PRE - FEASIBILITY REPORTenvironmentclearance.nic.in/writereaddata/FormB/TOR/… · · 2018-01-30CHAPTER-4 PLANNING BRIEF ... manufactured from raw materials through both chemical

PRE - FEASIBILITY REPORT

For Proposed Active Pharma Ingredient

Manufacturing Unit

at

C-1/511, Kerala GIDC Estate, At-Kerala,

Ta-Bavla, Ahmedabad

By

SHREE HARIKRISHNA PHARMACEUTICALS

Prepared by:

En-vision Enviro Technologies Pvt. Ltd.

2nd

Floor, Shree Ram Complex, Above Bank of India,

Near Kargil Chowk, Surat Dumas Road, Piplod, Surat-395007, Gujarat, India

Contact No: +91 2612223003, 2224004

E-mail: [email protected]; Website: www.en-vision.in

January – 2018

INDEX

CHAPTER-1 INTDOUCTION OF THE PROJECT ............................................................................. 1

CHAPTER-2 PROJECT DESCRIPTION .............................................................................................. 3

CHAPTER-3 SITE ANALYSIS ............................................................................................................... 8

CHAPTER-4 PLANNING BRIEF ......................................................................................................... 10

CHAPTER-5 PROPOSED INFRASTRUCTURE ................................................................................ 12

CHAPTER-6 REHABILITATION AND RESETTLEMENT (R & R) PLAN .................................. 13

CHAPTER-7 PROJECT SCHEDULE & COST ESTIMATES .......................................................... 14

CHAPTER-8 ANALYSIS OF PROPOSAL .......................................................................................... 15

PRE-FEASIBILITY REPORT OF PROPOSE API MANUFACTURING UNIT BY SHREE HARIKRISHNA PHARMACEUTICALS

1

CHAPTER-1 INTDOUCTION OF THE PROJECT

1.1 IDENTIFICATION OF PROJECT AND PROJECT PROPONENT

M/s. Shree Harikrishna Pharmaceuticals is planning set up the API manufacturing unit at C-1/511, Kerala

GIDC area, At-Kerala, Taluka Bavla, Ahmedabad.

Table 1-1: Proposed Product and Capacity

Sr.

No Product name

Capacity

(MTPM)

1 Deflazacort

10

2 Acebrophylline

3 Thiocolchicoside

4 Solifenacin Succinate

5 Anagliptin

6 Atazanavir sulphate

7 Esclicarbazepine Acetate

8 Febuxostat

9 Flupirtine maleate

10 Methyl cobalamine

11 Mirabegron

12 Pidotimod

13 Teneligliptin Hydrobromide Hydrate

14 Valsartan

15 Pirfenidone

16 N-Boc Amino acid

17 Fluconazole

18 Lostaran Potassium

19 Clopidogril Sulphate

20 Sertraline HCl

21 Oxcarbazepine

22 Nebivolol

23 Telmisartan

24 Clomipramine HCl

25 Bisoprolol Fumarate

26 Tadalafil

27 Ticagrelor 0.1

28 Vardenafil Hydrochloride Trihydrate 0.2

29 Atorvastatin Calcium 0.2

30 Rosuvastatin Calcium 0.1

The proposed products fall under Category 5(f) as stated in Environment Impact Assessment Notification

Published on 14th September, 2006. The unit is located in notified area of GIDC Kerala hence the project

proponent has to obtain the EC from the SEIAA, Gujarat.


2

The pharmaceutical industry is based primarily upon the scientific research and development (R&D) of

medicines that prevent or treat disease and disorder. Modern scientific and technology advances are accelerating

the discovery and development of innovative pharmaceuticals with improved therapeutic activity and reduced

side effects. Industrial chemicals are used in researching and developing active drug substances and

manufacturing bulk substances and finished pharmaceutical products. M/s. En-vision Enviro Technologies

Private Limited has been appointed to carry out EIA/EMP studies for Environmental Clearance.

Total plot area of the site is 703 m2 out of which 232 m

2 (33% of total land area) will

be developed as greenbelt.

The estimated project cost is 2.5 Crores. Total budget allocation towards Environmental Management Facilities

will be Rs. 50 lacs. Total 15 personnel will be required; including skilled persons, unskilled persons and office

staff.

1.2 PROMOTERS BACKGROUND

Dr. Kalpeshbhai Menpara, about age: 34 years, M.Sc. (Org. Chemistry) Ph.D.(Organic chemistry)

having 11 years experience in R. & D. department of pharmaceutical industry.

