1000L

Water 600L

Water + KCl692kg


Chlorpromazine Base 315kgCrude (content:: 300kg)

Carbon 10kg

Spent carbon 12kgwet

18


20


- 73 -

3.5.2.9 DOXYLAMINE SUCCINATE

NO

NO

OH

O

O

H

Doxylamine succinate

388

NO

N

Doxylamine base

270

HOOH

O

O

+

Succinic acid

118

SOlvent

NO

N

Doxylamine base

270

NCl

107

N

O

121

Cl

112

Mg

24

MgCl

58

NaOH

40

NaCl

58

H2O

18

Raection scheme

2-acetyl pyridine Chloro benzene dimethylamino ethylchloride

1st step

2nd step

Acetone


- 74 -

MANUFACTURING PROCESS This involves 2 steps 1st step A 2-Acetyl Pyridine (or 2-Benzoyl pyridine) is converted to Grignard base by reaction with Chloro benzene in solvent Toluene in SS reactor using Magnesium filings under Nitrogen atmosphere. The reaction is carried out at temp ~10-15*C. After the reaction Reaction mass is quenched in water to get the Grignard base in Toluene. (Top layer) This layer is taken for the next step. 1st step B This is immediately reacted with Diethylamino ethylchloride at temp 85*C to get Doxylamino base in solvent in SS reactor. After the reaction is complete, the Reaction mass is basified with sodium hydroxide in water to get 2 layers. The top organic layer is distilled to remove solvent completely to get Doxylamine base liquid. The recovered Toluene is purified in SRP which is recycled. 2nd step Doxylamine base is dissolved in Acetone solvent in SS reactor treated with carbon and filtered. The clear filtrate is treated with Succinic acid at temp 10-15*C to get Doxylamine succinate which is centrifuged to get pure product. Product is later dried. The mother liquor is distilled to recover Acetone which is re used.

DOXYLAMINE SUCCINATE MASS BALANCE SL NO PRODUCTION B size ::350kg No of batchs 5/Month

Raw material used

1 2-Acetyl pyridine 120kg

2 Chloro Benzene 112kg

3 Diethylamino ethyl chloride 107kg

4 Water 1200Lt(1st stage A& B)

5 Toluene 1200Lt(1st stageA)

6 THF 30Lt

7 NaOH 40kg

8 Carbon 15kg

9 Mg 24kg

10 Succinic acid 110kg

11 Acetone 1000Lt

Yield (Doxylamine Succinate) 345kgs


2-Acetyl pyridine – 120kg

SSR 2500L(for step 1 grignard reaction)

Doxylamine Succinate Yield 345kg Overall yield :: 89%


- 75 -

Chloro Benzene – 112kg SSR 2500L (for step 2 Toluene layer)

I.Product stage92.5% Stage : 96%

Diethylamino ethyl chloride – 107kg

SSR 3000Lfor dissolution Toluene: 1050L Loss: 150L Acetone: 825L Loss:175L P.Water stage1A::660kg/L (Contns MgCl) Stage 1B::676kg/L (Contns NaCl) Total water :: 1336kg/L Cleaning water ::500L goes to CETP Hazardous waste: 34-38kg Spent Carbon: 18kg

Water – 1200L GLR 3000L (for reaction)

Toluene – 1200L SSR 3000L (for solvent recovery)

THF – 30L/20kg

NaOH – 40kg

Carbon – 15kg

Mg – 24kg

Succinic acid – 110kg

Acetone – 1000L




& Centrifuge … 4-6hrs 2-4hrs 4-6hrs

3) Solvent recovery…… ----- ------ 12-16hrs(MLR-3)


along with process waste water 1336kgs


- 76 -

FLOW CHART FOR DOXYLAMINE SUCCINATE


Haz Waste 34-38kg Process Waste Water-1&2:; 1336kgCleaning Waste Water : 500L

Doxylamine base 250.0 kgs

Total water : 1836L/kg

GL reactorcap 3000Lreaction

2nd Step

Solvent recoveryMLR

Centrifuge

Solvent recovery Cap 3000LSSreactor MLR

Doxylamine succinate345 kgs

MLR-1 AcetoneLoss 75L

SS reactor-2cap 2500LToluene layer

SS reactor-1cap 2500Lgrignard

Toluene/THF1200L/ 30L

2_acetyl pyridine 120kg

Chloro benzene 112kg

Water 600L

Doxylamine baseCrude 270kg(content:250kg)


Tol Recovered 1050L Loss:150 L

1st step A Grignard reaction

Mg 24kg

Acetone 1000L

Acetone recov:825Lloss:100L

Carbon -15kgSpent carbon18 kgwet

Spent carbon 18 kg wet

Diethylamino ethylchloride 107kg

Water 600L

NaOH 40kg

Water-2 676kg / NaCl mix

Succinic acid110kg

20

15

1st step B


- 77 -

3.5.2.10 ORPHENADRINE CITRATE/ HCL

ONO

N

Orphenadrine Base

+

CO2H

CO2H

HO2C

OH

192

Citric Acid

citrate

269 461

Orphenadrine Citrate

Acetone

ON

Orphenadrine Base

269

NClHO

21689

NaOH

40

Toluene

NaCl H2O

58 18

1st step

2nd step

2-Methyl benzophenone

DimethylaminoEthanol

Reaction scheme


- 78 -

MANUFACTURING PROCESS The reaction involves 2 steps 1st step 2 methyl benzhydryl chlorides are reacted with Dimethylamino ethanol in SS reactor using solvent Toluene in presence of base like Sodium hydroxide by refluxing for 15-16hrs. After the reaction is complete the reaction mass is worked up by quenching with water. The organic layer is separated and Toluene is removed by distillation to get the Orphenadrine base. The recovered Toluene is purified in SRP which is reused. 2nd step The orphenadarine base is dissolved in SS reactor at 50-550 C in solvent Acetone; charcoaled and filtered and the clear solution is then transferred to GL reactor. The clear solution is treated with citric acid at slightly elevated temperature of 60-65*C to get orphenadrine citrate, for 14-16hrs, cooled to get solid; which is isolated by centrifuging. The product is then dried. The mother liquor is transferred to SS reactor for recovery. Solvent recovery The mother liquor from the centrifuge is distilled to recover ethyl acetate, which is recycled.

ORPHENADRINE CITRATE Gravimetric/MASS BALANCE SL NO PRODUCTION B size 400kg No of batchs 10/Month

Raw material used

1 2-methyl Benzo phenone 215kg

2 NaOH 40kg

3 Dimethylamino Ehtanol 90 kg

4 Toluene 1000Lt

5 Citric acid 180kg

6 Water 600L

7 Acetone 1500L

8 Carbon 10kg

Yield (Orphenadrine Citrate) 400kgs


- 79 -

Batch size 400kgs --- Orphenadrine Citrate DIHydrochloride


2-methyl Benzo phenone – 215kg


Orphenadrine Citrate Yield :400 kg Overall yield 86.7%

NaOH – 40kg SSR 3000L (for step 1 workup)

I.Product: 1st stage 92% 2nd stage ::94%

Dimethylamino Ehtanol – 90kg

SSR 3000L (for step 2 dissolution reaction)

Toluene: 900L Loss: 100L Acetone: 1250L Loss: 250L P.Water: 1st stage 676kg/ L Cleaning water ::1000L goes to CETP Hazardous waste: 45-48kg Spent Carbon: 12kgwet

Toluene – 1000L GLR 3000L (for step 2 condensation)

Citric acid – 180kg SSR 2000L (for solvent recovery)

Water – 600L

Acetone – 1500L

Carbon – 10kg





3) Solvent recovery…… ------ 10-12hrs(MLR-2) -----

Water used for washing/cleaning equipment, cleaning waste water 1000L goes to

CETP along with process waste water 676kgs


- 80 -

Orphenadrine base250 kgs

Acetone 1500LSS reactor-2cap 3000LDissolution

GL reactor cap:3000Lcondensation


Process Waste Water ::676.0L/ kgCleaning waste Water :1000L/kg

FLOW CHART FOR ORPHENADRINE CITRATE

MLR Acetonefor recovery

acetone


centrifuge

Acetone Reco: 1250LLoss:100L

Haz Waste 45-48kg

MLRAcetone

Citric acid180kg

Orphenadrine Citrate400.0kgs

2nd Step

Solvent AcetonLoss :150.0L



2-methyl BenzHydrylchloride 215kg

DimethylaminoEthanol 90kg

NaOH 40 kg

Toluene1000L

Water 600L

Water +Nacl676L/kg


Orphenadrine base270 crude (Cont 250kg)

1st step

Solvent recovery

Carbon 10kg

Spent carbon12kg

Spent carbon 12 kg

19

26


- 81 -

3.5.2.11 TRIMIPRAMINE MALEATE/ MESYLATE

Dimethylamino Methyl propyl chloride

135

Cl N

NH

Imino dibenzyl

195

Toluene

NaCl NH3NaNH2

39

58 17

Reaction scheme

N

N

Trimipramine

294 g

N

N

Maliec acid

116 g

OH

OH

OO

. C4H4O4

Trimipramine Maleate

410 g

N

N

Trimipramine

294

Acetone

N

N

.CH3SO3HCH3SO3H

390

96

Ethyl acetate

Methane sulphonic acid

Trimipramine Mesylate

1st step

2nd step


- 82 -


It involves 2 steps

1st step

Iminodibenzyl is dissolved in SS reactor in Solvent Toluene and to this was added

Sodamide base under nitrogen and then added slowly 2-Methyl Dimethylamino

propyl chloride. The reaction mass is then refluxed for 24 hrs to get Trimipramine

base. The product is then worked up, after the reaction is complete by quenching

in water, and separating the organic layer.


Trimipramine base is taken for the next step.


2nd step

Trimipramine base is dissolved in solvent Acetone in SS reactor treated with

carbon and filtered. The clear filtrate Is transferred to glass lined reactor. The

clear solution is cooled < 15*C in Glass lined reactor and treated with Maleic acid

solution in acetone to get Trimipramine Maleate crude.


Trimipramine Maleate in crystals which is centrifuged and dried.

The mother liquor is sent for recovering sovent which is recycled.

Also Trimipramine base in Ethyl acetate is treated with Methane sulphonic acid to

get another salt Trimipramine Mesylate in same condition as above.

TRIMIPRAMINE MALEATE MASS BALANCE

SL NO PRODUCTION B size 350kg No of batchs::2/Month

Raw material used

1 Sodamide 39kg

2 Imino Dibenzyl 195kg

3 Toluene 1000Lt

4 Water 600Lt

5 Dimethylamino Methylpropyl chloride 135kg

6 Acetone/EA 800Lt

7 Maleic acid 114kg

8 Carbon 10kg

Yield (Trimipramine Maleate)and salt 370kgs


- 83 -

Batch size 350kgs --- Trimipramine Maleate


Sodamide – 39kg SSR 3000L(for step 1 reaction)

Trimipramine Maleate / or Mesylate Yield 370kg/350kg 0verall yield :90%

Imino Dibenzyl – 195kg SSR 3000L (for step 2 reaction workup)

I . Product Stage-1: 95% Stage-2:94.5%

Toluene – 1000L SSR 2000L (for step 2 dissolution)

Toluene: 900L Loss: 100L Acetone/EA: 700L Loss:100L NH3 ::17kg P.Water stage-1::: 660 L Cleaning water :::500L goes to CETP Hazardous waste: 32-36kg Spent Carbon: 12kg

Water – 600L GLR 2000Lfor reaction)

Dimethylamino Methylpropyl chloride – 135kg


Acetone/EA – 800L

Maleic acid – 110kg or Methane sulfonic acid 92kg

Carbon – 10kg








- 84 -

Trimipramine base280 kgs

Acetone/ EA800L

SS reactor-22000L

GLreactor2000L

SSreactor2cap 1000Lfor solvent recovery

Solv Loss: 50LAcetone /EA


FLOW CHART FOR TRIMIPRAMINE MALEATE

MLR Acetonefor recycle(750L)

dissolution

Reaction


centrifuge +

Acetone/EA Pure700L Recycle

Haz Waste 34-36kgs

MLRAcetone

Maleic acid110kg/

or MSA-92kg

Trimipramine Maleate370.0kgs

2nd Step

Solvent lossAceton/EA50.0L



Imino Dibenzyl 195kg

DimethylaminoMethylPropyl chloride 135kg

Sodamide39kg

Toluene1000L

NH3 17kg

Water 600L

Water + NaCl660kg


Trimpramine base 295kg crude(content ::280kgs)

1st step

Trimipramine Mesylate:350kg

Carbon 10 kg



14

20


- 85 -

3.5.2.12 FLUPENTIXOL HCL

Reaction scheme

S

CF3

N

NOH

HO

S

CF3

N

NOH

.2 HCl

Flupentixol Hydrochloride

+ 2 HCl

Acetone

Flupentixol base Hydrochloric acid

452 73507

+ H2O

Water

18

2nd step

S

N

NHO

S

Cl

N

N

OH

+

F3C

F3C


Piperazino intermediate Flupentixol Grignard Base

Toluene,Mg 24

OH

O

207280

452

Mg Cl

59

1st step

Decanoyl chloride

Flupentxol decanoate

C9H19COCl

OH to ester decanoate

588

136

2 Na OH

2-H2O

36

NaCl

108

80


- 86 -



1st step

The Trifluro Thioxoanthrone is reacted with piperizine ethanol intermediate in SS

reactor in Solvent toluene and THF mixture in presence of Magnesium filings (Grignard

reaction) at <35*C.

After the reaction mass is quenched with water and the layers were separated.

Organic layer is concentrated by distillation to recover Toluene which is purified and

reused. The thick liquid mass is then treated with Methanol to get solid Grignard

product. (Grignard intermediate, flupentixol Grignard base) Solid is isolated by

centrifuging and mother liquor is sent for recovery of methanol which is reused.

2rd step

The Flupentixol Grignard base is dissolved in Toluene by heating at 40-50 * C in SS

reactor charcoaled and filtered. The clear solution is transferred to GLR eactor.

To the clear solution from above is added slowly to conc Hydrchloric acid in glass lined reactor (GLR) and then refluxed for 12-14 hrs with simultaneous removal of water Azetrope. After the removal of water reaction is complete, cooled gradually over a period of 2-4 hrs to temp < 15*C to get Flupentixol hydrochloride crystals. These are centrifuged and the solid is dried. Also Hydrochloride is converted to another salt Decanoate by treating with Decanoyl chloride in Glreactor in solvent Toluene. The mother liquor from the centrifuge is sent for solvent recovery and the recovered solvent is recycled.

FLUPENTIXOL HYDROCHLORIDE MASS BALANCE

SL NO PRODUCTION 50kg

Raw material used

1 THF 10L

2 TRIFLUOROTHIOXANTHONE 28kg

3 Mg 2.5kg

4 Toluene 700Lt(1st and 2nd stage)

5 Water 200L(1st stage)

6 Acetone 300L

7 Carbon 5kg

8 Con Hcl acid 21kg

9 Piperizino ehtanol intermediate 20kg

Yield (Flupentixol Hydrochloride) 40kgs


- 87 -

Batch size 50kgs --- Flupentixol Hydrochloride


THF – 10L(7KG) SSR 600L(for step 1 griganard)

Flupentixol Hydrochloride Yield ::40kg Overall yield80%

Triflurothioxanthone– 28Kg SSR 600L (for step 1 workup)

I.Product: stage-1::88% Stage-2::92%

Mg – 2.5kg SSR 1000L (for step 2 dissolution reaction)

Toluene: 630L Loss: 70L (Incl THF) Acetone: 265L Loss: 35L P.Water: stage-1 ::225 kg/L (Contns MgCl) Cleaning water ::500L/kg goes to CETP Hazardous waste: 6-8kg Spent Carbon: 6kg

Toluene – 700L GLR 1000L (for step 2 reaction)

Water – 200L

Acetone – 300L

Carbon – 5kg

Con Hcl acid – 21kg

Piperizino ehtanol intermediate – 20kg





3) Solvent recovery…… ---- 10-12hrs(MLR-2) 12-16hrs(MLR-3)

Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP along with process waste water 225kgs Piperizino ehtanol intermediate – 20kg


- 88 -

Toluene 500LSS reactor-21000L

Haz Waste1 &2 7-10 kgsProcess Waste Water 225 kgsCleaning Waste Water : 500L

FLOW CHART FOR FLUPENTIXOL HYDRCHLORIDE

FlupentixolGrignard base 40.0 kgs

Total waste water to CETP is 725L/kg

dissolution

GL reactor

2nd Step

Solvent recoveryMLR-1&MLR-2

Solvent lossTol: 25.0LSolvent loss Acetone:25L

Toluene Recov 450L Loss:25L

reaction

1000L

Conc HCL acid 21.0kgs(7.3+13.5)

Centrifuge

Solvent recovery MLRSSreactor 1000L

Flupentixolhydrochloride40.0 kgs

MLR-1 TolueneMLR-2 Acetone

Water 15.5kgs



Toluene/THF200L/10L

Trifluorothioxanthone28 kg Piperizino ethanol

Intermediate20kg

Water200L

Centrifuge


Flupentixol Grignard base 45kg wet (cont 40kg)

MLR


Solvent Loss:40L



Mg 2.5kg

Acetone wash 300L


Ester(Deconate)2nd Derivtive1:! Yield

Carbon -5kg

Spent carbon6 kgwet


2

5


- 89 -

3.5.2.13 MELITRACEN HCL

Reaction Scheme

N

.HCl+

Millitracen Grignard Base

Hydrochloric acid

Acetone

Millitracen Hydrochloride

309 36.5 327.5

OH

N

Water

18

.HCl

N

Millitracen Grignard Base

309

OHN

O

222

Cl

121

Dimethyl anthrone Dimethlamino propyl chloride

Toluene/THF

Mg

24

MgCl

59

H2O

MANUFACTURING PROCESS This involves 2 steps 1st step Dimethyl anthrone is reacted with Dimethyl amino propylchloride in Solvent mixture of THF and Toluene under nitrogen atmosphere using Magnessium catalyst (Grignard reaction) at temp <35*C. After the reaction is complete, the reaction mass is quenched with water and cooled < 15*C. Solid Hydroxy millitracene (Grignard intermediate is centrifuged to isolate the solid. Mother liquor from the centrifuge is taken to another SS reactor layers


- 90 -

separated and organic layer is sent for recovering the solvent Toluene. Recovered solvent is recycled. 2nd step The Hydroxy millitracene base is dissolved in Toluene by heating at 40-50 * C in SS reactor Char coaled and filtered. To the clear solution from above is added slowly to conc Hydrchloric acid in glass lined reactor and then refluxed for 12-14 hrs with simultaneous removal of water Azetrope. After the removal of water reaction is complete, cooled gradually over a period of 2-4 hrs to temp < 15*C to get Millitracen hydrochloride crystals. These are centrifuged and the solid is dried. The mother liquor from the centrifuge is sent for solvent recovery and the recovered solvent is recycled. MILLITRACEN HYDROCHLORIDE Gravimetric/MASS BALANCE

SL NO PRODUCTION B Size 300kgs No of batchs 1/Month

Raw material used

1 THF 30L

2 Dimethyl anthrone 220kg

3 Dimethylamino propyl chloride 120 kg

4 Toluene 2200Lt (1st and 2nd step)


6 Mg 24kg

7 Acetone 1000L

8 Carbon 15kg

9 Con Hcl acid 100kg

Yield (Millitracen Hydrochloride) 295kgs

Batch size 300kgs --- Millitracen Hydrochloride


THF – 30L SSR 2500L(for step 1 grignard Reaction)

Millitracen Hydrochloride Yield 295kg Overall yield 90%

Dimethyl anthrone – 220kg


I.Product:stage-1 ::94% Stage-2::96%:

Dimethylamino propyl chloride – 120kg

SSR 3000L (for step 2 dissolution)

Toluene: 1850L Loss: 380L (incld THF) Acetone: 825L Loss: 175L P.Water: Stage-1 ::660kg/L Conts MgCl Stage-2 :: 80kg Total water ::

Toluene – 2200L GLR 3000L (for step2 reaction)


Mg – 24kg

Acetone – 1000L


- 91 -

740kg/L Cleaning water ::500L goes to CETP Hazardous waste: 28-32kg Spent carbon: 18Kg

Carbon – 15kg

Con Hcl acid – 100kg





3) Solvent recovery…… ------ 10-12hrs(MLR-2) 12-16hrs(MLR-3)



- 92 -

FLOW CHART FOR MILLITRACEN HYDRCHLORIDE

Toluene 1000LSS reactor-2cap 3000LDissolution

Haz Waste1 &2 28-32kgProcess Waste Water-1&2:; 740kgCleaning Waste Water : 500L

MilitrceneGrignard base 290.0 kgs

Total water ::1240L/kg


2nd Step

Solvent recoveryMLR-1&MLR-2

Solvent lossTol: 75.0LSolvent loss Acetone:75L

Toluene Recov 850L Loss:75L

Conc HCL acid 100 kg(35.0+65kg)

Centrifuge


Militricene hydrochloride295 kgs

MLR-1 TolueneMLR-2 Acetone

Water-2 80kgs



Toluene/THF1200L/ 30L

Dimethyl anthrone 220kg

Dimetylamino propyl chloride 120kg

Water 600L

Centrifuge

RecoveredToluene 1000LLoss :100L

Militricin Grignard base 305 crude (content )290kg


Tol Solvent Loss:130 L



Mg 24kg

Acetone wash 1000L


Carbon -15kg

Spent carbon18 kgwet


MLR 19

11


- 93 -

3.5.2.14 CARBINOXAMINE MALEATE

Reaction scheme

NO

Cl

N NO

Cl

N+

CO2H

CO2H

Carbinoxamine Base Maleic acid Carbinoxamine Maleate

Acetone

.C4H4O4

290.5116

406.5

NO

Cl

N

Carbinoxamine Base

290.5

NClN

OH

Cl

219

107.5

Toluene

NaOH

40

NaCl H2O

58 18

Pyridine benz Hydrol

Dimethylamino ethyl chloride



1st step

The Carbinoxamine base is obtained by reacting pyridine Benz hydrol with

dimethylamino ethyl chloride in SS reactor in suitable solvent like Toluene in presence

of sodium hydroxide base. After the reaction is complete, mass is quenched with

water and organic layer is separated.

This organic layer is then concentrated to remove Toluene by distillation to get a

syrupy liquid base.

The recovered Solvent toluene is purified in Solvent recovery plant and reused.


- 94 -

2nd step

Carbinoxamine base is dissolved in Acetone in SS reactor, charcoaled and filtered. The

clear filtrate is transferred to Glass lined reactor and cooled to<10*C. The above

solution is cooled at temp <10*C treated with Maleic acid which is added slowly by

maintaining temperature below 10* C.

The above reaction mixture is refluxed for 6hrs at 65-70*C and the the mass is stirred

at temp <25*C for 2-4hrs and cooled to temp < 10 *C to get Carbinoxamine maleate

crystals which is separated by centrifuging to isolate the product and dried.

The mother liquor from the above centrifuge is sent for recovery of Acetone solvent

which is recycled.

CARBINOXAMINE MALEATE MASS BALANCE

SL NO PRODUCTION B Size350kg No of batchs 2/Month

Raw material used

1 Pyridine Benz Hydrol 220kg

2 NaOH 40kg

3 Dimethylamino Ethyl chloride 107kg

4 Toluene 1000Lt

5 Maleic acid 116kg

6 Water 600L

7 Acetone 1000L

8 Carbon 10kg

Yield (Carbinoxamine Maleate) 350kgs

Batch size 350kgs --- Carbinoxamine Maleate


Pyridine Benz Hydrol – 220kg

SSR 3000L(for step 1 condensation)

Carbinoxamine Maleate Yield 350kg Overall yield 86%

NaOH – 40kg SSR 3000L (for step 1 workup)

I.Product: 1st stage: 93% 2nd stage :92%

Dimethylamino Ethyl chloride – 107kg


Toluene: 900L Loss: 100L Acetone: 825L Loss: 175L P. Water: stage-1 ::676kg/ L Incl NaCl Cleaming water 500L goes to CETP

Toluene – 1000L GLR 3000L (for step 2 reaction)

Maleic acid – 116kg SSR 2000L (for solvent recovery)

Water – 600L


- 95 -

Acetone – 1000L

Hazardous waste: 45-48kg Spent Carbon: 12kg

Carbon - 10kg





3) Solvent recovery…… ---- 10-12hrs(MLR-) ---


along with process waste water 676kgs


- 96 -

Acetone 1000LSS reactor-2cap 3000L

Haz Waste 46-48kg

Process Waste Water- : 675L/kgCleaning Waste Water : 500L

FLOW CHART FOR CARBINOXAMINE MALEATE

Carbinoxaminebase 270.0 kgs


dissolution

2nd step

Maleic acid108kg

Centrifuge

SS reactorCap 2000LMLR

Recovered Acetone825L Loss :75L

Carbinoxamine Maleate 350kg

MLR AcetoneSolvent Loss :100L




condensation

Toluene 1000L

Pyridine BenzHydrol 220kg

DimethylaminoEthyl chloride 107kg

Water600L

RecoveredToluene900L Loss:100L

Carbinoxamine base290 kgcrude (content 270kg)

Water-1includes676 kgs/NaCL

1st stepNaOH 40kg

MLR

Solvent recovery

Carbon 10 kg

Spent carbon 12 kg

Spent carbon 12 kg

20

28


- 97 -

3.5.2.15 OPIPRAMOL HCL

Reaction scheme

N

N

NOH

.2HCl

N

N

NOH

Opipramol Base Opipramol Dihydrochloride

+ 2 HCl

Hydrochloric acid

36373 436

N

N

N

NOH

Opipramol Base

363

HN N

OH

Cl

269130

NaOH

Toluene

40

NaCl

58

H2O

18

Imino stilbene propyl chloride

Piperizino ethanol

N

Cl

269

Imino stilbene propyl chloride

Acetone

NH

ClBr

Imino stilbene Bromo chloro propane

193156

NaOH

Toluene

40

NaBr H2O

102 18

1st step

2nd step

3rd step


- 98 -



1st step

Imino stilbene is reacted with 3-Bromo chloro propane in SSreactor using Toluene

solvent in presence of base Sodium hydroxide by refluxing for 14 hrs .after the

reaction is completed the mass is cooled and quenched with water. Top organic layer

is separated and Toluene layer is removed by distillation to get imino stilbene propyl

chloride liquid.

