PART 2 ANNEXURE TO DRAFT ENVIRONMENTAL IMPACT … · Compliance Monitoring of Existing Plant A-287...

PART 2 ANNEXURE TO

DRAFT ENVIRONMENTAL IMPACT ASSESSMENT REPORT

PROPOSED EXPANSION PROJECT FOR MANUFACTURING OF SYNTHETIC ORGANIC CHEMICALS

(PHARMACEUTICAL BULK DRUGS & INTERMEDIATES) [CAPACITY: 287.77 TPM]

[SCHEDULE 5(f) - CATEGORY A]

SURVEY NO: 44/B, VILLAGE: NALDHARI SILUDI-VALIA ROAD, NEAR ANKLESHWAR,

TAL.: VALIA, DIST.: BHARUCH, STATE: GUJARAT

[TOR LETTER NO.: IA-J-11011/583/2017-IA-II(I) Dated 10/02/2018]

[STUDY PERIOD: MARCH 2017 – MAY 2017]

PREPARED BY:

(QCI-NABET ACCREDITED EIA CONSULTANT)

CERTIFICATE NO.: NABET/EIA/1619/SA 053 VALID UPTO 22/05/2019

3RD FLOOR, AKASHGANGA COMPLEX, B/S. SUVIDHA SHOPPING CENTRE, NR. PARIMAL UNDERPASS, PALDI, AHMEDABAD-380 007, GUJARAT

TELEFAX: (079) 2665 0878; E-MAIL: [email protected]

MAY, 2018

Doc. No.: EEC/A-188/16-17/EIA-21/Rev. 01

ANNEXURES

Intas Pharmaceuticals Ltd., Valia-Bharuch Environmental Impact Assessment Report Proposed Expansion Project for Manufacturing of Synthetic Organic Chemicals

List of Annexure

LIST OF ANNEXURES

ANNEXURE NO. TITLE PAGE

NO.

1. Land Possession Documents A-1

2. Details of Manufacturing Process A-35

3. Details of Raw Materials Requirement A-167

4. Details of storage of Products & Raw Materials A-177

5. Layout Plan A-183

6. Acknowledgement of CGWA Application Slip A-184

7. Copy of Membership (NECL, BEIL) & LOI (RSPL) A-185

8. Details of fly ash generation A-188

9. Copies of Consent to Establish A-189

10. Copies of Consolidated Consent & Authorization (CC&A) A-207

11. Compliance of CC&A A-247

12. Annual Compliance (Form V) A-251

13. Third Party Monitoring Reports A-257

14. Compliance Monitoring of Existing Plant A-287

15. Notice and its compliance A-292

16. Inspection Reports from GPCB XGN A-312

17. PLI Policy A-342

18. License from PESO for storage of hazardous chemicals A-344

19. Compliance of CREP guidelines A-347

20. Photographs of baseline monitoring activities A-351

21. Methodology for Baseline Environmental Monitoring & Analysis A-352

22. Analysis report of Baseline Environmental Monitoring A-357

23. Details of Traffic Survey A-379

24. Basic amenities in the study area A-382

25. EHS Policy A-386

26. List of SOP’s for EHS A-388

27. Characteristic of Hazardous Chemicals A-390

28. Health Check up Form A-400

29. Analysis of Maximum Credible Accident Scenarios A-401

30. Checklist for Safety Compliance A-469

Intas Pharmaceuticals Ltd., Valia-Bharuch Environmental Impact Assessment Report

Proposed Expansion Project for Manufacturing of Synthetic Organic Chemicals

List of Annexure

ANNEXURE NO. TITLE PAGE

NO. 31. Proposed CSR Activities A-477

32. Do’s and Don’ts A-478

ANNEXURE 1 LAND POSSESSION DOCUMENTS

Scanned by CamScanner A-14

ANNEXURE 2 DETAILS OF MANUFACTURING

PROCESS

Intas Pharmaceuticals Ltd., Valia-Bharuch Environmental Impact Assessment Report Proposed Expansion Project for Manufacturing of Synthetic Organic Chemicals

Manufacturing Process Details

MANUFACTURING PROCESS DETAILS

Product Code Name of Products PAGE

NO.

P1 Dabigatran Etexilate Mesylate A-35

P2 Lurasidone HCl A-43

P3 Lacosamide A-58

P4 Bendamustine HCl A-70

P5 Trazodone HCl A-81

P6 Gemcitabine HCl A-89

P7 Capecitabine A-98

P8 Erlotinib HCl A-104

P9 Imatinib Mesylate Alpha A-111

P10 Nilotinib A-116

P11 Dasatinib A-125

P12 Pazopanib HCl A-134

P13 Sorafenib A-143

P14 N-BZ-Bis-Lactam A-151

P15 N-BOC-Bis-Lactam A-154

P16 5-(4-(4-(5-Cyano-1H-indol-3-yl)-butyl)-piperazin-1-yl)

benzofuran-2-carboxamide

A-157

P17 2-acetamido-2-phenethylpropane-1,3-diyl-diacetate A-159

Intas Pharmaceuticals Ltd., Valia-BharuchEnvironmental Impact Assessment ReportProposed Expansion Project for Manufacturing of Synthetic Organic Chemicals


MANUFACTURING PROCESS DETAILS

P1. DABIGARTAN ETEXILATE MESYLATE

a) Manufacturing Process

Stage I (Intermediate)Amide formation of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)

benzamido)propanoate with 2-((4-cyanophenyl) amino) acetic acid in presence of 1,1’-

Carbonyldiimidazole and N, N’-Dimethylformamide to give intermediate of Dabigatran

Amidine Intermediate Stage-I; which is further cyclized in presence of Acetic acid and

further react with maleic acid in presence of Ethyl acetate and Denature Ethanol to

give Dabigatran Amidine Intermediate Stage-I.

Stage II (Intermediate)Synthesis of Amidine of Dabigatran Amidine Intermediate Stage-I in presence of

Denature Ethanol and hydrochloric acid gas to form intermediate of Dabigatran Amidine

Intermediate; which is further reacting with ammonium carbonate in presence of

Denature Ethanol to give crude Dabigatran Amidine Intermediate and isolated in

Denature Ethanol and Isopropyl acetate to give pure Dabigatran Amidine Intermediate.

Stage I (Product)Dabigatran Amidine Intermediate react with n-Hexyl chloroformate in presence of

aqueous Potassium carbonate solution and Tetrahydrofuran. Separate the organic

layer followed by product extraction in tetrahydrofuran from aqueous layer. Combined

organic layer concentrate by solvent distillation. give charcoal treatment in Methylene

chloride. Give the water wash to organic layer. Remove the solvent by distillation. and

precipitate product in mixture of isopropyl alcohol and methyl isobutyl ketone. Isolate

solid by filtration. Purify the wet cake with mixture of isopropyl alcohol and methyl

isobutyl ketone. Isolate solid by filtration. Dry the wet material to get stage-I product.

Stage II (Product)Stage-I is dissolve in acetone and filter the reaction mass. Filtrate react with Methane

sulphonic acid and convert in to Dabigartan etexilate mesylate. Product precipitate by

cooling and isolate solid by filtration. Dry the wet material to get Dabigartan etexilate

mesylte.

A-35

Intas Pharmaceuticals Ltd., Valia-BharuchEnvironmental Impact Assessment Report



b) Reaction Chemistry

Stage I (Intermediate)

Stage II (Intermediate)

Stage I

A-36



Stage II

c) Process Flow Diagram

Input Qty., kg Output Qty., kg

2-((4-cyanophenyl)amino) Acetic Acid 76.60

N,N-Dimethyl Formamide 311.00

1,1’-Carbonyldiimidazole 78.20 Recovered Dimethyl Formamide 308.00

Ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-

yl)benzamido) propanoate [DAP] 110.00 Recovery Loss 3.00

Acetic Acid (Glacial) 275.00

Recovered Acetic Acid 270.00 Recovery Loss 5.00

Ethyl Acetate 2,700.00 Sodium Carbonate 165.00

Sodium Chloride Solution 110.00 Aq. Effluent 5,892.90

Water 5,500.00

OLMaleic Acid 74.50

Ethanol 260.60

Ethyl Acetate 254.00 Org. Mother Liquor 3,280.00

Loss 9.00

Recovered Ethyl Acetate 7.00

Intermediate (Stage I) 140.00

Total 9,914.90 Total 9,914.90

Dabigatran Etexilate Mesylate (Stage-I)Process

Centrifugation

Reaction

Reaction

Distillation

Extraction & washing

Reaction

Drying

Dabigatran Amidine

Intermediate Stage-I

A-37





Intermediate (Stage I) 140.00 Ethanol 437.00 Recovered Ethanol 432.00

Hydrochloric Acid 9.30 Recovery Loss 5.00

Ethanol 1,100.00 Aluminium Carbonate 280.00

Ethanol 253.00 Solid Waste 280.00

Ethanol 530.00 Recovered Ethanol 1,868.00 Recovery Loss 15.00

Isopropyl Acetate 1,670.00

Isopropyl Acetate 157.00 Org Mother Liquor 1,862.30 Loss 13.00

Recovered Isopropyl Acetate 16.00

Intermediate (Stage II) 85.00

Total 4,576.30 Total 4,576.30

Dabigatran Etexilate Mesylate (Stage-II)Process

Dabigatran Amidine

Intermediate

Precipitation

Centrifugation

Drying

Reaction

Reaction

Filtration

Distillation

A-38




Dabigatran Amidine Intermediate 85.00

Water 255.00

Water 85.00 Aq. Effluent 325.00

wet cake

Tetrahydrofuran 1,513.00 Potassium Carbonate 65.75 n-Hexyl Chloroformate 31.32

Water 425.00

Tetrahydrofuran 227.00 Aq. Effluent 643.50

Methylene Chloride 226.00 Recovered Tetrahydrofuran 1,440.00 Recovery Loss 72.00 Recovered MDC+THF 215.00 Recovery Loss 9.00

Methylene Chloride 3,172.00 Aq. Effluent 860.00 Water 850.00 Spent Carbon 8.50

Activated Carbon 8.50 Loss 5.00

Rec MDC 2,980.00 Isopropyl Alcohol 134.00 Recovery Loss 150.00

Rec MDC+ IPA 150.00 Recovery Loss 3.00

Isopropyl Alcohol 1,128.00 Methyl Isobutyl Ketone 285.20

Isopropyl Alcohol 54.00 Methyl Isobutyl Ketone 14.00 Org Mother liquor 1,530.00

Loss 12.00

Toluene 148.00 Recovered Toluene 150.00 Recovery Loss 3.00

Toluene 370.00 Methyl Isobutyl Ketone 340.00

Toluene 74.00 Org. Mother Liquor 915.77 Methyl Isobutyl Ketone 68.00

Recovered Toluene + MIBK 34.00

Intermediate (Stage III) 53.00

Total 9,558.77 Total 9,558.77

Process

Intermediate (Stage III)

Centrifugation

Extraction

Distillation

Filtration

Distillation

Precipitation

Wet cake Purification

Precipitation

Centrifugation

Drying

Dabigatran Etexilate Mesylate (Stage-III)

Reaction

Centrifugation

Reaction

A-39




d) Summary of Mass Balance

Capacity of Finished Product, TPM : 0.8

Working Days Per Month : 26


S. No Input Kg/

Batch Remarks Output Kg/Batch Remarks

1

Ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido) propanoate [DAP]

110.00 Reactant Intermediate (Stage I) 140.00 Intermediate

(Stage I)

22-((4-cyanophenyl)amino) Acetic Acid

76.60 ReactantRecovered Dimethyl Formamide

308.00Sell to authorized recycler

3 1,1’-Carbonyldiimidazole 78.20 Reagent Recovery

Loss 3.00 Solvent Loss

4 N,N-Dimethyl Formamide 311.00 Solvent Recovered

Acetic Acid 270.00Sell to authorized recycler

5 Acetic Acid (Glacial) 275.00 Reagent Recovery


6 Maleic Acid 74.50 ReagentRecovered Ethyl Acetate


7 Ethyl Acetate 2,954.00 Solvent Org. Mother Liquor 3,280.00

Sell to authorized recycler


Intermediate (Stage III) 53.00 Acetone 1,256.00

Methane Sulfonic Acid 7.71

Acetone 42.00 Org. Mother Liquor 1,273.71

Recovered Acetone 30.00

Dabigatran Etexilate Mesylate 55.00

Total 1,358.71 Total 1,358.71

Drying

Finished Product

ProcessDabigatran Etexilate Mesylate (Stage-IV)

Reaction

Reaction

Centrifugation

A-40



S. No Input Kg/


8 Ethanol 260.60 Solvent Aq. Effluent 5,892.90 To ETP

9 Sodium Carbonate 165.00 Washing media Loss 9.00 Atmospheric Loss

10 Sodium Chloride Solution 110.00 Washing media

11 Water 5,500.00 Wash water

Total Input 9,914.90 Total Output 9,914.90


S. No Input Kg/


1 Intermediate (Stage I) 140.00 Reactant Intermediate

(Stage II) 85.00 Intermediate (Stage II)

2 Aluminium Carbonate 280.00 Reactant Recovered

Ethanol 2,300.00Sell to authorized recycler

3 Hydrochloric Acid 9.30 Reagent Recovery Loss 20.00 Solvent loss

4 Isopropyl Acetate 1,827.00 Solvent Recovered

Isopropyl Acetate 16.00Sell to authorized recycler

5 Ethanol 2,320.00 Solvent Org Mother Liquor 1,862.30


Solid Waste 280.00 Inorganic HW (landfill)

Loss 13.00 Atmospheric Loss


Stage I (Product)

S. No Input Kg/


1 Intermediate (Stage I) 85.00 Reactant Intermediate

(Stage III) 53.00 Intermediate Stage-I

2 n-Hexyl Chloroformate 31.32 Reactant Recovered

Tetrahydrofuran 1,440.00Sell to authorized recycler

3 Potassium Carbonate 65.75 Reagent Recovery Loss 72.00 Solvent Loss

4 Methylene Chloride 3,398.00 Solvent Recovered

MDC+THF 215.00Sell to authorized recycler

5 Tetrahydrofuran 1,740.00 Solvent Recovery Loss 9.00 Solvent Loss

6 Isopropyl Alcohol 1,316.00 Solvent Rec MDC 2,980.00 Sell to

authorized

A-41




S. No Input Kg/


recycler

7 Methyl Isobutyl Ketone 707.20 Solvent Recovery Loss 150.00 Solvent Loss

8 Toluene 592.00 Solvent Rec MDC+ IPA 150.00Sell to authorized recycler

9 Activated Carbon 8.50 For

Decolorization Recovery Loss 3.00 Solvent Loss

10 Water 1,615.00 Wash water Recovered Toluene 150.00


Recovery Loss 3.00 Solvent Loss

Recovered Toluene + MIBK 34.00


Org Mother liquor 2,445.77


Aq. Effluent 1,828.50 To ETP

Spent Carbon 8.50 Inorganic HW (landfill)

Loss 17.00 Atmospheric Loss


Stage II (Product)

S. No Input Kg/


1 Intermediate (Stage II) 53.00 Reactant

Dabigatran Etexilate Mesylate

55.00 Finished Product

2 Methane Sulfonic Acid 7.71 Reagent Recovered

Acetone 30.00Sell to authorized recycler

3 Acetone 1,298.00 Solvent Org. Mother Liquor 1,273.71



A-42



P2. LURASIDONE HCL

Stage I (Intermediate)Reduction of Cis-5-norbornene-exo-2, 3-dicarboxylic anhydride with hydrogen using

10% Palladium on carbon as a catalyst in present of tetrahydrofuran as solvent.

Resulting reaction mass filter on hyflow bed and remove Palladium on carbon. Remove

the solvent from filtrate by distillation. Give stripping with cyclohexane. Finally crystallize

the product in cyclohexane. Isolate solid by filtration. Dry the wet material to get Stage-

I.

Stage II (Intermediate)Lurasidone Amide Intermediate Stage-I is reacted with urea at higher temp to get the

Stage-II. After completion of reaction, Charge water and methylene chloride in reaction

mass. Product is extracted by methylene chloride. Remove the solvent from organic

layer by distillation. Precipitate the product by cyclohexane addition. Isolate solid by

filtration. Dry the wet material to get Stage-II.

Stage I (Product)Reduction of (1R, 2R)-cyclohexane-1, 2-dicarboxylic acid (KSM-I) using Vitride as

reducing agent in toluene, provide aq. HCl treatment to the reaction mass and extract

product with Methylene chloride. Wash MDC layer with aq. Sodium chloride solution

and then remove solvent by distillation. Precipitate and recrystallize the stage- I (Diol)

product using n-Heptane as a solvent.

Stage II (Product)Reaction of stage-I with methane sulphonyl chloride in presence of triethylamine in

Methylene chloride solvent gives stage-II. Provide aq. Sodium bicarbonate wash to the

reaction mass and remove solvent by distillation. This product is isolated using Methyl

tertiary butyl ether (MTBE).

Stage III (Product)Stage-II is condense with 3-(1-Piperazinyl)-1, 2-benzisothiazole (KSM-II) in the

presence of sodium carbonate in Dimethylformamide solvent gives stage-III. Isolate

inorganic salt by filtration and then remove solvent by distillation. The product is

isolated using n-hexane acetone mixture and in-situ purified in acetone.

A-43




Stage IV (Product)Condensation of Stage-III with Lurasidone amide Intermediate in the presence of

potassium carbonate in Dimethylformamide solvent gives stage-IV (Lurasidone base).

The product is isolated using methanol as a solvent and purify in Acetone.

Stage V (Product)Dissolve stage-IV in Acetone and provide activated charcoal treatment. Lurasidone

hydrochloride is prepared in acetone using IPA-HCl.




A-44



Stage I (Product)

Stage II (Product)

Stage III (Product)

A-45




Stage IV (Product)

Stage V (Product)

A-46





Exo-cis-5-norbornene-2,3-dicaroxylic anhydride 49.00

Tetrahydrofuran 174.00 Palladium on Carbon 0.49

Hydrogen Gas 0.49

Tetrahydrofuran 101.00 Solid Waste 0.05

Cyclohexane 98.00 Recovered Tetrahydrofuran 260.00 Recovery Loss 10.00 Rec THF+ Cyclohexane 40.00 Recovery Loss 1.50

Cyclohexane 98.00

Cyclohexane 36.00 Org Mother Liquor 194.50

Recovered Cyclohexane 5.30

Intermdediate Stage-I 45.63

Total 556.98 Total 556.98

Drying

Intermediate Stage I

Filtration

Lurasidone Amide Intermediate (Stage-I)

Reaction

Filtration

Distillation

Isolation

Process

A-47





Intermediate (Stage I) 45.63 CO2 Gas 7.20 Urea 9.90 Ammonia Gas 2.60

Water 46.00 Methylene Chloride 182.00

Aq. Effluent 46.00

Recovered Methylene Chloride 176.00 Recovery Loss 6.52

Cyclohexane 71.00

Cyclohexane 36.00 Org. Mother Liquor 102.58


Lurasidone Amide Intermediate 45.63


Intermediate (Stage II)

Lurasidone Amide Intermediate (Stage-II)

Reaction

Reaction

Layer Separation

Distilation

Isolation

Filtration

Drying

Process

A-48




Toluene 263.60 (1R,2R)-Cyclohexane-1,2-

Dicarboxylic acid 76.00

Vitride/Synhydrid 478.80 HPLCWater 608.00

Hydrochloric Acid 655.50

Toluene 131.78 Methylene Chloride 1,208.00 Aq. Effluent 2,812.40

Sodium Chloride 304.00 Water 760.00

Recovered Methylene Chloride & Toluene 1,550.00

n-Heptane 51.80 Recovery Loss 64.00 Recovered n-Heptane 50.00 Recovery Loss 2.20

n-Heptane 103.50

n-Heptane 38.80 Org. Mother Liqour 142.00 Filtration Loss 3.00

n-Heptane 103.50

n-Heptane 38.80 Org. MotherLliqour 142.00

Recovered n-Heptane 6.00


Methanol 60.12 Aq. Effluent 241.00 Water 228.00

Caustic flakes 11.40 Org. Mother Liquor 60.00

Total 5,121.60 Total 5,121.60

Lurasidone HCl (Stage-I)Process

Slurry wash

Intermediate

Decomposition of Vitride

Reaction

Quenching & Extraction

Distillation & stripping

Crystallization

Filtration

Filtration

Dryer

A-49





Intermediate (Stage I) 49.00 Methylene Chloride 324.63 HPLC

Triethyl Amine 110.05 Methane Sulfonyl Chloride 109.03

Water 735.00 Aq. Effluent 923.00 Methylene Chloride 129.85 Recovered Methylene Chloride 435.00 Sodium Bicabonate 12.25 Recovery Loss 19.00

Methyl Tertiary Butyl Ether 145.04

Methyl Tertiary Butyl Ether 108.78 Org. Mother Liqour 253.00 Filtration Loss 1.63

