Paracetemol Production

EXECUTIVE SUMMARY

0.1 INTRODUCTION

0.1.1 Paracetamol is an important antipyretic and analgesic agent withweak anti-inflammatory effects. Paracetamol has been around as adrug for more than thirty years. Paracetamol, being a safe and lowpriced analgesic, is quite popular world-wide. Medical opinionthroughout the world is in favour of using Paracetamol, either byitself or in combination, over the established drug 'Aspirin', due to itslower side effects.

0.2 MANUFACTURING PROCESS

0.2.1 World over, the following four routes have been established for the

manufacture of Paracetamol:

* Phenol Route

* Para Nitrochloro Benzene Route

* Nitrobenzene Route

* Para Hydroxyacetophenone Hydrazine RouteThe first three routes have been employed since quite long. The firstplant based on the fourth route {i.e. P-Hydroxyphenone Hydrazine)was set up in 1990.

0.2.2 All the routes primarily lead to the manufacture of Para Arninophenol(PAP) of which Acetaminophen (APAP), i.e. Paracetamol is aderivative.

Various processing steps by these steps by these routes are depictedin the Figure 2 in Section 2.2.1 of Chapter 2.

0.2.3 Comparative evaluation of the salient features of the various routes isgiven as follows :

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Ii Sr.

1.

2.

3.

4.

5.

6.

7.

Comparative Evaluation

Particulars

Type ofProcess

Major Inputs

Catalyst

Yield

Control ofOperation

Solid Waste,

Phenol Route

Batch

Phenol, SodiumNitrite,Sulphuric Acid,AmmoniumSulphate, AceticAnhydride

Not Required

Lower

Manual/SemiAutomatic

Nil

Liquid Effluents Yes

of Various Paracetamol Manufacturing Technologies

PNCB Route

Batch

PNCB, IronPowder, AceticAntydride

Not Required

Lower

Manual/SemiAutomatic

Iron Sludge

Yes

Nitrobenzene

ElectrolyticReduction

Continuous

Nitro Benzene,Sulphuric Acid,Ammonia, AceticAnhydride

Not Required

Much Higher

Automatic

Nil

Yes

Route

CatalyticReduction

Continuous

Nitrobenzene,Hydrogen,Ammonia,AceticAnhydride

Very ExpensivePlatinumCatalyst,which can beregenerated

Higher

Automatic

Nil

Yes

Para-HydroxyacetophenoneHydrazine Route

Continuous

Para-HydroxyphenpneHydrazine,AceticAnhydride

Not known

Much Higher

Automatic

Nil

Yes

Table Contd.

Table Contd.

Sr.No.

8.

9.

10.

11.


Particulars.

By-Products

Utilities

Manpowerrequirements

Hazards/Probl-ems

Phenol Route

Dilute AceticAcid

Steam, Power andChilling plantice consumptionis likely to behigh.

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Nitros compoundexplodes even atmoderatetemperature


PNCB Route

Dilute AceticAcid, SodiumSalt of ParaNitro Phenol

Nitrobenzene Route


Dilute AceticAcid, Aniline

Steam, Power and Steam, PowerChilling Plant

50

Hydrolysis ofPNCB is highlyexothermic

and ChillingPlantSteam andElectricityconsumptionlikely to behigh

30Highly skilledmanpower

CorrosionProblems

CatalyticReduction

Dilute AceticAcid, Aniline

Steam, Powerand ChillingPlant

30Highly skilledmanpower

Fire andExplosionhazards due tohydrogenleakage

Para-Hydroxyncptonhpnonp

Hydrazlne Route

Not known

Steam, Powerand Chillingplant.

Not Known

Table Contd.

Table Contd-

Comparative Evaluation of Various Paracetamol Manufacturing Technologies

Sr.No.

12.EconomicPlant size

13. Levelof

Investmentfor yiES Plans

14. Acq« i s l t lon

of Technology

15. Unit cost of

16.

Phenol Route PNCB Route Nitrobenzene Route


CatalyticReduction

Para-HydroxyacetophenoneHydrazlne Route

20-25 TPM

Rs. 1.0 Crores

Easy

20-25 TPM 300 TPM

Rs. 1.0 Crores Rs. 30.0 Crores

Easy Difficult

300 TPM

Rs. 30.0Crores

Difficult

500 TPM

Rs. 300 Crores

Very Difficult

Highest among all Higher but lower Higher thanroutes

Higher than Lowestthan Phenol PHAP route but PHAP route butroutes lower than lower than

phenol and PNCB phenol androutes PNCB routes

Ease of operation Ease of Lower cost of Lower cost of Lower cost ofoperation production production production

Lower investmentLower investment Continuous Continuous Continuous

process process process

Table Contd.

Table Contd.


Sr. Particulars Phenol RouteNo.