The toluene recovered is reused after purification in SRP.

2nd step

Iminostilbene propyl chloride is then converted to Opipramol base by refluxing with

Piperizine ethanol in Toluene solvent in SS reactor using base Sodium hydroxide for 20

hrs. After the reaction mass is quenched with water to get 2 layers which is

separated.

Top organic layer is concentrated by distilling toluene to get syrupy Opipramol liquid.

The recovered solvent from this is reused after purification in SRP.

3rd step

Opipramol base is dissolved in Acetone solvent in SS reactor to get clear solution,

which is charcoaled and filtered. Th clear solution is transferred to GLR Reactor.The

above solution is cooled to<10*C and hydrogen chloride gas is passed slowly over

aperiod of 2 hrs by maintaining temperature below 20* C till Ph 2 is achieved.

The above reaction mixture is stirred at temp <25*C for 4hrs and cooled to temp < 10

*C to get Opipramol Dihydrochloride crystals which is separated by centrifuging to

isolate the product and dried.

The mother liquor from the above centrifuge is sent for recovery of Acetone solvent in

SRP which is recycled.

OPIPRAMOL HYDROCHLORIDE Gravimetric/MASS BALANCE

SL NO PRODUCTION B size 200kg No of batchs 1/month

Raw material used

1 Imino stilbene 96kg

2 NaOH 40kg

3 Bromochloro Propane 78 kg


- 99 -

4 Toluene 2000Lt(1st stage& 2nd stage)

5 Piperizinoethanol 65kg

6 Water 1200kg(1st &2nd stage)

7 Acetone 1200L

8 Carbon 10kg

9 HCl 36

Yield (Opipramol Hydrochloride) 210kgs


Imino stilbene – 96Kg SSR 3000L(for step 1 Dissolution Reaction)

Opipramol Hydrochloride Yield :195kg Overall yield 89%

NaOH – 40Kg SSR 3000L (for step 1 workup)

I.Product: 1st stage not isolated 2nd stage 95% 3rd stage 94%

Bromochloro Propane 78kg


Toluene: 1800L Loss: 200L Acetone: 1000L Loss: 200L P.Water: stage-1 :: 660kg/L (Conts NaBr) Stage-2 :: 638kg/L ContsNaCl) Total P Water ::1300kg/ L Cleaning water ::1000L goes to CETP Hazardous waste: 20-22kg Spent Carbon: 12kg

Toluene – 2000L SSR 2000L (for step2 workup)

Piperizinoethanol – 65kg

SSR 3000L (for step 1 dissolution )

Water – 1200kg/L GLR 3000L (for step 1 reaction)

Acetone – 1200L SSR 3000L (for solvent recovery)

Carbon - 10kg

HCl – 36Kg




& Centrifuge… 4-6hrs 2-4hrs 4-6hrs-16hrs (MLR-3)

Water used for washing/cleaning equipment, cleaning waste water 1000L goes to CETP along with process waste water 1080kg


- 100 -

Opipramol base170.0 kgs

HCL 36 kgs

SS reactor cap 3000Lsolvent recovery

Solv Loss DistillationAcetone 100.0L

Process Waste Water 1300kg/LCleaning waste Water :1000L

FLOW CHART FOR OPIPRAMOL HYDROCHLORIDE

MLR

Total waste water 2300L/kg

+Solvent loss 100.0 L Acetone

Acetonefor recycle1000.0L

Haz Waste 20-22 kgs

Solvent recoveryMLR

Acetone 1200L

Opipramol hydrochloride195.0kgs

1st Step

3rd step

SSreactor-2cap3000LDissolution Reaction

Imino stibene propylchloride 135kg

Piperizinoethanol65kg Toluene

1000L

NaOH 20kg

SSreactor-2cap3000L Work Up

SSreactor-1cap3000LDissolution Reaction

SSreactor-1cap3000LWork up

Water 600L

W/U

Water 638kg

Opipramol base170kg Liquid


Water660kg


Water600L

W/U

Imino stilbene 96kg kg

Toluene1000L

Bromo chloroPropane 78 kg

NaOH 20kg

Imino stilbenePropylchloride 140 kg liquid(content 135kg)2nd step

SS reactor-2cap 3000Ldissolution

Centrifuge


Spent carbon 12 kgCarbon 10kg

Spent carbon 12kg

11

10


- 101 -

3.5.2.16 SULFADOXINE

Reaction scheme

N N

Cl

OCH3

Cl

N N

Cl

OCH3HN

NH2

H2N

O

S

O

NH2

O

S

O

+ NaCl + H2O

Methoxydi-chloro pyrimidine

p-aminosulfonamide

IntermediateSOdiumchloride

Water

179 172

310

58.5 18

+

+ NaOH

SOdium hydroxide 40

315

N N

H3CO

OCH3HN

NH2

O

S

O

NaOCH3Mol WT: 54

Sulfadoxine

SodiumChloride

N N

Cl

OCH3HN

NH2

O

S

O

Intermediate

315

1st stage

2nd stage

NaCl

58

MANUFACTURING PROCEDURE The reaction involves 2 stages 1st stage (production of sulphone intermediate involves 2 steps) 1st step reaction Methoxy dichloro pyrimidine is reacted with p –amino sulfonamide in presence of sodium hydroxide in toluene media at an elevated temperature of 1000 C in SS reactor. Water formed during the reaction is removed azeotropically. After the reaction is complete the reaction mass is cooled < 300 C and centrifuged to remove by-product sodium chloride.


- 102 -

2nd step (Isolation of sulphone) The liquid mass from the centrifuge is taken in SS Reactor and treated with water and the reaction mass is cooled < 200 C. During this time sulphone intermediate crystallizes out. The product is separated by centrifuging and dried. The mother liquor is transferred for recovery of solvent. Solvent recovery The mother liquor in SS reactor is allowed to separate into 2 layers. The bottom aqueous layer is water, which goes to CETP. The top organic layer is distilled to recover toluene, which is recycled. 2nd stage (Involves 2-step) 1st step reaction The sulphone intermediate is refluxed in methanol solvent in presence of sodium methoxide. After the reaction is complete, the mass is cooled and centrifuged to remove sodium chloride by-product. The methanolic filtrate is taken back in SS reactor treated with carbon, filtered and the clear filtrate is concentrated by removing methanol, which is recycled. 2nd step (isolation of sulphadoxine) The concentrated mass is treated with water for 2-3 hrs and cooled to get Sulphadoxine, which is separated, by centrifuging and dried. The mother liquor is sent for recovery. Wastewater is sent to CETP. SULFADOXINE MASS BALANCE

SL NO PRODUCTION B Size 300kgs No of batchs 8/Month

Raw material used

1 P-Amino sulfonamide 172kg

2 Methoxy dichloro pyrimidine 179kg

3 Water 2000Lt(stage1&2)

4 Toluene 1500Lt(stage-1)

5 NaOH 40kg

6 Methanol 2000Lt(stage-2)

7 Sodium methoxide 54kg

8 Carbon 15kg

Yield (SULFADOXINE) 300kgs

Batch size 300kgs --- Sulfadoxine


P-Amino sulphonamide – 172kg

SSR 5000L(for step A condensation reaction)

Sulfadoxine Yield :300kg Overall yield ::96.5%

Methoxy dichloro SSR 5000L (for step B) I.Product stage-1 ::98%


- 103 -

pyrimidine – 179kg Stage-2::98%

Water – 2000L SSR 3000L(for reaction) Toluene: 1250L Loss: 250L Methanol: 1800L Loss:200L P.Water stage-1 :1018kg/L Stage-2: 1006kg/L Total P Water :::2024kg/L By product NaCl:116kg Cleaning water :::1500L goes to CETP Hazardous waste: 5-8kg Spent Carbon: 18kg

Toluene – 1500L SSR 3000L (for workup)

NaOH – 40kg SSR 2000L (for solvent recovery)

Methanol – 2000L

Sodium methoxide – 54kg

Carbon – 15kg





3) Solvent recovery…… 10-14hrs (MLR-1) ----- ------



- 104 -

SS reactor-2cap 3000Lwork up

Haz Waste 5-8kg Process Waste Water-1&2 :2020LCleaning Waste Water-1&2: 1500 L

FLOW CHART FOR SULFADOXINE


2nd step A

MLR Toluene from step1B

Recovered Toluene1250L Loss: 50L

Centrifuge

Solvent recovery MLRCap:;SSreactor 2000L

Recovered Methanol1800L Loss :100 L

Water-1000 kg/L

SS reactor-2cap 3000LReaction

SSreactor -1cap:5000Lcondensation

Toluene1500L

P-amino sulfonamide172kg

Methoxy di chloro pyrimidine 179kg

Centrifuge

Suphone Intermediate310kg

Solvent MethanolLoss:100L

1st step A


Centrifuge

Water18kg

Solvent Loss ::100L

Sodium Chloride 58.5kg

Water 1000L

CentrifugeSolvent Loss 100L

Sulphone Intermediate310kg

MLR 2-layers

Water layer 1000L and Tol layer toRecovery

Methanol 2000L

Sodium methoxide 54kg

Sodium chloride58 kg

Water1000L

!st step -B

2nd step B

Sulpha doxine300kg

Solvent recovery

NaOH 40kg

Carbon 15kg Spent carbon 18kg wet

spent carbon 18kg wet

5

5

By product NaCl 116kg


- 105 -

3.5.2.17 DOXEPIN HCL

Reaction scheme

O

N

OH

Doxiepinone Grignardbase

297

O

O

DoxiepinoneDimethylamino propyl chloride

210 121

THF/Toluene

Mg

MgClCl N

5924

+ HCl

O

N..HCl

31536

Hydrochloric acid Doxiepin HCl

TolueneO

N

OH

Doxiepinone Grignard base

297

H2O

18Acetone

MANUFACTURING PROCESS 1st step Doxiepinone is converted to Doxiepine Grignard base by reacting with dimethylamino propylchloride in solvent THF and Toluene (Grignard reaction) at <35*C.in SS reactor over a period of 20 hrs. After the reaction the mass is quenched in water and layers were separated. Top organic layer is transferred to other SS reactor and 50% Solvent is removed by distillation and the product Doxiepine Grignard base is isolated by cooling to < 5*C and centrifuging. The solid is taken for next step. The solvent is recovered and reused.


- 106 -

2nd step The Doxiepine Grignard base is dissolved in Toluene by heating at 40-50 * C in SS reactor. The clear solution from above is added slowly to conc Hydrchloric acid in glass lined reactor and then refluxed for 12-14 hrs with simultaneous removal of water Azetrope. After the removal of water reaction is complete, cooled gradually over a period of 2-4 hrs to temp < 15*C to get Doxiepine Hydrochloride crystals. These are centrifuged and the solid is dried. The mother liquor from the centrifuge is sent for solvent recovery and the recovered solvent is recycled.

DOXIEPINE HYDROCHLORIDE Gravimetric/MASS BALANCE SL NO PRODUCTION B size 300kg No of batchs ::1/Month

Raw material used

1 Mg 24kg


3 Toluene 2500L

4 Doxiepinone 210kg

5 THF 20Lt

6 Water 600Lt

7 Con Hcl 110kg

8 Acetone 1000Lt

9 Carbon 10kg

Yield (Doxiepine Hydrochloride) 280kgs

Batch size 300kg--- Doxiepine Hydrochloride


Mg – 24kg SSR 3000L(for step 1 Grignard reaction)

Doxiepine Hydrochloride Yield :280kg Overall yield:89%


SSR 3000L I.Product: stage-1::94% stage-2 ::94%

Toluene – 2500L SSR 3000L( for dissolution) Toluene: 2250L Loss: 250L (Contns 20L THF) Acetone: 825L Loss:175L P.Water: stage-1::660kg stage-2 ::90kg Total P water ::750kg/L Cleaming water ::500L goes to CETP Hazardous waste: 32-36kg

Doxiepinone – 210kg GLR 3000L(for reaction)

THF- 20L SSR 3000L (for solvent recovery)

Water – 600L

Con Hcl – 110kg

Acetone – 1000L


- 107 -

Carbon – 10kg

Spent Carbon: 12kg

Time cycle 1st stage 2nd stage 3rd stage final 1) Reaction ………… 20-23hrs 14-16hrs - Drying



Solvent recovery…… 10-12 hrs (MLR-1, 2) 10-14hrs (MLR-3) ----- Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP along with process waste water 750kgs


- 108 -




FLOW CHART FOR DOXIEPINE HYDRCHLORIDE

Doxiepine Grignard base280.0 kgs


dissolution

2nd step

MLR -1MLR-2




Centrifuge


825L Loss :75L

Doxiepinehydrochloride280.0 kgs

Water-290.0kgs






Grignard

Toluene/THF1000/20L

Doxiepinone210kg


Water600L

Centrifuge


Doxiepine Grignard base280 Kg

MLR


Solvent Loss:120L(contains THF20L)


1st step

Mg 24

Carbon 10 kg



17

17


- 109 -

3.5.2.18 NITRAZEPAM

Reaction sheme

N

HN

O2N

O

+ 2NH4Cl

+ Ammonia3

51

281

Nitrazepam

Ammonium chloride

106

O

NH2

O2NCl

O

318.5

O

HN

O2N

Cl

O

Nitro chloro intermediate

5-nitro 2amino benzophenone

Cl

chloro ethyl acetyl chloride

112

+

H2O

18

+

242

Toluene

Methanol

MANUFACTURING PROCESS 5-Nitro 2-Amino Benzophenone ( Nitro amino Ketone) is reacted with chloro acetyl chloride in toluene by refluxing for 12 hrs to get Nitro chloro intermediate in GLreactor , During the reaction Hcl generated is treated / scubbed with ammonia to get by product Ammonium chloride. After the reaction the mass is cooled and centrifuged .Wet cake is taken for next step .Toluene layer is distilled to recover solvent. Wet cake is dissolved in Methanol and the clear solution is Nitro chloro intermediate which is taken in SS reactor.


- 110 -

The Nitro Chloro intermediate in SS reactor is then reacted with ammonia by refluxing in solvent methanol for 8 hrs at temp 65* C and cooled to isolate by product Ammonium chloride which is removed by filtration.The resultant filtrate is concentrated 50% to recover solvent (which is recycled). The concentrated mass is further cooled to 15* C to get Nitrazepam which separates as crystals. These crystals are centifuged and the pure Nitrazepam is dried. The mother liquor from the centrifuge is sent for recovery of solvent at 65*C to recover methanol. The last portion of solvent distilling bet 85*C and 95*C is methanolic water which is sent as effluent. The residual mass remaining as undistilled is taken as Haz waste.

NITRAZEPAM MASS BALANCE SL NO PRODUCTION 250kg

Raw material used

1 Chloroacetyl chloride 112kg

2 2-amino 5-nitro benzophenone 242kg

3 Toluene 1000L

4 Ammonia 51kg

5 Carbon 10kg

6 Methanol 1250Lt

Yield (Nitrazepam) 250kgs

Batch size 250kgs --- Nitrazepam


Chloroacetyl chloride – 112kg

GLR 2000L(for step 1 reaction)

Nitrazepam Yield ::240kg Overall yield :85%

2-amino 5-nitro chloro benzophenone – 242kg

SSR 2000L (for reaction) Product: stage-1:94% wet stage-2 ::91%

Toluene – 1000L SSR 2000L( for methanol solution)

Toluene: 850L Loss: 150L Methanol: 1000L Loss:250L P.Water: nil Am Chloride:125kg incl water and scrubbed HCL Cleaning water ::1000L goes to CETP Hazardous waste: 40-45kg Spent Carbon: 12kg

Ammonia – 51kg SSR 2000L (for solvent recovery)

Carbon – 10kg

Methanol – 1250L


- 111 -





Solvent recovery…… 10-12 hrs (MLR-1, 2) 10-14hrs (MLR-3) ----- Water along with cleaning water sent to CETP


- 112 -

Process Waste Water :: NilCleaning waste Water :1000LTotal water ::1000L/kg

SS reactor-2 cap 2000LMethanol solution

SSreactor 2000Lfor solvent recoveryMLR

FLOW CHART FOR NITRAZEPAM

Methanol 1000LSolv loss 100L

Haz Waste1&2 ::40-45kg

MLR-1 TolueneMLR-2 Methanol

GL reactor-1 cap:2000LRection

Chloroacetylchloride 112kg

2-amino 5-Nitro benzophenone 242kg

Toluene 1000L

1st step


Centrifuge Solv loss75L MLR-1

Nitrochloro intermediatewet 315kg(actual 300kg)

Methanol1250L

HCl 36 kg scrubber

Ammonia 51kg

Filter-Nutch Wet Am.Cl 125kg inclu 18kg water

Solv methanolloss 75L

Centrifuge

2nd step

Am.Choride 125kg wet

Tolu recov 850Lloss 75L

Nitrochloro intermediate 300kg

SS reactor-1 cap 2000L reaction

Carbon10kg

Spent C12kg

Solution Reaction mass Taken back

Solv loss 75LMLR-2

Nitrazepam240kg 23

18


- 113 -

3.5.2.19 DOTHIEPIN HCL

Reaction scheme S

N

OH

Dothiepinone Grignardbase

313

S

O

DothiepinoneDimethylamino propyl chloride

226 121

THF/Toluene

Mg

MgClCl N

5924

+ HCl

S

N..HCl

331.536.5

Hydrochloric acid Dothiepin HCl

TolueneS

N

OH

Dothiepinone Grignard base

313

H2O

18Acetone

Manufacturing process 1st step Dothiepinone is converted to Dothiepinone Grignard base by reacting with dimethylamino propylchloride in solvent THF and Toluene (Grignard reaction) at <35*C.in SS reactor over a period of 20 hrs. After the reaction the mass is quenched in water and layers were separated. Top organic layer is transferred to other SS reactor and 50% Solvent is removed by distillation and the product Dothiepine Grignard base is isolated by cooling to < 5*C and centrifuging. The solid is taken for next step.


- 114 -

The solvent is recovered and reused. 2nd step The Dothiepine Grignard base is dissolved in Toluene by heating at 40-50 * C in SS reactor. The clear solution from above is added slowly to conc Hydrchloric acid in glass lined reactor and then refluxed for 12-14 hrs with simultaneous removal of water Azetrope. After the removal of water reaction is complete, cooled gradually over a period of 2-4 hrs to temp < 15*C to get Dothiepine hydrochloride crystals. These are centrifuged and the solid is dried. The mother liquor from the centrifuge is sent for solvent recovery and the recovered solvent is recycled.

DOTHIEPINE HYDROCHLORIDE Gravimetric/MASS BALANCE SL NO PRODUCTION B size 300kg No of batchs : 4/Month

Raw material used

1 Mg 24kg


3 Toluene 1000L

4 Dothiepinone 226kg

5 THF 20Lt

6 Water 600Lt

7 Con Hcl 110kg

8 Acetone 1000Lt

9 Carbon 10kg

Yield (Dothiepine Hydrochloride) 295kgs

Batch size 300kgs --- Dothiepine Hydrochloride


Mg – 24kg SSR 3000L(for step 1 Grignard reaction)

Dothiepine Hydrochloride Yield :295kg Oveall yield :89%


SSR 3000L Product: stage -1 :94% Stage-2 :: 94.5%

Toluene – 2500L SSR 3000L( for dissolution) Toluene: 2250L Loss: 250L Acetone: 825L Loss:175L P.Water: stage-1:660kg/L (Contns Mg Cl ) Stage-2 :: 90kg/L Total P water ::750kg/L Cleaning water :500L goes to CETP Hazardous waste: 35 -

Dothiepinone – 226kg GLR 3000L(for reaction)

THF- 20L SSR 3000L (for solvent recovery)

Water – 600L

Con Hcl – 110kg

Acetone – 1000L


- 115 -

Carbon – 10kg

40kg Spent Carbon: 12kg





Solvent recovery…… 10-12 hrs (MLR-1, 2) 10-14hrs (MLR-3) -----



- 116 -




FLOW CHART FOR DOTHIEPINE HYDRCHLORIDE

Dothiepine Grignard base295.0 kgs


dissolution

2nd step

MLR -1MLR-2




Centrifuge


825L Loss :75L

Dothiepinehydrochloride295.0 kgs

Water-290.0kgs






Grignard

Toluene/THF1000/20L

Dothiepinone226kg


Water600L

Centrifuge


Dothiepine Grignard base295 Kg

MLR


Solvent Loss:120L(contains THF20L)


1st step

Mg 24

Carbon 10 kg



17

18


- 117 -

3.5.2.20 BROMAZEPAM

N

HN

Br

N

O

2NH4Cl

+

Ammonia3

51

353.5

316

Bromazepam

Ammonium chloride

106

+ Water (18)

O

HN

Br

N

Cl

O

bromo chloro intermediate

O

NH2

Br

N

Cl

O

Cl

277112

Chloro acetyl chloride2-amino 5-bromo benzoyl pyridine

Reaction scheme

Toluene

Methanol

MANUFACTURING PROCESS 5-Bromo2-Amino Benzoyl pyridine ( Bromo amino Ketone) is reacted with chloro acetyl chloride in toluene by refluxing for 12 hrs to get Bromo chloro intermediate in GLreactor , During the reaction Hcl generated is treated / scubbed with ammonia to get by product Ammonium chloride. After the reaction the mass is cooled and centrifuged .Wet cake is taken for next step .Toluene layer is distilled to recover solvent. Wet cake isdissolved in Methanol and the clear solution is Bromo chloro intermediate which is taken in SS reactor.


- 118 -

The Bromo Chloro intermediate in SS reactor is then reacted with ammonia by refluxing in sovent methanol for 10hrs at temp 65* C and cooled to isolate by product Ammonium chloride which is removed by filtration.The resultant filtrate is concentrated 50% to recover solvent (which is recycled). The concentrated mass is further cooled to 15* C to get Bromazepam which separates as crystals. These crystals are centifuged and the pure Bromazepam is dried. The mother liquor from the centrifuge is sent for recovery of solvent at 65*C to recover methanol. The last portion of solvent distilling bet 85*C and 95*C is methanolic water which is sent as effluent. The residual mass remaining as undistilled is taken as Haz waste.

BROMAZEPAM MASS BALANCE SL NO PRODUCTION B Size 60 kg No of batchs ::1/Month

Raw material used


2 2-amino 5-bromo benzoyl pyridine 70kg

3 Toluene 600L

4 Ammonia 14kg

5 Carbon 5kg

6 Methanol 800Lt

Yield (Bromazepam) 60kgs

Batch size 100kgs --- Bromazepam




Bromazepam Yield ::60kg Overall yield :75%

2-amino 5-bromo benzoyl pyridine – 70kg

SSR 2000L (for reaction) Product: stage-1:90% wet stage-2 :: 83%


Toluene: 500L Loss: 100L Methanol: 600L Loss:200L P.Water: nil Am Chloride: 30kg incl water and scrubbed HCL Cleaning water ::1000L goes to CETP Hazardous waste: 20-25kg Spent Carbon: 7kg


Carbon – 5kg

Methanol – 800L


- 119 -




Solvent recovery…… 10-12 hrs (MLR-1,) 10-14hrs (MLR-2) ----- Water used for washing/cleaning equipment, cleaning waste water 1000L goes to CETP


- 120 -




FLOW CHART FOR BROMAZEPAM






2-amino 5-bromo benzoyl pyridine 70kg

Toluene 600L

1st step



Bromochloro intermediate88kg wet (actual 80kg)

Methanol800L

HCl 9 kg scrubber

Ammonia 14kg



Centrifuge

2nd step

Am.Choride 30kg wet


Bromo chloro intermediate 80kg


Carbon5kg

Spent C7kg


Solv loss 50LMLR-2

Bromazepam60kg 12

8


- 121 -

3.5.2.21 FLUNARAZINE HCL

HN

NH

F

F

HO

N

NF

F

+

Cinnamyl alcohol

Flunarazine Base

N

NF

F

Flunarazine Base

N

NF

F

Flunarazine Dihydrochloride

.2HCl

OH

4,4'-difulorobenzhydrol

HCl

Piperizine

86

134

36

NaOH

40

NaCl 3 H2O

58 54

404220

404 477

2 HCl

Acetone

Methanol

2nd step

1st step

Reaction scheme

73

MANUFACTURING PROCESS The process involves 2 steps 1st step A 4, 4’DifluoroBenzhydrol is reacted with HCl in Glass reactor to get corresponding Benzhydryl chloride at temp ~60-70*C which, after10hrs, the reaction is checked for completion and the reaction is worked up by extraction with Toluene solvent. The resultant mass is having 2 layers which is separated .Top toluene layer contains Chloro fluro Benzhydryl intermediate which is taken in SS reactor for conversion to Chloro FluroBenzhydryl piperizine .


