ENCLOSURES - environmentclearance.nic.inenvironmentclearance.nic.in/writereaddata/FormB/TOR/Additional... · M/s.Salubrious Laboratories Pvt.Ltd. Prepared By Rightsource Industrial

ENCLOSURES

TOPO MAP

LIST OF PRODUCTS

M/s.Salubrious Laboratories Pvt.Ltd.

Prepared By Rightsource Industrial Solutions Pvt. Ltd.

LIST OF PRODUCTS

S.No. Product Name Quantity In Kg/Month

Quantity In Kg/Day

1 Amlodipine Besylate 2500.00 83.33

2 Atorvastatin Calcium 2500.00 83.33

3 Domperidon 2500.00 83.33

4 Duloxetine Hydrochloride 1500.00 50.00

5 Fluconazole 2000.00 66.67

6 Lansoprazole 2000.00 66.67

7 Losartan potassium 2000.00 66.67

8 Pantoprazole sodium 5000.00 166.67

9 Rabeprazole Sodium 2500.00 83.33

10 Simvastatin 2500.00 83.33

11 Zidovudin 5000.00 166.67

Total 30000.00 1000.00

MANUFACTURING PROCESS

DESCCRIPTION



AMLODIPINE BESYLATE

Process Description

Stage-1

Phthalic anhydride reacted with Mono ethanol amine in Toluene media forms

phthalimido ethanol

Stage-2

Phthalimido ethanol reacted with Ethyl-4-chloro aceto acetate in presence of sodium

hydride, Toluene forms ethyl phthalimido ethoxy aceto acetate.

Stage-3

Ethyl phthalimido ethoxy aceto acetate condensate with orthochloro Benzaldehyde to

give Stage-3 as product.

Stage-4

Ethyl phthalimido ethoxy aceto acetate and orthochloro Benzaldehyde condensate

reacted methyl β-amino crotonate in Acetic acid media and further purified in Ethyl

acetate and forms phthalimido Amlodipine

Stage-5

Phthalimido Amlodipine reacted with Mono methyl amine forms Amlodipine Base.

Stage-6

Amlodipine Base reacted with Benzene sulphonic acid in water media forms Amlodipine

Besylate

Stage-7 (Purification)

Amlodipine Besylate further purified in Methanol and Ethyl Acetate to get Pure

Amlodipine Besylate Product



AMLODIPINE BESYLATE

Route of Synthesis:

Stage-1

Phthalic anhydride

O

O

O

Mono ethanol amine

NH2

HO+

Phthalimido ethanol

OH

O

O

N+ H2O

Water

C8H4O3

148.12

C2H7NO

61.08

C10H9NO3

191.18

18.0

Toluene

Stage-2

Phthalimido ethanol

OH

O

O

N

C10H9NO3

191.18

Ethyl-4-chloro acetoacetate

OO

O

Cl

+ + NaH

Sodium hydride

Toluene

C6H9ClO3

164.59

24.0

Ethyl-4(2-Phthalimido)ethoxy acetoacetate

O

O

O

O

O

O

N

C16H17NO6

319.31

+ NaCl + H2

Sodium Chloride Hydrogen

58.44 2.0



Stage-3

Ethyl-4(2-Phthalimido)ethoxy acetoacetate

O

O

O

O

O

O

N

C16H17NO6

319.31

+

Orthochloro benzaldehyde

O

Cl

Piperadine (Catalyst)

C7H5ClO

140.57

2-(2-Chloro-benzylidene)-4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-3-oxo-butyric acid ethyl ester

O

O

O

O

N

O

O

Cl

C23H20ClNO6

441.86

+ H2O

18.0



Stage-4

2-(2-Chloro-benzylidene)-4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-3-oxo-butyric acid ethyl ester

O

O

O

O

N

O

O

Cl

C23H20ClNO6

441.86

+

Methyl Amino crotonate

O

OH2N

C5H9NO2

115.13

Phthalimido amlodipine

NH

O

COOC2H5

N

O

O

H3C

H3COOC

ClH

C28H27ClN2O7

538.98

+ H2O

18.0

Acetic Acid



Stage-5

Phthalimido amlodipine

NH

O

COOC2H5

N

O

O

H3C

H3COOC

ClH

C28H27ClN2O7

538.98

+

Mono methylamine

H3C NH2

CH5N

31.06

NH

O

COOC2H5

NH2H3C

H3COOC

ClH

Amlodipine Base

C20H25ClN2O5

408.88

+

C9H7NO2

161.16

N

O

O

2-Methyl-isoindole-1,3-dione



Stage-6

NH

O

COOC2H5

NH2H3C

H3COOC

ClH

Amlodipine Base

C20H25ClN2O5

408.88

Benzene Sulfonic Acid

SO O

OH

+

NH

O

COOC2H5

NH2H3C

H3COOC

ClH SO O

OH

Amlodipine Besylate

C26H31ClN2O8S

567.05

C6H6O3S

158.18



Stage-7 (Purification)

NH

O

COOC2H5

NH2H3C

H3COOC

ClH SO O

OH

Amlodipine Besylate

C26H31ClN2O8S

567.05

Ethyl Acetate

Methanol

NH

O

COOC2H5

NH2H3C

H3COOC

ClH SO O

OH

Amlodipine Besylate Pure

C26H31ClN2O8S

567.05



AMLODIPINE BESYLATE

Flow Chart:

Phthalic anhydrideMono ethanolamineTolueneWater

Stage-1120.50Kg

Effluent Water

Stage-21536.00Kg

Stage-1TolueneSodium Hydride (60%)Ethyl-4-ChloroacetoacetateAcetic AcidWater

Stage-2Ortho chloro benzaldehydeHexanePiperidineAcetic AcidTolueneWater

Stage-3Methyl-3-amino crotonateAcetic AcidHexaneEthyl Acetate

Stage-4Mono methyl amineWater

Stage-5 (Amlodipine Base)Benzene Sulphonic AcidWater

Amlodipine Besylate TechMethanolEthyl AcetateActivated Carbon

Toluene Rec

Effluent WaterH2

Toluene Rec

Stage-3273.00Kg

Effluent Water

Stage-4150.00Kg

Toluene RecHexane Rec

spent acid

Ethyl acetate RecHexane Rec

Stage-5100.00Kg

Effluent Water

Stage-6130.00Kg

MMA Rec

Effluent Water

Stage-7120.00Kg

Spent Carbon

Methanol RecEthyl Acetate Rec

AMLODIPINE BESYLATE



AMLODIPINE BESYLATE

Material Balance:

Material balance of Amlodipine Besylate Stage-1

Batch Size: 120.0Kg

Name of the input Quantity in Kg

Name of the out put Quantity In Kg

Phthalic anhydride 100.50 Stage-1 120.50

Mono ethanolamine 42.00 Toluene Recovery 380.00

Toluene 400.00 Toluene Loss 6.00

Water 350.000 Effluent Water 366.78

(Water-350, generated water-12.22,Toluene-4, Mono ethanol amine-0.56)

Organic Residue 19.22

(Organic impurities-9.22,Toluene-10)

Total 892.50 Total 892.50


Batch Size: 120.0Kg



Stage-1 120.50 Stage-2 in Toluene and Paraffin Oils

1536.00

Toluene 1326.00 Effluent Water 537.20

Sodium Hydride (60%) 25.50 (Water-480,Sodium chloride-37.2,Acetic Acid-20)

Ethyl-4-Chloroacetoacetate 104.00 Process Emission 1.27

Acetic Acid 20.00 (Hydrogen)

Water 480.00 Organic Residue 1.53

Total 2076.00 Total 2076.00




Batch Size: 120.0Kg



Stage-2 In Toluene and Paraffin

1536.00 Stage-3 and Paraffin 273.00

Ortho chloro benzaldehyde 90.00 Toluene Recovery 1278.00

Hexane 240.00 Toluene Loss 44.00

Piperidine 6.00 Hexane Recovery 228.00

Acetic Acid 4.00 Hexane Loss 12.00


Water 450.00 (Water-450,generated water-11.27,Acetic Acid-4,Toluene-14.00,Piperidine-6)


Organic Impurities-15.73,Toluene-10)

Total 2346.00 Total 2346.00


Batch Size: 120.0Kg



Stage-3 and Paraffin 273.00 Stage-4 150.00

Methyl-3-amino crotonate 160.00 Hexane Recovery 360.00

Acetic Acid 814.00 Hexane Loss 40.00

Hexane 400.00 Ethyl Acetate Recovery 360.00

Ethyl Acetate 380.00 Ethyl Acetate Loss 20.00

Paraffin recovery 140.00

Spent Acetic Acid sent to Auth. Prt

926.17

(Acetic Acid-814,Methyl-3-amino crotonate-91.47, Paraffin-10,gen. water-10.7)

Organic residue 30.83

Total 2027.00 Total 2027.00




Batch Size: 120.0Kg



Stage-4 150.00 Stage-5 (Amlodipine Base) 100.00

Mono methyl amine 700.00 MMA Recovery 657.00

Water 300.00 MMA Loss 34.00

Effluent Water 345.85

(Water-300,2-Methyl isoindole-1,3-dione-44.85)


Total 1150.00 Total 1150.00


Batch Size: 120.0Kg



Stage-5 (Amlodipine Base) 100.00 Amlodipine Besylate Tech 130.00

Benzene Sulphonic Acid 42.00 Effluent Water 403.30

Water 400.00 (Water-400,Benzene Sulfonic Acid-3.3)



Material balance of Amlodipine Besylate Stage-7 (Purification) Batch Size: 120.0Kg



Amlodipine Besylate Tech 130.00 Amlodipine Besylate Pure 120.00

Methanol 700.00 Methanol Recovery 670.00

Ethyl Acetate 819.00 Methanol Loss 25.00

Activated Carbon 5.00 Ethyl Acetate Recovery 745.00

Ethyl Acetate Loss 69.00

Spent Carbon 5.00


(Methanol-5,Ethyl acetate-5,Organic Impurities-10)

Total 1654.00 Total 1654.00




ATORVASTAIN CALCIUM

Process Description:

Stage-1

Tert-Butyl-2-[(4R,6S)-6-(cyano methyl)-2,2-dimethyl-1,3-dioxan-4-yl] acetate

reduction with Hydrogen on Palladium Carbon in presence of Methanol gives tert-

Butyl-2-[(4R,6S)-6-(amino ethyl)-2,2-dimethyl-1,3-dioxan-4-yl] acetate.

Stage-2

Aniline on condensed with Dimethyl Carbonate and 2-Methyl-2-butanone in presence of

Methanol gives 4-Methyl-3-oxo-N-Phenyl pentanamide.

Stage-3

4-Methyl-3-oxo-N-phenyl pentanamide upon reaction with Benzaldehyde in presence of

Potassium Carbonate, Acetone and Toluene media gives 2-Benzylidene-4-methyl-3-oxo

pentanoic acid phenyl amide.

Stage-4

2-Benzylidene-4-methyl-3-oxo pentanoic acid phenyl amide on reaction with tert-Butyl-

2-[(4R, 6S)-6(amino ethyl)-2,2-dimethyl-1,3-dioxan-4-yl] acetate and fluoro benzaldehye

in presence of Para toluene sulfonic acid, Isopropyl alcohol and toluene media to give

Atorvastatin ester.

Stage-5

Atorvastatin ester undergoes hydrolysis in presence of sulfuric acid and methanol gives

Atorvastatin.

Stage-6

Atorvastatin upon salt formation with calcium acetate in presence of Isopropyl alcohol

gives Atorvastatin Calcium.


ATORVASTATIN CALCIUM

Procedure:

Stage-1

tert-Butyl-2-[(4R,6S)-6-(Cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate

O

O

O

O

N + 2 H2

Hydrogen

tert-Butyl-2-[(4R,6S)-6-(aminoethyl)-2,2-dimethyl-1,3-dioxan-4yl]acetate

O O

O O

H2N

269.0 4.0

273.0

Stage-2

Aniline

NH2

+

Dimethyl carbonate

O

O

O +

2-Methyl-2-butanone

CO

4-Methyl-3-oxo-N-phenyl pentanamide

O

NH

O

+ 2CH3OH

93 90 86 205 64.0


Stage-3

4-Methyl-3-oxo-N-phenyl pentanamide

O

NH

O

205

Benzaldehyde

O

+

106

2-Benzylidine-4-methyl-3-oxo pentanoic acid phenylamide

O

NH

O

293

+ H2O

18

Stage-4

2-Benzylidine-4-methyl-3-oxo pentanoic acid phenylamide

O

NH

O

293

tert-Butyl-2-[(4R,6S)-6-(aminoethyl)-2,2-dimethyl-1,3-dioxan-4yl]acetate

O O

O O

H2N

273.0

+

Fluoro benzaldehyde

O

F

+

124

NH

O

N

O O

O

O

C

CH3

CH3

CH3

F

+ 2 H2O

65436.0


Stage-5

NH

O

N

O O

O

O

C

CH3

CH3

CH3

F

654

+ 2 H2O

NH

O

N

OH OH

OH

O

F

36.0

+

558 58

O

+ C

CH3

CH3

CH3

HO

74


Stage-6

NH

O

N

OH OH

OH

O

F

558

+ CH3COOCa

158

NH

O

N

*OH OH

O

O

F 2

Ca2+

+ 2 CH3COOH

Atorvastatin Calcium

1154120.0



Flow Chart:

Stage-164.00Kg

Stage-252.00Kg

Methanol Rec

Stage-368.00Kg

Effluent Water

Stage-4132.00Kg

TolueneRecAcetone Rec

Effluent water

Toluene RecIPA Rec

Methanol Rec

H2

Stage-5106.40.00Kg

Effluent Water

Stage-6100.00Kg

Methanol Rec

IPA Rec

Tert-Butyl-2-[(4R,6S)]-6-(cyanomethyl)-2,2-dimethyl-1,3-Dioxan-4-yl] acetatePalladium carbonMethanolHydrogen