Easy availabilityof technology

Less operationalskills required

17. Major Higher cost ofdrawbacks production

Batch process

H2S emissionscauses inconveni-ence to workers

Unreacted phenolin effluentsdifficult toremove

Explosion hazards


PNCB Route

Easyavailability oftechnology

Less operationalskills required

Higher cost ofproduction

Batch process

Corrosionproblems

Explosionhazards

Nitrobenzene Route


High capitalinvestment

Highoperationalskillsrequired

CatalyticReduction



Fire andexplosionhazards

Para-HydroxyacetophenoneHydrazine Route



Closely guardedtechnology.

0.3 WORLD INDUSTRY STATUS

0.3.1 Market

The total world market for Paracetamol bulk drug is estimated to beabout 1,10,000 tonnes per annum, with Europe and North Americaaccounting for nearly 40% of the totaTmarket.

The world market for Paracetamol is growing at an average growthrate of 5-6% per annum. Increasing global demand for Paracetamol isprimarily attributed to the growing third world market. The growth ofParacetamol market in countries like USA and Japan is due to incor-poration of Paracetamol in cough and cold drug formulations. Worldover, Paracetamol continues to effect the market share of Aspirin.However, Paracetamol in turn, is facing competition from newer drugs.

0.3.2 Major Players

USA, Germany, Turkey, China and India are the leading producers ofParacetamol bulk drug. However, most large producers are in USA.The major players in the world Paracetamol bulk drug market are :

* Hoechst Celanese Corp., USA

* Mallinckrodt, USA

* Rhone Poulenc, USA

* Sterling Organics, UK

* RTZ Chemicals, UK

0.4 INDIAN INDUSTRY STATUS

0.4.1 Market

Manufacture of Paracetamol, in India, started in the late 1960s. Tillthe late 1970s, the domestic consumption was hardly about 700-800tonnes per annum. During this phase, 'Aspirin' and 'Analgin' werewidely used as analgesic/antipyretic agents.

The domestic market for paracetamol has grown substantially in thelast decade. The current (1992-93) domestic market for paracetamolhas been estimated to be around 8000 tons. A growth rate of 10%per annum has been envisaged in the domestic consumption duringthe next decade, considering population growth, increasingurbanisation and increasing medical facilities in the rural areas.

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The current export demand for paracetamol, which is about 2400tons, is likely to grow at an average annual growth rate of 15%,considering the tremendous opportunities for exports.

Based on the above, demand for paracetamol has been estimated toreach about 12,850 MT and 22,900 MT by 1994-95 and 1999-2000respectively.

0.4.2 Installed Capacity and Production

At present, there are more than 60 units, both in the orgnised andother sectors, in India, manufacturing paracetamol. The totalinstalled capacity for paracetamol bulk drug manufacture in thecountry is about 18,000 tons per annum.

The domestic production of paracetamol has increased from about580 MTin 1980-81 to almost 10,400 MT in 1992-93.

0.4.3 Exports and Imports

Exports of paracetamol have been reported in the last few years.Exports were made to Germany, United Kingdom, Malaysia,Bangladesh, Sri Lanka, etc.

The manufacturers are convinced that the quality of paracetamolproduced by them meets international standards. Thus, they do notface major problems in exporting the products, at least as far asquality is concerned. India, reportedly, has an edge over China interms of quality and Indian products command a premium overChinese drugs.

The exports of paracetamol during 1992-93 from India were estimatedto be about 2400 MT.

Exports of paracetamol is likely to grow at an average annual growthrate of 15% considering the tremendous scope that exists for exportof paracetamol. However, this will be possible only if Indian produc-ers can continue to compete with large international producers ofparacetamol both on the price and quality fronts. Adoption of nitro-benzene route by few manufacturers abroad has already threatenedmanufacturers producing paracetamol by phenol/PNCB routes, asthe former route has proved to be most cost-effective. The domesticindustry must assess the strategic implications of the new techno-logy and take necessary actions to meet such competition effectively.

Since 1989-90. no imports of paracetamol have taken place. This isdue lo the fact that a large manufacturing capacity already exists inthe country. Further import of paracetamol seems unlikely in thefuture.

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0.5 DOMESTIC TECHNOLOGY STATUS

0.5.1 Currently, paracetamol is being produced in India only by phenoland PNCB routes. Of these two routes, the PNCB route is morepopular. The equipments are standardised. The end-product con-forms to IP specifications. The end-product from few manufacturersconform to BP/USP specifications. Many companies have claimedthat their product assay is consistently above 98%. It is, however,felt that some manufacturers do not have proper quality control checks.Their product quality may barely meet IP standards and maycontain higher percentage of impurities.