- 122 -

1st step B Chloro Fluro Benzhydryl intermediate in Toluene is condensed with Piperizine in presence of NaOH base and water is removed azeotropicaly to get Di FluroBenzhydryl piprizine and refluxed for 6hrs more. After the reaction the toluene layer is washed with water and Top organic layer containing Piperizine derivative is taken in another SS reactor in next step. 1st stepC The above Di FluroBenzhdryl piperizine in toluene solvent treated with Cinnamyl alcohol which is slowly added over a period of 5-6 hrs. The resultant reaction mixture is then refluxed for 10-12 hr with slow removal of water by azeatropic distillation. After complete removal of water, the reaction is checked for completion .The solvent is totally removed to get Flunarizine base crude. Recovered toluene is reused. 2nd step The crude Flunarizine base is dissolved in Acetone solvent to get clear solution which is reacted with HCl to get Flunarizine DiHydrochloride which is centrifuged. This Flunarizine Dihydrochloride is purified by dissolving in Methanol and clear solution is chrcoaled and filtered.The clear solution is 50% concentrated and mass is cooled to <10*C during which period crystals of Flunarizine separates out. The product is centrifuged, and dried. The mother liquor from the centrifuge is sent for recovering acetone and Methanol which is recycled. FLUNARIZINE MASS BALANCE SL NO PRODUCTION 400kg

Raw material used

1 Difluro Benzhydrol 220kg

2 Piperizine 86kg

3 Toluene 1500L

4 HCl 36kg

5 NaOH 40kg

6 Water 1425Lt

7 Cinnamyl alcohol 134kg

8 Acetone/IPA 2000Lt

9 Carbon 15kg

10 Methanol 2000L

11

Yield (Flunarizine) 430kgs


- 123 -

Batch size 400kgs --- Flunarizine Input Reactors Output

Difluro Benzhydrol – 220kg GLR 4000L(for step 1 reaction)

Flunarizine Yield ::430kg Oveall yield :90%

Piperizine – 86kg SSR 4000L (for condensation) I.Product: stage-1 ::(not isolated wet) is taken for next step Stage-2 :: 90%

Toluene – 1500L SSR 4000L( for condensation) Toluene: 1300L Loss: 200L Methanol: 1700L Loss:300L Acetone+IPA: 1650L Loss:350L P.Water: stage-1 ::300L/kg Stage1B ::695kg/L (Contns NaCl) Stage-1C :620kg/L Total P water :: 1615kg/L Cleaning water ::1500L goes to CETP Hazardous waste: 45-48kg Spent Carbon: 18kg

HCl – 110kg(36kg+74kg) GLR 4000L(for step 2 reaction)

NaOH – 40kg SSR 4000L (for crystalisation)


Cinnamyl alcohol – 134kg

Acetone/IPA – 2000L

Carbon – 15kg

Methanol – 2000L

HCl Gas::73kg








- 124 -

Process Waste Water-1,2&3 :1615kg/LCleaning Waste Water-1&2 :1500 LTotal water ::3115kg/L

FLOW CHART FOR FLUNARIZINE

2nd step A

Centrifuge

Solvent recovery Cap:;3000LSSreactor MLR-1&2

GLR reactor-1cap 4000LReaction

GLRreactor -1cap:4000Lreaction

Toluene 1500L

DifluroBenzhydrol220kg

HCl acid110kg( 36 + 74kgwater)

Centrifuge

Flunarizine crude405kg wet

1st step A

SSreactor -1cap:4000LCondensation-1

Piperizine 86kg

Acetone/IPA2000L

1st step -B

2nd step B


Water-2695L/Kgcont NaCl

Water-1300L

Water 225L

SS REactor-2cap 4000Lcondensation -2Tolu layer

NaOH 40kg

Water 600L

Cinnamyl alcohol134 kg

Water 600L

Recov Toluene1300L

Water-3620kg

Flunarizine crude405kg wet

1st step C

Solv Acetoneloss 200L MLR-1

Flunarizine hydrochloride 455kg wet

MLR-1 acetoneMLR-2 methanol

Recov Acetone1650L loss:150L

Haz waste 45-48kgSpent Carbon 18kg wet

HCl 73kg

SS reactor-3cap 4000LCrystallisation

Methanol2000L

Carbon 15 kg

Flunarizine hydrochloride430kg

Centrifuge Solv methanolloss:: 200L MLR-2

20

25


- 125 -

3.5.2.22 CINNARAZINE

HN

NH

Benzhydrol

+

HO

Cinnamyl Alcohol

N

N

CinnarizineCrude

N

N

CinnarizineCrude

N

NAcetoneCharcoalcrystalize

Cinnarizine pure

OH

134

Piperizine

86

184

HCl

NaOH

40

36

Toluene

368

3 H2O

54

1st step

2nd step

NaCl

58

Reaction scheme

MANUFACTURING PROCESS The process involves 2 steps 1st stepA Benzhydrol is reacted with HCl acid in Glass reactor to get Benzhydryl chloride at tem ~60-70*C which , after10hrs , the reaction is checked for completion and the reaction is worked up by extraction with Toluene .The resultant mass is having 2 layers which is separated .Top toluene layer contains Chloro Benzhydryl intermediate which is taken in SS reactor for conversion to Benzhydryl piprizine .


- 126 -

1st step B Chloro Benzhydryl intermediate in Toluene is condensed with Piperizine in presence of NaOH base and water is removed azeotropicaly to get Benzhydryl piprizine and refluxed for further 6hrs. After the reaction the toluene layer is washed with water and Top organic layer containing Piperizine derivative is taken in another SS reactor in next step. 1st stepC The above Benzhydryl piperizine in toluene solvent is then treated with Cinnamyl alcohol which is slowly added over a period of 5-6 hrs. The resultant reaction mixture is then refluxed for 10-12 hr with slow removal of water by azeatropic distillation. After complete removal of water, the reaction is checked for completion .The solvent is totally removed and quenched with water to get Cinnarizine crude which is centrifuged. Recovered toluene is reused. 2nd step The crude Cinnarizine is dissolved in Acetone or IPA solvent to get clear solution which is charcoaled and filtered. The clear solution is 50% concentrated and mass is cooled to <10*C during which period crystals of Cinnarizine separates out. The product is centrifuged, and dried. The mother liquor from the centrifuge is sent for recovering acetone which is recycled. CINNERIZINE MASS BALANCE SL NO PRODUCTION B size 400kg No of batchs ::7/Month

Raw material used

1 Benzhydrol 184kg

2 Piperizine 86kg

3 Toluene 1500L

4 HCl 36kg

5 NaOH 40kg

6 Water 1425Lt

7 Cinnamyl alcohol 134kg

8 Acetone/IPA 2000Lt

9 Carbon 15kg

10 Methanol 2000L

Yield (Cinnerizine) 330kgs

Batch size 400kgs --- Cinnerizine Input Reactors Output

Benzhydrol – 184kg GLR 4000L(for step 1 reaction)

Cinnerizine Yield :330kg Overall yield ::90%

Piperizine – 86kg SSR 4000L (for condensation) I.Product: stage1A,B C not


- 127 -

isolated Stage-2:90%

Toluene – 1500L SSR 4000L( for condensation) Toluene: 1300L Loss: 200L Methanol: 1700L Loss:300L Acetone+IPA: 1650L Loss:350L P.Water: stage-1A::300kg/L Stage -1B :::695kg/L (Contns NaCl) Stage -1C ::620kg Total P water ::: 1615kg/L Cleaning water 1500L goes to CETP Hazardous waste: 34-38kg Spent Carbon: 18kg

HCl – 110kg(36kg+74kg) GLR 4000L(for step 2 reaction)

NaOH – 40kg SSR 4000L (for crystalisation)


Cinnamyl alcohol – 134kg

Acetone/IPA – 2000L

Carbon – 15kg

Methanol – 2000L





Solvent recovery…… 10-12 hrs (MLR-1,2) 10-14hrs (MLR-3) -----



- 128 -

Process Waste Water-1,2&3 :1615kg/LCleaning Waste Water-1&2 :1500 LTotal water ::3115kg/L

FLOW CHART FOR CINNERIZINE

2nd stepCrystallisation

Centrifuge



GLRreactor -1cap:4000Lreaction

Toluene 1500L

Benzhydrol 184kg

HCl acid110kg( 36 + 74kgwater)

Centrifuge

Cinnarizine crude 370kg

1st step A

SSreactor -1cap:4000LCondensation-1

Piperizine 86kg

Acetone/IPA2000L

1st step -B

Carbon 15kg


Water-2695L/Kgcont NaCl

Water-1300L

Water 225L

SS REactor-2cap 4000Lcondensation -2Tolu layer

NaOH 40kg

Water 600L

Cinnamyl alcohol134 kg

Water 600L

Recov Toluene1300L

Water-3620kg

Cinnarizine crude370kg wet

1st step C

Solv loss 200LMLR

Cinnarizine Pure330kg

MLR

Recov Acetone1650L loss:150L

Haz waste 34-38kgSpent Carbon 18kg wet

38


- 129 -

3.5.2.23 CLONAZEPAM

Reaction scheme

N

HN

O2N

O

+ 2NH4Cl

+ Ammonia3

51

315.5

Clonazepam

Ammonium chloride

106

O

NH2

O2NCl

OCl

Cl

353

O

HN

O2N

Cl

O

Nitro Dichloro intermediate

Cl

5-nitro 2amino 2'chlorobenzophenone

276

Cl

chloro ethyl acetyl chloride

112

+

H2O

18

+

Toluene

Methanol

MANUFACTURING PROCESS 5-Nitro 2-Amino 2’Chloro Benzophenone ( Nitro chloro amino Ketone) is reacted with chloro acetyl chloride in toluene by refluxing for 12 hrs to get Nitro Di chloro intermediate in GLreactor , During the reaction Hcl generated is treated / scubbed with ammonia to get by product Ammonium chloride. After the reaction the mass is cooled and centrifuged .Wet cake is taken for next step .Toluene layer is distilled to recover solvent. Wet cake isdissolved in Methanol and the clear solution is Nitro dichloro intermediate which is taken in SS reactor. The Nitro Di Chloro intermediate in SS reactor is then reacted with ammonia by refluxing in sovent methanol for 10 hrs at temp 65* C and cooled to isolate by product Ammonium chloride which is removed by filtration.The resultant filtrate is concentrated 50% to recover solvent (which is recycled).


- 130 -

The concentrated mass is further cooled to 15* C to get Clonazepam which separates as crystals. These crystals are centifuged and the pure Clonazepam is dried. The mother liquor from the centrifuge is sent for recovery of solvent at 65*C to recover methanol. The last portion of solvent distilling bet 85*C and 95*C is methanolic water which is sent as effluent. The residual mass remaining as undistilled is taken as Haz waste.

CLONAZEPAM MASS BALANCE SL NO PRODUCTION B size 100kg No of batchs 1/Month

Raw material used


2 2-amino 5-nitro chloro benzophenone 138kg

3 Toluene 600L

4 Ammonia 25kg

5 Carbon 5kg

6 Methanol 800Lt

Yield (Clonazepam) 135kgs

Batch size 100kgs --- Clonazepam

Input Reactors Out put



Clonazepam Yield ::130kg Overall yield :83%

2-amino 5-nitro chloro benzophenone – 138kg

SSR 2000L (for reaction) Product: stage-1:91% wet stage-2 ::91%


Toluene: 500L Loss: 100L Methanol: 600L Loss:200L P.Water: nil Am Chloride: 60kg incl water and scrubbed HCL Cleaning water ::1000L goes to CETP Hazardous waste: 26-30kg Spent Carbon: 7kg


Carbon – 5kg

Methanol – 800L





Solvent recovery…… 10-12 hrs (MLR-1,) 10-14hrs (MLR-2) -----



- 131 -




FLOW CHART FOR CLONAZEPAM






2-amino 5-Nitro Chloro benzophenone 138kg

Toluene 600L

1st step



Dichloro nitrointermediate160kg

Methanol800L

HCl 18 kg scrubber

Ammonia 25kg



Centrifuge

2nd step

Am.Choride 60kg wet


Dichloro Nitro intermediate160kg


Carbon5kg

Spent C7kg


Solv loss 50LMLR-2

Clonazepam130kg 13

16


- 132 -

3.5.2.24 LORAZEPAM

N

N

Cl

H O

Cl

O+ (CH3CO)2O

N-Oxide intermediate

320

Acetic anhydride

102

+ 2 NaOH

Sodium Hydroxide

80

N

N

Cl

HO

Cl

OH

Lorazepam

320

+ 2 CH3CO2Na

Sodium acetate

164

O

NH2

Cl

+

266

+

Cl

ClO

112

2-amino-2'5 Dichloro benzophenone

Chloroacetyl chloride

2 Water

Methanol

NH2OH

Hydroxylamine

33

Cl

N

N

Cl

H O

Cl

O

N-Oxide intermediate

320

2nd stage

1st stage

Reaction scheme

NaCl

NaOH

40

58 36

H2O

18

O

NH

Cl

Cl

ClO

341.5

Trichloro intermediate

HCl

36.5

O

NH

Cl

Cl

ClO

341.5

Trichloro intermediate

Toluene


- 133 -

MANUFACTURING PROCESS 1st step 2-Amino 2’5 DiChloro Benzophenone ( Di chloro amino Ketone) is reacted with chloro acetyl chloride in solvent toluene in presence of Sodium hydroxide by refluxing for 10-12 hrs ;to get Tri chloro intermediate in GLreactor , After the reaction the mass is cooled and centrifuged. Wet cake is taken for next step .Toluene layer is distilled to recover solvent. Wet cake isdissolved in Methanol and the clear solution is Trichloro intermediate which is taken in SS reactor. The Tri Chloro intermediate in SS reactor is then reacted with Hydroxylamine by refluxing in solvent methanol for 12hrs at temp 65* C in presence of Sodium hydroxide After the reaction is complete the mass is cooled to isolate by product sodium chloride which is removed by filtration.The resultant filtrate is concentrated 50% to recover solvent (which is recycled). The concentrated mass is further cooled to 15* C to get Lorazepam N-oxide intermediate which separates as crystals. These crystals are centrifuged and the pure N-oxide intermediate is dried. 2nd step The N-oxide intermediate is taken in toluene solvent in GL reactor and refluxed for 6hrs with Acetic anhydride and the resultant reaction mass is quenched with Sodium hydroxide solution.The layers separated and top organic layer is charcoaled with carbon and filtered The filtrate is transferred to ss reactor back and concentrated to recover solvent which is reused after purification in Solvent recovery plant The aqueous layer contains sodium acetate. The concentrated mass is treated with methanol solvent to get slurry of Lorazepam. This slurry is further chilled to 15*C and centrifuged to get Lorazepam which is dried The mother liquor from the centrifuge is sent for recovery of solvent at 65*C to recover methanol. Both recovered solvents are purified in Solvent recovery plant and reused. The residual mass remaining as undistilled is taken as Haz waste.

LORAZEPAM MASS BALANCE SL NO PRODUCTION B size 100kg No of batchs :1/Month

Raw material used


2 2-amino dichloro benzophenone 133kg

3 Water 600Lt

4 Toluene 1200Lt

5 NaOH 60kg


- 134 -

6 Hydroxyl amine 16kg

7 Carbon 10kg

8 Methanol 1300L

9 Acetic anhydride 45kg

Yield (Lorazepam) 130kgs

Batch size 100kgs --- Lorazepam




Lorazepam Yield ::130kg Overall yield ::81%

2-amino dichloro benzophenone – 133kg

SSR 2000L (for reaction) I.Product: stage-1 :87.5% Stage-2 :93%

Water – 600L SSR 2000L(for methanol solution)

Toluene: 1000L Loss: 200L Methanol: 1050L Loss:250L P.Water: stage-2 690kg/ L By product : Hcl : 18kg sent for scrubbing Na Cl ::48kg (contns 9kg water) Cleaning water 1000L goes to CETP Hazardous waste: 24-28kg Spent Carbon: 12kg

Toluene – 1200L GLR1000L (for reaction)

NaOH – 60kg SSR 2000L (for workup)

Hydroxyl amine – 16kg SSR 2000L (for concentration & isolation)

Carbon – 10kg SSR 2000L (for solvent recovery)

Methanol – 1300L

Acetic anhydride – 45kg






P Water used 690kg and for washing/cleaning equipment, cleaning waste water 1000Lalong with process water goes to CETP


- 135 -

Process Waste Water ::690 kgCleaning waste Water :1000LTotal water ::1690L/kg


GLreactor cap1000LReaction


FLOW CHART FOR LORAZEPAM


Haz Waste1A 1B&2 ::31-35kg

MLR-1 TolueneMLR-2&3 Methanol

2nd Step


SS Reactor-1cap:2000L reaction


2-amino dichlorobenzophenone 133kg

Toluene 600L

1st step A



Trichlorointermediate160kg

11

Methanol800L

HCl 18 kg scrubber

Hydroxylamine 16kg

NaOH 20kg

Filter-Nutch Wet NaCl48kg


CentrifugeSolv methanolloss 75LMLR-2

N-Oxide intermediate140Kg

10

N-oxide intermediate140kg

Acetic anhydride45kg

SS Reactor-3cap2000Lw/up

NaOH 40kg

Water 600L

SS Reactor-3cap2000LConc & isolatn

Water layer690kg(sod acet)

Recov Toluene550L loss::50L

Toluene 600L

Methanol500L

CentrifugeSol methanolloss:50L MLR-3Lorazepam

130kg

10

1st step1B

Carbon 10kg

Spent Carbon 12kg

Sod chloride 48kg wet



- 136 -

3.5.2.25 DULOXETINE HCL

SO S

O

N

SOH

N

SO

N

F

Duloxetine base

2-Acetyl thiophene

CH2O

S O

N

183

Keto intermediate

NH

Hydroxy Intermedite

SOH

N

297

311

S O

NH

SO

N

Reaction scheme

1st step

2nd step

Keto intermediate

183

Methanol

Toluene

185

Hydroxy intermediate

185Fluro naphthaleene

146 Ether intermediate

Ether intermediate

311

KOH

56

DMSO

KF H2O

58 18

H2

2

Cat

3rd step

4th step

KOH

56

Toluene

S O

NH

.HCl

Duloxetine Hydrochloride

333

HCl 36

Acetone

126

3045

H2O

18

KOCH3

70


- 137 -

Manufacturing process This involves 4 steps 1st step 2- Acetyl thiophene is mixed with Formaldehyde and Dimethylamine in SS reactor in Solvent Toluene. The reaction is carried at reflux temp ~105*C for 18hrs and after the reaction is complete the mass is quenched with water, to get Keto intermediate as fine crystalline solid. This is isolated by centrifuging and solid is dried and taken for next step. The Mother liquor is separated off 2 layers and Top toluene layer is sent for recovery of solvent toluene which is reused. 2nd step The keto intermediate is dissolved in Methanol and reduced by hydrogen using Ni catalyst to get Hydroxy intermediate in SS reactor at 50*C . After 10hrs the reaction will be completed and the mass is filtered to remove catalyst. The clear filtrate is concentrated to get thick mass which is dissolved in DMSO and taken for 3rd step. The solvent is sent for recovery and reuse. The catlalyst is used in next step. 3rd step The hydroxy intermediate solution in DMSO is heated in SS reactor is condensed with Fluoro naphthalene using base KOH by refluxing for 12hrs, to get Ether intermediate which is obtained after work up with water and extraction with Toluene This solution is taken for next step. 4th step The Ether intermediate from above in toluene is reacted with KOH in SS reactor by refluxing at temp ~105*C for 16hrs The mass is worked up with water and organic layer is concentrated by distillation under vacuum as thick liquid which is Duloxetine base. The recovered toluene is purified and reused. Benzoic acid is recovered and sold The Duloxetine base (thick liquid mass) is dissolved in Acetone, charcoaled and filtered. The clear filtrate is treated with HCl to get Duloxetine Hydrochloride as fine crystals which separate out after cooling to < 5*C .The solid is centrifuged, and dried. The mother liquor is sent for recovery of solvent Acetone which is recycled. DULOXETINE HYDROCHLORIDE MASS BALANCE

SL NO PRODUCTION B Size 60kg No of batchs :1/Month

Raw material used

1 Formaldehyde 30kg

2 2-Acetyl thiophene 126kg

3 Water 1800Lt


- 138 -

4 Toluene 1800Lt

5 Dimethyl amine 45kg

6 Acetone 1000Lt

7 HCl 36kg

8 Carbon 10kg

9 H2 gas

10 Methanol 1000Lt

11 Ni cat 2kg

12 DMSO 600kg

13 Fluro naphthalene 145kg

14 KOH 112kg

Yield (Duloxetine Hydrochloride) 300kgs


Formaldehyde – 30kg SSR 3000L(for step 1 reaction) Duloxetine Hydrochloride Yield 300 kg Overall yield 90%

2-Acetyl thiophene – 126kg

SSR 3000L (for workup) I.Product:stage-1,2&3 not isolated . Stage-4::90%

Water – 1800L SSR 2000L(for dissolution) Toluene: 1500L Loss: 300L Acetone: 800L Loss:200L Methanol: 800L loss: 200L DMSO ::550L loss 50L P.Water: stage-1::620kg/L Stage-2 ::675kg/L contns KF Stage-3 ::670kg/L Contns KOCH3 Total P water ::: 1965kg/L Cleaning water :: 1500L goes to CETP Hazardous waste: 32-35kg Spent Carbon: 12kg


Dimethyl amine – 45kg SSR 2000L (for solvent recovery)

Acetone – 1000L

HCl – 36kg

Carbon – 10kg

H2 gas

Methanol – 1000L

Ni cat – 2kg

DMSO – 600kg

Fluro naphthalene – 145kg

KOH – 112kg

Time cycle 1st stage 2nd stage 3rd stage final 1) Reaction ………… 12-14hrs 12-14hrs 14-16hrs Drying



Solvent recovery…… ---- ---- 10-14hrs (MLR-1)


- 139 -

Water 1940kg along with cleaning water is sent for CETP FLOW CHART FOR DULOXETINE HYDROCHLORIDE

Process Waste Water-1,2&3 ::1965kg/LCleaning waste Water : 1500L

SS reactor-3cap 3000LToluene/EtherIntermediate

GLreactor2000L

SSreactor MLR-1&2cap 2000Lsolvent recovery

AcetoneLoss :;100LMLR-2Reaction


centrifuge

Acetone Pure800LLoss 100L(MLR-2)

Haz waste 30-35kg

Duloxetine Hydrochloride300kg

2nd Step

SS reactor-2 cap:2000LReduction

SS Reactor-3cap:3000Lcondensationwork up

Ni cat 2.0kg

Keto intermediate180kg

Methanol 1000L

Methanol 800Lloss ::200L

1st step

Toluene 1000L


Centrifuge

Solvent recovery

SS reactor-1 cap: 1000LReaction andisolation

2-Acetyl thiophene126kg Toluene 800L

Dimethyl amine45kg

Water 600kg

Water-1(618kg/L)

Keto intermediate180kg

3rd step

Water-2 (675kg/L)

SS reactor-4cap 2000LReaction/w/up

Recovered Toluene 850LLoss 150L

Acetone 1000L

HCl 36kg

4th step

Formadehyde 30kg

Toluene MLR-1Loss:: 75L

H2 gas

FiterSpent cat :2.2kgrecycle

Methanol solutionHydroxy intermediate

DMSO 600kg

Fluro naphthalene145kg

Water 600L

Recov DMSO550L loss 50L

KOH 56kg

Toluene layerEther intermediate

SS reactor-3cap 2000LIsolation Conc.base

KOH 56kg

Water 600L

Water-3670kg/L

Recov Toluene 650Lloss 75L(MLR-1)


