PRE - FEASIBILITY REPORT · 35 Solifenacin Succinate - 5 36 Montelukast Sodium - 5 37 Silodosin - 5 38 Cinacalcet Hydrochloride - 5 39 Maraviroc - 5 40 Vilazodone Hydrochloride -

PRE - FEASIBILITY REPORT

FOR

PROPOSED EXPANSION OF

AEROMATIC CHEMICALS, BULK DRUGS,

BULK DRUG INTERMEDIATES

MANUFACTURING UNIT

LOCATED AT

PLOT No. 1203, PHASE-III, G.I.D.C ESTATE, VAPI-396 195,

DISTRICT: VALSAD, GUJARAT

OF

M/s. MANGALAM DRUGS & ORGANICS Ltd.

(UNIT-II)

SUMMARY

M/s. MANGALAM DRUGS & ORGANICS Ltd. (UNIT-II) is planning for the expansion of their

existing Aeromatic Chemicals, Bulk Drugs & Bulk Drug Intermediates manufacturing unit at Plot No.

1203, Phase-III, G.I.D.C Estate, Vapi-396 195, District: Valsad, Gujarat

PROJECT COST

The total project cost for the proposed expansion project would be around Rs. 1 crore. Total capital cost of

pollution control measures will be Rs. 7 Lacs & recurring cost per annum will be 3 Lacs.

DETAILS OF PRODUCTS

Details of existing and proposed products are given in following table.

LIST OF PRODUCTS

SR.

NO PRODUCT

PRODUCTION CAPACITY (MT/MONTH)

EXISTING PROPOSED TOTAL

(A) BULK DRUGS

Group 1

1 Nimesulide 31 49 80

2 Lumefantrine 7 63

3 Sulfadoxine - 80

Group 2

4 Furosemide 5 25

30

5 Hydroxy Chloroquine Sulphate 3 27

6 Allopurinol - 30

7 Colesevelam Hydrochloride - 30

Group 3

8 Amodiaquine Hydrochloride 5 25

30 9 Piperaquine Phosphate 5 25

Group 4

10 Tenofovir Disoproxil Fumarate 7 23

30 11 Efavirenz - 30

Group 5

12 Artemether 2 18

20 13 Artesunate 2 18

Group 6

14 Emtricitabine 1 9 10

15 Pyrimethamine - 10

16 Dihydroartemisinin - 10

17 Bisoprolol Fumarate - 10

Group 7

18 Pyronaridine 0.5 4.5 5

19 Atazanavir Sulfate - 5

20 Primaquine Phosphate - 5

21 Chloroquine Phosphate 2 3

Group 8

22 Tenofovir Alafenamide Fumarate - 10 10

23 Tenofovir DipivoxilOrotate - 10

24 Sofosbuvir - 10

Group 9

25 Dolutegravir Sodium - 5 5

26 Velpatasvir - 5

27 AdefovirDipivoxil Fumarate - 5

28 Ledipasvir - 5

29 DaclatasvirDihydrochloride - 5

30 Tafenoquine Succinate - 5

Group 10

31 Ursodiol - 5 5

32 Terizidone - 5

33 Delamanid - 5

34 Tariquidar Analog - 5

35 Solifenacin Succinate - 5

36 Montelukast Sodium - 5

37 Silodosin - 5

38 Cinacalcet Hydrochloride - 5

39 Maraviroc - 5

40 Vilazodone Hydrochloride - 5

41 Metoprolol succinate

(B) BULK DRUGS INTERMEDIATES

1. Meta Chloro Aniline (MCA) - 6 6

2. 2,7-Dichloro-9H-fluorene (DCF) 30 -15 15

3. 2-(2,7-dichloro-9H-fluoren-4-yl)oxirane - 15 15

4. [2-Dibutylamino-1-(2-7-dichloro-9H-florine-

4-yl)] ethanol(DBA) 30 -10 20

5. Dihydroartemisinin (DHA) 2 13 15

6. 4-cyanoethyl-2-methyl-phenol (MHPN) 5 - 5

7. (R)-9-(2-phosphonylmethoxypropyl)-adenine

(PMPA) 10 15 25

8. 4,7-Di ChloroQuinoline (4,7-DCQ) 12 8 20

9. N-(2-phenoxyphenyl)-methanesuphonamide

(OPMSA) 46 4 50

10. Meta Amino Acetanilide (MAA) 4 1 5

11. N-{3-[(diethylamino)methyl]-4-

hydroxyphenyl}acetamide (Mannich Base) - 20

12. 4,6-dichloro-5-methoxypyrimidine - 25

13.

L-Menthyl-5-(2R,5S)-[4-amino-5-fluoro-2-

oxopyrimidin-1(2H)-yl]-1,3-oxathiolane-2-

carboxylate (FCME)

- 40 40

14.

(S)-2-(2-amino-5-chlorophenyl)-4-

cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol

(E-6)

- 24 24

15. Tenofovir Disoproxil Free Base (TD Base) - 10 10

BY-PRODUCT

1. Eutectic Oil - 6.0 6.0

2. Sodium ThioSulphate - 6.0 6.0

3. Hydrochloric Acid - 10.0 10.0

* Note: Following products are discontinued from the existing product list.

1. Meta Nitro Aniline (MNA) (4 MT/M)

2. Meta Amino Propionilide (MAP) (4 MT/M)

3. 2,4,5, Trichloro Aniline (4 MT/M)

4. LF-2 ASCF (30 MT/M)

5. Ortho Phenoxy Aniline OPA (25 MT/M)

6. Arteether (0.5 MT/M)

7. Losartan Potassium (7 MT/M)

8. Acetazolamide (2 MT/M)

REQUIREMENTS FOR THE PROJECT

LAND

No new land will be acquired for the proposed expansion project. The proposed expansion project will get

established in existing premises by doing small modification and in available open space in existing

premises. Total plot area of the project is 10,000 m2 from which around 3300 m2 (33% of total land area)

will be required for the development of green belt.

WATER Total water requirement for the proposed expansion project would be estimated as 220 KLD, which will be

sourced from G.I.D.C

ELECTRICAL ENERGY Total power requirement for the proposed expansion project will be around 750 KVA and will be sourced

from DGVCL (Daxin Gujarat Vij Corporation Limited). During emergency purpose D. G. Set of 320 KVA

will be utilized.

MANPOWER For proposed expansion project total 445 (existing 350 and additional 95) personnel will be required.

SOURCES OF AIR POLLUTION AND CONTROL MEASURES

EMISSIONS FROM COMBUSTION OF FOSSIL FUELS FROM STATIONARY OR MOBILE

SOURCES

SR.

NO.

STACK ATTACHED

TO FUEL USED

STACK

HEIGHT

POLLUTION

CONTROL

SYSTEM

FINAL

CONCENTRATION

EXISTING

1 IBR Boiler

Natural Gas

(193 m3/Hr)

30

meter Scrubber

SPM ≤ 150 mg/Nm3

SO2≤ 100 ppm

NOX≤ 50 ppm

2 Non IBR Boiler &

Thermopack no. 1

15

meter -

3 Thermopack no. 2 15

meter -

3 D.G. Set (320 KVA) Diesel

(70 Lit/Hr)

11

meter -

4 D.G. Set (75 KVA)* Diesel

(70 Lit/Hr)

11

meter -

PROPOSED

1. Gas Generator

(1 MW)

Natural Gas

5000 m3/Day

15

meter

adequate stack

height will be

provided

SPM ≤ 150 mg/Nm3

SO2≤ 100 ppm

NOX≤ 50 ppm

* Existing D.G.Set of 75 KVA shall be removed after proposed expansion

PROCESS EMISSION

SR.

NO.

STACK

ATTACHED TO

STACK

HEIGHT

POLLUTION

CONTROL

SYSTEM

Type of

Pollutants FINAL

CONCENTRATION

EXISTING

1. Reaction vessel 11

meter Alkali Scrubber

Cl2

HCl

Cl2 ≤ 09 mg/Nm3

HCl ≤ 20 mg/Nm3

2. Incinerator

(200 kg/hr)

30

meter Venturay Scrubber

PM

SO2

NOX

PM ≤ 150 mg/Nm3

SO2≤ 100 ppm

NOX≤ 50 ppm

WASTE WATER GENERATION AND IT’S TREATMENT: Total wastewater i.e. 125 KLD will be generated from the proposed expansion project, which will be

treated in ETP consisting primary & secondary treatment. Treated effluent will be sent to CETP for further

treatment and final disposal.

NOISE POLLUTION AND CONTROL MEASURES:

� From the proposed expansion manufacturing unit noise pollution will be generated which will be

controlled by adopting different types of noise pollution control measures. Main sources of the noise

pollution - machineries, electric motors, boiler, D. G. set and TFH, etc.

Following noise control measures to be adopted in the proposed expansion manufacturing project,

� Encasement of noise generating equipment.

� Greenbelt will be developed all around the plant boundary to act as noise attenuator.

� In addition, personnel, working near high noise level generating sources, will be provided with ear

muffs.

� Proper and suitable acoustic barrier will also be provided around, areas generating high noise.

� Effective preventive maintenance and vibration measurement of all rotating equipment will help in the

improvement of plant life and also noise reduction.

SOLID WASTE GENERATION AND ITS DISPOSAL METHOD The sources of solid wastes, generation and its management are as given in the following table.

SR.

NO.

NAME OF THE

WASTE

CAT

NO.

EXISTING

(MT/Year)

PROPOSED

(MT/Year)

TOTAL

(MT/Year)

METHOD OF

STORAGE AND

DISPOSAL

1 ETP Waste 34.2 27.6 322.4 350

Collection, storage,

Transportation,

disposal at TSDF-

VWEMCL

2 Distillation

Residue 20.3 112 1088 1200 Collection, storage and

disposed in captive

incinerator/ Sent to

CHWIF 3 Process Residue 28.1 146 354 500

4 Spent Solvents 28.6 112 188 300 Recovered & reused/

Sent to end user.

5 Used Oil 5.1 0.0924 0.0276 0.12

Collection, storage and

reuse as lubricants in

the machineries within

the premises only or

send to authorized re-

processors.

6

Discarded

Containers/

Bags

33.3 1716

Nos./Year

3784

Nos./Year

5500

Nos./Year


send to authorized

recycler after

decontamination.

7 Iron Sludge 28.1 840 200 1160


Transportation,

disposal at TSDF

8 Used/ Waste

filter clothes 35.1 0.06 0.09 0.15


Transportation,

disposal at TSDF

9 Sludge from wet

Scrubber 36.1 0.024 0.096 0.12


Transportation,

disposal at TSDF

10 Spent Carbon 28.2 78 222 300


disposed in captive

incinerator within

premises/ CHWIF

11

Salt from

evaporator 35.3 672 228 900


Transportation,

disposal at TSDF

12 Incineration Ash 37.2 30 30 60


Transportation,

disposal at TSDF

13 Distillation

residue 20.3 43.2 1156.8 1200

Reception from unit-I

through manifest

14 Proocess residue 28.1 6 494 500 system, storage,

Incineration at caprive

Incinerator within

premises/ CHWIF 15 Spent carbon 28.6 78 222 300

16 Used oil from

unit-I 5.1 0.06 0.06 0.12

GREEN BELT DEVELOPMENT Company has proposed 33% of total land area for green belt development approx 3300 m2 land area.

INDEX

CHAPTER

NO. CONTENT

1 Introduction of the project

2 Project description

3 Site analysis

4 Planning brief

5 Proposed infrastructure

6 Rehabilitation and resettlement (R & R) plan

7 Project schedule & cost estimates

8 Analysis of proposal

1

CHAPTER-1

INTDOUCTION OF THE PROJECT

1.1 IDENTIFICATION OF PROJECT AND PROJECT PROPONENT

M/s. MANGALAM DRUGS & ORGANICS Ltd. (UNIT-II) is planning for the expansion of their existing

Aeromatic Chemicals, Bulk Drugs & Bulk Drug Intermediates manufacturing unit at Plot No. 1203, Phase-III,

G.I.D.C Estate, Vapi-396 195, District: Valsad, Gujarat.

1.2 PROMOTERS BACKGROUND

Details of project promoters are as below:

Mr. Govardhan M Dhoot Shri G.M.Dhoot has a commerce background and more than four decades of experience in the chemical and

pharma industry. He has been a driving force behind phenomenal expansion and diversification of the company

over last decade. His strategic interventions to inculcate strong regulatory focus have earned the company its

prestigious status among the top 5 companies approved by the Bill Clinton Foundation.

Mr. Brijmohan M Dhoot: Shri B. M. Dhoot has a commerce background and more than 40 years experience in chemical and pharma

industry.

Mr. Subhash C. Khattar Mr Subhash Khattar is a chartered accountant with above 50 years experience. He specialises in taxation and

auditing. He is on the statutory panel of bank audits and of other public sector undertakings and Private

Companies.

Mrs. Anuradha Sukhani Ms. Anuradha Sukhani has an arts background. She has been partner in Sourcing Solutions since 2002. It runs a

buying agency for leather goods. Product was souced from leather manufacturers all over India and exported to

niche markets in Northern Europe (Sweden, Finland, Germany, Amsterdam, Denmark)

1.3 BRIEF DESCRIPTION OF NATURE OF THE PROJECT



G.I.D.C Estate, Vapi-396 195, District: Valsad, Gujarat

LIST OF PRODUCTS

SR.

NO PRODUCT

PRODUCTION CAPACITY (MT/MONTH)

EXISTING PROPOSED TOTAL

(A) BULK DRUGS

Group 1

1 Nimesulide 31 49 80

2 Lumefantrine 7 63

3 Sulfadoxine - 80

Group 2

4 Furosemide 5 25

30

5 Hydroxy Chloroquine Sulphate 3 27

6 Allopurinol - 30

7 Colesevelam Hydrochloride - 30

Group 3

8 Amodiaquine Hydrochloride 5 25

30 9 Piperaquine Phosphate 5 25

Group 4

2

10 Tenofovir Disoproxil Fumarate 7 23

30 11 Efavirenz - 30

Group 5

12 Artemether 2 18

20 13 Artesunate 2 18

Group 6

14 Emtricitabine 1 9 10

15 Pyrimethamine - 10

16 Dihydroartemisinin - 10

17 Bisoprolol Fumarate - 10

Group 7

18 Pyronaridine 0.5 4.5 5

19 Atazanavir Sulfate - 5

20 Primaquine Phosphate - 5

21 Chloroquine Phosphate 2 3

Group 8

22 Tenofovir Alafenamide Fumarate - 10 10

23 Tenofovir DipivoxilOrotate - 10

24 Sofosbuvir - 10

Group 9

25 Dolutegravir Sodium - 5 5

26 Velpatasvir - 5

27 AdefovirDipivoxil Fumarate - 5

28 Ledipasvir - 5

29 DaclatasvirDihydrochloride - 5

30 Tafenoquine Succinate - 5

Group 10

31 Ursodiol - 5 5

32 Terizidone - 5

33 Delamanid - 5

34 Tariquidar Analog - 5

35 Solifenacin Succinate - 5

36 Montelukast Sodium - 5

37 Silodosin - 5

38 Cinacalcet Hydrochloride - 5

39 Maraviroc - 5

40 Vilazodone Hydrochloride - 5

41 Metoprolol succinate


1. Meta Chloro Aniline (MCA) - 6 6

2. 2,7-Dichloro-9H-fluorene (DCF) 30 -15 15

3. 2-(2,7-dichloro-9H-fluoren-4-yl)oxirane - 15 15

4. [2-Dibutylamino-1-(2-7-dichloro-9H-florine-

4-yl)] ethanol(DBA) 30 -10 20

5. Dihydroartemisinin (DHA) 2 13 15

6. 4-cyanoethyl-2-methyl-phenol (MHPN) 5 - 5

7. (R)-9-(2-phosphonylmethoxypropyl)-adenine

(PMPA) 10 15 25

8. 4,7-Di ChloroQuinoline (4,7-DCQ) 12 8 20

9. N-(2-phenoxyphenyl)-methanesuphonamide

(OPMSA) 46 4 50

10. Meta Amino Acetanilide (MAA) 4 1 5

11. N-{3-[(diethylamino)methyl]-4-

hydroxyphenyl}acetamide (Mannich Base) - 20

12. 4,6-dichloro-5-methoxypyrimidine - 25

3

13.

L-Menthyl-5-(2R,5S)-[4-amino-5-fluoro-2-

oxopyrimidin-1(2H)-yl]-1,3-oxathiolane-2-

carboxylate (FCME)

- 40 40

14.

(S)-2-(2-amino-5-chlorophenyl)-4-

cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol

(E-6)

- 24 24

15. Tenofovir Disoproxil Free Base (TD Base) - 10 10

BY-PRODUCT

1. Eutectic Oil - 6.0 6.0

2. Sodium ThioSulphate - 6.0 6.0

3. Hydrochloric Acid - 10.0 10.0

* Note: Following products are discontinued from the existing product list.

1. Meta Nitro Aniline (MNA) (4 MT/M)

2. Meta Amino Propionilide (MAP) (4 MT/M)

3. 2,4,5, Trichloro Aniline (4 MT/M)

4. LF-2 ASCF (30 MT/M)

5. Ortho Phenoxy Aniline OPA (25 MT/M)

6. Arteether (0.5 MT/M)

7. Losartan Potassium (7 MT/M)

8. Acetazolamide (2 MT/M)

1.4 NEED FOR THE PROJECT AND ITS IMPORTANCE TO THE COUNTRY AND OR REGION.

The proposed expansion project will provide a potential & required growth opportunity for the

Company.Moreover company has strong presence with leading pharma cos. locally as-well-as internationally;

mainly in regulated market. The company & the products are well approved & registered with the leading

regulatory authorities & the pharma customers’ in local & international markets.

The Active Pharmaceutical Ingredient Industry is the organ by which active pharmaceutical ingredients are

manufactured from raw materials through both chemical and physical means. Depending on the complexity of

the molecule required, synthesis of APIs might need multi-step complex chemistry utilizing a range of

processing technologies.

1.5 DEMANDS-SUPPLY GAP The pharma / health industrial sector in the past many years has seen a consistent growth and also keeping in

mind our strong presence in the local & global market. Hence we have identified the demand for the proposed

products which are meant for very new medicines meant for fast growing therapeutic segments with pilot plant

developed our own process patents we can take a lead & produce commercially in bulk for domestic market as

well as with strong presence in export markets.

1.6 EMPLOYMENT GENERATION For proposed expansion project total 445 (existing 350 and additional 95) personnel will be required.

4

CHAPTER-2

PROJECT DESCRIPTION

2.1 TYPE OF PROJECT




Industrial development in India has increased economic growth and improved living standards of people. These

growths are achieved through industrialization, infrastructure development. The industrialization has played a

major role in development of the country. This industrialization is also has many other benefits. Although the

industrial development leads to rapid consumption of natural resources, fuel etc.in day to day operational

activity. To control the pollutions from industrial activity, government has framed regulations which are

governed by Ministry of Environment, Forests and Climate Change in India.

2.2 LOCATION M/s. Mangalam drugs & organics ltd. (unit-II) is planning for the expansion of their existing Aeromatic

Chemicals, Bulk Drugs & Bulk Drug Intermediates manufacturing unit at Plot No. 1203, Phase-III, G.I.D.C

Estate, Vapi-396 195, District: Valsad, Gujarat. Total plot area of the project is 10000 m2 from which around

3300 m2 (33% of total land area) will be required for the development of green belt. A map showing project site

is given in following figure-1 & a detailed map of the project site & surrounding is showing in following figure.

Latitude - 20°22'10.29"N

Longitude - 72°56'35.56"E

LOCATION MAP

5

2.3 SIZE OR MAGNITUDE OF OPERATION M/s. MANGALAM DRUGS & ORGANICS Ltd. (UNIT-II) is planning for the expansion of their existing



2.4 PROCESS DESCRIPTION

MANUFACTURING PROCESSES

A. BULK DRUGS

GROUP 1

1. Nimesulide - COS

Process Description:

Stage - 1: OPMSA is nitrated in presence of Acetic acid with Nitric Acid forms Nimesulide Crude which is Centrifuged

and Dried.

Stage - 2: Nimesulide crude dry is purified using methanol as a solvent to give Nimesulide Pure Wet Cake. Nimesulide

pure wet cake is dried, Milled, Jet milled, Sifted and packed in double LDPE bag; i.e. both are White

transparent, followed by HDPE/Fiber drum

FLOW DIAGRAM

Stage: I

CENTRIFUGE

NITRATION

OPMSA

ACETIC ACID

NEUTRALISATION

MCB & C. LYE

NIMESULIDE CRUDE

PROCESS RESIDUE

(HNO3)

ML MCB RECOVERED

DISTILLATION

RESIDUE

W.W. TO ETP

HNO3

WATER

6

Stage: II

CARBON

TREATMENT

METHANOL

CARBON

FILTRATION

CENTRIFUGE

DRYING

METHANOL ML RECOVERED &

RECYCLED

NIMESULIDE

ACETIC ACID

NIMESULIDE CRUDE

DISTILLATION RESIDUE

SPENT CARBON

PROCESS RESIDUE

7

2. Lumefantrine


Stage-1:

4 – Chlorobenzaldehyde is condensed with DBA in presence of Sodium Methoxide to get the Lumefantrine

crude using Methanol as a solvent.

Stage-2:

Lumefantrine crude is purified using Ethyl Acetate as solvent to get Lumefantrine pure. Lumefantrine pure is

dried, Milled (if required), Sifted and packed in double LDPE bag; i.e. Inner bag is white transparent & Outer

bag is black followed by HDPE drum

Flow Diagram

Stage: I

Stage: II

METHANOL

DBA

4 CHLORO

BENZYLDEHYDE

CONDENSATION

FILTRATION

ML FOR

RECOVERY

LUMEFANTRINE

CRUDE (STAGE-I)

SODIUM

METHOXIDE

METHANOL

RECOVERED & REUSED


LUMEFANTRINE

CRUDE (STAGE-I)

DISSOLUTION

FILTRATION

ETHYL ACETATE

RECOVERED & REUSED

DRYING

ETHYL ACETATE

DISTILLATION

LUMEFANTRINE

WATER

W.W. TO ETP

ACTIVATED CARBON

CENTRIFUGE HEXANES ML HEXANES RECOVERED &

REUSED

SPENT CARBON


8

3. Sulfadoxine


Stage-1:

� Charge sulfanilamide, NaOH and water at room temperature.

