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Prefeasibility Report: QPPL/2018/01

Quantinental Pharmachem Private Limited (QPPL) P a g e | 1

PRE-FEASIBILITY REPORT

For Proposed

Active Pharmaceutical Ingredients (APIs) and

API Intermediates Manufacturing Unit

At,

A-106/1, MIDC Paithan Industrial Area, Village: Mudhalwadi, Taluka: Paithan,

Aurangabad, Maharashtra. Pin Code: 431148

For

M/s. Quantinental Pharmachem Private

Limited

Recognized



INDEX Chapter No. Contents Page No.

1. Executive Summary 4-6

2. Introduction of the Project/ Background Information 7-9

2.1 Identification of the Project and Project Proponent 7

2.2 Nature of the Project 7

2.3 Need of project with description for region and country 8

2.4 Demand and Supply Gap 8

2.5 Employment generation due to project 9

3. Project Description 10-29

3.1 Type of Project 10-11

3.2 Location of Project 12-14

3.3 Products & Raw Material. 15

3.4 Manufacturing Process 15-26

3.5 Plant Machinery and Equipment’s 26

3.6 Technology Selection 26

3.7 Raw Material for finished Product 27

3.8 Availability of Resources 27-28

3.9 Quantity of waste to be generated 28-29

3.10 Reuse/ Recycle/ Recovery Systems proposed along with

Details

29

4. Site Analysis 30-32

4.1 Connectivity 30

4.2 Land form, Land use, Land ownership 30

4.3 Topography 31

4.4 Soil classification 31

4.5 Climate data for secondary sources 31

4.6 Social infrastructure Demand 31

5. Planning Brief 32

5.1 Planning Concept 32

5.2 Facilities 32

5.3 Land Use Planning 32

5.4 Population Projection 32

6. Proposed Infrastructure 33-36

6.1 Industrial area 33

6.2 Residential area 33

6.3 Green belt 33

6.4 Connectivity 33



6.5 Water management 33

6.66 Sewerage system/ETP 33-34

6.7 Air Pollution 34-35

6.8 Solid waste management 35-36

6.9 Power requirement & supply /source 36

7. Rehabilitation and Resettlement 37

7.1 Policy to be adopted 37

8. Project Schedule & Cost Estimate 38

8.1 Time schedule for the project 38

8.2 Estimated Project cost 38

9. Analysis of Proposal 39

9.1 Financial and Social Benefit 39



Chapter 01

Executive Summary

The project is being promoted by M/s Quantinental Pharmachem Pvt. Ltd. (QPPL).The proposed

plant is located at A-106/1, MIDC Paithan Industrial Area, Pin Code: 431148, Village: Mudhalwadi,

Taluka: Paithan, Aurangabad, Maharashtra.

QPPL is “Start-Up India” recognized as a startup by the Department of Industrial Policy and

Promotion with Certificate No.: DIPP19012. QPPL is also having 50% shareholding of Women

entrepreneurs and both Directors as women for Women empowerment.

The aim of the Quantinental Pharmachem Pvt. Ltd is to set up the API and its intermediate

manufacturing facility. QPPL is planning to start R&D and subsequent commercialization of

innovative and patented chemicals which can prevent further import from other countries. The

company is in the process of setting up State of art manufacturing unit and manufacture any

product based on market and according to the changing marketing environment. The project is



being promoted to cater domestic market, Export & Govt. supply as per the requirements of the

prospective customers.

The proposed products shall fall under category of Synthetic Organic Chemicals. As per the

EIA Notification 2006 & amendments thereof, for manufacturing of Bulk drug & intermediate

chemicals require environmental clearance from MoEF&CC under the 5 (f) category A.