1.3 BRIEF DESCRIPTION OF NATURE OF THE PROJECT

The proposed unit is a small scale project for production of Bulk Drugs & Bulk Drug Intermediates

manufacturing.

1.3.1 Need for the Project and Its Importance to the Country and/or Region

The proposed project will provide a potential & required growth opportunity for the Company. Moreover

company has strong presence with leading pharma customers 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.

1.3.2 Demand-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.

1.3.3 Employment Generation (Direct and Indirect)

Total 15 personnel will be employed during operation phase.

PRE-FEASIBILITY REPORT OF PROPOSE

CHAPTER-2 PROJECT DESCRIPTION

2.1 TYPE OF PROJECT INCL

PROJECTS

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

growths are achieved through industrialization, infr

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.

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. Shree Harikrishna Pharmaceuticals

Ta-Bavla, Ahmedabad. Total plot area of the site is 703 m2 from which 232 m2 will be developed as greenbelt,

thus 33% of total land area will be covered with green belt.

EPORT OF PROPOSE API MANUFACTURING UNIT BY SHREE HARIKRISHNA PHARMACEUTICALS

PROJECT DESCRIPTION

TYPE OF PROJECT INCLUDING INTERLINKED AND INTERDEPENDENT


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


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

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

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

M/s. Shree Harikrishna Pharmaceuticals is planning to set up plant at C-1/511, Kerala GIDC Estate, At

Total plot area of the site is 703 m2 from which 232 m2 will be developed as greenbelt,

thus 33% of total land area will be covered with green belt. A map showing project site is given in

Identification

1

2

3

4

HARMACEUTICALS

3

D INTERDEPENDENT


astructure development. The industrialization has played a


ay to day operational

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

1/511, Kerala GIDC Estate, At-Kerala,

Total plot area of the site is 703 m2 from which 232 m2 will be developed as greenbelt,

roject site is given in Figure 2-1.

Identification Latitude &

Longitude

22°46'12.52"N

72°20'12.08"E

1 22°46'13.19"N

72°20'12.02"E

2 22°46'12.90"N

72°20'12.66"E

3 22°46'11.87"N

72°20'12.10"E

4 22°46'12.14"N

72°20'11.47"E


4

Figure 2-1: Location of the Project Site


5

Table 2-1: Salient Features within 10 km Radius of project site

Sr.

No. Feature Description

1. GPS Co-ordinates 22°46'12.52"N

72°20'12.08"E

2. Mean Sea Level 23 m

3. Temperature Range 9-45 °C

4. Annual Rainfall 500-1000 m

5. Nearest Airport Ahmedabad airport 43.94 km in NE

6. Nearest Road NH-8A 1.48 km in W and SH-74 7.06 km in E

7. Nearest Railway Station Bavla railway station 7.46 km in NNE

8. Nearest City Bavla Town 6.35 km in NNE

9. Nearest River None within 10 km radius.

10. Seismic Zone Zone – III (Medium Risk Zone)

11. National Park and Sanctuary None within 10 km radius.

2.2 PROCESS DESCRIPTION

For detailed manufacturing process, chemical reactions, material balance and process flow diagram please refer

Annexure – 1.

2.3 RAW MATERIALS REQUIREMENT

Raw material will be purchased from local market and convenient mode of transportation is either road/

railways. raw material consumption is attached as Annexure – 2.

2.4 RESOURCE OPTIMIZATION / RECYCLING AND REUSE IN THE PROJECT

The materials will be packed in drums and stored in a very organized way, segregated as Solid and Liquid area

in ware house. Good house-keeping, good Manufacturing practices, best Environment control, safety and health

practices will be obtained. 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.

2.5 AVAILABILITY OF WATER AND POWER

2.5.1 Water

The fresh water requirement for domestic and industrial activities is estimated 20.5 KLD, which will sourced

from GIDC, Kerala.


6

Table 2-2: Water Consumption and Wastewater Generation

Sr.

No Category

Water

Requirement

(KLD)

Wastewater

Generation

(KLD)

Wastewater Treatment

(A) Domestic 0.7 0.6 Septic tank/soak pit

(B) Industrial

1 Processing 10.3 21.1 High COD stream to CHWIF and

Low COD stream to ETP

2 Cooling Tower 1.5 0.3 To ETP

3 Boiler 5 1 To ETP

4 Washing 2 1.7 To ETP

(C) Green Belt 1 -- --

Total (A+B+C) 20.5 24.7

2.5.2 Power

Power requirement will be around 50 HP which will be sourced from Uttar Gujarat Vij Company Limited

(UGVCL). One DG set (80 kVA) will be installed as backup source of power and used only in case of power

failure.