� Heat the reaction mass to 75-80°C.

� Distilled out water under vacuum completely.

� Charge IPA and stir the reaction mass at 25-30°C.

� Filter it and wash with IPA.

� Dry it.

Stage-2:

� Charge DMF and sodium salt of sulfanilamide.

� Charge 4,6-DCMP under stirring.

� Maintain the reaction mass at 60-65°C for 3 hrs.

� Charge methanol and adjust pH with H3PO4.

� Slowly add water at chilled to 5-10°C.

� Filter it and wash with water.

� Dry it.

Stage-3:

� Charge 4,6-ACMS, sodium hydroxide and methanol .

� Maintain the reaction mass at 60-65°C for 10 hrs.

� Cool the reaction mass and slowly adds water.

� Charge carbon and filter it.

� Adjust pH with dilute hydrochloric acid.

� Chilled the reaction mass up to 20-25°C


Stage-4:

� Charge methanol and Sulfadoxine crude.

� Adjust pH with NaOH solution.

� Charge carbon and filter it.

� Adjust pH with dilute hydrochloric acid.

� Chilled the reaction mass up to 20-25°C


� Dry it.

9

Centrifuge

Flow Diagram:

Stage-I: Sodium salt of sulfanilamide.

Potable water

NaOH

Maintaining the reaction mass

Distillation out water

IPA

Wash the wet cake ML for IPA

Recovery

with IPA

For complete intermediate analysis

Reactor

Reactor

Fluid Bed Dryer

Sulfanilamide

Reactor

SStage-I

10

Centrifuge

Stage-II: 4-amino-N-(6-chloro-5-methoxy pyrimidin-4-yl) benzene sulfonamide (4,6-ACMS)

4, 6-DCMP

DMF

Check reaction completion by TLC

Methanol

H3PO4 + potable

water

Potable Water

Wash the wet cake ML for

Methanol/DMF

with potable water Recovery

For Complete Intermediate analysis

Reactor

Reactor

Fluid Bed Dryer

Stage-I

Reactor

Stage-II

11

Stage-III: 4-Amino-N-(5,6-dimethoxy pyrimidin-4-yl)benzene (Sulfadoxine crude)

Stage-II

Methanol

Heat to 50-55°C

NaOH Check TLC

Charge water

(Activated carbon + potable

water)

Filtration

HCl+ Potable

Water

Potable water ML for Methanol recovery

For complete Intermediate analysis

Reactor

Reactor

Reactor

Centrifuge

Stage-III

Check Clarity of Solution Sparkler Filter

Reactor

12

Stage-IV: 4-Amino-N-(5,6-dimethoxy pyrimidin-4-yl)benzene (Sulfadoxine Pure)

Stage-III

Methanol

NaOH soln

(Activated carbon + methanol)

Filtration

Purge N2 Gas

HCl + purified

water

Methanol washing ML for Methanol recovery

Check water content

If Required

If Required

For complete analysis

Reactor

Rotocon Vacuum Dryer

Reactor

Reactor

Centrifuge

Multi Mill

Jet Mill

Sifter

Packing

Check Clarity of Solution Sparkler Filter

Reactor

13

GROUP 2

4. Furosemide


Stage-1: 5-(aminosulfonyl)-2,4-dichlorobenzoic acid [Lasamide] is condensed with 1-(2-furyl) methanamine [Furfuryl

amine] at 117 to 119°C and then hydrolyzed with caustic soda to form sodium salt of Furosemide in presence

of isopropyl alcohol.

Stage-2: The Furosemide Sodium Salt is Purified with Water, neutralized with acetic acid, Re-crystallized and isolate to

form Pure Furosemide which is Centrifuged, Dried, Milled (If Required), Jet Milled (If Required), sifted and

finally packed.

Flow Diagram

Stage-I

Stage-II

WET CAKE CHARCOALING

Purified WATER

FILTRATION

PRECIPITATION

CENTRIFUGIN

G

W/W TOETP ACETIC ACID

Spent Carbon

WATER/ DNS FOR

DRYING

FUROSEMIDE

Activated Carbon

DNS

RECOVERE

D & REUSED

Distillation

Residue ML

W/W TOETP

LASAMIDE

CONDENSATION

FURFURYL AMINE

PH ADJUSTMENT

FILTRATION

WET CAKE

W/W TO ETP C.Flakes

WATER

IPA, FFARECOVERED

& REUSED IPA FOR WASHING

Distillation

Residue

ML

Process

Residue

14

5. HCQS - Hydroxy Chloroquine Sulphate


Stage-1: 4, 7-DCQ is condensed with HNDA to form Hydroxyl Chloroquine Base which reacts with H3PO4 to form

HCQP Crude

Stage-2: This Hydroxy Chloroquine Phosphate Crude purified in Water-Methanol mixture, is recrystallised and isolated

to form pure Hydroxy Chloroquine Phosphate

Stage-3: Pure Hydroxy Chloroquine Phosphate is neutralized to form Hydroxyl Chloroquine Base which reacts with

Sulphuric Acid to form HCQS and then it is recrystallised by IPA to get pure wet cake. This HCQS pure is

dried, pulverized, analyzed and packed in HDPE or fiber drums followed by two liners, primary white &

secondary black

Flow Diagram:

Stage: I

4, 7-DCQ

HNDA

CODENSATION

WASHING

MDC

K.I.

SODIUM

CARBONATE

WATER

AQ.

LAYER

MDC, METHANOL

RECOVERED & REUSED

H3PO4

DISTILLATION

CENTRIFUGE

ACTIVATED

CARBON

METHANOL

ML


W/W TO

ETP

PROCESS RESIDUE

SPENT CARBON

Stage-I

15

Stage: II

Stage: III

METHANOL

WATER

PURIFICATION

CENTRIFUGE

ML

ACTIVATED

CARBON

Stage-I

METHANOL RECOVERED &

REUSED

SPENT CARBON

DISTILLATION RESIDUE Stage-II

W/W TO ETP

Stage-II

Methanol, Hexane, IPA, MDC

Recovered & Reused

Filtration

DRYING

HYDROXY

CHLOROQUINE

SULPHATE

IPA, MDC

Activated Carbon

Methanol, H2SO4

Liq. Ammonia

Hexane, Water

Process Residue

Distillation Residue

Spent Carbon

ML

W/W to ETP

16

CYNOACETAMIDE

REACTOR(REFLUX)

IPA

STAGE-1 PRODUCT

MORPHOLINE

TRIETHYL

ORTHOFORMATE

CENTRIFUGE

W.W. TO ETP

DRYING

ML

MORPHOLINE, TEOF, IPA

RECOVERED & REUSED


WATER

HYDRAMINE

HYDRATE

H2SO4

STAGE-2

PRODUCT

STAGE-1

W.W. To ETP CENTRIFUGE WATER

Process Residue

REACTOR

(REFLUX)

6. Allopurinol


Stage-1:

2-Cyanoacetamide and Morpholine reacts in presence of Isopropyl alcohol and Triethyl orthoformate at reflux

temperature to yield 3-Morpholino-2-Cyanoacrylamide.

Stage-2:

3-MCA and hydrazine hydrate in presence of water undergoes cyclization which on further forms 3-Amino-4-

carboxamide pyrazolehemisulfate by the addition of Sulfuric acid in controlled manner at predetermined

temperature range.

Stage-3: Formamide and 3-Amino-4-carboxamide pyrazolehemisulfate undergoes cyclization in presence of liquor

Ammonia and Water to form Allopurinol crude. Allopurinol crude undergoes purification using water yields

Allopurinol pure which is centrifuged, dried, analyzed and packed

Flow Diagram

Stage-1:

Stage-2:

17

Stage-3:

7. Cloesevelam Hydrochloride

Process Discription

Stage-I

Allyl amine is polymerized using 2, 2’- Azobis (amidinopropane) dihydrochloride in presence of hydrochloric

acid in water. Product isolated from methanol.

Stage-2 COL-Polyallyl is cross-linked with epichlorohydrin in aqueous sodium hydroxide. Product is isolated after

aqueous workup.

Stage-3 COL-sevelamer is alkylated with 6-Bromohexyl trimethylammonium bromide and 1-Bromodecane in presence

of aqueous sodium hydroxide and hydrochloric acid in methanol. Product is isolated after aqueous workup.

STAGE-2

REACTOR

(REFLUX)

FILTRATION

CENTRIFUGATION

WATER

LIQ. AMMONIA

DRYING

ALLOPURINOL

FORMAMIDE

WATER

Spent Carbon A.Carbon, Hyflow

ML Formamide Recovered

and Reused

Process

Residue

W.W. TO ETP

18

Flow Diagram

Stage-I

Stir at 0-10°C

Reactor-II

Stir at 25-30°C

Reactor-I

Cool at 0-10°C

Conc. Hydrochloric acid

Allyl amine

Stir at 48-52°C till

completion of reaction

Methanol

Stir at 25-30°C

Filtration

Reaction mixture from

reactor-I

Methanol

Drying

COL-Polyallyl

Analysis as per specification

Distillation

2,2’-

Azobis(amidinopropane)

dihydrochloride

Water

ML Solvent

recovered

& recycled

Distilled

Residue

W.W. TO

ETPCOD812mg/Ltr

19

Stage-II

At 25-30°C till completion of

reaction

Drying

Reactor-I

Stir at 25-30°C

COL-Polyallyl

Water

Aq. sodium hydroxide

Epichlorohydrin

Filtration

COL-Sevelamer


Stir at 25-30°C

Water

Isopropyl alcohol

W.W. TO ETP

COD 183mg/Ltr

ML

Distilled

Residue

Solvent

recovery&

recycled

20

Stage-III

At 25-30°C till completion of

reaction

Drying

Reactor-I

Stir at 25-30°C

Methanol

COL-Sevelamer

6-BHTAB

1-Bromodecane

Sodium hydroxide

Solution

Filtration

Colesevelam HCl


Stir at 25-30°C

Concentrated HCl

Isopropyl Alcohol

ML Solvent recovery recycled

Distillation

Residue

W.W. TO ETP COD

19mg/Ltr

21

GROUP-3

8. Amodiaquine Hydrochloride


Stage-1: N-{3-[(diethylamino) methyl]-4-hydroxyphenyl} acetamide undergoes hydrolysis in presence of HCl which

further condenses with 4, 7-DCQ using toluene as a solvent to form crude Amodiaquine hydrochloride

Stage-2: Crude Amodiaquine hydrochloride is crystallized in a mixture of water and DNS to give Amodiaquine

hydrochloride. It is dried, milled, sifted, analyzed & packed

Flow Diagram:

Stage: I

CONDENSATION

M.BASE

WATER

HCl

DCQ

CRUDE AMQ-HCl WET

CAKE

DNS

FOR DNS RECOVERY

(DISTILLATION)

TOLUENE RECOVERED &

REUSED

LAYER SEPARATION FOR TOLUENE

RECOVERY

FILTRATION

DNS RECOVERED &

REUSED

TOLUENE

PROCESS RESIDUE



W.W. TO ETP

W.W. TO ETP

22

Stage: II

FILTRATION

CRYSTALLISER

CENTRIFUGE

DRYING

AMQ-HCl

AMQ-HCl CRUDE

WATER

ML DNS RECOVERED &

DNS

DNS

WASHING

HYFLO

HCl

DISTILLATION

RESIDUE

PROCESS RESIDUE

W/W to ETP

23

9. Piperaquine Phosphate


Stage-1: 4, 7-DCQ (G-I) and Piperazine anhydrous condenses using IPA as solvent and converted to 7-chloro-4-

piperazin-1-ylquinoline, which on in-situ reaction with 1, 3 dibromo propane in presence of caustic flakes gives

Piperaquine base.

Stage-2: Piperaquine base is converted to respective hydrochloride salt in presence of water and given carbon treatment

and again converted to Piperaquine free base using caustic solution which on further reaction with phosphoric

acid at lower temperature gives Piperaquine phosphate.

Flow Diagram

Stage-I

Stage-II

Piperaquine Base

PHOSPHATE

FORMALDEHYDE

WATER

PHOSPHORIC ACID

FILTRATION

DRYING

DNS

w/w TO ETP

PIPERAQUINE

HCl


Process Residue

DNS FORRECOVERY

Activated Carbon

C. Flakes

Spent

Carbon

CONDENSATION WATER

1,3 DI BROMO PROPANE

FILTRATION

Piperaquine

Base

DNS + CYCLOHEXANE

WASHING

MDC

CAUSTIC SOLUTION

w/w TO ETP


Process Residue

DNS, MDC, Cyclohexane, IPA forRECOVERY

4,7 - DCQ

PIPERAZIN ANHYDROUS

IPA

24

GROUP-4

10. Tenofovir Disoproxil Fumarate


Stage-1:

(R)-9-(2-phosphonylmethoxypropyl)-adenine [PMPA] and chloromethyl isopropyl carbonate [CMIC] on

condensation in presence of base using NMP as a solvent forms Tenofovir disoproxil base.

Stage-2: Tenofovir disoproxil base further reacts with fumaric acid using isopropyl alcohol at lower temperature to get

Tenofovir Disoproxil Fumarate. It is then centrifuged, analyzed, dried, milled, sifted and packed.

Flow Diagram:

Stage -1:

NMP

PMPA

TBAB

CMIC & TEA

Water

REACTOR

CENTRIFUGE

REACTOR

REACTOR

OUTPUT- TENOFOVIR

DISOPROXIL BASE

ML NMP recovered

& reused

Distillation

residue

W/W to ETP

25

Stage-2:

MDC

BASE WET CAKE

Water

Sodium Sulphate

Filtration

MDC

IPA

Fumaric Acid

Cyclohexane

11. Efavirenz


� Charge E-6 and toluene.

� Add solution of triphosgene in toluene at reaction mass at 25 – 30 oC.

� Maintain the reaction mass for 3.0 hour at 25 – 30 oC.

� Reaction mass of completely distilled out at 40 – 49 oC.

� Charge Methanol in to reaction mass and stir it.

� Stir and maintain the reaction mass for 1 hour.

� Filter the reaction mass and wash it with the Methanol.

Reactor

Reactor

Reactor

Filtration

Reactor

Centrifuge

Output - Tenofovir Disoproxil

Fumarate

Reactor

Reactor

ML

Ipa, Cyclohexane

Recovered & Reused

Distillation

residue

W/W to ETP

MDC recovered &

reused

Process residue

26

Flow Diagram

SSR

SSR

SSR

SSR

SSR

SSR

SSR

SSR

E-6 raw material

Sodium bicarbonateTriphosgene solution in toluene

Toluene

Methanol

Distillation

Centrifuge

Portable water

10% sodium hydroxide solution

Aqueous layer

Ammonia+sodium hydroxide solution

Aqueous layer

Portable water washingAqueous layer

1% acetic acid solution

Aqueous layer

Portable water washingWater recovered & reused

Methanol azeotripic distillationToluene, Methanol recovered

& reused

Activated carbon

Sparkler filtration

Efavirenz Pharma

Portable water addition Methanol layer

Drying

ML

Distillation residue

ML Toluene, Methanol recovered

& reused

Distillation residueProcess residue

Spent carbon

27

Group-5

12. Artemether


Stage -1:

Dihydroartemisinin in presence of TMOA undergoes acetalation in methanol to form Artemether crude which

is centrifuged.

Stage-2: Artemether Crude is crystallized in methanol to obtain Artemether, which is centrifuged, dried, micronised (If

required), analyzed and packed.

Flow Diagram:

Stage – 1:

Stage – 2:

WASHING

DISTILLATION

DRYING

Methanolrecover

ed & reused

ARTEMETHER

TMOA

METHANOL& WATER

METHYLATION

Water + Methanol

Washing

HCl & TEA

DHA

W/W to ETP

Distillation

Residue

TMOA, Methanol

recovered & reused


CENTRIFUGE Process Residue

ARTEMETHER

CRUDE

W/W to ETP

ARTEMETHER CRUDE

28

13. Artesunate


Stage-1:

Dihydroartemisinin reacts with Succinic Anhydride and TEA in presence of solvent Acetone produced

Artesunate crude.

Stage-2: Artesunate crude purified with methanol & it gives Artesunate pure.

Artesunate is dried, Mill & Sifted packed in HDPE or fiber drums along with two LDPE bag. Primary is white

& secondary is black

Flow Diagram

Stage -1:

Acetone

DHA

REACTION

WATER WASHING&

CRYSTALISATION Water

TEA

S.Anhydride

W/W to ETP Acetic Acid

Hyflow, A. Carbon Spent Carbon

Acetone Recovered

& reused

CENTRIFUGING ML

Distillation Residue ARTESUNATE

Crude

29

Group- 6

14. Emtricitabine


Stage-1: Emtricitabine Hydrochloride

A solution of dipotassium hydrogen phosphate in Water was stirred till clear solution obtained. DNS was added

and the mass was cooled to 0-5°C. (2S,5R)-5-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)-[1,3]-oxathiolane-2-

carboxylic acid, 2S-isopropyl-5R-methyl-1R-cyclohexyl ester (F-CME) was added at 0-5°C. A solution of

sodium borohydrate in NaOH was added at 0-5°C within 1.0 h. Raise the temperature of reaction mass to 5-

10°C and maintained the reaction mass till reaction complies. Emtricitabine was isolated as hydrochloride salt

(Emtricitabine HCl) using IPA.HCl (20.0-25.0%).

Stage-2: Emtricitabine Free base Emtricitabine HCl was dissolved in methanol. The mixture was stirred for 15 mins. Triethylamine was added to

the solution at 25-30°C. The solution was heated to 40-45°C for 30.0 mins. Methanol was distilled out

completely from reaction mass at 40-45°C under vacuum till dry solid obtain. MDC was charged to the dry

solid and maintained it for 1.0 h at 25-30°C under stirring. Solid was collected by filtration and leached with

MDC and washed with MDC. The solid was dried to get emtricitabine free base.

Stage-3: Emtricitabine Pharma

The technical grade free base emtricitabine was decolorized in IPA to get pharmaceutically accepted quality

product Emtricitabine.

30

Flow Diagram:

Stage-1:

DNS

NaOH

IPA

IPA

Purified water

Dipotassium hydrogen phosphate ReactorF-CME

Addition pot

Reactor

Purified waterSodium borohydride

DNS recovered & reused

Nutch filtration

Filtrate

DistillationPurified water

Toluene

Layers sepration

Nutch Hot filtration and

Distillation

Isolation

Reactor

Filtrate

Reactor

pH adjestment10% Sulphuric acid solution

Liq. ammonia

Layers sepration

Toluene layerReactor

20.0-25.0 % IPA.HCl

Centrifuge

Stage-1

Drying

ML


Methanol & Toluene

IPA recovered & reused


Distilation residue

W/W to ETP


Process residue

31

Stage-II

Triethyl amine

MDC

MDC

Stage-1

MethanolReactor

Reactor

methanol recovered & reused

ReactorMDC recovered & reused

Centrifuge

Stage-2

Reactor

Distillation

Distillation

Drying

Motherliquor


Process Residue (TEA)


32

Stage-3:

Activated carbon

IPA

Stage-2Reactor

Reflux

Distillation IPA recovered & reused

Layers sepration

Sparkler Hot filtration

Filtrate

Reactor

Mother liquor

CentrifugeIPA

washing

Stage-3

(Emtricitabine Pharma)

Drying

Hot filtrate

Isolation


Spent carbon



33

15. Pyrimethamine


Stage-1:

� Charge 4-chloro phenyl acetonitrile and ethyl propionate.

� Charge sodium Methoxide at room temperature.

� Maintain at 80-85°C for 4 hour.

� Distilled out ethyl propionate completely; charge water and MDC.

� Adjust pH with acetic acid.

� Separate layer and take organic layer. (three water washing)

� Distilled out MDC completely.

� Charge cyclo hexane and ethylene glycol at room temperature.

� Charge PTSA and heat the reaction mass u to reflux temp for 10-12 hrs.

� Chilled the reaction mass to 10-15°C; Charge sodium Methoxide and water.

� Separate layer and take organic layer. (three water washing)

� Distilled out cyclo hexane completely.

� Charge methanol and carbon in reaction mass.

� Filter it and slowly add water at room temperature.

� Chilled the reaction mass up to 5-10°C.


� Dry it.

Stage-2: � Charge guanidine hydrochloride and methanol.

� Charge sodium Methoxide and stir for 30 min.

� Filter the salt sodium chloride and wash with methanol.

� Charge 4-CPDA and methanol at room temperature.

� Charge carbon in reaction mass and filter it.

� Mix both filtrate ML and heat the reaction mass up to reflux temperature.

� Maintain it for 9 hrs and cool to room temperature.

� Filter it and wash with water and then with methanol.

� Dry it.

34

Flow Diagram:

Stage-I: 2-(4-Chlorophenyl)-2-(2-ethyl-1,3-dioxolan-2-yl)acetonitrile (4-CPDA):

4-CPA

Ethyl propionate (EP)

CH3ONa

Check TLC % of 4-CPA

Distilled out ethyl propionat

MDC + WATE

Layer separation

Distillation of MDC

Reactor

Reactor

Reactor

Reactor

Layer separate out Reactor

Reactor MDC + potable

Distillation of EP

Adjust pH 4.5-5.5

MDC

Potable water Layer separate out


Reactor Potable water Layer separate out

Reactor Cyclo hexane

PTSA Remove water

azeotropic.

Reactor NaOCH3 Layer separate out

Reactor Potable water Layer separate out

35

Continue………

Distilled out cyclohexane

ML for Methanol

recovery

Stage-I for Complete analysis

Reactor


Reactor


Sparkler filter

Methanol

Reactor

Addition of

potable water

Centrifuge

Drying

36

Stage-II: 5-(4-Chlorophenyl)-6-ethylpyrimidine-2,4-diamine (Pyrimethamine):

Stage-I Guanidine HCl

Methanol CH3ONa

Methanol

Mainataining Filtration Check TLC

Wash with purified water

+Methanol ML for Methanol recovery

Check water content

If Required

If Required

Pyrimethamine for

Complete Analysis.