The list of proposed products is as per Table No. 1.1;

Table No. 1.1

Sr.no Name of the Product Pharmaceutical Activity

Qty MT per Month

1. m- Bromoanisole Phase-transfer catalyst 0.800

2. Etorocoxib Non-steroidal anti-inflammatory

0.200

3. Ethyl Triphenylphosphonium Bromide Phase-transfer catalyst 10.0

4. Fluconazole Anti-fungals 0.475

5. Linezolid Anti-biotic 0.094 6. Telmisartan Anti-hypertensive 0.400 7. Tetrabutyl Ammonium Bromide Phase-transfer catalyst 0.130 8. Glimepiride Anti-diabetic 0.150 9. Tri-Ortho Phenyl Phosphine Phase-transfer catalyst 02.00 10. Cilnidipine Anti-hypertensive 0.150

11. Triclabendazole Anti-helmintic 0.082 12. Voglibose Anti-diabetic 0.005 13. Darunavir Anti-HIV 0.100 14. Montelucast Sodium Anti-allergic 0.750 15. Losartan Anti-hypertensive 0.975

16. Sparfloxacin Anti-bacterial 0.05 17. Salbutamol Sulphate Bronchodilators 02.00 18. Pantoprazole Sodium Proton Pump Inhibitor 0.450 19. Fenofibrate Anti-hyperlipidemic 0.500 20. Clopidogrel Hydrogen Sulphate Anti-platelet 0.175 21. Rosuvastatin Calcium Anti-hyperlipidemic 0.500 22. Domeperidone Anti-emetic 0.100 23. Nebivolol Hydrochloride Anti-hypertensive 0.360 24. R&D Products 3 no. 0.100



Area Requirement- The total plot area in possession is 2499 Sq.mt.

Water Requirement: The total water requirement will be 42 CMD and shall be supplied by [MIDC]

Maharashtra Industrial Development Corporation, Paithan.

Power Requirement: The total power requirement will be 150 KVA. The source of electricity

supply is Maharashtra State Electricity Distribution Company Limited (MSEDCL).

Man Power: The total manpower requirement will be 10 nos. of skilled and unskilled Category.

Project Cost: The total cost of the project will be around Rs. 404.96 Lakhs. Cost for Environment

Management Plan is Capital Cost 94.5 Lakhs/annum and Recurring Cost: Rs. 7.17 Lakhs/annum.



Chapter 02

Introduction of the Project/Background Information

2.1 Identification of the Project and Project Proponent-

The project is being promoted by M/s Quantinental Pharmachem Pvt. Ltd. (QPPL). QPPL

is“Start-Up India” recognized as a startup by the Department of Industrial Policy and Promotion

with Certificate No.: DIPP19012. QPPL is also having 50% shareholding of Women entrepreneurs

and two Directors as women for Women empowerment. Mrs. Varsha A Padalkar and Mrs.

Manisha M Thube and Mr. Mahesh Thube are the Directors of the Company.

The aim of the Quantinental Pharmachem Pvt. Ltd is to set up the API and its intermediate

manufacturing facility. The directors of M/s Quantinental Pharmachem Pvt. Ltd. intend to

extrapolate business by way of Manufacturing, Exporting & selling of all kinds of API and

intermediates and chemicals as Raw materials.

For this project the proponent is having the land in MIDC at plot no. A-106/1, Paithan, Taluka-

Paithan, District-Aurangabad. As per the present pollution control norms, the project is having Zero

Liquid Discharge.

This Pre-Feasibility Report is prepared for forming a framework for EIA study, Scoping and

finalizing the Terms of Reference. M/s Quantinental Pharmachem Pvt. Ltd. (QPPL) has retained

the services to the M/s. Green Circle Consultants (India) Pvt. Ltd., Vadodara, Gujarat as EIA

Consultant for this project. M/s Green Circle Consultants (India) Pvt. Ltd. is provisional

accredited EIA Consultant with the National Accreditation Board for Education and Training

(NABET), an organization working under the Quality Council of India (QCI), a mandatory

requirement for working as on projects requiring EC.

2.2 Nature & Magnitude of project

The proposed products are Active Pharmaceutical Ingredient’s (API) and API intermediates of

Pharma products. The project falls within 5.0 km of notified eco-sensitive area (as per Gazette

Notification No. S.O. 2202E) hence it falls under Category A, section 5(f) of EIA notification

September 2006 and its Amendment.



2.3 Need of project and its importance to the country and region

The project is being promoted by M/s. Quantinental Pharmachem Pvt. Ltd. (QPPL), with a view

to tap tremendous scope of the pharmaceutical industry supported by the following facts. The

drugs and pharmaceutical industry have shown significant growth and improvement in

profitability. This growth rather is more significant as it has been achieved despite frequent

changes made in the drug policy and has been achieved as an outcome of some dynamic strategies

adapted by the industry. The pharmaceutical industry is considered lifeline industry as it is directly

concerned with the health of the people.