- 140 -

3.5.2.26 DAPOXETINE HCL

Cl

O

Cl

OH

O

NCH3H3C

3-chloro-1-phenylpropan-1-one

3-chloro-1-phenylpropan-1-ol

305

OH

144

O

OH

Hydroxy NaphthylEther

278

Dapoxetine base

CH3SO3H

96

Methane sufonic acid

45

Dimethylamine

NH

Toluene

O

NCH3H3C

Dapoxetine Hydrochloride

.HCl

341

HCl

36

Acetone

H2SO4CH4

9816

H2

Cl

OH

3-chloro-1-phenylpropan-1-ol

KOH

170

170

168

Alfa naphthol

O

OH

Hydroxy NaphthylEther

278

KCl

74

H2O

18

56

Toluene

Methanol

Reaction scheme

1st step

2nd step

3rd step


- 141 -

Manufacturing process This involves 3 steps 1st step 3-Chloro propiophenone is reduced with Hydrogen in SS reactor in presence of Catalyst in Methanol solvent to get hydroxy intermediate (3-chloro 1- phenyl propanol). After 10hrs reaction will be completed and the reaction mass is filtered to remove catalyst (which is reused), and the clear filtrate is concentrated to recover solvent. The recovered Methanol is purified in SRP and reused. After the concentration is complete mass is quenched with water and solid Hydroxy compound is isolated by cooling the slurry to < 5*C, and centrifuging. The wet product is taken for next step. 2nd step The Hydroxy intermediate is dissolved in Toluene in SS reactor and to this was added Alfa naphthol solid. Again the mass is heated to dissolve the contents and cooled. Added KOH and slowly raised the temp to reflux. Reaction is completed by refluxing for 10hrs to get Hydroxy Naphthyl Ether intermediate and after the reaction; the mass is cooled to RT and quenched with water. Layers were separated and top organic layer containing the Ether intermediate which is taken for the next step. 3rd step The ether intermediate solution in Toluene is dried and then treated with Methane sulfonic acid in SS reactor at temp < 30 *C and then stirred with Dimethyl amine which is added over a period of 2 hrs. The resultant reaction is slowly heated to 60 *C and maintain for 8 hrs during this time Dapoxetine base is formed. The mass is quenched with water and top toluene Organic layer is separated. This layer is concentrated by distillation under vacuum, to get viscous liquid Dapoxetine base Recovered solvent toluene is reused. This base is dissolved in acetone In SS reactor and transferred to GLReactor and treated with HCl gas at temp, <5*C, to get Dapoxetine Hydrochloride. Sirred at RT for 6hrs during which product is pptd which is isolated by centrifuging and drying. The mother liquor is sent for recovering Solvent acetone which is reused. DAPOXETINE HYDROCHLORIDE MASS BALANCE

SL NO PRODUCTION B Size 60kg No of batchs ::1/month

Raw material used

1 3-Chloro propio phenone 34kg

2 Methanol 300Lt

3 Water 900Lt

4 Ni 1kg

5 Toluene 500Lt


- 142 -

6 Alfa Napthol 30kg

7 Methane sulfonic acid 19kg

8 Carbon 10kg

9 Dimethyl amine 9kg

10 HCl 7kg

11 KOH 11kg

12 Acetone 500L

Yield (Dapoxetine Hydrochloride) 60kgs


3-Chloro propio phenone – 34kg

SSR 1000L(for step 1 reaction)

Dapoxetine Hydrochloride Yield 60 kg Overall yield 88%

Methanol – 300L SSR 2000L (for reaction)

I.Product: stage-1,2&3 not isolated . Stage-4::88%

Water – 900L SSR 3000L(for workup) Toluene: 450L Loss: 50L Acetone: 350L Loss:150L Methanol: 250L loss: 50L P.Water: stage-1::300kg/L Stage-2 ::320kg/L contns KCl Stage-3 ::320kg/L CH4 : 3.0kg, Ni 1.0kg(reuse) Total P water ::: 940kg/L Cleaning water :: 1000L goes to CETP Hazardous waste: 7-9kg Spent Carbon: 12kg

Ni – 1kg SSR3000L (for condensation)

Toluene – 500L SSR 2000L (for solvent isolation)

Alfa Napthol –30kg GLR 2000L (for reaction)

Methane sulfonic acid – 19kg


Carbon - 10

Dimethyl amine – 9kg

HCl – 7kg

KOH – 11kg

Acetone – 500L





Solvent recovery…… ---- ------ 10-14hrs (MLR-1)

Water 940kg along with cleaning water is sent for CETP


- 143 -

FLOW CHART FOR DAPOXETINE HYDROCHLORIDE

Process Waste Water :: 940kg/LCleaning waste Water : 1000L

SS reactor-2cap 3000Lcondensation

GLreactor1000L

SSreactor MLRcap 2000Lsolvent recovery

AcetoneLoss :;50LMLRReaction


centrifuge

Acetone Pure350L RecycleLoss 100L

Haz Waste 7-9kgs

Dapoxetine Hydrochloride60kg

2nd Step


SS Reactor-2cap:2000LWork-up/Org layerEther compound

Alfa Naphthol30kg

Hydroxy compund34.0 kg

Toluene500L

Water 300 kg/L

Water-2 + KCl320kg

1st step

Dimethyl amine 9 kg


Centrifuge

Solvent recovery

SS reactor-1 cap: 1000LReaction

3-chloro propiophenone 34kg

Methanol 300L

Ni 1kgRecovered cat 1.1 kg wet recycle

Recov Methanol 250L loss :50L

Water 300kg

Water-1 300kg/L

Hydroxy compound 34.0kg(wet)

KOH 11kg

3rd step

Methane sufonic acid 19.2kg

Water 300L/kg

Water-3 320kg/L

SS reactor-3cap 1000LIsolation Concbase

Carbon 10kg Spent carbon 12kg

Recovered Toluene 450LLoss 50L

Acetone 500L

HCl 7kg

4th step

7


- 144 -

3.5.2.27 DESVENLAFAXINE HCL

N

CH3

H3CO

CH3

HCl

N

CH3

HO

CH3

COOH

COOHN

CH3

HO

CH3COOH

COOH

H2O

Venlafaxine Hydrochloride

Succinic acid

OH OH

OH

313 263

118

NaOH

399

40

CH3OH

32

NaCl

58

N

CH3

HO

CH3OH

263

Acetone

H2O

18

Des venlafaxine base

Des venlafaxine base

Deavenlafaxine succinate

Reaction scheme

1st step

2nd step

Toluene

Manufacturing process This involves 2 steps 1st step Venlafaxine hydrochloride is treated with sodium hydroxide solution (50%) at temp 110*C in SS reactor. After the reaction is complete, the mass is diluted with water and extracted with toluene. Layers are separated and Top organic layer is concentrated to get Desvenlafaxine base. Recovered solvent toluene is recycled.


- 145 -

2nd step Des velafaxine base is dissolved in Acetone, in SS reactor, charcoaled and filtered. The clear filtrate is treated with Succinic acid and small qty of water and the mass is heated to reflux for 14 hrs. After the reaction is complete, the reaction mass is cooled to< 10*C and centrifuged. The mother liquor from centrifuge is taken for solvent recovery. The crude Des evnlafaxine succinate is purified by crystallization by re dissolving in acetone, by heating and chilling to get pure product which is centrifuged and dried. The solvent is recovered from the mother liquor.

DESVENALAFAXINE SUCCINATE Gravimetric/MASS BALANCE SL NO PRODUCTION B Size 400kg No of batchs 1/Month

Raw material used

1 Venalafaxine hydrochloride 313kg

2 Toluene 2000kg

3 NaOH 40kg

4 Acetone 1000Lt

5 Succinic acid 112kg

6 Water 1018Lt(1st & 2nd stage)

7 Carbon 15kg

Yield (Venalafaxine Succinate) 380kgs

Batch size 400kgs --- Venalafaxine Succinate


Venalafaxine hydrochloride – 313kg


Venalafaxine Succinate Yield ::380kg Overall yield ::;95%

Toluene – 2000L SSR 4000L (for concentration & dissolution)

I.Product:stage-1 not isolated stage-2 95%

NaOH – 40kg SSR 3000L Toluene: 1850L Loss: 150L Acetone: 800L Loss:200L P.Water 1st stage :1090kg/L Cleaning water ::500L goes to CETP Hazardous waste: 13-15kg Spent Carbon: 18kg

Acetone – 1000L SSR 3000L (for solvent recovery)

Succinic acid – 112kg

Water – 1018L

Carbon – 15kg


- 146 -

Time cycle 1st stage 2nd stage 3rd stage final 1) Reaction ………… 22-24hrs 12-14hrs ---- Drying



3) Solvent recovery…… --- 8-10hrs (MLR-1) -----



- 147 -

Toluene 2000LSS reactor-1 cap4000LReaction

Haz Waste 13-15 kgProcess Waste Water :1090kg/LCleaning Waste Water : 500L

FLOW CHART FOR DES VENALAFAXINE SUCCINATE

Venalafaxinehydrochloride 313kg

MLR


SS REactor-2

3000L

Water 18kg/L

NaOH 40 kg

Solvent recovery

Recovered Toluene 1850Lloss 150L residue ~255kg

CentrifugeSolvent loss :100 L

MLR

Des venlafaxine Hydrochloride 380kg

Recovered Acetone:800LLoss :100L

Water 1000L

Water 1090kg/L

SS reactor-1 cap4000LConcentration& Dissolution

Acetone 1000L

Carbon 15kg Spent carbon 18kg

Succinic acid112 kg

8+5

Total water :: 1590kg/L

1st step

2nd step


- 148 -

3.5.2.28 TRIHEXYPHENADYL HCL

N

O Cl

N

OH+

Trihexphenadyl Base3-Piperidino propiophenone

Cyclohexyl chloride

N

OHHCl, acetone

Trihexphenadyl Hydrochloride

.HCl

N

OH

N

O

3-Piperidino propiophenone

217

217118

Mg

24

THF/toluene

301

Trihexaphenayl base

301 337

HN

O

CH2O

120

30Acetophenone

FormaldehydePiperidine

Water

85

Reaction scheme

H20

18

MgCl

59

36

1st step

2nd step

3rd step


- 149 -

Manufacturing process This involves 3 steps 1st step Acetophenone is reacted with Formaldehyde and Piperidine in water in SS reactor at reflux at 90-95*C to get Pipridino propiophenone solid which is cooled , centrifuged and isolated. 2nd step Pipridino propiophenone is then taken for Grignard reaction with Cyclohexyl chloride in Toluene/ THF solvent media under Nitrogen atmosphere, at temp < 15*C .After the reaction the mass is quenched in water and top organic layer is separated .Toluene is totally removed by distillation and concentrated mass is Trihexaphenadyl base which is Dissolved in acetone and taken for next step. Toluene is recovered, purified in column distillation and reused. 3rd step The Trihexaphenadyl base in Acetone solvent is charcoaled in SS reactor, filtered and the clear filtrate is taken in GLreactor and is converted to Trihexaphenadyl hydrochloride by passing HCl gas to pH 2 at temp < 10*C.The crystals of Trihexaphenadyl hydrochloride solid is isolated by centrifuging. The product is then dried. The mother liquor is sent for recovery of solvent acetone which is reused.

TRIHEXAPHENADYL HYDROCHLORIDE MASS BALANCE SL NO PRODUCTION No of batchs:1/Month

Raw material used

1 Acetophenone 120kg

2 Formaldehyde 30kg

3 Piperidine 85kg

4 Water 1200Lt (1st & 2nd stage)

5 Toluene 1100Lt (2nd stage)

6 THF 30Lt

7 Cyclohexyl chloride 118kg

8 Carbon 15kg

9 Mg 24kg

10 HCL 36kg

11 Acetone 1000Lt(final)

Yield (Trihexaphenadyl Hydrochloride) 300kgs


Acetophenone – 120kg SSR 2500L(for step 1 condensation reaction)

Trihexaphenadyl Hydrochloride Yield


- 150 -

300kg Overall yield 89%

Formaldehyde – 30kg SSR 2500L (for step 2 grignard reaction)

I.roduct:stage-1 ::96.5% Stage-2 ::96% Stage-3::95.5%

Piperidine – 85kg SSR 600L (for step 2 Toluene layer)

Toluene: 1000L Loss: 100L Acetone: 825L Loss:175L P.Water: stage-1::625kg/L stage-2:: 680kg/L (contnsMgCl/THF) Total water ::: 1305kg/L Cleaning water :: 500L goes to CETP Hazardous waste: 25-28kg Spent Carbon: 18kg

Water – 1200L SSR 3000Lfor dissolution

Toluene – 1100L GLR 3000L (for reaction)

THF – 30L(20kg) SSR 3000L (for solvent recovery)

Cyclohexyl chloride – 118kg

Carbon – 15kg

Mg – 24kg

HCL – 36kg

Acetone – 1000L




& Centrifuge… 4-6hrs 2-4hrs 4-6hrs

3) Solvent recovery…… ----- ------ 12-16hrs(MLR-3)

Water used for washing/cleaning equipment, cleaning waste water 500L goes

to CETP along with process waste water 1315kgs


- 151 -

FLOW CHART FOR TRIHEXAPHENADYLHYDRCHLORIDE


Haz Waste 25-28kg

Process Waste Water-1&2:; 1305kgCleaning Waste Water : 500L

TrihexaphenadylGrignrd base 280.0 kgs



2nd Step

Solvent recoveryMLR

AcetoneLoss:75L HCl 36 kg

Centrifuge


Trihexaphenadylhydrochloride300 kgs



Toluene/THF1100/30L

3-Piperidinopropiophenone 210kg

Cyclohexyl chloride118kg

Water 600L

RecoveredToluene 1000LLoss :100L

Tri hexa phenadyl Grignard base 280kg

Water-1 680 kgsincludes(/MgCL/THF)

1st step

Grignard reaction Mg 24kg

Acetone 1000L


Carbon -15kg



SS reactor-1cap 2500LCondensation

Acetophenone 120kg

Formadehyde 30kg

Piperidine 85kg

Centrifuge Water-1 625.L(incldes p phenone 7kg)

Water 600L

3-Pipridino Propiophenone 210kg

11

13


- 152 -

3.5.2.29 TRAMADOL HCL

N

O

+

Br

OCH3 N

OH

OCH3

N

OH

OCH3

.HCl

Tramadol BaseMeta -Bromo

methoxyanisole2-methyldimethylamino

cyclohexanone

Tramadol Hydrochloride

N

O

2-methyldimethylaminocyclohexanone

O

CH2O NH

45

30

98155

Toluene

H2O

18

1st step

Reaction scheme

2nd step

N

OH

OCH3

Tramadol Base

HCl

Acetone

263

299.5

36.5

263

Mg

THF/Toluene

24

Mg Br

103

155 187

3rd step

Cclohexanone Dimethylamine

Formaldehyde

Manufacturing process This involves 3 steps 1st step Cyclohexanone is reacted in SS reactor with Formaldehyde and Dimethylamine in Solvent Toluene by refluxing the reaction mass at 105*C for 12hrs. After the reaction is complete the mass is quenched with water and cooled to get 2-


- 153 -

Dimethylaminomethyl cyclohexanone crystals .This is isolated by centrifuging and dried. The Mother liquor is separated and top organic layer is distilled to get pure Toluene which is recycled. 2nd step 2-Dimethylaminomethyl cyclohexanone is dissolved in Toluene solvent in SS reactor and stirred with Magnessium filings and treated with solution of Meta bromo anisole in THF solvent under Nitrogen atmosphere (Grignard reaction ) at temp < 15*C . After the addition the reaction is carried out at 65*Cfor 10hrs to complete the reaction. Reaction mass is then quenched with water. Layers were separated and top organic layer is then distilled to recover Toluene .The concentrated mass is intermediate Tramadol Base which is immediately dissolved in Acetone and taken for next step. Both recovered solvents are purified and reused. 3rd step The Tramadol Base in acetone is charcoaled and the clear filtrate after filtration is taken in GL reactor and cooled to < 10 *C. HCl gas is passed and after the reaction stirred for 10-12 hrs extra during which complete rection takes place and Tramadol hydrochloride separates out as crystalline solid . This is isolated by centrifuging and dried. The mother liquor is sent for recovery of solvent Acetone which is reused.

TRAMADOL HYDROCHLORIDE MASS BALANCE SL NO PRODUCTION B Size 250kg No of batchs 10/Month

Raw material used

1 Cyclo hexanone 98kg

2 Formaldehyde 30kg

3 Dimethylamine 45kg

4 Toluene 1100Lt

5 THF 30Lt

6 Water 1200Lt

7 Metabromo methoxy anisole 187kg

8 Mg 24kg

9 Carbon 15kg

10 Acetone 1000Lt

11 HCl 36kg

Yield (Tramadol Hydrochloride) 270kgs



- 154 -

Cyclo hexanone – 98kg SSR 4000L(for step 1 reaction)

Tramadol Hydrochloride Yield :270kg Overall yield ::90%

Formaldehyde – 30kg SSR 4000L (for concentration & dissolution)

I.Product: stage-1 :98% wet Stage-2:95% Stage-3 ::94.5%

Dimethylamine – 45kg SSR 3000L Toluene: 1000L Loss: 100L Acetone: 825L Loss:175L P.Water: stage-1 :: 625kg/L Incl 7kg cycl hexanone Stage-2 ::723kg/L (Contns Mg Br Total P water ::; 1347kg/L Cleaning water :: 1000L goes to CETP Hazardous waste: 25-30 kg Spent Carbon: 18kg

Toluene -1100L SSR 3000L (for solvent recovery)

THF – 30L/20kg

Water – 1200L

Metabromo methoxy anisole -187kg

Mg – 24kg

Carbon – 15kg

Acetone – 1000L

HCl – 36kg





3) Solvent recovery…… 8-10hrs (MLR-1) 10-12hrs(MLR-2) 12-16hrs(MLR-3)



- 155 -

FLOW CHART FOR TRAMADOL HYDRCHLORIDE


Haz Waste 28-30kg

Process Waste Water-1&2:; 1350kgCleaning Waste Water : 1000L

Tramadol Grignrd base 250.0 kgs



2nd Step

Solvent recoveryMLR

AcetoneLoss:75L HCl 36 kg

Centrifuge


Tramadolhydrochloride270 kgs



Toluene/THF1100/30L

2-dimethylamino methylcyclohexanone 155kg

Metabromo methoxyanisole 187kg

Water 600L

Rec.toluene 1000LLoss :100L for recycle

Tramadol base crude265kg(pure content 250kg)

Water-2:: 725 kgsincludes(MgBr/THF)

1st step

Grignard reaction Mg 24kg

Acetone 1000L


Carbon -15kg



SS reactor-1cap 2500LCondensation

Cyclo hexanone 98kg

Formadehyde 30kg

Dimethylamine 45kg

Centrifuge Water-1 625Lincludes 5kg c hexanone

Water 600L

2-dimethylaminomethylcyclohexanone 155kg(wet)

13+15


- 156 -

3.5.2.30 SULFAMETHOXY PYRAZINE HCL

N

N Cl

Cl N

NHN

Cl

NH2

NH2OS

O

NH2

O

S

O

+

Dichloropyrazine Sulfanilamide Intermediate

N

NHN

Cl

NH2

O

S

O

N

NHN

OCH3

NH2

O

S

OKOCH3

Intermediate Sulfamethoxypyrazine

148 172284

284 280

KHCO3

100

DMF

70

Methanol

Reaction scheme

1st step

2nd step

KCl H2O CO2

18 4474

KCl

74


This involves 2 steps 1st step Dichloropyrazine is reacted with Sulfanilamide in SSreactor by heating for 14hrs to temp 85-90*C in DMF solvent media in presence of base Potassium bicarbonate During the reaction Evolution of gas CO2 is observed.. After the reaction is complete the solution is filtered to remove Pot.chloride and the clear filtrate is distilled under vacuum to recover the solvent DMF .The concentrated mass is quenched with water to get Sulfa-Intermediate as solid which is isolated by centrifuging. This is dried and taken for the next step. The recovered DMF is reused.

2nd step This Sulfa-intermediate is dissolved in solvent methanol in another SS reactor and treated with Potassium methoxide under nitrogen.The reaction mass is then refluxed


- 157 -

for 16 hrs to get Sulamethoxy pyrazine. After the reaction is complete the mass is filtered to remove Potassium chloride.

The clear filtrate is concentrated to 25% volume by distilling Methanol .Added carbon and filtered. The clear filtrateis transferred to another SS reactor and the resultant mass is cooled to <15 *C to get solid Sulamethoxy pyazine which separates out as crystals.This is centrifuged to get pure product which is dried.

The mother liquor is sent for recovery of solvent Methanol which is reused.

SULFAMETHOXY PYRAZINE MASS BALANCE SL NO PRODUCTION B size 250 kg No of batchs 2/month

Raw material used

1 P-amino sulfonamide 172kg

2 DMF 1500L

3 Dichloro pyazine 148kg

4 KHCO3 100kg

5 Potassium methoxide 70kg

6 Water 1000Lt

7 Carbon 15kg

8 Methanol 2000Lt

9

10

11

Yield (Sulfamethoxy Pyrazine) 250kgs

Batch size 250kgs --- Sulfamethoxy Pyrazine


P-amino sulphonamide- 172kg


Sulfamethoxy Pyrazine Yield ::250kg Overall yield ::89%

DMF – 1500L SSR 4000L (for concentration & dissolution)

I.Product:stage-1 :95% Stage-2 :93.5%

Dichloro pyazine – 148kg SSR 3000L DMF: 1400L Loss: 100L Methanol: 1650L Loss:350L CO2 :: 44kg KCl::::148kg P.Water: stage-1::1018kg/L Cleaning water ::1000L goes to CETP Hazardous waste: 30-32kg Spent Carbon: 18kg

KHCO3 – 100kg SSR 3000L (for solvent recovery)

Potassium methoxide – 70kg

Water – 1000L

Carbon – 15kg

Methanol – 2000L


- 158 -




3) Solvent recovery…… ----- 10-12hrs(MLR-2) -----



- 159 -

SS reactor-2cap 3000Lwork up

Haz Waste 1& 2:: 30-32kg Process Waste Water-1:1020kgCleaning Waste Water-1&2:1000 L

FLOW CHART FOR SULFAMETHOXY PYRAZINE


2nd step A

Recov. Methanol1650L Loss:150L

Centrifuge


MLR Methanol loss 100L


SSreactor -1cap:4000Lcondensation

DMF1500L

P-amino sulfonamide172kg

Dichloro pyazine148kg

Centrifuge

Suphone Intermediate270kg

Solvent MethanolLoss:100L

1st step A

SSreactor -2cap:4000Lisolation

CentrifugeSolvent DMFLoss ::50L

Potassium Chloride 74kg

Water 1000L

CentrifugeSulphone Intermediate270kg

Water 1018kg

Methanol 2000L

Potassium methoxide 70 kg

Potassium chloride74 kg

1st step -B

2nd step B

Sulpha Methoxy pyrazine 250kgSolvent recovery

MLR

KHCO3 100kg

Carbon 15kgSpent carbon 18kg wet

spent carbon 18kg wet

CO244kg

DMF Recov1400LLoss 50L

14

16


- 160 -

3.5.2.31 ALIMEMAZINE TARTARATE

N Cl N

NPhenothiazine

Sodium methoxide2-methyl-3-Dimethyl

amino propylchloride54g

135

Alimemazine Base

298

+ CH3OH + NaCl

32 58

L Tartaric acid

150

Alimemazine Tartarate

747

Isopropyl alcohol

+

S

N

N

S

NH

S

199

2

.Tartarate

N

N

S

OO

Oxomemazine Base

N

N

S

OO

Oxomemazine Hydrochloride

.HCl

N

N

Alimemazine Base

298

S

2

366.5330

HCl

Acetone

36.5

NaOCH3

THF

Reaction scheme

1st step

2nd step A

2nd step B

2-H2O2

68

2-H2O

36


- 161 -

Manufacturing process This involves 2 steps 1st step Phenothiazine is dissolved in THF in SS Reactor and to this solution 2-Methyl-N, N-dimethyl amino propyl chloride in THF is added slowly at temp <35*C. To this solution was added sodium methoxide and the reaction mass was refluxed for 8-10 hrs .After the reaction is complete, the mass is cooled to< 10*C and filtered to remove Sod chloride. The filtrate is concentrated by distillation to remove solvent THF which is later reused. The concentrated mass is viscous liquid of Almimazine base 2nd step A The Almimazine base is dissolved in Iso propyl alcohol, in SS reactor, charcoaled with carbon and filtered. The clear filtrate is converted to the Almimazine tartarate with L-tartaric acid by refluxing for 4 hrs and cooling the mass below <10*C when crystals of Almimazine tartarate. This is centrifuged to isolate the crude product. This product is further purified by crystallization in acetone and dried. The Solvent mother liquor IPA and Acetone is recovered, purified and reused. 2nd step B The Almimazine base is treated with molar quantity of Hydrogen peroxide 20% at < 10 *C in SS reactor in 3 hrs time; to get Oxomemezine base which is isolated as solid and separated by centrifuging . The Oxomemezine base thus obtained is dissolved in acetone in SS reactor treated with carbon and filtered. The clear filtrate is converted to hydrochloride salt by passing HCL gas. After the reaction the mass refluxed for 5hrs, and is cooled to 0*C and centrifuged to get pure Oxomemezine Hydrchloride. The mother liquor is sent for recovery of acetone which is reused. ALMEMAZINE TARTARATE AND OXOMEMAZINE