Reactor

Rotocon vacuum dryer

Sparkler

Centrifuge

Multi mill

Jet mill

Sifter

Packing

Reactor

37

Sparkler Filter

16. Dihydroartemisinin


Dihydroartemisinin is dissolved in Methanol followed by carbon treatment. Then water is added in to filtrate, to

get Dihydroartemisinin pure, which is dried milled (If required), Jet Milled (if required), sifted, Analyzed and

packed.

Flow Diagram:

Methanol

Dihydroartemisinin crude

Activated Carbon

Hyflow

Methanol

Clear Filtrate

Add

Water

Dihydroartemisinin Pure

Wet Cake

(If required)

(If required)

Reactor

Reactor

Centrifuge

RotoconVacuum Dryer

Multi mill

Jet mill

Dihydroartemisinin

Sifter

Reactor

Material transfer equipment

W/W to ETP

ML Methanol

recovered &

reused Process

residue

Spent Carbon

Distillation

residue

38

17. Bisoprolol Fumarate


Stage-1:

� Charge 2-Isopropoxy ethanol and 4-Hydroxy Benzyl alcohol.

� Charge Amberlyst-15 at room temperature.

� Maintain at room temperature for 3 hour.

� Filter the reaction mass and adjust pH with sodium bicarbonate.

� Distilled out solvent completely; charge water and MDC. (Repeat three times)

� Stir for 30 min.

� Separate layer and take organic layer.


� Collect liquid as a product. (BS-1)

Stage-2:

� Charge Epichlorohydrin and BS-1.

� Charge K2CO3 and heat the reaction mass up to reflux temp for 12 hrs.

� Cool to RT and filter K2CO3.

� Distilled out Epichlorohydrin completely.


Stage-3:

� Charge methanol and BS-2.

� Charge mono isopropyl amine and heat the reaction mass up to reflux temp for 12 hrs.

� Cool to RT and distilled out methanol completely.

� Charge water and MDC. (Repeat three times)

� Stir for 30 min.

� Separate layer and take organic layer.



Stage-4:

� Charge acetone and BS-3.

� Charge fumaric acid heat the reaction mass up to reflux temp for 30 min.

� Filter the reaction mass and cool to room temperature.

� Chilled up to 10 – 15 °C and maintain it for 3-4 hrs.

� Filter it and wash with acetone.

39

Flow Diagram:

Stage-I: 4-[(2-Isopropoxyethoxy)Methyl]Phenol [BS-1]

SS Reactor

Nutch Filter

SS Reactor

Nutch Filter / Sparkler Filter

2-IPE

4-HBA

Amberlyst-15

MIPA

2-Isopropoxy ethanol pad

washing

Check pH Sodium Bicarbonate + Water

SS Reactor Distill out

2-Isopropoxy

SS Reactor

SS Reactor

DM Water

MDC 1st Extraction

MDC 2nd & 3rd Extraction

SS Reactor

2-Isopropoxy ethanol pad

washing

Separate layer

Separate layer

Separate layer

Check TLC

All organics layers

DM water washing

SS Reactor

Collect liquid material [BS-1]

SS Reactor

Complete Analysis

DM water washing Separate layer

MDC Distillation Charge Organic layer

40

Stage-II : 2-[[4-(2-Isopropoxyethoxy)Methyl]-Phenoxymethyl]Oxirane [BS-2]

SS Reactor

Nutch Filter

SS Reactor

Collect Liquid

Epichlorohydrin

BS-1

Potassium carbonate

SS Reactor

Collect Liquid [BS-2]

Complete Analysis

Epichlorohydrin pad washing

Distill out

Epichlorohydrin

Complete Analysis

1st to 3

rd Fraction

41

Stage-III: Bisoprolol Base [BS-3]

SS Reactor

SS Reactor

SS Reactor

SS Reactor

Methanol

BS-2

NaBH4

MIPA

Check BS-2 Content

by GC

DM Water

MDC

Aq. Layer

Separated

Organic Layer

Separated

Organic Layer

Aq.LayEffluent Treatment Plant

Combined Organic Layer

Aq.Lay Effluent Treatment Plant

MDC

SS Reactor

Org.La

DM Water

DM Water Aq.LayEffluent Treatment Plant

Org.La

SS Reactor

Org.La Aq.LayEffluent Treatment Plant

SS Reactor

DM Water

Activated Carbon

MDC Wash

Sparkler Filter

Circulation

Clear Solution

Reactor PR-2 MDC Distillation

Bisoprolol Base [BS-3] Complete Analysis

Methanol Distillation

42

Stage – IV : Bisoprolol Fumarate [BS-4]

SS Reactor

Sparkler Filter

SS Reactor

Centrifuge

Acetone

Bisoprolol

Base

Bisoprolol Fumarate

Crude Wet Cake

SS Reactor

Chilled Acetone Washing

Sparkler Filter

SS Reactor

Centrifuge

Clear Solution

Acetone

Clear Solution

Chilled Acetone Washing

Rotocon Vacuum Dryer

Multi Mill

Jet Mill

Sifter

If Required

Check Moisture

Content

If Required

Packing

Complete Analysis

43

Group- 7

18. Pyronaridine Tetraphosphate:


Stage-1: o Charge Compound-A, Compound-B, ethanol and HCl.

o Stir at 40-45 0C for 24 hrs.

o Cool to 10-15 0C.

o Filter it.

o Dry It.

Stage-2:

o Charge stage-1

o Charge DMF

o Stir at 100-105 0C

o Clear sol. obtained

o Filter it

o Take filtrate.

o Adjust pH 5-5.6 with H3PO4

o Stir at RT for 24 hrs

o Cool to 15-20 0C & stir for 1 hrs

o Filter it

o Wash material with chill DMF

o Dry It

Flow Diagram:

Stage-1:

Ethanol recovered

& reused

Process Residue

44

Stage-2:

DMF recovered &

reused


45

19. Atazanavir

Manufacturing process:

Stage-I: Preparation of Atazanavir di-tert butyl analogue

1. Arrange dry and clean 1.0 lit. four necks round bottom flask equipped with stopper, thermo pocket and

water condenser.

2. Charge IPA into RB flask at 25-30°C under stirring.

3. Charge Boc hydrazine into RB flask at 25-30°C under stirring.

4. Charge Boc epoxy into RB flask at 25-30°C under stirring.

5. Raise the temperature of the reaction mass up to 65-70°C under stirring.

6. Maintain the reaction mass for 24.0 h at 65-70°C under stirring. [Observations: light to dark yellow

color thick semi solid reaction mass observe.]

7. Reaction was monitored by TLC. Send the reaction mass first sample to QC for reaction monitoring by

TLC.

8. If TLC complies, Charge potable water into reaction mass at 65-70°C under stirring.

9. Maintain reaction mass for 1.0 h at 65-70°C under stirring.

10. Cool reaction mass to 25-30°C under stirring.

11. Further cool reaction mass to 15-20°C under stirring.

12. Maintain the reaction mass for 1.0 h at 15-20°C under stirring.

13. Filter the solid from reaction mass at 15-20°C.

14. Wash the wet solid with IPA + Potable water.

15. Dry the material at 50-55°C for 12.0 h under vacuum.

Stage-II: Preparation of Atazanavir free base

(Part A)

1. Arrange dry and clean 1.0 lit. Four necks round bottom flask equipped with stopper, thermo pocket,

addition funnel and water condenser.

2. Charge MDC into RB flask at 30±2°C under stirring.

3. Charge stage-1 into RB flask at 30±2°C under stirring.

4. Slowly added conc. HCl into reaction mass within 30.0±5.0 min. at 30±2°C under stirring

5. Slowly raise the temperature of reaction mass to 35-40°C.


7. Send the sample of upper oily layer of reaction mass to QC for reaction monitoring of part A by TLC,

8. If TLC complies, Cool the reaction mass to 30±2°C under stirring.

9. Separate the layers of reaction mass at 30±2°C.

10. Collect the upper oily layer in RB Flask at 30±2°C.

11. Charge MDC into oily layer at 30±2°C under stirring.

12. Cool the reaction mass at 15-20°C under stirring.

13. Addition of tri ethyl amine (150.0 ml) into RB flask within 30.0±5.0 min. at 15-20°C under stirring.

Part-B: 1. Arrange dry and clean 2.0 lit. four necks round bottom flask equipped with stopper, thermo pocket,


2. Charge MDC lot 3 into RB flask at 30±2°C under stirring.

3. Charge N-methoxy carbonyl L-tert leucine into RB flask at 30±2°C under stirring.

4. Charge HOBT mono hydrate into RB flask at 30±2°C under stirring.

5. Charge EDC.HCl into reaction mass at 30±2°C under stirring.

6. Stir the reaction mass for 15.0 min. at 30±2°C.

7. Addition of Part A into reaction mass of Part-B within 30.0±5.0 min. at 30±2°C under stirring.

8. Maintain the reaction mass for 2.0 hrs at 30±2°C under stirring.

9. Send the sample of reaction mass to QC for reaction monitoring of Part B by TLC,

10. If TLC result complies then MDC layer given 3 potable water washings.

11. Distill off the MDC completely from reaction mass under vacuum at NMT 45°C.

12. Charge ethyl acetate into reaction mass at NMT 45°C under stirring.

13. Raise the temperature of reaction mass to 55-60°C under stirring.


15. Cool the reaction mass to 30±2°C under stirring.

46

16. Maintain the reaction mass for 3.0 h at 30±2°C under stirring.

17. Filter the solid from reaction mass at 30±2°C.

18. Dry the material at 50-55°C for 12.0 hrs ±5.0 min. under vacuum.

19. Charge methanol into RB flask at 30±2°C under stirring.

20. Charge dry stage-2 into RB flask at 30±2°C under stirring.

21. Stir and heat the reaction mass at 60-65°C.

22. Slowly addition of potable water into reaction mass with in 1.0 h at 60-65°C under stirring.


24. Cool the reaction mass to 30±2°C under stirring.

25. Maintain the reaction mass for 2.0 h at 30±2°C.

26. Filter the solid from reaction mass and wash with potable water + methanol.

27. Dry the material at 50-55°C for 12.0 hrs±5.0 min. under vacuum.

Stage-III: Preparation of Atazanavir sulphate:

1. Arrange dry and clean 2.0 lit. Four necks round bottom flask equipped with stopper, thermo pocket


2. Charge methanol into RB flask at 30±2°C under stirring.

3. Charge stage-2 into RB flask at 30±2°C under stirring.


5. Charge activated carbon into reaction mass at 40-45°C under stirring.


7. Hot filter the reaction massthrough hyflo bed and wash the bed with methanol.

8. Distill off the Methanol completely from reaction mass under vacuum at NMT 45°C under stirring.

9. Charge acetone into reaction mass and stir it for 15.0 min. at 40-45°C.

10. Distill off the methanol + acetone completely from reaction mass under vacuum (NLT 710 mm Hg) at

NMT 45°C under stirring.

11. Charge acetone into reaction mass at 40-45°C under stirring.

12. Charge con. H2SO4 into reaction mass at 40-45°C under stirring.

13. Maintain the reaction mass for 1.0 h at 30±2°C under stirring.

14. Filter the solid from reaction mass at 30±2°C

15. Wash the wet solid with acetone.

16. Check the weight of wet cake.


18. Check the weight of the dry solid at 30±2°C.

19. Send the dry sample to QC for Finished product complete analysis.

FLOW DIAGRAM:

Stage-I: Atazanavir di-tert butyl analogue

47

Stage-II:Atazanavir free base:

48

Stage-III:Atazanavir sulphate

49

20. PRIMAQUINE PHOSPHATE


Stage-1:

1,4-Dibromo pentane on reaction with potassium phthalimide at 50-55 °C in solvent acetone afford 4-bromo-1-

phthalimido pentane. After acetone recovery thick oily mass collected as stage-1 for further reaction.

Stage-2: Primaquine stage-1, 8-aminoquinoline and aq. solution of disodium hydrogen phosphate were added in to the

methanol and heated to 75-80°C. The reaction mass was maintained at 75-80°C for 45-50 hrs. After completion

of reaction cool the reaction mass to RT and MDC was added in to the reaction mass and stirred well. Separate

layer of the reaction mass and MDC layer was given a Conc. HCl washing. MDC layer was concentrated till

dryness and cooled to RT. Methanol and hydrazine hydrate were added in to the concentrated oily reaction mass

& was heated to reflux.Stirred the mass for 2 hrs at reflux to complete the reaction. Cool the reaction mass to

RT and filter the solid, washed with chilled methanol. Filtrate was taken for phosphate salt preparation by

adding 80% phosphoric acid in it. Reaction mass was heated to reflux and maintained for 1 hr. Cool the

reaction mass to RT and further cooled to 0-5°C. The isolated solid was filtered, washed with chilled methanol

and dried by suction. The solid was dried in hot air oven to obtain stage-2 of Primaquine phosphate.

Stage-3: Primaquine phosphate stage-2 was added into the Methanol at 25-30°C. Heat the reaction mass up to reflux to

obtain clear solution. Activated carbon was added into the clear reaction mass and stirred the mass for 30

minutes at reflux. Filter the reaction mass through hyflo bed and the carbon bed was washed with Methanol.

The reaction mixture was cooled to RT and further cooled to 0-5 °C. The isolated solid was stirred at 0-5 °C for

4 hrs then filtered,washed with chilled water and dried by suction. The solid was dried in hot air oven to obtain

stage-2P of Primaquine phosphate.

Flow Diagram:

Stage-1:

SSR

SSR

SSR

ML

1,4-DBP

Acetone

Distillation

SSR(Oily mass)

Potassium phthalimide

50-55°C

Centrifuge

Stage-1

Acetone/1,4 DBP recovered & reused

2-3 dihydrophthalazine-1,4-dione

[Salt (By product)]

50

Stage-2:

MDCSSR

SSR

SSR

SSR

SSR

8-AMQ, MDC & Methanol recovered & reused

8-AMQ

Na2HPO4 solution

Stage-1

Methanol

W/W to ETP

75-80°C

Distillation

Methanol

Hydrazine hydrate

Aq. HCl

Centrifuge

60-65°C

Phosphoric acid

Centrifuge

Drying

Stage-2

Mother liquor

60-65°C

Water

Conc. HCl

Process residue


Hydrazine Hydrate recovered & reused

4, BPP


Mother liquor

Methanol

Methanol recovered & reused


51

Stage-3:

Stage-2

MethanolReactor

Sparkler

Distillation

Stage-3 (Primaquine Phosphate Pharma)

Drying

Methanol recovered & reused

Reactor

55-60°C

Activated carbon

W/W to ETPCentrifugeWater

Spent Carbon


52

21. Chloroquine Phosphate


Stage-1: 4, 7-DCQ is condensed with NDA to obtain Chloroquine base, which is then taken in Solvents and reacted with

Phosphoric Acid to give Crude Chloroquine Phosphate (CQP).

Stage-2: Chloroquine Phosphate Crude is taken in Solvent and recrystallised to obtain pure Chloroquine Phosphate. This

Chloroquine Phosphate pure is dried, pulverized, analyses and packed in HDPE or fiber drums followed by two

liners, primary is black & secondary is white.

Flow Diagram:

Stage-1:

.

Caustic Lye

Activated Carbon

Phenol

Silica


Process Residue

Phenol

Recovered

Spent

Carbon

4,7 DCQ

NDA

Water

CONDENSATION

EXTRACTION Aq. Layer

WATER

EDTA

Toluene

W/W to ETP

DISTILLATION Methanol Toluene

recovery

Phosphate Formation

Phosphoric

acid Methanol Recovery

Crude CQP

53

Stage-2:

CARBON

TREATMENT

FILTRATION

CRYSTALISATION

CENTRIFUGING

DRYING

CQP

CQP CRUDE

WATER

CARBON

W/W to ETP

DNS

DNS Recovered

& Reused

H2O + DNS

WATER Washing

EDTA

Phosphoric acid

Hyflow

Silica

Process

Residue

Distillation

Residue

Spent Carbon

54

Group-8

22. Tenofovir Alafenamide Fumarate Manufacturing process

Stage-1:

1. Arrange dry and clean RBF with TP, stopper, water condenser, addition funnel and oil bath at

25-30°C.

2. Charge Acetonitrile into RBF at 25-30°C.

3. Charge PMPA into RBF under stirring at 25-30°C.

4. Charge Triphenyl phosphite into RBF under stirring at 25-30°C.

5. Add Triethylamine using addition pot within 30 mins at 25-30°C.

6. Charge DMAP to RBF.

7. Charge Toluene into RBF at 25-30°C.

8. Raise temperature up to 80-85°C.

9. Maintain reaction for 40-42 hrs at 80-85°C.

10. Check TLC after 40 Hrs. If TLC ok cool the reaction to 10-15°C.

11. Charge toluene in same RBF at 10-15°C.

12. Charge purified water in RBF at 10-15°C.

13. Stirrer reaction mass for 1 hr at 15-20°C.

14. Separate the layers, aqueous layer transferred to RBF at 15-20°C.

15. Adjust pH 2.0 to 3.0 slowly by using conc. HCl at 10-15°C.

16. Further cool reaction mass 0-5°C.

17. Maintain reaction mass 3-4 hrs at 0-5°C.

18. Filter the reaction mass at 0-5°C.

19. Wash the wet cake with chilled mixture of Acetonitrile and purified water at 0-5°C and suck

dry well.

20. Charge wet material in Toluene at 25-30°C.

21. Maintain for 4-8 hrs at 70-75°C.

22. Filter and suck dry well.

23. Unload w/c and dry at 60-65°C.

24. Unload dry material, Check weight of material.

Stage-2:

Part A: 1. Arrange dry and clean RBF with TP, stopper, water condenser, addition funnel and oil bath at

25-30°C.

2. Charge Toluene into RBF at 25-30°C.

3. Charge Mono phenyl PMPA into RBF under stirring at 25-30°C.

4. Add thionyl chloride using addition pot into RBF under stirring at 25-30°C.

5. Raise temp up to 85-100°C.

6. Maintain reaction mass under stirring for 60-65 hrs at 85-100°C.

7. Cool reaction mass at 60°C

8. Charge toluene at 60°C.

9. Distilled out reaction mass until about 4 vol up to 85-100°C.

10. Cool reaction mass to 25-30°C.

11. Charge MDC at 25-30°C.

12. Cool to 19-25 0C. Stir 1 hr at 19-25°C.

13. Further cool reaction mass below -10°C.

Part B: 14. Charge L-alanine isopropyl ester hydrochloride in another RBF.

15. Charge THF in RBF at 25-30°C


17. Add slowly Triethyl amine using addition pot below 0-5°C

18. Maintain 1 hr at 0-5°C.

19. Filter the reaction mass, wash by chilled THF.

20. Collect filtrate in Clean RBF.

21. Cool reaction mass to 0-5°C

22. Further cool reaction mass below -10 to -20°C.

55

23. Add Part A reaction mass to Part B slowly below -10°C.

24. Maintain reaction for 1 hr at -10°C.

25. Raise temperature of reaction mass at 20-25°C.



28. Charge Acetonirile in RBF at 15-25°C.



31. Charge MDC in reaction mass at 20-25°C.

32. Charge sodium phosphate monobasic solution in reaction mass at 20-25°C.

33. Stir 30 mins at 20-25°C.

34. Settle & layer separated.

35. The product MDC layer is transferred to RBF at 20-25°C.

36. Charge purified water in reaction mass.

37. Stir 30 mins at 20-25°C.

38. Settle & layer separated.

39. The product MDC layer is transferred to RBF at 25-30°C.

40. Distilled out reaction, strip out by Acetone up to 40-45°C.

41. Charge Acetone in reaction mass, stir for 15 mins at 50-55°C.


43. Filter the wet cake and suck dry well.

44. Unload w/c and dry at 55-60°C.

Stage-3: 1. Arrange dry and clean RBF with TP, stopper, water condenser, addition funnel and oil bath at

25-30°C.

2. Charge Stage-II in RBF at 25-30°C.

3. Charge Acetonitrile in RBF at 25-30°C.

4. Raise temp of reaction mass up to 65-70°C.

5. Charge fumaric acid in RBF at 65-70°C.

6. Stir for 45-60 min at 65-70°C.

7. Filter the Reaction mass at 65-70°C.

8. Filtrate further heat to 70-75°C.

9. Charge TAF (seed) into reaction mass 55-60°C.

10. Reactions mass gradually cool to 25-30°C.

11. Further cool the reaction mass upto 0-5°C.

12. Stir 1 hr at 0-5°C.

13. Filter the material and wash by clilled Acetonirtile.

14. Suck dry well.

15. Unload w/c and dry in VTD at 50-55°C.

16. Unload dry material, Check weight of material.

56

Stage-I:

Stage-II:

57

Stage-III:

23. Tenofovir DipivoxilOrotate Manufacturing process:

Stage-1: Tenofovir Disoproxil base: 1. Arrange dry and clean RBF.

2. Charge NMP into RB flask at 30 ± 5°C under stirring.

3. Charge PMPA into RB flask at 30 ± 5°C under stirring.

4. Charge TBAB into RB flask at 30 ± 5°C under stirring.

5. Raise the temperature of the reaction mass up to 49 ± 4°C under stirring.

6. Addition of CMIC + TEA mixture into reaction mass in 1.0 h ± 5 min at 49 ± 4°C.

7. Maintain the reaction mass for 2.0 h ± 5 min at 50 ± 2°C under stirring.

8. Chill the reaction mass to 0-5°C under stirring.

9. Add chilled water into reaction mass at in 1.0 h ± 10 min at 0-5°C.

10. Maintain the reaction mass for 16.0 h ± 15 min at 0-5°C under stirring.


12. Charge MDC into RB flask at 0-5°C under stirring.

13. Charge wet cake into RB flask at 0-5°C under stirring.

14. MDC layer given chilled water washings at 0-5°C.

15. Combine aqueous layer given MDC extraction at 0-5°C.

16. Combine both MDC layers into RB flask and charge sodium sulphate at 0-5°C.

17. Stir the reaction mass for 30 ± 5 min at 0-5°C.

18. Filter the reaction mass and wash with MDC at 0-5°C.

19. Distill out MDC completely under vacuum at temperature below 35°C.

20. Cool the reaction mass at 20-25°C.

21. Charge ethyl acetate into reaction mass at 20-25°C.

22. Charge Cyclohexane into reaction mass at 30-35°C.



58


Stage-2: Tenofovir Disoproxil Orotate

1. Arrange dry and clean RBF.

2. Charge Acetone into RB flask at 30 ± 2°C.

3. Charge Stage-1 into RB flask at 30 ± 2°C.

4. Charge Purified water into reaction mass at 30 ± 2°C.

5. Stir reaction mass for 15.0 min. at 30 ± 2°C.

6. Filter the reaction mass at 30 ± 2°C and wash with purified water.

7. Addition of orotic acid solution + DMSO solution in 1.0 hr ± 5 min. into reaction mass at 30 ±

2°C.