Recovered MTBE 10.00

Intermediate Stage-II 82.00

Total 1,723.63 Total 1,723.63

Reaction

Extraction and distillation

Crystallisation

Lurasidone HCl (Stage-II)Process

Filtrartion

Dryer

Intermediate

A-50




Dimethyl Formamide 774.10 Intermediate (Stage II) 82.00 3-(1-Piperazinyl)-1,2-

benzisothiazole 59.86 HPLC

Sodium Carbonate Anhydrous Powder 30.34

Dimethyl Formamide 164.00 Solid Waste 65.00

Recovered Dimethyl Formamide 925.00 Acetone 64.90 Recovery Loss 13.00

Recovered DMF + Acetone 63.70 Recovery Loss 1.20

Acetone 129.70 n-Hexane 108.10

Acetone 32.40 Org. Mother Liqour 316.30 n-Hexane 27.00 Filtration Loss 2.20

Acetone 194.60

Acetone 64.90 Org. Mother Liqour 256.00



Total 1,731.90 Total 1,731.90

Drying

Intermediate

Lurasidone HCl (Stage-III)Process

Filtration

Reaction

Filtration

Distillation

Crystallization

Filtration

Slurry wash

A-51





Dimethyl Formamide 515.00 Intermediate (Stage III) 78.00

Lurasidone amide intermediate 45.63 Potassium Carbonate

(anhydrous) 50.93


Recovered Dimethyl formamide 650.00 Methanol 61.70 Recovery Loss 13.00

Recovered DMF + Methanol 59.00 Recovery Loss 1.70

Methanol 185.10

Methanol 123.40 Org. Mother Liqour 312.00 Filtration Loss 2.36

Acetone 185.10

Acetone 61.70 Org. Mother Liqour 245.00 Filtration Loss 1.80


Intermediate (Stage-IV) 81.00

Total 1,453.86 Total 1,453.86

Process

Crystallization

Distillation

Filtration

Reaction

Lurasidone HCl (Stage-IV)

Intermediate

Drying

Filtration

Filtration

Slurry wash

A-52







S. No Input Kg/


1Exo-cis-5-norbornene-2,3-dicaroxylic anhydride

49.00 Reactant Intermediate Stage-I 45.63 Intermediate

(Stage-I)

2 Hydrogen Gas 0.49 Reactant Recovered Tetrahydrofuran 260.00


3 Palladium on Carbon 0.49 Catalyst Recovery Loss 10.00 Solvent loss

4 Tetrahydrofuran 275.00 Solvent Rec THF+ Cyclohexane 40.00


5 Cyclohexane 232.00 Solvent Recovery Loss 1.50 Solvent loss




Acetone 866.20 Intermediate (Stage IV) 81.00

Activated Carbon 4.05

Acetone 243.00 Spent Carbon (wet cake) 6.00

Isopropyl Alcohol HCl 41.37

Acetone 64.04 Org. Mother Liqour 1,205.00 Loss 5.66


Lurasidone HCl 80.00

Total 1,299.66 Total 1,299.66

Dissolution & charcolisation

Lurasidone HCl (Stage-V)Process

Finished Product

Drying

Centrifugation

Crystallisation

Filtration

A-53




S. No Input Kg/


Org Mother Liquor 194.50



Total Input 556.98 Total Output 556.98


S. No Input Kg/


1 IntermdediateStage-I 45.63 Reactant

Lurasidone Amide Intermediate

45.63Intermediate to be used in Stage IV of Lurasidone HCl

2 Urea 9.90 ReactantRecovered Methylene Chloride

176.00 Sell to authorized recycler

3 Methylene Chloride 182.00 Solvent Recovery Loss 6.52 Solvent loss

5 Cyclohexane 107.00 Solvent Recovered Cyclohexane 4.00 Sell to authorized

recycler

4 Water 46.00 Wash Water

Org. Mother Liquor 102.58 Sell to authorized

recyclerAq. Effluent 46.00 To MEECO2 Gas 7.20 To Atm.Ammonia Gas 2.60 To scrubber


Stage I (Product)

S. No Input Kg/


1(1R,2R)-Cyclohexane-1,2-Dicarboxylic acid

76.00 Reactant Intermediate (Stage I) 49.00 Intermediate

(Stage I)

2 Vitride/Synhydrid 478.80 Reagent

Recovered Methylene Chloride & Toluene

1,550.00Sell to authorized recycler

3 Hydrochloric Acid 655.50 Reagent Recovery Loss 64.00 Solvent Loss

4 Caustic flakes 11.40 Reagent Recovered n-Heptane 56.00


5 Toluene 395.38 Solvent Recovery Loss 2.20 Solvent Loss

6 Methylene Chloride 1,208.00 Solvent Org. Mother Liquor 344.00


7 Methanol 60.12 Solvent Aq. Effluent 3,053.40 To MEE

A-54



S. No Input Kg/


8 n-Heptane 336.40 Solvent Filtration Loss 3.00

9 Sodium Chloride 304.00 Salt for washing

10 Water 1,596.00 Washing media


Stage II (Product)

S. No Input Kg/


1 Intermediate (Stage I) 49.00 Intermediate

stage-IIntermediate Stage-II 82.00 Intermediate

stage-II

2 Triethyl Amine 110.05 ReagentRecovered Methylene Chloride


3Methane Sulfonyl Chloride

109.03 Reactant Recovery Loss 19.00 solvent loss

5 Sodium Bicabonate 12.25 Reagent Recovered

MTBE 10.00Sell to authorized recycler

4 Methylene Chloride 454.48 Solvent Org. Mother

Liqour 253.00Sell to authorized recycler

6 Methyl Tertiary Butyl Ether 253.82 Solvent Aq. Effluent 923.00 To MEE

7 Water 735.00 Media Filtration Loss 1.63 solvent lossTotal Input 1,723.63 Total Output 1,723.63

Stage III (Product)

S. No Input Kg/


1 Intermediate Stage-II 82.00 Inermediate

stage-IIIntermediate (Stage III) 78.00 Inermediate

stage-III

23-(1-Piperazinyl)-1,2-benzisothiazole



3

Sodium Carbonate Anhydrous Powder

30.34 Reagent Recovery Loss 13.00 solvent loss

4 Dimethyl Formamide 938.10 Solvent

Recovered DMF + Acetone


5 Acetone 486.50 Solvent Recovery Loss 1.20 solvent loss

6 n-Hexane 135.10 Solvent Recovered Acetone 11.50 Sell to

authorized

A-55




S. No Input Kg/


recycler

Org. Mother Liquor 572.30


Solid Waste 65.00 Inorganic HW (Landfill)

Filtration Loss 2.20 solvent lossTotal Input 1,731.90 Total Output 1,731.90

Stage IV (Product)

S. No Input Kg/


1 Intermediate (Stage III) 78.00 Intermediate

stage-IIIIntermediate (Stage-IV) 81.00 Intermediate

stage-III

2Lurasidone Amide Intermediate

45.63 ReactantRecovered Dimethyl formamide


3Potassium Carbonate (anhydrous)

50.93 Reagent Recovery Loss 13.00 solvent loss


Recovered DMF + Methanol


5 Methanol 370.20 Solvent Recovery Loss 1.70 solvent loss

6 Acetone 246.80 Solvent Recovered Acetone 3.00


Org. Mother Liqour 557.00



Filtration Loss 4.16 solvent lossTotal Input 1,453.86 Total Output 1,453.86

Stage V (Product)

S. No Input Kg/Kg Remarks Output Kg/Kg Remarks

1 Intermediate (Stage-IV) 81.00 Intermediate

stage-IVLurasidone HCl 80.00 Finished

product

2 Acetone 1,173.24 Solvent Recovered Acetone 3.00


3 Isopropyl Alcohol HCl 41.37 Reactant Org. Mother

Liqour 1,205.00Sell to authorized recycler

A-56



S. No Input Kg/Kg Remarks Output Kg/Kg Remarks

4 Activated Carbon 4.05 Decolourizing

agentSpent Carbon (wet cake) 6.00 Inorganic HW

(Landfill)Loss 5.66 solvent loss


A-57




P3. LACOSAMIDE

a) Manufacturing ProcessStage ID-serine is reacted with Benzyl chloroformate Benzyl chloroformate (50% in toluene) in

presence of aqueous Potassium carbonate and acetone. Separate the toluene from

reaction mass and wash the aqueous layer by toluene. Precipitate the product by

addition of hydrochlorid acid. Isolate the solid by filtration. Dry the wet material to get

stage-I product.

Stage IILacosamdie stage-I react with isobutyl chloroformate, N-methyl morpholine and Benzyl

amine in presence of tetrahydrofuran. Neutralize the reaction mass by aqueous sodium

bicarbonate solution. Remove aqueous layer by separation. Remove the solvent from

organic layer by distillation. Precipitate the product by adding water. Isolate the solid by

filtration. Dry the wet material to get stage-II product.

Stage IIILacosamide Stage-II react with hydrogen in presence of catalyst 10% palladium on

carbon and methanol at 4 to 6Kg/Cm2 hydrogen gas pressure to convert in to

lacosamid stage-III. Hydrogen is removed by flushing of nitrogen gas. Reaction mass

is filtered on hyflow bed to remove palladium carbon. Remove solvent from filtrate and

followed by toluene stripping. finally, product crystallize in toluene. Isolate the solid by

filtration. Dry the wet material to get stage-III product.

Stage IVLacosamide stage-III is react with triethyl amine and acetic anhydride in presence of

Methylene chloride and convert into stage-IV solid material. Isolate the solid by

filtration. Dry the wet material to get stage-IV product.

Stage VLacosamide stage-IV is react with Dimethyl sulphate in presence of catalyst Tetra butyl

ammonium bromide, Acetone and aqueous caustic solution to convert in to Stage-V.

Reaction mass neutralize by Acetic acid. Remove solvent by distillation. Charge water

to residue and extract product by methylene chloride from aqueous reaction mass. Give

the charcoal treatment to organic layer. Remove solvent from reaction mass. precipitate

the solid in Methyl tertiary butyl ether. Isolate the solid by filtration. Purify the wet

A-58



material in Methylene chloride and Methyl tertiary butyl ether by heating and followed

by cooling for precipitation. Isolate the solid by filtration. Dry the wet material to get

stage-V product.

Stage VILacosamide stage-V is purify in ethyl acetate by heating and followed by cooling for

precipitation. Isolate the solid by filtration. Dry the wet material to get stage-VI finished

product.


Stage I

Stage II

A-59




Stage III

Stage IV

Stage V

A-60



Stage VI


Input Qty. kg Output Qty. kg

Purified Water 1,000.00 D-Serine 50.00

Potassium Carbonate 197.00 Acetone 79.00

Bezyal Chloroformate 212.00

Toluene 523.00 Org. Mother Liquor 630.00 2061.00

Hydrochloric Acid 295.00 Purified Water 250.00

Toluene 260.00 Aq. Effluent 1,850.00 Loss 20.00 Org. Mother liquor 241.00

Recovered Toluene 19.00

Intermediate (Stage-I) 106.00

Total 2,866.00 Total 2,866.00

Reaction

Intermediate

Centrifugation

Drying

Precipitation

Extration

Lacosamide Stage-I

A-61





Tetrahydrofuran 1,411.90 Intermediate (Stage I) 106.00

Isobutyl Chloroformate 63.60 N-Methyl Morpholine 46.64

Benzyl Amine 61.48

Purified Water 564.23 CO2 gas 19.50 Sodium Bicarbonate 28.71 Aq. Effluent 670.00

Purified Water 1,060.00 Recovered Tetrahydrofuran 1,303.00 Loss 25.00

Purified Water 212.00 Aq. Effluent 1,400.00 Methyl Tertiary Butyl

Ether 470.64 Org. Mother Liquor 458.70

Drying Recovered MTBE 25.00

Intermediate (Stage-II) 124.00

Total 4,025.20 Total 4,025.20

Reaction

Lacosamide Stage-II

Washing

Distillation & Precipitation

Centrifugation

Intermediate

A-62




Methanol 1,468.00 Intermediate (Stage II) 124.00

10 % Palladium on Carbon 2.48

Hydrogen Gas 0.50 CO2 gas 15.50

Hyflow 4.00 Solid Waste 9.00 Methanol 82.00

Clear filtrate

Recovered Methanol 1,434.00 Toluene 269.04 Loss 50.00

Recovered Toluene + mix solvent 60.00

Toluene 107.24 Org. Mother Liquor 406.00

Recovered Toluene 17.76

Intermediate (Stage-III) 65.00

Total 2,057.26 Total 2,057.26

Lacosamide Stage-III

Reaction

Filtration

Intermediate

Distillation and Precipitatio

Centrifugation

Drying

A-63





Methylene Chloride 858.00 Intermediate Stage III 65.00

Triethyl Amine 33.87 Acetic Anhydride 35.88

Methylene Chloride 171.60 Org. Mother Liquor 1,059.00

Recovered Methylene Chloride 47.35


Total 1,164.35 Total 1,164.35

Reaction

Centrifugation

Drying

Lacosamide Stage-IV

Intermediate

A-64




Acetone 1,147.00 Intermediate Stage IV 58.00

Tetrabutyl Ammonium Bromide 5.80

Dimethyl Sulfate 62.06 Caustic flakes 17.40 Purified Water 290.00 Recovered Acetone 1,080.00

Acetic Acid 36.54 Recovery Loss 40.60 Methylene Chloride 1,566.00 Aq. Effluent 340.00


Methylene Chloride 158.00 Spent Carbon 8.00

Methyl tert-butylether 504.55

Methylene Chloride 855.00 Recovered Methylene Chloride 1,640.00 Recovery Loss 58.00

Methyl tert-butylether 53.45 Org. Mother Liquor 1,493.00

Recovered Methyl tert-butylether 65.00

Intermediate (Stage-V) 35.00

Total 4,759.60 Total 4,759.60

Lacosamide Stage-V

Reaction, Distillation & Extraction

Filtration

Distillation and Precipitatio

Centrifugation

Drying

Intermediate

A-65







Stage IS. No Input Kg/

batch Remarks Output Kg/batch Remarks

1 D-Serine 50.00 Reactant Intermediate (Stage-I) 106.00 Intermediate Stage-I

2 Benzyl Chloroformate 212.00 Reagent Org. Mother Liquor 871.00Sell to authorized recycler

3 Potassium Carbonate 197.00 Reagent Recovered Toluene 19.00Sell to authorized recycler

4 Hydrochloric Acid 295.00 Reagent Loss 20.00 Solvent loss

5 Acetone 79.00 Solvent Aq. Effluent 1,850.00 To MEE

6 Toluene 783.00 Solvent

7 Purified Water 1,250.00 Media



Ethyl Acetate 192.50 Lacosamide Stage-V 35.00

Ethyl Acetate 28.00 Org. Mother Liquor 198.50

Recovered Ethyl Acetate 24.00

Lacosamide 33.00


Finished Product

Drying

Centrifugation

Purification

Lacosamide Stage-VI

A-66



Stage IIS. No Input Kg/


1 Intermediate (Stage-I) 106.00 Reactant Intermediate

(Stage-II) 124.00 Intermediate Stage-II

2 Isobutyl Chloroformate 63.60 Reactant Recovered

Tetrahydrofuran 1,303.00Sell to authorized recycler

3 N-Methyl Morpholine 46.64 Reagent Loss 25.00 Solvent loss

4 Benzyl Amine 61.48 Reagent Recovered MTBE 25.00Sell to authorized recycler

5 Sodium Bicarbonate 28.71 Reagent Org. Mother

Liquor 458.70Sell to authorized recycler

6 Methyl Tertiary Butyl Ether 470.64 Solvent Aq. Effluent 2,070.00 To ETP

7 Tetrahydrofuran 1,411.90 Solvent CO2 gas 19.50 Atmospheric Loss

8 Purified Water 1,836.23 MediaTotal Input 4,025.20 Total Output 4,025.20

Stage IIIS. No Input Kg/batch Remarks Output Kg/batch Remarks

1 Intermediate (Stage-II) 124.00 Reactant Intermediate

(Stage-III) 65.00 Intermediate Stage-II

2 Hydrogen Gas 0.50 Reagent Recovered Methanol 1,434.00


3 Methanol 1,550.00 Solvent Loss 50.00 Solvent loss

4 Toluene 376.28 Solvent Recovered Toluene 17.76


5 Hyflow 4.00 Filter media

Recovered Toluene + mix solvent


610 % Palladium on Carbon

2.48 Catalyst Org. Mother Liquor 406.00



CO2 gas 15.50 Atmospheric Loss


A-67




Stage IVS. No Input Kg/


1 Intermediate (Stage-III) 65.00 Reactant Intermediate (Stage-IV) 58.00 Intermediate

Stage-IV

2 Triethyl Amine 33.87 ReagentRecovered Methylene Chloride


3 Acetic Anhydride 35.88 Reagent Org. Mother Liquor 1,059.00


4 Methylene Chloride 1,029.60 SolventTotal Input 1,164.35 Total Output 1,164.35

Stage VS. No Input Kg/batch Remarks Output Kg/batch Remarks

1 Intermediate (Stage-IV) 58.00 Reactant Intermediate

(Stage-V) 35.00 Intermediate Stage-V

2 Caustic flakes 17.40 Reagent Recovered Acetone 1,080.00


3 Dimethyl Sulfate 62.06 Reactant Recovery Loss 40.60 Solvent loss

4 Acetone 1,147.00 SolventRecovered Methylene Chloride


5Tetrabutyl Ammonium Bromide

5.80 Catalyst Recovery Loss 58.00 Solvent loss

6 Purified Water 290.00 MediaRecovered Methyl tert-butylether


7 Methylene Chloride 2,579.00 Solvent Org. Mother

Liquor 1,493.00Sell to authorized recycler

8 Methyl tert-butylether 558.00 Solvent Aq. Effluent 340.00 To ETP


Decolorization Spent Carbon 8.00 Inorganic HW (landfill)

10 Acetic Acid 36.54 ReagentTotal Input 4,759.60 Total Output 4,759.60

A-68



Stage VIS. No Input Kg/


1 Intermediate (Stage-V) 35.00 Product Lacosamide 33.00 Finished

product

2 Ethyl Acetate 220.50 Solvent Recovered Ethyl Acetate 24.00


Org. Mother Liquor 198.50Sell to authorized recycler


A-69




P4. BENDAMUSTINE HCL


Stage ICondensation of KSM-I (N-1-Methyl-4-nitrobenzene-1,2-diamine) with Glutaric

anhydride using sulphuric acid and IPA gave Stage-I.

Stage IISynthesis of Bendamustine Stage-II by catalytic hydrogenation of Stage-I using

Palladium on carbon in methanol as a solvent under H2 gas pressure.

Stage IIIBendamustine Stage-II react with 2-chloroethanol using DIPEA as a base in water and

product isolated by extraction with dichloromethane followed by distillation and isolation

using ethylacetate IPA mixture to get Stage-III.

Stage IVChlorination of stage-III with thionyl chloride using dichloromethane as a solvent.

Product isolated after work-up, solvent distillation and IPA addition to get pure stage-IV.

Stage VHydrolysis of stage-IV using Hydrochloric acid in water to get stage-V as monohydrate

Hydrochloride salt of Bendamustine Hydrochloride.

Stage VIPurifcation of Stage-V using acetonitre, acetone and and aquous HCl mixture to give

Bendamustine hydrochride


Stage I

A-70



Stage II

Stage III

Stage IV

A-71




Stage V

Stage VI

A-72




Input Qty., kg Process Output Qty., kg

N1-Methyl-4-nitrobenzene-1,2-diamine 7.370

Dihydro-2H-pyran-2,6(3H)-dione 6.279

Isopropyl Alcohol 110.550 CO2 emission 1.916

Sulphuric Acid 4.348

Water 412.720Potassium Carbonate 6.117

Aq. Mother liquor 515.849Filtration loss 19.167

n-Heptane 77.311Acetone 11.055 Aq. Mother liquor 83.064

Drying Loss 6.173

Stage-I Intermediate stage-I 9.581

Total 635.750 Total 635.750

Bendamustinen hydrochloride (Stage-I )

Reactor6-7 h at 80 0C

Reactor6-7 h at 45 0C

2 h Temp. 20 0C

Filtration 20 0C

Purify at 45 deg.for 2 hrs

Dryer45 0C for 8-10 hrs


Intermediate (Stage II) 9.581Methanol 201.201 Solid waste 0.958

10% Palladium on Carbon 0.958

Org. Mother liquor 194.015Methanol 28.743 Filtration loss 18.204

Methanol 9.581 Aq. Effluent 95.810Water 95.810 Filtration loss 18.204

Drying Loss 11.976

Stage-II Intermediate stage-II 6.707

Total 345.874 Total 345.874


Filtration 35 deg C

Autoclave 10LStir for 3-4 h at

45 0C

Purify at 0-5 deg.for 2 hrs

Bendamustinen hydrochloride (Stage-II)

A-73





Intermediate stage-II 6.7072-chloroethanol 5.298

N,N-Di Isopropyl Ethyl Amine 9.389Water 53.654

Cool the reaction mass to RT

Methylene Dichloride 134.134

Methylene Dichloride 43.594

Methylene Dichloride 43.594Aq. Effluent 53.654

Recovered Methylene Dichloride 199.189

Solvent Loss 22.132

Ethyl Acetate 23.473 Strip out with EtOAC Org. Mother Liquor 23.473

Ethyl Acetate 33.534Isopropyl Alochol 3.353

Ethyl Acetate 3.353 Org. Mother Liquor 51.239Filtration Loss 3.186

Drying loss 3.186

Stage-III Intermediate Stage-III 4.024

Total 360.083 360.083

Bendamustinen hydrochloride (Stage-III )

Degassed it well for 1h at 40-45 deg

Stit at 0-5 deg for 3 h


ReactorStir for 4-5 h Temp. 80 °C

Stir the reaction mass for 40 mts. At rt

Separated off the Organic layer A

Stir Aqueous layer again with MDC and

separeted off the Organic layer B

Stir and separeted off the Organic layer C

Filtration

Distill off the filtrate u/V at 40 deg.