2.6 WASTE MANAGEMENT/DISPOSAL

2.6.1 Water Environment

Industrial effluent (24.11 KLD) will be generated during operation phase of propose plant. There will be high

COD and low COD stream segregation at source. High COD stream (11 KLD) will be sent to CHWIF. Low

COD stream (12.68 KLD) will be treated in ETP of capacity 15 KLD having primary, secondary and tertiary

treatment units. Treated effluent (12.68 KLD) will further treated in single effect evaporate of capacity 15 KL to

achieve Zero Liquid Discharge. Sewage (0.6 KLD) will be treated in septic tank and soak pit system.

2.6.2 Air Environment

There will be flue gas emission expected from boiler of capacity 1000 kg/Hr. and D.G. set, while process

emission from reactor. Detail of flue and process emission is as under;

Table 2-3: Flue gas Emission

Stack

No.

Stack

Attached to Fuel Type

Fuel

Quantity

Stack

Height

(m)

Stack

Diameter

(m)

Air Pollution

Control System Permissible Limit

1. Boiler HSD 25 L/d 30 0.25 Adequate stack

height

SPM ≤ 150 mg/nm3

SO2 ≤ 100 ppm

NOX ≤ 50 ppm

2. D.G. SET Diesel 16 L/h 10 -- Adequate stack

height


7

Table 2-4: Process Emission

Sr.

No. Stack Attached To

Expected

Pollutant

Stack Height

(m)

Air Pollution Control

System Permissible Limit

1. Reactor HCl 20 Caustic Scrubber HCl ≤ 20 mg/Nm3

2.6.3 Solid/hazardous Waste

Following wastes will be generated at the end of manufacturing process or treatment process which will be

managed as per solid/hazardous waste management rule – 2016. All the wastes will be stored at designated area

having pucca floor, roof and leachate collection system.

Table 2-5: Waste Generation

Sr.

No Name of The Waste Category Quantity (MTPA)

Method of Storage and

Disposal

1. Process waste/residue 28.1 2.4 Collection, storage and

transport to TSDF site.

2. ETP Sludge 35.3 18 Collection, storage and


3. Used oil 5.1 30 L/annum

Collection, storage,

transportation, reuse/selling to

registered refiners.

4. Discarded Containers

/Barrels /Linear 33.1 600 Nos./ Annum

Collection, storage,

decontamination send to

authorized recycler.

5. Oily / Contaminated

Cotton waste 33.2 0.06

Collection, storage and


6. Spent Carbon 28.3 6 Collection, Storage and send

for Incineration.

7. Spent Solvent 28.6 120 Sent to distillation plant for

distillation

8. Date-expired products 28.5 So ever generated Incineration at common

facility


8

CHAPTER-3 SITE ANALYSIS

3.1 CONNECTIVITY

The unit is located in GIDC area which well connected to rest of the country through highways, railways and

airports. The details of the facility with distance from the unit is as under:

Sr.

No. Particular Description

Distance

(km) Direction

1. Nearest National Highway NH-8A

SH74

1.48

7.06

W

E

2. Nearest town Bavla 6.35 NNE

3. Nearest Airport Ahmedabad 43.94 NE

4. Nearest Railway station Bavla 7.46 NNE

3.2 COMMUNICATION

Proposed project site is within GIDC premises which is already well connected with telephone, telefax etc. all

the communications facilities are well developed in the area.

3.3 TOPOGRAPHY AND GEOGRAPHY OF THE STUDY AREA

It has been observed that the major area of study area is levelled plain to nearly level with small slopes. Over all

slope direction of the study area is noticed towards south to north.

The area forms part of North Gujarat Alluvial Plain with elevations ranging from 40 to 50 m MSL. The area is

under lain by post Miocene alluvium comprising sand, gravel, silt and clay. The alluvium is about 400 m thick

under lain by tertiary formation. The alluvium mainly consists of palaeo deltaic, fluvial and Aeolian sediments,

comprising alternate bands of fine to course grained sand, gravel and yellowish brownish sticky clay.

The soils found in the district are mostly of Black soil, Goradu soil, Kyari and Rocky soil. Medium Black Soils

are suitable for growing crops like bajri, jowar and cotton; all kinds of crops can grow in Goradu soil; varieties

of paddy such as Pankali, kamod, Jirasar, Sukhvel, Sutarsal and Basumati are grown on Kyari soil; and rocky

soils are fit for early maturing crops like cotton, Bajri, Jowar and Math.