AnilineDimethyl Carbonate2-Methyl-2-ButanoneSulfuric AcidMethanolWater

Effluent Water

Stage-2BenzaldehydePotassium carbonateAcetoneTolueneWater

Stage-3FluorobenzaldehydeStage-1TolueneParatoluene sulfonic acidIPAWater

Atrovastatin EsterSulfuric AcidMethanolWater

AtrovastatinCalcium AcetateIPA Activated Carbon

Spent Carbon




Material Balance:

Material Balance of Atorvastatin Calcium Stage-1

Batch Size:100.0Kg


Name of the out put Quantity in Kg

Tert-Butyl-2-[(4R,6S)]-6-(cyanomethyl)-2,2-dimethyl-1,3-Dioxan-4-yl] acetate

66.40 Stage-1 64.00

Palladium carbon 1.20 Methanol Recovery 370.00

Methanol 400.00 Methanol Loss 24.00

Hydrogen 5.00 Spent Palladium carbon Reuse

1.20

Process Emission 4.00

(Hydrogen )


(Organic impurities-3.4, Methanol-6)



Batch Size:100.0Kg



Aniline 27.20 Stage-2 52.00

Dimethyl Carbonate 27.20 Methanol Recovery 140.00

2-Methyl-2-Butanone 27.20 Methanol Loss 7.10

Sulfuric Acid 0.80 Effluent Water 330.40

Methanol 136.00 (Water-328,sulfuric Acid-0.8,Methanol-1.6)






Batch Size:100.0Kg



Stage-2 52.00 Stage-3 68.00

Benzaldehyde 27.60 Acetone Recovery 130.00

Potassium carbonate 5.00 Acetone Loss 5.00

Acetone 140.00 Toluene Recovery 200.00



(Water-380,generated water-4.6,Potassium carbonate-5, Toluene-2)


(Organic impurities-7,Acetone-5, Toluene-7)



Batch Size:100.0Kg



Stage-3 68.00 Atorvastatin Ester 132.00

Fluorobenzaldehyde 28.80 IPA Recovery 300.00

Stage-1 64.00 IPA Loss 16.00

Toluene 520.00 Toluene Recovery 480.00

Paratoluene sulfonic acid 2.00 Toluene Loss 26.00

IPA 320.00 Effluent Water 394.40

Water 380.00 (Water-380,generated water-8.4,PTSA-2,Toluene-4)


(Organic impurities-20.4,IPA-4, Toluene-10)

Total 1382.80 Total 1382.80



Batch Size:100.0Kg



Atorvastatin Ester 132.00 Atorvastatin 106.40

Sulfuric Acid 2.40 Methanol Recovery 450.00



(Water-392.8,Sulfuric acid-2.4, Acetone-11.7,tert-butanol-14.9)



Total 1014.40 Total 1014.40

Material Balance of Atorvastain Calcium Stage-6

Batch Size:100Kg



Atorvastatin 106.40 Atorvastatin Calcium 100.00

Calcium Acetate 15.00 IPA Recovery 370.00

IPA 400.00 IPA Loss 20.00

Activated Carbon 2.00 Acetic Acid 11.40

Spent Carbon 2.00


(Organic impurities-10,IPA-10)



DOMPERIDONE


Stage-1

N-carbethoxy-4-piperidone is reacted with Hydrogen and Ammonia in the presence of

Raney nickel as catalyst and Methanol as solvent media to give stage-1 as product.

Stage-2

Stage-1 reacts with 2, 5-Dichloro nitrobenzene & Sodium Carbonate in presence of

Methanol as a solvent media to give Stage-2 as product.

Stage-3

Stage-2 reacts with Hydrogen in presence of Raney Nickel as catalyst and Toluene as

solvent media to give Stage-3 as product.

Stage-4

Stage-3 reacts with Urea in the presence of Sodium Hydroxide as a solvent media to

give Stage-4 as product.

Stage-5

Stage-4 undergoes hydrolysis with Sodium Hydroxide to give Stage-5 as product.

Stage-6

Stage-5 reacts with 1-(3-chloropropyl)-1, 3-dihydro-2H-benzimedazole-2-one and

Sodium Carbonate in the presence of Methyl Isobutyl Ketone as solvent media to give

Domperidone as product.


DOMPERIDONE

Route of synthesis:

Stage-1

N-Carbethoxy-4-piperidone

N

O

O O CH3

C8H13NO3

171.19

+ H2

Hydrogen

2.00

+ NH3

Ammonia

17.03

+ H2O

4-Amino-piperidine-1-carboxylic acid ethyl ester

N

NH2

O O CH3

18.00

C8H16N2O2

172.22

Raney Nickel

Stage-2

4-Amino-piperidine-1-carboxylic acid ethyl ester

N

NH2

O O CH3

C8H16N2O2

172.22

+

2,5-Dichloro Nitrobenzene

Cl

Cl

NO2

C6H3Cl2NO2

192.00

+ 1/2 Na2CO3

Sodium carbonate

1/2X105.98=52.99

N

HN

O O CH3

NO2

Cl

4-(4-Chloro-2-nitro-phenylamino)-piperidine-1-carboxylic acid ethyl ester

+

C14H18ClN3O4

327.76

NaCl

Sodium chloride

58.44

+ 1/2 H2O1/2 CO2

Carbon dioxide

1/2X44=22.00

+

1/2X18=9.00

Methanol


Stage-3

N

HN

O O CH3

NO2

Cl

4-(4-Chloro-2-nitro-phenylamino)-piperidine-1-carboxylic acid ethyl ester

C14H18ClN3O4

327.76

+ 3 H2

3X2=6.00

Hydrogen

N

HN

O O CH3

NH2

Cl

4-(2-Amino-4-chloro-phenylamino)-piperidine-1-carboxylic acid ethyl ester

C14H20ClN3O2

297.78

+ 2H2O

2X18=36.00

Raney Nickel

Toluene

Stage-4

N

HN

O O CH3

NH2

Cl

4-(2-Amino-4-chloro-phenylamino)-piperidine-1-carboxylic acid ethyl ester

C14H20ClN3O2

297.78

+

Urea

H2N

O

NH2

CH4N2O

60.05

N

O O CH3

N

HNCl

O

4-(5-Chloro-2-oxo-2,3-dihydro-enzoimidazol-1-yl)-piperidine-1-

carboxylic acid ethyl ester

C15H18ClN3O3

323.77

+ 2NH3

2X17.03=34.06

Ammonia

NaOH


Stage-5

N

O O CH3

N

HNCl

O

C15H18ClN3O3

323.77

+

Sodium hydroxide

NaOH

40.00

4-(5-Chloro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester

NH

N

HNCl

O

5-Chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one

+ C2H5ONa

Sodium ethoxide

68.05

+ CO2

Carbon dioxide

44.00

C12H14ClN3O

251.71


Stage-6

NH

N

HNCl

O

5-Chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one

C12H14ClN3O

251.71

+

1-(3-chloropropyl)-1,3-dihydro -2H-(Benzimidazole-2-one)

N

HN

O

Cl

C10H11ClN2O

210.66

+ 1/2Na2CO3

Sodium carbonate

NH

N

ON

NH

N

O Cl

425.91

Domperidone

C22H24ClN5O2

+ NaCl

Sodium chloride

58.44

+ 1/2 H2O +1/2 CO2

Carbon dioxideWater

1/2X44=22.001/2X18=9.00

1/2X105.98=52.99

MIBK


DOMPERIDONE

Flow Chart:

Stage-1

Stage-2

Stage-3

Stage- 4

Stage-5

Stage-6

N-Carbethoxy-4-piperidoneAmmonia gasMethanolRaney NickelHydrogen

Methanol Rec

Stage-12,5-Dichloro NitrobenzeneSodium CarbonateMethanol

Stage-2HydrogenRaney NickelToluene

Toluene Rec

Stage-3UreaSodium Hydroxide (48%)

Effluent water

Stage-4Sodium Hydroxide Effluent water

Stage-51-(3-Chloropropyl)-1,3-dihydro2H-benzimedazole-2-oneSodium CarbonateMethyl Isobutyl Ketone

MIBK Rec

DOMPERIDONE

Methanol Rec

Carbon dioxide

Effluent water


DOMPERIDONE

Material Balance:

Material Balance of Domperidone Stage-1

Batch Size:50Kg



N-Carbethoxy-4-piperidone 80.00 Stage-1 70.00

Ammonia gas 28.00 Methanol Recovery 283.00


Raney Nickel 20.00 Raney Nickel Reuse 20.00

Hydrogen 5.00 Generated water 8.40


(Organic Impurities-10.6,Methanol-2)


(Ammonia-20,Hydrogen-4)


Material Balance of Domperidone

Stage-2

Batch Size:50Kg

Name of the input Quantity

in Kg

Name of the out put Quantity

in Kg

Stage-1 70.00 Stage-2 95.00

2,5-Dichloro Nitrobenzene 78.00 Methanol Recovery 470.00

Sodium Carbonate 30.00 Methanol Loss 25.00

Methanol 500.00 Effluent Water 388.85

Water 350.00 (Water-350,generated water-

3.65,Sodium chloride-23.7,Sodium

carbonate-8.5,Methanol-3)


(Carbon dioxide)


(Organic Impurities-38.22,Methanol-

2)

Total 1028.00 Total 1028.00



Stage-3

Batch Size:50Kg


in Kg


in Kg

Stage-2 95.00 Stage-3 75.00

Hydrogen 5.00 Toluene Recovery 330.00

Raney Nickel 10.00 Toluene Loss 17.00

Toluene 350.00 Raney Nickel Reuse 10.00


(Water-200,generated water-10.43,

Toluene-1)


(Hydrogen)


(Organic Impurities-11.3,Toluene-2)



Stage-4

Batch Size:50Kg


in Kg


in Kg

Stage-3 75.00 Stage-4 67.00

Urea 20.00 Effluent Water 414.90

Sodium Hydroxide (48%) 60.00 (Water-350,Urea-4.9,Sodium

hydroxide-28.8,water from sodium

hydroxide-31.2)

Water 350.00 Process Emission 8.57

(Ammonia)





Stage-5

Batch Size:50Kg


in Kg


in Kg

Stage-4 67.00 Stage-5 45.00

Sodium Hydroxide 15.00 Effluent Water 320.70

Water 300.00 (Water-300,Sodium hydroxide-6.7,

Sodium ethoxide-14)


(Carbon dioxide)




Stage-6

Batch Size:50Kg


in Kg


in Kg

Stage-5 45.00 Domperidone 50.00

1-(3-Chloropropyl)-1,3-dihydro-

2H-benzimedazole-2-one

40.00 Methyl Isobutyl Ketone Recovery 1135.00

Sodium Carbonate 20.00 Methyl Isobutyl Ketone Loss 60.00

Methyl Isobutyl Ketone 1200.00 Effluent Water 424.50

Water 400.00 (Water-400,generated water-

1.6,Sodium chloride-10.4,Sodium

carbonate-10.5,MIBK-2)


(Carbon Dioxide)


(Organic Impurities-28.57,MIBK-3)

Total 1705.00 Total 1705.00



DULOXETINE HYDROCHLORIDE


Stage-1

N-Methyl N-Acetylamine-1-thiophen-2-naphthoxy propan Hydrochloride reacts with

Sodium Hydroxide in presence of Dimethyl Sulfoxide and Ethyl acetate as a solvent

media to give Stage-1 as a product.

Stage-2

Stage-1 undergoes Racemisation with Di-P-Tolyl-L-Tartaric acid in presence of

Methanol and acetone as a solvent media to give Stage-2 as a product.

Stage-3

Stage-2 reacts with Sodium Hydroxide in presence of MDC to give S-Duloxetine.This is

further reacts with Isopropyl Alcohol Hydrochloride in presence of Acetone as a solvent

media to give Duloxetine Hydrochloride as a product.




Route of synthesis:

Stage-1

S

O

N

O

O

HCl

CH3

N-Methyl N-Acetylamine-1-thiophen-2-naphthoxy propan Hydrochloride

C25H24ClNO3S

+ 2 NaOH

Sodium hydroxide

2X40=80.00

DMSOEthyl acetate

S

O

NH

CH3

R,S-Duloxetine

C18H19NOS

297.41

+

O

O

ONa

Sodium Perbonzoate

C7H5NaO3

160.10

+ NaCl

Sodium chloride

58.44

+ H2O

18.00

453.98



Stage-2

S

O

NH

CH3

R,S-Duloxetine

C18H19NOS

297.41

+

O

O

H3COHO

O

HO O

O

CH3

Di-P-Tolyl-L-Tartaric acid

C20H18O8

386.35

Methanol

S

O

NH

CH3

1/2

O

O

H3COHO

O

HO O

O

CH3

S-Duloxetine DPTTA Salt

C3H37NO9S

1/2X683.77=341.88

S

O

NH

CH3

1/2

O

O

H3COHO

O

HO O

O

CH3

R-Duloxetine DPTTA Salt

C3H37NO9S

1/2X683.77=341.88

+



Stage-3

Step-A

SO

NH

CH3

O

O

H3COHO

O

HO O

O

CH3

S-Duloxetine DPTTA Salt

C3H37NO9S

683.77

+ 2 NaOH

Sodium hydroxide

2X40=80.00

SO

NH

CH3

O

O

H3CONaO

O

NaO O

O

CH3+

S-Duloxetine Di-P-Tolyl Tartarate Sodium

C20H16Na2O8

430.32

+ 2 H2O

2X18=36.00

C18H19NOS

297.41

Methylene dichloride



Step-B

SO

NH

CH3

+

S-Duloxetine

C18H19NOS

297.41

Isopropyl alcohol Hydrochloride

CH3

CH3HO HCl

Acetone

SO

NH

CH3

HCl

CH3

CH3HO+

Duloxetine Hydrochloride

C18H20ClNOS

333.88

Isopropyl alcohol

C3H8O

60.10

C3H9ClO

96.56




Flow chart:

Stage-1262.00Kg

Effluent Water

Stage-2285.00Kg

Dimethyl Sulfoxide RecEthyl acetate Rec

Stage-3100.00Kg

Effluent Water

Acetone Rec

HCl

Acetone RecMethanol Rec

N-Methyl N-Acetylamine-1-thiophen-2-naphthoxy propan hydrochlorideSodium HydroxideDimethyl SulfoxideEthyl acetateWater