Temp. 25-30 0C

A-74




Intermediate Stage-III 4.024Methylene Dichloride 60.360

Thionyl Chloride 3.944 SO2 Gas 1.408

Cool the reaction mass to 15-20 deg.

Methylene Dichloride 60.360Water 40.260

Separate the Organic layer Aq. Effluent 43.762

Water 40.261Sodium Bicarbonate 2.011 Aq. Effluent 41.850


Solid waste 0.402

Recovered MDC 108.649Solvent Loss 12.072

Isopropyl Alcohol 4.024 Strip out with IPA

Isopropyl Alcohol 4.024

filtered off the solid

Isopropyl Alcohol 1.046 Org. Mother Liquor 8.422Filtration Loss 0.909

Drying loss 0.820

Stage-IV Intermediate Stage IV 2.422

Total 220.716 220.716

Bendamustinen hydrochloride (Stage-IV)

washed with IPA

Stir the reaction mass at 23-25 deg.

Distill off the filtrate u/V at 40 deg.

Temp. 35-40 0C

Degassed it well for 1h at 40-45 deg

Stit at 0-5 deg for 3 h

Dried u/V 45 0C for 8-10 hrs

Settle the layers

Stir for 30 mts. At 25 deg. Organic layer

ReactorStir for 4-5 h

Temp. 40-42 °C

Stir the reaction mass for 40 mts. At

Filter

A-75





Intermediate Stage IV 2.422Water 9.690



Filter Solid waste 0.242

Water 2.422 wash the bed with hot water

Distillate 17.442

Water 7.267

Aq. Effluent 5.814Filtration Loss 5.110

Drying loss 1.453

Stage-V Intermediate Stage V 1.672


Bendamustinen hydrochloride (Stage-V)


Filtration

Stir the reaction mass for 40 mts. at

Stirred the reaction mass at 10-15 deg.

ReactorStir for 3-4 h Temp. 45 °C

Distilled off the filtrate u/v at 55 deg.

A-76







Intermediate (Stage V) 1.672Acetone 11.700

Acetonitrile 11.700Water 2.507


Activated Carbon 0.167Stir the reaction

mass for 40 mts. at 40-45 deg.

Filtered it through Hyflow Solid waste 0.167

Acetonitrile 5.014 Recovered Solvent 14.035Solvent Loss 2.005

Acetonitrile 5.014 Recovered Solvent 14.035Solvent Loss 2.005

Acetonitrile 1.655Acetone 5.014

Org. Mother Liquor 8.020Filration Loss 2.205

Drying Loss 1.221


1.003

Bendamustinen hydrochloride (Stage-VI )

Finished Product Bendamustine HCl

strip out the residue with acetonitrile at 40-


ReactorStir for 15-20 mts.at

Temp. 45 °C

RM stirred for 2 hr at 2-5 deg.

Distilled off the solvent at 40-45 deg.

Filteration

A-77






1N1-Methyl-4-nitrobenzene-1,2-diamine

7.37 Reactant Intermediate stage-I 9.58 Intermediate

stage-I

2 Dihydro-2H-pyran-2,6(3H)-dione 6.28 Reactant CO2 emission 1.92 To atmosphere

throught vent

3 Sulphuric Acid 4.35 Reactant Aq. Mother liquor 598.91 To MEE

4 Isopropyl Alcohol 110.55 Solvent Filtration loss 19.17 Atmospheric Loss

6 Acetone 11.06 Solvent Drying Loss 6.17 Atmospheric Loss

7 n-Heptane 77.31 Solvent

8 Potassium Carbonate 6.12 Neutralization

9 Water 412.72Total Input 635.75 Total Output 635.75



1 Intermediate stage-I 9.58 Intermediate

stage-IIntermediate stage-II 6.71 Intermediate

stage-II

2 10% Palladium on Carbon 0.96 Catalyst Solid waste 0.96 For catalyst

regeneration

3 Methanol 239.53 Solvent Org. Mother liquor 194.02


4 Water 95.81 Aq. Effluent 95.81 To MEEFiltration loss 36.41Drying Loss 11.98


Stage IIIS. No Input Kg/


1 Intermediate stage-II 6.71 Intermediate

stage-IIIntermediate Stage-III 4.02 Intermediate

stage-III

2 2-chloroethanol 5.30 ReactantRecovered Methylene Dichloride


3 N,N-Di Isopropyl Ethyl Amine 9.39 Reactant Org. Mother


5 Methylene Dichloride 221.32 Solvent Aq. Effluent 56.84 To MEE

A-78



S. No Input Kg/


6 Isopropyl Alochol 3.35 Solvent Solvent Loss 22.13 Solvent loss

7 Ethyl Acetate 60.36 Solvent Drying loss 3.19 Atmospheric Loss

4 Water 53.65Total Input 360.08 Total Output 360.08



1 Intermediate Stage-III 4.02 Intermediate

stage-IIIIntermediate Stage IV 2.42 Intermediate

stage-IV

2 Thionyl Chloride 3.94 Reactant SO2 Gas 1.41

3 Methylene Dichloride 120.72 Solvent Solid waste 0.40 Inorganic HW

(landfill)

4 Isopropyl Alcohol 9.09 Solvent Recovered

MDC 108.65Sell to authorized recycler

5 Activated Carbon 0.40 Solvent Org. Mother


6 Sodium Bicarbonate 2.01 Filtration Aid Aq. Effluent 85.61 To MEE

7 Water 80.52 Base Solvent Loss 12.07 Solvent loss

Filtration Loss 0.91 Atmospheric Loss

Drying loss 0.82 Atmospheric Loss


Stage VS. No Input Kg/


1 Intermediate Stage IV 2.42 Intermediate

stage-IVIntermediate Stage V 1.67 Intermediate

stage-V

2 Hydrochloric Acid 9.69 Reactant Solid waste 0.24 Inorganic HW

(landfill)

3 Activated Carbon 0.24 Filtration Aid Aq. Effluent 10.92 To MEE

4 Water 19.38 Distillate 17.44

Drying loss 1.45 AtmosphericLoss


A-79




Stage VIS. No Input Kg/Batch Remarks Output Kg/Batch Remarks

1 Intermediate Stage V 1.67 Intermediate

stage-VBendamustine HCl 1.00 Finished

product

2 Acetone 16.71 Solvent Solid waste 0.17 Inorganic HW (landfill)

3 Acetonitrile 23.38 Solvent Recovered Solvent 28.07


4 Hydrochloric Acid 0.25 Acid Org. Mother


5 Activated Carbon 0.17 Filtration Aid Filration Loss 2.21 To MEE

6 Water 2.51 Solvent Loss 4.01 Solvent loss

Drying Loss 1.22 Atmospheric Loss


A-80



P5. TRAZODONE HCL

a) Manufacturing ProcessStage I[1,2,4]Triazolo[4,3-a]pyridin-3(2H)-one (KSM-01) is reacted with aq. Caustic solution in

presence of IPA and convert in to Stage-I. Product precipitate by stirring the reaction

mass at lower temperature. Isolate the solid by filtration. Dry the wet material to get

stage-I product.

Stage II1-(3-Chlorophenyl)piperazine (KSM-02) is condensed with 3-Chloro-1-propanol in

presence of sodium iodide and triethyl amine in Toluene to give Stage-II. Give water

wash to the reaction mass and acidify organic layer with aq. HCl solution. Charolaise

the mass & filter thru hyflow bed. Crystallize solid stage-II by adjusting alkaline pH with

aq. caustic solution. Isolate the solid by filtration. Dry the wet material to get stage-I

product.

Stage IIITrazodone hydrochloride stage-II is reacted with methane sulfonyl chloride in presence

of Triethyl amine in presence of DMF to give mesyl TRZ-A. Filter the reaction mass and

isolate inorganic salt. Charge Stage-I in filtrate and stir the reaction mass to convert in

to stage-III. Remove solvent by distillation. Dissolve product in Methanol and precipice

the product by adding water. Isolate the solid by filtration. Dry the wet material to get

stage-III product.

Stage IVTrazodone hydrochloride stage-III is dissolve in methanol and provide charcoal

treatment. Filter the reaction mass to remove charcoal. Slowly add hydrochloride to

filtrate to convert in to trazodone hydrochloride salt. Isolate the solid by filtration. Dry the

wet material to get stage-IV product.

Stage VTrazodone hydrochloride stage-IV is purified with methanol to give Trazodone

hydrochloride. Precipitate the product by stirring the reaction mass at lower

temperature. Isolate the solid by filtration. Wet material dissolve in methanol. Filter the

clear reaction mass. Precipitate the material by cooling and stirring of reaction mass.

Isolate the solid by filtration. Dry the wet material to get stage-IV product.

A-81





Stage I

Stage II

Stage III

A-82



Stage IV

Stage V

b) Process Flow Diagram

Input Qty., kg Process Out put Qty., kg

Purified Water 114.00 Caustic Flakes 12.40

Isopropyl Alcohol 506.30 [1,2,4]Triazolo[4,3-a]pyridin-

3(2H)-one 38.00

Isopropyl Alcohol 60.50 Org. Mother Liquor 681.20

Recovered Isopropyl Alcohol 8.00

Intermediate Stage I 42.00


Trazodone HCl Stage-I

Centrifugation

Drying

Stage-I

Reaction

A-83





Toluene 119.60

1-(3-Chlorophenyl)-piperazine 46.00 3-Chloro -1-propanol 26.50

Triethyl Amine 30.80 Sodium Iodide 3.50

Purified Water 138.00 Aq. Effluent 175.00 364.40

Hydrochloric Acid 37.00 Purified Water 135.00 Recovered Toluene 119.60

Activated Carbon 2.30 Purified Water 23.00

Hyflow 5.00 Spent Carbon 2.30 Purified Water 122.00 Filtration Spent Hyflow 5.00

Caustic Flakes 13.10 Purified Water 108.00

Purified Water 230.00 Centrifugation Aq. Effluent 670.90

Drying Aq. Effluent 15.00

Intermediate Stage II 52.00 Total 1,039.80 Total 1,039.80

Reaction

pH adjustment and layer seperation

Charcoal treatment

pH adjustment

Trazodone HCl Stage-II

Stage-II

Reaction

A-84




Intermediate Stage II 52.00 Dimethyl Formamide 147.30

Methane Sulfonyl Chloride 28.10 Triethyl Amine 26.80


Dimethyl Formamide 39.60 Intermediate (Stage I) 42.00

Recovered Dimethyl Formamid 245.00 Recovery Loss 0.40

Methanol 205.40 Purified Water 780.00

Purified Water 260.00 Centrifugation Aq. Effluent 1,281.30

Drying Aq. Effluent 20.00

Intermediate (Stage III) 68.00 Total 1,639.70 Total 1,639.70

Distillation

Stage-III

Precipitation

Reaction

Reaction

Filtration

Trazodone HCl Stage-III

A-85





Intermediate (Stage III) 68.00 Methanol 212.50


Methanol 105.90 Spent Carbon 3.40

Hydrochloric Acid 26.30 Precipitation

Methanol 53.60 Centrifugation Org. Mother Liquor 396.60

Drying Recovered Methanol 7.20

Intermediate (Stage IV) 62.50 Total 469.70 Total 469.70

Reaction

Trazodone HCl Stage-IV

Filtration

Stage-IV


Intermediate (Stage IV) 62.50 PurificationMethanol 816.00

Distillation Recovered Methanol 670.00 Recovery Loss 7.00

Methanol 49.80 Centrifugation Org. Mother Liquor 188.30

Drying Recovered Methanol 6.00

Trazadone HCl 57.00 Total 928.30 Total 928.30

Finished Product

Trazodone HCl Stage-V

A-86




Capacity of Finished Product, TPM : 4




1 [1,2,4]Triazolo[4,3-a]pyridin-3(2H)-one 38.00 Reactant Intermediate

Stage I 42.00 Intermediate Stage-I

2 Caustic Flakes 12.40 ReagentRecovered Isopropyl Alcohol


3 Isopropyl Alcohol 566.80 Solvent Org. Mother Liquor 681.20


4 Purified Water 114.00 Wash water


Stage II

S. No. Input Kg/


11-(3-Chlorophenyl)-piperazine

46.00 Reactant Intermediate Stage II 52.00 Intermediate

stage-II

2 3-Chloro -1-propanol 26.50 Reactant Recovered

Toluene 119.60Sell to authorized recycler

3 Triethyl Amine 30.80 Reagent Aq. Effluent 860.90 To MEE

4 Sodium Iodide 3.50 Reagent Spent Carbon 2.30 Inorganic HW

(Landfill)

5 Hydrochloric Acid 37.00 Reagent Spent Hyflow 5.00 Inorganic HW

(Landfill)6 Caustic Flakes 13.10 Reagent

7 Toluene 119.60 Solvent


decolourization9 Hyflow 5.00 Filter aid10 Purified Water 756.00 Washing media


A-87






1 Intermediate (Stage I) 42.00 Intermediate Intermediate

(Stage III) 68.00 Intermediate product

2 Intermediate Stage II 52.00 Intermediate

Recovered Dimethyl Formamide



28.10 Reactant Recovery Loss 0.40 Solvent loss

4 Triethyl Amine 26.80 Reagent Aq. Effluent 20.00 To MEE

5 Dimethyl Formamide 245.40 Solvent Solid Waste 25.00 Inorganic HW

(Landfill)6 Methanol 205.40 Solvent Aq. Effluent 1,281.30 To MEE7 Purified Water 1,040.00 Wash media


Stage IVS.No Input Kg/


1 Intermediate (Stage III) 68.00 Intermediate Intermediate

(Stage IV) 62.50 Intermediate Stage IV

2 Hydrochloric Acid 26.30 Reagent Recovered

Methanol 7.20Sell to authorized recycler

3 Methanol 372.00 Solvent Org. Mother Liquor 396.60



Decolourization Spent Carbon 3.40 Inorganic HW (Landfill)


Stage VS. No Input Kg/


1 Intermediate (Stage IV) 62.50 Intermediate Trazadone HCl 57.00 Finished Product

2 Methanol 865.80 Solvent Recovered Methanol 676.00 Sell to authorized

recyclerRecovery Loss 7.00 solvent lossOrg. Mother Liquor 188.30 Sell to authorized

recyclerTotal Input 928.30 Total Output 928.30

A-88



P6. GEMCITABINE HCL

a) Manufacturing ProcessStage IDi benzoyl lactum is react with Vitride in presence of Toluene, Methanol, and diluted

HCl solution. Organic layer is separated and solvent is removed under vacuum. It

further reacts with Methane sulphonyl chloride, Triethyl amine using Toluene. Solvent is

distill out under vacuum and the residue is Gemcitabine Hydrochloride Stage-I (In situ).

Stage IIN4 Acetyl cytosine, Hexamethyl disilazane ,Tri methyl silyl chloride, Tri methyl silyl

triflate are react with stage-I using Ethyl acetate as a media. Organic layer is separated,

and solvent is distilled out under vacuum. It further reacts with methanol, ammonia

solution by using purified water. Water is distilled out from Product layer under

vacuum. Product is crystallized by IPA, methanol and HCl. The product is filtered and

dried to get stage-II.

Stage IIIGemcitabine hydrochloride Stage-II is dissolved in purified water and re-precipitation of

pure Gemcitabine hydrochloride material is done by using Acetone. Slurry is cooled,

filtered and dried to get stage-III (pure gemcitabine hydrochloride)

Stage IVMother liquor (Methanol-ML) of stage-II (Process-II) having around higher percentage

of alpha anomer and it is neutralized with potassium hydroxide and reflux in highly

basic condition (Potassium hydroxide) in methanol solvent for 72 hours to obtain alpha

and beta anomers are in equal proportion.

Stage VCrude Gemcitabine hydrochloride is purifying in water & acetone.

A-89





Stage I

Stage II

Stage III

Stage IV

A-90



Stage V



Toluene 448.05 Dibenzoyl Lactum 75.00

Vitride 47.25 Methanol 8.93

579.23

Hydrochloric Acid 65.25 Toluene 65.25 Sodium

Bicarbonate 1.00 Effluent to ETP 725.00

Purified Water 551.00

536.73

Toluene 17.40 Recovered Toluene 520.00 Recovery Loss 10.00

24.13

Toluene 121.80 Methane Sulfonyl

Chloride 34.13 Effluent to ETP 413.00

Triethyl Amine 40.13 Purified Water 338.00

145.19

Ethyl Acetate 152.10 Toluene Recovery 120.00 Recovery Loss 2.69


Total 1,965.29 Total 1,965.29

Gemcitabine HCl (Stage-I) [Process I]

STAGE-I

Reaction and work up

Reaction

Distillation

work up

Distillation

A-91





Ethyl Acetate 810.00 N4 Acetyl Cytosine 45.75 Recovered Ethyl Acetate 348.00

Hexamethyl Disilazane 64.13 Recovery Loss 7.00

Trimethyl Silyl Chloride 1.88

Trimethyl Silyl Triflate 70.88

Stage-I 174.60 812.24

Purified Water 751.00 Effluent to ETP 1,126.10 Sodium

Bicarbonate 11.25

Ethyl Acetate 162.00

610.39

Methanol 468.47 Recovered Ethyl Acetate 640.00 Liquor Ammonia 165.00 Recovered Methanol 430.00

Isopropyl Alcohol 118.50 Recovered Isopropyl Alcohol 116.00

Recovery Loss 72.84

103.52

Methanol 23.70 ReactionHydrochloric Acid 34.78

162

Acetone 35.55 Organic Mother Liquor 177.75 Filtration Filtration Loss 11.80

8

Purified Water 48.00 Hydrochloric Acid 2.85 Purification

58.85

Acetone 28.44 Aq. Mother Liquor 45.00 Organic Mother Liquor 29.00 Filtration Loss 2.24

11.05Drying Recovered Acetone 1.30

Stage-II Intermediate (Stage II) 9.75

Total 3,016.78 Total 3,016.78

Filtration

Workup

Reaction & washing

Gemcitabine HCl (Stage-II) [Process I]

Reaction

A-92




Purified Water 69.00 Stage-II 9.75

Activated Carbon 0.98 Solid Waste 3.50 Hyflow 2.00

78.23

Acetone 639.90

718.13

Organic Mother liquor 695.00 Filtration loss 11.00 Recovered Acetone 3.73

Final product Gemcitabine HCl 8.40


Crystallisation

Filtration & Drying

Gemcitabine HCl (Stage-III) [Process I]

Charcolisation

A-93





Mother Liquor 177.75 Recovered Methanol + IPA 210.00

Potassium Hydroxide 31.88 Recovery loss 4.00

Methanol 177.75 173.38

Methanol 30.02 Inorganic Salt 36.70

166.7

Methanol (Flush) 142.20 Recovered Methanol 147.00

Isopropyl Alcohol 237.00 Recovered Isopropyl alcohol 232.00

Recovery loss 41.22 125.68

Methanol 283.61 Pottasium Hydroxide 37.50

Hydrochloric Acid (Cp Grade) 69.55

516.34

Methanol (Washing) 44.24 Inorganic salt 44.00

Methanol 15.80 532.38

Isopropyl Alcohol 237.00 Recovered Methanol 450.80 Recovered Isopropyl Alcohol 232.00

Recovery loss 5.00 81.58

Methanol 142.20 Hydrochloric Acid

(Cp Grade) 32.02

255.8

Acetone 30.02 Filtration Organic Mother Liquor 263.42 22.4

Purified Water 103.00 Hydrochloric Acid

(Cp Grade) 31.43

156.83

Acetone 60.04 Aq. Mother Liquor 140.49 Organic Mother Liquor 59.00 Filtration loss 8.50 Recovered Acetone 5.50

Stage-I Intermediate Stage IV 3.38

Total input 1,883.01 Total output 1,883.01

Purification

Filtration & Drying

Reaction

Filtration

Distillation

Reaction

Gemcitabine HCl (Stage-I) [Process II]

Reaction

Filtration

Distillation

A-94






Stage IS.No Input Kg/


1 Dibenzoyl Lactum 75.00 Reactant Intermediate

(Stage I) 174.60 Intermediate stage-I


34.13 Reactant Recovered Toluene 640.00


3 Vitride 47.25 Reactant Recovery Loss 12.69 Solvent Loss

4 Methanol 8.93 Reagent Effluent 1,138.00 To MEE

5 Hydrochloric Acid 65.25 reagent

6 Triethyl Amine 40.13 Reactant

7 Sodium Bicarbonate 1.00 For

Neutralization8 Toluene 652.50 solvent9 Ethyl Acetate 152.10 Solvent

10 Purified Water 889.00 Water washTotal input 1,965.29 Total output 1,965.29


Water 30.00 Stage-II 3.38

Activated Carbon 0.34 Solid Waste 2.34 Hyflow 2.00

78.23

Acetone 237.79

718.13

Organic Mother Liquor 265.00 Filtration loss 3.64 Drying loss -

Final product(Anomerized) Gemcitabine HCl 2.53


Filtration & Drying

Charcolisation

Gemcitabine HCl (Stage-II) [Process II]

Crystallisation

A-95




Stage IIS.No Input Kg/


1 Intermediate Stage I 174.60 Intermediate

stage-IIntermediate Stage II 9.75 Intermediate

stage-II

2 N4 Acetyl Cytosine 45.75 Reactant Organic Mother

Liquor 177.75 To be used in Stage IV

3 Hexamethyl Disilazane 64.13 Reactant Recovered

Ethyl Acetate 988.00Sell to authorized recycler

4 Trimethyl Silyl Chloride 1.88 Reactant Recovered


5 Trimethyl Silyl Triflate 70.88 Reactant

Recovered Isopropyl Alcohol


7 Liquor Ammonia 165.00 Reactant Recovered

Acetone 1.30Sell to authorized recycler

8 Hydrochloric Acid 37.63 Reagent Recovery Loss 79.84 Solvent loss


neutralization Filtration Loss 14.04 Solvent loss

9 Ethyl Acetate 972.00 Solvent Effluent 1,126.10 To MEE

10 Isopropyl Alcohol 118.50 Solvent Aq. Mother

Liquor 45.00 To MEE

11 Methanol 492.17 Solvent Organic Mother Liquor 29.00


12 Acetone 63.99 Solvent13 Purified Water 799.00 Water wash


Stage IIIS.