3.4 CLIMATE OF THE STUDY AREA

The unit is located in Bavla Taluka of Ahmedbad district. The general agro-climatic zone of the study area is

Semi-arid to dry sub-humid. Period of March to May is one of the continuous rise in temperature. May is the

hottest month while January is the coldest month. Temperature range is 9°-45°C.

Winds are generally light with some strengthening in force in summer and in the south-west monsoon season.

During South west monsoon winds are generally SW to W. during end of monsoon NW winds also starts. Wind

direction is between NW & NE in morning; between SW & NW in afternoon in February & March. Rest of

summer wind direction is between SW & NW

The climate of the district is characterized by hot summer and general dryness except during the southwest

monsoon seasons. The year can be divided into four seasons. The period from March to May is the hot season


9

(summer) followed by southwest monsoon from June to September. October and November constitute the post-

monsoon or retreating monsoon season. The cold season (winter) starts from December and ends in February

The annual rainfall is received during SW monsoon season from June-September, with July being the highest

rainfall month. Average annual rainfall is 500 – 700 mm.

3.5 EXISTING LAND USE PATTERN

There is no Forest, National park; Wild life sanctuary within a radius of 10 km. The study area comprises of

• Industrial estates of Kerala GIDC; other industries.

• Residential areas of Bavla town and other small villages

• Small talav and canal from Vasna Barrage

• Cropped area

3.6 EXISTING SOCIAL STRUCTURE

Project site is located at Kerala, G.I.D.C. All the infrastructures are available within city like Schools, Colleges,

Hospitals & community facilities even nearby area of the project site is also developed.


10

CHAPTER-4 PLANNING BRIEF

4.1 PLANNING CONCEPT

The unit is located in Kerala GIDC which has different types of industries, such as Pharmaceutical, resins,

chemicals. The proponent is intending to manufacture Active Pharmaceutical Ingredients, 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 general Plant Layout has been planned considering production facilities, auxiliary and ancillary facilities

and plant utilities & services. Total plot area of the project is 703 m2. Land use shall be as build up area of

buildings, storage facility, roads, greenbelt, open land etc. Layout plant of proposed unit is given in figure 4-1

and the land use break-up is as under:

Sr. No Particular Land Area (m2)

1. Built up area 332

2. Green belt Area 232

3. Open/paved area 139

Total 703

4.3 AMENTIES / FACILITIES

Following facilities will be provided in the proposed unit:

• Adequate storage facility for chemicals, machinery spares and consumables

• Time and security offices

• Internal fire hydrants system


11

Figure 4-1: Plant Layout


12

CHAPTER-5 PROPOSED INFRASTRUCTURE

5.1 INDUSTRIAL AREA

The company has already acquired land area of 703 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. 232 m2 area across about 33% of the total area will

developed as green belt area with Lawn, plants and flowers spread. Green belt will 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

Expansion in existing infrastructure such as drinking water facility, canteen, proper sanitation, etc. will be

carried out as per requirement for the workers working in plant.

The Project proponent will contribute annually 2.5% of total profit towards CSR (Corporate Social

Responsibility) activity like following in nearby villages;

Education Facilities:- Facilities for village schools like game kits, drawing kits, table-chairs; school

construction (classroom/toilet/school boundary), ceiling fans or books for school library

Health Facilities:- to provide assistance to existing health facilities in Nearest Hospital, for improvement in

health facilities or services.


13

CHAPTER-6 REHABILITATION AND RESETTLEMENT (R & R) PLAN

The unit is located in GIDC area, which is already acquired for industrial purpose and there is no habitat. So the

project proposal does not involve any Rehabilitation & Resettlement.


14

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 project would be around Rs. 250 Lacs. Total capital cost of pollution

control measures will be Rs. 50 lacs & recurring cost per annum will be 25 Lacs.

Sr. No. Particulars Rs. In lacs

1 Land 60

2 Plant Machineries/Utilities 100

3 Building construction 40

4 Environmental Management System 50

Total 250

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.

Sr.

No. Particulars Rs. In lacs

1. Capital Expenditure 50

2. Recurring expenditure on environmental management cell and on

pollution control systems per annum. 25


15

CHAPTER-8 ANALYSIS OF PROPOSAL

8.1 FINANCIAL AND SOCIAL BENEFITS

The total cost of the proposed project is estimated at about Rs. 2.5 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.