Stage-1R,S-DuloxetineDi-P-Tolyl-L-Tartaric acidMethanolAcetone

Stage-2Sodium HydroxideMethylene DichlorideAcetoneIsopropyl Alcohol HydrochlorideCarbonWater





Material Balance:

Material Balance of Duloxetine Hydrochloride

Stage-1 Batch Size: 100.0Kgs



N-Methyl N-Acetylamine-1-thiophen-2-naphthoxy propane Hydrochloride

380.00 Stage-1 240.00

Sodium hydroxide Solution (48%)

180.00 Di methyl Sulfoxide Recovery 950.00

Dimethyl Sulfoxide 1000.00 Di methyl sulfoxide Loss 30.00

Ethyl Acetate 600.00 Ethyl acetate Recovery 560.00

Water 650.00 Ethyl acetate Loss 30.00

Effluent water 970.53

(Water-650,Water from sodium hdyroxide-93.6,generated water-17.86, Sodium chloride-58.05, Sodium hydroxide-7.02, Sodium perbenzoate-134, DMSO-10)


(Organic Impurities-9.47,Ethyl acetate-10,DMSO-10)

Total 2810.00 Total 2810.00



Material Balance of Duloxetine Hydrochloride

Stage-2 Batch Size: 100.0Kgs



Stage-1 240.00 Stage-2 265.00

Di-P-Tolyl-L-Tartaric acid 320.00 Methanol Recovery 665.00


Acetone 600.00 Acetone Recovery 558.00

Acetone Loss 37.00

(R)-Duloxetine DPTTA Salt Recovered for reuse

265.00


(Organic Impurities-30.00, Methanol-10,Acetone-5)

Total 1860.00 Total 1860.00

Material Balance of Duloxetine Hydrochloride Stage-3

Batch Size: 100.0Kgs



Stage-2 265.00 Duloxetine Hydrochloride 100.00

Sodium Hydroxide 41.50 MDC Recovery 460.00

Methylene Dichloride 500.00 MDC Loss 30.00


Isopropyl Alcohol Hydrochloride

90.00 Acetone Loss 40.00

Carbon 10.00 IPA Recovery 67.00

Water 820.00 IPA Loss 3.50


(Water-820,Generated water-15,Di-p-Tolyl tartarate sodium-179.4,Sodium hydroxide-8.1, Acetone-20)

Spent carbon 10.00


(Hydrogen chloride)


(Organic Impurities-19.2,MDC-10,Acetone-10,IPA-1.5)

Total 2726.50 Total 2726.50





FLUCONAZOLE


Stage-1

1, 3-Difluorobenzene reacts with Chloroacetyl Chloride in the presence of Aluminum chloride

to get 2-Chloro-1-(2, 4-difluorophenyl) ethanone.

Stage-2

2-Chloro-1-(2,4-difluorophenyl) ethanone reacts with 1,2,4-triazole in the presence of Triethyl

amine and Ethyl Acetate as a Solvent media to get 1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)

ethanone.

Stage-3

1-(2, 4-difluorophenyl)-2-(1, 2, 4-triazol-1-yl) ethanone reacts with Tri methyl sulfoxonium

iodide in the presence of potassium hydroxide to get 1-[2-(2, 4-difluorophenyl)-2, 3-

epoxypropyl]-1H-1, 2, 4-Triazole

Stage-4

1-[2-(2, 4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-Triazole reacts with 1,2,4-triazole in the

presence of Potassium carbonate and Toluene solvent media to get Fluconazole Tech.

Finally Purified with Isopropyl Alcohol in the presence of Magnesium sulfate to get pure

Fluconazole



FLUCONAZOLE

Route of Synthesis:

Stage-1:

1,3-Difluorobenzene

F F

+

Chloroacetyl chloride

O

ClCl

F F

Cl

O

2-Chloro-1-(2,4-difluorophenyl)ethanone

AlCl3

C6H4F2

114.09

C2H2Cl2O

112.94

C8H5ClF2O

190.57

+ HCl

36.5

Stage-2:

F F

Cl

O

2-Chloro-1-(2,4-difluorophenyl)ethanone

C8H5ClF2O

190.57

1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)ethanone

N

N

N

F F

O

1,2,4-triazole

++ HCl

C2H3N3

69.07

C10H7F2N3O

223.18

36.46

TEANH

NN



Stage-3:

1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)ethanone

N

N

N

F F

O

C10H7F2N3O

223.18

+

Trimethyl sulfoxonium iodide

S+

O

H3C

CH3

CH3

I-

+ KOH

1-[2-(2,4-di fluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-Triazole

N N

N

O

F F

C3H9IOS

220.07

56.11

C11H9F2N3O

237.21

+ (CH3)2SO + KI + H2O

Dimethyl Sulfoxide

78.13

Potassium Iodide Water

166.0 18.0



Stage-4:

1-[2-(2,4-di fluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-Triazole

N N

N

O

F F

C11H9F2N3O

237.21

1,2,4-Triazole

NH

NN

C2H3N3

69.07

+ + K2CO3

OH

N

N

N

NN

N

F F

Fluconazole

C13H12F2N6O

306.27

138.21

+ 2 HCl

2X36.5=73.0

+ 2 KCl + H2O + CO2

2X74.55=149.1 18.0 44.0



FLUCONAZOLE

Flow Chart:

Stage-170.00Kg

Effluent Water

Stage-278.00Kg

MDC Rec

Stage-380.00Kg

Effluent Water

Stage-4100.00Kg

TolueneRec

Effluent water

DMF RecIPA Rec

1,3 Difluoro benzeneChloro Acetyl chlorideAluminium ChlorideMDCDM Water

Stage-11,2,4-triazoleTriethyl AmineEthyl AcetateWater

Ethyl acetate Rec

Effluent Water

Stage-2Tri methyl Sulfoxonium iodidePotassium HydroxideTolueneWaterStage-31,2,4-TriazoleCetyl tri methyl Ammonium BromidePotassium carbonateDMFHydrochloric AcidMagnesium SulfateIPADM Water

FLUCONAZOLE

CO2



FLUCONAZOLE

Material Balance:

Material Balance of Fluconazole

Stage-1

Batch Size: 100Kg


in Kg


in Kg

1,3 Difluoro benzene 50.00 Stage-1 70.00

Chloro Acetyl chloride 49.50 MDC Recovery 760.00

Aluminium Chloride 15.00 MDC Loss 35.00

MDC 800.00 Effluent Water 431.00

DM Water 400.00 (Water-400,Hydrochloric Acid-16,

Aluminium chloride-15)


(Organic impurities-13.50,MDC-5)

Total 1314.50 Total 1314.50


Stage-2

Batch Size: 100Kg


in Kg


in Kg

Stage-1 70.00 Stage-2 78.00

1,2,4-triazole 26.00 Ethyl Acetate Recovery 665.00

Triethyl Amine 37.00 Ethyl Acetate Loss 30.00

Ethyl Acetate 700.00 Effluent Water 350.40

Water 300.00 (Water-300,Triethyl Amine

hydrochloride-50.4)


(Organic Impurities-4.60,Ethyl

Acetate-5)

Total 1133.00 Total 1133.00




Stage-3

Batch Size: 100Kg


in Kg


in Kg

Stage-2 78.00 Stage-3 80.00

Tri methyl Sulfoxonium iodide 78.00 Toluene Recovery 760.00

Potassium Hydroxide 20.00 Toluene Loss 20.00


Water 550.00 (Water-550,generated water-6.28,

Potassium iodide-58,DMSO-27.3,

Toluene-10)


(Organic Impurities-4.42, Toluene-

10)

Total 1526.00 Total 1526.00




Stage-4

Batch Size: 100Kg


in Kg


in Kg

Stage-3 80.00 Fluconazole 100.00

1,2,4-Triazole 24.00 DMF Recovery 712.50

Cetyl tri methyl Ammonium

Bromide

10.00 DMF Loss

22.00

Potassium carbonate 47.00 IPA Recovery 450.00

DMF 750.00 IPA Loss 40.00

Hydrochloric Acid 25.00 Effluent Water 624.36

Magnesium Sulfate 5.00 (Water-550,generated water-6.16,

Potassium chloride-50.7,

Magnesium sulfate-5,DMF-

7.5,IPA-5)

IPA 500.00 Spent Carbon 10.00

Activated Carbon 10.00 Organic Residue 27.18

DM Water 550.00 (Organic Impurities-14.18,DMF-

8,IPA-5)


(Carbon dioxide)

Total 2001.00 Total 2001.00



LANSOPRAZOLE

Process Description

Stage-1

2, 3-Lutidine oxidized with Hydrogen Peroxide in the Presence of Acetic acid and

subsequently on Nitration with Nitric Acid, Sulfuric Acid to produces stage-1.

Stage-2

Stage-1 Product reacts with 2, 2, 2- tri fluoro ethanol and Sodium hydroxide to give

Stage-2A reaction mass. Reaction Mass (Stage-2A) reacts with Acetic Anhydride in

presence of Acetic Acid, an intermediate is formed. Further it is treated with dry

hydrochloric acid and Sodium hydroxide to give stage-2 Compound.

Stage-3

Above compound Chlorinated with Thionyl chloride in presence of Toluene solvent

media to give stage-3 Chloro compound

Stage-4

Stage-3 Condensed with 2-Mercapto benzimidazole in Presence of Sodium Hydroxide

and Toluene solvent media to give Stage-4 Compound.

Stage-5

Stage-4 Compound reacts with Hydrogen peroxide in presence of IPA produces

Pharma. The product is further purified with carbon and Water to get pure compound of

Lansoprazole.



LANSOPRAZOLE

Route of Synthesis:

Stage-1:

N

CH3

CH3

2,3-Lutidine

107.00

+ H2O2

Hydrogen peroxide

34.00

+ HNO3

Nitric acid

63.00

N

NO2

CH3

CH3

O

+ 2

4-Nitro-2,3-Dimethyl pyridine-N-Oxide

168.00

Water

36.0

H2O

C7H9N C7H8N2O3

Stage-2:

N

NO2

CH3

CH3

O

+

4-Nitro-2,3-Dimethyl pyridine-N-Oxide

168.00

CF3CH2OH + K2CO3 + (CH3CO)2O + NaoH + HCl

Trifluoro ethanol

Potassium carbonate

Acetic anhydride

Sodium hydroxide

Hydrogen chloride

100 138 102 40 36.5

N

OCH2CF3

CH3

CH2OH

. HCl

2-Hydroxy methyl-3-methyl pyridine hydrochloride

257.5

+ KHCO3

Potassium bicarbonate

100

+ KNO2

Potassium nitrite

85

+ CH3COONa

Sodium acetate

82

+ CH3COOH

Acetic acid

60

C7H8N2O3

C9H11ClF3NO2



Stage-3:

N

OCH2CF3

CH3

CH2OH

. HCl

2-Hydroxy methyl-3-methyl pyridine hydrochloride

257.5

+ SOCl2

Thionyl chloride

119

N

OCH2CF3

CH3

CH2Cl

. HCl

2-Chloromethyl-3-methyl pyridine hydrochloride

276

+ SO2

64

+ HCl

36.5

C9H11ClF3NO2C9H10Cl2F3NO

Stage-4:

N

OCH2CF3

CH3

CH2Cl

. HCl

2-Chloromethyl-3-methyl pyridine hydrochloride

276

+N

HN

HS + 2 NaoH

2-Mercapto benzimidazole

Sodium hydroxide

2x40=80.0

150

N

OCH2CF3

CH3

CH2 SN

HN

2[4-(2,2,2-Tri fluoro ethoxy)-3-methylpyridinyl]methyl thio]-1H-Benzimidazole

+ 2 NaCl

Sodium chloride

2x58.5=117.0

+ 2H2O

Water

36.0

C9H10Cl2F3NO C7H6N2S

C16H14F3N3OS

353.0



Stage-5:

N

OCH2CF3

CH3

CH2 S

N

HN

2[4-(2,2,2-Tri fluoro ethoxy)-3-methylpyridinyl]methyl thio]-1H-Benzimidazole

353

+ H2O2

Hydrogen peroxide

34

N

OCH2CF3

CH3

CH2 S

N

HN

O

Lansoprazole

369

+ H2O

Water

18

C16H14F3N3OS

C16H14F3N3O2S



LANSOPRAZOLE

Flow Chart:

Stage-166.00Kg

Effluent Water

Stage-269.80Kg

Acwtic acid Rec

Stage-374.80Kg

Effluent Water

Stage-495.70Kg

Effluent water

Toluene RecMIBK RecAcetic Anhydride Rec

Effluent Water

2,3-LutidineAcetic AcidHydrogen Peroxide (33%)Sulfuric AcidNitric AcidWater

SO2

Stage-1Sodium HydroxidePotassium CarbonateTri Fluoro EthanolMIBKAcetic AnhydrideTolueneHydrochloric acid (33%)Activated CarbonWaterStage-2Thionyl ChlorideMethylene DichlorideTolueneWater

Methylene Dichloride RecToluene Rec

Stage-3Sodium Hydroxide2-Mercapto BenzimidazoleWater

Stage-5100.00Kg

Effluent water

Stage-4Isopropyl AlcoholHydrogen Peroxide (33%)CatalystAcetoneSodium HydroxideWater

Isopropyl Alcohol RecAcetone Rec

LANSOPRAZOLE



LANSOPRAZOLE

Material Balance:

Material Balance of Lansoprazole Stage-1

Batch Size:100Kg



2,3-Lutidine 42.00 Stage-1 66.00

Acetic Acid 40.00 Acetic acid Recovery 40.00

Hydrogen Peroxide (33%) 45.00 Effluent water 595.70

Sulfuric Acid 50.00 (Water-500,Generated water-14.1,Hydrogen peroxide-1.4, Sulfuric acid-50,Water from hydrogen peroxide-30.2)