No. Input Kg/batch Remarks Output Kg/

batch Remarks

1 Intermediate Stage II 9.75 intermediate

stage-IIGemcitabine-HCl 8.40 Finished

product



3 Hyflow 2.00 Filtration media Organic Mother liquor 695.00



decolorization Filtration loss 11.00 Solvent loss

5 Purified Water 69.00 Water wash Solid Waste 3.50 Inorganic HW (landfill)


A-96



Stage IVS.No Input Kg/


1 Mother Liquor from Stage II 177.75

ML of intermediate stage-II

Intermediate Stage IV 3.38 Intermediate

stage-Iv

2 Isopropyl Alcohol 474.00 Solvent

Recovered Methanol + IPA


3 Methanol 835.82 SolventRecovered Isopropyl alcohol


4Hydrochloric Acid (Cp Grade)

133.00 reagent Recovered Acetone 5.50


5 Acetone 90.06 Solvent Recovery loss 50.22 Solvent loss

6 PotassiumHydroxide 69.38 For

neutralization Filtration loss 8.50 Solvent loss

7 Purified Water 103.00 Aq. Mother Liquor 140.49 To MEE

Organic Mother Liquor 322.42


Inorganic Salt 80.70 Inorganic HW (landfill)


Stage VS.No Input Kg/


1 Intermediate Stage IV 3.38 Intermediate

stage-IvGemcitabine-HCl 2.53 Finished

product

2 Acetone 237.79 Solvent Org. Mother liquor 265.00


3 Hyflow 2.00 Filtration media Filtration loss 3.64 Solvent loss

4 Activated carbon 0.34 For

Decolorization Solid waste 2.34 Inorganic HW (landfill)

5 Purified water 30.00 Wash waterTotal Input 273.51 Total Output 273.51

A-97




P7. CAPECITABINE

a) Manufacturing ProcessStage I5-Fluoro cytosine, Hexamethyl disilazane, Tri methyl silyl chloride reacts in presence of

toluene as a media to form Silyl compound. Silylated compound further reacts with 5-

Deoxy-1,2,3-tri-o-acetyl-D-ribofuranside in presence of Stannic chloride and Methylene

chloride. Neutralize the reaction mass with Sodium bicarbonate and purified water.

Organic layer is separated and wash with sodium bicarbonate solution followed by

drying over sodium sulphate. Remove solvent by vacuum distillation. Precipitate solid in

IPA, isolate solid by filtration and followed by drying. This is Capecitabine Stage-I.

Stage IICapecitabine Stage-I condense with n-Pentyl chloro formate in presence of pyridine

using MDC as a solvent. Add catalic amount Methanol to the reaction mass and then

washed it with purified water. MDC layer is dried over sodium sulphate and then

remove solvent by vacuum distillation. Resulting residue is Capecitabine Stage-II (In

situ).

Stage IIICapecitabine Stage-II is hydrolyze by aqueous sodium hydroxide (Caustic flakes)

solution using Methanol as a media, after reaction adjust pH ~5 of reaction mass with

HCl and extract product in MDC. Provide water washes to MDC layer and then give

Activated carbon treatment for the depolarization. Remove solvent by vacuum

distillation. Finally precipitate the product in Ethyl acetate, methanol and Hexane &

isolate solid by filtration. Dry the wet material to get Capecitabine Stage-III (Pure

Capecitabine).

A-98




Stage I

Stage II

A-99




Stage III



5- Fluoro Cytosine 60.00 5-Deoxy-1,2,3-Tri-O-Acetyl-D-

Ribofuranos 125.00 Toluene 716.00

Hexamethyl Disilazane 75.00 Ammonia Gas To Scrubber 7.90 Tri Methyl Silyl Chloride 9.30 Recovered Toluene 709.00

Methylene Chloride 3,300.00 Solid Waste 75.00 Stannic Chloride 137.70 Co2 Gas To Vent 56.10

Sodium Bicarbonate 236.30 Inorganic Salt 400.00 Isopropyl Alcohol 99.00 Sodium Sulphate 63.30

Purified Water 80.00 3717.60

Purified Water 1,127.00 Aq. Effluent 1,086.00

3694.60

Recovered Methylene Chloride 3,135.00 Recovered Isopropyl Alcohol 97.00 Recovery Loss 173.00

289.60

Org. Mother Liquor 335.00 Isopropyl Alcohol 349.00 Recovered Isopropyl Alcohol 178.60

125.00



Stage-I

Distilation

Capecitabine (Stage-I)

Reaction

Washing

Filtration & Drying

Process

A-100




Intermediate Stage I 125.00 Methylene Chloride 1,964.00

Pyridine 62.50 N-Pentyl Chloroformate 126.30 Solid Waste 74.80

Methanol 6.00

2209.00

Purified Water 750.00 Aq. Effluent From Process 870.00 Sodium Sulphate 62.50

2151.50

Recovered Methylene Chloride 1,866.00 Recovery Loss 98.00

187.50



Capecitabine (Stage-II)

Reaction

Washing

Distilation

Process

Residue stage-II


Capecitabine Stage-Ii 187.50 Methanol 346.00

Caustic Flakes 25.00 Hydrochloric Acid 73.75

Methylene Chloride 2,277.00 Purified Water 750.00

3659.25

Purified Water 1,500.00 Aq. Effluent 2,700.00 Activated Carbon 6.25 Solid Waste 25.00

2440.50

Ethyl Acetate 338.00 Recovered Methylene Chloride 2,162.00 Recovered Ethyl Acetate 332.00 Recovery Loss 121.00

163.50

Ethyl Acetate 315.00 Org. Mother Liquor 871.90 Methanol 16.00 Recovered Ethyl Acetate 15.00

Hexane 504.00 Drying Loss 10.00 101.60

Capecitabine 101.60


Finished Product

Distillation

Capecitabine (Stage-III)

Reaction

Washing

Filtration & Drying

Process

A-101









1 5- Fluoro Cytosine 60.00 Reactant Intermediate (Stage I) 125.00 Intermediate

(Stage I)

25-Deoxy-1,2,3-Tri-O-Acetyl-D-Ribofuranos

125.00 Reactant Recovered Toluene 709.00


3 Toluene 716.00 SolventRecovered Isopropyl Alcohol


4 Isopropyl Alcohol 448.00 SolventRecovered Methylene Chloride


5 Methylene Chloride 3,300.00 Solvent Recovery Loss 173.00 Solvent

Loss

6 Hexamethyl Disilazane 75.00 Reagent Aq. Effluent 1,086.00 To MEE

7 Tri Methyl Silyl Chloride 9.30 Reagent Ammonia Gas

To Scrubber 7.90To vent through scrubber

8 Stannic Chloride 137.70 Reagent CO2 Gas 56.10To atmospheric vent

9 Sodium Bicarbonate 236.30 Neutralizat-

ion Solid Waste 75.00 Inorganic HW (landfill)

10 Sodium Sulphate 63.30 For Drying Inorganic Salt 400.00 Inorganic HW (landfill)

11 Purified Water 1,207.00 Wash water

Org. Mother Liquor 335.00



Stage IIS.No Input Kg/



(Stage I)Intermediate (Stage II) 187.50 Intermediate

(Stage II)

2 Pyridine 62.50 Reagent Recovery Loss 98.00 Solvent loss

3 N-Pentyl Chloroformate 126.30 Reactant

Recovered Methylene Chloride


A-102



S.No Input Kg/


4 Methanol 6.00Reagent (to neutralize excess n-PCF)

Aq. Effluent From Process 870.00 To MEE

5 Methylene Chloride 1,964.00 Solvent Solid Waste 74.80 Inorganic HW

(Landfill)

6 Sodium Sulphate 62.50 For drying

7 Purified Water 750.00 Wash waterTotal input 3,096.30 Total output 3,096.30

Stage IIIS.No Input Kg/


1 Capecitabine Stage-Ii 187.50 Intermediate

(Stage II) Capecitabine 101.60 Finished Product

2 Methanol 362.00 SolventRecovered Methylene Chloride


3 Caustic Flakes 25.00 Reagent Recovered

Ethyl Acetate 347.00Sell to authorized recycler

4 Hydrochloric Acid 73.75 Reagent Recovery Loss 121.00 Solvent Loss

5 Methylene Chloride 2,277.00 Solvent Org. Mother


6 Ethyl Acetate 653.00 Solvent Aq. Effluent 2,700.00 To MEE


Decolorization Solid Waste 25.00 Inorganic HW (Landfill)

8 Hexane 504.00 For Crystalization Drying Loss 10.00 Atmospheric

Loss9 Purified Water 2,250.00 Wash water


A-103




P8. ERLOTINIB HCL

a) Manufacturing ProcessStage IEthyl 4,5-bis(2-methoxyethoxy)-2-aminobenzoate hydrochloride is react with

Ammonium formate in presence of Formamide as a media to form Erlotinib HCl stage-I,

Aqueous layer is separated with methylene chloride. Remove solvent by vacuum

distillation. Precipitate solid in IPA, isolate solid by filtration and washing followed by

drying. This is Stage-I.

Stage IIErlotinib HCl stage-I is reacted with oxalyl chloride in presence of methylene chloride

and Di methyl formamide as a media. Wash it with purified water and separate organic

layer. Activated charcoal is used to de-colorization of organic layer and distilled out

methylene chloride 7 to 10 volume of erlotinib HCl stage-I. Precipitate solid in n-

Heptane by distillate n-Heptane up to 70 to 75° C temperature reach atmospherically.

Isolate solid by filtration and washing followed by drying. This is stage-II.

Stage IIIErlotinib HCl stage-II is condensed with 3-ethnyl benzamine in presence of toluene and

isopropyl alcohol as media and isolate solid by filtration and washing followed by drying.

This is stae-III.

Stage IVErlotinib HCl stage-III is purified in isopropyl acetate and isolate solid by filtration and

washing followed by drying. This is stage-IV.


Stage I

A-104



Stage II

Stage III

Stage IV

A-105






Formamide 136.00 Ammonium Formate 21.63

Ethyl- 4,5-bis-(2-methoxyethoxy)-2-amino

benzoate hydrochloride (KSM1)

60.00

Purified Water 300.00 517.63

Methylene Chloride 1,425.60 Work up Aq. Effluent 472.60 1470.63


1,355.00

Isopropyl Alcohol 94.80 Recovered Isopropyl Alcohol 92.80

Recovery Loss 72.60 45.03

Isopropyl Alcohol 355.50 Organic Mother Liquor 310.00 Filtration Loss 21.33

69.2

Drying Recovered Isopropyl Alcohol 25.00

Stage-I Intermediate Stage-I 44.20


Erlotinib HCl (Stage-I)

Reaction

Distillation

Filtration

A-106




Intermediate Stage I 44.20 Dimethyl Formamide 8.36

Oxalyl Chloride 28.60 Methylene Chloride 623.04

704.2

Purified Water (Chilled) 354.00 Work up Aq. Effluent 473.00 585.2

Methylene Chloride 233.64 Solid Waste 4.50 Activated Carbon 4.42

818.76


n-Heptane 360.40 Recovered n-Heptane 95.00 Recovery Loss 210.50

398.66

n-Heptane 90.44 Organic Mother Liquor 392.00 Filtration Loss 33.00 Recoverd n-Heptane 22.10

Stage-II Intermediate Stage-II 42.00


Filtration & Drying

Erlotinib HCl (Stage-II)

Filtration

Reaction

Distillation


Toluene 328.86 3-Ethynyl Benzamine 16.55

Activated Carbon 2.10 347.51

Hyflow 4.00 Recovered Toluene 17.40 Toluene 17.40 Solid Waste 6.80

344.71

Toluene 73.08 Isopropyl Alcohol 132.72

Intermediate Stage-II 42.00 592.51

Toluene 109.62 Organic Mother Liquor 615.00 Isopropyl Alcohol 33.18 Filtration Loss 32.81

87.5

Drying Recovered Isopropyl Alcohol 35.00

Stage-III Intermediate Stage III 52.50

Total input 759.51 Total output 759.51

Erlotinib HCl (Stage-III)

Filtration

Carbon filtration

Filtration

Reaction

A-107




b) Summary of Mass Balance



Stage I

S. No. Input Kg/


1 Ammonium Formate 21.63 Reactant Intermediate Stage-I 44.20 Intermediate

(Stage I)

2

Ethyl- 4,5-bis-(2-methoxyethoxy)-2-amino benzoate hydrochloride (KSM1)

60.00 ReactantRecovered Methylene Chloride


3 Methylene Chloride 1,425.60 SolventRecovered Isopropyl Alcohol


4 Isopropyl Alcohol 450.30 Solvent Recovery Loss 72.60 Solvent Loss

5 Formamide 136.00 Solvent Aq. Effluent 472.60 To MEE

6 Purified Water 300.00 Wash water Filtration Loss 21.33 To MEE

7 Organic Mother Liquor 310.00




Intermediate Stage III 52.50 Isopropyl Acetate 685.56

Isopropyl Acetate 91.35 Organic Mother Liquor 710.00 Filtration Loss 36.50

Drying Recovered Isopropyl Acetate 34.35

Finished Product Erlotinib HCl 48.56


Purification

Filtration

Erlotinib HCl (Stage-IV)

A-108



Stage IIS.


batch Remarks


(Stage I)Intermediate Stage-II 42.00 Intermediate

(Stage II)

2 Oxalyl Chloride 28.60 Reactant



3 Methylene Chloride 856.68 Solvent Recovered n-

Heptane 117.10Sell to authorized recycler

4 Dimethyl Formamide 8.36 Solvent Recovery Loss 210.50 Solvent Loss

5 n-Heptane 450.84 Solvent Aq. Effluent 473.00 To MEE


Decolorization Filtration Loss 33.00 To MEE

7Purified Water (Chilled)

354.00 Wash water Organic Mother Liquor 392.00


8 Solid Waste 4.50 Inorganic HW (landfill)


Stage IIIS.

No. Input Kg/batch Remarks Output Kg/batch Remarks

1 Intermediate Stage-II 42.00 Intermediate

stage-IIIntermediate Stage III 52.50 Intermediate

stage-III

2 3-Ethynyl Benzamine 16.55 reactant Recovered

Toluene 17.40Sell to authorized recycler

3 Toluene 528.96 SolventRecovered Isopropyl Alcohol


4 Isopropyl Alcohol 165.90 Solvent Organic

Mother Liquor 615.00Sell to authorized recycler

5 Activated Carbon 2.10 Decoloriation Solid Waste 6.80 Inorganic HW

(landfill)

6 Hyflow 4.00 Filtration media Filtration Loss 32.81 To MEE


A-109




Stage IVS.


batch Remarks

1 Intermediate Stage III 52.50 Intermediate

stage-III Erlotinib HCl 48.56 Finished Product

2 Isopropyl Acetate 776.91 Solvent

Recovered Isopropyl Acetate


Filtration Loss 36.50 To MEE

Organic Mother Liquor 710.00



A-110



P9. IMATINIB MESYLATE ALPHA

a) Manufacturing ProcessStage I & IIAcid compound react with 1,1'-carbonyldiimidazole (CDI) with dimethylformamide as a

solvent to form stage-I (Insitu) which is further react with amine compound to form

stage-II. Stage-I is isolated by adding purified water and adjusting pH with ammonia

solution followed by filtration and drying to get dry stage-II

Stage IIIStage-I is purified by charcolization in methanol solvent followed by crystallization in

methanol & Dimethyl sulfoxide solvent mixture. Wet cake is re-purified in methanol &

Dimethylsulfoxide solvent mixture followed by filtration and drying to get dry stage-II.

Stage IVStage-II react with methane sulfonic acid in presence of Methanol & Dimethylsulfoxide

solvent mixture to form stage-III (Imatinib mesylate). Dry Imatinib mesylate obtained by

filtration and drying.


Stage I

Stage II

A-111




Stage III

Stage IV



Acid Compound 33.20 Dimethyl Formamide 118.00 1-1' Carbonyl Di Imidazole 17.50

168.7Stage-IIAmine Compound 25.00 Ammonia Solution 25.00 Purified Water 475.00

693.7

Aq. Mother Liquor 605.00 Filtration Loss 25.30

63.4

Drying Loss 19.00



Stage-I insitu Reaction

Filtration

Imatinib Mesylate (Stage-I & II)

Reaction

Drying

Stage II

A-112




Intermediate Stage-II 44.40 Methanol 933.00 Solid Waste 4.40 Activated Carbon 4.40

977.40

Recovered Methanol 793.00 Recovery Loss 12.80

171.60

Isopropyl Alcohol 69.50 Org. Mother Liquor 262.10 Methanol 69.50 Filtration Loss 8.00

40.50

Drying Drying Loss 5.00

Stage III Intermediate (Stage-III) 35.50


Charcolisation and Filtration

Filtration & Washing

Distillation

Imatinib Mesylate (Stage-III)


Intermediate (Stage III) 35.50 Isopropyl Alcohol 701.50 Methane Sulfonic Acid 6.85

743.85

Isopropyl Alcohol 112.00 Org. Mother Liquor 790.00 Filtration Loss 17.50

42.35

Isopropyl Alcohol 280.50 Purified Water 10.70

333.55

Isopropyl Alcohol 28.50 Org. Mother Liquor 310.00 Purified Water 1.07 Filtration Loss 8.52

Drying Drying Loss 12.00

Imatinib Mesylate 38.60


Finished Product


IPA + Water Purification


Reaction

Imatinib Mesylate (Stage-IV)

A-113







Stage I & IIS.


batch Remarks

1

4-(1(4-methylpiperaziynl)methyl) benzoic acid dihydrochloride(Acid Compound)

33.20 Reactant Intermediate (Stage II) 44.40 Intermediate

(stage-II)

21,1'-Carbonyldiimidazole

17.50 Reactant Aq. Mother Liquor 605.00 To MEE

3

N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidine amine (amine compound)

25.00 Reactant Filtration Loss 25.30 To MEE

4 Ammonia Solution 25.00 Reagent Drying Loss 19.00 Atmospheric Loss


6 Purified Water 475.00 Wash waterTotal Input 693.70 Total Output 693.70

Stage IIIS.


batch Remarks

1 Intermediate (Stage II) 44.40 Intermediate

(stage-II)Intermediate (Stage-III) 35.50 Intermediate

(stage-III)

2 Methanol 1,002.50 Solvent Recovered Methanol 793.00


3 Isopropyl Alcohol 69.50 Solvent Recovery


4 Activated Carbon 4.40

For Decolorizat-ion

Org. Mother Liquor 262.10 Organic HW

(CHWIF)



Drying Loss 5.00 Atmospheric Loss


A-114



Stage IVS.


batch Remarks

1 Intermediate (Stage-III) 35.50 Intermediate

(stage-III) Imatinib Mesylate 38.60 Finished Product

2 Methane Sulfonic Acid 6.85 Reagent Org. Mother Liquor 1,100.00 Organic HW

(CHWIF)

3 Isopropyl Alcohol 1,122.50 solvent Filtration Loss 26.02 To MEE

4 Purified Water 11.77 Wash water Drying Loss 12.00 Atmospheric Loss


A-115




P10. NILOTINIB

a) Manufacturing ProcessStage ICondensation of Ethyl 3-guanidino-4-methylbenzoate nitrate (KSM-I) and 3-

(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one (KSM-II) was done by using

dimethylformamide as solvent and sodium bicarbonate as base at 12 h at 120 0C. After

addition of water reaction mass was filtered and wet cake was dry u/v at 55-60 0C to

afforded stage-II.