Annexure 1

Contents

Annexure-1 Manufacturing Process, chemical reaction and mass balance ......................... 2

1. Deflazacort ................................................................................................................... 2

2. Acebrophylline ............................................................................................................ 3

3. Thiocolchicoside .......................................................................................................... 4

4. Solifenacin Succinate ................................................................................................... 5

5. Anagliptin .................................................................................................................... 7

6. Atazanavir sulphate ..................................................................................................... 8

7. Esclicarbazepine Acetate ........................................................................................... 11

8. Febuxostat .................................................................................................................. 13

9. Flupirtine maleate ...................................................................................................... 14

10. Methylcobalamine ..................................................................................................... 16

11. Mirabegron ................................................................................................................ 17

12. Pidotimod ................................................................................................................... 18

13. Teneligliptin Hydrobromide Hydrate ........................................................................ 19

14. Valsartan .................................................................................................................... 21

15. Pirfenidone ................................................................................................................. 23

16. N-Boc Amino acid ..................................................................................................... 24

17. Fluconazole ............................................................................................................... 25

18. Lostaran Potassium .................................................................................................... 26

19. Clopidogril Sulphate .................................................................................................. 28

20. Sertraline HCl ............................................................................................................ 29

21. Oxcarbazepine ........................................................................................................... 30

22. Nebivolol ................................................................................................................... 31

23. Telmisartan ................................................................................................................ 32

24. Clomipramine HCl ..................................................................................................... 32

25. Bisoprolol .................................................................................................................. 33

26. Tadalafil ..................................................................................................................... 34

27. Ticagrelor ................................................................................................................... 36

28. Vardenafil Hydrochloride Trihydrate ........................................................................ 40

29. Atorvastatin Calcium ................................................................................................. 40

30. Rosuvastatin Calcium: ............................................................................................... 44

Annexure-2 Raw Materials consumption .......................................................................... 47

Annexure 2

ANNEXURE-1 MANUFACTURING PROCESS, CHEMICAL REACTION AND

MASS BALANCE

1. Deflazacort

Acetylation of KSM-1 in the presence of acetic anhydride and DMAP to yield deflazacort.

Product: Deflozacort (Material flow sheet):

Annexure 3

2. Acebrophylline

a. Manufacturing Process

Theophylline-7-acetic acid react with ambroxol base in toluene as a solvent to give acebrophylline.

b. Chemical Reaction

c. Flow Diagram

Annexure 4

3. Thiocolchicoside


KSM-1 react with 1,2,3,4,6-penta-O-acetyl-beta-D-glucopyranose in acetonitrile in the presence of

borontrifluoride etherate and sodium hydroxide to yiled thiocolchicoside.


c. Flow Diagram

Annexure 5

4. Solifenacin Succinate


Stage-I: KSM-I on reaction with ethylchloroformate in presence of trietyhl amine in toluene gives

intermediate stage-IA which on reaction with KSM-II in presence of sodium ethoxide in toluene gives

intermediate stage-IB which on reaction with succinic acid in acetone gives stage-I

Stage-II: Stage-I on treatment with isopropyl alcohol and successive workup gives stage-II

(Solifenacin Succinate)


NH

(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline(KSM-I)

N O

O

1) R-(-)-3-quinuclidinol (KSM-II)Sodium ethoxide solution,Toluene

1) Succinic acid, Acetone

Stage-1A

N O

ON

Stage-1B

Ethylchloroformate, TEA

N O

ON

COOH

COOH

Stage-I

IPA

N O

ON

COOH

COOH

Stage-II, Solifenacin Succinate

Annexure 6

c. Flow Diagram

Annexure 7

5. Anagliptin


KSM-I react with KSM-II in the presence of EDC HCl, HOBT H2O, and potassium carbonate in MDC to give

anagliptin.


c. Flow Diagram

Annexure 8

6. Atazanavir sulphate


KSM-I react with KSM-II in IPA to give stage-I then deprotection of Boc group carried out using conc. HCl

followed by reaction with leucine ester in the presence of EDC HCl, HOBt in MDC to give stage-II. Atazanavir

sulphate was prepared by using sulfuric acid in methanol and acetone.