The company is in the process of setting up State of art manufacturing unit and manufacture any

product based on market and according to the changing marketing environment. The project is

being promoted to cater domestic market, Export & Govt. supply as per the requirements of the

prospective customers.

The unit will use good faith efforts to employ local people from the nearby villages depending upon

the availability of skilled & un-skilled manpower surrounding the project site. In operation phase,

the proposed project would require significant workforce of nontechnical and technical grade.

2.4 Demand supply gap and market scenario

Natural Product and broadly Chemical Industry is one of the oldest industries in India, which

contributes significantly towards industrial and economic growth of the nation. It is highly scientific

type of industry and provides valuable raw material/chemicals for various types of industries such

as Food, Feed, Pharma, Nutraceutical and Personal Care etc., are required in almost all walks of life.

The Indian Chemical Industry forms the backbone of the industrial and agricultural development of

India and provides building blocks for downstream industries.

The Indian pharmaceutical industry has registered phenomenal growth since independence from

an annual turnover of 10 million; the industry is expected to achieve a turnover of Rs. 20,000 Cr by

2020. India today enjoys the recognition and respect as one of the leading producers of quality

pharmaceuticals products and formulations in the world. In the present scenario every drug

industry has to operate under strict norms of cGMP governed by Drugs & Cosmetics Act. 1940 in



order to maintain quality at par with the global requirement. Hence immense potential in exports is

another opportunity for this industry.

2.5 Employment Generation

The Project creates direct & indirect employment opportunities to people living in the surrounding

region. The Management of the Company has always preferred to engage (employment) local

people from the nearby villages depending upon skilled & unskilled man-power available and train

them in the required field. Total direct employment is around 10 people initially. After that as when

required it will be upgraded.



Chapter 03

Project Description

3.1 Type of project

Quantinental Pharmachem Pvt. Ltd is to set up the API and it’s intermediate manufacturing

facility. QPPL is planning to start R&D and subsequent commercialization of innovative and

patented chemicals which can prevent further import from other countries.

The details of project are given in the Table 3.1.

Table 3.1 Project Details

# particulars Details A. Nature & Size of

the Project List of the products is mentioned in Table no.1

B. Category of the Project

As per EIA Notification dated 14th Sep., 2006 as amended from time to time; the project falls in Category ‘A’, Project or Activity -5(f).

C. Location Details Village Mudhalwadi Tehsil Paithan District Aurangabad State Maharashtra Latitude 19031’ 56.2” N Longitude 75023’ 02.2” E Mean sea level 470 m

D. Area Details Total Project Area and Green belt development area

Total area required:- 2499 Sq.Mt Built up area for Factory shed:- 243.04 Sq.Mt Built up area for storage:- 236.04 Sq.Mt Built up area for office:- 13.36 Sq.Mt Open Space for utility:- 65.73 Sq.Mt` Other:- Open Land 1940.83 Sq.Mt

E. Environmental Setting Details (with approximate aerial distance & direction from plant site) 1. Nearest Village Mudhalwadi approx. -0.75 Km 2. Nearest town and

City Paithan–6 Km

3.

Nearest National Highway / State Highway

Aurangabad – Paithan Road

4. Nearest Railway station

Aurangabad Railway Station - 37.06 Km

5. Nearest Airport Aurangabad Airport –36.70 Km 6. National Parks,

Wildlife Sanctuaries, Biosphere Reserves, Tiger/

Jayakwadi Bird Sanctuary reserved for the migratory birds, is 1.8km towards South-West Direction [As per Gazette Notification S.O. 2202 (E) amended Dated 12th July 2017]



Elephant Reserves, Wildlife Corridors etc. within 10 km radius

7. Reserved Forests (RF)/Protected Forests (PF)

No

8. Water Body (within 10 km radius)

Jayakwadi Dam- 1.8 Km. Google image is attached as Annexure.