0.5.2 The yield obtained by various domestic manufacturers varies widely(i.e. from 70% to 95%). The batch time for processing is also found tobe varying significantly from unit to unit.

0.5.3 Research and development efforts by domestic manufacturers areconcentrated on improving end-product quality, improving yield andreducing cost of production. R&D work to develop other routes, i.e.Nitro Benzene and PHAH, are insignificant, as of now. Exports arehowever underway to improve the situation.

0.5.4 The technology to manufacture paracetamol thought Phenol and PNCBroutes is very well established and is available from indigenous sources.It seems that the technology based on these two routes has beenabsorbed quite well.

0.5.5 Paracetamol manufacture via Nitro Benzene route is yet to start inthe country. Although some efforts in this direction were made, theyhave not been successful.

0.5.6 Except few quality control equipments, most of the equipmentsrequired for the manufacture of Paracetamol through Phenol andPNCB routes can be fabricated locally.

0.5.7 Continuous efforts are being made by domestic manufacturers toenhance process efficiencies and to reduce batch processing time.With these efforts, significant improvement in the process yields andconsiderable reduction in batch processing time has been reportedby a few domestic manufacturers.

0.5.8 These improvements were made by incorporating sophisticated equip-ments, enhancing automation level in the process, using better qual-ity raw materials and devising better plant and equipment layouts.

0.6 TECHNOLOGY GAPS

0.6.1 Several areas of technology gaps have been found to exist in the

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Indian paracetamol industry. Gaps have been observed not onlybetween the industry in India and abroad, but also within thevarious domestic units.

0.6.2 Technology Gaps within the Indian ParacetamolIndustry

Various gaps within the domestic industry has been identified inseveral areas and are as follows.

TECHNOLOGY GAPS

WITHIN INDIAN PARACETAMOL INDUSTRY

Sr. AreaNo.

Remarks

1. Scale of operation

Yield and raw material consumption

Raw material quality

Product quality

Plant capacity varies for 50-100TPA to 700-1000 TPA, henceeconomies of scale also vary sig-nificantly.

Wide variations in the yield andraw materials consumption havebeen observed among the variousunits using the same route (i.e.20-30% variation in case ofphenol route and about 10-15%variation in case of PNCB route).These variations are due to typeof equipments and controlsemployed, quality of raw materialsused etc.

Quality of Phenol, PNCB, ActivatedCarbon and Hydrogen are notconsistent and vary from sourceto source.

Variations in end-product qualityhave been observed amongseveral units. Very few qualityconscious manufacturers have putin an extra efforts to establishquality that conforms to IP, BP andUSP standards.

Table Contd.

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Table Contd.

Sr. AreaNo.

Remarks

Degree of Automation

6. Choice of equipments

Level of automation in variousprocessing steps have been foundto be differing significantly amongthe various units. Only a fewbetter equipped units have ahigher degree of automation (i.e.as high as 100%) in reaction,filtration and pulverisation sec-tions. Majority of the units haveeither lower degree of automationor manually controlled process.

Wide variations have beenobserved in the type of equipmentsemployed for the same processstep.

Some domestic manufacturers usewooden vats while some use M.S.reactors. Some of the manufac-turers do not get reactors prop-erly designed and some purchasethem second hand.

In the case of filtration, some useconventional filter press, whilesome use sophisticated centri-fuges and Neutsche filters.

In the case of drying, some manu-facturers use conventional traydryers, while some use fluidizedbed dryers, vacuum dryers.

For separation and drying opera-tions, some manufacturers havededicated sets of equipment foreach important process stage,whereas some of the manufactur-ers use the same equipments.

0.6.3 Technology Gaps Between Paracetamol IndustryIndia and Abroad

i n

Several areas where gaps exist in the domestic paracetamol industryin comparison to the industry abroad have been identified as follows :

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Sr.No.

1.

2.

3.

4.

5.

COMPARATIVE TECHNOLOGY STATUS

Particulars India

Use of Technology Phenol and PNCB are the onlyroutes established in India.

Scale of operation Most units below 500 TPA ca-pacity.

Qualify of inputs Qualify of inputs not consis-tent. Batch to batch varia-tions have been reported.The desired quality of NitroBenzene required in Nitrobenzene Route to manufac-turer paracetamol is not avail-able indigenously. Also noblemetal catalyst required in theprocess is not available indig-enously.

End product Majority of domestic manufac-qualily furers obtain fairly good and

consistent quality, howeverfew match the BP/USP stan-dards which are quite strin-gent.

Yield Average yield obtained by do-mestic manufacturers is quitelow compared to manufactur-ers abroad, because of lack ofsophistication in each pro-cessing step, lower degree ofautomation etc.

ANALYSIS

Abroad

Apart from Phenol andPNCB. other routessuch as Nitrobenzeneroute also is use.

The average plant sizeis not less than 1500TPA.