Annexure 9

c. Flow Diagram

Annexure 10

Annexure 11

7. Esclicarbazepine Acetate


Oxcarbazepine reacted with Catalyst, Catalyst-1, Catalyst-2 in the presence of IPA and

triethanolamine buffer solution, filtered & dried to give stage-1. Stage-1 reacted with acetic

anhydride, DMAP in the presence of MDC to give Esclicarbazepine acetate.


c. Flow Diagram

Annexure 12

Annexure 13

8. Febuxostat


Hydrolyzed the KSM-1 by using 1N NaOH solution in the presence of IPA and then acidify by using

1N HCl to give Febuxostat.


c. Flow Diagram

Annexure 14

9. Flupirtine maleate


Condensation of KSM-I and KSM-II in the presence of sodium carbonate to give Stage-I. Stage-I

reacted with Raney Ni and Hydrazine hydrate in the presence of IPA than reacted with ECF and

Maleic acid to give Flupirtine maleate.


c. Flow Diagram

Annexure 15

Annexure 16

10. Methylcobalamine


KSM-I react with trimethylsulfoxonium bromide in the presence of cobalt chloride, sodium

borohydride in 2-butanone to give Methylcobalamine.


c. Flow Diagram

Annexure 17

11. Mirabegron


Condensation of KSM-I and KSM-II by using DEC in the presence of process water and conc. HCl,

basify it by using liq. NH3 to give mirabegron.


c. Flow Diagram

Annexure 18

12. Pidotimod


Condensation of KSM-1and KSM-2 by using DCC in the presence of MDC to give Int-1 which was

then treated with sodium hydroxide and conc. HCl to give Pidotimod crude. Purified it by using IPA:

WATER solution filtered & dried to give pidotimod.


c. Flow Diagram

Annexure 19

13. Teneligliptin Hydrobromide Hydrate


Condensation of KSM-I and KSM-II by using STAB in the presence of MDC to give stage-I which

was then treated with MSA to give teneligliptin base (Stage-II). Reaction of stage-II with HBr in

Dysol as solvent to give teneligliptin hydro bromide hydrate.


Annexure 20

c. Flow Diagram

Annexure 21

14. Valsartan


Hydrochloride salt of KSM-I was broken by using NaHCO3 solution and then reacted with valeryl chloride in

the presence of DIPEA as a base to give Stage-I. Stage-I then reacted with sodium azide and tributyl tin chloride

in toluene to give Stage-II. Hydrolysis of Stage-II was carried out using NaOH solution to give Valsartan.


Annexure 22

c. Flow Diagram

Annexure 23

15. Pirfenidone


KSM-I was reacted with sulfuric acid and sodium nitrite in water to give Stage-I which was then

reacted with bromo benzene in the presence of potassium carbonate and copper(II)oxide in NMP as

solvent to give pirfenidone.


c. Flow Diagram

Annexure 24

16. N-Boc Amino acid


KSM-I was reacted with t-Boc anhydride in the presence of sodium hydroxide in water to give Stage-I

to give N-Boc Amino acid.


c. Flow Diagram

Annexure 25

17. Fluconazole


Epoxi decompounds intermediate &1, 2,4Triazolearetreated in presence of potassium carbonate. Once

reaction is over treated with ethylacetate, purified from IPA, filtered & dried to give Fluconazole.


c.

c. Flow Diagram

Annexure 26

18. Lostaran Potassium


2-Butyl-4chloro-5hydroxymethylimidazole reacted with4-bromomethyl-2 cyanobiphenyl & Na

Methoxide. Further treated with sodiumazide & NH4 Clinpresence of DMF. The mass is crystallized

from methanol to give lostaran potassium.


Annexure 27

c. Flow Diagram

Annexure 28

19. Clopidogril Sulphate


AminoEster(VIII)(+)-10-Camphor sulphonic acid reacted with Formic acid & Formaldehyde. The

mass is treated with Sulphuric acid, IPA+Water. The crude obtained is crystallized using water +

Methanol, filtered, and dried to give Clopidogril Sulphate.


c. Flow Diagram

Annexure 29

20. Sertraline HCl


4- (3, 4-Dichlorophenyl)-3,4-dihydro-1(2H)-naphthalene, Methylamine Lewis acid & Hydrogen; D(-)

Mandelic acid with Conc. HCl. The crystallized from Methanol + Water, filtered & dried to give

Steraline HCL.


c. Flow Diagram

Annexure 30

21. Oxcarbazepine


5H-Dibenz [b,f]azepine-5-carbonitrile;Sodium nitrite treated in presence of Acetic acid & Iron Boron

Trifluoride is added. The mass is filtered to give crude product, crystallized from IPA, filtered & dried

to give Oxcarbazepine.


c. Flow Diagram

Annexure 31

22. Nebivolol


Benzopyran-2-Carboxaldehyde Derivative treated with Trimethyl sulfoxoniumiodide. In presence of

Potassium hydroxide & Water. The mass is further treated with Benzyl amine &Toluene, Ammonium

formate using Pd/Catalyst. The mass is crystallized from Methanol, filtered &dried to give Nebivolol.


c. Flow Diagram

Annexure 32

23. Telmisartan


Charge Benzaimidazole compound, N-methyl-O-phenylenediamine, toluene, Poly phosphoric Acid

heat and reflux distilled out Toluene. Add Toluene and Bromoester cool & filters drying RCVD to get

Telmisartan.


c. Flow Diagram

24. Clomipramine HCl


Charge ChloroIminodibenzyl Dimethylaminopropylchloride, Toluene, KOH heat and reflux distilled

out Toluene. Add DMWater, Acetone, HCl cool & filters drying RCVD to get Clomipramine HCl.

