LIST OF ANNEXURES S. No Content ... LIST OF ANNEXURES S. No Content Annexure 1 List of Proposed Products & By-Products Annexure - I 2 Site Plan Annexure - II 3 Manufacturing Process

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LIST OF ANNEXURES

S. No Content Annexure

1 List of Proposed Products & By-Products Annexure - I

2 Site Plan Annexure - II

3 Manufacturing Process Description Annexure - III

4 Water Consumption Details Annexure - IV

5 Solid & Hazardous Waste Generation And Disposal

Annexure -V

6 Stack Emission Details Annexure - VI 7 Process Emission Details Annexure -VII

8 List of Raw Materials Annexure - VIII

9 Waste water Details Annexure - IX

10 Consolidated Statement- Pollution Details Annexure –X

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ANNEXURE – I

LIST OF PROPOSED PRODUCTS

S. No Name of the Product Quantity in Kg/Month CAS Number Therapeutic Category

1 Atorvastatin Calcium 10000.00 134523-03-8 Antihyperlipidemic 2 Dapoxetine Hydrochloride 4000.00 129938-20-1 Premature ejaculation 3 D-penicillamine 5000.00 52-67-5 Antibiotic 4 Duloxetine Hydrochloride 5000.00 136464-34-9 Anti depressant 5 Lansoprazole 10000.00 103577-45-3 Anti ulcer 6 Lopinavir 5000.00 192725-17-0 Anti viral 7 Moxifloxacin hydrochloride 2000.00 186826-86-8 Anti bacterial 8 Nebivolol 5000.00 152520-56-4 Anti hypertensive 9 Ritonavir 5000.00 155213-67-5 Anti viral

10 Sildenafil citrate 15000.00 171599-83-0 Erective dysfunction 11 Valsartan 15000.00 137862-53-4 Anti hypertensive

Total 81000.00

LIST OF BY-PRODUCTS

S. No Name of the Product Name of the By-Product Quantity in Kg/Day

1 Dapoxetine Hydrochloride Isomer for product Recovery 138.67

2 D-penicillamine 2-Phenyl-N-(2-Phenylimino-ethyl)-acetamide 313.57

3 Duloxetine Hydrochloride Isomer for product Recovery 98.75

Mandelic acid 80.79

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ANNEXURE - II SITE PLAN

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ANNEXURE - III

MANUFACTURING PROCESS DESCRIPTION

1. ATORVASTATIN CALCIUM TRIHYDRATE

Process Description Stage-1 (6-Cyanomethyl-2, 2-dimethyl- [1, 3] dioxan-4-yl)-acetic acid tert-butyl ester

undergoes hydrogenation in presence of Raney Nickel and Methanol to give Stage-1

product.

Stage-2 Stage-1 reacts with 4-(4-fluorophenyl)-2-isobutyryl-3 phenyl-4-oxo-N-phenyl-

butyramide in presence of IPA and Cyclohexane to give Stage-2 product.

Stage-3 Satge-2 undergoes hydrolysis in presence of Hydrochloric acid and IPA to give

stage-3 product.

Sateg-4 Stage-3 product reacts with Calcium acetate in presence of Methanol and toluene to

give Atorvatatin calcium Trihydrate

ATORVASTATIN CALCIUM TRIHYDRATE

Route of Synthesis

Stage-1

O

OOO NC

O

OOO

H2N + 2 H2

(6-Cyanomethyl-2,2-dimethyl- [1,3]dioxan-4-yl)-acetic acid

tert-butyl ester C14H23NO4

269.34

4.00 [6-(2-Amino-ethyl)-2,2-dimethyl-

[1,3]dioxan-4-yl]-acetic acid tert-butyl ester

C14H27NO4 273.37

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Stage-2

O

OOO

H2N

[6-(2-Amino-ethyl)-2,2-dimethyl- [1,3]dioxan-4-yl]-acetic acid

tert-butyl ester C14H27NO4

273.37

NN H

F

O CH3 H3C OO

H3C CH3

O O

+

O

H N

O

O

F

+ 2 H2O

2-[2-(4-Fluoro-phenyl)-2-oxo-1- phenyl-ethyl]-4-methyl-3-oxo- pentanoic acid phenylamide

C26H24FNO3 417.47

(6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3- phenyl-4-phenylcarbamoyl-pyrrol-1-yl]- ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-

acetic acid tert-butyl ester C40H47FN2O5

654.81

2X18=36.0

Stage-3

NN H

F

O CH3 H3C OO

H3C CH3

O O

(6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3- phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-

ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)- acetic acid tert-butyl ester