Quality of inputs arefairly consistent. De-sired quality of raw ma-terials are availableeasily.

Quality standardshave been adhered tostrictly.

Higher yields havebeen attained due tothe use of sophisti-cated equipment andhigher degree of auto-mation.

Table Contd.

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Table Contd.

COMPARATIVE TECHNOLOGY STATUS ANALYSIS

Sr.No.

Particulars India Abroad

6. Choice ofequipment

7. Plant layout

Equipments used by major-ity of demestic manufactur-ers lack sophistication andhave lower degree of automa-tion.

Some of the domestic manu-facturers have installed sec-ond hand equipments havingdimensions not suitable intheir plant capacity.

Selection of equip-ments is done withgreat care. Use ofsophisticated equip-ments with higher de-gree of automation toobtain higher yield andbetter end productquality.

Majority of domestic units Plant layout is de-have set up plants without signed with great careany proper layout designing considering variousand planning. factors such as :

* convenience inmaterial handlingand transport

* better spaceutilisation

* future expansionetc.

0.7 RECOMMENDATIONS

0.7.1 A review of the domestic paracetamol industry has indicated that theindustry needs to attend to several important pertinent issues.Efforts should be made by the industry and research orgnaisationsto upgrade the overall technological status of the industry. Thefollowing actions have been suggested to attain this objective.

A major thrust is required for the indigenous development ofnitrobenzene route. The Central Electro Chemical Research

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Institute (CECRI). Karaikudi has developed a laboratory scaleprocess for the manufacture of paracetamol by electrolyticreduction of nitrobenzene.

Research and development efforts are required to develop thenitrobenzene route based on catalytic reduction of nitroben-zene. A research programme may be undertaken at NationalLaboratories for the development of necessary catalyst andcatalyst regeneration technology.

A task group to co-ordinate the R&D efforts in this area may beconstituted with representatives of research bodies, like NCL,Pune: CDRI. Lucknow; IICT, Hyderabad: representatives of theParacetamol industry and venture finance institutions.

With a view to achieve more effective pollution control and costreduction, research efforts should also be directed at creativeutilisation of by-products. The following specific projects weresuggested by the industry :

(i) Creative use of iron sludge for manufacture of pigments.

(ii) Development of membrane technology for recovery of paracetamolfrom the liquid residue.

(iii) Creative use of sodium sulphate, a tonne of which is producedfor each tonne of paracetamol.

(iv) Creative use of dilute acetic acid which is another by-productproduced in large quantities.

Need for collective effluent treatment facilities for SSI unitshave been recognised by the State and Central Governments.Provisions of such facilities wherever feasible, has beenencouraged through subsidies. The Paracetamol industry mayconsider the possibilities of setting up such common facilities,wherever feasible, and avail of the facilities, provided by theGovernments.

Industry must make efforts to-enhance exports of paracetamol.To achieve this objective, industry should overcome certainconstraints like stringent quality standards and stiff competi-tion in the international market. The following actions aresuggested lo overcome these constraints :

(i) Awareness of GMP Standards

The industry must take it up as a mission to train manpowerabout GMP requirements, provide the requisite infrastructure

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and manufacturing facilities and develop an overall qualityassurance concept in the organisation. Very few companiesrealise that elaborate quality assurance and GMP procedures donot really cost much. In order to develop a particular cultureand operating method in the plant, the prime requisites aretime, efforts and energy. To be internationally competitive,however, both in quality and consistency. GMP awareness mustimprove.

(ii) Formation of Common "Regulatory Affairs Group" by theIndustry

The second major constraint in respect of export of paracetamolbulk drug to many countries, are the formalities of registration/approval. Each country has certain rules and regulations ofregistration for pharmaceutical imports and marketing. Theseformalities involve substantial paper work, record keeping,documentation and sometimes also approval of manufacturingfacilities. Such a task may not be feasible for most manufactur-ers as most of them are operating in the small scale sector.Hence, collective efforts are required by the industry to developa separate "Regulatory Affairs Group" to handle all regulatoryregistration aspects.

(iii) Bring About Cost Competitiveness

In order to counter tough competition from other countries likeChina and Taiwan, the domestic producers need to strive hardto be cost competitive. This is rather difficult in the presenttype of industry set-up. Most plants are small sized and hencecannot attain better economies of scale. In future, it may benecessary to set up large export oriented units based oncontinuous process (like Nitro benzene route) for paracetamolmanufacture and export.

New capacities may be encouraged through either by expansionor by large size plants to attain better capacity utilisation levelsand economies of scale.

Industry must pay proper attention and take suitable stepstowards improving safety levels in the plant. Industry shouldorgnise seminars and training programmes to bring aboutawareness of various safely aspects.

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Documents

Paracetemol Production