Nitric Acid 24.70

Water 500.00




Material Balance of Lansoprazole Stage-2

Batch Size:100Kg



Stage-1 66.00 Stage-2 69.80

Sodium Hydroxide 10.95 MIBK Recovery 225.00

Potassium Carbonate 37.80 MIBK Loss 5.00

Tri Fluoro Ethanol 27.50 Toluene Recovery 475.00

MIBK 236.00 Toluene Loss 5.00

Acetic Anhydride 136.00 Acetic Anhydride Recovery 102.10

TBAB 1.20 Acetic Anhydride Loss 6.00


Hydrochloric acid (33%) 30.30 (Water-350, Water from hydrochloric acid-20.4,Potassium bicarbonate-27.3,Potassium nitrite-23.2,Sodium acetate-22.4,Acetic acid-16.42, TBAB-1.2,Toluene-7.5)

Activated Carbon 3.00 Organic Residue 39.43

Water 350.00 (Organic Impurities-20.93,Toluene-12.5,MIBK-6,)

Spent Carbon 3.00

Total 1398.75 Total 1398.75



Material Balance of Lansoprazole

Stage-3

Batch Size:100Kg


in Kg


in Kg

Stage-2 69.80 Stage-3 74.80

Thionyl Chloride 32.25 Toluene Recovery 285.00

Methylene Dichloride 300.00 Toluene Loss 4.50

Toluene 300.00 MDC Recovery 270.00

Water 500.00 MDC Loss 15.00


(Water-500, Toluene-4.5)


(Sulfur dioxide-17.34,Hydrogen

chloride-9.9)


(Organic Impurities-0.01,Toluene-

6,MDC-15)

Total 1202.05 Total 1202.05


Stage-4

Batch Size:100Kg


in Kg


in Kg

Stage-3 74.80 Stage-4 95.70


2-Mercapto Benzimidazole 40.60 (Water-300,Generated water-

9.8,Sodium chloride-31.6)

Water 300.00





Stage-5

Batch Size:100Kg


in Kg


in Kg

Stage-4 95.70 Lansoprazole Pharma 100.00

Isopropyl Alcohol 220.00 Isopropyl Alcohol Recovery 198.00

Hydrogen Peroxide (33%) 28.00 Isopropyl Alcohol Loss 13.00

Catalyst 0.20 Chloroform Recovery 220.00

Chloroform 240.00 Chloroform Loss 12.00


Sodium Hydroxide 4.00 Acetone Loss 2.00


(Water-300,Generated water-

4.87,Water from Hydrogen peroxide-

18.8,Sodium hydroxide-4,Acetone-

2,IPA-3.5)


(Organic Impurities-0.23,Acetone-

6,Chloroform-8,IPA-5.5)

Total 1087.90 Total 1087.90


LOSARTAN POTASSIUM


Stage-1

OTBN and Sodium nitrate are made to react together in Toluene solvent medium

using TEA HCl as catalyst. Product is isolated by using Hydrochloric acid.

Stage-2

The Above stage-1 material is treated with Trityl chloride. Methylene dichloride is

used as solvent. Product is washed with water and crystallized in Methanol

Stage-3

Stage-2 is dissolved in Methylene dichloride and treated with a mixture of AIBN and

DDH. Methylene dichloride is distilled-off to obtain the product. Finally the product is

treated with Sodium Metabisulhite solution. The product is washed with Ethyl acetate

while centrifuging.

Stage-4

Stage-3 mass is dissolved in sodium borohidride solution. Butyl chloro formyl

imidazole(BCFI) , TBAB are made to react with stage-III solution. Finally stage-III

product is purified with Carbon and water

Stage-5

Stage-4 mass is dissolved in IPA and HCL mixture. The mass is isolated by

precipitated with water. The reaction mass pH is adjusted with Sodium hydroxide to

get the Losartan Base.

Stage-6

The stage-5 mass is treated with Potassium hydroxide in Methanol solvent medium.

Product is purified with Carbon. Pharma is isolated by distilling of Methanol.

LOSARTAN POTASSIUM


Route of Synthesis:

Stage-1

CH3

N

2-Cyano-4-Methyl biphenyl

C14H12NMol. Wt.: 193.24

Na+N-N+-N

Sodium azide

N3NaMol. Wt.: 65.01

Toluene,TEA HCl

HN

N N

N

CH3

5-[(4-Methylbiphenyl)-yl]-tetrazole

C14H12N4

Mol. Wt.: 236.74

+2 NaCl

Sodium Chloride

Mol. Wt.:117

+ +

Hydrochloric acid

Mol. Wt.: 73

2 HCl

+

NaNo2

SodiumNitrite

Mol. Wt.69

+N2

Nitrogen

Mol. Wt.:28

+

H2O

Mol. Wt.18

Stage-2

HN

N N

N

CH3 +

5-[(4-Methylbiphenyl)-yl]-tetrazole

C14H12N4

Mol. Wt.: 236.74

Cl

Trityl chloride

C19H15ClMol. Wt.: 278.78

TEA,MDC

Methaol

HN N

NN

H3C

5-(4-methyl biphenyl-yl)-trityltetrazole

C33H26N4

Mol. Wt.: 478.59

+ HCl

Hydrochloric acid

Mol. Wt.: 36.5


Stage-3

HN N

NN

H3C

5-(4-methyl biphenyl-yl)-trityltetrazole

C33H26N4

Mol. Wt.: 478.59

N

N

O

OCH3

H3C

Br

Br

1,3-Dibromo-5,5-dimethyl-imidazolidine-2,4-dione

C5H6Br2N2O2

Mol. Wt.: 288

+

HN N

NN

BrH2C

5-[(4'-Bromomethyl-[1,1';2',1'']terphenyl-3''-yl)-diphenyl-methyl]

-1H-tetrazole

C33H25BrN4

Mol. Wt.: 557.48

+

+ HBr

Hydrobromic acid

Mol. Wt.:81

N

NH

O

OCH3

H3C

H

C5H8N2O2

Mol. Wt.: 128.13

5,5-Dimethyl-imidazolidine-

2,4-dione

Stage-4

HN N

NN

BrH2C

5-[(4'-Bromomethyl-[1,1';2',1'']terphenyl-3''-yl)

-diphenyl-methyl]-1H-tetrazoleC33H25BrN4

Mol. Wt.: 557.48

+TBAB,MeoH

Water,Sodium borohydride

Stage-IV

C41H36ClN6OMol. Wt.: 663.5

+ HBr

Hydrobromicacid

Mol. Wt.: 81

N

HN

C

OCl

H3C

butylchloroformyl imidazole


NHN

NN

N

N

C

O

Cl

H3C


Stage-5

NHNN

N

N

N

C

OCl

H3C

Stage-IVC41H36ClN6O

Mol. Wt.: 663.5

Sodium hydroxide

OH Cl

N

CH3N

NN

N NH

losartan


IPA+ HCl+

C•

trityl

C19H13•+

Mol. Wt.: 241

+

Stage-6

OH Cl

N

CH3N

NN

N NH

losartan


KOH+MeOH

K

HO

Cl

N

H3C

NN

NN

HN

Losartan Potassium

C22H22ClKN6OMol. Wt.: 460.5

+ H2O

Mol. Wt.: 18PotassiumHydroxide

Mol. Wt.: 56


LOSARTAN POTASSIUM

Flow-Chart:

2-Cyano-4-Methyl biphenyl Sodium AzideTEA HClHydrochloric acidToluene

Stage-1 Toluene Rec

Stage-2 MDC Rec

Stage-1TritylchlorideTEAMDC

Stage-3 MDC Rec

Stage-21,3-Dibromo-5,5-dimethyl-imidazolidine-2,4-dioneSodium metabishlphiteMDC

Stage-4 Methanol Rec

Stage-3Butylchloroformyl imidazole(BCFI)TBABMethanol

Stage-5 IPA RecStage-4Hydrochloric acidIsoPropyl alcohol

Stage-6 Methanol Rec

Stage-5Caustic PotashMethanol

LOSARTAN POTASSIUM


LOSARTAN POTASSIUM

Material Balance:

Material balance of Losartan potassium Stage-1

Batch Size:100kg



2-Cyano-4-Methyl biphenyl (OTBN)

50.00 Stage-1 55.00

Sodium Azide 16.82 Toluene Recovery 370.00

TEA HCl 35.63 Toluene Loss 20.00

Hydrochloric acid 19.00 Effluent water 380.54

Sodium nitrite 17.85 (Water-300,gen.water-4.65, Sodium Chloride-30.26,TEA HCl-35.63,Toluene-10)

Toluene 400.00 Organic Residue 10.14


(Nitrogen)



Batch Size:100kg



Stage-1 55.00 Stage-2 105.00

Trityl chloride 65.00 MDC Recovery 380.00

TEA 23.50 MDC Loss 20.00

MDC 400.00 Methanol Recovery 90.00


Water 300.00 Waste Water 337.00

(Water-300,TEA-23.5,HCl-8.5,Methanol-5)





Batch Size:100kg



Stage-2 105.00 Stage-3 122.30

1,3-Dibromo-5,5-dimethyl-(DDH) imidazolidine-2,4-dione

63.20 MDC Recovery 380.00

Sodium metabishlphite 2.00 MDC Loss 20.00


Water 300.00 (Water-300,Hydrobromide-17.8,Sodium metabisulfite-2)

Organic Solid Waste 28.10

(5,5-Dimethyl-imidazolidine- 2,4-dione)



Batch Size:100kg



Stage-3 122.30 Stage-4 145.00

Butylchloroformyl imidazole(BCFI)

41.20 Methanol Recovery 755.00

TBAB 5.00 Methanol Loss 30.00

Methanol 800.00 Effluent Water 337.80

Water 300.00 (Water-300,HBr-17.8,TBAB-5,Methanol-15)


Total 1268.50 Total 1268.50



Batch Size:100kg



Stage-4 145.80 Stage-5 92.00

Hydrochloric acid 8.00 IPA Recovery 660.00

IsoPropyl alcohol 700.00 IPA Loss 35.00


Water 400.00 (Water-400,gen.water-3.7, Sodium Chloride-12.7, IPA-5)


(Trityl)

Total 1262.30 Total 1262.30

Material balance of Losartan potassium Stage-6:Pharma Batch Size:100kg



Stage-5 92.00 Losartan potassium 100.00

Caustic Potash 12.20 Methanol Recovery 370.00


Activated Carbon 15.00 Effluent Water 213.90

Water 200.00 (Water-200,gen.water-3.9, Methanol-10)

Spent Carbon 15.00





PANTOPRAZOLE SODIUM

Process Description

Stage-1

Maltol and Dimethyl sulphate condense in Acetone solvent medium. Excess Dimethyl sulphate

is removed by treating the reaction mass with Potassium Carbonate.

Stage-2

Stage-1 compound on treating with Liquor Ammonia solution to give stage-2 as product.

Stage-3

Stage-2 compound on reaction with Phosphorous oxy chloride produces stage-3 compound.

Further reaction is stopped by treating the reaction mass with water. Final product is extracted

with MDC and after distilling out MDC compound is obtained.

Stage-4

Stage-3 compound reacts with Hydrogen peroxide in presence of Acetic acid & Methanol,

stage-4 compound is obtained.

Stage-5

Stage-4 compound reacts with sodium hydroxide in presence of Methanol to produces stage-5

compound.

Stage-6

Above stage-5 compound on reaction with Acetic anhydride produces an intermediate.MDC

used as solvent. Product is precipitated with C.S. Flakes.

Stage-7

Stage-6 compound when reacts with Thionyl chloride an intermediate is formed.MDC is used

as solvent. Product is crystallized in Methanol. Finally product is purified with Acetone.

Stage-8

When 2-Chloromethyl-3, 4-dimethoxy-pyridine Hydrochloride reacts with 5-diFluoro methoxy-2-

mercapto-benzimidazole, in presence of Sodium hydroxide, product is formed. Mythylene

dichloride is the solvent.

Stage-9

Stage-8 is treated with Sodium hypochlorite in presence of Sodium hydroxide, to produce the

Pantoprazole sodium .This is purified in Acetone. Methylene dichloride is used as solvent.

PANTOPRAZOLE SODIUM



Route of Synthesis:

Stage-1

O

O

OH

CH3

Maltol

C6H6O3

2X126.11=252.22

Dimethyl sulphate

(CH3)2SO4

126.13

K2CO3

138.21

Acetone

O

O

OCH3

CH3

Stage-1

C7H8O3

2x140.14=280.28

K2SO4

174.26

CO2

44.0

+ + +

+ + H2O

18.0

2 2

Stage-2

O

O

OCH3

CH3

Stage-1

C7H8O3

140.14

(NH4)2CO3

Ammonium carbonate

96.0

NH

O

OCH3

CH3

Stage-2

C7H9NO2

139.15

+ + NH4OH + CO2 + H2O

35.0 44.0 18.0

Stage-3



NH

O

OCH3

CH3

Stage-2

C7H9NO2

3X139.15=417.45

+ POCl3

Phosphorous oxychloride

153.33

MDC

waterN

Cl

OCH3

CH3

Stage-3

C7H8ClNO

3X157.60=472.8

+ H3PO4

Phosphoric Acid

98.0

3 3

Stage-4

N

Cl

OCH3

CH3

Stage-3

C7H8ClNO

157.60

+ H2O2

Hydrogen peroxide

34.01

MeOH

Acetic acidN

Cl

OCH3

CH3

O

Stage-4

C7H8ClNO

173.60

+ H2O

18.0



Stage-5

N

Cl

OCH3

CH3

O

Stage-4

C7H8ClNO

173.60

+ CH3OH + NaOHMeOH

32.0 40.0

N

OCH3

OCH3

CH3

O

Stage-5

C8H11NO3

169.18

+ NaCl

58.5

+ H2O

18.0

Stage-6

Step-A

N

OCH3

OCH3

CH3

O

Stage-5

C8H11NO3

169.18

+ (CH3CO)2O

Acetic anhydride

102.09

MDC

N

OCH3

OCH3

CH2OCOCH3

Stage-6

C10H13NO4

211.21

+ CH3COOH

Acetic acid

60.0



Step-B

N

OCH3

OCH3

CH2OCOCH3

Stage-6A

C10H13NO4

211.21

+ NaOHMDC

N

OCH3

OCH3

CH2OH

Stage-6B

C8H11NO3

169.18

+ CH3COONa

Sodium acetate

82.03

Sodium hydroxide

40.0

Stage-7

N

OCH3

OCH3

CH2OH

Stage-6B

C8H11NO3

169.18

+ SOCl2

Thionyl chloride

118.97

MDC,MeOH

N

OCH3

OCH3

CH2Cl

HCl

Stage-7

C8H10ClNO2.HCl

224.12

+ SO2

Sulphur dioxide

64.0



Stage-8

N

OCH3

OCH3

CH2Cl

HCl

Stage-7

C8H10ClNO2.HCl

224.12

+

NHN

O

F

F

SH

5-Difluoromethoxy-2-mercaptobenzimidazole

C8H6F2N2OS

216.21

+ NaOHMDC

Sodium hydroxide

2x40.0=80

N

OCH3

OCH3

CH2 S

N

HN

O

F

FStage-8

C16H15F2N3O3S

367.37

+ NaCl + H2O

Sodium chloride

2x58.5=117

Water

2x18.0=36

2

2 2



Stage-9

N

OCH3

OCH3

CH2 S

N

HN

O

F

FStage-8

C16H15F2N3O3S

367.37

+ NaOCl + NaOHMDC

Acetone

N

OCH3

OCH3

CH2 S

N

N

O

F

F

O

+ NaCl +

Na

H2O

Pantoprazole sodium

C16H14F2N3NaO4S

405.35

Sodium chloride

58.5

Water

18.0

Sodium hypochlorite

74.44

Sodium hydroxide

40.0

PANTOPRAZOLE SODIUM



Flow Chart:

Stage-185.00Kg

Stage-275.00Kg

Acetone Rec

Stage-370.00Kg

Effluent Water

Stage-465.00Kg

Effluent water

Tolulene Rec

Effluent Water

MDC Rec

Stage-560.00Kg

Effluent water

Methanol Rec

CO2

MaltolDimethyl sulphatePotassium carbonateAcetone

Stage-1Ammonium CarbonateTolueneWater

CO2Stage-2Phosphorous oxy chlorideSodium HydroxideMethylenedichlorideWaterStage-3Hydrogen peroxide (30%)Acetic acidMethanolSodium Hydroxide MDCWater

Methanol RecMDC Rec

Stage-4MethanolSodium HydroxideAcetic AcidWater

Stage-655.00Kg

Effluent Water

Stage-765.00Kg

Chloroform + Acetic Anhydride Recovery

Stage-895.00Kg

Effluent water

Toluene Rec

Methanol RecMDC Rec

Stage-5Acetic AnhydrideChloroformSodium hydroxideWater

Stage-6Thionyl chlorideMethylenedichlorideMethanolAcetone

SO2

Stage-75-diFluoromethoxy-2-mercapto-benzimidazoleSodium Hydroxide flakesTolueneWater

Stage-8Sodium hypochlorite (4%)Sodium Hydroxide flakesAmmonium Chloride Methylene dichlorideActivated CarbonAcetoneWater

Stage-9100.00Kg

Effluent water

Acetone RecMDC Rec

PANTOPRAZOLE SODIUM



PANTOPRAZOLE SODIUM

Material Balance:

Material Balance of Pantoprazole Sodium Stage-1

Batch Size: 100 Kg


Name of the output Quantity in Kg

Maltol 85.00 Stage-1 85.00

Dimethyl sulphate 45.00 Acetone Recovery 475.00

Potassium carbonate 46.50 Acetone Loss 15.00

Acetone 500.00 Generated water 6.00

Inorganic Solid Waste 58.80

(Potassium Sulphate-58.8)


(Organic Impurities-11.7, Acetone-10)


(Carbon dioxide)



Batch Size: 100Kg



Stage-1 85.00 Stage-2 75.00

Ammonium Carbonate 65.00 Toluene Recovery 280.00



(Water-400,Ammonium hydroxide-21.2,Ammonium carbonate-6.7,generated water-10.9,Toluene-2)


(Organic Impurities-9.48, Toluene-3)


(Carbon dioxide)





Batch Size: 100Kg



Stage-2 75.00 Stage-3 70.00

Phosphorous oxy chloride 35.00 MDC Recovery 280.00

Sodium Hydroxide 30.00 MDC Loss 15.00

Methylenedichloride 300.00 Effluent Water 480.00

Water 425.00 (Water-425,Phosphoric acid-18,Phosphorus oxychloride-7, Sodium hydroxide-30)


(Organic Impurities-15,MDC-5)



Batch Size: 100Kg



Stage-3 70.00 Stage-4 65.00

Hydrogen peroxide (30%) 50.00 MDC Recovery 668.00

Acetic acid 35.00 MDC Loss 30.00


Sodium Hydroxide 20.00 Methanol Loss 12.50


Water 300.00 (Water-300,Sodium Acetate-41,Acetic Acid-5,generated water-17.6,water from hydrogen peroxide-35, Methanol-2.5)


(Organic Impurities-11.4,MDC-2,Methanol-2)

Total 1425.00 Total 1425.00




Batch Size: 100 Kg



Stage-4 65.00 Stage-5 60.00


Sodium Hydroxide 31.00 Methanol Loss 20.00

Acetic Acid 10.00 Effluent Water 451.45

Water 400.00 (Water-400,gen.water-9.85, Sodium Chloride-22,Sodium Acetate-13.6,Methanol-6)


(organic Impurities-0.55,Methanol-9)

Total 1006.00 Total 1006.00


Batch Size: 100Kg



Stage-5 60.00 Stage-6 55.00

Acetic Anhydride 45.00 Chloroform + Acetic Anhydride Recovery

198.80

Chloroform 200.00 Chloroform Loss 10.00

Sodium hydroxide 20.00 Effluent Water 355.00

Water 300.00 (Water-300,Acetic Acid-21.3, Sodium hydroxide-7,Sodium Acetate-26.7)






Batch Size: 100Kg



Stage-6 55.00 Stage-7 65.00

Thionyl chloride 39.00 MDC Recovery 810.00

Methylenedichloride 850.00 MDC Loss 40.00


Acetone 200.00 Methanol Loss 25.00

Acetone Recovery 189.00

Acetone Loss 10.00


(Sulphur Dioxide)


(Organic Impurities-8, Methanol-1,Acetone-1)

Total 1269.00 Total 1269.00


Batch Size: 100Kg



Stage-7 65.00 Stage-8 95.00

5-diFluoromethoxy-2-mercaptobenzimidazole

70.00 Toluene Recovery 475.00

Sodium Hydroxide flakes 25.00 Toluene Loss 10.00


Water 400.00 (Water-400,Sodium Chloride-34,gen.Water-10.4, Sodium hydroxide-1.8, Toluene-7.5)


(Organic Impurities-18.8, Toluene-7.5)

Total 1060.00 Total 1060.00



Material Balance of Pantoprazole Sodium Stage-9:Pharma

Batch Size: 100Kg



Stage-8 95.00 Pantoprazole Sodium 100.00

Sodium hypochlorite (4%) 500.00 MDC Recovery 950.00

Sodium Hydroxide flakes 12.00 MDC Loss 40.00

Ammonium Chloride 25.00 Acetone Recovery 380.00

Methylene dichloride 1000.00 Acetone Loss 8.00

Activated Carbon 10.00 Effluent Water 1330.85

Acetone 400.00 (Water-800,gen.water-4.65, Sodium chloride-15.2,water from sodium hypochlorite-480, Aluminum chloride-25, Acetone-6

Water 800.00 Spent carbon 10.00


(Organic impurities-7.15,MDC-10,Acetone-6)

Total 2842.00 Total 2842.00



RABEPRAZOLE SODIUM

Process Description

Stage-1

2, 3-Lutidine is reacted with Hydrogen Peroxide in presence of Acetic Acid to give N-Oxide it

further reacts with Nitration mixture (Nitric Acid + Sulfuric Acid) to give Stage-1

Stage-2

Stage-1 is reacted with 3-Methoxy-1-Propanol and Sodium Hydroxide to get Stage-2

Compound

Stage-3

Stage-2 Compound is reacted with Acetic Anhydride, Sodium Hydroxide and Hydrochloric Acid to get Stage-3 Compound

Stage-4

Stage-3 Compound is reacted with Thionyl Chloride in presence of MDC as a solvent media to

give as stage-4 as product.

Stage-5

Stage-4 Compound is reacted with 2Mercapto benzimidazole and sodium hydroxide in the

presence of Toluene as a solvent media to give stage-5 as product.

Stage-6

Stage-5 reacts with Sodium Hypochlorite to get Rabeprazole Base.

Stage-7

Stage-6 reacts with Sodium hydroxide to get Rabeprazole Sodium.



RABEPRAZOLE SODIUM

Route of Synthesis:

Stage-1:

N

CH3

CH3

2,3-Lutidine

C7H9N

107.15

+ H2O2

Hydrogen peroxide

34.01

+ HNO3

Niric acid

63.0

H2SO4

N

CH3

CH3

+

O

NO2

C7H8N2O3

168.15

2H2O

36.04-Nitro-2,3-Dimethyl pyridine-N-oxide

Stage-2:

N

CH3

CH3

O

NO2

C7H8N2O3

168.15

4-Nitro-2,3-Dimethyl pyridine-N-oxide

3-Methoxy-1-Propanol

HO O

4(3-Methoxy propoxy)-2,3-Dimethyl pyridine-N-oxide

N+

O-

H3C

H3C

O O

+ NaOH+

C4H10O2

90.12

C11H17NO3

211.26

+ NaNO2 + H2O

Sodium Nitrite

69.0

18.0

40.0



Stage-3:

4(3-Methoxy propoxy)-2,3-Dimethyl pyridine-N-oxide

N+

O-

H3C

H3C

O O

C11H17NO3

211.26

+ (CH3CO)2O + NaOH

4(3-methoxy propoxy)-2-hydroxy methyl -3-methyl pyridine hydrochloride

N

O O

HO

+ CH3COONa + CH3COOH

82.0 60.0

AceticAnhydride

102.0

40.0

C11H17NO3 HCl

H

Cl

247.72

+ HCl

36.5

Stage-4:

4(3-methoxy propoxy)-2-hydroxy methyl -3-methyl pyridine hydrochloride

N

O O

HO

C11H17NO3 HCl

H

Cl

247.72

+ SOCl2

N

O O

Cl

4-(3-methoxy-propoxy)-2-Chloromethyl-3-methyl-pyridine

ThionylChloride

118.97 C11H16ClNO2

229.7

+ SO2 + 2 HCl

64.0 2X36.5=73



Stage-5:

N

O O

Cl

4-(3-methoxy-propoxy)-2-Chloromethyl-3-methyl-pyridine

C11H16ClNO2

229.7

2-Mercapto benzimidazole

N

HN

HS+ +

40.0

NCH2

O O

N

NH

S

2-[4-(3-Methoxy-propoxy)-3-methyl-pyridin-2-ylmethylsulfanyl]-1H-benzoimidazole

NaOH

C18H21N3O2S

343.44

+ NaCl + H2O

58.5 18.0

C7H6N2S

150.25



Stage-6:

NCH2

O O

N

NH

S

2-[4-(3-Methoxy-propoxy)-3-methyl-pyridin-2-ylmethylsulfanyl]-1H-benzoimidazole

C18H21N3O2S

343.44

+ NaOCl NCH2

O O

N

NH

S

O

SodiumHypochlorite

2-[4-(3-Methoxy-propoxy)-3-methyl-pyridin-2-ylmethanesulfinyl]-1H-benzoimidazole

C18H21N3O3S

359.44

+ NaCl

58.5

74.44

Stage-7:

NCH2

O O

N

NH

S

O

2-[4-(3-Methoxy-propoxy)-3-methyl-pyridin-2-ylmethanesulfinyl]-1H-benzoimidazole

C18H21N3O3S

359.44

+ NaOH NCH

O O

N

NH

S

O

Na

Rabeprazole Sodium40.0

+ H2O

18.0

C18H20N3NaO3S

381.42



RABEPRAZOLE SODIUM

Flow Chart:

Stage-165.00Kg

Stage-280.00Kg

Stage-390.00Kg

Effluent Water

Stage-480.00Kg

Effluent water

Tolulene RecDMSO Rec

Acetic anhydride RecToluene Rec

Stage-5100.00Kg

Effluent water

Toluene Rec

MDC Rec

Stage-6100.00Kg

Effluent Water

Stage-7100.00Kg

MDC RecAcetone Rec

IPA Rec

2,3-LutidineHydrogen Peroxide (50%)Nitric acidSulphuric acidAcetic acidWater

Effluent Water

Stage-13-Methoxy-1-PropanolSodium HydroxideTolueneDMSO

Stage-2Acetic anhydrideSodium HydroxideHydrochloric acidTolueneWaterStage-3Thionyl ChlorideMDCSodium SulphateWater

Stage-42-MercaptobenzimidazoleSodium hydroxideTolueneWaterStage-5Sodium Hypochlorite (8%)MDCAcetoneSodium hydro sulphateMMA in MethanolWaterStage-6Sodium HydroxideIsopropyl AlcoholActivated Carbon

Spent Carbon

RABEPRAZOLE SODIUM



RABEPRAZOLE SODIUM

Material Balance:

Material balance of Rabeprazole Sodium Stage-1

Batch Size: 100Kg



2,3-Lutidine 46.00 Stage-1 65.00

Hydrogen Peroxide (50%) 33.00 Spent Acids for sale 140.00

Nitric acid 38.00 (Sulfuric Acid-100,Acetic Acid-40)

Sulphuric acid 100.00 Effluent Water 400.80

Acetic acid 46.00 (Water-350 ,Acetic Acid-6,Hydrogen Peroxide-1.9,Nitric Acid-10.9, gen. water-15.5,Water from Hydrogen peroxide-16.5)




Batch Size: 100Kg



Stage-1 65.00 Stage-2 80.00

3-Methoxy-1-Propanol 43.00 Toluene Recovery 235.00

Sodium Hydroxide 15.50 Toluene Loss 12.00

Toluene 250.00 DMSO Recovery 188.00

DMSO 200.00 DMSO Loss 10.00

Generated water 7.00


(Sodium Nitrite-29.7)


(Organic Impurities-6.8, Toluene-3,DMSO-2)