SL NO PRODUCTION 250kg

Raw material used

1 Phenothiazine 199kg

2 Sodium methoxide 54kg

3 THF 800L


5 IPA 600L

6 Carbon 20kg

7 L-Tartaric acid 50kg

8 Hydrogen peroxide20% solu 100kg


- 162 -

9 HCl 11kg

10 Acetone 1600L(for 1A & 1B)

Yield (Almemazine tartarate)/Oxomemazine HCl

230kgs/100kg

Batch size 250kgs --Almemazine tartarate)/Oxomemazine HCl -


Pheno thiazine 199kg SSR 4000L(for step 1 reaction)

Almemazine tartarate/ Oxomemazine HCl Yield 230/100kg Oveall yield 90%

Sodium methoxide 54kg

SSR 4000L (for concentration & dissolution)

I.Product:stge1 :: not isolated Stage1A ::92% Stage-1B::91%

Dimethylamino propyl chloride 135kg

SSR 3000L THF :700L loss100L Acetone: 1200L Loss:400L IPA 500L loss 100L P.Water: 80 L NaCl ::58kg Methanol ::32kg Cleaning water 1000L Goes toto CETP Hazard waste:1A :28-30kg Stage 1B::12-16kg Spent Carbon: 24kg

IPA 600L SSR 3000L (for solvent recovery)

THF – 800L

L-Tartaric acid 50kg

Hydrogen peroxide20% solu 100kg

Carbon

HCl 11kg

Acetone – 1600L

Time cycle 1st stage 2nd stage (A) 2rd stage (B) final




Solvent recovery…… ---- 10-14hrs (MLR-1) 12-14hrs -----

Water 80kg along with cleaning water 1000L goes to CETP


- 163 -

Almemazine base200 kgs

IPA 600LSS reactor-22000L

SS reactor-3cap 2000Lreaction

SSreactor2Noscap 1000Lfor solvent recovery

IPA recov500Lloss 50L(from 1)


FLOW CHART FOR ALMEMAZINE and OXOMEMAZINE

dissolution


centrifuge +

Acetone pure1200L(from 2&3)Loss 200L

Haz Waste 1A 28-30kgHaz waste 1B 10-12kgSpent C 24kg wetSod chloride 58kg

MLR-1,2& 3 IPA &Acetone

L-tartaric acid50kg

2nd Step-1A

Solvent IPALoss 50.0L


SS Reactor-1cap:3000Lorganic layer

Pheno thiazine 199kg

DimethylaminoMethylPropyl chloride 135kg

Sodium methoxide54 kg

THF 800L

Recov THF 700L Loss:130L(mix THF/CH3OH)

Almemazine base300kg (cont:290kg)

1st step

Carbon 10 kg

Spent carbon12kg wet

Centrifuge NaCl 58kg

AlmemazineTartarate

MLR-1IPA

SS reactor-3 cap 2000L crystallistion

Acetone 800L

Centrifuge Solv Acetone loss 100L

Almemazine Tatarate pure230kg

MLR-2Acetone

SS reactor -2cap 2000LReaction

Almemazine base 90kg

Centrifuge Water80kg

Oxamomezine155kg

SS reactor -3cap 2000LDissolution

C 10kg

Acetone800L

GLreactorcap 2000Lreaction

HCl 11kg

Spent C12kg wet

Centrifuge Sol loss100L

OxomemezineHCl 100 kg

MLR-3

2nd step-1B

8

H2O2100kg(20+80)

11

20


- 164 -

3.5.2.32 ALPRAZOLAM

O

NH2

Cl

O

HN

Cl

Cl

O

+N

HN

Cl

O

231

308

+

Cl

ClO

112

2-amino-5-chloro benzophenone


1st stage intermediate

Ammonia3

51

270

Alprazolam

+ Water

Reaction scheme

2NH4Cl

106 18Methanol

Toluene

MANUFACTURING PROCESS 2-Amino 5-Chloro Benzophenone ( chloro amino Ketone) is reacted with chloro acetyl chloride in toluene by refluxing for 12 hrs to get Di chloro intermediate in GLreactor , During the reaction Hcl generated is treated / scubbed with ammonia to get by product Ammonium chloride. After the reaction the mass is centrifuged, and solid is dried. The Di Chloro intermediate in SS reactor is dissolved in Methanol and then reacted with ammonia by refluxing in solvent methanol for 14 hrs at temp 65* C and cooled to


- 165 -

isolate by product Ammonium chloride which is removed by filtration. The resultant filtrate is charcoaled, filtered and concentrated 50% to recover solvent (which is recycled). The concentrated mass is further cooled to 15* C to get Alprazolam which separates as crystals. These crystals are centifuged and the pure Alprazolam is dried. The mother liquor from the centrifuge is sent for recovery of solvent at 65*C to recover methanol. The last portion of solvent distilling bet 85*C and 95*C is methanolic water which is sent as effluent. The residual mass remaining as undistilled is taken as Haz waste.

ALPRAZOLAM MASS BALANCE SL NO PRODUCTION B size 100kg No of batchs :1/month

Raw material used


2 2-amino 5-chloro benzophenone 115kg

3 Toluene 600L

4 Ammonia 25kg

5 Carbon 5kg

6 Methanol 800Lt

Yield (Alprazolam) 110kgs

Batch size 100kgs --- Alprazolam




Alprazolam Yield :: 110kg Oveall yield ::82%

2-amino 5-chloro benzophenone – 115kg

SSR 2000L (for reaction) I.Product: stage-1 :91% Stage-2 :90%


Toluene: 500L Loss: 100L Methanol: 600L Loss:200L P.Water: nil By product NH4Cl ::60kg (Contns water HCL scrub) Cleaning water :1000L goes to CETP Hazardous waste: 24-26kg Spent Carbon: 7kg


Carbon – 5kg

Methanol – 800L


- 166 -




Solvent recovery……10-12 hrs (MLR-1, 2) 10-14hrs (MLR-3) -----



- 167 -




FLOW CHART FOR ALPRAZOLAM






2-amino 5-chlorobenzophenone 115kg

Toluene 600L

1st step A



Dichloro intermediate150kgwet(actual 140kg)

Methanol800L

HCl 18 kg scrubber

Ammonia 25kg



Centrifuge

2nd step

Am.Choride 60kg wet


Dichloro intermediate140kg


Carbon5kg

Spent C7kg


Solv loss 50LMLR-2

Alprazolam110kg 12

14


- 168 -

3.5.2.33 DIAZEPAM

O

NH

Cl

O

N

Cl

Cl

O

+N

N

Cl

O

245.5

322

+

Cl

ClO

112

2-Methylamino-5-chloro benzophenone


1st stage intermediate

Ammonia3

51

284.5

Diazepam

+ Water

Reaction scheme

2NH4Cl

106 18Methanol

Toluene


2-MethylAmino 5-Chloro Benzophenone (chloro Methylamino Ketone) is reacted by

refluxing for 14hrs with chloro acetyl chloride in toluene to get Di chloro intermediate

in GLreactor. During the reaction Hcl generated is treated / scrubbed with ammonia

to get by product Ammonium chloride. After the reaction the mass is cooled

centrifuged and product is dried.MLR is sent for recovery of solvent toluene.

The Di Chloro intermediate in SS reactor is then reacted with ammonia by refluxing in

solvent methanol at temp 65* Cfor 12 hrs and cooled to isolate by product Ammonium


- 169 -

chloride which is removed by filtration. The resultant filtrate is concentrated 50% to

recover solvent (which is recycled).

The concentrated mass is further cooled to 15* C to get Diazepam which separates as

crystals. These crystals are centrifuged and the pure Diazepam is dried.

The mother liquor from the centrifuge is sent for recovery of solvent at 65*C to

recover methanol. The last portion of solvent distilling bet 85*C and 95*C is

methanolic water which is sent as effluent.

The residual mass remaining as undistilled is taken as Haz waste.

SL NO PRODUCTION B size 120kg No of batchs 1/Month

Raw material used


2 2-methyklamino 5-chloro benzophenone 123kg

3 Ammonia 25kg

4 Toluene 600Lt

5 Methanol 800Lt

6 Carbon 5kg

Yield (Diazepam) 120kgs

Batch size 100kgs --- Diazepam




Diazepam Yield ::120kg Overall yield 84%

2-methyklamino 5-chloro benzophenone – 123kg

SSR 2000L (for reaction) I.Product: ::stage-1::93% Stage-2::91%

Ammonia – 25kg SSR 2000L(for methanol solution)

Toluene: 500L Loss: 100L Methanol: 650L Loss:150L P.Water: stage-2 ::Nil By product NH4Cl:: 60kg (Contns water 9kg) Cleaning water ::1000 L goes to CETP Hazardous waste: 22-25kgkg Spent Carbon: 7kg

Toluene – 600L SSR 2000L (for solvent recovery)

Methanol – 800L

Carbon – 5kg


- 170 -




Solvent recovery…… 10-12 hrs (MLR-1) 10-14hrs (MLR-1) -----



- 171 -




FLOW CHART FOR DIAZEPAM






2-Methylamino 5-chlorobenzophenone 123kg

Toluene 600L

1st step A



Dichlorointermediate150kg

Methanol800L

Ammonia 25kg



Centrifuge

2nd step

Am.Choride 60kg wet


Dichloro intermediate150kg


Carbon5kg

Spent C7kg


Solv loss 50LMLR-2

Diazepam120kg 12

11


- 172 -

3.5.2.34 BUCLAZINE HCL

N

NHCl

286

p-Chloro benzhydryl piperazine

182

P-t butyl benzyl chloride

+ N

NCl

Buclizine Base

N

NCl

. 2HCl

Buclizine dihydrochloride

Cl

NaOH

40

Toluene

N

NCl

Buclazine base

2 HCl

Acetone

73

505432

NaCl

H2O

18

58

432

Reaction scheme

1st step

2nd step

Manufacturing Process- This involves 2 steps 1st step Para chloro benzhydryl piperazine is dissolved in solvent Toluene and then reacted with p-Tertiary buthyl benzyl chloride in SS Reactor in presence of base Sodium hydroxide is refluxed for 14 hrs at temp ~105*C . After the reaction is complete, the mass is cooled to< 15*C and the solid sodium chloride is removed by filtration. The clear filtrate is then concentrated to remove solvent Toluene, to get Buclazine base as thick liquid.


- 173 -

The recovered solvent is purified and reused. 2nd step The Buclazine base is dissolved in Acetone in SS reactor, charcoalised and filtered. The clear filtrate is transferred to GLreactor and treated with HCl gas and the resultant reaction mass is refluxed for 12 hrs and cooled <10*during this period, DiHydrochloride salt of Buclazine base separates out. This Buclazine dihydrochloride is isolated by centrifuging and dried. The mother liquor is sent for recovery of solvent which is re used.

BUCLAZINE HYDROCHLORIDE MASS BALANCE SL NO PRODUCTION B Size 450kg No of batchs 1/month

Raw material used

1 P-Chloro benzhydryl piperizine 286kg

2 P-Tert butyl benzyl chloride 182kg

3 Water 600Lt(1st stage)

4 Toluene 1000Lt

5 NaOH 40kg

6 Acetone 800Lt

7 HCl 73kg

8 Carbon 10kg

Yield (Buclazine Hydrochloride) 460kgs

Batch size 450kgs --- Buclazine Hydrochloride


P-Chloro benzhydryl piperizine – 286kg


Buclazine Hydrochloride Yield ::450kg Overall yield:90%

P-Tert butyl benzyl chloride – 182kg

SSR 3000L (for workup) I.Product: stage-1::95% Stage-2::94%

Water – 600L SSR 2000L(for dissolution) Toluene: 900L Loss: 100L Acetone: 675L Loss:125L P.Water stage-1 :676kg/L Cleaning water ::500L goes to CETP Hazardous waste: 52-55kg Spent Carbon: 12kg



Acetone – 800L

HCl -70kg

Carbon – 10kg


- 174 -




Solvent recovery…… ---- 10-14hrs (MLR-1) -----



- 175 -

Process Waste Water :: 676 kgCleaning waste Water :500L

Buclazine base 410kgs

Acetone 800L

SS reactor-22000L

GLreactor2000L


FLOW CHART FOR BUCLAZINE HYDROCHLORIDE

acetone

dissolution

Reaction


centrifuge +

Acetone 675Lloss 75L

Haz Waste 50-54 kgs

MLRAcetone

HCl 70kg

Buclazine dihydrochloride450.0kgs

2nd Step




P-chloro benzhydrylpiperizine 286kg

P-tert butylbenzyl chloride 182kg

NaOH 40kg

Toluene1000L

Water 600L

Water +NaCl676kg


Buclazine Base 235kg(contains 410kg pure)

1st step



22

MLR

30


- 176 -

3.5.2.35 MECLAZINE HCL

N

Cl

NH

+

Cl

N

Cl

N

N

Cl

N

Meclizine Base

Meclizine dihydrochloride

p-Chloro benzhydryl piperazine

meta methylbenzylchloride

286 140

NaOH

Toluene

390

N

Cl

N

Meclizine Base

390

HCl

Acetone

NaCl H2O

58 18

.2HCl

463

Reaction scheme

1st step

2nd step

40

73

Manufacturing Process- This involves 2 steps 1st step Para chloro benzhydryl piperazine is dissolved in solvent Toluene and then reacted with m-Methyl benyl chloride in SS Reactor in presence of base Sodium hydroxide is refluxed for 14 hrs at temp ~105*C . After the reaction is complete, the mass is cooled to< 15*C and the solid sodium chloride is removed by filtration.


- 177 -

The clear filtrate is then concentrated to remove solvent Toluene, to get Meclazine base as thick liquid. The recovered solvent is purified and reused. 2nd step The Meclazine base is dissolved in Acetone in SS reactor, added carbon and filtered. The clear filtrate is transferred to GLreactor and treated with HCl and the reaction mass is refluxed for 12 hrs and cooled <10*during this period, DiHydrochloride salt of Meclazine base separates out. This Buclazine dihydrochloride is isolated by centrifuging and dried. The mother liquor is sent for recovery of solvent which is re used.

MECLAZINE HYDROCHLORIDE MASS BALANCE SL NO PRODUCTION B size 400kg No of batchs::1/Month

Raw material used

1 P-Chloro benzhydryl piperizine 286kg

2 Meta metyl benzyl chloride 140kg

3 Water 600Lt(stage-1)

4 Toluene 1000Lt

5 NaOH 40kg

6 Acetone 800Lt

7 HCl 70kg

8 Carbon 10kg

Yield (Meclazine Hydrochloride) 410kgs

Batch size 400kgs --- Meclazine Hydrochloride


P-Chloro benzhydryl piperizine – 286kg


Meclazine Hydrochloride Yield ::410kg Overall yield:: 88.5%

Meta metyl benzyl chloride – 140kg

SSR 3000L (for workup) I.Product stage-1:93.5% Stage-2: 95%

Water – 600L SSR 2000L(for dissolution) Toluene: 900L Loss: 100L Acetone: 675L Loss:125L P. Water: stage-1:676kg/L Cleaning water ::500L goes to CETP Hazardous waste: 48-50kg Spent Carbon: 12kg



Acetone – 800L

HCl -70kg

Carbon – 10kg


- 178 -




Solvent recovery…… ---- 10-14hrs (MLR-1) -----



- 179 -

Process Waste Water :: 676 kgCleaning waste Water :500L

Meclazine base 365kgs

Acetone 800L

SS reactor-22000L

GLreactor2000L


FLOW CHART FOR MECLAZINE HYDROCHLORIDE

acetone

dissolution

Reaction


centrifuge +

Acetone 675Lloss 75L

Haz Waste 48-50 kgs

MLRAcetone

HCl 70kg

Meclazine dihydrochloride410.0kgs

2nd Step




P-chloro benzhydrylpiperizine 286kg

Meta methylbenzyl chloride 140kg

NaOH 40kg

Toluene 1000L

Water 600L

Water +NaCl676kg


Meclazine Base 390kg(contains 365kg pure)

1st step



MLR

25

23


- 180 -

3.5.2.36 CARBAMEZAPINE

Reaction scheme

N

Cl O

+ 2 NH3

N

H2N O

236

CarbamazepineIminostilbine carbonylchloride

255

Ammonia

2 x 17

AmmoniumChloride

NH4Cl

54

Manufacturing Procedure The process involves 2 steps and solvent recovery. 1st step reaction Iminostilbene carbonyl chloride is reacted with ammonia in SS reactor by refluxing for 20hrs in isopropyl alcohol (IPA) solvent. 2nd step isolation After the reaction is complete the reaction mass is cooled to <300C and centrifuged to remove the by-product ammonium chloride. The clear liquid is transferred to SS reactor and treated with water for isolation purpose and further cooled to 200C, during which carbamazepine crystallizes out. This will be centrifuged to separate the product from the IPA and water and then the product is dried. Solvent recovery The mother liquor from the centrifuge is sent for solvent recovery in SS reactor to recover isopropyl alcohol. The mother liquor i.e. IPA & water will be separated based on their boiling point in the solvent recovery unit.


- 181 -

CARBAMEZAPINE MASS BALANCE SL NO PRODUCTION B size 220kg No of batchs 5/Month

Raw material used

1 Ammonia 40kg

2 IPA 2000L

3 Iminostibene Carconyl chloride 255kg

4 Water 700Lt

Yield (Carbamezapine) 225kgs

Batch size 200kgs --- Carbamezapine


Ammonia – 40Kg SSR 4000L(for step 1 reaction)

Carbamezapine Yield ::225kg Oveall yield:97%

IPA – 2000L SSR 3000L (for step 1 workup)

I.Product: Nil Am chloride :54kg

Iminostibene Carconyl chloride – 255Kg


IPA: 1750L Loss: 250L P.Water: 705kg/ L NH3 :7kg Cleaning water :500L goes to CETP Hazardous waste: 5kg

Water – 700L


1) Reaction ………… 20-22hrs ---------- -------- Drying


& Centrifuge… 4-6hrs --------- ---------

3) Solvent recovery……… 12-16hrs ----------



- 182 -

Isopropyl alcohol 2000L

SS reactor-1

4000L

Haz Waste 5 kg

Process Waste Water :710LCleaning Waste Water : 500L

FLOW CHART FOR CARBAMEZAPINE

Iminostilbene Carconyl chloride 255kg

Reaction

MLR


Total water 1210L

SS REactor-2

3000L

Water 700L

Centrifuge

Ammonia 40 kg

Solvent recovery

AmmoniaLoss 7kg

Sovent loss100L

Ammoniumchloride 53 kg

CentrifugeSolvent loss :50 L

MLR

Carbamezapine225kg

Recovered IPA::1750LLoss :100L

Undistilled water,solv mix710kg


- 183 -

3.6 RAW MATERIALS

3.6.1 Quantity requirement

The raw materials required for the manufacture of APIs are appended in the table 3.2 below. Raw materials as listed will be procured as per the production requirement.

Table 3.2: Raw materials requirement

Sl. No.