9. Seismic Zone Seismic Zone - II as per IS: 1893 (Part-I): 2002 F Cost Details

Total Cost of the Project

Rs. 404.96 Lakhs

Cost for Environment Management Plan

Capital Cost: Rs. 94.5 Lakhs Recurring Cost: Rs. 7.17 Lakhs/annum

No. Description Capital Cost (Rs. in Lakhs)

Recurring Cost per annum (Rs. in Lakhs)

1. Air Pollution Control system 21.00 1.05 2. Water Pollution Control 65.0 4.0 3. Environment monitoring and

Management 1.5 0.40

4. Rain water Harvesting 1.00 0.10 5. Occupational Health 1.00 0.20 6. Green Belt 1.00 0.82 7. Solid waste management 3.00 0.50 8. Energy Saving Devices and

Solar Heating System 1.00 0.10

Total 94.5 7.17

G Basic Requirements for the project Water Requirement

Total water consumption: 42.0 CMD (Source: - MIDC, Paithan)

Loss due to consumption and evaporation: 21.7 CMD

Total effluent generation & used for plantation: 9.8 CMD Effluent Treatment System (capacity)

Zero Liquid Discharge plant proposed

Power Requirement/ Boiler details

150 KVA (Source: - MSEDCL) Boiler details 600 kg/hr; Fuel – Bricks. DG Set 80KVA

ManPower Requirement

10 nos. (Source: - Unskilled / Semi-Skilled - Local Area; Skilled- Local & Outside)

H Working Days 300 days/annum



3.2 Location of Project

The proposed production shall be at A-106/1, MIDC Paithan Industrial Area, Village: Mudhalwadi,

Taluka: Paithan, Aurangabad, Maharashtra. Pin Code: 431148. The Geographical location of this

industry is 19031’ 56.2” N Latitude and 75023’ 02.2” E Longitude with an elevation 470 m. of above

mean sea level. This candidate site is in premises of MIDC Industrial Area which is meant for

various types of industries. Government has provided all infrastructure like electrical power,

continues water supply with purification from water, the internal road network, external approach

road. Annexure I shows the distance of Jayakwadi Dam to project site.

Fig. No. 3.1 Google Image

19031’ 56.2” N Latitude 75023’ 02.2” E Longitude



Figure 3.2: Location map of the Project



Figure 3.3: Master Layout



3.3 Details of Alternate Site

No alternate site was examined as already existing infrastructure is present.

The Industrial area of Paithan provides all necessary facilities viz. link roads, sewerage, sanitary

facilities, modern state of the art communication systems, banking and commercial facilities for

development of industrial units. The industrial township is well connected with the adjacent states

and other part of India through a network of roads, which facilitates travelling as well as

transportation of goods both inwards and outwards. This further facilitates the marketing of

products anywhere in the country. There is a regular flow of workers from nearby as well as far off

Aurangabad city. Power connection required for the units are easily available especially in

Industrial towns promoted by the state government.

There is no sensitive establishment in the vicinity such as health resort, hospital, archaeological

monuments, sanctuaries, etc.

3.4 Products and Raw Materials-

Sr.no Name of the Product Pharmaceutical Activity

Qty MT per Month

1. m- Bromoanisole Phase-transfer catalyst 0.800

2. Etorocoxib Non-steroidal anti-inflammatory

0.200

3. Ethyl Triphenylphosphonium Bromide Phase-transfer catalyst 10.0

4. Fluconazole Anti-fungals 0.475

5. Linezolid Anti-biotic 0.094 6. Telmisartan Anti-hypertensive 0.400 7. Tetrabutyl Ammonium Bromide Phase-transfer catalyst 0.130 8. Glimepiride Anti-diabetic 0.150 9. Tri-Ortho Phenyl Phosphine Phase-transfer catalyst 02.00 10. Cilnidipine Anti-hypertensive 0.150

11. Triclabendazole Anti-helmintic 0.082 12. Voglibose Anti-diabetic 0.005 13. Darunavir Anti-HIV 0.100 14. Montelucast Sodium Anti-allergic 0.750 15. Losartan Anti-hypertensive 0.975