Batch Size: 100Kg



Stage-2 80.00 Stage-3 90.00

Acetic anhydride 150.00 Toluene Recovery 660.00

Sodium Hydroxide 15.00 Toluene Loss 30.00

Hydrochloric acid 20.00 Acetic Anhydride Recovery 107.00

Toluene 700.00 Acetic Anhydride Loss 4.00


(Water-300,Sodium Acetate-34.5,Acetic Acid-25.2, Toluene-5,)


(Organic Impurities-4.3,Toluene-5)

Total 1265.00 Total 1265.00


Batch Size: 100Kg



Stage-3 90.00 Stage-4 80.00

Thionyl Chloride 53.00 MDC Recovery 710.00

MDC 750.00 MDC Loss 30.00

Sodium Sulphate 10.00 Effluent Water 326.50

Water 300.00 (Water-300,Hydrochloric acid-26.5)


(Sodium Sulphate)


(Organic Impurites-13.3, MDC-10)


(sulfur dioxide)

Total 1203.00 Total 1203.00




Batch Size: 100Kg



Stage-4 80.00 Stage-5 100.00

2-Mercaptobenzimidazole 53.00 Toluene Recovery 370.00

Sodium hydroxide 15.00 Toluene Loss 20.00


Water 300.00 (Water-300,Sodium chloride-20.4,generated water-6.3,Toluene-5, Sodium hydroxide-1)


(Organic Impurites-20.3, Toluene-5)



Batch Size: 100Kg



Stage-5 100.00 Stage-6 100.00

Sodium Hypochlorite 27.00 MDC Recovery 570.00

MDC 600.00 MDC Loss 20.00


Sodium hydro sulphate 12.00 Acetone Loss 15.00

MMA in Methanol 10.00 Effluent Water 347.30

Water 300.00 (Water-300,Sodium Chloride-17,Sodium Hypochlorite-5.3,MMA-10, Sodium hydrosulphate-12,Acetone-3)


(Organic Impurities-4.7, Acetone-5,MDC-10)

Total 1299.00 Total 1299.00



Material balance of Rabeprazole Sodium Stage-7:Pharma

Batch Size: 100Kg



Stage-6 100.00 Rabeprazole Sodium 100.00

Sodium Hydroxide 13.00 IPA Recovery 280.00

Isopropyl Alcohol 300.00 IPA Loss 15.00

Activated Carbon 10.00 Generated water 5.00

Spent carbon 10.00


(Organic Impurities-8,IPA-5)




SIMVASTATIN


Stage-1

Lovastatin reacts with n-Butylamine under nitrogen atmosphere in Toluene media to

give lovastatin.

Stage-2

Lovastatin Amide reacts with imidizole and tert-Butyl dimethylsilychloride in presence of

dimethylformamide and Cyclohexane solvent media to give Diprotected Simvastatin

Amide.

Stage-3

Diprotected Lovastatin Amide reacts with n-Butyl Lithium and Methyl iodide in presence

of Tetrahydrofuran and hydrochloric Acid to give Diprotected Simvastatibn Amide.

Stage-4

Diprotected Simvastatin Amide reacts with Ammonia and Water solution in the presence

of methanol and Ethyl Acetate to give Simvastatin Amide.

Stage-5

Simvastatin Amide cyclised in the presence of BHT in o-xylene,Cyclohexane and

Methanol media to give Simvastatin as product.



SIMVASTATIN

Route of synthesis:

Stage-1:

H3C

OO

CH3

H3C

CH3

O

OHO

H

OO

CH3

H3C

CH3

OHO

HO

H

+

Lovastatin

C24H36O5

404.54

n-Butyl amine

H2N CH3

C4H11N

73.14

HN CH3

2-Methyl-butyric acid 8-(6-butylcarbamoyl-3,5-dihydroxy-hexyl)-3,7-dimethyl-1,2,3,7,8,8a-

hexahydro-naphthalen-1-yl ester

C28H47NO5

477.68



Stage-2:

OO

CH3

H3C

CH3

OHO

HO

H

HN CH3

2-Methyl-butyric acid 8-(6-butylcarbamoyl-3,5-dihydroxy-hexyl)-3,7-dimethyl-1,2,3,7,8,8a-

hexahydro-naphthalen-1-yl ester

C28H47NO5

477.68

+ 2

Imidazole

N

HN

C3H4N2

2X68.08=136.16

+

Tert-Butyl Dimethylsilyl chloride

Si

CH3

CH3

Cl

CH3

CH3

CH3

C6H15ClSi

2X150.72=301.44

NH

N

2

H3C

OH3CCH3

H

O

HN

O

CH3

OSi

CH3

H3CCH3

CH3H3C

OSi

H3C

CH3

H3C

H3CCH3

CH3

2-Methyl-butyric acid 8-[6-butylcarbamoyl-3,5-bis-(tert-butyl-dimethyl-silanyloxy)-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-

naphthalen-1-yl ester

C40H75N05Si2

706.20

+2

HCl

1H-Imidazole Hydrochloride

C3H5ClN2

2X104.54=209.08



Stage-3:

H3C

OH3CCH3

H

O

HN

O

CH3

OSi

CH3

H3CCH3

CH3H3C

OSi

H3C

CH3

H3C

H3CCH3

CH3

2-Methyl-butyric acid 8-[6-butylcarbamoyl-3,5-bis-(tert-butyl-dimethyl-silanyloxy)-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-


C40H75N05Si2

706.20

+

N-Butyl Lithium

Li CH3

C4H9Li

64.06

+ CH3I

Methyl Iodide

141.98

H3C

OH3CCH3

CH3

O

HN

O

CH3

OSi

CH3

H3CCH3

CH3H3C

OSi

H3C

CH3

H3C

H3CCH3

CH3

2,2-Dimethyl-butyric acid 8-[6-butylcarbamoyl-3,5-bis-(tert-butyl-dimethyl-silanyloxy)-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-


C41H77NO5Si2

720.22

+ H3CCH3 + LiI

Lithium iodide

133.85

Butane

58.12



Stage-4:

H3C

OH3CCH3

CH3

O

HN

O

CH3

OSi

CH3

H3CCH3

CH3H3C

OSi

H3C

CH3

H3C

H3CCH3

CH3

2,2-Dimethyl-butyric acid 8-[6-butylcarbamoyl-3,5-bis-(tert-butyl-dimethyl-silanyloxy)-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-


C41H77NO5Si2

720.22

+ 3 H2O

3X18=54.0

+ NH3

Ammonia

17.03

H3C

OH3CCH3

CH3

O

ONH4

O

OH

HO

CH3

OHSi

H3C

CH3

H3C

H3CCH3

tert-Butyl-dimethyl-silanolStage-4

C25H43NO6

453.61

+2

2X132.28=264.56

C6H16OSi

+

N-Butyl amine

H2N CH3

73.14



Stage-5

H3C

OH3CCH3

CH3

O

ONH4

O

OH

HO

CH3

Stage-4

C25H43NO6

453.61

H3C

OH3CCH3

CH3

O

CH3

O

OHO

Simvastatin

C25H38O5

418.57

+ NH3

Ammonia

17.03

+ H2O

18.00



SIMVASTATIN

Flow Chart:

Stage-160.00Kg

Stage-275.00Kg

Stage-368.00Kg

Effluent Water

Stage-432.00Kg

Effluent water

Cyclo Hexane RecDMSO Rec

Acetic anhydride RecToluene Rec

Stage-525.00Kg

Effluent water

O-Xylene RecCyclohexane RecMethanol Rec

Ethylacetate RecMethanol Rec

n-Butyl amine RecToluene Rec

Lovastatinn-ButylamineToluene

Stage-1DimethylformamideImidazoleTert-Butyl dimethylsilylchlorideMethanolCyclohexaneSodium BicarbonateWater

Effluent WaterCO2

Stage-2n-Butyl Lithium in n-Hexane(13.5%)TetrhydrofuranMethyl IodideHydrochloric acid (35%)Water

Stage-3MethanolAmmonia (20%) SolutionEthyl AcetateWater

Stage-4O-XyleneBHTCyclohexaneMethanol Activated CarbonWater

NH3

SIMVASTATIN



SIMVASTATIN

Material Balance:

Material Balance of Simvastatin Stage-1

Batch Size: 25Kg

Name of the input Quantity in K


Lovastatin 51.00 Stage-1 60.00

n-Butylamine 32.00 Toluene Recovery 43.00


n-Butylamine Recovery 21.00

n-Butylamine Loss 2.00


Material Balance of Simvastatin Stage-2

Batch Size: 25Kg



Stage-1 60.00 Stage-2 75.00

Dimethylformamide 10.00 Cyclohexane Recovery 228.00

Imidazole 21.00 Cyclohexane Loss 12.00

Tert-Butyl dimethylsilylchloride 47.00 Effluent Water 455.34

Methanol 2.00 (Water-395,Sodium Chloride-3.55, Sodium bicarbonate-30.9,DimethylFormamide-10,Imidazole-3.89,tert-ButylDimethylsilyl alcohol-10,Methanol-2)

Cyclohexane 245.00 Organic Residue 42.99

Sodium Bicarbonate 36.00 (Organic Impurities-37.99,Cyclohexane-5)


(Carbon dioxide)




Material Balance of Simvastatin

Stage-3

Batch Size: 25Kg


in Kg

Name of the out put Quantity in

Kg

Stage-2 75.00 Stage-3 68.00

n-Butyl Lithium in n-Hexane(13.5%) 100.00 Tetrahydrofuran Recovery 293.00

Tetrahydrofuran 315.00 Tetrahydrofuran Loss 16.00

Methyl Iodide 22.00 n-Hexane Recovery 80.50

Hydrochloric acid (35%) 18.00 n-Hexane Loss 4.00


(Lithium Iodide-14.26,Lithium

Chloride-4.44,Hydrochloric acid-

2.49,THF-6,Methyl Iodide-6.89,

water from HCl-11.7,water-125)



(Butane)





Stage-4

Batch Size: 25Kg


in Kg


in

Kg

Stage-3 68.00 Stage-4 32.00


Ammonia (20%) Solution 20.00 Methanol Loss 10.00

Ethyl Acetate 280.00 Ethyl Acetate Recovery 260.00

Water 200.00 Ethyl Acetate Loss 14.00


(Water-194.89,tert- Butyl dimethyl

silyl alcohol-24.97,Methanol-4,n-Butyl

amine-6.91,NH3-2.39,water from

Ammonia solution-16,)






Stage-5

Batch Size: 25Kg


in Kg

Name of the out put Quantity in

Kg

Stage-4 32.00 Simvastatin 25.00

O-Xylene 350.00 O-Xylene Recovery 332.00

BHT 0.10 O-Xylene Loss 14.00

Cyclohexane 485.00 Cyclohexane Recovery 455.00

Methanol 60.00 Cyclohexane Loss 25.00

Activated Carbon 10.00 Methanol Recovery 55.00

Water 400.00 Methanol Loss 3.00

BHT 0.10


(Water-400,Methanol-2,gen.water-

1.27)

Spent Carbon 10.00



(Ammonia)

Total 1337.10 Total 1337.10


ZIDOVUDINE

Process Description

Stage – 1

β-Thymidine is reacted with Trityl chloride and Tri ethyl amine in the presence of 1, 4-

dioxane to give 5’-O-Trityl Thymidine.

Stage –2

5’-O-Trityl Thymidine is reacted with methane sulphonyl chloride and tri ethylamine in

the presence of Toluene to give mesyl thymidine intermediate, which is reacted with

tri ethylamine in the presence of methanol to give 5’-O- Trityl -2,3’-Anhydro Thymidine.

Stage – 3

5’-O-Trityl -2, 3’-Anhydro Thymidine is reacted with sodium azide and ammonium

chloride in the presence of di methyl sulphoxide to give 5’-O-Trityl -Zidovudine.

Stage – 4

5’-O-Trityl –Zidovudine is reacted with p-Toluene sulphonic acid monohydrate in the

presence of Methanol to give Zidovudine.


ZIDOVUDINE

Route of Synthesis:

Stage-1

OHO

HO

N

HN

O

O

CH3

+ (C6H5)3CCl

Triethyl amine

+ C6H15N

1,4-Dioxane

C OO

HO

N

HN

O

O

CH3

+

Thymidine

C10H14N2O5

242.23

Trityl chloride

278.78 101.19

Trityl thymidine

C29H28N2O5

484.54

C6H15N.HCl

Triethyl amine hydrochloride

137.69


Stage-2

Step-A

C OO

HO

N

HN

O

O

CH3

Trityl thymidine

C29H28N2O5

484.54

+ CH3SO2Cl + C6H15N

114.55 101.19

Toluene

C OO

O

N

HN

O

O

CH3

+

SO2CH3

C6H15N.HCl

Methanesulfonic acid 5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-trityloxymethyl-tetrahydro-furan-3-yl ester

137.69

C30H30N2O7S

562.63


Step-B

C OO

O

N

HN

O

O

CH3

SO2CH3

Methanesulfonic acid 5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-trityloxymethyl-tetrahydro-furan-3-yl ester

C30H30N2O7S

562.63

C OO

N

N

O

CH3

O

Methanol

5-O-Trityl-2,3-anhydro thymidin

C29H26N2O4

466.53

+ C6H15N

101.19

+

C7H16O3S

Triethyl methane sulfonate

SO O

O

180.27

+ NH3

17.0


Stage-3

C OO

N

N

O

CH3

O

5-O-Trityl-2,3-anhydro thymidin

C29H26N2O4

466.53

+ NaN3 + NH4Cl

C OO

N

HN

O

CH3

+

O

N3

NaCl + NH3

5-O-Trityl-Zidovudine

C29H27N5O4

509.56

58.5

Sodium azide

65.01

53.49

17.0


Stage-4

C OO

N

HN

O

CH3

O

N3

5-O-Trityl-Zidovudine

C29H27N5O4

509.56

+

+ H2OMethanol

HOO

N

HN

O

CH3

O

N3

+ C O +

Zidovudine

C10H13N5O4

267.24

Trityl methyl Ether

CH3

S OO

OH

p-Toulenesulfonic Acid

C7H8SO3

172.2

CH3

C20H18O

274.36

S OO

Sulfonic Acid

OH

C6H6O3S

158.18

18.0


ZIDOVUDINE

Flow Chart:

Alpha-Thymidine1,4-DioxaneTri ethyl amine

Stage-1 1,4-Dioxane Rec

Stage-1TolueneMethyl sulfonyl chloride

Stage-2 Toluene Rec

Stage-2Sodium azideDMSO

DMSO RecStage-3

Stage-3TolueneMethanolPTSA Monohydrate

Toluene RecStage-4

ZIDOVUDINE


ZIDOVUDINE

Material Balance:

Material balance of Zidovudine Stage-1

Batch Size:50.0 Kg



β-Thymidine 70.00 Stage-1 110.00

1,4-Dioxane 700.00 1,4-Dioxane Recovery 665.00

Tri ethyl amine 23.00 1,4-Dioxane Loss 35.00

Trityl chloride 64.00 Toluene Recovery 472.00


Water 250.00 Effluent water 284.30

(Water-250,Triethyl Amine Hydrochloride-31.3,Toluene-3)


Total 1607.00 Total 1607.00


Batch Size:50.0 Kg



Stage-1 110.00 Stage-2 100.00


Methyl sulfonyl chloride 26.00 Toluene Loss 60.00

Tri ethyl amine 50.00 Methanol Recovery 663.00



(Water-300,Triethyl Amine Hydrochloride-31.3,TEA-4.5,Toluene-2,Methanol-2)

Organic solid waste 46.40

(Tri ethyl methane sulfonate-40,Organic Impurities-6.40)


(Ammonia)

Total 2386.00 Total 2386.00



Batch Size:50.0 Kg



Stage-2 100.00 Stage-3 100.00

Sodium azide 14.00 DMSO Recovery 565.00

Ammonium chloride 12.00 DMSO Loss 30.00

DMSO 600.00 Effluent water 317.60

Water 300.00 (Water-300,Sodium Chloride-12.6,DMSO-5)



(Ammonia)

Total 1026.00 Total 1026.00


Batch Size:50.0 Kg



Stage-3 100.00 Zidovudine 50.00


Methanol 800.00 Toluene Loss 94.00

PTSA Monohydrate 34.00 Ethyl Acetate Recovery 1235.00

Sodium carbonate 10.00 Ethyl Acetate Loss 65.00

Ethyl Acetate 1300.00 Methanol Recovery 758.00

Activated Carbon 5.00 Methanol Loss 40.00


(Water-396.5,Sulfonic Acid-31.2,Sodium carbonate-10, Methanol-2,Toluene-2)

Spent Carbon 5.00

Organic solid waste 56.30

(Trityl methyl Ether-53.84, Organic Impurities-2.46)

Total 4569.00 Total 4569.00

PROCESS EMISSIONS DETAILS


PROCESS EMISSION DETAILS

S.No Name of the Gas Type of the Gas

Quantity In

Kgs/Day

Treatment Method

1 Carbon dioxide Non polluting Gas

119.00 Dispersed into Atmosphere

2 Nitrogen Non-polluting 3.00 Dispersed into atmosphere

3 Hydrogen Non Polluting Gas

17.00 Diffused with Nitrogen through Flame arrestor

4 Butane Non Polluting gas

10.00 Dispersed into atmosphere

5 Hydrogen chloride Polluting gas 8.00 Scrubbed by using Chilled water media

6 Sulphur dioxide Polluting gas 66.00 Scrubbed by using C.S Lye Solution

7 Ammonia Polluting gas 62.00 Scrubbed by using water media

LIST OF RAW MATERIALS

M/s. Salubrious Laboratories Pvt. Ltd. Enclosure - 1

Prepared By Rightsource Industrial Solutions Pvt. Ltd. Page 1

1. AMLODIPINE BESYLATE

S. No Raw Material Used/ Batch in Kgs

Used / Day in Kgs Source

1 Phthalic anhydride 100.50 69.78 Indigenous 2 Mono ethanolamine 42.00 29.16 Indigenous 3 Toluene 1746.00 1212.31 Indigenous 4 Sodium Hydride (60%) 25.50 17.71 Indigenous 5 Ethyl-4-Chloroacetoacetate 104.00 72.21 Indigenous 6 Conc. Hydrochloric Acid 500.00 347.17 Indigenous 7 Acetic Acid 20.00 13.89 Indigenous 8 Ortho chloro benzaldehyde 90.00 62.49 Indigenous 9 Hexane 640.00 444.37 Indigenous

10 Piperidine 6.00 4.17 Indigenous 11 Methyl-3-amino crotonate 160.00 111.09 Indigenous 12 Acetic Acid 818.00 567.96 Indigenous 13 Mono methyl amine 700.00 486.03 Indigenous 14 Benzene Sulphonic Acid 42.00 29.16 Indigenous 15 Methanol 700.00 486.03 Indigenous 16 Ethyl Acetate 1199.00 832.51 Indigenous 17 Activated Carbon 5.00 3.47 Indigenous



2. ATORVASTAIN CALCIUM



1 Tert-Butyl-2-[(4R,6S)]-6-(cyanomethyl)-2,2-dimethyl-1,3-Dioxan-4-yl] acetate

66.40 55.33 Indigenous

2 Palladium carbon 1.20 1.00 Indigenous 3 Methanol 1016.00 846.67 Indigenous 4 Hydrogen 5.00 4.17 Indigenous 5 Aniline 27.20 22.67 Indigenous 6 Dimethyl Carbonate 27.20 22.67 Indigenous 7 2-Methyl-2-Butanone 27.20 22.67 Indigenous 8 Sulfuric Acid 0.80 0.67 Indigenous 9 Benzaldehyde 27.60 23.00 Indigenous

10 Potassium carbonate 5.00 4.17 Indigenous 11 Acetone 140.00 116.67 Indigenous 12 Toluene 740.00 616.67 Indigenous 13 Fluorobenzaldehyde 28.80 24.00 Indigenous 14 Paratoluene sulfonic acid 2.00 1.67 Indigenous 15 IPA 720.00 600.00 Indigenous 16 Sulfuric Acid 2.40 2.00 Indigenous 17 Calcium Acetate 15.00 12.50 Indigenous 18 Activated Carbon 2.00 1.67 Indigenous



3. DOMPERIDONE



1 N-Carbethoxy-4-piperidone 80.00 133.33 Indigenous 2 Ammonia gas 28.00 46.67 Indigenous 3 Methanol 300.00 500.00 Indigenous 4 Raney Nickel 20.00 33.33 Indigenous 5 Hydrogen 10.00 16.67 Indigenous 6 2,5-Dichloro Nitrobenzene 78.00 130.00 Indigenous 7 Sodium Carbonate 350.00 583.33 Indigenous 8 Methanol 500.00 833.33 Indigenous

10 Raney Nickel 10.00 16.67 Indigenous 11 Toluene 350.00 583.33 Indigenous 12 Urea 20.00 33.33 Indigenous 13 Sodium Hydroxide 75.00 125.00 Indigenous 14 1-(3-Chloropropyl)-1,3-

dihydro-2H-benzimedazole-2-one


15 Methyl Isobutyl Ketone 1200.00 2000.00 Indigenous



4. DULOXETINE HYDROCHLORIDE



1 N-Methyl N-Acetylamine-1-thiophen-2-naphthoxy propane Hydrochloride


2 Dimethyl Sulfoxide 1000.00 500.00 Indigenous 3 Ethyl Acetate 600.00 300.00 Indigenous 4 Di-P-Tolyl-L-Tartaric acid 320.00 160.00 Indigenous 5 Methanol 700.00 350.00 Indigenous 6 Sodium Hydroxide 41.50 20.75 Indigenous 7 Methylene Dichloride 500.00 250.00 Indigenous 8 Acetone 1600.00 800.00 Indigenous 9 Isopropyl Alcohol

Hydrochloride 90.00 45.00 Indigenous

10 Carbon 10.00 5.00 Indigenous



5. FLUCONAZOLE



1 1,3 Difluoro benzene 50.00 33.33 Indigenous 2 Chloro Acetyl chloride 49.50 33.00 Indigenous 3 Aluminium Chloride 15.00 10.00 Indigenous 4 MDC 800.00 533.33 Indigenous 5 1,2,4-triazole 50.00 33.33 Indigenous 6 Triethyl Amine 37.00 24.67 Indigenous 7 Ethyl Acetate 700.00 466.67 Indigenous 8 Tri methyl Sulfoxonium iodide 78.00 52.00 Indigenous 9 Potassium Hydroxide 20.00 13.33 Indigenous

10 Toluene 800.00 533.33 Indigenous 12 Cetyl tri methyl Ammonium

Bromide 10.00 6.67 Indigenous

13 Potassium carbonate 47.00 31.33 Indigenous 14 DMF 750.00 500.00 Indigenous 15 Hydrochloric Acid 25.00 16.67 Indigenous 16 Magnesium Sulfate 5.00 3.33 Indigenous 17 IPA 500.00 333.33 Indigenous 18 Activated Carbon 10.00 6.67 Indigenous



6. LANSOPRAZOLE



1 2,3-Lutidine 42.00 28.00 Indigenous 2 Acetic Acid 40.00 26.67 Indigenous 3 Hydrogen Peroxide (33%) 73.00 48.67 Indigenous 4 Sulfuric Acid 50.00 33.33 Indigenous 5 Nitric Acid 24.70 16.47 Indigenous 6 Sodium Hydroxide 36.65 24.43 Indigenous 7 Potassium Carbonate 37.80 25.20 Indigenous 8 Tri Fluoro Ethanol 27.50 18.33 Indigenous 9 MIBK 236.00 157.33 Indigenous

10 Acetic Anhydride 136.00 90.67 Indigenous 11 TBAB 1.20 0.80 Indigenous 12 Toluene 800.00 533.33 Indigenous 13 Hydrochloric acid (33%) 30.30 20.20 Indigenous 14 Activated Carbon 3.00 2.00 Indigenous 15 Thionyl Chloride 32.25 21.50 Indigenous 16 Methylene Dichloride 300.00 200.00 Indigenous 17 2-Mercapto Benzimidazole 40.60 27.07 Indigenous 18 Isopropyl Alcohol 220.00 146.67 Indigenous 19 Chloroform 240.00 160.00 Indigenous 20 Acetone 200.00 133.33 Indigenous



7. LOSARTAN POTASSIUM



1 2-Cyano-4-Methyl biphenyl (OTBN) 50.00 33.33 Indigenous

2 Sodium Azide 16.82 11.21 Indigenous 3 TEA HCl 35.63 23.75 Indigenous 4 Hydrochloric acid 27.00 18.00 Indigenous 5 Sodium nitrite 17.85 11.90 Indigenous 6 Toluene 400.00 266.67 Indigenous 7 Tritylchloride 65.00 43.33 Indigenous 8 TEA 23.50 15.67 Indigenous 9 MDC 800.00 533.33 Indigenous

10 Methanol 900.00 600.00 Indigenous 11 1,3-Dibromo-5,5-dimethyl-

(DDH) imidazolidine-2,4-dione


12 Sodium metabishlphite 2.00 1.33 Indigenous 13 Butylchloroformyl

imidazole(BCFI) 41.20 27.47 Indigenous

14 TBAB 5.00 3.33 Indigenous 15 IsoPropyl alcohol 700.00 466.67 Indigenous 16 Sodium Hydroxide 8.70 5.80 Indigenous 17 Methanol 400.00 266.67 Indigenous 18 Activated Carbon 15.00 10.00 Indigenous



8. PANTOPRAZOLE SODIUM



1 Maltol 85.00 141.67 Indigenous 2 Dimethyl sulphate 45.00 75.00 Indigenous 3 Potassium carbonate 46.50 77.50 Indigenous 4 Acetone 1100.00 1833.33 Indigenous 5 Ammonium Carbonate 65.00 108.33 Indigenous 6 Toluene 800.00 1333.33 Indigenous 7 Phosphorous oxy chloride 35.00 58.33 Indigenous 8 Hydrogen peroxide (30%) 50.00 83.33 Indigenous 9 Acetic acid 45.00 75.00 Indigenous

10 Methanol 875.00 1458.33 Indigenous 11 MDC 2850.00 4750.00 Indigenous 12 Sodium Hydroxide 138.00 230.00 Indigenous 13 Acetic Anhydride 45.00 75.00 Indigenous 14 Chloroform 200.00 333.33 Indigenous 15 Thionyl chloride 39.00 65.00 Indigenous

16 5-diFluoromethoxy-2-mercaptobenzimidazole


17 Sodium hypochlorite (4%) 500.00 833.33 Indigenous 18 Ammonium Chloride 25.00 41.67 Indigenous 19 Activated Carbon 10.00 16.67 Indigenous



9. RABEPRAZOLE SODIUM



1 2,3-Lutidine 46.00 38.33 Indigenous 2 Hydrogen Peroxide (50%) 33.00 27.50 Indigenous 3 Nitric acid 38.00 31.67 Indigenous 4 Sulphuric acid 100.00 83.33 Indigenous 5 Acetic acid 46.00 38.33 Indigenous 6 3-Methoxy-1-Propanol 43.00 35.83 Indigenous 7 Sodium Hydroxide 58.50 48.75 Indigenous 8 Toluene 1350.00 1125.00 Indigenous 9 DMSO 200.00 166.67 Indigenous

10 Acetic anhydride 150.00 125.00 Indigenous 11 Hydrochloric acid 20.00 16.67 Indigenous 12 Thionyl Chloride 53.00 44.17 Indigenous 13 MDC 1350.00 1125.00 Indigenous 14 Sodium Sulphate 10.00 8.33 Indigenous 15 2-Mercaptobenzimidazole 53.00 44.17 Indigenous 16 Sodium Hypochlorite 27.00 22.50 Indigenous 17 Acetone 250.00 208.33 Indigenous 18 Sodium hydro sulphate 12.00 10.00 Indigenous 19 Isopropyl Alcohol 300.00 250.00 Indigenous 20 Activated Carbon 10.00 8.33 Indigenous