Product Raw materials Quantity required Solvents required after recycling

kg/annum kg/batch kg/month kg/annum

1 Amtriptyline hydrochloride

THF 40 1360 16320

Dibenzo suberone 208 7072 84864

Toluene 2200 74800 897600 163200

Water 1600 54400 652800

Mg 24 816 9792


120 4080 48960

Con Hcl acid 110 3740 44880

N-Butanol 1000 34000 408000 40800

HCl gas 36 1224 14688

Acetone 1800 61200 734400 163200

NaOH 80 2720 32640

H2O2 (20%) 80 2720 32640

Carbon 20 680 8160

2 Imipramine HCl/Desipram

ine HCl



120 480 5760

Sodamide 39 156 1872

Toluene 1000 4000 48000 4800

Water 600 2400 28800


Acetone 800 3200 38400 4800

Carbon 10 40 480

3 Cyproheptadine HCl

THF 25 75 900

Dibenzo Suberenone

206 618 7416

N-Methylchloro Piperidine

133 399 4788

Toluene 2600 7800 93600 7200

Water 500 1500 18000

Methanol 600 1800 21600 3600

Con. HCl 110 330 3960

IPA 1500 4500 54000 9000


- 184 -

Carbon 15 45 540

Magnesium 24 72 864

4 Pitofenone HCl

Potassium bicarbonate

100 200 2400


256 512 6144

Chloro ethyl piperidine

147 294 3528

Toluene 1000 2000 24000 2400

Water 600 1200 14400


Acetone 1000 2000 24000 3600

Carbon 10 20 240

5 Pyrimethamine

PCBC 150 450 5400

Ester 116 348 4176

Toluene 750 2250 27000 3600

Water 1000 3000 36000

MEG 60 180 2160

Methanol 1200 3600 43200 4500

Guanidine 60 180 2160

Carbon 10 30 360



120 360 4320

Dibenzo Suberenone

206 618 7416

Toluene 2500 7500 90000 9000

Water 600 1800 21600

Con. Hcl 110 330 3960

Acetone 1000 3000 36000 6300

Mg 24 72 864

Carbon 10 30 360

7 Clomipramine HCl

3-Chlorolmino Dibenzyl

230 460 5520


120 240 2880

Sodamide 39 78 936

Toluene 1000 2000 24000 2400

Water 600 1200 14400


Acetone 800 1600 19200 2400

Carbon 10 20 240


KOH 59 295 3540


233 1165 13980


- 185 -

Toluene 1000 5000 60000 6000

Water 600 3000 36000


120 600 7200

Acetone 1000 5000 60000 12000


Carbon 10 50 600


2-Acetyl pyridine 120 600 7200

Chloro Benzene 112 560 6720

Diethylamino ethyl chloride

107 535 6420

Water 1200 6000 72000

Toluene 1200 6000 72000 9000

THF 30 150 1800

NaOH 40 200 2400

Carbon 15 75 900

Mg 24 120 1440


Acetone 1000 5000 60000 10500


2-methyl Benzo phenone

215 2150 25800

NaOH 40 400 4800

Dimethylamino Ehtanol

90 900 10800

Toluene 1000 10000 120000 12000

Citric acid 180 1800 21600

Water 600 6000 72000

Acetone 1500 15000 180000 30000

Carbon 10 100 1200


Sodamide 39 78 936


Toluene 1000 2000 24000 2400

Water 600 1200 14400

Dimethylamino Methylpropyl chloride

135 270 3240

Acetone/EA 800 1600 19200 2400


Carbon 10 20 240

12 Flupentixol HCl

THF 10 10 120


28 28 336

Mg 2.5 2.5 30

Toluene 700 700 8400 840

Water 200 200 2400


- 186 -

Acetone 300 300 3600 420

Carbon 5 5 60


Piperizino ehtanol intermediate

20 20 240

13 Melitracen HCl

THF 30 30 360

Dimethyl anthrone

220 220 2640


120 120 1440

Toluene 2200 2200 26400 4200

Water 600 600 7200

Mg 24 24 288

Acetone 1000 1000 12000 2100

Carbon 15 15 180



Pyridine Benz Hydrol

220 440 5280

NaOH 40 80 960

Dimethylamino Ethyl chloride

107 214 2568

Toluene 1000 2000 24000 2400


Water 600 1200 14400

Acetone 1000 2000 24000 4200

Carbon 10 20 240

15 Opipramol HCl

Imino stilbene 96 96 1152

NaOH 40 40 480

Bromochloro Propane

78 78 936

Toluene 2000 2000 24000 2400

Piperizinoethanol 65 65 780

Water 1200 1200 14400

Acetone 1200 1200 14400 2400

Carbon 10 10 120

HCl 36 36 432

16 Sulfadoxine P-Amino sulfonamide

172 1376 16512

Methoxy dichloro pyrimidine

179 1432 17184

Water 2000 16000 192000

Toluene 1500 12000 144000 24000

NaOH 40 320 3840

Methanol 2000 16000 192000 19200


- 187 -

Sodium methoxide

54 432 5184

Carbon 15 120 1440

17 Doxepin HCl Mg 24 24 288


120 120 1440

Toluene 2500 2500 30000 3000

Doxiepinone 210 210 2520

THF 20 20 240

Water 600 600 7200

Con Hcl 110 110 1320

Acetone 1000 1000 12000 2100

Carbon 10 10 120

18 Nitrazepam Chloroacetyl chloride

112 112 1344

2-amino 5-nitro benzophenone

242 242 2904

Toluene 1000 1000 12000 1800

Ammonia 51 51 612

Carbon 10 10 120

Methanol 1250 1250 15000 3000

19 Dothiepin HCl Mg 24 96 1152


120 480 5760

Toluene 2500 10000 120000 12000

Dothiepinone 226 904 10848

THF 20 80 960

Water 600 2400 28800

Con Hcl 110 440 5280

Acetone 1000 4000 48000 8400

Carbon 10 40 480

20 Bromazepam Chloroacetyl chloride

30 30 360

2-amino 5-bromo benzoyl pyridine

70 70 840

Toluene 600 600 7200 1200

Ammonia 14 14 168

Carbon 5 5 60

Methanol 800 800 9600 2400

21 Flunarazine HCl

Difluro Benzhydrol

220 220 2640


Toluene 1500 1500 18000 2400

HCl 110 110 1320

NaOH 40 40 480


- 188 -

Water 1425 1425 17100


Acetone/IPA 2000 2000 24000 4200

Carbon 15 15 180

Methanol 2000 2000 24000 3600

HCl Gas 73 73 876

22 Cinnarazine Benzhydrol 184 1288 15456


Toluene 1500 10500 126000 16800

HCl 110 770 9240

NaOH 40 280 3360

Water 1425 9975 119700


Acetone/IPA 2000 14000 168000 29400

Carbon 15 105 1260

Methanol 2000 14000 168000 25200

23 Clonazepam Chloroacetyl chloride

56 56 672

2-amino 5-nitro chloro benzophenone

138 138 1656

Toluene 600 600 7200 1200

Ammonia 25 25 300

Carbon 5 5 60

Methanol 800 800 9600 2400

24 Lorazepam Chloroacetyl chloride

56 56 672

2-amino dichloro benzophenone

133 133 1596

Water 600 600 7200

Toluene 1200 1200 14400 2400

NaOH 60 60 720

Hydroxyl amine 16 16 192

Carbon 10 10 120

Methanol 1300 1300 15600 3000

Acetic anhydride 45 45 540

25 Duloxetine HCl


2-Acetyl thiophene

126 126 1512

Water 1800 1800 21600

Toluene 1800 1800 21600 3600


Acetone 1000 1000 12000 2400

HCl 36 36 432

Carbon 10 10 120


- 189 -

H2 gas

Methanol 1000 1000 12000 2400

Ni cat 2 2 24

DMSO 600 600 7200 600

Fluro naphthalene

145 145 1740

KOH 112 112 1344

26 Dapoxetine HCl

3-Chloro propio phenone

34 34 408

Methanol 300 300 3600 600

Water 900 900 10800

Ni 1 1 12

Toluene 500 500 6000 600

Alfa Napthol 30 30 360

Methane sulfonic acid

19 19 228

Carbon 10 10 120


HCl 7 7 84

KOH 11 11 132

Acetone 500 500 6000 1800


Venalafaxine hydrochloride

313 313 3756

Toluene 2000 2000 24000 1800

NaOH 40 40 480

Acetone 1000 1000 12000 2400


Water 1018 1018 12216

Carbon 15 15 180


Acetophenone 120 120 1440


Piperidine 85 85 1020

Water 1200 1200 14400

Toluene 1100 1100 13200 1200

THF 30 30 360

Cyclohexyl chloride

118 118 1416

Carbon 15 15 180

Mg 24 24 288

HCL 36 36 432

Acetone 1000 1000 12000 2100

29 Tramadol HCl Cyclo hexanone 98 980 11760


Dimethylamine 45 450 5400

Toluene 1100 11000 132000 12000


- 190 -

THF 30 300 3600

Water 1200 12000 144000

Metabromo methoxy anisole

187 1870 22440

Mg 24 240 2880

Carbon 15 150 1800

Acetone 1000 10000 120000 21000

HCl 36 360 4320


P-amino sulfonamide

172 344 4128

DMF 1500 3000 36000 2400

Dichloro pyazine 148 296 3552

KHCO3 100 200 12000

Potassium methoxide

70 140 1680

Water 1000 2000 24000

Carbon 15 30 360

Methanol 2000 4000 48000 8400


Phenothiazine 199 199 2388

Sodium methoxide

54 54 648

THF 800 800 9600 1200


135 135 1620

IPA 600 600 7200 1200

Carbon

L-Tartaric acid 50 50 600

Hydrogen peroxide20% solu

100 100 1200

HCl 11 11 132

Acetone 1600 1600 19200 4800

32 Alprazolam Chloroacetyl chloride

56 56 672

2-amino 5-chloro benzophenone

115 115 1380

Toluene 600 600 7200 1200

Ammonia 25 25 300

Carbon 5 5 60

Methanol 800 800 9600 2400

33 Diazepam Chloroacetyl chloride

56 56 672

2-methyklamino 5-chloro benzophenone

123 123 1476

Ammonia 25 25 300


- 191 -

Toluene 600 600 7200 1200

Methanol 800 800 9600 1800

Carbon 5 5 60

34 Buclazine HCl P-Chloro benzhydryl piperizine

286 286 3432

P-Tert butyl benzyl chloride

182 182 2184

Water 600 600 7200

Toluene 1000 1000 12000 1200

NaOH 40 40 480

Acetone 800 800 9600 1500

HCl 70 70 840

Carbon 10 10 120

35 Meclazine HCl

P-Chloro benzhydryl piperizine

286 286 3432

Meta metyl benzyl chloride

140 140 1680

Water 600 600 7200

Toluene 1000 1000 12000 1200

NaOH 40 40 480

Acetone 800 800 9600 1500

HCl 70 70 840

Carbon 10 10 120

36 Carbamezapine

Ammonia 40 320 3840

IPA 2000 16000 192000 24000

Iminostibene Carconyl chloride

255 2040 24480

Water 700 5600 67200

3.6.2 Source of supply of raw materials

The raw materials are either obtained from local suppliers (Gujarat, Maharashtra, Karnataka, and Andhra Pradesh) or imported (China) & transportation mode is by air, road & sea.

Table 3.2 A: Raw materials suppliers

Sl. no.

Raw material Supplier

1 THF NAN YA PLASTICS CORPORATION

2 Dibenzosuberone LUNA CHEMICALS CO LTD

3 Toluene BPCL

4 Methanol Hcl CHEMIELIVA PHARMACEUTICALS LTD

5 Magnesium NANGTONG CHEM-TECH CO LTD


- 192 -

6 Con Hcl acid NANJING FINE TECH CHEMICALS CO LTD

7 N-Butanol WENZHOU CHEMICAL MATERIAL FACTORY

8 HCl gas BHURUKA GASES LIMITED

9 Acetone HOCL /RONDER CORPORATION

10 NaOH BEIJING CERAMETEK MATERIALS CO LTD

11 Carbon POLYCHEIMIE SA

12 IminoDibenzyl ZHEJIANG JIUZHOU PHARMACEUTICAL CO LTD

13 Sodamide TILLEY CHEMICALS

14 Methanol DAIREN CHEMICAL CORPORATION

15 N-MethylchloroPiperidine ANHUI RUISAI BIOCHEMICAL TECHNOLOGY CO LTD

16 IPA DEEPAK FERTILISERS PVT LTD

17 Potassium bicarbonate CHANGZHOU SINOWA CHEMICAL CO LTD

18 Methyl ester intermediate HAIHANG INDUSTRY CO.LTD.

19 Chloro ethyl piperidine HUEI-HO INTERNATIONAL CO., LTD.

20 PCBC HEBEI CHENGXIN CO., LTD

21 Ester SUZHOU WUGAN PHARMACEUTICAL CO., LTD.

22 MEG SHAOXING XINGXIN CHEMICAL CO LTD

23 Guanidine PERI NITRATES PVT.LTD.

24 3-Chlorolmino Dibenzyl ZHEJIANG CHEMSYN PHARMA CO., LTD.

25 KOH TAIZHOU BEST PHARM CO LTD

26 2-Chloro pheno thiazine CHANGZHOU SINOWA CHEMICALS CO LTD

27 2-Acetyl pyridine QINGDAO FREE TRADE ZONE UNITED INTERNATIONAL CO LTD

28 Chloro Benzene JIANGXI SYNERGY PHARMACEUTICAL CO., LTD.

29 Succinic acid XUZHOU NHWA PHARMACHEM ENTERPRISE CO LTD

30 2-methyl Benzophenone SINO-HIGH (CHINA) CO., LTD

31 Dimethylamino Ethanol AKI SHOKAI CO., LTD.

32 Citric acid CHANGZHOU UNITED CHEMICAL CO LTD

33 Dimethylamino Methylpropyl chloride

HAIHANG INDUSTRY CO.LTD.

34 Maleic acid JIANGSU GUO TAI INTERNATIONAL GROUP

35 Trifluorothioxanthone SHANGHAI DOMEN INTERNATIONAL CO LTD

36 Piperizino ethanol intermediate

ZHEJIANG MEDICINES AND HEALTH PRODUCTS IMP. AND EXP. CO., LTD

37 Dimethyl anthrone SHANGHAI PINEWOOD INTERNATIONAL TRADE CO., LTD.

38 Pyridine Benz Hydrol SUZHOU WUGAN PHARMACEUTICAL CO., LTD.

39 Dimethylamino Ethyl chloride

TAIZHOU BEST PHARM CO LTD

40 Iminostilbene ZHEJIANG ZONEBANNER JIUZHOU IMP & EXP CO LTD

41 Bromochloro Propane SHAOXING XINGXIN CHEMICAL CO LTD


- 193 -

42 P-Amino sulfonamide SHANGHAI DOMEN INTERNATIONAL CO LTD

43 Methoxydichloro pyrimidine

XUZHOU NHWA PHARMACHEM ENTERPRISE CO LTD

44 Sodium methoxide QINGDAO FREE TRADE ZONE UNITED INTERNATIONAL CO LTD

45 Doxiepinone SHOUGUANG FUKANG PHARMACEUTICAL CO. LTD.

46 Chloroacetyl chloride JIANGXI SYNERGY PHARMACEUTICALS IMP & EXP CO LTD

47 Ammonia CHANGSHU WANXING CHEMICAL CO LTD

48 Dothiepinone ANHUI RUISAI BIOCHEMICAL TECHNOLOGY CO LTD

49 2-amino 5-bromo benzoyl pyridine

SYNCHEM INTERNATIONAL CO. LTD.

50 DifluroBenzhydrol LEVA CHEM

51 Piperizine SHAOXING XINGXIN CHEMICAL CO LTD

52 Cinnamyl alcohol XINCHANG GUOBANG IMPORT & EXPORT CO LTD

53 Benzhydrol SHANGHAI DOMEN INTERNATIONAL CO LTD

54 2-amino 5-nitro chlorobenzophenone

ZHEJIANG MEDICINES AND HEALTH PRODUCTS IMP. AND EXP. CO., LTD

55 Hydroxyl amine HANGZHOU PROSERRE CHEMICAL CO. LTD.

56 Acetic anhydride JIANGSU GUO TAI INTERNATIONAL GROUP

57 Formaldehyde QINGDAO FREE TRADE ZONE UNITED INTERNATIONAL CO LTD

58 2-Acetyl thiophene SUZHOU WUGAN PHARMACEUTICAL CO., LTD.

59 Dimethyl amine ZHEJIANG HUAZHOU PHARMACEUTICAL CO.,LTD

60 H2 gas BHURUKA GASES LIMITED

61 Ni cat JINTAN DEPEI CHEMICAL CO. LTD.

62 DMSO XINGJIANG BLUE RIDGE TUNHE POLYESTER CO., LTD.

63 Fluro naphthalene ZHEJIANG JIUZHOU PHARMACEUTICAL CO LTD

64 3-Chloro propiophenone ZHEJIANG TONGXIANG FOREIGN TRADE (GROUP) CO., LTD.

65 Ni HANGZHOU VIWA CO LTD

66 Alfa Napthol CHANGZHOU UNITED CHEMICAL CO LTD

67 Methane sulfonic acid XUZHOU NHWA PHARMACHEM ENTERPRISE CO LTD

68 Dimethyl amine ZHEJIANG XIANJU JUNYE PHARMACEUTICAL CO LTD

69 Venalafaxine hydrochloride ZHEJIANG XIANJU JUNYE PHARMACEUTICAL CO LTD

70 Acetophenone ZHEJIANG TONGXIANG FOREIGN TRADE (GROUP) CO., LTD.


- 194 -

71 Cyclohexyl chloride GUJARAT HALOGEN PETROCHEM CORPN.

72 Cyclohexanone SHAOXING XINGXIN CHEMICAL CO LTD

73 Metabromomethoxyanisole TAIZHOU BEST PHARM CO LTD

74 P-amino sulfonamide JINTAN DEPEI CHEMICAL CO. LTD.

75 DMF HANGZHOU QICHUANG CHEMICAL CO.LTD.

76 Dichloropyazine ANHUI RUISAI BIOCHEMICAL TECHNOLOGY CO LTD

77 KHCO3 CHANGSHU WANXING CHEMICAL CO LTD

78 Potassium methoxide SHAOXING XINGXIN CHEMICAL CO LTD

79 Phenothiazine ZHEJIANG TONGXIANG FOREIGN TRADE (GROUP) CO., LTD.

80 Sodium methoxide HANGZHOU PROSERRE CHEMICAL CO. LTD.

81 Dimethylamino propyl chloride

HUEI-HO INTERNATIONAL CO., LTD.

82 L-Tartaric acid SYNCHEM INTERNATIONAL CO. LTD.

83 Hydrogen peroxide20% solu HANGZHOU VIWA CO LTD

84 P-Chlorobenzhydrylpiperizine

CHANGZHOU HUASHAN CHEMICAL CO LTD

85 P-Tert butyl benzyl chloride

SHANGHAI DOMEN INTERNATIONAL CO LTD

86 P-Chlorobenzhydrylpiperizine

SUZHOU WUGAN PHARMACEUTICAL CO., LTD.

87 Meta metyl benzyl chloride ZHEJIANG CHEMSYN PHARMA CO., LTD.

3.6.3 STORAGE FACILITY FOR RAW MATERIALS AND PRODUCTS Adequate storage facilities are proposed to be provided for the raw materials, products etc.

Table 3.3:- Details of Storage Facilities

Sl. No. Storage Facility for Facility

1 Raw Materials Warehouse

2 Products Bonded finished good store

3 Industrial Effluent Effluent treatment Plant with Multiple Effective Evaporator (MEE) followed by RO filtration with adequate storage tanks

4 Hazardous Waste Process residue is sent to cement industries for co-incineration (as an auxiliary fuel) during the manufacture of cement. Spent carbon will be disposed for coincineration during the manufacture of cement.


- 195 -

The inorganic residue from the process and as well from the MEE will be stored scientifically and will be sent to TSDF for scientific treatment and disposal.

3.6.4 MACHINERY & EQUIPMENT DETAILS The detailed list of machinery & equipments in the industry are appended in the tables below

Table 3.4: List of the machinery & equipments

Block – A Equipments

SL.NO Description of Main Machineries / Plant Capacity Nos

1 GLR 1 KL 1

2 GLR 2 KL 1

3 GLR 2 KL 1

4 GLR 3 KL 1

5 GLR 2 KL 1

6 GLR 2 KL 1

7 GLR 3 KL 1

8 SS 0.75 KL 1

9 SS 1 KL 1

10 SS 2 KL 1

11 SS 2 KL 1

12 SS 2 KL 1

13 SS 2 KL 1

14 SS 2 KL 1

15 SS 3 KL 1

16 SS 3 KL 1

17 SS 3 KL 1

18 SS 5 KL 1

19 SS 7.5 KL 1

20 SS 3 KL 1


- 196 -

Block – B Equipments

SL.NO Description of Main Machineries / Plant Capacity Nos

1 SS 1.5 KL 1

2 SS 3 KL 1

3 GLR 3 KL 1

4 GLR 5 KL 1

5 GLR 5 KL 1

6 GLR 3 KL 1

7 GLR 3 KL 1

8 GLR 5 KL 1

9 SS 2 KL 1

10 SS 2 KL 1

11 SS 2 KL 1

12 SS 2 KL 1

13 SS 2 KL 1

14 SS 2 KL 1

15 SS 2 KL 1

16 SS 3 KL 1

17 SS 3 KL 1

18 SS 3 KL 1

19 SS 3 KL 1

20 SS 5 KL 1

21 SS 5 KL 1

22 SS 7.5 KL 1

23 SS 3 KL 1

3.7.1 SOLVENT RECOVERY & RE-USE Various solvents are proposed to be used during the process of manufacture of APIs. The solvents proposed to be recovered and recycled during the process of manufacture of each product are detailed in table 3.5.

3.7 RESOURCE OPTIMIZATION/RECYCLING AND RE-USE ENVISAGED IN THE PROJECT


- 197 -

Table 3.5: Solvent recovery

Sl.No Product Raw materials Quantity (kg/annum)

Recovered and recycled

Lost

1 Amtriptyline hydrochloride Stage 1

Toluene 775200

122400

Acetone 326400 81600

Stage 2 Toulene 367200 40800

Acetone 244800 81600

N-Butanol 367200 40800

2 Imipramine

HCl/Desipramine HCl

Toluene 43200 4800

Acetone 33600 4800

3 Cyproheptadine HCl Toluene 86400 7200

Methanol 18000 3600

IPA 45000 9000

4 Pitofenone HCl Toluene 21600 2400

Acetone 20400 3600

5 Pyrimethamine Toluene 23400 3600

Methanol 38700 4500

6 Cyclobenzaprine HCl Toluene 81000 9000

Acetone 29700 6300

7 Clomipramine HCl Toluene 21600 2400

Acetone 16800 2400

8 Chlorpromazine HCl Toluene 54000 6000

Acetone 48000 12000

9 Doxylamine Succinate Toluene 63000 9000

Acetone 49500 10500


Toluene 108000 12000

Acetone 150000 30000


Toluene 21600 2400

Acetone/EA 16800 2400

12 Flupentixol HCl Toluene 7560 840

Acetone 3180 420

13 Melitracen HCl Toluene 22200 4200

Acetone 9900 2100


Toluene 21600 2400

Acetone 19800 4200

15 Opipramol HCl Toluene 21600 2400

Acetone 12000 2400

16 Sulfadoxine Toluene 120000 24000

Methanol 172800 19200

17 Doxepin HCl Toluene 27000 3000

Acetone 9900 2100


- 198 -

18 Nitrazepam Toluene 10200 1800

Methanol 12000 3000

19 Dothiepin HCl Toluene 108000 12000

Acetone 39600 8400

20 Bromazepam Toluene 6000 1200

Methanol 7200 2400

21 Flunarazine HCl Toluene 15600 2400


Methanol 20400 3600

22 Cinnarazine Toluene 109200 16800


Methanol 142800 25200

23 Clonazepam Toluene 6000 1200

Methanol 7200 2400

24 Lorazepam Toluene 12000 2400

Methanol 12600 3000

25 Duloxetine HCl Toluene 18000 3600

Acetone 9600 2400

Methanol 9600 2400

DMSO 6600 600

26 Dapoxetine HCl Methanol 3000 600

Toluene 5400 600

Acetone 4200 1800

27 Desvenlafaxine HCl Toluene 22200 1800

Acetone 9600 2400

28 Trihexyphenadyl HCl Toluene 12000 1200

Acetone 9900 2100

29 Tramadol HCl Toluene 120000 12000

Acetone 99000 21000


DMF 33600 2400

Methanol 39600 8400


THF 8400 1200

IPA 6000 1200

Acetone 14400 4800

32 Alprazolam Toluene 6000 1200

Methanol 7200 2400

33 Diazepam Toluene 6000 1200

Methanol 7800 1800

34 Buclazine HCl Toluene 10800 1200

Acetone 8100 1500

35 Meclazine HCl Toluene 10800 1200

Acetone 8100 1500

36 Carbamezapine IPA 168000 24000


- 199 -

Note: * The solvent lost during the process of solvent distillation is mainly due to organic thermal disintegration and in form of residue left behind from the bottom un-distilled product. Evaporation loss is minimized by the passage of chilled water through the condenser. SOLVENT RECOVERY SYSTEM

After the reaction is complete the solvents are recovered in a distillation unit. The distillation unit has two condensers in series (shell and tube type). The first condenser is passed with chilled cooling tower water at 7-12 oC, while

the second condenser will be passed with chilled brine solution at -10 - 200 C as coolants.

After the vapors are condensed, the condensate along with un-condensed vapors is passed through a trap which is cooled externally with chilled water.

The vents of condenser and receiver are connected to scrubber system. All the reaction vessels and centrifuges are connected to a common line. These

fumes and exhausts are sucked by ID fan and scrubbed by alkali solution. The air after scrubbing is let out into the atmosphere and the scrubbed water is

sent to ETP for further treatment. This wet scrubber absorbs acidic vapors, traces of solvents etc. and purified gas

stream is let out into the atmosphere.

Fig 3.2: Typical solvent recovery system

Condenser 2

Condenser 1

Chilled water

Cooling tower water

Distillation

column

Receiver

To scrubber

Recovered solvent

Residue to storage


- 200 -

3.7.2 SPENT CARBON Spent carbon is used during the process of manufacture of different APIs. The spent carbon will be dispoed to co-incinerator as axilaury fuel during manufacture of cement. The detailed list of the quantities is appended in table 3.6 below

Table 3.6: Spent carbon recovery and disposal

Sl. No. APIs Quantity of spent carbon generated, kg/annum

1 Amtriptyline hydrochloride 9,792

2 Imipramine hydrochloride 576

3 Cyproheptadiene HCl 720

4 Pitofenone HCl 288

5 Pyrimethamine 432

6 Cyclobenzaprine HCl 432

7 Clomipramine HCl 288

8 Chlorpromazine HCl 720

9 Doxylamine Succinate 1,080

10 Orphenadrine Citrate/ HCl 1,440


288

12 Flupentixol HCl 72

13 Melitracen HCl 216

14 Carbinoxamine Maleate 288

15 Opipramol HCl 144

16 Sulfadoxine 1,728

17 Doxepin HCl 144

18 Nitrazepam 144

19 Dothiepin HCl 576

20 Bromazepam 84

21 Flunarazine HCl 216

22 Cinnarizine 1,512

23 Clonazepam 84

24 Lorazepam 144

25 Duloxetine HCl 144

26 Dapoxetine HCl 144

27 Desvenlafaxine HCl 216

28 Trihexyphenadyl HCl 216

29 Tramadol HCl 2,160

30 Sulfamethoxy Pyrazine HCl 432

31 Alimemazine Tartarate 288

32 Alprazolam 84

33 Diazepam 84

34 Buclazine HCl 144


- 201 -

35 Meclazine HCl 144

36 Carbamezapine -

TOTAL 25,464

3.7.3 DOMESTIC SOLID WASTE RE-USE The total quantity of domestic wastes generated is about 22 kg/day which will be segregated at source, collected in bins and composted. The composted waste will be used as manure for landscape development.

3.8 WATER, ENERGY/POWER REQUIREMENT & SOURCE

3.8.1 Water

The water demand is met from Bore well water supply. The requirement of water for the unit is for domestic, industrial purposes. Details are appended in section 3.9.1 later in the report.

3.8.2 Power

The total power requirement of the industry is 750 kVA. Further one diesel generator of 500 kVA capacity is proposed to be installed to serve as an alternative source of power supply to this unit.

3.9 WASTES GENERATED & SCHEME FOR THEIR MANAGEMENT/DISPOSAL

3.9.1 Water demand and wastewater/effluent discharge

Source of water supply: Borewell Total number of employees: 110 people Per capita water demand: 45 LPCD

The total quantity of water required for the industry is about 186.050 KLD. The break-up of the consumption of water is as presented below.

Table 3.7: Water consumption and discharge

Water consumed for Consumption (LPD)

Discharge (LPD)

(a) Domestic (toilet, canteen etc.) 4,950 4,455

(b) Gardening/Landscape development

5,000 -

(c) Industrial purpose 1,76,100 68,500

1 Process

DM plant and its rejects 20,400 or say 20,500+2,000=22,500

22,459 (from process) + 2,000 (DM


- 202 -

reject)= 24,459 or say 25,500

2 Washing/Cleaning 29,810 or say 30,000 30,000

3 Softener rejects 20,000 2,000 (blow-down) Boiler feed for 3 MT boiler 18,000

4 Cooling tower – 5 nos. 75,600 (make-up water)

1,000 (bleed off)

5 Scrubber – 4 no. 5,000 5,000

6 R&D 5,000 5,000

Total 1,86,050 LPD or say 186.050 KLD

72,955 LPD or say 72.955

KLD Note: LPD – liter per day; KLD – kilo liter per day The treatment methods and the final disposal of each type of wastewater generated is appended in the table 3.6 below

Table 3.8: Sewage/effluent treatment and discharge

Sewage/effluent generated from

Treatment units provided Final disposal point

(a) Domestic Sewage is mixed and treated along with Low strength Effluent treatment plant

Recycle and on land irigation

(b) Industrial Collection tanks of 10 KL capacity (3 no.s) are proposed to be provided.

Industrial effluent is proposed to be treated in Effluent Treatment Plant with Multiple Effect Evaporator (MEE) followed by RO fitration for treatment, reuse and disposal.