Annexure 33


c. Flow Diagram

25. Bisoprolol


Charge Isopropylamino propanol, Isopropylethoxy-p-tolyl compound, IPA, KOH flakes, DM Water

heat and reflux distilled out IPA. Add DMwater Acetone, Fumaric Acid cool & filters drying RCVD

to get Bisoprolol.

Annexure 34


c. Flow Diagram

26. Tadalafil


Stage-I: KSM-I on reaction with KSM-II in IPA gives Stage-I

Stage-II: Stage-I on reaction with chloroacetyl chloride in presence of sodium bicarbonate in MDC

gives stage-II.

Stage-III: Stage-II on reaction with mono methylamine in methanol gives Stage-III (Tadalafil) on

successive workup

Annexure 35


c. Flow Diagram

Annexure 36

27. Ticagrelor


Stage –I: KSM-I on reaction with KSM-II in DMSO and Toluene in presence of triethyl amine gives

intermediate stage-IA which on deportation with hydrochloric acid in ethanol and toluene gives stage-

I

Stage-II: Stage-I on reaction with sodium nitrite in acetic acid and toluene gives intermediate stage-II

which on reaction with KSM-III in toluene in presence of triethyl amine gives stage-II

Stage-III: Stage-II on reduction with sodium borohydride in diglyme gives ticagrelor on successive

workup

Annexure 37


Annexure 38

c. Flow Diagram

Annexure 39

Annexure 40

28. Vardenafil Hydrochloride Trihydrate


Stage-I:

KSM-I on reaction with chlorosulfonic acid gives intermediate stage-IA which on reaction with KSM-

II in MDC gives intermediate stage-I.

Stage-II

Stage-I on treatment with conc. Hydrochloric acid in isopropyl alcohol gives stage-II (Vardenafil

Hydrochloride Trihydrate)


29. Atorvastatin Calcium

c. Manufacturing Process

KSM-I hydrogenated with Raney Ni to give stage-I which is react with KSM-II in the presence of

pivalic acid and cyclohexane to give stage-II which on Deprotection with hydrochloric acid and

hydrolysis with NaOH to give atorvastatin acid and further to form calcium salt of atorvastatin with

calcium chloride.

Annexure 41

d. Chemical Reaction

Annexure 42

e. Flow Diagram

Annexure 43

f. Flow Diagram

Annexure 44

30. Rosuvastatin Calcium:


KSM-I hydrolyzed by sodium hydroxide solution to produce Int-1 followed by oxidation with sodium

hypochlorite and TEMPO to give Int-2 which is react with KSM-II in the presence of potassium

carbonate and toluene to give stage-II which on Deprotection with hydrochloric acid and hydrolysis

with NaOH to give rosuvastatin acid and further to form calcium salt of rosuvastatin with calcium

chloride.