16. Sparfloxacin Anti-bacterial 0.05 17. Salbutamol Sulphate Bronchodilators 02.00 18. Pantoprazole Sodium Proton Pump Inhibitor 0.450 19. Fenofibrate Anti-hyperlipidemic 0.500 20. Clopidogrel Hydrogen Sulphate Anti-platelet 0.175 21. Rosuvastatin Calcium Anti-hyperlipidemic 0.500 22. Domeperidone Anti-emetic 0.100 23. Nebivolol Hydrochloride Anti-hypertensive 0.360 24. R&D Products 3 no. 0.100



There are total 24 numbers of products. The detailed manufacturing processes of the product are

mentioned below;

1. Name of the Product –m- Bromo Anisole

Quantity per Month -800.00 Kg

Batch Output- 400 Kg

Number of batches per Month - 2

Number of working days- 25

Detailed Manufacturing Process-

3- Bromo Nitro Benzene is Charged in toluene, in a Glass lined Reactor at ambient temperature. To

the reaction mass at ambient is charged catalyst and potassium hydroxide. The temperature of the

reaction mass is maintained below 55 0C and controlled with cooling water circulation in the jacket

of the Reactor. Reaction completion is confirmed by analyzing sample on GC, If the result is within

acceptable range, to the resulting slurry, Methanol is added slowly. The reaction mass is then

washed with water to remove water soluble salts. The organic layer is again washed dilute

sulphuric acid and then with water. The organic mass is subjected to distillation and toluene is

recovered initially, and then pure MBA is distilled, stored and packed. Recovered Toluene is

recycled for the successive batches.

Table no 1: Input and output and mass Balance of m- Bromo Anisole

Input UOM Qty Output Qty Remark

MNBB kg 500 Product MBA 400 Final Product

Toluene kg 731 Toluene 584.8 Recovered and recycled

Methanol kg 200 Aqueous Effluent HCOD

1191.2 To ETP for treatment

KOH kg 283 Distillation residue

100 For CHWTSDF

NaOH kg 157 Toluene 10 Distillation loss

TBAB kg 95 Toluene 10 In aq.Effluent

Sulphuric acid kg 30 ----------------- ---------- -----------------------

Water kg 300 -------------- ----------- -----------------------

Total 2296 Total 2296 ----------------

Route of Synthesis for m-Bromo Anisole: -



N+

O O-

m-Nitro Bromo benzene(M.W. 202)

Br

+ KOH + CH3OH

O

Br

m Bromo Anisole(M.W. 187)

+ KNO2+ H20

Process Flow Diagram for m-Bromo Anisole.

1. Toluene 731 kg 2. MNBB 500 kg 3. Methanol 200 kg 4. KOH 283 kg 5. TBAB 95 kg 6. NaoH 157 kg 7. Sulphuric acid 30 kg 8. Water 300 kg

Reactor Aq.Effluent to ETP 1191.20kg

kg

Vacuum

Distillation Reactor

Recovered Toluene: - 584 kg

Organic Residue for II nd Recovery 100 kg

MBA Product: - 400 kg Total: - 1896 kg Total: - 2296



Table no. 2:-Pollution load of m- Bromo Anisole. Effluent in m3, rest all figures are in kg

Stage Effluent in lit

Solvent Residue

Carbon Hyflow Spent Solvent

Gas Generated

Inorganic Salt

Organic Residue LCOD HCOD Name Qty

I ------ 1191.20 ----- ------ ------- ----- ------ ----- ------- 100

M ------- 2382.40 ----- ----- ----- ---- ----- ---- ---- 200

D -------- 95.296 ------- ----- ---- ----- ----- ---- ----- 08.00 M- Pollution load per month

D- Pollution load per day

1. No gas is produced or generated during the reaction processing.

2. The reaction is not exothermic or run away or pressure.

3. Toxic and hazardous raw material used 1. Toluene 2. Sulphuric acid.

Table no. 3:- Solvent Balance of m- Bromo Anisole.