Stage IIStage-I was hydrolyzed by sodium hydroxide (2M Aq. solution) using ethanol and water

as solvent for 5 h at 45-50 0C. Reaction mass was neutralized by using hydrochloric

acid (1N). After filtration, wet cake was dry u/v at 55-60 0C to afforded stage-II (Acid).

Stage IIIFirst converted acid (stage-II) to acid chloride (Intermediate) by using thionylchloride,

toluene and dimethyl formamide and stir for 5h at 60-65 0C. Acid chloride was

condensed with 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (KSM-III) by

using THF as solvent and N,N-Diisopropylethylamine, 4-Dimethylaminopyridine as base

and stir for 12h at 25-30 0C. After addition of S

Stage IVNilotinib dihydrochloride dehydrate was prepared by using hydrochloric acid and water,

methanol as solvent. After addition of ethyl acetate as anti solvent stir for 48 h to

crystallize the product. Filter the reaction mass and dry u/v at 55-60 0C to afforded

stage-IV (Nilotinib Dihydrochloride Dihydrate).

A-116




Stage I

Stage II

A-117




Stage III

A-118





Dimethyl Formamide 59.10 Ethyl 3-guanidino-4-

methylbenzoate nitrate (KSM-I)

100.00

3-(dimethylamino)-1-(pyridin-

3-yl)prop-2-en-1-one62.00

Sodium Bicarbonate 60.00 CO2 Gas 15.48 265.62

CoolingTemp. 25 -30 0C

265.62

Purified Water 1,050.00 1315.62

Aqueous Mother liquor 1,220.00 Filtration Loss 10.00

85.62

0.62

85.00

Intermediate Intermediate Stage-I 85.00

Total 1,331.10 Total 1,331.10

Recovered Dimethyl Formamide

Nilotinib (Stage-I)

Dryer55-60 0C

ReactorStir for 12 h at

125 0C to 130 0C

Process

Stir for 4 h Temp. 25-30 0C

Filtration 25-30 0C

A-119





Intermediate Stage I 85.00 Ethanol 425.00

Purified Water 425.00 Sodium Hydroxide (aq) 25.42

960.42

960.42

Hydrochloric Acid 23.45 Reactor Stir for 1 h Temp. 25-30 °C

983.87

Org. Mother Liquor 490.67 Recovered Ethanol 382.50 Recovery Loss 42.50

68.20

68.20

68.20

Intermediate Stage-II 66.00 Recovered Ethanol 2.20


Dryer55-60 °C

CoolingTemp. 25 -30 °C

Nilotinib (Stage-II)Process

ReactorStir for 5 h

Temp. 45-50 °C

FiltrationTemp. 25-30 °C

Stage-II

Unload wet cack

A-120




Intermediate (Stage II) 66.00 Toluene 924.00 HCl gas 13.80

Dimethyl Formamide 6.30 Thionyl Chloride 25.63

1008.13

1008.13

3-(4-methyl-1H-imidazol-1-yl)-5-

(trifluoromethyl)aniline49.37

4-Dimethyl Amino Pyridine 1.05

N,N-Diisopropylethylamine 69.62

Tetrahydrofuran 660.00 1788.17

Sodium Bicarbonate (aq) 1,320.00 3108.17

Org. Mother Liquor 1,461.23 RecoveredToluene 831.60 Recovered Tetrahydrofurane 594.00

Solvent Loss 158.40 62.94

62.94

Intermediate (Stage III) 60.00 Recovered Toluene 2.94

Total 3,121.97 Total 3,121.97

Dryer55-60 0C

Process

Distilation U/VTemp. 60-65 °C

Stir for 8 hTemp. 25-30 0C

Stage-III

CoolingTemp 25-30 0C

Stir for 12 h

ReactorStir for 5 h

Temp. 60-65 °C

FiltrationTemp. 25-30 0C

Nilotinib (Stage-III)

A-121









1Ethyl 3-guanidino-4-methylbenzoate nitrate (KSM-I)

100.00 Reactant Intermediate Stage-I 85.00 Intermediate

stage-I

2

3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one


0.62 To MEE


neutralizationAqueous Mother liquor 1,220.00 To MEE

4 Dimethyl Formamide 59.10 Solvent Filtration Loss 10.00 To MEE

5 Purified Water 1,050.00 Wash water CO2 Gas 15.48To Atmospheric vent


Intermediate (stage III) 60.00 Hydorchloric Acid 36.25

Purified Water 40.79 Methanol 1,200.00

1337.04

Ethyl Acetate 3,900.00

5237.04

Org. Mother Liquor 77.00 Recovered Methanol 1,080.00 Recovered Ethyl Acetate 3,510.00

Recovery Loss 510.00 60.04

60.04

Nilotinib 58.00 Recovered Methanol 2.04

Total 5,237.04 Total 5,237.04

ProcessNilotinib (Stage-IV)

Dryer55-60 0C

Finished Product

Stir for 48 hTemp. 25 -30 0C

ReactorStir for 5 h

Temp. 25-30 °C

FiltrationTemp. 25-30 0C

A-122



S. No Input Kg/





1 Intermediate Stage-I 85.00 Intermediate

stage-IIntermediate Stage-II 66.00 Intermediate

stage-II

2 Sodium Hydroxide (aq) 25.42 Reactant Recovered

Ethanol 384.70Sell to authorized recycler

3 Ethanol 425.00 Solvent Recovery Loss 42.50 Solvent loss

4 Purified Water 425.00 Solvent Org. Mother Liquor 490.67


5 Hydrochloric Acid 23.45 For

neutralizationTotal Input 983.87 Total Output 983.87




stage-IIIntermediate (Stage III) 60.00 Intermediate

stage-III

2 Thionyl Chloride 25.63 Reactant RecoveredToluene 834.54


3

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline

49.37 Reactant Recovered Tetrahydrofurane 594.00


4 4-Dimethyl Amino Pyridine 1.05 Reactant Solvent Loss 158.40 Solvent loss

5N,N-Diisopropylethylamine

69.62 Reagent Org. Mother Liquor 1,461.23Sell to authorized recycler

6 Dimethyl Formamide 6.30 Solvent HCl gas 13.80

To vent through scrubber

7 Toluene 924.00 Solvent8 Tetrahydrofuran 660.00 Solvent

9 Sodium Bicarbonate aq 1,320.00 For

neutralizationTotal Input 3,121.97 Total Output 3,121.97

A-123






1 Intermediate (Stage III) 60.00 Intermediate

stage-III Nilotinib 58.00 Finished product

2 Hydorchloric Acid 36.25 Reactant Recovered

Methanol 1,082.04Sell to authorized recycler

3 Purified Water 40.79 Solvent Recovered Ethyl Acetate 3,510.00


4 Methanol 1,200.00 Solvent Recovery Loss 510.00 Solvent loss

5 Ethyl Acetate 3,900.00 Solvent Org. Mother Liquor 77.00



A-124



P11. DASATINIB

a) Manufacturing ProcessStage I2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide is reacted with 4,6-

dichloro-2-methylpyrimidine in presence of 20 % Sodium tertiary-butoxide in

tetrahydrofuran as solvent. Neutralize reaction mass using aqueous Hydrochloric acid

solution to give Dasatinib Stage – I. Isolate the solid by filtration. Purify the wet material

by water slurry. Finally isolate the solid by filtration. Dry the wet material to get

Dasatinib Stage-I

Stage IIDasatinib Stage – I is condensed with 2-(piperazin-1-yl)ethan-1-ol in presence of

Diisopropylethyl amine in n-butanol as solvent. Remove solvent by distillation.

Precipitate the solid by n-Butanol. Isolate the solid by filtration. Purify the Wet material

by preparing slurry in water. Again isolate solid by filtration. Dry wet material to get

Dasatininb Stage-II.

Stage IIIDasatinib Stage – II is purified by using Ethanol and Purified water mixture as solvent.

Recrystallise the product by adding water. Isolate solid by filtration. Dry wet material to

get Dasatininb Stage-III.

Stage IVPrepare solution of formic acid in ethanol and charge Dasatinib Stage – III. Stage-III is

reacted with Fumaric to convert into Dasatinib Stage – IV. Isolate solid by filtration. Dry

wet material to get Dasatininb Stage-IV.

Stage VDasatinib Stage – IV is dissolved in purified water and filter the mass on hyflow bed.

Resulting reaction mass neutralized by using Ammonium carbonate solution in Purified

water to give Dasatinib. Isolate the solid by filtration. Purify the Wet material by

preparing slurry in water. Again isolate solid by filtration. Dry wet material to get

Dasatininb.

A-125




b) Reaction ChemistryStage I

Stage II

Stage III

Stage IV

A-126



Stage V

A-127






2-amino-N-(2-chloro-6-methylphenyl)-5-

thiazolecarboxamide 86.20

Tetrahydrofuran 1,120.70 4,6-dichloro-2-methyl

pyrimidine 62.90

Sodium Tertiary Butoxide solution (20%)

in THF 543.10

Hydrochloric Acid 86.20 Purified Water 258.60

Aq. Mother Liquor 390.50 Tetrahydrofuran 172.40 Org. Mother Liquor 1,836.20


Purified Water 172.40 Aq. Mother Liquor 594.80

Aq. Effluent 8.60

Intemediate (Stage-I) 103.40

Total 2,933.50 Total 2,933.50

Dastinib (Stage-I)Process

Reaction

Filtration

Reaction

Reactor

Filtration

Purification

Drying

Dasatinib Stage - I

A-128




Intermediate (Stage I) 103.40 2-(piperazin-1-yl)ethan-1-

ol 239.00

N,N-Diisopropylethylamine 67.80

n-Butanol 827.60

Recovered n-butanol 676.00

Recovery Loss 13.50

n-Butanol 103.40 Org. Mother Liquor 537.80


Purified Water 103.40 Aq. Mother Liquor 605.20

Aq. Effluent 15.50


Total 1,961.80 Total 1,961.80

Dastinib (Stage-II)Process

Dasatinib Stage - II

Reaction

Filtration

Purification

Distilation

Dryer

Filtration

A-129





Intermediate Stage II 113.80 Ethanol 2,275.90



Ethanol (aq) for washing 113.80 Aq. & Org. Mix ML 3,889.70

Aq. Effluent 13.80


Total 3,982.80 Total 3,982.80

Dastinib (Stage-III)

Purification

Crystallisation

Filtration

Drying

Dasatinib Stage III

Process


Ethanol 1,586.20 Fumaric Acid 54.70


Ethanol 79.30 Org. Mother Liquor 1,714.10

Recovered Ethanol 13.80

Intermediate Stage-IV 71.60

Total 1,799.50 Total 1,799.50

Filtration

Drying

Dasatinib Stage - IV

Preparation of solution

Reaction

Dastinib (Stage-IV)Process

A-130







Intermediate Stage IV 71.60 Purified Water 3,148.30

Purified Water 143.10 Purified Water 143.10 -

Carbon dioxide gas 10.50

Ammonia gas 4.30

Ammonium Carbonate 21.40 Purified Water 357.80

Purified Water 71.60 Aq. Mother liquor 3,857.00


Purified Water 143.10 Aq. Mother liquor 1,026.50

Aq. Effluent 10.30

Dasitinib 50.00

Total 4,958.60 Total 4,958.60

Finished Product

Filtration

Reaction

Purification

Dastinib (Stage-V)Process

Dryer

Filtration

Water slurry

Filtration

A-131




Stage I

S. No Input Kg/


12-amino-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide

86.20 Reactant Intemediate (Stage-I) 103.40 Intermediate

(Stage-I)

2 4,6-dichloro-2-methyl pyrimidine 62.90 Reactant Org. Mother


3 Hydrochloric Acid 86.20 Reactant Aq. Mother Liquor 985.30 To MEE

4 Tetrahydrofuran 1,293.10 Solvent Aq. Effluent 8.60 To MEE

5Sodium Tertiary Butoxide solution (20%) in THF

543.10 Catalyst

6 Purified Water 862.00 Media


Stage II

S. No Input Kg/


1 Intermediate (Stage I) 103.40 Intermediate (Stage I)

Intermediate (Stage-II) 113.80 Intermediate

(Stage-II)

3 2-(piperazin-1-yl)ethan-1-ol 239.00 Reactant Recovered

n-butanol 676.00Sell to authorized recycler

2 n-Butanol 931.00 Solvent Recovery Loss 13.50 Solvent loss

4 N,N-Diisopropylethylamine 67.80 Solvent Org. Mother


5 Purified Water 620.60 Media Aq. Mother Liquor 605.20 To MEE

Aq. Effluent 15.50


A-132



Stage III

S. No Input Kg/


1 Dasatinib Stage – II 113.80 Intermediate

(Stage II)Intermediate (Stage-III) 79.30 Intemediate

(Stage-III)

2 Ethanol 2,389.70 Solvent Aq. & Org. Mix ML 3,889.70


3 Purified Water 1,479.30 Media Aq. Effluent 13.80 To MEE


Stage IV

S. No Input Kg/


1 Intermediate (Stage III) 79.30 Reactant Intermediate

Stage-IV 71.60 Intermediate Stage-IV

2 Fumaric Acid 54.70 Reactant Recovered Ethanol 13.80 Sell to authorized

recycler

3 Ethanol 1,665.50 Solvent Org. Mother Liquor 1,714.10 Sell to authorized

recyclerTotal Input 1,799.50 Total Output 1,799.50

Stage V

S. No Input Kg/


1 Intermediate Stage-IV 71.60 Reactant Dasitinib 50.00 Finished

product

2 Ammonium Carbonate 21.40 Reactant Aq. Mother liquor 4,883.50 To MEE

3 Purified Water 4,865.60 Media Aq. Effluent 10.30 To MEEAmmonia gas 4.30 To scrubber

Carbon dioxide gas 10.50

Toatmosphere through vent


A-133




P12. PAZOPANIB HCl

a) Manufacturing ProcessStage I2,3-dimethyl-2H-indazol-6-amine hydrochloride (KSM-I) and 2,4-dichloropyrimidine

(KSM-II) are reacting in presence of sodium bicarbonate and methanol to give

Pazopanib stage – I. After reaction, isolate solid by filtration. Wet material is purified in

methanol. Precipitate the product in water. isolate solid by filtration. Dry the wet material

to get Pazopanib stage – I.

Stage IIPazopanib Stage – I react with dimethylcarbonate using anhydrous potassium

carbonate as base in Dimethyl formamide as solvent to give Pazopanib stage – II.

Crystallize product by water and methanol. Isolate the solid by filtration. Dry the wet

material to get Pazopanib stage – II.

Stage IIIPazopanib Stage – II is purified by carbon treatment in methanol solvent. Filter the

reaction mass on hyflow bed and remove carbon. Resulted filtrate is cooled and

precipitate the solid. Isolate the solid by filtration. Dry the wet material to get Pazopanib

stage – III.

Stage IVPazopanib Stage – III and 5-amino-2-methylbenzenesulfonamide (KSM-III) are reacted

in presence of catalytic amount of Conc. Hydrochloric acid in methanol to convert into

Pazopanib Stage – IV. Precipitate the product by stirring. Isolate the solid by filtration.

Dry the wet material to get Pazopanib stage – III.

Stage VPazopanib Stage – IV is converted to hydrated form by dissolving and crystallized in

acetonitrile & water mixture. Precipitate the product by cooling the reaction mass.

Isolate the solid by filtration. Purify the wet material by ethanol. Isolate the solid by

filtration. Dry the wet material. After drying hydrated form again converted in anhydrate

form Pazopanib HCl.

A-134



b) Reaction ChemistryStage I

Stage II

Stage III

A-135




Stage IV

Stage V

A-136





Methanol 923.10 2,3-dimethyl-2H-indazol-6-amine

hydrochloride (Indazol HCl)

76.90 Carbon Dioxide Gas 33.80

Sodium Bicarbonate 98.10 2,4-dichloropyrimidine 92.80

Org. Mother Liqour 1,072.20

Methanol 307.70

Methanol 153.90 Org. Mother Liqour 461.50

Water 769.20

Water 269.20 Aq. Mother Liqour 1,092.30 Methanol 76.90

Recovered Methanol 23.40

Intermediate (Stage-I) 84.60

Total 2,767.80 Total 2,767.80

Pazopanib HCl (Stage-I)Process

Reaction

Reaction

Stage-I

Filtration

Filtration

Reaction

Filtration

Drying

A-137





Dimethyl Formamide 304.60 Intermediate Stage-I 84.60 Carbon Dioxide Gas 12.30

Potassium Carbonate (anhydrous) 128.50

Dimethyl Carbonate 152.30

Water 1,353.90

Water 169.20 Aq. Mother Liqour 2,173.10 Methanol 84.60

Aq. Effluent 20.00


Total 2,277.70 Total 2,277.70

Reaction

Crystallisation

Filtration

Drying

Stage-II

Pazopanib HCl (Stage-II)Process


Methanol 1,446.20 Intermediate Stage II 72.30


Hyflow 5.00 Solid waste (Hyflow + Carbon) 9.00

Methanol 144.60

Methanol 72.30 Org. Mother Liquor 1,664.20



Total 1,744.00 Total 1,744.00

Purification

Pazopanib HCl (Stage-III)Process

Filtration

Drying

Stage-III

Crystallisation

Filtration

A-138




Methanol 1,384.60 Intermediate Stage-III 55.40

5-amino-2-methylbenzenesulfona

mide36.50


Methanol 110.80 Org. Mother Liquor 1,500.00



Total 1,591.20 Total 1,591.20

Drying

Stage-IV

Reaction

Filtration

Pazopanib HCl (Stage-IV)Process

A-139









1

2,3-dimethyl-2H-indazol-6-amine hydrochloride (Indazol HCl)

76.90 Reactant Intermediate (Stage-I) 84.60 Intermediate

(Stage-I)

2 2,4-dichloropyrimidine 92.80 Reactant Recovered



Acetonitrile 370.00 Water 205.40

Intermediate Stage IV 74.60

Acetonitrile 33.10 Water 18.50

Acetonitrile 67.70 Org. Mother Liquor 731.00 Water 37.70

Ethanol 320.80

Ethanol 74.60 Org. Mother Liquor 392.00

Recovered Ethanol 19.40

Pazopanib HCl 60.00

Total 1,202.40 Total 1,202.40

Cystallisation

Filtration

Reaction

Finished Product

Drying

Purification

Filtration

Pazopanib HCl (Stage-V)Process

Filtration

A-140



S. No Input Kg/


3 Sodium Bicarbonate 98.10 Reagent Org. Mother

Liqour 1,533.70Sell to authorized recycler

4 Methanol 1,461.60 Solvent Aq. Mother Liqour 1,092.30 To MEE

5 Water 1,038.40 Media Carbon Dioxide Gas 33.80

To atmospheric vent


Stage II

S. No Input Kg/


1 Intermediate (Stage-I) 84.60 Reactant Intermediate

(Stage-II) 72.30 Intermediate stage-II

2Potassium Carbonate (anhydrous)

128.50 Reagent Aq. Mother Liqour 2,173.10 To MEE

3 Dimethyl Carbonate 152.30 Reactant Aq. Effluent 20.00 To MEE

4 Methanol 84.60 Solvent Carbon Dioxide Gas 12.30 To atmospheric

vent


6 Water 1,523.10 MediaTotal Input 2,277.70 Total Output 2,277.70

Stage III

S. No Input Kg/


1 Intermediate (Stage-II) 72.30 Reactant Intermediate

(Stage-III) 55.40 Intermediate Stage-III

2 Activated Carbon 3.60

For decolouriza-tion

RecoveredMethanol 15.40


3 Hyflow 5.00 Filter aidSolid waste (Hyflow + Carbon)

9.00 Inorganic HW (landfill)

4 Methanol 1,663.10 Solvent Org. Mother Liquor 1,664.20



A-141




Stage IV

S. No Input Kg/batch Remarks Output Kg/batch Remarks

1 Intermediate (Stage-III) 55.40 Reactant Intermediate

(Stage-IV) 74.60 Intermediate (Stage-IV)

25-amino-2-methylbenzenesulfonamide

36.50 Reactant Recovered Methanol 16.60


3 Hydrochloric Acid 3.90 Reagent Org. Mother


4 Methanol 1,495.40 SolventTotal Input 1,591.20 Total Output 1,591.20

Stage V


1Intermediate (Stage-IV) 74.60 Reagent Pazopanib

HCl 60.00 Finished product

2 Acetonitrile 470.80 Solvent Recovered Ethanol 19.40


3 Water 261.60 Media Org. Mother Liquor 1,123.00


4 Ethanol 395.40 SolventTotal Input 1,202.40 Total Output 1,202.40

A-142



P13. SORAFENIB

a) Manufacturing ProcessStage IA mixture of 4-chloro-pyridine-2-carboxylic acid methyl amide hydrochloride, 4-

aminophenol and aqueous potassium hydroxide in Tetrahydrofuran was stirred at 65oC.