8. Charge Purified water into reaction mass at 30 ± 2°C.

9. Maintain reaction mass for 1.5 hr at 30 ± 2°C.

10. Filter the solid from reaction mass at 30 ± 2°C.


Flow Diagram Stage-1: Tenofovir Disoproxil base

59

Stage-2:

24. Sofosbuvir Manufacturing Process:

Preparation of Stage-1: 1. Arrange clean & dry RB flask equipped with addition funnel, thermo pocket and water condenser in

icebath.

2. Charge dry THF into RB flask at 25-30°C.

3. Charge Uridine into RB flask at 25-30°C under stirring.

4. Cool the reaction mixture up to 0 to 5°C under stirring.

5. Addition of t-BuMgCl into RB flask within at 0 to 5°C under stirring.

6. Charge Fluoro compound into the reaction mixture at 0 to 5° C under stirring.

7. Maintain the reaction mass at 0 to 5°C for 15 hrs under stirring.

8. After completion of reaction, add 2N HCl solution into the reaction mixture at 0 to 5°C under

stirring.

9. Charge MDC into the reaction mixture at 0 to 5°C under stirring.

10. Take the organic layer and give 5% aqueous Na2CO3 washing and brine washing respectively at 25-

30°C.

11. Take upper organic layer and give Na2SO4 treatment at 25-30°C and filter the mass.

12. Distill out MDC completely at 45-50°C under vacuum.

13. Cool the reaction mass to 25-30°C and charge MDC and Toluene in it at 25-30°C under stirring.


15. Filter the solid from reaction mass at 0-5° suck dry well and dry the mass in oven at 50-55 °C.

Preparation of Stage-2: 1. Arrange clean & dry RB flask equipped with thermo pocket and water condenser in waterbath.

2. Charge Methanol in it at 25-30°C

3. Charge stage-1 in it at 25-30°C under stirring.


5. Charge activated carbon into reaction mass.

6. Filter the hot reaction mass at 65-70°C through hyflo bed and wash the bed with Methanol.

7. Distill out methanol completely at 45-50°C under vacuum till oily mass obtained.



10. Further cool reaction mass to 0-5°C under stirring.

11. Filter the solid from reaction mass at 0-5°C under vacuum and suck dry well and dry the solid in

oven at 50-55°C.

Preparation of Stage-3 or Sofosbuvir: 1. Arrange clean & dry RB flask equipped with thermo pocket and water condenser in waterbath.

2. Charge purified water into RB flask at 25-30°C.

60

3. Charge stage-2 into RB flask at 25-30°C under stirring.


5. Maintain the reaction mass for 1.0 hrs at 50-55°C under stirring.


7. Filter the solid from reaction mass at 25-30°C under vacuum and suck dry well & dry the mass in

oven at 50-55°C.

Flow Diagram

Stage-1

61

Stage-2

Stage-3

62

GROUP-9

25. Dolutegravir Sodium Manufacturing process:

Preparation of Stage-I:

1. Arrange dry clean RBF with T.P., stopper and condenser in heating water bath at 25-30 °C.

2. Charge Acetonitrile in to the RBF at 25-30 °C.

3. Charge methoxy compound in it at 25-30 °C under stirring.

4. Heat the reaction mass up to 75-80°C under stirring.

5. Maintain the reaction mass at 75-80°C under stirring for 3.0-5.0 hrs or till TLC complies.

6. After completion of reaction cool the reaction mass to 25-30 °C under stirring.

7. Add 1N HCl using addition funnel within 15.0 min. at 25-30 °C under stirring.

8. After completion of addition heat the reaction mass up to 45-50 °C under stirring.

9. Distilled out acetonitrile completely from the reaction mass at 45-50 °C under vacuum.

10. Cool the reaction mass to 25-30 °C under stirring.

11. Charge methanol and stir the mass for 15.0 min. at 25-30 °C.

12. Add 30% HCl using addition funnel within 15.0 min. at 25-30 °C under stirring

13. After completion of addition add purified water in to the above reaction mass at 25-30 °C under

stirring.

14. Heat the reaction mass up to 60-65 °C under stirring.


16. Further cool the reaction mass to 0-5 °C under stirring.

17. Filter the reaction mass at 0-5 °C.

18. Wash the solid with chilled methanol at 0-5 °C and suck dry well.

19. Transfer the solid and dry the solid in hot air oven at 50-55 °C.

Preparation of Stage-II or Dolutegravir Na:

1. Arrange dry clean RBF with T.P., stopper and condenser in heating water bath at 25-30 °C.

2. Charge Methanol in to the RBF at 25-30 °C.

3. Charge hydroxy compound in it at 25-30 °C under stirring.


5. Add aq. NaOH solution using addition funnel within 15.0 min. at 25-30 °C under stirring.

6. Maintain the reaction mass at 60-65°C under stirring for 2.0 hrs.


8. Further cool the reaction mass to 0-5 °C under stirring.

9. Filter the reaction mass at 0-5 °C.

10. Wash the solid with chilled methanol at 0-5 °C and suck dry well.

11. Transfer the solid and dry the solid in hot air oven at 50-55 °C.

63

Flow Diagram :

Stage-I

Stage-II

64

26. Velpatasvir


Preparation of Stage-1: 1. Arrange dry and clean four necks round bottom flask

2. Charge (2S,4S)-4-(Methoxymethyl)-1,2-pyrrolidinedicarboxylicacid2-[2-(9-bromo-8,9,10,11-

tetrahydro-8-oxo-5H-benzo[d]naphtho[2,3-b]pyran-3-yl)-2-oxoethyl]1-(1,1-dimethylethyl) ester into

RB flask at 25-30°C under stirring.

3. Charge (2S,5S)-1-((S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl pyrrolidine-2-

carboxylic acid into RB flask at 25-30°C under stirring.

4. Charge THF into RB flask at 25-30°C under stirring.

5. Charge Cesium carbonateinto RB flask at 25-30°C under stirring.

6. Stir and heat RM at 50-55°C and maintain for 20.0 h.

7. Distilled out RM completely at 50-55°C u/v and cool to RT.

8. Charge Ethyl acetate into the above concentrated mass.

9. Stir RM at 25-30°C for 1.0 h.

10. Filter and dry the solid.

Preparation of Stage-2:

1. Arrange dry and clean four necks round bottom flask

2. Charge Stage-1 into RB flask at 25-30°C under stirring.

3. Charge Sodium acetate into RB flask at 25-30°C under stirring.

4. Charge Toluene into RB flask at 25-30°C under stirring.



7. Charge Methanol into the above concentrated mass.






3. Charge Manganese dioxide into RB flask at 25-30°C under stirring.


5. Maintain RM at 25-30°C for 13.0 h.

6. Charge Methanol at 25-30°C under stirring.







4. Charge Conc. HCl into RB flask at 25-30°C under stirring.


6. Charge (R)-2-((methoxycarbonyl) amino)-2-phenylacetic acid into RB flask at 25-30°C under stirring.

7. Charge COMU ( (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-

carbenium hexafluorophosphate) into RB flask at 25-30°C under stirring.

8. Charge DIPEA into RB flask at 25-30°C under stirring.



11. Charge Ethyl acetate into the above concentrated mass.

12. Stir RM at 25-30°C for 1.0 h.


65

Flow Diagram

Stage-1:

Stage-2:

66

Stage-3:

Stage-4:

67

27. AdefovirDipivoxil Fumarate Manufacturing process:

Stage-1: Adefovir Dipivoxil base

1. Arrange dry and clean RBF.

2. Charge NMP into RB flask at 25-30°C under stirring.

3. Charge Adefovir into RB flask at 25-30°C under stirring.

4. Raise the temperature of the reaction mass up to 45-50°C under stirring.

5. Addition of t-Butyl (chloromethyl) carbonate [t-BCMC] and TEA mixture into reaction mass in

1.0 h ± 5 min at 45-50°C.



8. Add chilled water into reaction mass at in 1.0 h ± 10 min at 0-5°C.





13. MDC layer separate and given chilled water washings at 0-5°C.

14. MDC layers into RB flask and charge sodium sulphate at 0-5°C.




18. Charge IPA into reaction mass at 20-25°C.




Stage-2: Adefovir Dipivoxil Fumarate 1. Arrange dry and clean RBF.

2. Charge Acetone into RB flask at 30 ± 2°C.

3. Charge Stage-1 into RB flask at 30 ± 2°C.

4. Stir reaction mass for 15.0 min. at 50-55°C.

5. Charge fumaric acid into reaction mass at 50-55°C.


7. Maintain reaction mass for 30 min. at 50-55°C.

8. Stop heating and cool to room temp. then 0-5°C.

9. Maintain reaction mass for 2.0 hr at 0-5°C.



68

Stage-1:

Stage-2:

Reactor

Reactor

Centrifuge

Fumaric acid

Stage-1

Acetone

API

MLSolvent recovered

and Recycled

Distillation

residue

W.W to ETP

69

28.Ledipasvir Manufacturing process:

Preparation of Stage-I:

1. Arrange dry and clean four necks round bottom flask equipped with stopper, thermo pocket and water

condenser.

2. Charge (1R,3S,4S)-tert-butyl 3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1] heptane-2-

carboxylate into RB flask at 25-30°C under stirring.

3. Charge bis(pinacato)diboron into RB flask at 25-30°C under stirring.

4. Charge potassium propionate into RB flask at 25-30°C under stirring.

5. Charge Isopropyl acetate into RB flask at 25-30°C under stirring.

6. Stir and heat RM at 70-75°C and maintain for 4 h.

7. Cool RM to RT.

8. Charge 1M K3PO4 solution into RB flask at 25-30°C under stirring.

9. Charge N-acetyl-L-Cysteine into RB flask at 25-30°C under stirring.


11. Cool RM to RT and separate layer.

12. Take organic layer and distilled out IPAc completely at 50-55°C u/v and cool to RT.

13. Charge Acetonitrile and 1.5 N HCl solution into the above concentrated mass.

14. Stir and heat RM at 60-65°C and maintain for 2 h.

15. Cool RM upto 20°C and maintain for 2 h.


Preparation of Stage-II: 1. Arrange dry and clean 1.0 lit. four necks round bottom flask equipped with stopper, thermo pocket and

water condenser.

2. Charge EDC.HCl into RB flask at 25-30°C under stirring.

3. Charge HOBT.H2O into RB flask at 25-30°C under stirring.

4. Charge MOC-Valine into RB flask at 25-30°C under stirring.

5. Charge DMF into RB flask at 25-30°C under stirring and further cool to 0-5°C

6. Charge Stage-1 and N-methyl morpholine at 0-5°C under stirring.

7. Raise temperature upto 25-30°C and maintain for 4 h.

8. Charge Ethyl acetate, stir for 15.0 min.and separate layer.

9. Distill out ETOAc completely at 50-55°C u/v and cool to RT.

10. Charge acetone into RB flask at 25-30°C under stirring.

11. Filter and dry the solid

Flow Diagram

Stage-1:

70

Stage-2:

29. Daclatasvir Dihydrochloride Manufacturing process:

Stage-I: 1. Arrange dry and clean RBF with TP, stopper, water condenser, addition funnel and oil bath at

25-30°C under nitrogen atmosphere.

2. Charge MDC into RBF at 25-30°C.

3. Charge 1,1'-(biphenyl-4,4'-diyl) diethanone into RBF under stirring at 25-30°C.

4. Add Bromine into RBF under stirring at 25-30°C.

5. Reaction mass stirrer for 20 hrs at 25-30°C under nitrogen atmosphere.

6. Charge MDC into RBF at 25-30°C.

7. Distill out solvent up to under vacuum at 35-40°C.

8. Stripping out solvent with THF up to under vacuum at 35-40°C.

9. Concentrated mass slowly cool to 20- 25°C.

10. Reaction mass stirrer for 1 hr at 20- 25°C.

11. Reaction mass filter and wash with MDC at 20- 25°C.

12. Material dry at 55-60°C.

Stage-II:



2. Charge Acetonirtile into RBF at 25-30°C.

3. Charge Stage-Iinto RBF under stirring at 25-30°C.

4. Charge Boc L-Proline into RBF under stirring at 25-30°C.

5. Reaction mass cool to 15-20°C.

6. Add slowly DIPEA into RBF under stirring below 20°C.

7. Reaction mass stirrer for 3 hr at 25-30°C

8. After completion of maintaining, reaction mass wash with 13% Aq. NaCl solution.

9. Organic layer take into RBF and distill out Acetonitrile under vacuum by stripping with

Toluene

10. Charge Ammonium acetate at 25-30°C.

11. Reaction mass heat up to 95-100°C for 15 hrs.

12. After completion of reaction mass cool to 70-80°C.

13. Add Acetic acid, n-Butanol and (5 vol%) aqueous Acetic acid at 70-80°C.

71

14. Layer separate at 50-55°C.

15. Distill out solvent under vacuum at 60-65°C from organic layer and stripping out with Toluene

16. Charge Methanol to the above concentrated mass and heat to 70-75°C for 1 hr.

17. Reaction mass cool to 25-30°C, then stirrer for 1 hr.

18. Reaction mass filter and wash with Toluene: Methanol (10:3) mixed solvent at 25-30°C.

19. Material dry under vacuum under vacuum at 65-70°C.

Stage-III:



2. Charge Methanol into RBF at 25-30°C.

3. Charge stage-IIinto RBF under stirring at 25-30°C.

4. Charge 6M aqueous HCl solution into RBF under stirring at 25-30°C.

5. Reaction mass heat to 50-55°C, for 5 hrs.

6. Reaction mass cool to 25-30°C, and stirrer for 18 hrs. at 20-25°C.

7. Reaction mass filter and wash with 90% Methanol/Water (w/v) and Methanol at 25-30°C.


Stage-IV:

1. Arrange dry and clean RBF with TP, stopper, water condenser, addition funnel and oil bath

under nitrogen atmosphere at 25-30°C.

2. Charge Acetonirtile into RBF at 25-30°C.

3. Charge hydroxybenzotriazole hydrate into RBF under stirring at 25-30°C.

4. Charge N-(methoxycarbonyl)- L-valine into RBF under stirring at 25-30°C.

5. Charge l-(3-dimethyaminopropyl)-3- ethylcarbodiimide hydrochloride into RBF under stirring

at 25-30°C

6. Reaction mass cool to 20°C, for 1 hr.

7. Add Stage-III into RBF under stirring below 20°C.

8. Reaction mass cool to 0-5°C.

9. Add slowly DIPEA into RBF under stirring below 10°C.

10. Reaction mass slowly heat up to 15ᴼC, for 12 hrs.

11. After completion of maintaining, reaction mass wash charge to 13% Aq. NaCl solution.

12. Reaction mass heat up to 50ᴼC, for 1 hrs.

13. Reaction mass cool to 20°C, and add Isopropyl acetate.

14. Layer separation, organic layer wash with 0.5N NaOH solution containing 13% Aq. NaCl

solution.

15. Layer separation, organic layer wash with 13% Aq. NaCl solution.

16. Organic layer take into RBF and distill out Isopropyl acetate under vacuum at 50-55°C.and

stripping out by Ethanol.

17. Add 1.24M HCl in Ethanol at 50-55°C.

18. Reaction mass stirrer at 50-55ᴼC, for 3 hrs.

19. Reaction mass cool to 20ᴼC, and stirrer for 22 hrs.

20. Reaction mass filter and wash with (2:1) Acetone:Methanol at 20-25°C.


72

Flow Diagram

Stage-I:

Stage-II:

73

Stage-III:

Stage-IV:

74

30. Tafenoquine Succinate Manufacturing process :

Preparation of stage-1 1. Arrange dry clean four neck RB flask equipped with thermo pocket, water condenser, stopper and

addition pot and water bath.

2. Charge acetone into RB flask at 25-30°C.

3. Add slowly 1, 4-dibromo pentane using addition pot into reaction mass with in 15.0 min. at 25-

30°C under stirring.

4. Rinse addition pot with acetone at 25-30°C.

5. Charge potassium phthalimide into reaction mass at 25-30°C under stirring.


7. Maintain the reaction mass for 24.0 hr at 50-55°C under stirring.

8. After completion of reaction; cool the reaction mass to R.T. then to 5-10°C under stirring.

9. Filter the reaction mass at 5-10°C & Wash the solid with chilled acetone.

10. Take filtrate for distillation and acetone completely distilled out from the reaction mass under

vacuum at 50-55°C till oily residue remain.

11. Cool the reaction mass to 25-30°C.

12. Collect the oily reaction mass as Stage-I.

Preparation of stage-11

1. Arrange dry and clean four neck RB flask equipped with thermo pocket, condenser, stopper and

addition pot.

2. Charge stage-I into the RB flask at 25-30°C.

3. Charge methanol by rinsing the container of stage-I at 25-30°C.

4. Charge 6-methoxy-8-amino quinoline at 25-30°C under stirring.


6. Maintain the reaction mass for 40.0 hr at 75-80°C under stirring.

7. After completion of reaction distilled out MDC completely from the reaction mass at 40-45°C.

8. Charge methanol into RB flask at 40-45°C under stirring.

9. Charge hydrazine hydrate into the RB flask at 40-45°C under stirring.


11. Maintain the temperature of the reaction mass for 2.0 hrs at 60-65°C under stirring.

12. After completion of reaction cool the mass to 25-30°C.

13. Filter the reaction mass and wash the solid with methanol

14. Charge filtrate into RB flask at 25-30°C.

15. Add slowly succinic acid solution into reaction mass at 25-30°C.

16. After completion of addition heat the mass up to 50-55°C.

17. Cool the reaction mass to RT and further cool to 5-10°C.

18. Filter the solid and wash with methanol and dry the solid in oven to get final compound.

75

Flow Diagram

Stage-I

Stage-II

76

GROUP-10

31. Ursodiol Manufacturing process

Stage-1:Preparation of Ketolithocholic acid. KSM (Chenodeoxycholic acid) oxidized using N-Bromosuccinamide in Acetone Water as solvent at

room temperature to get 7-Ketolithocholic acid crude which is further purified in Ethyl acetate,

methanol, and water to get pure 7-Ketolithocholic acid (Stage-1).

Stage-2 : Preparation of Ursodiol Crude 7-Ketolithocholic acid (Stage-1) reduced in presence of Metal Alloy (Ra/ni) in presence of Base

Potassium tert. Butoxide in IPA to get Ursodiol crude

Stage-3: Preparation of Ursodiol Triethyl amine Salt.

Ursodiol crude, which is salting with Triethyl amine in Acetone, water to get URSO TEA salt. This TEA

salt is desalting with 10% HCl solution to get Ursodiol

Stage-4: Preparation of Ursodiol Extra Pure

Purification of Ursodiol Extra pure by Acetone+ water/IPA+Acetonitrile purification method.

Flow Diagram

Stage-I

Stir Reaction Mixture

Acetone

Water

N-Bromosuccinaamide

Maintained Reaction

Mixture

Water Maintained Reaction

Mixture

Filter

Stir Reaction Mixture Crude

Ethylacetate

Methanol

Water Maintained Reaction

Mixture

Filter the reaction mixture

Wet Cake

Drying

ML

Residue after distillation

Solvent Recovery

Acetone recovery

Stage-I

77

Stage-II

Maintained Reaction

Mixture

After Completion of

Reaction

Organic Layer

Distil the Organic Layer


Oil Obtained Water

Ethyl acetate

Dil HCl

Maintain the reaction

mixture

Filter the reaction mix

Wet Cake

Drying

7-Ketolithocholic acid

IPA

Potassium Tert Butoxide

Ra/Ni


Stage-II

Aqueous layer ETP

Solvent recovery

Solvent recovery

ML

Residue distillation

Sludge

78

Stage- III

Maintained Reaction

Mixture


Wet Cake

ML

Maintained Reaction

Mixture


Drying

Stage-III

Solvent recovery

Stir Reaction Mixture Ursodiol TEA Salt

Water

Ethylacetate

HCl Solution

Ursodiol Crude Acetone

Water

Triethyl amine


Solvent Recovery

Residue Distillation

MLR

79

Stage- IV

Maintained Reaction

Mixture

Filter the reaction

mixture

Filtrate

Stir Reaction Mixture Ursodiol Pure

Acetone

Water

Water

Maintained Reaction

Mixture

Filter the reaction

mixture

Drying

Wet Cake

Product

MLR COD

Residue distillation

80

32. Terizidone


Preparation of stage-1 1. D-Serine was dissolved in chloroform and dry HCl was added to the mixture for 10 min.

2. Then, the mixture was cooled to 0-8 °C and thionyl chloride was added drop wise into the mixture

within 1 hr.

3. The mixture was stirred at room temperature for 2 hr and then under reflux for 4 hr.

4. The reaction mixture was cooled subsequently and the solid was removed by filtration.

5. The solid was washed with chloroform and dried in vacuo to get a white powder Yield: 90%; m. p.:

128–1308C;


1. To a cooled solution of hydroxylamine hydrochloride in absolute ethanol of 0.91 N sodium

methoxide in methanol were added.

2. The mixture was cooled to 0-8 °C, the sodium chloride was filtered, and a solution of intermediate

stage-1 in absolute ethanol was added to the filtrate.

3. This solution was cooled to 0-8°C and 0.91 N sodium methoxide was added slowly.

4. The solution was concentrated in vacuo at room temperature to about 45 mL.

5. The water was added to the solution and 0.46 N hydrochloric acid was added drop wise and the

product was crystallized.

6. The product was filtered and dried in vacuo. Yield: 84%; m. p.: 191–1938C;

Preparation of stage-3 1. A solution of intermediate 2 in water was stirred and cooled.