Sr.No

/ Stage

Qty in Kg/Day Name of

the solvent

Qty Used

Recovered [Distilled]

Fugitive loss

Distillation

Process loss

To wast

e Wate

r

Distillation

Residue

Product

drying loss

Spent

Solvent

Fresh Make Up

I Methanol 16 Nil Nil Nil 16 Nil Nil Nil 16

I Toluene 58.48 46.72 ------- 0.8 0.8 8 ----- ------ 1.12

I Water 24 --------- 0.16 ------ 23.84 ---- --- ---- 24

Table no. 4:- Matrix showing Molecular weight, Moles, molar ratio andconsumption

Name of Key RM

Details Mol.Wt Qty kg

Moles Molar Ratio

Existing Consumption

Proposed Consumptio

n

Net Consumpt

ion

Toluene Solvent ---- 731 ---- ---- ----- 147 147 MNBB Raw

Material 202 500 2.475 1 ------ 500 500

NaoH Reagent 40 157 3.925 1.58 ---- 157 157 KOH Regent 56 283 5.05 2.041 ------- 283 283

TBAB Catalyst 322.37 95 0.295 0.11 ------- 95 95 Water Solvent ------- 300 ------ ----- ----- ----- -----

Note: - Solvents is in terms of volume and not based on mole ratio.

Key Raw materials are considered as they are involved to build the desired molecule.

The above figures of the respective raw material are representative of a batch.



2. Name of the Product—Etoricoxib

Qty/Month 200.00kg. Batch Output 100 kg No of Batches/ Month 2 No of working days 25

Detailed Manufacturing process of Etoricoxib -

In a clean and dry Reactor is charged a mixture of KetoSulphone and 3-chloro dimethyl

aminehexafluro phosphate at ambient. To the reaction mass is added slowly potassium

tertairybutoxide in 2-3 hrs at ambient. The reaction mass is stirred for 2 hrs and the temperature of

the reaction mass is raised to reflux. Reaction completion is ensured on TLC, if the result complies,

the reaction mass is cooled to ambient and then quenched in acid water mixture. After completion

of quenching operation toluene is added and stirred for 20-30 minutes stalked for 30-40 minutes.

The layer is separated and distilled for recovery.

The recovered Toluene is recycled. To the aq layer, ammonia is added at ambient to adjust pH of the

reaction mass to 7-7.5.The product as base is extracted in Toluene. The toluene layer is separated

and aq layer is let to ETP for treatment. To the toluene layer p-Nitro Toluene Sulphonic acid added

and the reactions mass is stirred for 2030 minutes.The product as salt is centrifuged and spin dried.

The salt of Etoricoxib base is basified with ammonia solution and filtered to get Crude Etoricoxib

,Aq.Layer is send to ETP for treatment. The crude Etoricoxib is purified in Isopropyl acetate. The

pure Etoricoxib is centrifuged to get pure Etoricoxib, which is dried in tray dryer. The mother liquor

is distilled and recycled.

Table No. 1:- Input and output and mass Balance of Etoricoxib


KetoSulphone kg 100 Etoricoxib 100 Final Product

KOBt kg 40 Toluene 2660 Recovered and recycled

Intermediate I kg 115 Toluene 10.7 Distillation loss

Tetrahydrofuran kg 250 Aq.Effluent HCOD 1293 To ETP for Treatment

p-NTSA kg 100 Tetra Hydrofuran 225 Recovered and recycled

Acetic acid kg 150 Tetra Hydro Furan 20 Evaporation loss

Toluene kg 2800 Carbon 7 CHWTSDF

Activated Carbon kg 7 Hyflow 7 CHWTSDF

Hyflow kg 7 Isopropyl acetate 230 Recovered and recycled

Aq.Ammonia kg 370 Isopropyl acetate 05 Distillation loss

Isopropyl acetate kg 250 Solvent Distillation Residue

26.3 Send to CHWTSDF

Water kg 400 Product Drying loss 05 Evaporation loss during drying of product-

Total kg 4589 Total 4589 -----------------

KOBt—Potassium Tertiary Butoxide Intermediate I- 2-Chloro-1,3bis[dimethylamino ] trimethyl hexa fluoro phosphate P-NTSA-p-Nitro Toluene Sulphonic acid.