Product is isolated as hydrochloride salt. Thus obtained salt is dissolved in purified

water and neutralized using 10% NaOH solution to obtain crude Stage-I which is

crystalize in Isopropanol to get Stage-I.

Stage IIStage-II is prepared by reacting Stage-I with 4-chloro-3-(trifluoromethyl) phenyl

isocyanate in methylene chloride and dimethyl formamide at lower temperature.

Stage IIISorafenib base crude is purified by acetone and Dimethyl formamide

Stage IVSorafenib tosylate is prepared from Stage-III and PTSA in Methanol. Wet material is

dried to get API.


Stage I

Stage II

A-143




Stage III

Stage IV

A-144





Tetrahydrofuran 392.23 Paracetamol 48.27

Purified Water 32.65 Potassium Hydroxide 85.92 Potassium Carbonate 2.91 Tetrabutyl Ammonium

Bromide (TBAB) 17.16

4-chloro-pyridine-2-

carboxylic acid methyl amide

hydrochloride (Amide KSM)

44.12


Tetrahydrofuran 156.89 Org. Mother Liquor 948.29 Filtration Loss (Org ML 10.00


Purified Water 44.12 Solid Waste 0.04

Caustic flakes 23.82 Purified Water 301.78

Purified Water 88.24 Aq. Mother Liquor 867.34 Filtration Loss 8.00

Isopropyl Alcohol 101.04

Isopropyl Alcohol 20.21 Org. Mother Liquor 121.39 Filtration Loss 17.65

Recovered Isopropyl Alcohol 5.30

Intermediate stage-I 22.06


Filtration

Sorafenib Tosylate (Stage-I)

Filtrate/Cooling

Filteration

Reaction Mass/Heating

Wet Cake


Filteration

Reaction

Cool Reaction Mass

Reaction

Intermediate

Wet Cake/Heating

Cooling

Filtration

Drying

A-145





Intermediate Stage I 22.06 Methylene Chloride 97.95

Dimethyl Formamide 13.88

4-chloro-3-(trifluoromethyl) phenyl

isocyanate(Isocyanate KSM)

34.13

Methylene Chloride 48.75 Dimethyl Formamide 6.93

Methylene Chloride 117.36 Org. Mother Liquir 285.00 Purified Water 88.24 Filtration Loss (org ML 14.30

Aq. Mother Liquor 87.25 Filtration Loss 1.00

Recovered MDC 5.00

Intermediate Stage-II 36.75


Sorafenib Tosylate (Stage-II)

Drying

Intermediate

Filtration

Reaction Mass

Reaction Mass/Cooling/

Stirring

A-146




Intermediate Stage II 36.75 Acetone 641.95

Dimethyl Formamide 6.94

Activated carbon 1.83

Acetone 58.36 Solid Waste 1.83

Recovered Acetone 555.00 Recovery loss 4.96

Acetone 29.18 Org. Mother Liquor 167.95 Filtration loss 14.90


Intermediate Stage-III 28.37



Reaction Mass

Sorafenib Tosylate (Stage-III)

Sparkler Filtration

Distillation/Cooling

Filtration

Drying

Intermediate

A-147








Intermediate Stage III 28.37Methanol 89.88

Methanol 44.944-methyl benzene sulfonic acid monohydrate (PTSA) 12.18

Methanol 44.94 Org. Mother Liquor 166.00Filtration Loss 4.32


Sorafenib Tosylate 34.99


Finished Product

Reaction Mass

Reaction Mass

Cooling

Filtration

Drying

Sorafenib Tosylate (Stage-IV)

A-148





1

4-chloro-pyridine-2-carboxylic acid methyl amide hydrochloride (Amide KSM)

44.12 Reactant Intermediate stage-I 22.06 Intermediate

stage-I

2 Paracetamol 48.27 ReactantRecovered Isopropyl Alcohol


3Tetrabutyl Ammonium Bromide (TBAB)

17.16 Reactant Org. Mother Liquor 1,069.68


4 Potassium Hydroxide 85.92 Reactant Aq. Mother

Liquor 867.34 To MEE

5 Potassium Carbonate 2.91 Reactant Filtration

Loss 8.00 To MEE

6 Hydrochloric Acid 199.51 Reagent Solid Waste 0.04 Inorganic HW (landfill)

7 Tetrahydrofuran 549.12 SolventFiltration Loss (Org ML)

27.65

8 Isopropyl Alcohol 121.25 Solvent

9 Caustic flakes 23.82 Neutralizing agent

10 Purified Water 907.99 Wash waterTotal Input 2,000.07 Total Output 2,000.07



1 Intermediate stage-I 22.06 Intermediate stage-I

Intermediate Stage-II 36.75 Intermediate

stage-II

2 Methylene Chloride 264.06 Solvent Recovered MDC 5.00


3 Dimethyl Formamide 20.81 Solvent Org. Mother Liquir 285.00


4

4-chloro-3-(trifluoromethyl) phenyl isocyanate(Isocyanate KSM)

34.13 Reactant Aq. Mother Liquor 87.25 To MEE

5 Purified Water 88.24 Wash waterFiltration Loss (org ML)

15.30 To MEE


A-149







stage-IIIntermediate Stage-III 28.37 Intermediate

stage-III



3 Dimethyl Formamide 6.94 Solvent Recovery loss 4.96 Solvent loss

4 Activated carbon 1.83 For

DecolorizationOrg. Mother Liquor 167.95


Filtration loss 14.90 To MEE



Stage IVS. No Input Kg/batch Remarks Output Kg/batch Remarks

1 Intermediate Stage-III 28.37 Intermediate

stage-IIISorafenib Tosylate 34.99 Finished

Product

2

4-methyl benzene sulfonic acid monohydrate (PTSA)

12.18 Reactant Recovered Methanol 15.00


3 Methanol 179.76 Solvent Org. Mother Liquor 166.00




A-150



P14. N-BZ-BIS-LACTAM

a) Manufacturing Process1,5-bis[di isopropyl-(+)- 4’phenyl -2’-azetidinone-3’- hydroxyl-silyl] pentane reacts with

benzoyl chloride in presence of methylene chloride, 4- dimethyl amino pyridine and

triethyl amine. After completion of reaction, reaction mass washed with aqueous

solution of sodium bicarbonate and followed by aqueous sodium chloride solution. Give

Sodium sulphate treatment to organic layer. Romove methylene chloride by distillation.

Dilute the reaction mass with hexane. Product 1,5-bis[di isopropyl-(+)-(3’R,4’S)-1’-

benzoyl-4’-phenyl-2’-azetidinone-3’- hydroxyl -silyl] pentane (N-BZ bis lactam) is

seperated by column chromatography. Wash crometography with diethyl ether.

Remove the solvent by distillation. Strip out the reaction mass with Tetrahydrofuran.

Distillied out the solvent by distillation to get finished product.


A-151





Input Qty., kg Out put Qty., kg

1,5-bis[di isopropyl-(+)- 4’phenyl -2’-azetidinone-3’- hydroxyl-

silyl]pentane5.00

Methylene Chloride 66.00 4-Dimethyl Amino Pyridine 0.10

Triethyl Amine 3.26 Benzoyl Chloride 2.42

Benzoyl Chloride 0.61

Water 15.00 Aq. Effluent 21.69 Sodium Bicarbonate 0.30

Water 30.00 Sodium Chloride 4.50 Aq. Effluent 34.50 Sodium Sulphate 5.00 Solid Waste (Sodium Sulfate) 5.00

Methylene Chloride 26.40

Recovered Methylene Chloride 89.00 Recovery Loss 3.40

Hexane 13.08

Silica Gel 140.00 Hexane 2,275.92

Diethyl Ether 242.42

Recovered Hexane + Diethyl Ether 2,480.42 RecoveryLoss 51.00 Solid Waste (Silica gel) 141.00

Diethyl Ether 7.13 Recovered Diethyl Ether 7.00 Tetrahydrofuran 35.56 Recovery Loss 0.13

Recovered Tetrahydrofuran 34.50 Recovery Loss 1.06

N-BZ-BIZ Lactam 4.00

Total 2,872.70 Total 2,872.70

ProcessProduct: N-BZ-BIS-LACTAM Stage-I

Organic layer

Organic layer Distillation

Residue

Column Chromatography

Reaction mass

Reaction mass

Reaction mass

Column Effluent

Distillation

Rotavapor

Paclitaxel

A-152






S. No Input Kg/


1

1,5-bis[di isopropyl-(+)- 4’phenyl -2’-azetidinone-3’-hydroxyl-silyl]pentane

5.00 Reactant N-BZ-BIZ Lactam 4.00 Finished

Product

2 4-Dimethyl Amino Pyridine 0.10 Reagent



3 Triethyl Amine 3.26 Reagent Recovery Loss 3.40 Solvent loss

4 Benzoyl Chloride 3.03 ReactantRecovered Hexane + Diethyl Ether


5 Diethyl Ether 249.55 Solvent RecoveryLoss 51.00 Solvent loss

6 Hexane 2,289.00 Solvent Recovered Diethyl Ether 7.00


7 Tetrahydrofuran 35.56 Solvent Recovery Loss 0.13 Solvent loss

8 Methylene Chloride 92.40 Solvent Recovered Tetrahydrofuran 34.50


9 Sodium Bicarbonate 0.30 Washing

media Recovery Loss 1.06 Solvent loss

10 Sodium Chloride 4.50 Washing media Aq. Effluent 56.19 To MEE

11 Sodium Sulphate 5.00 Drying agent

Solid Waste (Sodium Sulfate) 5.00

Inorganic HW (landfill)

12 Silica Gel 140.00Absorbing agent for column

Solid Waste (Silica gel) 141.00


13 Water 45.00 Media


A-153




P15. N-BOC-BIS-LACTAM


1,5-bis[di isopropyl-(+)- 4’phenyl -2’-azetidinone-3’- hydroxyl-silyl] pentane reacts with

ditertiary butyl di carbonate in presence of methylene chloride, 4- dimethyl amino

pyridine and triethyl amine. After completion of reaction, reaction mass washed with

aqueous solution of sodium bicarbonate and followed by aqueous sodium chloride

solution. Give Sodium sulphate treatment to organic layer. Remove methylene chloride

by distillation. Dilute the reaction mass with hexane. Product 1,5-bis[di isopropyl-(+)-

(3’R,4’S)-1’-tert butoxycarbonyl-4’-phenyl-2’azetidinone – 3’- hydroxyl -silyl]pentane (N-

Boc bis lactam) is separated by column chromatography. Wash crometography with

diethyl ether. Remove the solvent by distillation. Strip out the reaction mass with

Tetrahydrofuran. Distil out the solvent by distillation to get finished product.


A-154





1,5-bis[di isopropyl-(+)- 4’phenyl -2’-azetidinone-3’-

hydroxyl-silyl]pentane2.50



Ditertiary Butyl Dicarbonate 3.50

Methanol 1.60

Water 26.00 Aq. Effluent 26.25

Water 12.00 Sodium Chloride 3.75 Aq. Effluent 15.75

Sodium Sulphate 2.50 Solid Waste (Sodium Sulphate) 2.50


Recovered Methylene Chloride + Methanol 90.70

Recovery Loss 3.30

Hexane 6.60

Silica Gel 50.00 Hexane 521.40

Ethyl Acetate 90.00

Recovered Hexane + Ethyl Acetate 605.50

Recovery Loss 12.50 Solid Waste (Silica Gel) 54.00

Recovered Tetrahydrofuran 22.00

Tetrahydrofuran 22.50 Recovery Loss 0.50

N-BOC-BIS Lactam 2.00


N-Boc-Bis-LactamProcess

Reaction mass

Reaction mass

Reaction mass

Residue

Organic layer Distillation

Column Chromatography

Colum Effluent

Distillation

Rotavapor

Finished Product

Organic layer

A-155








1

1,5-bis[di isopropyl-(+)-4’phenyl -2’-azetidinone-3’-hydroxyl-silyl]pentane

2.50 Reactant N-BOC-BIS Lactam 2.00 Finished

product

2 4-Dimethyl Amino Pyridine 0.25 Reactant

Recovered Methylene Chloride + Methanol


3 Ditertiary Butyl Dicarbonate 3.50 Reagent Recovery Loss 3.30 Solvent

loss

4 Methylene Chloride 92.40 Solvent

Recovered Hexane + Ethyl Acetate


5 Methanol 1.60 Solvent Recovery Loss 12.50 Solvent loss

6 Ethyl Acetate 90.00 Solvent Recovered Tetrahydrofuran 22.00


7 Hexane 528.00 Solvent Recovery Loss 0.50 Solvent loss

8 Tetrahydrofuran 22.50 Solvent Aq. Effluent 42.00 To MEE

9 Sodium Chloride 3.75 Washing media

Solid Waste (Sodium Sulphate)

2.50Inorganic HW (landfill)

10 Sodium Sulphate 2.50 Drying agent

Solid Waste (Silica Gel) 54.00


11 Silica Gel 50.00Absorbing agent for column

12 Water 38.00 MediaTotal input 835.00 Total Output 835.00

A-156



P16. 5-(4-(4-(5-CYANO-1H-INDOL-3-YL)-BUTYL)-PIPERAZIN-1-YL)BENZOFURAN-2-CARBOXAMIDE

a) Manufacturing ProcessEthyl-5-(4-(5-Cyno-1H-indol-3-yl)butyl)piprazin-1-yl)benzfuran-2-carboxylate

hydrochloride reacts with ammonia gas in presence of di methyl fromamide. After

reaction filter the reaction mass and remove inorganic salt. Charge water in to filtrate

and isolate the product by filtration. Dry the wet material to get product.


A-157








S. No Input Kg/


1

Ethyl 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl) benzofuran-2-carboxylate hydrochloride

43.50 Reactant Intermediate of Vilazodone 26.00 Finished

product

2 Ammonia Gas 6.71 Reactant Aq. Effluent 4,428.21 To MEE

3 Dimethyl Formamide 2,613.00 Solvent Solid Waste 40.00Inorganic HW (landfill)

4 Purified Water 1,831.00 MediaTotal Input 4,494.21 Total Output 4,494.21


Ethyl 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)

benzofuran-2-carboxylate hydrochloride

43.50

Ammonia Gas 6.71 Dimethyl Formamide 2,000.00


Purified Water 1,831.00 Aq. Effluent 4,428.21

Vilazodone 26.00

Total 4,494.21 Total 4,494.21

5-(4-(4-(5-Cyano-1H-indol-3-yl)-butyl)-piperazin-1-yl)benzofuran-2-carboxamide

Ammination Reaction

Crystallisation & Filtration

Finished Product

Filtration

A-158



P17. 2-ACETAMIDO-2-PHENETHYLPROPANE-1,3-DIYL-DIACETATE

a) Manufacturing ProcessStage IPhenyl ethyl bromide react with diethyl acetamido malonate in presence of cesium

carbonate and dimethyl sulphoxide, resulting reaction mix was quenched with purified

water and precipitated product was collected with filtration. Wet cake crude compound

was purified with ethyl acetate: methyl tertiary butyl ether to get pure stage-I. Solid

material isolated by filtration. Wet material dried to get stage-I

Stage IIStage-I is reduced with sodium borohydride and calcium chloride in presence of ethanol

to give hydroxy intermediate. Reaction mass quenched in acetic acid solution. Remove

solvent by distillation. Extract product by Methylene chloride from residue. Wash the

organic layer with solution of sodium metabisulphate and followed by sodium chloride

solution. Remove the solvent by distillation from organic layer. Resulting reaction mass

further acylated with acetic anhydride and triethyl amine in presence of methylene

chloride to gave stage-II. Reaction mass quenched in acetic acid solution and extract

product by methylene chloride. Remove the solvent by distillation. Purify the Crude

compound with ethyl acetate: methyl tertiary butyl ether to gave pure stage-II. Solid

material isolated by filtration. Wet material dried to get stage-II.


Stage I

A-159




Stage II

A-160





Dimethyl Sulphoxide 206.25 Cesium Carbonate 57.20

Diethyl Acetamidomalonate 29.25 Phenyl Ethyl Bromide 12.50

Water 625.00

Water 25.00 Aq. Mother Liquor 935.87

Ethyl Acetate 11.20

Methyl Tertiary Butyl Ether 27.75

Methyl Tertiary Butyl Ether 4.62 Org. Mother Liquor 46.00

Recovered MTBE 3.50

Intemediate Stage-I 13.40


Reaction

Process2-ACETAMIDO-2-PHENETHYLPROPANE-1,3-DIYL-DIACETATE STAGE I

Precipitation

Centrifuge

Drying

Intermediate

Reaction

Centrifugation

Wet Cake

A-161





Ethanol 105.30 Intermediate Stage I 13.40

Calcium chloride dihydrate 15.31 Sodium Borohydride 9.43

Water 66.75

Acetic Acid 21.02 Water 113.50

Sodium Chloride 8.00

Mix Solvent 101.00 Recovery Loss 2.00

Water 26.70 Methylene Chloride 98.48 Aq. Mother Liquor 190.00

Sodium Metabisulphite 8.01 Sodium Bicarbonate 3.34


Recovery Loss 6.96

Triethyl Amine 9.70 Acetic Anhydride 9.35


Water 26.70 Methylene Chloride 98.48 Aq. Mother Liquor 44.00

Acetic Acid 7.04

Ethyl Acetate 13.35 Methyl Tertiary Butyl Ether 29.60

Methyl Tertiary-butyl Ether 9.88 Org. Mother Liquor 148.20

Recovered MTBE 2.60

Fingolimod HCl 9.58


2-ACETAMIDO-2-PHENETHYLPROPANE-1,3-DIYL-DIACETATE STAGE IIProcess

Reaction

Finished Product

Quenching

Distillation

Work up

Distillation

Reaction mass

Work up

Drying

Purification

Centrifuge

A-162








1 Phenyl Ethyl Bromide 12.50 Reactant Intermediate Stage-I 13.40 Intermediate

(Stage-I)

2 Diethyl Acetamidomalonate 29.25 Reactant Recovered

MTBE 3.50Sell to authorized recycler

3 Cesium Carbonate 57.20 Reagent Org. Mother Liquor 46.00


4 Dimethyl Sulphoxide 206.25 Solvent Aq. Mother Liquor 935.87 To MEE

5 Methyl Tertiary Butyl Ether 32.37 Solvent

6 Ethyl Acetate 11.20 Solvent7 Water 650.00 Media




1 Intermediate Stage-I 13.40 Reactant Intermediate of

Fingolimod HCl 9.58 Finished Product

2 Sodium Borohydride 9.43 Reagent Recovered MTBE 2.60


3 Calcium chloride dihydrate 15.31 Reagent Mix Solvent 101.00


6 Acetic Acid 28.06 Reagent Recovery Loss 2.00 Solvent Loss

7 Acetic Anhydride 9.35 ReagentRecovered Methylene Chloride


8 Triethyl Amine 9.70 Reagent Recovery Loss 6.96 Solvent Loss

9 4-Dimethyl Amino Pyridine 1.00 Reagent Aq. Mother Liquor 234.00 To MEE

10 Methyl Tertiary Butyl Ether 39.48 Solvent Org. Mother


11 Ethyl Acetate 13.35 Solvent12 Ethanol 105.30 Solvent

13 Methylene Chloride 196.96 Solvent

A-163




S. No Input Kg/


14 Sodium Chloride 8.00 Washing media

15 Sodium Metabisulphite 8.01 Washing

media

16 Sodium Bicarbonate 3.34 Washing

media17 Water 233.65 Media


A-164



E4 SODIUM METHOXIDE


By using sodium hydroxide and methanol, prepare solution and distil out solvent and

water by distillation column and finally get desired mass. Reaction of sodium methoxide

with methanol will give sodium methoxide and water. Remove excess methanol and

water by column distillation. Remaining mass will be dry sodium methoxide.