C40H47FN2O5 654.81

H2O NN

H

F

O CH3 H3C OHHO

O O

+

+

18.0 7-[2-(4-Fluoro-phenyl)-5-isopropyl-3- phenyl-4-phenylcarbamoyl-pyrrol-1-yl]- 3,5-dihydroxy-heptanoic acid tert-butyl

ester C37H43FN2O5

614.75

O

Acetone 58.08

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Stage-4

NN H

F

O CH3 H3C OHHO

O O

7-[2-(4-Fluoro-phenyl)-5-isopropyl-3- phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-

dihydroxy-heptanoic acid tert-butyl ester

C37H43FN2O5 2X614.75=1229.5

+ Ca(COOCH3)2

(158.17)

+ 3 H2O

54.0

NN H

F

O CH3 H3C OHOH

O- O

2

Ca+2. 3H2O

(1209.26)

+ OH2

(148.24)

+ 2 CH3COONa

(164)

+

(80)

2 NaOH

2

Atorvastatin calcium trihydrate 2-Methyl-propan-2-ol Sodium acetate

ATORVASTATIN CALCIUM TRIHYDRATE

Flow Chart

Stage-1

Stage-2

Stage-3

Stage-4

ATORVASTATIN CALCIUM TRIHYDRATE

(6-Cyanomethyl-2,2-dimethyl- [1,3]dioxan-4-yl)-acetic acid tert-butyl ester Raney Nickel Methanol

Methanol Rec spent catalyst

Stage-1 4-(4-fluorophenyl)-2- isobutyryl-3 phenyl -4-oxo-N-phenyl-butyramide cyclohexane Isopropylalcohol

Cyclo hexane Rec Isopropyl alcohol Rec

Stage-2 Sodium carbonate Acetonitrile IPA Hydrochloric acid

Acetonitrile Rec IPA Rec

Stage-3 Calcium acetate Sodium hydroxide flakes Hydrochloric acid Methanol Toluene

Methanol Rec Toluene Rec

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ATORVASTATIN CALCIUM TRIHYDRATE

Material Balance:

Material balance of Atorvastatin calcium Trihydrate Stage-1 Batch Size: 500.0Kg

Name of the input Quantity in Kg

Name of the out put Quantity In Kg

(6-Cyanomethyl-2,2-dimethyl- [1,3]dioxan-4-yl)-acetic acid tert-butyl ester

252.00 Stage-1 248.00

Hydrogen 0.68 Methanol Recovery 152.00 Raney Nickel 1.00 Methanol Loss 8.00 Methanol 160.00 Spent catalyst 1.00 Organic residue 4.68 Process residue-4.68 Total 413.68 Total 413.68

Material balance of Atorvastatin calcium Trihydrate Stage-2 Batch Size: 500.0Kg

Name of the input Quantity in Kg

Name of the out put Quantity In Kg

Stage-1 248.00 Stage-2 570.00 4-(4-fluorophenyl)-2- isobutyryl-3 phenyl -4-oxo-N-phenyl-butyramide

378.50 Generated water 32.48

Pivalic acid 2.00 Cyclohexane Recovery 190.00 cyclohexane 200.00 Cyclohexane Loss 10.00 Isopropylalcohol 150.00 Isopropylalcohol Recovery 143.00 Isopropylalcohol Loss 7.00 Organic residue(Pivalic acid) 26.02 Process residue-26.02

(organic impurities-24.02, Pivalic acid-2)

Total 978.50 Total 978.50

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Material balance of Atorvastatin calcium Trihydrate Stage-3 Batch Size: 500.0Kg

Name of the input Quantity in Kg

Name of the out put Quantity In Kg

Stage-2 570.00 Stage-3 522.00 Sodium carbonate 7.00 Acetonitrile Recovery +

Acetone-50.16 335.16

Acetonitrile 300.00 Acetonitrile Loss 15.00 IPA 150.00 IPA Recovery 143.00 Water 2000.00 IPA Loss 7.00 Effluent water 1991.60 (water-1984.60, Sodium

carbonate-7) 0

Organic Residue 13.24 Process residue-13.24 Total 3027.00 Total 3027.00

Material balance of Atorvastatin calcium Trihydrate Stage-4 Batch Size: 500.0Kg

Name of the input Quantity in Kg

Name of the out put Quantity In Kg

Stage-3 522.00 Atorvastatin calcium Trihydrate

500.00

Calcium acetate 66.82 Methanol Recovery 280.00 Sodium hydroxide flakes 33.95 Methanol Loss 15.00 Hydrochloric acid 3.36 Toluene Recovery 185.00 Methanol 300.00 Toluene Loss 10.00 Toluene 200.00 Effluent water 1549.98 Activated carbon 5.00 (water-1477.56,sodium

acetate-69.42,Toluene-3) 0

Hyflow 3.00 Spent carbon & Hyflow 8.00 Water 1500.00 Organic residue 86.15 Process residue-79.15

Organic Impurities-16.51,2- Methyl-propan-2-ol-62.64, Distillation residue-7 (Toluene-2, Methanol-5)

Total 2634.13 Total 2634.13

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