2. The mixture’s pH was adjusted to 11 by an aqueous sodium hydroxide solution (30% wt).

3. The mixture was stirred at 25 °C for 2 h.

4. Then mixture of 1:1 ethanol/isopropyl alcohol was added.

5. The precipitated salts were filtered and the filtrate was cooled to 5°C.

6. To the cold well-stirred solution sufficient glacial acetic acid was added drop wise over a 35-40 min

period to bring the alcoholic solution to pH 6.0.

7. The crystalline precipitate was filtered, washed twice with l:l ethanol/isopropyl alcohol and twice

with ether.

8. Colorless crystals of D-4-amino-3-isoxazolidone were obtained. Yield: 50%; m. p.: 153–155 C;

Preparation of stage-4 or Terizidone 1. Terephthalaldehyde was dissolved in methanol and the solution is heated to boiling.

2. Highly purified D-4-amino-3-isoxazolidone was suspended in methanol and added to the aldehyde

solution with rapid agitation.

3. The isoxazolidone is employed in excess and the mixture was kept at boiling temperature for about 2

minutes and then rapidly chilled to about 0 °C.

4. Stir the mass at 0 °C for 2 hr. and the separated solid was filtered through suction.

5. The solid was washed with cold methanol and with cold water and suck dry well.

9. The washed solid again washed with boiling methanol and dried in vacuum oven at about 40 ºC.

Yield: 94%; m. p.: 204-205 °C

81

Flow Diagram

Stage-I

Stage-II

82

Stage-III

Stage-IV

83

33. Delamanid Manufacturing process:


1. To a solution of (R)-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-methylpropane-1,2-diol in pyridine

was added methanesulfonyl chloride at below 15 °C drop wise over 30 min.

2. After addition the solution was stirred for 2 h, 6 M hydrochloric acid was added to the reaction

mixture at below 30 °C.

3. The resulting mixture was extracted with ethyl acetate, and the combined organic layer was

concentrated under reduced pressure, and to the residue was added toluene.

4. The resulting precipitates were collected by filtration to afford crude R)-3-(2-chloro-4-nitro-1H-

imidazol-1-yl)-2-hydroxy-2-methylpropyl methanesulfonate

5. To a solution of this crude in ethyl acetate was added 1,8-diazabicyclo [5.4.0]-7-undecene and the

mixture was stirred at room temperature for 2 h.

6. The reaction mass was concentrated under reduced pressure.

7. The residue was purified ethyl acetate/hexane (1/1) to give Stage-1 as colorless needles.

Preparation of stage-2 1. To a mixture of (R)-2-Chloro-1-(2-methyl-2,3-epoxypropyl)-4-nitroimidazoleand 4-[4-(4-

trifluoromethoxyphenoxy)piperidin-1-yl]phenol in N,N-dimethylformamide (1600 mL) was added

60% sodium hydride at 0 °C portion wise.

2. After the mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere, the reaction mixture was

cooled in an ice bath and carefully quenched with ethyl acetate and ice water.

3. Thus-obtained mixture was poured into water and stirred for 30 min.

4. The resulting precipitates were collected by filtration, washed with water, and dried at 60 °C

overnight.

5. The residue was recrystallized from ethyl acetate-isopropyl alcohol to afford final compound as a

pale yellow crystalline powder. Mp 195-196 °C.

Flow Diagram

Stage-I

84

Stage-II

34. Tariquidar Analog Manufacturing process:

Preparation of stage-1 1. A solution of compound 4,5-dimethoxy-2-nitrobenzoic acid in toluene at 25-30 ᵒC was added

thionyl chloride through addition funnel within 30 min. & slowly heated to 100 ᵒC.

2. Catalytic amount of DMF was added in to the reaction mass and stirred for 2 hrs at 100 ᵒC till clear

solution obtained.

3. After completion of reaction the mass was cooled to RT and concentrated.

4. The above acid chloride was dissolved in MDC and to this the compound 4-(2-(6,7-dimethoxy-3,4-

dihydroisoquinolin-2(1H)-yl)ethyl)aniline in pyridine and MDC was added drop wise manner at 0

ᵒC.

5. After completion of addition, the mass was slowly warmed to RT and stirred for 2 hrs.

6. The reaction mass then quenched with Saturated NaHCO3 solution and concentrated.

7. The obtained solid was filtered.

8. This solid was again dissolved in MDC and dried with Na2SO4 and filtered and concentrated.

9. The crude compound was triturated with 10% Acetone in ethyl acetate and filtered and dried and

collected as yellow solid.


1. A solution of N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl) -4,5-

dimethoxy-2-nitrobenzamide in 1:1 mixture of Methanol+THF was added, 10% Pd/C wet in parr

shaker vessel at 25-30 ᵒC.

2. The reaction mass was hydrogenated for 24 hr. under H2 pressure.

3. After completion of reaction the mass was filtered through celite bed washed with (1:1) mixture of

Methanol+THF.

85

4. The combined filtrate was concentrated and the solid was filtered, washed with ethyl acetate and

with methanol and dried as white solid.

Preparation of stage-3 1. A solution of compound Quinoline-3-carbonyl chloride in dry MDC at ᵒC was added in to the

solution of compound 2-amino-N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-

yl)ethyl)phenyl)-4,5-dimethoxybenzamide in pyridine through addition funnel.

2. The reaction mass was stirred for 24 hrs at 25-30 ᵒC.

3. The reaction mass then quenched with Saturated NaHCO3 solution.

4. The layers were separated and the aq. layer was extracted twice with MDC.

5. The combined organic layer was washed with brine, dried with Na2SO4 and filtered and

concentrated.

6. The obtained compound was triturated with methanol, filtered and dried to obtain the final

compound.

Flow Diagram

Stage-I

86

Stage-II

Stage-III

87

35. Solifenacin Succinate

Manufacturing Process:

Stage-1 : Preparation of N-(2-phenyl ethyl) benzamide [SOL-Benzamide] 2-Phenyl ethyl amine (KSM-1) reacts with benzoyl chloride in presence of base like Sodium

Hydroxide to Produce N-2 Phenethylbenzamide (Stage-1).

Stage-2 : Preparation of 1-phenyl-1, 2, 3, 4-tetrahydroisoquinolin[SOL-Isoquinoline]

N-2 phenethylbenzamide cyclized in presence of POCl3 and P2O5 to produce 3, 4-dihydro-1-

phenylisoquinoline (Stage-02 A) which reduce in-situ by sodium borohydride in alcoholic

solvent like methanol to get 1-Phenyl-1, 2, 3, 4-tetrahydroisoquinoline..

Stage-3 :Preparation of (S)-1-Phenyl-1, 2, 3, 4-tetrahydro isoquinoline tartrate [SOL-

Tartrate]

Resolution of 1-phenyl-1,2,3,4-tetrahydroquinoline carried out by reaction with D-(-) Tartaric acid

in solvent like isopropyl alcohol, water mixture to get (S)-1-Phenyl-1,2.3,4-tetrahydroisoquinoline

tartrate [Stage-3]

Stage-4 : Preparation of (S)-1-Phenyl-1, 2, 3, 4-tetrahydro isoquinoline [SOL (S)

Isoquinoline]

Desalting of pure (S)-1-phenyl-1,2,3,4-tetrahydroisoquinioline tartrate by base like sodium

hydroxide to produce (S)-1-phenyl-1,2,34, -tetrahydroisoquinoline,

Stage-5: Preparation of (1S, 3'R)-3'-quinuclidinyl-1-phenyl-1,2,3,4-tetrahydro-2-

isoquinolinecarboxylate succinate [Solifenacin succinate crude]

(S)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline (Stage-04) react ethyl chloroformate using solvent like

toluene: water and base like sodium carbonate to get (1S)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2-

isoquinoline carboxylate (Stage-5A), which in-situ further react with R-(-)-(3)-Quinuclidinol

(KSM-2) in presence of base like sodium hydride in solvent toluene to get (1S, 3'R)-3'-

quinuclidinyl-1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (Stage-5B) which is further

convert to salt reacting with Succinic acid in solvent like acetone to (1S, 3'R)-3'-quinuclidinyl-1-

phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate succinate [Solifenacin succinate crude]

Stage-6: Preparation of Solifenacin succinate [SOL]

Purification of 1S, 3'R)-3'-quinuclidinyl-1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate

succinate [Solifenacin succinate crude] carried out in solvent like acetone to get pure Solifenacin

Succinate.

88

Flow Diagram

Stage I

Charge Water & Sodium

hydroxide in Reactor Water

Sodium Hydroxide

2-Phenylethylamine Charge 2-Phenylethylamine

in Reactor

Benzoyl Chloride Charge Benzoyl Chloride

Addition in Reactor

Maintain till completion of

reaction then filter

Wet-Cake Filtrate for ETP Sodium

bicarbonateWash

Dry in Tray Dryer

Stage-1

89

Stage: II

Charge Stage I, POCl3,

P2O5 in a Reactor


reaction

Distillation

Wet Cake

Dry in Tray Dryer

Stir Reaction Mixture&

Filter

Crushed ice & Water ice

Stir the reaction mixture &

Separate the layer

Quenching Part-I

Quenching Part-II

Toluene., NaOH

Stage-I

Phosphorous Oxychloride

Phosphorous Pentaoxide

Methanol

Sodium Borohydride

Methanol Recovery

Stage-2

Aqueous layer ETP

COD 4.8602

Toluene Recovery

90

Stage-III

Charge Stage-III, IPA &

Water a Reactor


clear solution observed

Isopropyl alcohol

Slurry Wash

Cool Reaction Mixture &

Filter

Wet Cake

Dry in Tray Dryer

Heat RM 60° to 65°C

Charge Crude in Reactor at

25°C to 30°C

Filter

Wet Cake

Dry in Tray Dryer

Stage-II

Isopropyl Alcohol

Water

Isopropyl Alcohol

Water

IPA Recovery

D-(-) Tartaric Acid

Stage-3

ML

91

Stage- IV

Charge Stage-III, & Water in

a Reactor


Filter

Wet Cake

Dry in Tray Dryer

Water Slurry Wash

Stage-III

Purified Water

50% NaOH solution

WW for ETP Wet Cake Purified Water

WW for ETP

Wet Cake Water Wash

Stage-4

92

Stage: V (A)

Stage: V (B)

Charge Stage-IV, Water,

K2CO3, & Toluene in a

Reactor

Stir Reaction Mixture and

Cool

Stir Reaction Mixture &

Separate the layer

Organic Layer Distillation

Stage-5 A

Sodium Sulphate

Water

Stage-IV

Potassium Carbonate

Water

Toluene

Ethylchloroformate

Toluene Recovery

Aqueous layer ETP

Charge Stage-5A, & Toluene

in a Reactor

Charge R-Quinuclidinol,

DMF & NaH in a Reactor

Heat Reaction Mixture

Stir Settled and Separate

the layers Toluene

15% Brine Solution

Stage-5A

Toluene

R-Quinuclidinol

Dimethyl Sulphoxide

Sodium Hydride

Stir Reaction Mixture at

till completion of reaction

Distillation

Stage-5 B

Toluene Recovery

Methanol

Sodium Carbonate

HCl

Aqueous layer ETP

93

Stage: V (B)

Charge Acetone & Stage

5B in a Reactor

Charge Succinic acid in a

Reactor

Heat Reaction Mixture

Dry in tray Dryer

Stage-5B

Acetone

Succinic Acid

Filter the Reaction Mixture

Acetone recovery

Wet Cake

Acetone wash Acetone Recovery

Maintain Reaction Mixture

for 2.0 h

Stage-5

94

Stage: VI

36. Montelukast Sodium


Stage-1 (S)-1-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propan-1-ol [MON-Diol ]reacts with Methane sulphonyl chloride in presence of base like N,N-Diisopropyl ethyl amine to Produce MON-Mesyl which is then substituted with MON-Mercapto acid to get MON-Acid Salting of MON-Acid with tert. Butyl amine to get Tert-butylamine 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-(2-hydroxypropan-2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetic (MON-TBA salt) Stage-2

Tert-butylamine 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-(2-hydroxypropan-2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetic (MON-TBA salt crude) purified in Toluene to give pure Tert-butylamine 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-(2-hydroxypropan-2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetic acid

Charge Acetone & Stage 5

in a Reactor

Heat reaction mixture


Dry in tray Dryer

Stage-5

Acetone

Activated Charcoal

Acetone

Hyflo

Filter the Reaction Mixture

Acetone Recovery

Wet Cake

Acetone Acetone Recovery

Cool reaction mixture

Stage-6 (PRODUCT)

95

Stage-3

Tert-butylamine 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-(2-hydroxypropan-2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetic acid desalted to 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-(2-hydroxypropan-2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetic acid using 5% acetic acid in MDC, further sodium salt made using sodium hydroxide in Methanol and isolated in N-Heptane to give [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl) ethenyl]-3-[2-(1-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid, monosodium salt.

Flow diagram

Stage-1 Part A

Stage-1 Part-B

Dichloromethane

MON-Diol

Diisopropyethylamine


Methane Sulphonyl

Chloride

Maintained Reaction

Mixture


Hexanes


Stage-I (Part A)

Mon-Mesyl

ML

Solvent Recovery

ETP

Maintained Reaction

Mixture

After Completion of

Reaction

Organic Layer, Cool

Stir and Allow Layer to

Separate

Sodium Methoxide

Mon-Mesyl Compound

Filter

Wet-CakeWet Cake

Dimethyl Sulphoxide

Mon-Mercaptoacid


ML

Solvent Recovery


Sodium Hydroxide

Acetic acid

n-Heptane

Toluene

Aqueous layer

ETP

96

Stage-1 Part-C

Stage-2

Maintained Reaction

Mixture

Cool the reaction mixture

Wet Cake

Drying


Stage-I (Part C)

TBA

Mon-Acid

Acetone

Acetonitrile


ML

Solvent Recovery


Cool the reaction

mixture

Wet Cake

Drying

Filter the reaction

mixture

Stage-II

Maintained Reaction

Mixture

Toluene

MON-TBA

Stir the Reaction

Mixture

ML

Solvent Recovery


97

Stage-3

Stir Reaction Mixture MON-TBA

Dichloromethane

Stir the Reaction Mixture Acetic Acid

Organic Layer

Distill the Organic Layer


Separate

Drying

Cool the reaction mixture

Filter the reaction

mixture

Wet-Cake

Stage-III

MON-Na

Sodium hydroxide

Methanol

Distillation N-Heptane


MLCOD 91.5 mg/Ltr

&71.45 mg/Ltr

Solvent Recovery

Solvent Recovery

Aqueous layer for

ETPCOD 380 mg/Ltr

98

37. Silodosin

Process Discription

Stage-1 3-[5-((2R)-2-Aminopropyl)-7-cyano-2, 3-dihydro-1H-indol-1-yl] propyl benzoate (2R, 3R)-monotartrate

neutralized with aqueous Sodium carbonate in Toluene at room temperature to produce 3-[5-((2R)-2-

Aminopropyl)-7-cyano-2, 3-dihydro-1H-indol-1-yl] propyl benzoate as an oil. 3-[5-((2R)-2-Aminopropyl)-7-

cyano-2, 3-dihydro-1H-indol-1-yl] propyl benzoate alkylated with 2-[2-(2, 2, 2-Trifluoroethoxy) phenoxy] ethyl

methane sulfonate in presence of Sodium carbonate in t-Butanol to get 3-{7-Cyano-5-[(2R)-2-({2-[2-(2, 2, 2-

trifluoroethoxy) phenoxy] ethyl} amino) propyl)-2, 3-dihydro-1H-indol-1-yl)-propyl benzoate further purify

with salt formation of L-(+)-Tartaric acid in Ethyl acetate to get pure compound 3-{7-Cyano-5-[(2R)-2-({2-[2-

(2, 2, 2-trifluoroethoxy) phenoxy] ethyl} amino) propyl)-2, 3-dihydro-1H-indol-1-yl)-propyl benzoate (2R, 3R)

monotartrate.

Stage-2 A solution of Potassium hydroxide in purified water was added to 3-{7-Cyano-5{(2R)-2-({2-[2-(2, 2, 2-

trifluoroethoxy) phenoxy] ethyl} amino) propyl)-2, 3-dihydro-1H-indol-1-yl)-propyl benzoate (2R, 3R)

monotartarate and Methanol at 25-30°C to get 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2, 2, 2-trifluoroethoxy)

phenoxy] ethyl} amino) propyl]-2, 3-dihydro-1H-indole-7-carbonitrile as oil.

Stage-3 A solution of Sodium hydroxide in water was added to mixture of SIO-Nitrile (Stage-2) and Dimethyl sulfoxide

at 25-30°C. 30% Hydrogen peroxide solution was added to reaction mass at 20-25°C to get 1-(3-

hydroxypropyl)-5-[(2R)-2-({2-[2-(2, 2, 2-trifluoroethoxy) phenoxy] ethyl} amino) propyl]-2, 3-dihydro-1H-

indole-7-carboxamide. Crystallization using Ethyl acetate as solvent to get 1-(3-hydroxypropyl)-5-[(2R)-2-({2-

[2-(2, 2, 2-trifluoroethoxy) phenoxy] ethyl} amino) propyl]-2, 3-dihydro-1H-indole-7-carboxamide.

Stage-4

Silodosin crude crystals was added to Ethyl acetate and mixture was heated to dissolve. After insoluble

materials were filtered off, the filtrate was allowed to stand at room temperature. The resulting crystals were

collected by filtration and dried under vacuum to get Silodosin.

99

Flow Diagram

Stage-I

Stage- 2

Reactor -I (Under nitrogen)

Cool to 20-25°C

Heat the reaction mass

Stage-I

Dry in Vacuum Tray Dryer


reaction

Settled and separate layers

Distillation

Ethyl acetate & Filter

2-[2-(2, 2, 2-

Trifluoroethoxy)

phenoxy] ethyl methane

sulfonate

t-Butanol

Toluene

Sodium chloride

Sodium sulphate

(Anhydrous)

L-(+)-Tartaric acid

3-[5-((2R)-2-

Aminopropyl) -7-cyano-

2, 3-dihydro-1H-indol-1-

yl] propyl benzoate (2R,

3R)-monotartrate

Purified water

Sodium Carbonate

Ethyl acetate

recovery

Toluene for

recovery& Solid

waste

Aqueous layer for

ETP

Reactor -I (Under Nitrogen)

Cool to 25-30°C


reaction

Settled and separate layers

Distillation Toluene

Sodium bicarbonate

Sodium Sulphite

Stage-I

Methanol

Purified water

Potassium hydroxide

Stage-II

Toluene for

recovery& Solid

waste

Aqueous layer for

ETP

Organic Layer Distillation

100

Stage-3

Reactor-1 (Under Nitrogen)

Stir at 25-30°C

Stir at 25-30°C

Stage-III



reaction

Settle and separate layers

Distillation


Sodium hydroxide

Purified Water

30% Hydrogen

peroxide

Sodium sulphite

Dichloromethane

Conc. Hydrochloric

acid

Sodium Bicarbonate

SIO-Nitrile

Dimethyl sulfoxide

Ethyl acetate

recovery

Dichloromethane

for recovery&

Solid waste

Aqueous Layer ETP

COD 250.0 mg/Ltr

101

Stage-4

Reactor-1

Stir at 70-75°C

Stir at 70-75°C

Silodosin


Filtration through hyflow

supercell and

crystallization

Filtration


Activated Charcoal

Ethyl acetate

SIO-Crude

Ethyl acetate

Filtrate for ETP

Ethyl acetate for

recovery

102

38. Cinacalcet Hydrochloride

Process Discription Stage-1

3-(3-(trifluoromethyl) phenyl) propan-1-ol [CIN-Alcohol] using methane sulfonyl chloride[Mesylchloride]

in Dichloromethane [MDC] and Triethylamine [TEA] at 5-15 C to give3-[3-(trifluoromethyl) phenyl]

propyl methane sulfonate [CIN-Mesyl].

Stage-2

3-[3-(trifluoromethyl) phenyl] propyl methane sulfonate [CIN-Mesyl] react with (R)-1-(naphthalene-1-yl)ethanamine [CIN-Amine] in presence of N, N-Dimethyl formamide [DMF] and Diisopropyl amine at 80-85° C give 3-(3-(trifluoromethyl) phenyl)-N-((R)-1-(naphthalen-5-yl) ethyl) propan-1- amine [CIN-Base]Which is further salting with IPA.HCl gives Cinacalcet Hydrochloride crude. Stage-3 Purified Crude Cinacalcet hydrochloride first with methanol then with acetonitrile to give Pure Cinacalcet hydrochloride.

Flow Diagram

Stage-1

Maintained Reaction

Mixture

After Completion of

Reaction

Organic Layer



Separate

Mesyl Chloride

Stage-I

CIN-Mesyl

Dichloromethane 3-(3-

(trifluoromethyl)

phenyl) propan-1-ol Tri

Ethylamine


MDC Recovery

Aqueous Layer for

ETPCOD804 mg/Ltr

103

Stage- II

Maintained Reaction

Mixture

After Completion of

Reaction


CIN-Mesyl (Stage-I)

Stage-II

CIN-Base

Oil Obtained DichloromethaneSodiu

m Bicarbonate Solution


Separate

Organic Layer


Stage-II

CIN-Hydrochloride

Diisopropyl ether

IPA HCl.

Stir reaction mass at RT

Filter

Acetonitrile

(R)-1-(naphthalene-1-

yl)ethanamine

Diisopropylethylamine


ACN Recovery

MDC Recovery

W.W. TO ETP

ML

Solvent recovered&

recycled

Aqueous layer for ETP

104

Stage- III

39. Maraviroc

Process Discription

Stage-1

Step-1

Thionyl chloride add to solution of (S)-3-Amino-3-phenylpropanoic acid, DMF and Ethanol at Heat to

reflux temperature and stir for 1 h at reflux temperature. Distill out Ethanol and excess Thionyl chloride

a. Charge water to dissolve residue

Step-2 Thionyl chloride add to solution of 4, 4-Difluoro cyclohexane carboxylic acid and Toluene at 2 Heat

reaction mass to reflux temperature. Stir for 1 h at reflux temperature. Distill out excess Thionyl

chloride and Toluene under vacuum, Toluene add to the reaction mass

Step-3 Condensation of step-1 and step-2 by using Sodium carbonate and MDC Stir for 3 h , Water add to

reaction mass, Separate layers. Aqueous layer extract with MDC. Combine both layers and wash with 1

m NaOH. Distill out solvents under vacuum. Toluene and Heptane add to residue and cool. Stir for

Filter solid product and wash with Heptane. Dry product under vacuum to get compound (S)-ethyl 3-(4,

4-difluorocyclohexanecarboxamido)-3-phenylpropanoate.