10. SIMVASTATIN



1 Lovastatin 51.00 170.00 Indigenous

2 n-Butylamine 32.00 106.67 Indigenous 3 Toluene 45.00 150.00 Indigenous 4 Dimethylformamide 10.00 33.33 Indigenous 5 Imidazole 21.00 70.00 Indigenous 6 Tert-Butyl dimethylsilylchloride 47.00 156.67 Indigenous 7 Cyclohexane 730.00 2433.33 Indigenous 8 Sodium Bicarbonate 36.00 120.00 Indigenous

9 N-Butyl Lithium in n-Hexane (13.5%) 100.00 333.33 Indigenous

10 Tetrahydrofuran 315.00 1050.00 Indigenous 11 Methyl Iodide 22.00 73.33 Indigenous 12 Hydrochloric acid (35%) 18.00 60.00 Indigenous 13 Methanol 262.00 873.33 Indigenous 14 Ammonia (20%) Solution 20.00 66.67 Indigenous 15 Ethyl Acetate 280.00 933.33 Indigenous 16 O-Xylene 350.00 1166.67 Indigenous 17 BHT 0.10 0.33 Indigenous 18 Activated Carbon 10.00 33.33 Indigenous



11. ZIDOVUDINE



1 β-Thymidine 70.00 116.67 Indigenous 2 1,4-Dioxane 700.00 1166.67 Indigenous 3 Tri ethyl amine 73.00 121.67 Indigenous 4 Trityl chloride 64.00 106.67 Indigenous 5 Toluene 3620.00 6033.33 Indigenous 6 Methyl sulfonyl chloride 26.00 43.33 Indigenous 7 Methanol 1500.00 2500.00 Indigenous 8 Sodium azide 14.00 23.33 Indigenous 9 Ammonium chloride 12.00 20.00 Indigenous

10 DMSO 600.00 1000.00 Indigenous 11 PTSA Monohydrate 34.00 56.67 Indigenous 12 Sodium carbonate 10.00 16.67 Indigenous 13 Ethyl Acetate 1300.00 2166.67 Indigenous 14 Activated Carbon 5.00 8.33 Indigenous

WATER CONSUMPTION DETAILS


WATER REQUIREMENT DETAILS

S.No Purpose Water Requirement In KLD

1 Process 22.00

2 Washings 2.00

3 Boiler make up 23.00

4 Cooling towers make up 70.00

5 Scrubbing system 1.00

6 Domestic 5.00

7 Gardening 4.00

8 Dm Plant 3.00

Total 130.00

WASTE WATER DETAILS


WASTE WATER DETAILS

S.No Purpose Effluent In KLD

1 Process 25.00

2 Washings 2.00

3 Boiler blow down 3.00

4 Cooling towers blow down 14.00

5 Scrubbing system 1.00

6 Domestic 4.00

7 Gardening 0.00

8 Dm Plant 3.00

Total 52.00


HTDS &LTDS DETAILS

Unit HTDS In

KLD

LTDS In

KLD

Effluent Generation

In KLD

Method of Disposal

Process 22.00 3.00 25.00

HTDS Sent to stripper followed

by MEE and ATFD.

Condensate will be send to

ETP followed by RO.

LTDS Effluents sent to ETP followed by RO system.RO Rejects sent to MEE system and RO Permeate to Reuse.

Washings 0.00 2.00 2.00

Boiler blow down 0.00 3.00 3.00

Cooling towers

blow down 0.00 14.00 14.00

Scrubbing system 1.00 0.00 1.00

DM Plant 3.00 0.00 3.00

Domestic 0.00 4.00 4.00 Septic tank followed by soak pit

Total 26.00 26.00 52.00

SOLID WASTE DETAILS


SOLID & HAZARDOUS WASTE DETAILS

S. No Name of the

Hazardous Waste Quantity Kg/Day

Disposal Method

1 Organic waste 1422.00 Sent to Cement Industries

2 Spent Carbon 91.00 Sent to Cement Industries

3 Solvent Distillation Residue 321.00 Sent to Cement Industries

4 Inorganic Waste 132.00 Sent to TSDF

5 MEE Salts 2210.00 Sent to TSDF

6 ETP Sludge 150.00 Sent to TSDF

7 Used Oils 700Ltrs/Annum

TSPCB Authorized Agencies for Reprocessing/Recycling

8 Container liners 500 No’s/Month

After Detoxification sent back to suppliers/Buyers

9 Used Lead Acid Batteries 4 No’s/ Annum

Send back to suppliers for buyback of New Batteries

Solid Waste Details

10 Coal ash from boiler 4000.00 Sent to Brick Manufacturers

STACK EMISSION DETAILS



STACK EMISSION DETAILS FOR BOILER

Particulars Units 4.0 TPH Coal fired Boiler

(Proposed)

Type of Fuel -- Indian Coal

Coal Consumption TPD 16.0

Ash Content % 25

Sulphur Content % 0.8

Nitrogen Content % 1.07

No. of Stacks No 1

Height of stack M 32

Diameter of Stack M 0.60

Temperature of Flue Gas oC 110

Velocity of Flue Gas m/s 8.5

Particulate Matter at outlet of Bag filter (Based on 115 mg/Nm3 at outlet)

gm/sec 0.27

Sulphur dioxide emission gm/sec 0.96

Oxides of Nitrogen emission gm/sec 1.44



STACK EMISSION DETAILS FOR D.G.SET

Capacity In KVA

Emission of SPM

in mg/Nm3

Emission Of SO2

in mg/Nm3

Emission of NOx

in mg/Nm3

Stack dia. In m

Flue Gas

Temp. in OC

Stack Height in m

Flue gas Velocity In m/sec.

250 KVA (Existing)

58.0 24.0 30.0 0.30 250 10 18.24

125 KVA (Existing)

60.0 85.0 110.0 0.15 220 10 16.10

180KVA

(Proposed)

65.0

110.0

135.0

0.3

220.0

10.0

18.5

SOLVENTS DETAILS


Prepared By Rightsource Industrial Solutions Pvt. Ltd Page 1

SOLVENTS DETAILS

S. No Product Name Production Kgs / Day

Quantity as Kgs/Day

Solvent Name Solvent Input

Solvent Recovery

Solvent Loss

Solvent to

waste water

Solvent to

Residue

1 Amlodipine Besylate 83.33 Toluene 1212.50 1151.39 34.72 12.50 13.89

Hexane 444.37 408.27 43.05 0.00 0.00 ethyl acetate 832.51 767.24 61.80 0.00 3.47 Methanol 486.03 465.20 17.36 0.00 3.47 MMA 486.03 456.18 23.61 0.00 0.00 Total 3461.45 3248.28 180.53 12.50 20.83

2 Atorvastatin Calcium 83.33 Toluene 616.67 566.67 30.83 5.00 14.17 IPA 600.00 308.33 30.00 0.00 11.67 Methanol 846.67 800.00 45.92 1.33 15.00 Acetone 116.67 108.33 4.17 0.00 4.17 Total 2180.00 1783.33 110.92 6.33 45.00

3 Domperidone 83.33 Methyl Isobutyl Ketone 2000.00 1891.67 100.00 3.33 5.00

Toluene 583.33 550.00 28.33 1.67 3.33 Methanol 1333.33 1255.00 66.67 5.00 6.67 Total 3916.67 3696.67 195.00 10.00 15.00

4 Duloxetine Hydrochloride 50.00 Dimethyl

Sulfoxide 500.00 467.50 20.00 10.00 2.50

Ethyl Acetate 300.00 285.00 15.00 0.00 0.00



Methanol 350.00 332.50 12.50 0.00 5.00 Acetone 800.00 749.50 40.00 9.00 1.50

Methylene Dichloride 250.00 234.50 15.00 0.00 0.50

Isopropyl Alcohol 45.00 33.50 1.75 0.00 0.75

Total 2245.00 2102.50 104.25 19.00 10.25

5 Fluconazole 66.67 Methylene Dichloride 533.33 506.67 23.33 0.00 3.33

Ethyl acetate 466.67 443.33 20.00 0.00 3.33 DMF 500.00 475.00 14.67 5.00 5.33 Toluene 533.33 506.67 13.33 6.67 6.67 IPA 333.33 300.00 26.67 3.33 3.33 Total 2366.67 2231.67 98.00 15.00 22.00

6 Lansoprazole 66.67 MIBK 157.33 150.00 3.33 0.00 4.00 Toluene 533.33 506.67 6.33 8.00 12.33 Acetic Anhydride 90.67 68.00 4.00 0.00 0.00 MDC 200.00 180.00 10.00 0.00 10.00 Chloroform 160.00 146.67 8.00 0.00 5.33 IPA 146.67 132.00 8.67 2.33 3.67 Acetone 133.33 126.67 1.33 1.33 4.00 Total 1421.33 1310.00 41.67 11.67 39.33

7 Losartan Potassium 66.67 Toluene 266.67 246.67 13.33 6.67 0.00 MDC 533.33 506.67 26.67 0.00 0.00 Methanol 866.67 810.00 36.67 20.00 0.00 IPA 466.67 440.00 23.33 3.33 0.00



Total 2133.33 2003.33 100.00 30.00 0.00

8 Pantoprazole sodium 166.67 Methanol 1458.33 1328.33 95.83 14.17 20.00 Toluene 1333.33 1258.33 41.67 15.83 17.50 Acetone 1833.33 1740.00 55.00 10.00 28.33 MDC 4750.00 4513.33 208.33 0.00 28.33 Total 9375.00 8840.00 400.83 40.00 94.17

9 Rabeprazole Sodium 83.33 DMSO 166.67 156.67 8.33 0.00 1.67 MDC 1125.00 1066.67 41.67 0.00 16.67 Toluene 1125.00 1054.17 51.67 8.33 10.83 Acetic Anhydride 125.00 89.17 3.33 21.00 0.00 Acetone 208.33 189.17 12.50 2.50 4.17 IPA 250.00 233.33 12.50 0.00 4.17 Total 3000.00 2789.17 130.00 31.83 37.50

10 Simvastatin 83.33 Toluene 150.00 143.33 6.67 0.00 0.00 Cyclo hexane 2433.33 2276.67 123.33 0.00 16.67 THF 1050.00 976.67 53.33 20.00 0.00 n-Hexane 283.33 266.67 13.33 0.00 3.33 Methanol 866.67 803.33 43.33 20.00 0.00 Ethyl Acetate 933.33 866.67 46.67 0.00 0.00 O-Xylene 1166.67 1106.67 46.67 0.00 0.00 Total 6883.33 6440.00 333.33 40.00 20.00

11 Zidovudine 166.67 Methanol 1166.67 1091.67 58.33 13.75 16.67 Toluene 6033.33 5723.33 298.33 11.67 0.00 1,4-Dioxane 1166.67 1108.33 58.33 0.00 0.00



DMSO 1000.00 941.67 50.00 8.33 0.00 Ethyl Acetate 2166.67 2058.33 108.33 0.00 0.00

Total 11533.33 10923.33 573.33 33.75 16.67

Grand Total 1000.00 48516.11 45368.28 2267.87 250.08 320.75

CONSOLIDATED STATEMENT –

POLLUTION LOAD DETAILS

Water Input

Water In Effluent TDS COD HTDS LTDS

Total Effluent Water

Organic Inorganic Spent Carbon

Total Solid Waste

Process Fugitive

Kgs/Day Litres/Day Litres/Day Kgs/Day Kgs/Day Litres/Day Litres/Day Litres/Day Kgs/Day Kgs/Day Kgs/Day Kgs/Day Kgs/Day Kgs/Day1 Amlodipine Besylate 83.33 1375.00 1391.31 64.52 56.83 1230.29 254.71 1485.00 82.75 0.00 3.47 86.22 0.88 137.502 Atorvastatin Calcium 83.33 1240.00 1244.83 8.50 71.30 1006.50 275.33 1281.83 93.25 0.00 1.67 94.92 3.33 110.923 Domperidon 83.33 2666.67 2758.80 182.50 12.70 2581.58 366.38 2947.96 199.03 0.00 0.00 199.03 96.33 195.004 Duloxetine Hydrochloride 50.00 735.00 798.23 205.67 30.25 1018.90 0.00 1018.90 57.59 0.00 0.00 57.59 1.40 73.755 Fluconazole 66.67 1200.00 1208.29 130.07 67.77 1371.56 0.00 1371.56 46.47 0.00 6.67 53.14 9.97 61.336 Lansoprazole 66.67 1433.33 1498.78 107.40 45.21 1292.46 336.33 1628.79 53.45 0.00 2.00 55.45 18.16 41.677 Losartan Potassium 66.67 1200.00 1208.17 102.13 58.80 1197.69 142.60 1340.29 66.36 0.00 10.00 76.36 2.41 100.008 Pantoprazole sodium 166.67 5041.67 5332.33 448.67 138.40 5854.83 10.00 5864.83 237.97 98.00 16.67 352.64 104.53 384.179 Rabeprazole Sodium 83.33 1291.67 1333.58 116.25 59.34 1476.67 10.00 1486.67 91.33 33.08 8.33 132.74 19.33 130.0010 Simvastatin 83.33 3733.33 3813.53 395.70 88.80 2911.00 1344.90 4255.90 279.50 0.00 33.33 312.83 53.67 340.0011 Zidovudine 166.67 2083.33 2077.50 201.50 65.18 2305.67 0.00 2305.67 213.58 0.00 8.33 221.91 12.42 640.00

Total 1000.00 22000.00 22665.35 1962.91 694.58 22247.15 2740.25 24987.40 1421.28 131.08 90.47 1642.83 322.43 2214.34

Production Capacity

Water Input

HTDS

LTDS

Total Effluent

Organic Residue

Inorganic Residue

Spent Carbon

Consolidated statement of M/s.Salubrious Laboratories Pvt. Ltd. Enclosure - 5

S.No. Product Name

Effluent Water Details Solid Waste Details Emissions DetailsProduction/

Day

COPY OF GO’S

COPY OF G.O.Ms.No:95 (Ban Notification), Dt.21/09/2007

COPY OF G.O.Ms.No:64 (Ban Relaxation Dt.24/07/2013

COPY OF CFO

TSDF MEMBERSHIP

ACCEREDITATION DETAILS

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