c. Flow Diagram

Annexure 45

Annexure 46

Annexure 47

ANNEXURE-2 RAW MATERIALS CONSUMPTION

No. Name of Raw Material Consumption in MTPM

1 KSM-I 115.5

2 Raaney Ni 0.4

3 Liq. Ammonia 6.5

4 IPA 748.3

5 Hyflow 1.3

6 Cyclohexane 5.9

7 KSM-II 67.7

8 pivalic Acid 0.0

9 water 1988.2

10 5 % Sodium Bicarbonate 1.2

11 Methanol 410.1

12 2% Dil. HCl 7.1

13 10% NaOH solution 0.9

14 MTBE 2.5

15 Calcium Chloride Dihydrate 0.1

16 Toluene 664.1

17 ethyl acetate 531.7

18 acetic Anhydride 7.6

19 DMAP 0.3

20 Aq. Buffer 77.3

21 Acetonitrile 105.6

22 1,1,3,3-tetramethylguanidine 5.3

23 borontriflouride etherate 14.4

24 Sodium Hydroxide solution 41.7

25 Sodium thiosulphite solution 27.8

26 Sodium bicarbonate solution 133.0

27 Sodium Chloride Solution 117.7

28 Diethylamine 17.8

29 potassium carbonate 21.7

30 MDC 516.2

31 Potassium Bromide 0.0

32 TEMPO 0.0

33 Sodium Hypochlorite 0.6

34 Sodium Thiosulphate 0.0

35 potassium chloride 0.1

36 DMSO 5.1

37 EDC HCl 10.1

38 HOBT water 1.3

39 35% K2CO3 Solution 57.2

Annexure 48


40 Activate Carbon 2.3

41 celite 4.1

42 EToAC 7.9

43 conc.Hcl 81.2

44 leucine ester 9.2

45 DIPA 19.0

46 NaHCO3 151.6

47 DNS solution 103.9

48 Conc. H2SO4 19.1

49 Acetone 190.1

50 oxcarbazepine 9.5

51 triethanol amine buffer solution 38.1

52 Catalyst 0.1

53 10% Na2CO3 Solution 23.6

54 0.35%dil.HCl Sol. 22.4

55 1N NaOH Solution 43.6

56 1N HCl Solution 17.8

57 Sodium Carbonate 7.3

58 Hydrazine hydrate 6.8

59 ECF 3.4

60 Maleic Acid 3.6

61 Aq. IPA 25.2

62 Cobalt chloride hexahydrate 0.8

63 2-Butanone 8.6

64 Ion Exchanged water 206.9

65 Sodium Borohydride 4.6

66 Trimethyl Sulfonium Bromide 4.4

67 DEC 6.3

68 DCC 9.6

69 NaOH 6.2

70 DCM 26.3

71 STAB 10.5

72 MSA 7.1

73 DYSOL 74.7

74 Hydrobromic Acid Solution 6.3

75 Sodium sulphate 2.1

76 DIPEA 5.4

77 Vleryl Chloride 4.2

78 Sodium bicarbonate 3.5

79 Sodium Azide 7.2

80 Trybutyl Tin Chloride 18.4

81 KOH 16.5

82 Sodium Nitrite 11.8

Annexure 49


83 NMP 12.5

84 Bromo Benzene 13.5

85 Copper(II) Oxide 0.5

86 Sodium Chloride 21.2

87 Amino Acid 7.7

88 48% NaOH Solution 2.3

89 t-BOC Anhydride 17.6

90 EpoxideIntermediate 12.0

91 1,2,4-Triazole 14.3

92 Dimethyl Formamide DMF 43.2

93 Acetic Acid 29.7

94 2-Butyl-4chloro-5 hydroxy methylimidazole 19.5

95 4-bromomethyl-2- cyanobiphenyl 10.1

96 Sodium Methoxide 33.6

97 Ammonium Chloride 2.1

98 Methanol +m Water 39.9

99 Aminoester (VIII)

(+)-10-Camphorsulphoic acid

28.2

100 Formic Acid 18.5

101 Formaldehyde 3.3

102 4-(3, 4-Dichlorophenyl)-3,4-dihydro-1(2H)-

naphthalene

14.2

103 Methylamine 3.7

104 Lewis Acid 2.9

105 Hydrogen 1.6

106 D(-)Mandelicacid 8.5

107 5H-Dibenz[b,f]azepine-5- carbonitrile 13.5

108 Iron 0.8

109 BoronTrifluoride 3.5

110 Benzopyran-2- Carboxaldehyde Derivative 14.0

111 Trimethyl sulfoxonium Iodide 11.5

112 Benzyl Amine 4.0

113 Ammonium Formate 6.0

114 pd/c 0.1

115 Benzaimidazolecompound 14.3

116 NMethyl-O- Phenylenediamine 12.1

117 Poly Phosphoric Acid 35.7

118 Bromo ester 8.6

119 ChloroIminodibenzyl 13.3

120 Dimethylaminopropyl chloride 11.3

121 Isopropylaminopropanol 0.6

122 Isopropylethoxy-p- tolylcompound 12.5

123 KOH Flake 0.3

Annexure 50


124 Fumaric Acid 5.0

125 Triethyl Amine 4.1

126 Ethyl Chloroformate 4.3

127 Succinic Acid 4.2

128 Chlorosulfonic Acid 0.6

129 Chloroacetyl chloride 8.8

130 40% Methyl amine solution in water 50.0

131 Ethanol 4.3

132 KHCO3 0.4

133 Diglyme 1.6

Annexure 51

PRE - FEASIBILITY REPORTenvironmentclearance.nic.in/writereaddata/FormB/TOR/… · · 2018-01-30CHAPTER-4 PLANNING BRIEF ... manufactured from raw materials through both chemical

Documents