Stage-2 Charge lot wise Sodium borohydride to (S)-Ethyl-3-(4, 4-difluorocyclohexanecarboxamido)-3-

phenylpropanoate and Tetrahydrofuran. Heat to 50°C. Add very slowly Methanol to reaction mass at.

Temperature raised to reflux and stir for 2 h .Add slowly Acetone to reaction mass and charge Cyclohexane.

Isolate the material by using Tetrahydrofuran and Cyclohexane to get 4, 4-Difluoro-N-((S)-3-hydroxy-1-

phenylpropyl) cyclohexanecarboxamide.

Maintained Reaction

Mixture


Filter Water Wash

Drying

Maintain the Reaction

Mixture

Stage-III

CIN-HCl

Acetonitrile

Methanol

CIN-HCl

Water


ML

Solvent

recovered

& recycled

W.W. TO ETP

105

Stage-3 Potassium bromide and TEMPO take in MDC at 25-30°C. (1S)-4, 4-Difluoro-N-(3-hydroxy-1-phenylpropyl)

cyclohexane Carboxamide charge to reaction mass at 25-30°C. Sodium hypochlorite solution (pH-8 to 9

adjusted with NaHCO3 addition. Stir for 3 h at 10-15°C. Sodium thio sulphate solution in water add to reaction

mass, Separate layers and extract with MDC. Combine organic layers and distill out solvent under vacuum and

isolation using Toluene and Heptane to get compound (1S)-4, 4-Difluoro-N-(3-oxo-1-phenylpropyl)

cyclohexane Carboxamide.

Stage-4 8-benzyl-3-(3-isopropyl-5-methyl-4H-1, 2, 4-triazol-4-yl)-8-aza-bicyclo [3.2.1] octane and Ammonium formate

charge to Ethanol at 25-30°C under nitrogen atmosphere. Pd/C (10%) add to reaction mass at 25-30°C. Slowly

heat the reaction mass to reflux temperature. Stir for 3 h at reflux temperature. Ammonia solution (25%) add to

reaction mass. Stir for 1 h at reflux temperature. Cool to 25-30°C. Filter through Hyflo bed and wash with

Ethanol. Distill out solvents from filtrate under vacuum at 50-55°C to get solid residue. Ethyl acetate add to

residue. Heat to reflux temperature. Stir for 1 h at reflux temperature. Cool to 25-30°C. Stir for 30 min at 25-

30°C. Filter and wash with Ethyl Acetate. Dry under vacuum at 25-30°C to get compound 3-(3-Isopropyl-5-

methyl-4H-1, 2, 4-triazol-4-yl)-exo-8-azabicyclo [3.2.1] octane.

Stage-5

3-(3-Isopropyl-5-methyl-4H-1, 2, 4-triazol-4-yl)-exo-8-azabicyclo [3.2.1] octane phosphate salt and MDC stir

at 25-30°C under Nitrogen atmosphere. (1S) - 4, 4-Difluoro-N-(3-oxo-1-phenylpropyl) cyclohexane

carboxamide in MDC add at 25-30°C. Sodium triacetoxy borohydride add lot wise to reaction mass at 25-30°C.

Stir for 5 h at 25-30°C. Water add after completion of reaction at 25-30°C. Settle and separate layers. Aqueous

layer extract with MDC. Combine both organic layers and wash with 1M KOH solution at 25-30°C. Organic

layer wash with water. Organic layer wash with brine solution. Solution of o-Phosphoric acid in water add to

organic layer at 20-25°C. (pH 5 to 6). Separate layers. Aq. layer wash with MDC. Solution of Sodium carbonate

in water add to the aqueous layer at 20-25°C. (pH 7 to 7.5) MDC add to extract the product at 25-30°C.

Separate layers. Aqueous layer extract with MDC. Combine MDC layers and dry over anhydrous Sodium

sulphate. Distill out solvents under vacuum to get Maraviroc.

Flow Diagram Stag-1

Stir the Reaction Mixture 3-amino-3- phenyl

propionic acid Ethanol

DMF

Thionyl Chloride

Solvent Recovery


Mixture

Sodium Carbonate

MDC

Acid Chloride

Distillation of Reaction

Mixture


reaction then filter

Stir and Separate the layer

Aqueous layer ETP

Cyclohexane

n-Heptane

Distillation

Filtration

Stage-I

Solvent Recovery

106

Stage-2

Stir the reaction mixture


reaction

Distillation

Wet Cake

Dry in Tray Dryer

Filter the reaction

mixture

Stir the reaction mixture &

Separate the layer

Acetone

Cyclohexane

Sodium Hydroxide Solution

MAR-Amide

Tetrahydrofuran

Sodium Borohydride

Methanol

Tetrahydrofuraan

Cyclohexane

Sodium Borohydride Solvent Recovery

Stage-2

Aqueous layer ETP

Solvent Recovery

107

Stage-3



mixture

Wet Cake

Dry in Tray Dryer



and separate layer

Distillation


MAR-Amide Hydroxy

Dichloromethane

TEMPO

Potassium Bromide

Water

Toluenen-Heptane

Solvent Recovery

Sodium hypochlorite

solution

Solvent Recovery

Stage-3

Aqueous layer ETP

108

Stage- 4

Reactor-I (Under Nitrogen)

Reactor-I

Stage-4

Dry in Tray Dryer


reaction at reflux

temperature.

Filter

Pd/C (10%) (50% wet)

Ammonium formate

Solid waste

Ammonium solution

Distillation

Crystallization & Filter

Ethanol for

recovery

Ethyl acetate MLR

recovery Ethyl acetate

8-benzyl-3-(3-

isopropyl-5-methyl-

4H-1, 2, 4-triazol-4-yl)-

8-aza-bicyclo [3.2.1]

octane

Ethanol

109

Stage-5

Reactor-I

Reactor-I

Stage-5



reaction

Filter

(1S)-4, 4-Difluoro-N-(3-

oxo-1-phenylpropyl)

cyclohexane

carboxamide

Solid waste

Sodium triacetoxy

borohydride

Distillation

Filter

Solvent recovery

3-(3-Isopropyl-5-

methyl-4H-1, 2, 4-

triazol-4-yl)-exo-8-

azabicyclo [3.2.1]

octane

Dichloromethane

110

40. Vilazodone Hydrochloride

Process Discription

Stage-I VIL-Piprazine-Esterinpresence of solvent methanol and Ammonia to get VIL-Piperazine Caboxamide.

Stage-2 Compound (VIL- Piperazine Carboxamide) in presence of Chloroindole and triethylamine to get VIL-Base

Stage-3

Compound (VIL-Base) in presence of solvent IPA and aqueous HCl to get Vilazodone hydrochloride.

Flow Diagram

Stage-I

Methanol

VIL-Piperazine Ester


Ammonia gas Maintained Reaction

Mixture

Water After Completion of

Reaction


Wet Cake

Stage-IA

Stage-IA

DMF

Sodium Hydroxide

Solution


Maintained Reaction

Mixture

Filter the Reaction

Mixture

Wet Cake & Drying

Stage-I

ML

WW for ETP

Solvent Recovery

Solvent Recovery

WW for ETP

ML

111

Stage-II

Maintained Reaction

Mixture

After Completion of

Reaction

Filter

Filtrate

Wet Cake

VIL-Base

Dimethylformamide Stir the reaction mixture


mixture


Stage-II

Sodium Bicarbonate

Solution

Filter

Wet Cake & Drying

MLR for ETP COD

102.6 mg/Ltr

MLR COD 1062

mg /Ltr

Water

Triethyl amine

VIL-Piperazineamide

Chloroindole


112

Stage- III

Maintained Reaction

Mixture


Filter

Drying

Filtrate

Stage-III

VIL-HCl

IPA.HCl

Wet Cake

IPA

VIL-Base

Water


MLR

IPA Recovery

WW for ETP

Distilled residue

113

41. Metoprolol succinate

Process Discription

Stage-1 Condensation of 4-(2-methoxyethyl) phenol with Epichlorohydrin in water, in presence of NaOH at 35-40°C.

After reaction completion quenched the reaction mass with water, then Extracted with Toluene .Toluene layer

washed with water. Toluene layer distilled at 40°C to 45°C under vacuum to get Step-I (2-((4-(2-

methoxyethyl)phenoxy)methyl)oxirane) MET-Epoxide

Stage-2 2-((4-(2-methoxyethyl)phenoxy)methyl)oxirane (MET-Epoxide) suspended in water at 5°C to 10°C then

Isopropyl amine added slowly at 5°C to 10°C. After reaction completion add water then extracted with Toluene.

Toluene layer washed with water & brine. Toluene layer is distilled at 45°C to 50°C under vacuum to get1-(4-

(2-methoxyethyl)phenoxy)-3-(isopropylamino)propan-2-ol. MET-Base

1-(4-(2-methoxyethyl)phenoxy)-3-(isopropylamino)propan-2-ol (MET-Base) is dissolve in acetone at 25°C to

30°C. Then Succinic acid dissolved in Acetone added to the reaction mixture at 25°C to30°C within 01 hr. then

raised temperature up to reflux, maintain for 02 hr. at same temperature. Cool reaction mixture at 25°C to

30°C.Solid filtered and washed with Chilled acetone to get Step-II Metoprolol succinate crude (MET-Crude)

Stage-3 Metoprolol Crude dissolved in Methanol at 50°C to 60°C, then cool to 0°C to 5°C and stir for 1hr. filter solid

wash with chilled methanol we get Metoprolol Succinate

114

Stage-1 : Preparation of 2-((4-(2-methoxyethyl)phenoxy)methyl)oxirane (MET-

Epoxide)

Maintained Reaction

Mixture

After Completion of

Reaction

Organic Layer



Separate

Stage-I MET-Epoxide

Purified Water

Sodium Hydroxide

2-((4-(2-

methoxyethyl)phenoxy)

methyl)oxirane

Epichlorohydrin


Toluene Recovery

Aqueous Layer for

ETPCOD404 mg/Ltr

115

Stage-2 :Preparation of MET-Crude

Maintained Reaction

Mixture

After Completion of

Reaction


Stage-II CIN-Base

Oil Obtained


Separate

Organic Layer


Stage-II MET-Crude

Acetone

Succinic acid


Cool and Filter

Purified Water

Isopropyl amine

Stage-I


Iso propyl amine

Recovery

Toluene Recovery

COD 331.0 mg/Ltr

ML

Solvent (Acetone) recovered

Aqueous layer for ETP

COD 280.1 mg/Ltr

116

Stage-3 : Purification of MET-Crude

Maintained Reaction

Mixture

Filter the reaction

mixture

FilterMethanol Wash

Drying

Stage-III Metoprolol Succinate

Activated Charcoal

Methanol

Stage-2 (MET-Crude)


Solvent recovered &

recycled

Maintained Reaction

Mixture

Solid Waste

117

(C) BULK DRUG INTERMEDIATES

1. MCA


Dehydrated Nitrobenzene is partially chlorinated in presence of Iodine which give acidic crude material

containing unreacted Nitrobenzene + MCNB + PNCB + OCNB.

Acidic crude material is washed and neutralized to get pH or crude material (at V301)

At V501, above neutral crude is fractionated to recover unreacted Nitro benzene and pure MCNB.

At V601 pure MCNB is reduced to crude Meta Chloro Aniline with caustic + sulphur or NaHS and finally

washed.

The above product is a mixture of two products like MCA and Eutactic oil. The same is separated in to two

products namely MCA and Eutactic oil which is sellout in the open market

Flow Diagram

118

2. 2, 7 Dichloro - 9 H - Fluorene (LF1 / DCF)

Process Description: Charge acetonitrile, fluorine and N-chlorosuccinimide, after completion of reaction, add HCl, stir at 600 C then

filter solids is separated & Mother liquor is taken for recovery

Flow Diagram:

DMF

Fluorine

Chlorine

CONDENSATION

FILTRATION

ML

L-1/ DCF

FeCl3

DMF recovered

& reused

Process residue

119

3. 2-(2,7-dichloro-9H-fluoren-4-yl)oxirane Process Description:

Stage:

� Charge ADCF and methanol at room temperature.


� Slowly add NaBH4 and maintain at 0-5°C.

� Filter it and wash with methanol.

� Dry it.

Flow Diagram:

LF-2/ ADCF

Sodium boro hydride

Methanol

Recovered &

reused

Distillation

residue

Process

residue

CONDENSATION

Methanol

FILTRATION

ML

Oxirane

120

4. [2-Dibutyl amino-1-(2, 7- Dichloro-9H-fluorene-4-yl)ethanol] (LF3/DBA)

Process Discription

� Charge ADCF and methanol at room temperature.


� Slowly add NaBH4 and maintain at 0-5°C.

� Charge N,N-dibutyl amine and heat up to reflux temp.

� Cool to RT and distilled out solvent.

� Charge ethyl acetate and cool to RT

� Chilled the reaction mass and filter it and wash with methanol.

� Dry it.

Flow Diagram:

Methanol/Ethyl acetate

LF-2/ ADCF

Sodium boro

hydride

CONDENSATION

FILTRATION

ML

LF-3/ DBA

Methanol

Recovered &

reused

Distillation

residue

N,N- dibutyl amine

Process

residue

121

Centrifuge


Process Description: Artemisinin react with Sodium Borohydride in presence of Methanol, gives Dihydroartemisinin crude

which is centrifuged and dried.

Flow Diagram:

Artemisinin

Sodium Borohydride

Acetic Acid

Adjust pH 6 to 7

Water

Wash the wet cake

with water

Reactor

Reactor

Fluid Bed Dryer

Methanol

Reactor

Dihydroartemisinin

Crude

W/W to ETP

ML Methanol

recovered &

reused Process

residue

Distillation

residue

122

6. 4-Cyanoethyl-2-methyl –phenol: (MHPN)

Process Description

� Charge o-cresol at 25-30°C.

� Charge Acrylonitrile and Hydroquione under N2 gas.

� Heat up to 60-65°C Charge AlCl3.

� Maintain reaction mass at 60-65°C for 2.0 hrs.

� Cool to RT.

� Charge water and stir for 1.0 hrs.

� Separate Aq. Layer and Org. layer.

� Collect Org. layer in drum

Flow Chart:

AlCl3 Acrylonitrile Hydroquione

Reactor

Heating

O-cresol

Separation

Cooling

Water

Aq. Layer

Org. Layer

123

7. (R)-9-(2-phosphonylmethoxypropyl)-adenine: (PMPA)


Stage-1: � Charge DMF and Adenine.

� Charge R-Propylene at room temperature.

� Charge NaOH at room temperature.

� Heat up to 124 – 130 oC and maintain it for 12 hour.

� Cool to rum temperature.

� Slowly add Toluene at room temperature.

� Stir for 1.0 hour.

� Filter it and wash with methanol

Stage-2: � Charge stage 1 and DMF

� Charge DESMP and MTS stir for 30 min at room temperature.

� Heat up to 85 to 90 oC and maintain it for 6 hour.

� Cool to rum temperature and slowly add acetic acid.

� Distilled out DMF u/v completely. ( Recovery 85 to 90% )

� Charge water, methylene chloride and 48% HBL.

� Separate layer and take aqueous layer and heat up to 85 to 90 oC.

� Maintain it for 15 hour.

� Cool to rum temperature and adjust pH with NaOH.

� Chilled up to 0 – 5 oC and maintain it for 5 hrs.


Flow Diagram:

Stage-1:

Crystallization

Filtration

Reactor

Dimethyl formamide

R-1,2-Propylene carbonate

Adenine

NaOH

Reactor Methanol,

Toluene

Centrifuge

Mother liquor

(R)-9-(2-Hydroxypropyl) adenine[HPA]

Methanol, Toluene

Recovered and reused

R-propylene carbonate

Recovered and reused

124

Stage- 2:

Isolation

Filtration

Extraction

Filtration

Reactor

DMF

HPA

DESMP

MTB

Reactor

Acetic acid

Reactor Hydrobromic acid

Separation

Reactor

Centrifuge Mother liquor

MDC, NaOH

Wash with Water

PMPA

DMF, DESMP

recovered and

reused

MDC recovered

and reused

Distillation

residue

W/W to ETP

Process residue

125

8. 4, 7-Dichloro Quinoline: (4, 7- DCQ)


Stage-1:

� Charge Toluene and 4-hydroxy and heat reaction mass up to 85-112°C.

� Maintain at to 85-112°C for 12 hour.

� Cool the reaction mass 30 + 5°C.

� Slowly add POCl3 and heat up to 90 + 5 °C

� Maintain at to 90 + 5 °C for 4 hour.

� Cool the reaction mass and charge water, than adjust pH 6.5 to 7.5 using caustic lye.

� Stop stirring and settle for 1.0 hrs. (three water washing)

� Distilled out toluene completely and collect product after flaking.

Stage-2:

� Charge methanol 4, 7-DCQ and heat reaction mass up to 65 + 2°C.

� Charge activated carbon, hyflow and EDTA at 65 + 2°C.

� Maintain reaction mass at 65 + 2°C for 1.0 hrs.

� Filter it and wash with methanol.

� Cool the reaction mass up to 40 to 35°C

� Chilled up to 15 + 3°C and maintain for 1.0 hrs.

� Maintain at 15 + 3°C for 1.0 hrs.

� Filter it and dry it.

Flow Diagram:

Stage-1 4,7-DCQ Crude

4-Hydroxy

Toluene

POCl3

Chlorination

Layer

Separation

Water

Distillation

Caustic lye

Flaker

Waste water to ETP

4,7-DCQ

(Crude)

Toluene

Recovered and Reused

126

Stage-2 4,7-DCQ Pure

Heat 65+ 2 °C

4,7-DCQ Crude

Methanol

EDTA/ Hyflow

Reactor

Sparkler filter

Filtrate ML

Process residue

Activated Carbon

Cool 15 + 3°C

Centrifuge ML

Methanol wash

4,7-DCQ

(Pure)

127

9. N-(2-phenoxyphenyl) methane sulfonamide (OPMSA)


Stage:

� Charge OPA and DMA at room temperature.

� Slowly add MSC below 62°C in 5.0 hrs.

� Maintain the reaction mass at 62 + 2°C for 3.0 hrs.

� Charge water and adjust pH with hydrochloric acid.

� Cool the reaction mass up to 30°C.


Flow Diagram:

Dimethyl aniline (DMA)

Methan Sulfonyl Chloride

(MSC)

Rector

Rector

Ortho Phenoxy Aniline (OPA)

Water

Centrifuge

ML

OPMSA

DMA recovered

& reused

Process residue

HCl

Waste water to ETP

128

10. Meta Amino Acetanilide:(MAA)


Stage-1: � Charge MNA and Acetic anhydride and heat reaction mass up to 130-140°C.

� Maintain at to 130-140°C for 2 hour.

� Distilled out acetic acid under vacuum.

� Charge water and cool to 30 + 5°C.

� Filter it.

Stage-2: � Charge water and cast iron powder and heat reaction mass up to 60°C.

� Charge acetic acid and Acetyl MNA at 80 to 100°C.

� Maintain reaction mass till TLC complies.

� Adjust pH 7.5 to 8.0 with hydrate Lime and charge Activated carbon.

� Filter it and add sodium hydrosulphite in filtrate ML.

� Cool the reaction mass up to 30 to 35°C

� Chilled up to 22 +2°C and maintain for 1.0 hrs.

� Slowly add common salt in 4.0 to 5.0 hrs.

� Maintain at 22 +2°C for 1.0 hrs.

� Filter it and dry it.

Flow Diagram:

Stage-1 Acetyl MNA

m-Nitro Aniline

Acetic anhydride

Water

Acetylation

FILTRATION

ML

Acetyl MNA

Distillation

residue

129

Stage-2 Meta Amino Acetanilide

Heat 90-100°C

11. N-{3-[(diethylamino)methyl]-4-hydroxyphenyl}acetamide:(Mannich Base) Process Description

� Charge methanol and paracetamole.

� Start stirring and charge formaldehyde at room temperature.

� Slowly add diethyl amine at 35 + 5°C in 4.0 hrs.

� Heat the reaction mass up to 65-70°C.

� Maintain the reaction mass for 12. Hrs.

� Chilled up to 15-20°C.

� Filter it.

� Again charge wet cake and water for slurry preparation.

� Heat up to 30-35°C and maintain reaction mass at 30-35°C for 1.0 hrs.

� Filter it.

Acetyl MNA

Acetic Acid

Water

Acetylation

Reaction mass

Filtrate ML

Process residue

Cast Iron

Hydrate Lime

Carbon

Sodium hydro

sulphite

Cool 22 + 2°C

Centrifuge ML

Common salt

Product

130

Flow Diagram:

Heat 65-70°C

12. 4,6-Dichloro-5-methoxy pyrimidine: (4,6-DCMP)


Stage-1: � Charge Methyl methoxy acetate and methanol.

� Charge Dimethyl malonate at room temperature.

� Slowly add sodium Methoxide at 25-30°C.

� Heat the reaction mass up to reflux temperature.

� Maintain at reflux temperature for 8 hour.

� Distilled out methanol completely under vacuum and rise temp up to 180-190°C.

� Cool the reaction mass and collect oily mass as product. (Stage-1)

Stage-2: � Charge stage-1 and toluene with stirring.

� Charge formamide at room temperature.

� Slowly add sodium Methoxide at 25-30°C.

� Heat the reaction mass up to reflux temperature.

� Maintain at reflux temperature for 15 hour.

� Cool the reaction up to 25-30°C and slowly add POCl3.

� Maintain it for 5-6 hrs.

� Charge water in reaction mass and stir for 30 min.

� Separate aqueous layer and toluene layer.


Paracetamole

Formaldehyde

Methanol

Recovered &

reused

Distillation

residue

DEA

CONDENSATION

Methanol

Centrifuge

ML

Slurry

preparation Water

Centrifuge

ML Waste water to ETP

Mannich Base

131

� Filter it and wash it with chilled toluene.