- 203 -

LANDSCAPING 5,000 LPD

BOREWELL WATER SUPPLY

Cooling Tower bleed off 1,000 LPD

Mixed with low strength wastewater

stream

WATER CONSUMPTION 1,86,050 LPD

DOMESTIC WATER DEMAND 4,950 LPD

Scrubber

5,000 LPD

39.455 KLD (low strength stream) – equalization, aeration & reverse osmosis (RO) & 33.500 KLD (high strength stream) –Effluent Treatment Plant with Multiple Effect Evaporator followed by

RO filtration

* Process effluent & DM

rejects 25,500 LPD

Washing effluent

30,000 LPD

Boiler blow down

2,000 LPD

Boiler consumption 18,000 LPD

Cooling tower Make - up water 75,534.8 or say 75,535 LPD

(75,600-65.314)

Washing/ Cleaning

30,000 LPD

Scrubber effluent

5,000 LPD

INDUSTRIAL WATER DEMAND 1,76,100 LPD- Start up requirement Daily requirement after recycling:

1,76,100-65.314=1,76,034.6 or say 1,76,035 LPD

Fig 3.2: Water balance chart

DM water plant

22,500 LPD

Process consumption 20,500 LPD

Domestic wastewater

4,455 LPD

R&D

5,000 LPD

R&D effluent

5,000 LPD

Softener 20,000 LPD

M/s. R L Fine Chem Pvt. Ltd.,

- 204 -

*Excess quantity is because of inert water content in the chemnicals used in the process 3.9.1.1 PRODUCT-WISE WATER CONSUMPTION AND DISCHARGE Table 3.7: Product-wise water consumption and effluent discharge Table:9 PRODUCT-WISE WATER CONSUMPTION, DISCHARGE, BYPRODUCTS & INORGANIC SALTS GENERATIO

S N

Product Batch-wise water consumption, discharge, Byproduct & Inorganic salt generation

No. of batches /month

Total water

consumption

(L/month)

Total effluent

discharge (L/month)

Total inorganic

salt (kg/month)

Total byproduct (kg/month) Utility

of water Water

consumption (L/batch)

Effluent discharge (L/batch)

Inorganic salt (kg/batch)

By produ

ct (kg/batch)

1 Amtriptyline hydrochloride

Process 4,800 5,200 60 - 34 1,63,200 1,76,800 2040 -

Cleaning 8,250 8,250 2,80,500 2,80,500

Total 13,050 13,450 4,43,700 4,57,300


Process 2,400 2,640 60 17 Ammo

nia

4

9600 10560 240 68

Cleaning 2,750 2,750 11000 11000

Total 5,150 5,390 20600 21560

3 Cyproheptadiene HCl

Process 2000 2700 60 - 3 6000 8100 180 -

Cleaning 8250 8250 24750 24750

Total 10250 10950 30750 32850

4 Pitofenone HCl

Process 2400 2780 75 - 2 4800 5560 150 -

Cleaning 2750 2750 5500 5500

Total 5150 5530 10300 11060

5 Pyrimethamine

Process 4000 4320 - 50 MEG

3 12000 12960 - -

Cleaning 2750 2750 8250 8250


- 205 -

Total 6750 7070 20250 21210


Process 2400 3000 60 - 3 7200 9000 180 -

Cleaning 2750 2750 8250 8250

Total 5150 5750 15450 17250

7 Clomipramine HCl

Process 2400 2640 60 17 Ammo

nia

2 4800 5280 120 -

Cleaning 2750 2750 5500 5500

Total 5150 5390 10300 10780


Process 2400 2780 75 - 5 12000 13900 375 -

Cleaning 2750 2750 13750 13750

Total 5150 5530 25750 27650


Process 4800 5340 120 - 5 24000 26700 600 -

Cleaning 2750 2750 13750 13750

Total 7550 8090 37750 40450


Process 2400 2700 60 - 10 24000 27000 600 -

Cleaning 5500 5500 55000 55000

Total 7900 8200 79000 82000


Process 2400 2640 60 17 Ammo

nia

2 4800 5280 120 34

Cleaning 2750 2750 5500 5500

Total 5150 5390 10300 10780

12 Flupentixol HCl

Process 800 900 6 - 1 800 900 6 -

Cleaning 2750 2750 2750 2750

Total 3550 3650 3550 3550

13 Melitracen HCl

Process 2400 2960 60 - 1 2400 2960 60 -

Cleaning 2750 2750 2750 2750


- 206 -

Total 5150 5710 5150 5710


Process 2400 2700 60 - 2 4800 5400 120 -

Cleaning 2750 2750 5500 5500

Total 5150 5450 10300 10900

15 Opipramol HCl Process 4800 5200 80 - 1

4800 5200 80 -

Cleaning 5500 5500 5500 5500

Total 10300 10700 10300 10700

16 Sulfadoxine Process 8000 8080 - 115 Sodiu

m Chlori

de

8 64000 64640 - -

Cleaning 8250 8250 66000 66000

Total 16250 16330 13000 130640

17 Doxepin HCl Process 2400 3000 60 - 1 2400 3000 60 -

Cleaning 2750 2750 2750 2750

Total 5150 5750 5150 5750

18 Nitrazepam Process - 80 - 106 Ammonium chlori

de

1 - 80 - 106

Cleaning 5500 5500 5500 5500

Total 5500 5580 5500 5580

19 Dothiepin HCl Process 2400 3000 60 - 4 9600 12000 240 -

Cleaning 2750 2750 11000 11000

Total 5150 5750 20600 23000

20 Bromazepam Process - - - 26 ammo

1 - - - 26

Cleaning 5500 5500 5500 5500


- 207 -

Total 5500 5500 nium bromi

de

5500 5500

21 Flunarazine HCl

Process 5700 6460 58 - 1 5700 6460 58 -

Cleaning 8250 8250 8250 8250

Total 13950 14710 13950 14710

22 Cinnarizine Process 5700 6460 58 - 7 39900 45220 406 -

Cleaning 8250 8250 57750 57750

Total 13950 14710 97650 102970

23 Clonazepam Process - - - 54 Ammonium chlori

de

1 - - - 54

Cleaning 5500 5500 5500 5500

Total 5500 5500 5500 5500

24 Lorazepam Process 2400 2760 60 30 Sodiu

m chlori

de

1 2400 2760 60 30

Cleaning 5500 5500 5500 5500

Total 7900 8260 7900 8260

25 Duloxetine HCl

Process 7200 7860 130 - 1 7200 7860 130 -

Cleaning 8250 8250 8250 8250

Total 15450 16110 15450 16110

26 Dapoxetine HCl

Process 3600 3760 - 75 Potass

1 3600 3760 - 75

Cleaning 5500 5500 5500 5500


- 208 -

Total 9100 9260 ium chlori

de

9100 9260


Process 4072 4360 60 - 1 4072 4360 60 -

Cleaning 2750 2750 2750 2750

Total 6822 7110 6822 7110


Process 4800 5120 60 - 1 4800 5120 60 -

Cleaning 2750 2750 2750 2750

Total 7550 7870 7550 7870

29 Tramadol HCl Process 4800 5400 103 - 10 48000 54000 1030 -

Cleaning 5500 5500 55000 55000

Total 10300 10900 103000 109000


Process 4000 4080 - 150 Potassium

chloride

2 8000 8160 - 300

Cleaning 5500 5500 11000 11000

Total 9500 9580 19000 19160


Process 320 320 - 60 SodimChlori

de

1 320 320 - 60

Cleaning 5500 5500 5500 5500

Total 5820 5820 5820 5820

32 Alprazolam Process - - - 54 Ammonium chlori

de

1 - - - 54

Cleaning 5500 5500 5500 5500

Total 5500 5500 5500 5500


- 209 -

33 Diazepam Process - - - 55 Amm onium chlori

de

1 - - - 55

Cleaning 5500 5500 5500 5500

Total 5500 5500 5500 5500

34 Buclazine HCl Process 2400 2700 60 - 1 2400 2700 60 -

Cleaning 2750 2750 2750 2750

Total 5150 5450 5150 5450

35 Meclazine HCl Process 2400 2700 60 - 1 2400 2700 60 -

Cleaning 2750 2750 2750 2750

Total 5150 5450 5150 5450

36 Carbamezapine

Process 2800 2840 - 54 Ammonium chlori

de

8 22400 22720 - 432

Cleaning 2750 2750 22000 22000

Total 5550 5590 44400 44750

GRAND TOTAL 2,70,792 2,82,480 1,665 880 11,40,642

13,06,640

7,095 1,294

Note: Considering no. of working days/month = 25

1. Daily water consumption from process and washings/cleaning = 1140642/25 = 45625.6 or say 45626 LPD 2. Daily effluent discharge from the process and washings = 1306640/25 = 52265.6 or say 52266 LPD 3. Process water demand = 5,09,992/25 = 20399.68 or say 20400 LPD 4. Process effluent discharge = 561460/25 = 22458.4 or say 22459 LPD 5. Cleaning/washing water demand = 745250/25 = 29810 or say 30000 LPD 6. Cleaning/washing effluent discharge = 745250/25 = 29810 or say 30000 LPD


- 210 -

3.9.1.2 RAINWATER HARVESTING & GROUNDWATER RECHARGING

The total amount/quantity of water i.e., received in the form of rainfall over an

area is called the rain water endowment of that area, out of which the amount of

water that can be effectively harvested is called the rain water harvesting

potential.

Rain water harvesting potential = Intensity of rainfall (m) x Roof area x

Impermeability factor

The collection efficiency accounts for the fact that all the rain water falling over an area can not be effectively harvested due to losses on account of evaporation, spillage or run off etc., According to the data available from the Indian Meteorological Department, the Average annual rainfall around month of September = 194.80 mm. Assuming that about 90 % Rainfall can be effectively harvested.

Number of Rainy Days = 9.3

Therefore the I.R = 194.80/9.3= 20.94 mm/day or 0.02094 m/Day or 0.021 m/day

Quantity of roof top rain water harvested from the project:

The Ground Coverage area of the proposed project is about 8,016 sq m.

For rain water harvesting consider 75% of this total area = 6012 sq m.

Quantity of Rain Water that can be harvested from the proposed project is calculated as below.

Water Harvested per Year = Mean Annual Rainfall x Area x Collection Efficiency

= 0.021 x 6,012 x 0.9

= 113.6 or say 114 m3/day

However, it proposed to initially utilize the entire quantity of the rainfall potential

by providing adequate storage facilities (RCC tank of 100 m3 capacity).

The amount of storm water that the landscaped/open area will produce can be

determined by considering the impermeability factor to be 0.3.

Q = 0.021 x 10000 x 0.3

= 63 m3/day

The amount of storm water that the paved area will produce can be determined

by considering the impermeability factor to be 0.3.

Q = 0.021 x 6274 x 0.9

= 118.5 m3/day or say 119 m3/day


- 211 -

The total amount of storm water = landscaped area + paved area

= 63 + 119 m3/day

= 182 m3/day

The project Proponents will also provide recharging pits along the inner periphery

of the boundary wall. Each recharging pit will be of size 1.2 m dia x 2.5 m deep

spaced at 20 m center to center. These recharging pits are filled with graded

media comprising of boulder at bottom and with coarse aggregates to facilitate

percolation of harvested rainwater to recharge ground water table. The recharge

pits are interconnected in such a way that the rain led to the first recharge pit is

also led to the next pit.

3.9.1.3 PROCESS EFFLUENT CHARACTERISTICS The characteristics of the effluent generated during the manufacturing process is indicated in the tables below

Table 3.10: High strength wastewater characteristics

Parameter Results

pH 5 – 6

Biological Oxygen Demand, mg/L 10,000 – 15,000

Total dissolved solids, mg/L 25,000 – 30,000

Chemical Oxygen Demand, mg/L 25,000 – 50,000

Table 3.11: Low strength wastewater characteristics

Parameter Results

pH 5 – 6

Biological Oxygen Demand, mg/L 2,000 – 5,000

Total dissolved solids, mg/L 10,000 – 15,000

Chemical Oxygen Demand, mg/L 5,000 – 8,000

3.9.1.4 STORAGE FACILITIES PROVIDED FOR INDUSTRIAL EFFLUENTS The industrial effluent is proposed to be treated in Effluent Treatment Plant with Multiple Effect Evaporator followed by RO Filtration for treatment, reuse and disposal. The industry proposes to provide adequate storage facilities for the industrial effluents. The details of which are appended below.


- 212 -

Storage facilities at the project site

The industrial effluent is transferred to collection tanks (3 no.s) through ceramic pipes with secondary containment. The collection tanks will be of HDPE and of 10KL capacity (each).

3.9.1.5 TREATMENT SCHEME FOR WASTEWATER The wastewater from the industry is bifurcated into low strength & high strength wastewater streams & subjected to differential treatment as shown below.

Table 3.12: Source, quantity & treatment of industrial wastewater

Type of wastewater

Source Quantity, KLD

Treatment Re-use of treated wastewater

Low strength

Washings, R&D, domestic sewage

39.455 Equalization, aeration & reverse osmosis (RO). The reject from RO goes to MEE

Landscape development, cooling tower make-up water etc.

High strength

Process wastewater (DM rejects), boiler blow-down (softener rejects), scrubber, cooling tower bleed-off

33.500 Multiple Effect Evaporator (MEE).


- 213 -

3.9.1.6 Treatment scheme for high strength wastewater and low strength wastewater

Figure 3.3: Treatment scheme for high strength wastewater and low strength wastewater

Oil Trap/Seperator

Screening

Neutralization/

Equalization tank

ATFD

Stripper column

Organic fraction

1.675 KLD Condensate 33.75 KLD

33.500 KLD (high strength)

Sent to TSDF

Feed tank

MEE

Loss 3.17

kKkkKLD

Residue (MEE salts) 283.8 kg or say

300 kg + 200 kg= 500 kg

Sent to spent

solvent recycler

Raw sewage pump

RO

Rejects 7.891 KLD

Permeate 31.564 KLD

Permeate + Condensate=65.314 KLD

. KLD

39.455 KLD (Low)

Equalization cum neutralization tank

SBR Tank

Decant Tank

Decant Valve

Filter feed pump

Domestic sewage 5 KLD

Filter back wash

ETP sludge 40 kg/day

TSDF/Cement industries

Pressure sand filter

Activated Carbon filter

Floor washings & other non

process effluents 30 KLD


- 214 -

The major air pollution sources from the industry are DG set and boiler apart from the process sections. These sources are provided with stacks of adequate height so as to disperse the emanating flue gases containing SPM, oxides of sulfur and nitrogen without affecting the ground level concentrations and packed column scrubbers (2 no.s) are proposed to the process section & R&D facility with adequate stack height as per the regulatory requirements.

The sources of air pollution, type of fuel used, fuel consumption and chimney heights for each of the air pollution sources of the proposed project are indicated in the table 3.10 below.

Table 3.13: Air pollution sources, fuel consumption and chimney height details

SI. no.

Stack attached to

Fuel used Fuel consumption

Number of

stacks

Stack/s height

Air pollution control unit

Predicted emissions

1 Process section

- - 1 5 m ARL


Acid mist/ VOCs

2 R&D - - 1 3 m ARL


-

3 Steam boiler – 3Ton capacity – 2 no.s

Briquette 300 L/hr 1 30.5 m AGL

Stack SO2, NOx, SPM

4 D.G. set – 500 kVA – 1 no.

HSD 117.5 L/hr 1 7 m AGL

Stack SOx, NOx, SPM

5 Thermic Fluid Heater

Briquette Fired- 1 no

75 Kgs/hr 1 30.5 m AGL

Stack SOx, NOx, SPM


25 L/Hr 1 13 m AGL

Stack SOx, NOx, SPM


13 L/Hr 1 13 m AGL

Stack SOx, NOx, SPM


6 L/Hr 13 m AGL

Stack SOx, NOx, SPM

* Stack height calculation for DGs

3.9.2 Air pollution sources


- 215 -

Formula adopted for stack height calculation

H = 14(Q)0.3

Where, H is stack height Above Ground Level Q is sulfur content in exhaust in kg/hr (As per Handbook on Environmental Legislations and Technologies) Fuel consumption = 117.5 L/hr = 0.1175 m3/hr Sulfur content in HSD = 0.25% Density of sulfur = 2046 kg/m3 Therefore, Q = 0.1175 x (0.25/100) x 2046 = 0.0601 kg/hr Therefore, height of chimney = 14 (0.0601)0.3 = 6.02 m AGL Or say 7 m AGL Therefore it is proposed to provide 1 stack of height 7 m AGL for one diesel generator of 500 kVA capacity. ** Stack height calculation for boiler Formula adopted for stack height calculation

H = 74(Q)0.27

Where, H is stack height Above Ground Level Q is ash produced in tons/hr Type of fuel used – briquittes, husk, wood Capacity of boiler = 3 MT 1) For 3 MT boiler single use Fuel consumption = 0.3 tons/hr For agro based fuel ash produced per ton of fuel burnt = 6.5 kg (As per Handbook on Environmental Legislations and Technologies) Therefore, Q = 1.95 kg/hr = 0.00195 tons/hr Therefore, height of chimney = 74 (0.00195)0.27 = 13.72m AGL Or say 30.5 m AGL However it is proposed to install a stack of height 30.5 m AGL with Mechanical dust collector to collect the fly ash. The exhaust temperature will be nearly ambient and adequate port holes with access platform will be provided as per KSPCB guidelines as under


- 216 -

1. Location of port holes and approach platform The sampling porthole will be provided at a distance equal to at least eight times the stack diameters downstream and two diameters upstream from source of low disturbance such as bend, expansion, and construction valve fitting or visible flame for rectangular stacks. The equivalent diameter is calculated from the following equation Equivalent diameter = 2 (Length x Width) (Length x Width) 2. The diameter of the sampling port will be minimum 3”. Arrangement will be made to close the port hole firmly during the period when it is not used for sampling. 3. An easily accessible platform will be provided to accommodate 3 to 4 persons to conveniently sample stack emissions from the portholes. Ambient air quality and stack emission monitoring Ambient air quality monitoring will be conducted once in a month as per the guidelines of KSPCB for SPM, RSPM, SOx, NOx, HC and CO and the record of monitoring reports will be maintained and made available to authorities. Similarly stack monitoring will also be conducted for SOx. Scrubber details Scrubber systems are a diverse group of air pollution control devices that can be used to remove particulates and/or gases from industrial exhaust streams. Traditionally, the term "scrubber" has reference to pollution control devices that used liquid to "scrub" unwanted pollutants from a gas stream. Recently, the term is also used to describe systems that inject a dry reagent or slurry into a dirty exhaust stream to "scrub out" acid gases. Scrubbers are one of the primary devices that control gaseous emissions, especially acid gases.

Wet scrubber is a form of pollution control technology in which the polluted gas stream is brought into contact with the scrubbing liquid by spraying it with the liquid, by forcing it through a pool of liquid, or by some other contact method, so as to remove the pollutants.

The design of wet scrubbers or any air pollution control device depends on the industrial process conditions and the nature of the air pollutants involved. Inlet gas characteristics and dust properties (if particles are present) are of primary importance. Scrubbers can be designed to collect particulate matter and/or gaseous pollutants. Wet scrubbers remove dust particles by capturing them in liquid droplets; remove pollutant gases by dissolving or absorbing them into the liquid. Any droplets that are in the scrubber inlet gas must be separated from the outlet gas stream by means of another device referred to as a mist eliminator or entrainment separator (these terms are interchangeable). Also, the resultant


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scrubbing liquid must be treated prior to any ultimate discharge or before being reused in the plant. There are numerous configurations of scrubbers and scrubbing systems, all designed to provide good contact between the liquid and polluted gas stream. The process and solvent recovery sections are provided with scrubber to scrub the fumes and vapors generated in order to remove such emissions before it is let out into the atmosphere. Packed column scrubber specifications Air volume – 6000 CMH Velocity through duct – 8 m/s Scrubbing pad height – 1 m Velocity through scrubbing pads – 1.5 m/s Nozzle type – Full cone type Nozzle spray area – 0.07 m2 Spray chamber height – 350

Fig 3.5: Column scrubber


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DUST COLLECTOR Designed to handle heavy dust loads, a dust collector system consists of a blower, dust filter, a filter-cleaning system, and a dust receptacle or dust removal system. It is distinguished from air cleaners which use disposable filters to remove dust. Specifications FILTER BAGS Size & height of filter bags : 195 mm dia x 900 mm length Material : Non-woven polyster Quantity of bags : 8 no.s Air permeability : 183 L/Dm2/min at 20 mm WG Filteration efficiency : 90% down to 10 microns Temperature of the filter media : 1400 C CENTRIFUGAL BLOWER Capacity : 950 m3/hr Static pressure : 7” (170 mm) WG Fan speed : 2800 RPM Motor : 2 HP/2P


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Fig 6: Dust collector

720

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The major source of noise pollution in the industry is the DG set for which acoustic enclosure is proposed. Also ambient noise levels will be ensured within the ambient standards by inbuilt design of mechanical equipment and building apart from vegetation (tree plantations) along the periphery and at various locations within the industry premises.

The quantity of solid waste generated from the industry is calculated as follows

Table 3.14: Solid waste generation

Total no. of employees 110

Assuming per capita solid waste generation rate as 0.25 kg/capita/day

Quantity of solid waste generated 27.5 kg/day

Organic solid waste : 60 % of the total waste

16.5 kg/day

Inorganic solid waste : 40 % of the total waste

11 kg/day

Disposal of domestic solid waste The domestic wastes are segregated at source, collected in bins and composted.

3.9.5.1 HAZARDOUS RAW MATERIALS The following raw materials used during the process of manufacture of APIs are hazardous in nature according to Manufacture, Storage and Import of Hazardous Chemical (Amendment) Rules, 19th January 2000, Schedule I, Part II

Table 3.15: Hazardous raw materials

Hazardous raw material

Sl. No. as per Manufacture, Storage and Import of Hazardous Chemical (Amendment) Rules, 19th January 2000, Schedule I, Part II

Hydrochloric acid 313

N- Butanol 412

Sodium Hydroxide 571

Magnesium 350

Potassium hydroxide

522

3.9.3 Noise generation and its management

3.9.4 Solid waste generation and management

3.9.5 Hazardous raw materials used in the manufacturing process and hazardous waste generation and management

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Methanol 377

Ammonia 31

Toulene 628

Iso Propyl Alcohol 334

Formaldehyde 295

Dimethyl Amine 215

Acetone 4

Chloroacetyl Chloride

124

Acetic anhydride 45

Cyclohexanone 161

Hydrogen peroxide

318

3.9.5.2 HAZARDOUS WASTE GENERATION AND MANAGEMENT

The hazardous wastes generated during the process of manufacture of different APIs are stored at hazardous waste storage area and sent to cement industries for co-incineration (as an auxiliary fuel) during the manufacture of cement. The quantities of hazardous waste generated from various processes are shown in the following tables. Organic process/solvent residue and spent carbon

Table: 3.16 Quantity of process residue generation from solvent recovery and

spent carbon generation from manufacturing process

Sl. No.

APIs Quantity of hazardous waste generated,

kg/annum

Quantity of spent carbon generated, kg/annum

1 Amtriptyline hydrochloride 1st stage

9,384 9,792

2nd stage 9,384


1,584 576

3 Cyproheptadiene HCl 1,908 720

4 Pitofenone HCl 864 288

5 Pyrimethamine 2,016 432

6 Cyclobenzaprine HCl 936 432

7 Clomipramine HCl 744 288

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8 Chlorpromazine HCl 2,280 720


2,160 1,080


5,520 1,440


840 288


13 Melitracen HCl 360 216


1,128 288

15 Opipramol HCl 252 144

16 Sulfadoxine 576 1728

17 Doxepin HCl 408 144

18 Nitrazepam 516 144

19 Dothiepin HCl 1,728 576


37 Flunarazine HCl 552 216

38 Cinnarizine 3,024 1512

39 Clonazepam 336 84

40 Lorazepam 396 144

41 Duloxetine HCl 396 144


43 Desvenlafaxine HCl 168 216

44 Trihexyphenadyl HCl 312 216

45 Tramadol HCl 3,480 2160


744 432

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47 Alimemazine Tartarate 1st step A

348 288

2nd step B 132

48 Alprazolam 300 84

49 Diazepam 276 84

50 Buclazine HCl 624 144

51 Meclazine HCl 588 144

52 Carbamezapine 480 -

TOTAL 55,200 25,464

Spent carbon is used during the process of manufacture of different APIs. The spent carbon will be disposed for co-incineration in cement manufacturing. Others

Table 3.17 : Miscellaneous types of hazardous waste generated

Sl. No.

Particulars Quantity of hazardous waste

generated kg/annum

Disposal Options Category


200 L Disposed through authorized recyclers

5.1

2 Residue from solvent recovery plant

55,200 Disposed through Cement industries for co incinerations

28.1

3 Used MS drums (either reused if it cannot scrapped)

120 Disposed through authorized recyclers

33.3

4 Used poly bags 180 Disposed through authorized recyclers

33.3

5 Inorganic salt from MEE

85,140 Dispoded to TSDF for scientific landfill.