Sodium Hydroxide + Methanol Sodium methoxide +

M.F : NaOH MF : CH3OH M.F : CH3NaOM.W : 40 M.W : 32 M.W : 54

Water

M.F : H2OM.W : 18


Sodium hydroxide 500.0 Methanol 1,580.0

2080 kgMethanol recovery 2,997.0

Methanol 4,000.0 Methanol loss 158.0 Water 225.0

Sodium Methoxide 2,700.0


ProcessSodium Methoxide

Reaction

Column distillation

Sodium methoxide in Methanol 25 %

A-165





Capacity of Finished Product, TPM : 275


S. No Input Kg/


1 Sodium hydroxide 500.0 Reactant Sodium

Methoxide 2,700.0 Finished Product

2 Methanol (Fresh) 2,583.0 Solvent Methanol

recovery 2,997.0 Sell to authorized recycler OR Reuse

3 Methanol (Recovered) 2,997.0 Recovered

SolventMethanol loss 158.0 Sell to authorized

recyclerEffluent 225.0 To MEE


Bendamustine stage-I:Condensation of KSM-I (N-1-Methyl-4-nitrobenzene-1,2-diamine) with Glutaric anhydride using sulphuric acid and IPA gave Stage-I.

Bendamustine stage-II:Synthesis of Bendamustine Stage-II by catalytic hydrogenation of Stage-I using Palladium on carbon in methanol as a solvent under H2 gas pressure.

Bendamustine stage-III:Bendamustine Stage-II react with 2-chloroethanol using DIPEA as a base in water and

product isolatied by extraction with dichloromethane followed by distillation and isolation using ethylacetate IPA mixture to get Stage-III.

Bendamustine stage-IV:Chlorination of stage-III with thionyl chloride using dichloromethane as a solvent. Product isolated after work-up, solvent distillation and IPA addition to get pure stage-IV.

Bendamustine stage-V:Hydrolysis of stage-IV using Hydrochloric acid in water to get stage-V as monohydrate Hydrochloride salt of Bendamustine Hydrochloride.

Bendamustine stage-VI:Purifcation of Stage-V using acetonitre,acetone and and aquous HCl mixture to give Bendamustine hydrochride

A-166

ANNEXURE 3 DETAILS OF RAW MATERIALS

REQUIREMENT


Details of Raw Material Requirement

DETAILS OF RAW MATERIAL REQUIREMENT

Sr. No. Name of Raw Material Product

Code kg/kgRequirement, TPM

Product Wise Total

1 (1R,2R)-Cyclohexane-1,2-Dicarboxylic acid P2 0.950 0.10 0.10

2 [1,2,4]Triazolo[4,3-a]pyridin-3(2H)-one P5 0.667 2.67 2.67

3 1-(3-Chlorophenyl)-piperazine P5 0.807 3.23 3.23

4 1,1’-CarbonyldiimidazoleP1 1.422 1.14

1.36P9 0.45 0.23

5 1,5-bis[di isopropyl-(+)- 4’phenyl -2’-azetidinone-3’- hydroxyl-silyl]pentane

P14 1.25 0.060.13

P15 1.25 0.06

6 10 % Palladium on CarbonP3 0.075 0.04

0.05P4 0.96 0.01

7 2-((4-cyanophenyl)amino) Acetic Acid P1 1.393 1.11 1.11

8 2-(piperazin-1-yl)ethan-1-ol P11 4.78 0.24 0.24

9 2,3-dimethyl-2H-indazol-6-amine hydrochloride (Indazol HCl) P12 1.28 0.08 0.08

10 2,4-dichloropyrimidine P12 1.55 0.09 0.09

11 2-amino-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide P11 1.72 0.09 0.09

12 2-chloroethanol P4 5.28 0.05 0.05

13 3-(1-Piperazinyl)-1,2-benzisothiazole P2 0.748 0.07 0.07

14 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline P10 0.85 0.13 0.13

15 3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one P10 1.07 0.16 0.16

16 3-Chloro -1-propanol P5 0.465 1.86 1.86

17 3-Ethynyl Benzamine P8 0.34 0.03 0.03


P9 0.86 0.43 0.43

19 4,6-dichloro-2-methyl pyrimidine P11 1.26 0.06 0.06

20 4-chloro-3-(trifluoromethyl) phenyl isocyanate(Isocyanate KSM) P13 0.98 0.10 0.10


P13 1.26 0.13 0.13

A-167






Product Wise Total

22 4-Dimethyl Amino Pyridine

P10 0.02 0.0027

0.015P14 0.03 0.0013

P15 0.13 0.01

P17 0.10 0.01

23 4-methyl benzene sulfonic acid monohydrate (PTSA) P13 0.35 0.03 0.03

24 5- Fluoro Cytosine P7 0.44 2.67 2.67

25 5-amino-2-methylbenzenesulfonamide P12 0.61 0.04 0.04

26 5-Deoxy-1,2,3-Tri-O-Acetyl-D-Ribofuranos P7 0.93 5.56 5.56

27 Acetic Acid (Glacial)

P1 5.000 4.00

4.70P3 1.107 0.55

P17 2.93 0.15

28 Acetic AnhydrideP3 1.087 0.54

0.59P17 0.98 0.05

29 Acetone

P1 23.600 18.88

61.08

P2 23.832 2.38

P3 37.152 18.58

P4 27.69 0.28

P6 94.40 18.88

P13 20.85 2.08

30 AcetonitrileP4 23.32 0.23

0.70P12 7.85 0.47

31 Activated Carbon

P1 0.155 0.12

1.01

P2 0.051 0.01

P3 0.176 0.09

P4 0.81 0.01

P5 0.100 0.40

P6 0.12 0.02

P7 0.05 0.28

P8 0.13 0.01

P9 0.11 0.06

A-168





Product Wise Total

P12 0.06 0.00

P13 0.05 0.01

32 Aluminium Carbonate P1 5.091 4.07 4.07

33 Ammonia Gas P16 0.26 0.01 0.01

34 Ammonia SolutionP9 0.65 0.32

3.34P6 15.10 3.02

35 Ammonium Carbonate P11 0.43 0.02 0.02

36 Ammonium Formate P8 0.45 0.04 0.04

37 Benzoyl Chloride P14 0.76 0.04 0.038

38 Benzyl Amine P3 1.863 0.93 0.93

39 Bezyal Chloroformate P3 6.424 3.21 3.21

40 Calcium chloride dihydrate P17 1.60 0.08 0.08

41 Caustic flakes

P2 0.143 0.01

3.25

P3 0.527 0.26

P5 0.447 1.79

P7 0.19 1.11

P13 0.68 0.07

42 Cesium Carbonate P17 5.97 0.30 0.30

43 Cyclohexane P2 4.238 0.42 0.42

44 Dibenzoyl Lactum P6 6.86 1.37 1.37

45 Diethyl Acetamidomalonate P17 3.05 0.15 0.15

46 Diethyl Ether P14 62.39 3.12 3.12

47 Dihydro-2H-pyran-2,6(3H)-dione P4 6.26 0.06 0.063

48 Dimethyl Carbonate P12 2.54 0.15 0.15

49 Dimethyl Formamide

P2 20.005 2.00

26.35

P5 4.305 17.22

P8 0.17 0.02

P9 3.06 1.53

P10 1.13 0.17

P12 5.08 0.30

P13 0.79 0.08

A-169






Product Wise Total

P16 100.50 5.03

50 Dimethyl Sulfate P3 1.881 0.94 0.94

51 Dimethyl Sulphoxide P17 21.53 1.08 1.08

52 Ditertiary Butyl Dicarbonate P15 1.75 0.09 0.09

53 D-Serine P3 1.515 0.76 0.76

54 Ethanol

P1 46.920 37.54

43.64

P10 7.33 1.10

P11 81.10 4.06

P12 6.59 0.40

P17 10.99 0.55

55Ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido) propanoate [DAP]

P1 2.000 1.60 1.60

56 Ethyl 3-guanidino-4-methylbenzoate nitrate (KSM-I) P10 1.72 0.26 0.26

57Ethyl- 4,5-bis-(2-methoxyethoxy)-2-amino benzoate hydrochloride (KSM1)

P8 1.24 0.12 0.12

58Ethyl 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl) benzofuran-2-carboxylate hydrochloride

P16 1.67 0.08 0.08

59 Ethyl Acetate

P1 53.709 42.97

108.97

P3 6.682 3.34

P4 60.19 0.60

P6 102.85 20.57

P7 4.84 29.02

P10 67.24 10.09

P15 45.00 2.25

P17 2.56 0.13

60 Exo-cis-5-norbornene-2,3-dicaroxylic anhydride P2 0.613 0.06 0.06

61 Formamide P8 2.80 0.28 0.28

62 Fumaric Acid P11 1.09 0.05 0.05

63 Hexamethyl Disilazane P6 5.87 1.17 4.51

A-170





Product Wise Total

P7 0.56 3.33

64 Hexane

P7 3.73 22.40

64.21P14 572.25 28.61

P15 264.00 13.20

65 Hydrochloric Acid

P1 0.169 0.14

18.37

P2 8.194 0.82

P3 8.939 4.47

P4 9.91 0.10

P5 1.111 4.44

P6 21.58 4.32

P7 0.55 3.28

P10 1.03 0.15

P11 1.72 0.09

P12 0.07 0.00

P13 5.70 0.57

66 Hydrogen GasP2 0.006 0.001

0.01P3 0.015 0.01

67 Hyflow

P3 0.121 0.06

0.50

P5 0.088 0.35

P6 0.37 0.07

P8 0.08 0.01

P12 0.08 0.01

68 Isobutyl Chloroformate P3 1.927 0.96 0.96

69 Isopropyl AcetateP1 33.218 26.57

28.17P8 16.00 1.60

70 Isopropyl Alcohol

P1 23.927 19.14

107.95

P4 122.64 1.23

P5 9.944 39.78

P6 54.21 10.84

P7 3.32 19.91

P8 12.69 1.27

A-171






Product Wise Total

P9 30.88 15.44

P13 3.47 0.35

71 Isopropyl Alcohol HCl P2 0.517 0.05 0.05

74 Maleic Acid P1 1.355 1.08 1.08

75 Methane Sulfonic AcidP1 0.140 0.11

0.20P9 0.18 0.09

76 Methane Sulfonyl ChlorideP2 1.363 0.14

2.73P5 0.493 1.97P6 3.12 0.62

77 Methanol

P1 15.47 12.38

592.69

P2 19.867 1.987

P3 86.061 43.030

P4 638.87 6.39

P5 25.319 101.28

P6 349.49 69.90

P7 7.54 45.24

P8 23.36 2.34

P9 51.88 25.94

P10 34.48 5.17

P11 3.45 0.17P12 97.65 5.86P13 28.00 2.80

P14 31.25 1.56

P15 78.30 3.92

P16 3.85 0.19

P17 29.10 1.46

E4 0.957 263.08

78 Methyl Isobutyl Ketone P1 12.858 10.29 10.29

79 Methyl Tertiary Butyl EtherP2 3.173 0.32

16.28P3 31.171 15.59P17 7.50 0.38

80 Methylene Chloride P1 61.782 49.43 454.92

A-172





Product Wise Total

P2 23.056 2.31P3 109.352 54.68

P4 341.05 3.41

P7 55.86 335.16

P8 47.00 4.70P13 7.55 0.75P14 23.10 1.16

P15 46.20 2.31

P17 20.56 1.03

81N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidine amine (amine compound)

P9 0.65 0.32 0.32

82 N,N-Di Isopropyl Ethyl Amine

P4 9.36 0.09

0.34P10 1.20 0.18

P11 1.36 0.07

83 N,N-Dimethyl Formamide P1 5.655 4.52 4.52

84 N1-Methyl-4-nitrobenzene-1,2-diamine P4 7.35 0.07 0.073

85 N4 Acetyl Cytosine P6 4.19 0.84 0.84

86 n-Butanol P11 18.62 0.93 0.93

87 n-Heptane

P2 4.205 0.42

2.12P4 77.09 0.77

P8 9.28 0.93

88 n-Hexane P2 1.689 0.17 0.17

89 n-Hexyl Chloroformate P1 0.569 0.46 0.46

90 N-Methyl Morpholine P3 1.413 0.71 0.71

91 N-Pentyl Chloroformate P7 0.94 5.61 5.61

92 Oxalyl Chloride P8 0.59 0.06 0.06

93 Palladium on Carbon P2 0.006 0.001 0.001

94 Paracetamol P13 1.38 0.14 0.14

95 Phenyl Ethyl Bromide P17 1.30 0.07 0.07

96 Potassium CarbonateP1 1.195 0.96

4.20P2 0.637 0.06

A-173






Product Wise Total

P3 5.970 2.98

P4 6.10 0.06

P12 2.14 0.13

P13 0.08 0.01

97 Potassium HydroxideP6 6.35 1.27

1.52P13 2.46 0.25

98 Pyridine P7 0.46 2.78 2.78

99 Silica GelP14 35.00 1.75

3.00P15 25.00 1.25

100 Sodium Bicabonate

P2 0.153 0.02

11.47

P3 0.870 0.43

P4 2.01 0.02

P6 1.12 0.22

P7 1.75 10.50

P10 1.03 0.16

P12 1.64 0.10

P14 0.08 0.00

P17 0.35 0.02

101 Sodium Bicarbonate (aq) P10 22.76 3.41 3.41

102 Sodium Borohydride P17 0.98 0.05 0.05

103 Sodium CarbonateP1 3.000 2.40

2.44P2 0.379 0.04

104 Sodium Chloride

P2 3.800 0.38

2.17P14 1.13 0.06

P15 1.88 0.09P17 0.84 0.04P1 2.000 1.60

105 Sodium hydroxideE4 0.185 50.93

50.99P10 0.44 0.07

106 Sodium Iodide P5 0.061 0.25 0.25

107 Sodium Metabisulphite P17 0.84 0.04 0.04

108 Sodium Sulphate P7 0.93 5.59 5.72

A-174





Product Wise Total

P14 1.25 0.06

P15 1.25 0.06

109 Sodium Tertiary Butoxide solution (20%) in THF P11 10.86 0.54 0.54

110 Stannic Chloride P7 1.02 6.12 6.12

111 Sulphuric Acid P4 4.34 0.04 0.043

112 Tetrabutyl Ammonium BromideP3 0.176 0.09

0.14P13 0.49 0.05

113 Tetrahydrofuran

P1 31.636 25.31

52.62

P2 3.438 0.34

P3 42.785 21.39

P10 11.38 1.71

P11 25.86 1.29

P13 15.69 1.57

P14 8.89 0.44

P15 11.25 0.56

114 Thionyl ChlorideP4 3.93 0.04

0.11P10 0.44 0.07

115 Toluene

P1 10.764 8.61

82.30

P2 4.942 0.49

P3 35.130 17.56

P5 2.098 8.39

P6 59.70 11.94

P7 5.30 31.82

P8 10.89 1.09

P10 15.93 2.39

116 Trimethyl Silyl ChlorideP6 0.17 0.03

0.45P7 0.07 0.41

117 Triethyl Amine

P2 1.376 0.14

5.52P3 1.026 0.51

P5 1.011 4.04

P6 3.67 0.73

A-175






Product Wise Total

P14 0.82 0.04

P17 1.01 0.05

118 Trimethyl Silyl Triflate P6 6.48 1.30 1.30

119 Urea P2 0.124 0.01 0.012

120 Vitride/SynhydridP6 4.32 0.86

1.46P2 5.985 0.60

A-176

ANNEXURE 4 DETAILS OF STORAGE OF PRODUCTS

& RAW MATERIALS


Details of Product & Raw Materials Storage

DETAILS OF PRODUCTS & RAW MATERIAL STORAGE

� DETAILS OF PRODUCT STORAGE

Sr. No.

Name of Raw Material CAS Nos. Physical

FormType Of

Packing / Storage

Storage tank/ Container Max.

Storagecapacity

(MT)

Storage Pressure

Storage Temp Market Mode of

TransportSize (MT) Nos.

P1 Dabigatran Etexilate Mesylate 872728-81-9 Solid HDPE Drum 0.025 32 0.800 Atmosphere 2 to

8° CDomestic/

Export Road/Air/Sea

P2 LurasidoneHCl 367514-88-3 Solid HDPE Drum 0.025 4 0.100 Atmosphere NMT 25° C

Domestic/Export Road/Air/Sea

P3 Lacosamide 175481-36-4 Solid HDPE Drum 0.025 20 0.500 Atmosphere NMT 25° C


P4 BendamustineHCl 3543-75-7 Solid HDPE Drum 0.010 1 0.010 Atmosphere NMT 25° C


P5 Trazodone HCl 25332-39-2 Solid HDPE Drum 0.025 160 4.000 Atmosphere NMT 25° C


P6 Gemcitabine HCl 12211-03-9 Solid HDPE Drum 0.025 8 0.200 Atmosphere NMT 25° C


P7 Capecitabine 154361-50-9 Solid HDPE Drum 0.025 240 6.000 Atmosphere NMT 25° C


P8 Erlotinib HCl 183319-69-9 Solid HDPE Drum 0.025 4 0.100 Atmosphere NMT 25° C


P9 Imatinib Mesylate Alpha 220127-57-1 Solid HDPE Drum 0.025 25 0.500 Atmosphere NMT

25° CDomestic/

Export Road/Air/Sea

P10 Nilotinib 641571-10-0 Solid HDPE Drum 0.025 6 0.150 Atmosphere NMT 25° C


P11 Dasatinib 302962-49-8 Solid HDPE Drum 0.025 2 0.050 Atmosphere NMT 25° C


P12 Pazopanib HCl 635702-64-6 Solid HDPE Drum 0.025 3 0.060 Atmosphere NMT 25° C


P13 Sorafenib 475207-59-1 Solid HDPE Drum 0.025 4 0.100 Atmosphere NMT 25° C


P14 N-BZ-Bis-Lactam -- Viscous Liquid HDPE Drum 0.005 10 0.050 Atmosphere 2 to 8°

CDomestic/

Export Road/Air/Sea

P15 N-BOC-Bis-Lactam -- Viscous Liquid HDPE Drum 0.005 10 0.050 Atmosphere 2 to 8°

CDomestic/

Export Road/Air/Sea

P16

5-(4-(4-(5-Cyano-1H-indol-3-yl)-butyl)-piperazin-1-yl)benzofuran-2-carboxamide [Intermediate for Vilazodone]

-- Liquid HDPE Drum 0.200 01 0.050 Atmosphere NMT 25° C


P17

2-acetamido-2-phenethylpropane-1,3-diyl-diacetate [Intermediate for Fingolimod]

-- Solid HDPE Drum 0.025 2 0.050 Atmosphere NMT 25° C


� DETAILS OF RAW MATERIAL STORAGE

Sr. No.


FormType Of

Packing / Storage


Storage capacity

(MT)

Storage Pressure

Storage Temp Source Mode of


1 (1R,2R)-Cyclohexane-1,2- Dicarboxylic acid 2305-32-0 Solid Carboy 0.025 4 0.100 Atm. Ambient Import Air / Sea /

Road

A-177



Details of Product & Raw Material Storage

Sr. No.