� Dry it.

Flow Diagram:

Stage-1

Heat up to reflux temp.

Heat up to 180-190°C.

Stage-2

Heat up to reflux temp.

Heat up to 110-112°C.

Chilled up to 0-5°C

Methyl methoxy

acetate

Dimethyl malonate

Sodium Methoxide

CONDENSATION

Methanol

Distillation

Methanolreused

Oily mass

(stage-1)

Stage-1

Formamide

Sodium Methoxide

Cyclazation

Toluene

Chlorination

Aqueous layer to ETP

Reactor

POCl3

Layer

separation Water

Centrifuge Toluene

Recovered & reused

ML

Distillation

residue

Product

132

13. L-Menthyl-5-(2R,5S)-[4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl]-1,3-oxathiolane-2-carboxylate

(FCME)


Chlorination reaction

14. Arrange dry and clean 3.0 lit. four necks RBF

15. Charge DMF into RB flask at 25-30°C.

16. Charge MDC into RB flask at 25-30°C.

17. Cool the reaction mass to 15-20°C.

18. Add thionyl chloride in 30.0 min. into reaction mass at 15-20°C

19. Maintain the reaction mass at 15-20°C for 1 h

20. Cool the reaction mass to 5-10°C

21. Add HME + MDC solution into reaction mass in 1.0 h at 5-10°Cand maintain for 3 h.

22. Raise temperature of reaction mass to 40-45 °C (reflux) and maintain for 3 h.

23. MDC layer given 3 water washings.

24. Combine all aqueous layer given MDC extraction and sodium sulphate treatment.

25. Combine all lower Organic layer given sodium sulphate treatment

26. Stir reaction mass for 15 min.

27. Distill out MDC completely U/V at 40-45°C

28. Charge MDC into residue [CHLORO COMPOUND].

Silylation 1. Arrange dry and clean 2.0 lit. four RBF.

2. Charge HMDS at 25-30°C.

3. Charge 5-Fluoro Cytosine at 25-30°C.

4. Charge Ammonium Sulphate at 25-30°C.

5. Heat reaction mass at 125-130°C and maintain for 4 h.

6. Cool reaction mass at RT.

7. Charge MDC at 25-30°C.

8. Stir reaction mass for 15 min.

9. Addition of TEA in reaction mass in 30 min. at 25-30°C

10. Stir reaction mass for 30 min. at 25-30°C.

11. Raise temperature of reaction mass upto 40-45°C.

12. Addition of Chloro compound in reaction mass at 40-45°C in 1 h.

13. Maintain reaction mass at 40-45°C for 18 h.

14. Cool reaction mass at RT.

15. MDC layer given water washing.

16. MDC layer given HCl solution washing.

17. MDC layer given10% NaCl solution water washing.

18. Combine all aqueous layer given MDC extraction.

19. Distill out MDC completely U/V at 40-45°C till residue.

20. Charge Ethyl acetate at 25-30°C.

21. Raise temperature of RM to 50-55°C and maintain for 1.0 h.

22. Cool reaction mass to RT and maintain for 12 h.

23. Cool reaction mass at 0-5°C and maintain for 1 h.

24. Filter it and dry the solid.

133

Flow diagram:

134

14. (S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol (E-6)


Part-A: 26. Arrange dry and clean 3.0 lit. four necks RBF.

27. Charge water into RB flask at 30 ± 5°C under stirring.

28. Charge 4-chloro-2-trifluoro acetyl aniline hydrochloride hydrate into RB flask at 30 ± 5°C.

29. Cool RM at 10-15°C.

30. Adjust pH 7.0-10.0 using sodium hydroxide solution.

31. Stir RM at 10-15°C for 1.0 h.

32. Filter it and wash with water.

33. Arrange dry and clean 3.0 lit. four necks RBF.

34. Charge Toluene into RB flask at 30 ± 5°C under stirring.

35. Charge Wet cake into RB flask at 30 ± 5°C under stirring.

36. Stir and heat RM at 110 ± 5°C under stirring.

37. Maintain RM at 110 ± 5°C for 2.0 h.

38. Distill out toluene completely u/v at 55-60°C.

39. Cool RM to RT.

40. Charge THF

Part-B:

41. Arrange dry and clean 3.0 lit. four necks RBF.

42. Charge THF into RB flask at 30 ± 5°C under stirring.

43. Cool RM at 0-5°C.

44. Charge cyclopropyl acetylene at 0-5°C.

45. Addition of n-butyl magnesium chloride at 0-5°Cin 6.0 h.

46. Stir RM for 30.0 min.

Part-C: 47. Arrange dry and clean 3.0 lit. four necks RBF.

48. Charge NPN into RB flask at 30 ± 5°C under stirring.

49. Charge Toluene at 30 ± 5°C under stirring.

50. Charge 2,2,2-trifluoro ethanol at 30 ± 5°C under stirring.


52. Addition of Diethyl zinc solution at 0-5°C in 6.0 h.

53. Raise the temperature of RM to 30 ± 5°C and maintain for 30.0 min.


55. Addition of Part-A into RM at 0-5°C in 6.0 h.

56. Addition of Part-B into RM at 0-5°C in 4.0 h.

57. Raise the temperature of RM to 30 ± 5°C and maintain for 4.0 h.

58. Send sample to Q.C for TLC

59. Cool RM at 10-15°C.

60. Addition of Citric acid solution into RM at 10-15°C in 4.0 h.

61. Layer separation of RM

62. Distill out Toluene completely under vacuum at temperature below 60°C.

63. Cool RM at 30 ± 5°C.

64. Charge Toluene at 30 ± 5°C.

65. Cool RM at 0-5°C and maintain for 2.0 h


135

Flow diagram

136

15. Tenofovir Disoproxil Free Base (TD Base)


1. Arrange dry and clean four necks RBF.

2. Charge NMP into RB flask at 30 ± 5°C under stirring.

3. Charge PMPA into RB flask at 30 ± 5°C under stirring.

4. Charge TBAB into RB flask at 30 ± 5°C under stirring.

5. Raise the temperature of the reaction mass up to 49 ± 4°C under stirring.

6. Addition of CMIC + TEA mixture into reaction mass in 1.0 h ± 5 min at 49 ± 4°C.

7. Maintain the reaction mass for 2.0 h ± 5 min at 50 ± 2°C under stirring.


9. Add chilled purified water into reaction mass at in 1.0 h ± 10 min at 0-5°C.





14. MDC layer given chilled water washings at 0-5°C.

15. Combine aqueous layer given MDC extraction at 0-5°C.

16. Combine both MDC layers into RB flask and charge sodium sulphate at 0-5°C.

17. Stir the reaction mass for 30 ± 5 min at 0-5°C.




21. Charge ethyl acetate into reaction mass at 20-25°C.

22. Charge Cyclohexane into reaction mass at 30-35°C.



25. Wash the wet solid with Cyclohexane.


137

Flow diagram:

138

2.5 RAW MATERIALS REQUIREMENT WITH THEIR SOURCE AND TRANSPORATATION

Details of Raw material consumption and Mode of Transportation are given in following table.

LIST OF RAW MATERIALS

SR.NO NAME OF RAW MATERIAL MT/MT MODE OF

TRANSOPRTATION

A. BULK DRUGS

Group 1

1. Nimesulide

1. OPMSA 1.04

By Road

2. Acetic Acid 0.29

3. Nitric Acid 0.45

4. MCB 3.13

5. Caustic Lye 0.03

6. Methanol 19.48

7. Activated Carbon 0.06

8. Hyflow 0.01

2. Lumefantrine

1. DBA 0.89

By Road

2. Methanol 4.97

3. 4-Chlorobenzaldehyde 0.34

4. Sodium Methoxide 0.14

5. Ethyl Acetate 4.08


7. Hexane 0.34

3.Sulfadoxine

1. Sulfanilamide 1.74

By Road

2. NaOH 1.14

3. IPA 5.56

4. 4,6-DCMP 0.69

5. Dilute hydrochloric Acid 1.79

6. DMF 3.17

7. Methanol 11.28

8. Phosphoric Acid 0.45


10. Hyflow 0.01

11. Sodium hydroxide 0.17

Group-2

4. Furosemide

1. Lasamide 1.33

By Road

2. Furfuryl Amine 2.40

3. Caustic Flakes 0.39

4. IPA 4.99


6. Acetic Acid 0.36

7. De-natured Spirit (DNS) 0.04

8. Hydrose 0.001

9. EDTA 0.001

10. Citric Acid Anhydrous 0.001

5. Hydroxy Chloroquine Phosphate

1. 4,7-DCQ (crude) 0.70

By Road 2. HNDA 0.93

3. Sodium Hydroxide 0.14

4. Acetic Anhydride 0.07

139

5. Sodium Sulphate 0.14

6. MDC 13

7. Methanol 8.04

8. Phosphoric acid 0.77

9. Hyflow 0.03

10. Activated carbon 0.19

11. Ammonia 1.44

12. Ethyl Acetate 7

13. IPA 6.06

14. Sulphuric acid 0.27

6. Allopurinol

1. 2-Cyanoacetamide 1.14

By Road

2. Morpholine 1.53

3. TEOF 2.45

4. IPA 0.57

5. Hydrazine Hydrate 0.70

6. Sulphuric Acid 1.15

7. Formamide 4.34

8. Liquor Ammonia Solution 1.06


10. Hyflow 0.01

7. Colesevelam Hydrochloride

1. Allyl amine 0.51

By Road

2. Hydrochloric acid 1.93

3. Azobis catalyst 0.08

4. Methanol 28.99


6. Epichlorohydrin 0.04

7. Isopropyl alcohol 19.32

8. 6-BHTMAB 0.77

9. 1-bromodecane 0.53


11. Sodium chloride 6.71

12. Allyl amine 0.51

Group-3

8. Amodiaquine Hydrochloride

1. 4,7-DCQ 0.51

By Road

2. Mannich base 0.64

3. Toluene 1.34


5. HCl 0.73

6. Hyflow 0.00


9. Piperaquine Phosphate

1. 4,7-DCQ 0.78

By Road

2. Piperazine Anhydrous 1.01

3. 1,3-Dibromopropane 0.43


5. Isopropyl Alcohol (IPA) 1.82

6. Methylene Dichloride (MDC) 5.37


8. Denatured Spirit (DNS) 6.87

9. Cyclohexane 0.09

10. Acetic Acid 0.26

11. HCl 0.52

140



Group-4

10. Tenofovir Disoproxil Fumarate

1. PMPA 0.67

By Road

2. Chloromethyl isopropyl carbonate [CMIC] 1.60

3. TEA 0.56

4. N-methyl-2-pyrrolidone [NMP] 1.41

5. Tetra butyl ammonium bromide

[TBAB] 0.73

6. MDC 7.09

7. Sodium sulphate 0.13

8. IPA 4.19

9. Fumaric acid 0.27

10. Cyclohexane 10.53

11. Efavirenz

1.

(S)-5-Chloro-α-Cyclopropylethynyl-2-

amino-α-(trifluoromethyl) benzene

methanol (Short name: E-6) 1

By Road

2. Triphosgene 0.44

3. Sodium bicarbonate 0.87

4. Acetic acid 0.001

5. Ammonia 0.08


7. Toluene 6.09

8. Hyflo supercell 0.01


10. Methanol 4.73

Group- 5

12. Artemether

1. Dihydroartemisinin 1.06

By Road

2. HCl 0.02

3. Tri methyl ortho acetate (TMOA) 1.51

4. Triethyl Amine (TEA) 0.06

5. Methanol 7.24

13. Artesunate

1. Dihydroartemisinin 0.84

By Road

2. Acetone 1.98

3. Succinic Anhydride 0.42

4. Triethyl Amine (TEA) 0.42

5. Acetic Acid 1.59


7. Hyflow 0.02

8. Cyclohexane 7.55

9. Methanol 2.53

Group- 6

14. Emtricitabine

1.

(2S,5R)-5-(4-amino-5-fluoro-2-oxo-2H-

pyrimidin-1-yl)-[1,3]-oxathiolane-2-

carboxylic acid, 2S-isopropyl-5R-methyl-

1R-cyclohexyl ester (Short name: F-CME) 2.14 By Road

2. Di potassium hydrogen phosphate 2.94

3. Denatured spirit (DNS) 17.14

4. Sodium borohydride 0.43


141

6. Con. sulphuric acid 0.08

7. Liq. ammonia 0.11

8. Toluene 6.43

9. Isopropanol 49.01

10. 20.0-25.0 % IPA.HCl solution 2.14

11. Methanol 5.46

12. Triethylamine 0.83

13. MDC 29.39


15. Hyflo supercell 0.02

15. Pyrimethamine

1. 4-Chloro Phenyl Acetonitrile 0.91

By Road

2. Ethyl propionate 2.73

3. Sodium Methoxide 0.95

4. Acetic acid 0.73

5. MDC 4.84

6. Cyclo hexane 6.18

7. p-toluene sulfonic acid 0.53

8. Ethylene glycol 0.88

9. Methanol 1.89


11. Hyflow 0.01

12. 4-Chloro Phenyl Acetonitrile 0.91

13. Ethyl propionate 2.73


1. Artemisinin 1.05

By Road 2. Methanol 2.53

3. Sodium Borohydride 0.17

4. Acetic Acid 0.37

17. Bisoprolol Funarate

1. 4-Hydroxy Benzyl Alcohol 0.66

By Road

2. 2-Isopropoxy ethanol 6.6

3. Amberlyst -15 (Dry) 0.33

4. Sodium carbonate 0.008

5. MDC 7.23


7. Potassium carbonate 7.7

By Road

8. Methanol 1.33

9. Mono isopropyl amine 0.958



12. Hyflow 0.008

Group-7

18. Pyronaridine

1. 1,4 Di bromo pentane 1.63

By Road

2. Potassium phthalimide 1.64

3. Acetone 11.51

4. 6 methoxy 8 amino quinoline 1.16

5. 4 bromo 1 phthalimide pentane 1.97

6. MDC 43.26

7. Methanol 71.88

8. Hydrazine hydrate 1.16


10. Disodium hydrogen phosphate 0.98

11. Con. HCl (35.0%) 1.12

142

12. Hyflow 0.12


19. Atazanavir Sulfate

1. Boc Hydrazine 0.78

By Road

2. Boc Epoxy 0.75

3. IPA 3.69

4. N-methoxy carbonyl L-tert leucine (MOC-

L-tert Leucine) 1.05

5. 1- hydroxy benzotriazole mono hydrate

(HOBT mono hydrate) 0.82

6.

1-(3-imethylaminopropyl)-3-

ethylcarbodiimide hydrochloride

(EDC.HCl) 1.37

7. Conc. HCl 1.14

8. Triethyl amine 1.85

9. MDC 18.28

10. Methanol 19.5

11. Ethyl acetate 29.62

12. Sulphuric acid 0.13

13. Acetone 19.75


15. Hyflo 0.2

20. Primaquine Phosphate

1. 1,4 Di bromo pentane 1.63

By Road


3. Acetone 11.51

4. 6 methoxy 8 amino quinoline 1.16

5. 4 bromo 1 phthalimide pentane 1.97

6. MDC 43.26

7. Methanol 71.88



10. Disodium hydrogen phosphate 0.98

11. Con. HCl (35.0%) 1.12

12. Hyflow 0.12


21. Chloroquine Phosphate

1. 4,7-DCQ (crude) 0.41

By Road

2. NDA 0.35

3. Phenol 0.20

4. Caustic lye 0.17

5. Toluene 1.29


7. Methanol 2.12

8. Silica 0.00

9. EDTA 0.00


11. DNS 2.66


13. Hyflow 0.001

14. Silica 0.0002


Group-8

22. Tenofovir Alafenamide Hemifumarate

1. PMPA 1.67 By Road

143

2. Acetonitrile 8.01

3. Triphenyl phosphite 2.72

4. Toluene 20.99

5. Dimethyl aminopyridine 0.72


7. Conc. HCl 0.83

8. Toluene 97.45

9. Thionyl chloride 1.36

10. L-Alanine isopropyl ester HCl 9.54

11. MDC 64.28

12. THF 31.12

13. Sodium phosphate monobasic 4.33

14. Acetone 15.82

15. Fumeric acid 0.15


23. Tenofovir Disoproxil Orotate

1.

R)-(((1-(6-amino-9H-purin-9-yl)propan-2-

yl)oxy)methyl) phosphonic acid (PMPA

monohydrate)

1.05

By Road

2. N-methyl pyrrolidone (NMP) 2.22

3. Tetra butyl ammonium bromide (TBAB) 1.15

4. Triethylamine (TEA) 0.87

5. Chloromethyl isopropyl carbonate (CMIC) 2.52

6. MDC 9.77


8. Cyclohexane 8.19

9. Sodium sulphate 2

10. Orotic acid 0.49

11. Acetone 5.47

12. Dimethyl sulphoxide 4.15

24. Sofosbuvir

1. (Uridine compd.) 0.78

By Road

2. Fluoro compd 2.03

3. THF 10.4

4. Tertiary butyl magnesium chloride 3.49

5. Conc. HCl (30%) 6.04

6. Na2CO3 (Anhydrous) 1.56

7. NaCl 2.34

8. Na2SO4 0.78

9. MDC 46.68

10. Toluene 8.11

Group-9

25. Dolutegravir Sodium


By Road

2. Lithiumbromide (LiBr) 0.524

3. 1N HCl 0.619

4. 30% HCl 0.476

5. Methanol 23.47

6. Methoxy Compound 1.19

7. Aq. NaOH 1.547

26. Velpatasvir

1. THF 14.5

By Road 2. Cesium carbonate 0.95


4. Toluene 13.22

144

5. Sodium acetate 26.74

6. Methanol 64.34

7. MDC 80.79

8. Manganese dioxide 14.19

9. Conc. HCl 34

10. (R)-2-((methoxycarbonyl) amino)-2-

phenylacetic acid 0.36

11. DMF 29.62

12. DIPEA 2.78


27. Adefovir Dipivoxil Fumarate

1.

((2-(6-amino-9H-purin-9-yl)

ethoxy)methyl)phosphonic acid (Adefovir

monohydrate)

1.3

By Road



4. MDC 9.7

5. IPA 8


7. Fumaric acid 0.31

8. Acetone 5.54

28. Ledipasvir

1.

(1R,3S,4S)-tert-butyl 3-(6-bromo-1H-

benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]

heptane-2-carboxylate 0.82

By Road

2. bis(pinacolato)diboron 0.63

3. Potassium propionate 0.7

4. 1M K3PO4 solution 7.37

5. N-Acetyl-L-Cysteine 0.2


7. 1.5N HCl 6.15

8. EDC.HCl 1.09

9. HOBT.H2O 0.51

10. MOC-Valine 1

11. DMF 12.5

12. N-methyl morpholine 1.25


14. Acetone 11.72

29. Daclatasvir Dihydrochloride (API)

1. 1,1’-(Biphenyl-4,4’-diyl) diethanone 0.936

By Road

2. Bromine 1.269

3. MDC 33.453

4. THF 8.234

5. Boc-L-Proline 1.461


7. DIPEA 0.865

8. Toluene 55.681

9. Ammonium acetate 0.5

10. Acetic acid 3.294

11. n-Butanol 3.114

12. Methanol 5.569

13. NaCl 2.89

14. Methanol 23.1

15. Conc. HCl 0.49

145

16. (P)-L-Valine 0.68


18. DIPEA 0.834

19. EDC HCl 0.743

20. HOBT 0.618

21. Isopropyl acetate 3.294

22. Ethanol 3.114

23. NaOH 0.433

24. Acetone 2.357

30. . Tafenoquine succinate

1. 1,4-DBP 0.672

By Road


3. Acetone 4.247

4. 2,6-dimethoxy-4-methyl-5-(3-

(trifluoromethyl) phenoxy)quinolin-8-amine 1.065

5. MDC 1.11

6. Methanol 3.871


8. Succinic acid 0.206

Group 10

31. Ursodiol

1. Chenodeoxycholic acid 2.75

By Road

2. Acetone 72

3. NBS 2.24

4. Potassium tert butoxide 2.44

5. Raney Nickel 0.96


7. Isopropanol 34.2

8. Conc HCl 2.1

9. Triethylamine 0.55

10. Acetone 18.7


12. Ursodiol Crude 1.7

13. Ursodiol pure 1.27

32. Terizidone

1. (S)-2-amino-3-hydroxypropanoic acid or D-

Serine 2.02

By Road

2. Chloroform 57.31

3. Dry HCl 0.7


5. Ethanol (Absolute) 42.1

6. Hydroxyl amine hydrochloride 1.805

7. 0.91 N Sodium methoxide 29.87

8. Hydrochloric acid (30%) 1.94

9. 30% Aq. NaOH 2.539

10. Isopropyl alcohol 14.29

11. Glacial acetic acid 0.88

12. Ether 1.78

13. Methanol 24.82

14. Terephthalaldehyde 0.468

33. Delamanid

1. (R)-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-

2-methylpropane-1,2-diol 1.545 By Road

2. Pyridine 3.028

3. Methane sulphonyl chloride 1.126

146

4. Conc. HCl 5.88


6. Toluene 10.07

7. 1,8-diazabicyclo[5.4.0]-7-undecane 1.096

8. 4-(4-(4-(trifluoromethoxy)