34.3

6 Spent carbon 25,464 Disposed through Cement industries for co incinerations

28.2

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7 Spent organic solvent fraction from MEE stripper

205 KL/Annum Disposed through authorized solvent recyclers

28.5

Byproducts

Sl.No Product By product Kg/batch

Kg/month Kg/annum Application/ Uses of Byproducts


Ammonia 17 68 816 For neutralization captive use

2 Pyrimethamine

Ethylene glycol

50 150 1800 For chilling plant

3 Nitrazepam Ammonium Chloride

106 106 1272 Can be used as fertiliser

4 Bromazepam

Ammonium Chloride


5 Clomipramine Hcl


6 Trimipramine Hcl


7 Clonazepam

Ammonium chloride


8 Lorazepam Sodium chloride

30 30 360 For captive , used in soft water for boiler.

(Sodium acetate goes in Haz waste MEE)

9 Sulfadoxine Sodium Chloride

115 920 11040 For captive , used in soft water for boiler

10 Dapoxetine HCl-

Potassium Chloride

75 75 900 Sold to Ray pharma hindupur


Potassium Chloride

150 300 3600 Sold to Ray pharma, hindupur


Sodium Chloride

60 60 720 For captive , used in soft water for boiler

13 Alprazolam Ammonium chloride


14 Diazepam Ammonium chloride


15 Carbamezapine-

Ammonium chloride


Total 880 2398 28776

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Table 3.20: Characteristics of hazardous waste

Sl. No

Parameter Unit Method Observation / Result

CPCB Std. and WLT/TCLP Limit for Direct Landfill

1 Physical state - Visual observation Solid -

2 Color - Visual observation Light grey -

3 Texture - Visual observation Powder & lump

-

4 Bulk density gm/cc ASTM Std: D 5057 -1990 (Reapproved 2001)

1.25 -

5 Paint Filter Liquid Test

- SW-846:9095 A Pass Pass

6 pH (at 29.60 C) - SW-846:9040B, 9045 C 9.51 4.0 - 12.0

7 Calorific Value kcal/kg IS:1350 (Part II)-1970 (Reaffirmed 1983)

2400 <2500.0

8 Flash Point 0C SW-846:1020A 62 >60.0

9 Loss on drying at 103-1050 C

% (w/w) Std.Methods:2540 B 10% -

10 Loss on ignition at 5500 C (dry basis)

% (w/w) Std. Methods:2540 E <10.0 Non-Bio degradable <3.0 Bio degradable

< 20.0 (non-biodegradable) <5.0 (biodegradable)

11 Reactive cyanide

mg/kg SW-846: Ch.7 (7.3.3), 9014 <MDL -

12 Reactive sulfide mg/kg SW-846: Ch.7 (7.3.4), 9034 <10 -

13 Water soluble compounds except salts – in WLT extract

% (w/w) DIN:38414 Part 4 (S4) Std. Methods:2540 B,E

2.0 0.5

<10.0

14 Oil and grease (As n-hexane extractable)

% (w/w) SW-846:3540C, 9071A Nil <4.0

15 Cyanide-total mg/kg SW-846:9010B, 9014 1<MDL -

15 a

Cyanide-WLT mg/L DIN:38414 Part 4 (S4) Std. Methods:4500-CN-C SW-846:9014

<MDL <2.0

16 Fluoride-Total mg/kg Std.Methods:4500-F-B,D <0.1 -

16 a

Fluoride-WLT mg/L DIN:38414 Part 4 (S4) Std.Methods:4500F-B,D

<1.0 <50.0

17 Nitrate-WLT mg/L DIN:38414 Part4 (S4) Std.Methods:4500-NO3

- E <5 <30.0

18 Ammonia -WLT mg/L DIN:38414 Part4 (S4) <10 <1000.0

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Std.Methods:4500-NH3 B,C

19 Arsenic-Total mg/kg SW-846:3050B Std.Methods:3500-As B

<10 -

19 a

Arsenic- WLT mg/L DIN:38414 Part 4(S4) SW-846:3010A Std.Methods:3500-As B

<0.02 <1.0

20 Cadmium –Total mg/kg SW-846:3050B,7130 <0.5 -

20 a

Cadmium - WLT mg/L DIN:38414 Part4(S4) SW-846:3010A,7130

<0.01 <0.20

21 Chromium – Total

mg/kg SW-846 :3050 B, 7190 3<MDL -

21 a

Chromium (VI)-WLT

mg/L DIN:38414 Part4(S4) Std.Methods:3500-Cr B

<MDL <0.50

21 b

Chromium-TCLP mg/L SW-846:1311 SW-846:3010A, 7190

<0.05 <5.0

22 Copper-Total mg/kg SW-846:3050B, 7210 <MDL -

22 a

Copper-WLT mg/L DIN:38414 Part4(S4) SW-846:3010A, 7210

<0.05 <10.0

23 Lead-Total mg/kg SW-846:3050B, 7420 <MDL -

23 a

Lead-WLT mg/L DIN:38414 Part4(S4) SW-846:3010A, 7420

<0.05 <2.0

25 Nickel-Total mg/kg SW-846:3050B, 7520 <MDL -

25 a

Nickel-WLT mg/L DIN:38414 Part4(S4) SW-846:3010A, 7520

<MDL <3.0

27 Zinc-Total mg/kg SW-846:3050B, 7950 <0.5 -

27 a

Zinc-WLT mg/L DIN:38414 Part4(S4) SW-846:3010A, 7950

<MDL <10.0

28 Phenol-Total mg/kg SW-846:9065 <MDL -

28 a

Phenol-WLT mg/L DIN:38414 Part4(S4) SW-846:9065

<0.1 <100.0

3.9.5.3 STORAGE FACILITIES FOR HAZARDOUS WASTE

The industry proposes to provide adequate storage facilities for the hazardous wastes. The details are appended below.

Storage facilities at the project site

A designated impervious structure (sealed drums under cover roof) is proposed at the project site for collection and storage of hazardous waste.

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Hazardous waste disposal Process residue is sent to cement industries for co-incineration (as an auxiliary fuel) during the manufacture of cement. The spent carbon will be disposed for co-incineration in cement manufacturing. The inorganic residue from the process and as well from the MEE will be stored scientifically and will be sent to TSDF for scientific treatment and disposal.

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A schematic representation of the overall feasibility and environmental assessment process is shown in Figure 3.6.

Fig 3.6: Feasibility & environmental assessment process

CHAPTER 4

SITE ANALYSIS

4.1 CONNECTIVITY

3.10 SCHEMATIC REPRESENTATIONS OF THE FEASIBILITY DRAWING

Significant

Not

economic

Feasibility study conducted for newly proposed industry

Statement of intent by proponent

Guidelines for EIA by SEAC/MoEF

Abandon project

Determine the coverage of the EIA - scoping

Describe the environment – baseline study

Describe the project

Identify the impacts

Evaluate the impacts

Mitigation

Preventive measures

Prepare draft EIS

FINAL EIS REPORT

CONSIDER ALL PHASES OF PROJECT –

CONSTRUCTION, DEVELOPMENT, INSTALLATION &

FINAL OPERATION/ PRODUCTION

SO

CIO

-ECO

NO

MIC

ISSU

ES

MO

NIT

OR R

EVIE

W

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- 229 -

Fig 4.1: Google map showing connectivity Table 4.1: Connectivity from the project site

Sl. No.

Road Distance from the

project site (km)

Direction w.r.t.

project site

1 SH 9 0.5 West

2 Narasimha Devarbetta Reserve Forest

15 South East

3 Gollapuram Lake 3.5 North East

4 Kudumaldkunta Lake 1 South West

5 Yerrahalli Lake 2.5 South

6 Gaudasandra Lake 4 South East

7 Thumakunta Lake 2 North

8 Penner River 2.5 West

9 Melya Lake 5 East

10 Devarapalli railway station 3.5 North

11 Kempegowda International Airport

59 South

Note: All distances mentioned are aerial.

PROJECT SITE

NARASIMHA DEVARABETTA

RESERVE FOREST

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4.2 LAND FORM, LAND USE & OWNERSHIP

M/s. R L Finechem Pvt. Ltd., is an Active Pharmaceutical Ingredients (APIs), manufacturing industry is proposed to be established at Plot No. 27-29, KIADB Industrial Area, Gouribidanoor, Karnataka. The plot where the industry is being set-up is a designated KIADB industrial area. “M/s. R L Fine Chem Pvt. Ltd.,” has entered into a lease agreement with KIADB & a copy of the lease deed is attached as Annexure C.

4.3 TOPOGRAPHY

M/s. R L Finechem Pvt. Ltd., is located at latitude of 13°42'23.74"N & longitude 77°30'11.96"E at an elevation of 686 m above MSL. The topo map showing the location of the project site is appended as fig 4.2.

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Fig 4.2: Topo map

Source: Survey of India; Scale: 1:50000

PROPOSED SITE

720

- 232 -

4.4 EXISTING LAND USE PATTERN

Table 4.2: Existing land-use pattern

Sl. No.

Particulars Details Distance from the project

site (km)

Direction w.r.t.

project site

1 Agriculture Minor activities - scattered Beyond industrial

area

-

2 National park, forest

Narasimha Devarbetta Reserve Forest

15 South East

3 Water bodies Gollapuram Lake 3.5 North East

Kudumaldkunta Lake 1 South West

Yerrahalli Lake 2.5 South

Gaudasandra Lake 4 South East

Thumakunta Lake 2 North

Penner River 2.5 West

Melya Lake 5 East

Note: a) All distances mentioned are aerial. b) The project is a notified by KIADB, Karnataka Govt. industrial area. A copy of

the Allotment/Possession Certificate is enclosed as Annexure -B

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Fig 4.3: Google map showing surrounding environmental features

4.5 EXISTING INFRASTRUCTURE

The list of existing infrastructure at the project site is 1. Water supply from Bore well 2. Power supply will be from BESCOM 3. Storm water drainage system is proposed 4. Domestic sewage & domestic garbage treatment is proposed in-house 5. Industrial wastewater & hazardous waste generated from the industry is

proposed to be out-sourced to CETP & co-incinerated in cement industries respectively.

PROJECT SITE

GOLLAPURAM LAKE

MELYA LAKE

KUDUMALDKUNTA LAKE

DEVARAPALLI RAILWAY STATION

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4.6 METEOROLOGICAL DATA

Assessment of the micro and macro meteorology is important from the standpoint of understanding the nature and extent of air pollution in the study area. Climate has an important role in the build-up of pollution levels in Bangalore. The climatic condition of the area may be classified as moderately or seasonally dry, tropical or temperate savanna climate with four seasons in a year. Winter is critical for air pollution build-up because of frequent calm conditions with temperature inversions resulting in poor atmospheric mixing, natural ventilation and high emission loads during evening traffic peaks. The classification of months according to the seasons is given in the following table

Season Period

Summer March to May

Monsoon June to September

Post monsoon October to November

Winter December to February

The metrological data reflecting minimum, maximum temperature in 0C, relative humidity in %, rainfall in mm/hr, wind speed in m/s, mixing height in m, cloud cover in tenths and atmospheric pressure in mb for the year 2011 obtained from modeling studies carried out using U.S. EPA AERMOD dispersion model, 1996 – 2011 Lakes Environmental Software, Version 7.1.0 has been appended as table 4.3.

Table 4.3: Meteorological data of Bangalore for the year 2014

Month Temperature 0C

Relative humidity %

Precipitation rate (mm)

Atmospheric Pr. (mb)

Wind speed (m/s)

Inversion / mixing height

(m)

Cloud cover

(tenths)

Min Max Max Min Min Max Min Max Min Max Day Night Min Max

Jan 17 25 84.8 58.3 0 0 909 919 0 6.7 2303 2477 2 10

Feb 13 20 76.9 44.8 0 12 908 915 0 5.1 2517 1786 2 5

Mar 15 25 69 38.8 0 90 907 917 0 6.2 2798 2057 2 6

Apr 12 27 76.7 50.7 0 0 908 914 0 5.1 2910 1799 2 5

May 19 27 82.7 61.0 0 48 905 913 0 6.2 3319 2317 2 5

June 15 21 88.6 71.7 0 21 904 913 0 10.3 2828 4000 2 10

July 18 21 89 75.5 0 18 904 912 0 8.7 2691 3638 2 10

Aug 17 28 88.9 74.5 0 81 904 912 0 7.2 2678 2779 3 10

Sept 17 18 91.4 75.3 0 192 905 912 0 7.2 2802 2801 2 10

Oct 22 24 88.5 73.5 0 75 904 913 0 5.7 2575 2046 3 10

Nov 20 21 93.5 78.1 0 93 905 915 0 6.2 2177 2247 2 10

Dec 17 22 87.6 66.8 0 0 906 914 0 6.7 1756 2522 2 10

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4.6.1 Temperature

The mean maximum temperature is observed at (32°C) in the month of May and the mean minimum temperature at (11.8°C) is observed in the month of December. In the summer season the mean minimum temperature is observed during the month of March (16.4°C). During the monsoon the mean maximum temperature is observed to be 30.9°C in the month of June with the mean minimum temperature at 17°C during August. By the end of September with the onset of post monsoon season (October - November), day temperatures drop slightly with the mean maximum temperature at 28.8°C in October and mean minimum temperature is observed at 16.8°C for both October & November. The values are presented in table 4.3.

4.6.2 Relative humidity

Minimum and maximum values of relative humidity have been recorded. The minimum humidity is observed to be at 38.8% in the month of March and the maximum is 91.4% in the month of September. The mean minimum values of humidity during summer, monsoon, post-monsoon and rainy seasons are 38.8%, 71.7%, 73.5% & 44.8% during the months of March, June, October and February respectively. Similarly the maximum values are 82.7%, 91.4%, 93.5%, 87.6% in the months of May, September, November & December during the summer, monsoon, post monsoon & winter seasons. The values are presented in table 4.3.

4.6.3 Rainfall

The monsoon in this region usually occurs twice in a year i.e. from June to September and from October to November. The maximum annual rate of precipitation over this region ranges between 1.02 to 4.83 mm/hr.

4.6.4 Atmospheric pressure

The maximum and the minimum atmospheric pressures are recorded during all seasons. In the summer season, the mean maximum and minimum pressure values are observed to be 917 mb in the month of March and 905 mb in the month of May respectively. During monsoon season, the maximum pressure is 913 mb and minimum 904 mb. The maximum pressure during the post-monsoon season is observed to be 915 mb in November and minimum pressure is 904 mb in the month of October. During the winter season the minimum atmospheric pressure is 906 mb in December and the maximum is 919 mb in the month of January. The values are presented in table 4.3.

4.6.5 Wind

The data on wind patterns are pictorially represented by means of wind rose diagrams for the entire year as figure 4.5 (for different seasons).

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1. March to May (summer season)

WRPLOT View - Lakes Environmental Software

WIND ROSE PLOT:

Wind rose diagram - summer season

COMMENTS:

MODELER:

M/s. Aquatech Enviro Engineers

DATE:

1/18/2012

PROJECT NO.:

NORTH

SOUTH

WEST EAST

4%

8%

12%

16%

20%

WIND SPEED

(m/s)

>= 11.1

8.8 - 11.1

5.7 - 8.8

3.6 - 5.7

2.1 - 3.6

0.5 - 2.1

Calms: 9.19%

TOTAL COUNT:

2208 hrs.

CALM WINDS:

9.19%

DATA PERIOD:

Start Date: 3/1/2010 - 00:00End Date: 5/31/2010 - 23:00

AVG. WIND SPEED:

2.73 m/s

DISPLAY:

Wind SpeedFlow Vector (blowing to)

3/1/2011

5/31/2011

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2. June to September (monsoon season)


WIND ROSE PLOT:

Wind rose diagram - monsoon season

COMMENTS:

MODELER:


DATE:

1/18/2012

PROJECT NO.:

NORTH

SOUTH

WEST EAST

7%

14%

21%

28%

35%

WIND SPEED

(m/s)

>= 11.1

8.8 - 11.1

5.7 - 8.8

3.6 - 5.7

2.1 - 3.6

0.5 - 2.1

Calms: 1.91%

TOTAL COUNT:

2928 hrs.

CALM WINDS:

1.91%

DATA PERIOD:


AVG. WIND SPEED:

4.09 m/s

DISPLAY:


6/1/2011

9/30/2011

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3. October to November (post monsoon season)


WIND ROSE PLOT:

Wind rose diagram - post monsoon season

COMMENTS:

MODELER:


DATE:

1/18/2012

PROJECT NO.:

NORTH

SOUTH

WEST EAST

4%

8%

12%

16%

20%

WIND SPEED

(m/s)

>= 11.1

8.8 - 11.1

5.7 - 8.8

3.6 - 5.7

2.1 - 3.6

0.5 - 2.1

Calms: 3.76%

TOTAL COUNT:

1464 hrs.

CALM WINDS:

3.76%

DATA PERIOD:


AVG. WIND SPEED:

3.26 m/s

DISPLAY:


10/1/2011

11/30/2011

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4. December to February (winter season)


WIND ROSE PLOT:

Wind rose diagram - winter season

COMMENTS:

MODELER:


DATE:

1/18/2012

PROJECT NO.:

NORTH

SOUTH

WEST EAST

5%

10%

15%

20%

25%

WIND SPEED

(m/s)

>= 11.1

8.8 - 11.1

5.7 - 8.8

3.6 - 5.7

2.1 - 3.6

0.5 - 2.1

Calms: 2.73%

TOTAL COUNT:

2160 hrs.

CALM WINDS:

2.73%

DATA PERIOD:


AVG. WIND SPEED:

3.21 m/s

DISPLAY:


Fig 4.4: Wind rose diagrams

1/1/2011

12/31/2011 -

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4.6.6 Inversion height

The maximum inversion heights at the project site during the day time & night time for all the months of the year is as given in the table 4.3. The maximum mixing height of 4000 m is observed during the month of June during the night time and 3319 m during the month of May during the day time. The minimum inversion heights are 1756 m in the month of December during the day and 1786 m during the night in the month of February.

4.6.7 Cloud cover

The minimum cover measured in the unit of tenths is 2 during most of the months. The maximum observed cloud cover is 10 during the months of January, June to December.

4.7 SOCIAL INFRASTRUCTURE AVAILABLE

Infrastructure is the basic physical and organizational structures needed for the operation of a society or enterprise or the services and facilities necessary for an economy to function. The term typically refers to the technical structures that support a society, such as roads, water supply, sewers, electrical grids, telecommunications and so forth and can be defined as "the physical components of interrelated systems providing commodities and services essential to enable, sustain, or enhance societal living conditions. Viewed functionally, infrastructure facilitates the production of goods and services, and also the distribution of finished products to markets, as well as basic social services such as schools and hospitals; for example, roads enable the transport of raw materials to a factory.

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The list of hospitals & other infrastructural facilities available in the vicinity of the proposed industry is tabulated below

Table 4.4: List of health-care facilities in the surroundings

Hospital Distance

Direction w.r.t. the industry

1 DR Colony Ward Hospital, Hindupur

12.24 km North

2 Shri Shirdi Sai Hospital, Gouribidanoor

10.95 km South

3 Prasad Hospital, Gouribidanoor

10.47 km South

4 Primary Govt Hospital, Kirikera

7.17 km North

5 PSC, Chikaballapur 11.93 km South West

Note: All distances mentioned are aerial.

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CHAPTER 5

PLANNING BRIEF

5.1 PLANNING CONCEPT

M/s. R L Finechem Pvt. Ltd., is an Active Pharmaceutical Ingredients (APIs) manufacturing industry with R & D activity.

5.2 POPULATION PROJECTION

Maximum workforce employed during peak construction period: 50 people Total no. of people proposed to be employed during operation phase: 110 people

5.3 LAND-USE PLANNING

The industry is designed envisaging adequate area for landscape, process section and utilities, storage areas for raw materials, finished products and internal movement of vehicles as shown in the table below.

Table 5.1: Land-use pattern

Sl. No.

Particulars Area (SQM)

1 Total plot area 24,290 (100 %)

2 Hard paved area 6,274 (25.83 %)

3 Landscape/Green-belt area

10,000 (41.17 %)

4 Ground coverage area 8,016 (33 %)

5 Built-up area 8,000

The site area details are shown in the plot area drawing appended.

5.4 ASSESSMENT OF INFRASTRUCTURE DEMAND

“M/s. R L Finechem Pvt. Ltd.,” is basically an Active Pharmaceutical Ingredients (APIs) manufacturing industry with R & D activity. The infrastructure demand for the project is detailed in the following sections

5.4.1 Roadways

Roadways are required for

transportation of materials & workers during construction phase &

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transportation of employees to & from the industry during the operation phase.

The major roadways in the vicinity of the project site are shown in section 4.1, Chapter 4

5.4.2 Water supply & sewerage infrastructure

Water demand for the industry will be met by Bore well. The domestic sewage generated will be mixed with industrial effluent at aeration stage and treated. The industrial wastewater will be treated in Effluent treatment Plant (ETP) with MEE followed by RO filtration for treatment, reuse and disposal.

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CHAPTER 6

PROPOSED INFRASTRUCTURE

6.1 INDUSTRIAL AREA (PROCESSING AREA)

M/s. R L Finechem Pvt. Ltd., is an Active Pharmaceutical Ingredients (APIs) manufacturing industry with R & D activity.

6.2 GREEN-BELT

An area of 10,000 SQM (i.e. 41.17 % of the total plot area) is reserved exclusively for green-belt/landscape development. About 300 trees of various native/indigenous variety are proposed to be planted.

6.3 SOCIAL INFRASTRUCTURE

Detailed in Chapter 4, Section 4.8.

6.4 CONNECTIVITY

Detailed in Chapter 4, Section 4.1.

6.5 DRINKING WATER MANAGEMENT

The source of water supply for the industry is Bore well. The total water requirement is about 186.050 KLD.

6.6 SEWERAGE SYSTEM

At present the industry does not have the common Underground drainage system (UGD) facility. The domestic sewage generated from the project is proposed to be conveyed through closed conduits and mixed with industrial effluent at aeration stage and treated.

6.7 INDUSTRIAL WASTE MANAGEMENT

The industrial wastewater is proposed to be treated in Effluent Treatment Plant with Multiple Effect Evaporator followed by RO filtration for treatment, reuse and disposal.

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The domestic garbage is proposed to be composted within the industry premises & the product will be used as manure for green-belt/landscape development. The hazardous solid wastes generated will be stored at hazardous waste storage area and sent to cement industries for co-incineration (as an auxiliary fuel) during the manufacture of cement or returned to the vendors for recharge & re-use.

6.9 POWER REQUIREMENT & SUPPLY SOURCE

The total power requirement of the industry is 750 kVA which will be sourced from BESCOM. Further one diesel generator of 500 kVA capacity is proposed to be installed to serve as an alternative source of power supply to this unit.

6.8 SOLID WASTE MANAGEMENT

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CHAPTER 7

REHABILITATION & RESETTLEMENT PLAN

M/s. R L Finechem Pvt. Ltd., is coming up in a designated industrial area. No home outstees/land outstees are expected & hence no rehabilitation plan is envisaged.

CHAPTER 8

PROJECT SCHEDULE & COST ESTIMATES

8.1 TIME SCHEDULE

The time schedule for completion of the proposed project is given in the following table

Particulars Time schedule

Start of construction activity Existing plant

Completion July, 2015

8.2 ESTIMATED PROJECT COST

Total capital investment on the proposed Project is detailed as under

Sl. no.

Cost of ` (Crores)

1 Land 2.5

2 Construction 6.7

3 Proposed investment on Plant and machinery

21

4 Environment Management Budget 3

TOTAL 33.2

Rupees Thirty Three Crores & Two Lakhs Only

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CHAPTER – 9

ANALYSIS OF PROPOSAL

Observing the demographic pattern of the study area it can be inferred that occupational pattern is a mixture more of agriculture rather industrial. The proposed project will increase the employment potential by creating direct and in-direct employment opportunities and thus be beneficial for the local and near by populace The management of the industry proposes to give preference to local people with both direct and indirect employment.

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MATERIAL SAFETY DATA SHEETS (MSDS)

The MSDS of the below listed chemicals are enclosed 1. Acetone 2. Acetic anhydride 3. Ammonia 4. Chloroacetyl chloride 5. Cyclohexanone 6. Dimethylamine 7. Formaldehyde 8. Hydrochloric acid 9. Hydrogen peroxide 10. Iso propyl alcohol 11. Magnesium 12. Methanol 13. N- butanol 14. Potassium hydroxide 15. Sodium hydroxide 16. Toluene

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EXECUTIVE SUMMARY - environmentclearance.nic.inenvironmentclearance.nic.in/writereaddata/Online/... · Multiple Effect Evaporator (MEE) followed by RO Filtration. B Air pollution