FormType Of

Packing / Storage


Storage capacity

(MT)

Storage Pressure



2 [1,2,4]Triazolo[4,3-a]pyridin-3(2H)-one 6969-71-7 Solid HDPE Drum 0.100 10 1.000 Atm. Ambient Domestic Road

3 1-(3-Chlorophenyl)-piperazine 13078-15-4 Solid HDPE Drum 0.100 10 1.000 Atm. Ambient Domestic Road

4 1,1’-Carbonyldiimidazole 530-62-1 Solid Fiber Drum 0.025 20 0.500 Atm. Ambient Domestic Road

5

1,5-bis[di isopropyl-(+)-4’phenyl -2’-azetidinone-3’-hydroxyl-silyl]pentane

-- Liquid HDPE Container 0.005 10 0.050 Atm. 2 - 8 °C Domestic Air / Sea /

Road

6 10 % Palladium on Carbon

Carbon: 7440-40-0Palladium: 7440-05-3

Solid Carboy 0.005 3 0.015 Atm. Ambient Domestic Road

72-((4-cyanophenyl)amino) Acetic Acid

42288-26-6 Solid Fiber Drum 0.025 16 0.400 Atm. Ambient Domestic Road

8 2-(piperazin-1-yl)ethan-1-ol 103-76-4 Liquid HDPE Drum 0.050 5 0.250 Atm. 23-27

°CDomestic / Import

Air / Sea / Road

9

2,3-dimethyl-2H-indazol-6-amine hydrochloride (IndazolHCl)

635702-60-2 Solid HDPE Container 0.025 1 0.025 Atm. 23-27

°C Domestic Road

10 2,4-dichloropyrimidine 3934-20-1 Solid HDPE Container 0.025 1 0.025 Atm. 2 - 8 °C Domestic Road

112-amino-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide


°CDomestic / Import

Air / Sea / Road

12 2-chloroethanol 107-07-3 0.050 1 0.050

13 3-(1-Piperazinyl)-1,2-benzisothiazole 87691-87-0 Solid HDPE Drum 0.025 1 0.025 Atm. 23-27

°C Domestic Road

143-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline

-- Solid HDPE Container 0.050 1 0.050 Atm. 23-27

°C Domestic Road

153-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one


°C Domestic Road

16 3-Chloro -1-propanol 627-30-5 Liquid HDPE Drum 0.050 1 0.050 Atm. Ambient Domestic Road

17 3-Ethynyl Benzamine 54060-30-9 Solid Carboy 0.005 8 0.040 Atm. Ambient Imported Air / Sea / Road

18


-- Solid Fiber Drum 0.100 5 0.500 Atm. Ambient Imported Air / Sea / Road

19 4,6-dichloro-2-methyl pyrimidine 1780-26-3 Solid HDPE

Container 0.020 1 0.020 Atm. 23-27°C Domestic Air / Sea /

Road

20

4-chloro-3-(trifluoromethyl) phenyl isocyanate(Isocyanate KSM)

327-78-6 Solid HDPE Container 0.010 4 0.040 Atm. 2 - 8 °C Domestic Road

21


-- Solid Drum 0.010 5 0.050 Atm. Ambient Domestic Road

A-178



Sr. No.


FormType Of

Packing / Storage


Storage capacity

(MT)

Storage Pressure



22 4-Dimethyl Amino Pyridine 1122-58-3 Solid HDPE

Container 0.025 1 0.015 Atm. Ambient Domestic Road

234-methyl benzene sulfonic acid monohydrate (PTSA)

6192-52-5 Solid Bag 0.005 2 0.010 Atm. Ambient Domestic Road

24 5- Fluoro Cytosine 2022-85-7 Solid Fiber Drum 0.025 1 0.025 Atm. 2 - 8 °C Imported Air / Sea / Road

255-amino-2-methylbenzenesulfonamide


°C Domestic Road

26 5-Deoxy-1,2,3-Tri-O-Acetyl-D-Ribofuranos 6974-32-9 Solid HDPE

Container 1.000 5 5.000 Atm. 2 - 8 °C Domestic / Import

Air / Sea / Road

27 Acetic Acid (Glacial) 64-19-7 Liquid Carboy 0.250 6 1.500 Atm. Ambient Domestic Road

28 Acetic Anhydride 108-24-7 Liquid HDPE Carboy 0.050 4 0.200 Atm. Ambient Domestic Road

29 Acetone 67-64-1 Liquid MS Drum 2 5 10.000 Atm. Ambient Domestic Road

30 Acetonitrile 75-05-8 Liquid Drum 0.200 1 0.200 Atm. Ambient Domestic Road

31 Activated Carbon 7440-44-0 Solid Bag 0.050 6 0.300 Atm. Ambient Domestic Road

32 Aluminium Carbonate 1339-92-0 Solid Bag 0.500 3 1.500 Atm. Ambient Domestic Road

33 Ammonia Gas 7664-41-7 Gas Cylinder 0.001 5 0.005 Atm. Ambient Domestic Road

34 Ammonia Solution 7664-41-7 Liquid Carboy 0.200 6 1.200 Atm. Ambient Domestic Road

35 Ammonium Carbonate 506-87-6 Solid HDPE Container 0.005 2 0.010 Atm. Ambient Domestic Road

36 Ammonium Formate 540-69-2 Solid Fiber Drum 0.015 1 0.015 Atm. Ambient Domestic Road

37 Benzoyl Chloride 98-88-4 Liquid Bottle 0.015 1 0.015 Atm. Ambient Domestic Road

38 Benzyl Amine 100-46-9 Liquid Carboy 0.100 4 0.400 Atm. Ambient Domestic Road

39 Bezyal Chloroformate 501-53-1 Liquid HDPE Drum 0.600 2 1.200 Atm. 2 - 8 °C Domestic Road

40 Calcium chloride dihydrate 10035-04-8 Solid HDPE


41 Caustic flakes 1310-73-2 Solid Bag 0.100 10 1.000 Atm. Ambient Domestic Road

42 Cesium Carbonate 534-17-8 Solid HDPE Container 0.025 4 0.100 Atm. Ambient Domestic Road

43 Cyclohexane 110-82-7 Liquid HDPE Drum 0.150 1 0.150 Atm. Ambient Domestic Road

44 Dibenzoyl Lactum 122111-01-7 Solid HDPE COntainer 0.050 10 0.500 Atm. Ambient Imported Air / Sea /

Road

45 Diethyl Acetamidomalonate 1068-90-2 Solid HDPE

Container 0.025 2 0.050 Atm. Ambient Domestic Air / Sea / Road

46 Diethyl Ether 60-29-7 Liquid Drum 0.200 5 1.000 Atm. Ambient Domestic Road

47 Dihydro-2H-pyran-2,6(3H)-dione 108-55-4 Solid Drum 0.020 1 0.020 Atm. Ambient Domestic Road

48 Dimethyl Carbonate 616-38-6 Liquid Carboy 0.050 1 0.050 Atm. Ambient Domestic Road

49 Dimethyl Formamide 68-12-2 Liquid HDPE Drum 2.000 5 10.000 Atm. Ambient Domestic Road

50 Dimethyl Sulfate 77-78-1 Liquid HDPE Drum 0.200 2 0.400 Atm. Ambient Domestic Road

51 Dimethyl Sulphoxide 67-68-5 Liquid HDPE Drum 0.200 2 0.400 Atm. Ambient Domestic Road

A-179




Sr. No.


FormType Of

Packing / Storage


Storage capacity

(MT)

Storage Pressure



52 Ditertiary Butyl Dicarbonate 24424-99-5 Liquid Bottle 0.015 2 0.030 Atm. 2 - 8 °C Domestic Road

53 D-Serine 312-84-5 Solid HDPE Drum 0.050 16 0.800 Atm. Ambient Imported Air / Sea / Road

54 Ethanol 64-17-5 Liquid HDPE Drum 5.000 2 10.000 Atm. Ambient Domestic Road

55

Ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido) propanoate [DAP]

212322-56-0 Solid Fiber Drum 0.050 12 0.600 Atm. Ambient Domestic Road

56Ethyl 3-guanidino-4-methylbenzoate nitrate (KSM-I)


°C Domestic Road

57

Ethyl- 4,5-bis-(2-methoxyethoxy)-2-amino benzoate hydrochloride (KSM1)

183322-17-0 Solid Fiber Drum 0.025 6 0.150 Atm. Ambient Imported Air / Sea / Road

58

Ethyl 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl) benzofuran-2-carboxylate hydrochloride

163521-11-7 Solid Bag 0.025 1 0.025 Atm. Ambient Domestic Road

59 Ethyl Acetate 141-78-6 Liquid HDPE Drum 5.000 5 25.000 Atm. Ambient Domestic Road

60Exo-cis-5-norbornene-2,3-dicaroxylic anhydride


61 Formamide 75-12-7 Liquid Drum 0.100 1 0.100 Atm. Ambient Domestic Road

62 Fumaric Acid 110-17-8 Solid HDPE Container 0.020 1 0.020 Atm. Ambient Domestic Road

63 Hexamethyl Disilazane 999-97-3 Liquid HDPE Container 0.250 6 1.500 Atm. Ambient Domestic Road

64 Hexane 110-54-3 Liquid Drum 2.000 6 12.000 Atm. Ambient Domestic Road

65 Hydrochloric Acid 7647-01-0 & 7732-18-5 Liquid Drum 2.000 4 8.000 Atm. Ambient Domestic Road

66 Hydrogen Gas 1333-74-0 Gas Cylinder 0.00100 5.0 0.005 Atm. Ambient Domestic Road

67 Hyflow 14464-46-1 Solid Bag 0.050 4 0.200 Atm. Ambient Domestic Road

68 Isobutyl Chloroformate 543-27-1 Liquid Carboy 0.025 12 0.300 Atm. 2 - 8 °C Domestic Road

69 Isopropyl Acetate 108-21-4 Liquid HDPE Drum 2.000 5 10.000 Atm. Ambient Domestic Road

70 Isopropyl Alcohol 67-63-0 Liquid MS Drum 5.000 4 20.000 Atm. Ambient Domestic Road

71 Isopropyl Alcohol HCl 7647-01-0 Liquid Carboy 0.020 1 0.020 Atm. 23-27°C Domestic Road

72 Maleic Acid 110-16-7 Solid Bag 0.025 10 0.250 Atm. Ambient Domestic Road

73 Methane Sulfonic Acid 75-75-2 Liquid Carboy 0.050 1 0.050 Atm. Ambient Domestic Road

74 Methane Sulfonyl Chloride 124-63-0 Liquid HDPE Drum 0.250 4 1.000 Atm. Ambient Domestic Road

75 Methanol 67-56-1 Liquid MS Tank 20.000 4 80.000 Atm. Ambient Domestic Road

76 Methyl Isobutyl Ketone 108-10-1 Liquid MS Drum 1.000 4 4.000 Atm. Ambient Domestic Road

A-180



Sr. No.


FormType Of

Packing / Storage


Storage capacity

(MT)

Storage Pressure



77 Methyl Tertiary Butyl Ether 1634-04-4 Liquid MS Drum 2.000 3 6.000 Atm. Ambient Domestic Road

78 Methylene Chloride 75-09-2 Liquid HDPE Tank 20.000 5 100.000 Atm. Ambient Domestic Road

79

N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidine amine (amine compound)


80 N,N-Di Isopropyl Ethyl Amine 7087-68-5 Liquid HDPE

Container 0.025 4 0.100 Atm. 23-27°C Domestic Road

81 N,N-Dimethyl Formamide 68-12-2 Liquid HDPE Drum 0.150 10 1.500 Atm. Ambient Domestic Road

82N1-Methyl-4-nitrobenzene-1,2-diamine

41939-61-1 Solid Drum 0.010 3 0.030 Atm. Ambient Domestic Road

83 N4 Acetyl Cytosine 14631-20-0 Solid Drum 0.250 4 1.000 Atm. Ambient Imported Air / Sea / Road

84 n-Butanol 71-36-3 Liquid HDPE Drum 0.150 2 0.300 Atm. Ambient Domestic Road

85 n-Heptane 142-82-5 Liquid MS Drum 0.100 5 0.500 Atm. Ambient Domestic Road

86 n-Hexane 110-54-3 Liquid MS Drum 0.020 3 0.060 Atm. Ambient Domestic Road

87 n-Hexyl Chloroformate 6092-54-2 Liquid Carboy 1.500 0 0.150 Atm. 23-27°C Domestic Road

88 N-Methyl Morpholine 109-02-4 Liquid Carboy 0.050 5 0.250 Atm. Ambient Domestic Road

89 N-Pentyl Chloroformate 638-41-5 Liquid HDPE

Container 1.000 2 2.000 Atm. 23-27°C Domestic Road

90 Oxalyl Chloride 79-37-8 Solid Drum 0.025 1 0.025 Atm. Ambient Domestic Road

91 Palladium on Carbon

Carbon: 7440-40-0Palladium: 7440-05-3

Solid Drum 0.0001 2 0.000 Atm. Ambient Domestic Road

92 Paracetamol 103-90-2 Solid Drum 0.025 2 0.050 Atm. 23-27°C Domestic Road

93 Phenyl Ethyl Bromide 103-63-9 Liquid HDPE Carboy 0.025 3 0.075 Atm. Ambient Domestic

/ Import Road

94 Potassium Carbonate 584-08-7 Solid Bag 0.500 3 1.500 Atm. Ambient Domestic Road

95 Potassium Hydroxide 1310-58-3 Solid Bag 0.200 3 0.600 Atm. Ambient Domestic Road

96 Pyridine 110-86-1 Liquid Drum 0.250 4 1.000 Atm. Ambient Domestic Road

97 Silica Gel 63231-67-4 Solid Fiber Drum 0.250 4 1.000 Atm. Ambient Domestic Road

98 Sodium Bicarbonate 144-55-8 Solid HDPE Container 0.500 10 5.000 Atm. Ambient Domestic Road

99 Sodium Bicarbonate (aq) 144-55-8 Liquid Drum 0.300 5 1.500 Atm. Ambient Domestic Road

100 Sodium Borohydride 16940-66-2 Solid HDPE Container 0.020 1 0.020 Atm. Ambient Domestic Road

101 Sodium Carbonate 497-19-8 Solid Bag 0.250 4 1.000 Atm. Ambient Domestic Road

102 Sodium Chloride 7647-14-5 Solid Bag 0.050 4 0.200 Atm. Ambient Domestic Road

103 Sodium hydroxide 1310-73-2 Solid HDPE Container 5.000 4 20.000 Atm. Ambient Domestic Road

A-181




Sr. No.


FormType Of

Packing / Storage


Storage capacity

(MT)

Storage Pressure



104 Sodium Iodide 7681-82-5 Solid Fiber Drum 0.025 4 0.100 Atm. Ambient Domestic Road

105 Sodium Metabisulphite 7681-57-4 Solid HDPE Container 0.015 1 0.015 Atm. Ambient Domestic Road

106 Sodium Sulphate 7757-82-6 Solid HDPE Drum 0.500 5 2.500 Atm. Ambient Domestic Road

107Sodium Tertiary Butoxide solution (20%) in THF

109-99-9 Liquid HDPE Drum 0.200 1 0.200 Atm. 23-27°C Domestic Road

108 Stannic Chloride 7646-78-8 Liquid PTFE Container 0.500 4 2.000 Atm. Ambient Domestic Road

109 Sulphuric Acid 7664-93-9 Liquid MS Drum 0.010 1 0.010 Atm. Ambient Domestic Road

110 Tetrabutyl Ammonium Bromide 1643-19-2 Solid HDPE


111 Tetrahydrofuran 109-99-9 Liquid HDPE Drum 2.000 5 10.000 Atm. Ambient Domestic Road

112 Thionyl Chloride 7719-09-7 Liquid MS Container 0.025 1 0.025 Atm. Ambient Domestic Road

113 Toluene 108-88-3 Liquid MS Drum 5.000 4 20.000 Atm. Ambient Domestic Road

114 Trimethyl Silyl Chloride 75-77-4 Liquid Drum 0.100 2 0.200 Atm. Ambient Domestic Road

115 Triethyl Amine 121-44-8 Liquid MS Drum 0.500 4 2.000 Atm. Ambient Domestic Road

116 Trimethyl Silyl Triflate 27607-77-8 Solid Drum 0.250 4 1.000 Atm. Ambient Domestic / Import Road

117 Urea 57-13-6 Solid Bag 0.005 1 0.005 Atm. Ambient Domestic Road

118 Vitride / Synhydrid 22722-98-1 Solid Container 0.200 2 0.400 Atm. 23-27°C Domestic Road

A-182

ANNEXURE 5 LAYOUT PLAN

100.0 0.0

10.0

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30.0

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50.0

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70.0

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100.0

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150.0

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170.0

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SURVEY NO. 128

SURVEY NO. 130

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SURVEY NO. 122

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A-183

ANNEXURE 6 ACKNOWLEDGEMENT OF CGWA

APPLICATION SLIP

RECEIPTTransaction Ref.No. 0611170001166 Dated: Nov 4 2017 8:11PM

Received from M/S. INTAS PHARMACEUTICALS LTD with Transaction Ref.No. 0611170001166 Dated Nov 4 2017 8:11PM the sum of INR 1000 (One Thousand Only ) through Internet basedOnline payment in the account of PROCESSING FEE OF FRESH NOC FOR GROUND WATER EXTRACTION, , APPLICATION NO - 21-4/2635/GJ/IND/2017.Disclaimer:- This is a system generated electronic receipt, hence no physical signature is required for the purpose of authentication

Printed On: 06-11-2017 03:9:09

Courtesy :- Controller General of Accounts

A-184

ANNEXURE 7 COPY OF MEMBERSHIP

(NECL, BEIL) & LOI (RSPL)

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A-194

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In exercise of the power conferred under section-25 of the Water (Prevention and Control of Pollution) Act-1974, under section-21 of the Air (Prevention and Control of Pollution)Act-1981 and Authorization under rule 3(c)& 5(5)of the Hazardous Waste (Management, Handling and Transboundary Movement)Rules’2008 framed under the E(P)Act-1986.

/Survey No.44-B,, Village : Naldhari,Ta: Valia,City : Naldhari,Dist : Ankleshwar, Tal : Valia, SIDC : Not In GidcPhone : 270389

Besides streamlining and simplifying of regulatory regime,Gujarat Pollution Control Board has taken initiative in from of introduction of Consolidated Consent and Authorization (CC&A) which provides for a one shot application and clearance of the consents under Water Act,Air Act and Authorization under Hazardous Wastes Rules for a period of 5 years.

CConsolidated Consent and Authorisation

CCONSENT AND AUTHORISATION :

And whereas Board has received consolidated Application No.(CtO:CCA-Ammendment) 116333 and Dated 21/12/2016 for the consolidated consent and authorization(CC&A) of this Board under the provisions / rules of the aforesaid Acts Consent & Authorization is hereby granted as under.

Board issues consolidated consent and Authorization to an industrial unit for operation of plant/carrying out industrial activity specifying following conditions.

(under the provisions / rules of the aforesaid environmental acts)

Consented CETP: Not Linked to any CETP

2.

( Member Secretary )

For and on behalf ofGujarat Pollution Control Board

PPCB Id:15887Application : CtO:CCA-Ammendment, No. 116333 Dt. 21/12/2016, Granted On: 10/04/2017

3. GENERAL CONDITIONS :-a) This order is provisional order and detailed order is considered as final.b) All the conditions & provisions under the Water Act 1974, the Air Act 1981 and the Environment (Protection) Act – 1986 and the rules made there under shall be complied with *.c) All the conditions & provisions under the Hazardous Waste (Management, Handling and Trans boundary Movement) Rules 2008 as amended shall be compliedd) The applicant shall provide portholes, ladder, platform etc at chimney(s) for monitoring the air emissions and the same shall be open for inspection to/and for use of Board’s staff. The chimney(s) vents attached to various sources of emission shall be designed by numbers such as S-1, S-2, etc. and these shall be painted/ displayed to facilitate identification.e) The industry shall take adequate measures for control of noise levels from its own sources within the premises so as to maintain ambient air quality standards in respect of noise to less than 75dB(A) during day time and 70dB(A) during night time. Daytime is reckoned in between 6 a.m. and 10 p.m. and nighttime is reckoned between 10 p.m. and 6 a.m.f) In case of change of ownership/management the name and address of the new owners/ partners/ directors/ proprietor or equipment or working conditions as mentioned in the consents form / order should immediately be intimated to the Board.g) Industry shall have to display data outside the main factory gate with regard to quantity and nature of hazardous chemicals being handled in the plant, including waste water and air emissions and solid hazardous wastes generated within the factory premises.h) The CCA shall be produced for inspection at the request of an officer authorized by the Gujarat Pollution Control Board.i) Any unauthorized change in personnel, equipment or working conditions as mentioned in the CCA order by CCA holder shall constitute a breach of this CCA.j) Adequate plantation shall be carried out all along the periphery of the industrial premises in such a way that the density of plantation is atleast 1000 trees per acre of land and a green belt of 5 meters width is developed.K) The applicant shall have to submit the returns in prescribed form regarding water consumption and shall have to make payment of water cess to the Board under the Water Cess Act- 1977.

Consented TSDF: B.E.I.L, Ankleshwar [14983]

*** Note : ACT-Specific, Industry-specific, Area-specific Conditions alongwith Product, Waste water effluent details shall be precisely mentioned in the DETAILED Consent Order.

*** Note :This is only provisional communication. The final Consent/Authorization in hard copy with duly signed by competent authority shall the final and valid Consent/Authorization.

M/s. Intas Pharmaceuticals Ltd Formerly Zora Pharma Limited,To,

All Conditions under the AIR ACT-1981 WATER ACT-1974 HAZARDOUS ACT-2008 shall be Applicable to you as mentioned in the detailed Consent Order ***

Consent Order No:1. AWH-85219 Valid Upto: 01/11/2017

Computer generated Order thru XGN, does NOT require Physical Signature N CIPrinted On : 10/04/2017

Gujarat Pollution Control BoardParyavaran Bhavan, Sector-10/A,

Gandhinagar - 382010Tele : 23222756

Consent No. AWH-85219 Valid upto: 01/11/2017

Provisional Consent Order (CCA)

A-223

PART 2 ANNEXURE TO DRAFT ENVIRONMENTAL IMPACT … · Compliance Monitoring of Existing Plant A-287...

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