phenoxy)piperidin-1-yl) phenol 1.391

9. DMF 12.62

10. NaH (60%) 0.189

11. IPA 0.982

34. Tariquidar

1. 4-(2-(6,7-dimethoxy-3,4-

dihydroisoquinolin-2(1H)-yl)ethyl)aniline 3.339

By Road

2. 4,5-dimethoxy-2-nitrobenzoic acid 2.66

3. Toluene 28.65


5. DMF 0.5

6. MDC 700

7. Pyridine 0.845

8. NaHCO3 (Sat. Solution) 7.2

9. Na2SO4 0.01

10. Acetone 2.63

11. Ethyl acetate 90

12. Methanol 101

By Road

13. THF 87.97

14. 10% Pd/C wet (50% w/w) 1.333

15. Quinoline-3-carbonyl chloride 2

16. Pyridine 1.64

17. NaHCO3 2.664

18. NaCl 11.66

19. Na2SO4 0.2

20. Methanol 31.59

21. NaCl 11.66

22. Na2SO4 0.2

35. Solfinacin Succinate

1. 2-Phenylethylamine 1.76

By Road


3. Benzoyl Chloride 2.654

4. 5% Sodium Bicarbonate Solution 9.02

5. 2-Phenylethylamine 1.76

6. Phosphorous Pentaoxide 0.756

7. Phosphorous oxychloride 3.6

8. Ethylchloroformate 0.535

9. Toluene 70

10. NaOH Flakes 9


12. Methanol 15.3

13. Sodium Borohydride 0.467

14. IPA 28.27

15. D(-)-tartaric acid 1.792

16. Potassium Carbonate 0.544

17. R-Quinuclidinol 0.86

18. DMF 0.602

19. Sodium Hydride 0.155

20. Methanol 0.155

21. Sodium Chloride 0.645

147

22. HCl 0.568

36. Montelukast Sodium

1. MON-Diol 1.736

By Road

2. Methane sulphonyl chloride 0.478

3. Diisopropylethylamine 0.782

4. Dichloromethane 11.544

5. MON-Mercaptoacid 0.72

6. Sodium methoxide solution (25%) (d-0.945) 2.224

7. Hexanes 6.822

8. Dimethyl Sulfoxide 7.638


10. n-Heptane 1.186

11. Toluene 76

12. Acetic acid (12.8%) 1.888

13. MON-Acid 1.388

14. Tert-butylamine 0.19

15. Acetone 4.708


17. MON-TBA 1.25

18. Sodium hydroxide (97%) 0.078



21. Acetic acid (5%) 10.152

22. n-Heptane 9.412

23. Methanol 5.944

24. Activated charcoal 0.064

25. Hyflo 0.128

37. Silodosin

1. SIO-Tartrate 2.75

By Road

2. Sodium Carbonate 1.125

3. Toluene 155

4. Anhydrous Sodium Sulphate 2.75

5. SIO-Mesylate 1.675



8. L-(+)-Tartaric acid 0.88

9. Methanol 10.4

10. Potassium Hydroxide 1.22


12. Sodium Sulphite 1.3

13. SIO-Cyano 1.7

14. DMSO 21.25

15. NaOH 0.255

16. Hydrogen Peroxide 0.885

17. MDC 61.25


19. Conc HCl 0.85

20. Sodium Sulphite 0.74



38. Cincalcet HCl

1. 3-(Trifluoromethyl) benzene propanol 1

By Road 2. Mesyl Chloride 0.744

3. Dichloromethane 8


148


6. Concentrated HCl 2.4

7. (R)-1-(1-Naphthalenyl) ethylamine 1.516

8. Diisopropylethyl amine 0.86



11. Sodium Bicarbonate 1


13. Diisopropyl ether 9.954

14. IPA HCl 0.436

15. Activated Charcoal 0.1

16. Methanol 4.35

17. Hyflo Supercel 0.07


39. Maraviroc

1. (S)-3-Amino-3-phenyl propanoic acid 1.11

2. 4,4 Difluorocyclohexane carboxylic acid 1.32



By Road


6. Toluene 26.67

7. Ethanol 5.56

8. MDC 34.44

9. Heptane 20.00


11. THF 18.72

12. Methanol 1.20

13. Acetone 2.00

14. Cyclohexane 29.72




18. MDC 34.44

19. Toluene 7.58

20. Heptane 10.33

21. Potassium bromide 0.02

22. 2,2,6,6-Tetramethyl-1-piperidinyloxy, free

radical, 2,2,6,6-Tetramethylpiperidine 1-

oxyl 0.01


24. Sodium thiosulphate 1.32

25. Sodium hypochlorite 9.71

26. Ammonium formate 3.79

27. Pd/C 0.49

28. Ammonia 1.17


30. (1S)-4, 4-Difluoro-N-(3-oxo-1-

phenylpropyl) cyclohexane carboxamide 0.98

31. Potassium hydroxide 0.27

32. Methylene chloride 50.84

33. Sodium carbonate 0.49


35. Charcoal 0.05

36. water 67.86

37. Hyflo 0.10

149

40. Vilazodone HCl

1. VIL-Piperazine Ester HCl 2.35

By Road

2. Methanol 15.83

3. N,N Dimethyl formamide 19.32


5. VIL-Carboxamide 1.34

6. VIL-Chloroindole 1.27

7. NaHCO3 4.30

8. Methanol 5.31

9. Hyflow 0.30


11. Na2S2O5 Solution (5%) 2.75

12. IPA 53.59

13. IPA HCl 0.78

41. Metoprolol succinate

1. MET-Phenol 0.73

By Road



4. Toluene 8.1

5. MET-Epoxide 0.99

6. Isopropyl amine 1.48

7. Succinic acid 2.29

8. Acetone 6.21

9. MET-Crude 1.23

10. Methanol 5.37

11. Activated charcoal 0.02

12. Hyflo 0.12


1. Meta Chloro Aniline (MCA)

1 Nitrobenzene 1.00

By Road

2 Cl2 gas 0.39

3 FeCl3 0.02

4 NaHS 0.02

5 Na2CO3 0.00

2. 2,7-Dichloro-9H-fluorene (DCF)

1 DMF 3.28

By Road

2 Fluorine 1.11

3 Chlorine gas 0.94

4 FeCl3 0.04

5 Methanol 3.67

3. 2-(2,7-dichloro-9H-fluoren-4-yl)oxirane

1 LF-2/ ADCF 1.14

By Road 2 Methanol 9.14

3 Sodium boro hydride 0.06

4. [2-Dibutylamino-1-(2-7-dichloro-9H-florine-4-yl)] ethanol(DBA)

1 LF-2/ ADCF 0.98

By Road

2 Methanol 7.03

3 Sodium boro hydride 0.05

4 N,N- Dibutyl amine 2.05

5 Ethyl acetate 1.54

5. Dihydroartemisinin (DHA)

1 Artemisinin 1.05

By Road 2 Methanol 2.53

3 Sodium Borohydride 0.17

4 Acetic Acid 0.37

150

6. 4-Cyanoethyl-2-methyl –phenol: (MHPN)

1 o-cresol 0.72

By Road 2 Acrylonitrile 0.46

3 AlCl3 0.18

4 Hydroquione 0.0004

7. (R)-9-(2-phosphonylmethoxypropyl)-adenine: (PMPA)

1 Adenine 20.0

By Road

2 R-Propylene carbonate 17.9

3 Dimethyl formamide 9.5

4 NaOH 1.1

5 Toluene 15.6

6 Methanol 1.6

8. 4, 7-Dichloro Quinoline :( 4, 7- DCQ)

1. 4-hydroxy 1.419

By Road

2. Toluene 3.527

3. POCl3 1.195

4. Caustic lye 2.392

5. Methanol 4.822


7. EDTA 0.000

8. Hyflow 0.001

9. N-(2-phenoxyphenyl) methane sulfonamide (OPMSA)

1. Ortho Phenoxy Aniline 0.71

By Road 2. Dimethyl Aniline (DMA) 0.60

3. Methane Sulfonyl chloride (MSC) 0.46

4. Caustic Lye 0.15

10. Meta Amino Acetanilide:(MAA)

1. MNA 1.43

By Road

2. Acetic Anhydride 1.00

3. Acetyl MNA 1.43

4. Cast Iron powder 1.10

5. Acetic Acid 0.01

6. Hydrate Lime 0.04

7. Sodium hydrosulphite 0.01

8. Common salt 1.37


11. N-{3-[(diethylamino)methyl]-4-hydroxyphenyl}acetamide:(Mannich Base)

1. Mannich base 0.84

By Road 2. Formaldehyde 0.51

3. Diethyl amine 0.49

4. Methanol 0.88

12. 4,6-Dichloro-5-methoxy pyrimidine: (4,6-DCMP)

1. Methyl methoxy acetate 0.67

By Road

2. Dimethyl malonate 1.00

3 Sodium Methoxide 0.50

4. Methanol 2.67

5. Formamide 0.33

6. Toluene 3.60

7. POCl3 0.33

13. L-Menthyl-5-(2R,5S)-[4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl]-1,3-oxathiolane-2-

carboxylate (FCME)

1.

(2R,5R)-5-hydroxy-1,3-oxathiolane-2-

carboxylic acid (1R,2S,5R)-5-methyl -2-(1-

methylethyl) cyclohexyl ester (HME) 1.25

By Road

151

2. 5-Fluoro Cytosine (5-FC) 0.41

3. Methane sulphonic acid (MSA) 0.005

4. Thionyl chloride (TC) 1.03

5. N,N-Dimethyl formamide (DMF) 0.63

6. Hexamethyldisilazane (HMDS) 0.63


8. Ammonium sulfate 0.02

9. Conc. HCl 0.002

10. MDC 18.28




14. (S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol

(E-6)

1. 4-chloro-2-trifluoroacetyl aniline

hydrochloride hydrate 31.92

By Road

2. Diethyl Zinc (15% in Toluene) 79.68

3. 2,2,2-Trifluoro ethanol 6.72

4. Cyclo propyl acetylene 8.88

5. (1R,2S)-N-Pyrolidinyl Nerophredine (NPN) 35.04

6. n-Butyl Magnesium chloride (NBC) 13.2

7. Citric acid monohydrate 40.8

8. Tetrahydrofuran (THF) 21.12

9. Toluene 110.88

10. Sodium hydroxide (NaOH) 0.55

11. n-Butyl Magnesium chloride (NBC) 13.2

12. Citric acid monohydrate 40.8

13. Tetrahydrofuran (THF) 21.12

15. Tenofovir Disoproxil Free Base (TD Base)

1.

R)-(((1-(6-amino-9H-purin-9-yl)propan-2-

yl)oxy)methyl) phosphonic acid (PMPA

monohydrate)

8.3

By Road


3. Tetra butyl ammonium bromide (TBAB) 9.1


5. Chloromethyl isopropyl carbonate (CMIC) 19.9

6. MDC 77.2


8. Cyclohexane 65.5


2.6 RESOURCE OPTIMIZATION / RECYCLING AND REUSE IN THE PROJECT

The materials are packed in drums and stored in a very organized way, segregated as Solid and Liquid area in

warehouse. We have good practices in place like good house-keeping, good Manufacturing practices, best

Environment control, safety and health practices. By adoption of continuous improvement in technology and

processes the desired reduction in process waste generation will be achieved. By proper and efficient handling

of raw materials, wastages of raw materials will be reduced.

2.7 AVAILABILITY OF WATER ITS SOURCE, ENERGY / POWER REQUIREMENT AND

SOURCE

WATER

Total water requirement for the proposed expansion project would be estimated as 220 KLD, which would be

sourced from G.I.D.C

152

POWER

Total power requirement for the proposed expansion project will be 750 KVA.During emergency purpose

D.G. Set of 320 KVA will be utilized. .Power supply shall be full-filled by DGVCL (Daxin Gujarat Vij

Corporation Limited).

2.7.1 WATER REQUIREMENT AND WASTE WATER GENERATION

Total wastewater i.e. 125 KLD will be generated from the proposed expansion project, which will be treated in

ETP consisting primary & secondary treatment. Treated effluent will be sent to CETP for further treatment and

final disposal.

2.7.2 FUEL REQUIREMENT

Sr. No. Fuel

Daily Fuel Consumption

Existing Proposed Total

1. Natural Gas 193 m3/Hr 208 m

3/Hr 401 m

3/Hr

2. Diesel 70 Lit/Hr -- 70 Lit/Hr

2.7.3 AIR POLLUTION

EMISSIONS FROM COMBUSTION OF FOSSIL FUELS FROM STATIONARY OR MOBILE SOURCES

SR.

NO.

STACK ATTACHED

TO FUEL USED

STACK

HEIGHT

POLLUTION

CONTROL

SYSTEM

FINAL

CONCENTRATION

EXISTING

1 IBR Boiler

Natural Gas

(193 m3/Hr)

30

meter Scrubber

SPM ≤ 150 mg/Nm3

SO2≤ 100 ppm

NOX≤ 50 ppm

2 Non IBR Boiler &

Thermopack no. 1

15

meter -

3 Thermopack no. 2 15

meter -

3 D.G. Set (320 KVA) Diesel

(70 Lit/Hr)

11

meter -

4 D.G. Set (75 KVA)* Diesel

(70 Lit/Hr)

11

meter -

PROPOSED

1. Gas Generator

(1 MW)

Natural Gas

5000 m3/Day

15

meter

adequate stack

height will be

provided

SPM ≤ 150 mg/Nm3

SO2≤ 100 ppm

NOX≤ 50 ppm

* Existing D.G.Set of 75 KVA shall be removed after proposed expansion

153

PROCESS EMISSION

SR.

NO.

STACK

ATTACHED TO

STACK

HEIGHT

POLLUTION

CONTROL

SYSTEM

Type of

Pollutants FINAL

CONCENTRATION

EXISTING

1. Reaction vessel 11

meter Alkali Scrubber

Cl2

HCl

Cl2 ≤ 09 mg/Nm3

HCl ≤ 20 mg/Nm3

2. Incinerator

(200 kg/hr)

30

meter Venturay Scrubber

PM

SO2

NOX

PM ≤ 150 mg/Nm3

SO2≤ 100 ppm

NOX≤ 50 ppm

2.7.5 SOLID WASTE GENERATION AND ITS MANAGEMENT The sources of solid wastes, generation and its management are as given in the following table.

SR.

NO.

NAME OF THE

WASTE

CAT

NO.

EXISTING

(MT/Year)

PROPOSED

(MT/Year)

TOTAL

(MT/Year)

METHOD OF

STORAGE AND

DISPOSAL

1 ETP Waste 34.2 27.6 322.4 350


Transportation,

disposal at TSDF-

VWEMCL

2 Distillation

Residue 20.3 112 1088 1200 Collection, storage and

disposed in captive

incinerator/ Sent to

CHWIF 3 Process Residue 28.1 146 354 500

4 Spent Solvents 28.6 112 188 300 Recovered & reused/

Sent to end user.

5 Used Oil 5.1 0.0924 0.0276 0.12


reuse as lubricants in

the machineries within

the premises only or

send to authorized re-

processors.

6

Discarded

Containers/

Bags

33.3 1716

Nos./Year

3784

Nos./Year

5500

Nos./Year


send to authorized

recycler after

decontamination.

7 Iron Sludge 28.1 840 200 1160


Transportation,

disposal at TSDF

8 Used/ Waste

filter clothes 35.1 0.06 0.09 0.15


Transportation,

disposal at TSDF

154

9 Sludge from wet

Scrubber 36.1 0.024 0.096 0.12


Transportation,

disposal at TSDF

10 Spent Carbon 28.2 78 222 300


disposed in captive

incinerator within

premises/ CHWIF

11

Salt from

evaporator 35.3 672 228 900


Transportation,

disposal at TSDF

12 Incineration Ash 37.2 30 30 60


Transportation,

disposal at TSDF

13 Distillation

residue 20.3 43.2 1156.8 1200

Reception from unit-I

through manifest

system, storage,

Incineration at caprive

Incinerator within

premises/ CHWIF

14 Proocess residue 28.1 6 494 500

15 Spent carbon 28.6 78 222 300

16 Used oil from

unit-I 5.1 0.06 0.06 0.12

155

CHAPTER-3

SITE ANALYSIS

3.1 CONNECTIVITY

3.1.1 RAIL

The nearest railway station is Vapi Station, which is around 3.6 km in North West direction from the project

site.

3.1.2 ROAD

The site is well connected by road network to all the key places.The major highway passing near the project site

isNH-8which is around 2.11 km West direction from the project site.

3.1.3 AIR

The nearest airport from the project site is Daman Airport. The distance of airport from project site is around 13

km in North West direction.

3.1.4 COMMUNICATION

Proposed project site is within existing company premises which is already well connected with telephone,

telefax etc. all the communications facilities are well developed in the area.

3.2 TOPOGRAPHY

Topography of the land is plane.

3.3 EXISTING LAND USE PATTERN

There is no Forest, National park; Wild life sanctuary within a radius of 10 km. Details of existing land use is

given in the following table:

DETAILS OF EXISTING LAND USE

SR.NO. PARTICULAR NAME & ITS DISTANCE

1. Nearest National Highway NH-8 which is around 2.11 km west direction

2. Nearest city Vapi City is around 4 km in west direction

3. Nearest River Damanganaga at 5 km in south west direction

4. Nearest Railway station Vapi Station at around 3.6 km in North West direction

5. National park/Reserve Forest,

Biosphere, etc. None within 15 km

3.4 EXISTING SOCIAL STRUCTURE

Project site is located at Vapi, G.I.D.C. All the infrastructures are available within city like Schools, Hospitals

& community facilities even nearby area of the project site is also developed.

156

CHAPTER – 4

PLANNING BRIEF

4.1 PLANNING CONCEPT

Type of industries:

The Active Pharmaceutical Ingredient industry is the organ by which active pharmaceutical ingredients are

manufactured from raw materials through both chemical and physical means. Depending on the complexity of

the molecule required, synthesis of APIs might need multi-step complex chemistry utilizing a range of

processing technologies.

4.2 LAND USE PLANNING

The plant general Layout has been planned considering production facilities, auxiliary and ancillary facilities

and plant utilities & services.Total plot area of the project is 8737.82 m2 from which around 2880 m2 (33% of

total land area) will be required for the development of green belt. Land use shall be as build up area of

buildings, storage facility, roads, greenbelt, open land etc.,

4.3 AMENTIES / FACILITIES

Adequate storage facility for chemicals, machinery spares and consumables shall be provided. A small

mechanical and electrical/ instrument workshop facilities for repairs and maintenance shall be provided. Time

and security offices shall be provided in the plant. To avoid fire hazard, internal fire hydrants system in all

major plant unit will be provided.

157

CHAPTER – 5

PROPOSED INFRASTRUCTURE

5.1 INDUSTRIAL AREA

The company has already acquired land area of 10,000 m2 in which company will expand their production

capacity.

5.2 GREEN BELT

The main objective of the green belt is to provide a barrier between the source of pollution and the surrounding

areas. The green belt helps to capture the fugitive emission and to attenuate the noise generated apart from

improving the aesthetics. Development of green belt and other forms of greenery shall also prevent soil erosion

and washing away of topsoil besides helping in stabilizing the functional ecosystem and further to make the

climate more conducive and to restore water balance. The company will develop green belt area with Lawn,

plants and flowers spread across about 33% of the total area i.e. 3300 m2.

Green belt shall be developed at plant boundary, road side, around offices & buildings and Stretch of open land.

The selection of tree species suitable for plantation at the industry are governed by guiding factors as stated

below:

• The trees should be tolerant to air pollutants present in the area

• The trees should be able to grow and thrive on soil of the area, be evergreen, inhabitant, having

minimum of leaf fall.

• The trees should be tall in peripheral curtain plantation and with large and spreading canopy in primary

and secondary attenuation zone.

• The trees should posses extensive foliar area to provide maximum impinging surface for continued

efficient adsorption and absorption of pollutants.

• The trees should be fast growing and indigenous and should maintain ecological, land and hydrological

balance of the region.

• It is also recommended to plant few trees, which are sensitive to air pollution, as air pollution indicator.

• It is also recommended to carry out extensive plantation within premises.

Keeping in view the climatic conditions, status of soils and vegetation types in and around the project area the

species shall be selected for proposed green belt development.

5.3 SOCIAL INFRASTRUCTURE

Drinking water facility, Canteen, proper sanitation, etc. will be provided to the workers working in plant.

5.4 CONNECTIVITY

As discussed earlier, proposed location of the plant is already well connected with the network of road & rail.

So there is no need to construct any new road or rail for the transportation.

5.5 WASTE WATER MANAGEMENT

Total wastewater i.e. 125 KLD will be generated from the proposed expansion project, which will be treated in

ETP consisting primary & secondary treatment. Treated effluent will be sent to CETP for further treatment and

final disposal.

5.7 INDUSTRIAL SOLID WASTE MANAGEMENT

From the proposed expansion project activity there shall be mainlySpent/Used Oil, ETP Sludge, Process

Residue, Distillation rsidue, Spent Carbon, Discarded containers, Iron sludge, used/waste filter clothes &

Sludge from wet scrubber, Incineration ash, Evapartor salt & incinerable waste from unit I.

158

CHAPTER – 6

REHABILITATION AND RESETTLEMENT (R & R) PLAN

The project is located on private land, which is already acquired and there is no habitat. So the project proposal

does not involve any Rehabilitation & Resettlement.

159

CHAPTER – 7

PROJECT SCHEDULE & COST ESTIMATES

7.1 TIME SCHEDULE FOR THE PROJECT

The implementation of the project will involve major activities like preparation of specification / drawings,

issue of tenders, receipt of quotations, scrutiny of tenders, placing of orders, civil & structural construction,

delivery & erection of equipment, test trial runs of various items of equipment and commissioning of the plant

& equipment and completion of the project will take about 6 months after the necessary clearances are

available, and the funding for the project has been tied up.

7.2 ESTIMATED PROJECT COST

The total project cost for the proposed expansion project would be around Rs. 1 crore. Total capital cost of

pollution control measures will be Rs. 7 Lacs & recurring cost per annum will be 3 Lacs.

7.3 BUDGETORY PROVISIONS FOR EMP

Adequate budgetary provisions have been made by the management for execution of environmental

management plans. The details of capital and recurring (per annum) budget earmarked for pollution control /

monitoring equipment; operation and maintenance of pollution control facilities, for greenbelt development and

maintenance.

COST OF ENVIRONMENTAL PROTECTION MEASURES

SR.

NO. PARTICULATES RS. IN LACS

1. Capital Expenditure 7

2. Recurring expenditure on environmental management cell and on

pollution control systems per annum. 3

160

CHAPTER – 8

ANALYSIS OF PROPOSAL

8.1 FINANCIAL AND SOCIAL BENEFITS

The total cost of the proposed expansion project is estimated at about Rs. 1 crore.

For the coming of this project surrounding area will get developed due to this project and through the

Corporate Social Responsibility (CSR) activities, socio-economic status of the region will also get

developed.

Documents

PRE - FEASIBILITY REPORT · 35 Solifenacin Succinate - 5 36 Montelukast Sodium - 5 37 Silodosin - 5 38 Cinacalcet Hydrochloride - 5 39 Maraviroc - 5 40 Vilazodone Hydrochloride -