N

O

SH

O

O

KetosulphoneMol.Wt 289.35

Route of Synthessi for ETORICOXIB

+ N

Cl

NPF6 + OK

Chloro Compound

Mol.Wt306.62

SO3H

Tertiary Butoxide

Mol.Wt 112.21

PTSA

Mol.Wt 172.50

THF, Acetic acid, Ammoina.Tolueen

NO

SH

O

O

SO3H

PTSA Salt of EtoricoxibMol.Wt 531.04

+

OH

Mol.Wt 74.12

KPF6 + NH3+

CH3CH2OH

Ammoina, Water,Toluene

Isopropyl acetate, Carbon,Hyflow

N

NO

SH

O

O

N

Cl

Cl

ETORICOXIBMOL.WT 358.84



Process flow Diagram-



Table No.2:-Pollution load of Etoricoxib. Effluent in m3, Rest all figs in kg.

Stage Effluent in M3

Solvent Residue


Gas Generated

Inorganic Salt

Organic Residue

LCOD HCOD Name Qty

I ------ 1.293 26.3 7 7 ----- ------ ----- ---- -----

M ------- 2.586 52.60 14 14 ------ ------ ------ ----- ---- D -------- 0.103 2.104 0.56 0.56 ------ ----- ----- ---- -----

M- Pollution load per month, D- Pollution load per day.

No gas is produced or generated during the reaction processing. The reaction is not exothermic or run away or pressure. Toxic and hazardous raw material used - 1. Toluene 2. Sulphuric acid.

Table No.3:- Solvent Balance of Etoricoxib.

Sr.No/ Stage


the solvent

Qty Used


Fugitive loss

Distillation Process

loss

To waste Water

Distillation Residue

Product drying

loss

Spent Solvent

Fresh Make

Up

I Toluene 2800 2660 ----- 25 10 ---- ---- 140

I Tetra

Hydrofuran 250 225 ----- 20 5 ---- ---- --- 25

I Isopropyl

acetate 250 230 230 05 --- 16.30 --- --- 20

I Water 400 ----- ------ -------- 400 ---- --- --- 400

Table No. 4: - Matrix showing Molecular weight, Moles, molar ratio & consumption

The below figures of the respective raw material are representative of a batch.

Name of Key RM


Moles Molar Ratio


Proposed Consumption

Net Consumption

KOBT Reagent 112.3 40 0.356 --- --- --- --- KetoSulphone Raw

material 289.35 100 0.345 --- --- --- ---

Chloro compound

Raw material

306.62 115 0.375 --- --- --- ---

PTSA Reagent 172.30 100 0.580 --- --- --- --- Acetic acid Reagent 60 150 2.5 7.20 ---------- 150 150

THF Solvent ---- 230 ----- ----- ------------- 25 25 Toluene Solvent ---- 2800 ------ ------ ---------- 140 140

IPAC Solvent ---- 250 ------ ----- ---------- 25 25 Water Solvent --- 400 ------ ----- ----------- 400 400

Aq.Ammonia Reagent --- 370 ---- --- -------- 370 370


Key Raw materials are considered as they are involved building the desired molecule.



3. Name of the Product: Ethyl Triphenyl phosphonium Bromide

Qty/Month 10.00 MT.

Batch Output 135 kg

No of Batches/ Month 74

No of working days 25

Detailed Manufacturing Process-

Toluene is charged in a SS Reactor at ambient temperature. Triphenyl phosphine is charged

under stirring at ambient temperature. The reaction mass is heated to 40-50 °C and slowly ethyl

bromide is added in 4-5 hrs. After complete addition of ethyl bromide the reaction mass is stirred

for 12 hrs at 40-45°C. The temperature of the reaction mass is raised to 80°C and maintained for 20

hrs. The reaction mass is cooled to 20 °C and stirred for 3 hrs. The reaction mass is centrifuged and

washed with toluene, spin-dried and unloaded and dried at 50 °C to get dry Ethyl Triphenyl

phosphonium bromide.

Table No. 1:- Input ,Output and mass Balance.

Sr.No Input UOM Batch Qty

Output Qty Remark

1 Triphenyl Phosphine

kg 100 ETPPBr 135 Final Product

2

Toluene kg 150 Toluene 125.20 Recovered and used 3 Ethyl Bromide kg 42.50 Toluene 4.30 Distillation loss

4 -------------- kg -------- Distillation Residue

13. Used for II nd crop recovery

5 ------------------ kg ---------- Toluene 15 Product drying loss

Total kg 292.50 -------- 292.50 ----------------



P

+

Br

Mol.Wt 107

+

Toluene PH

Br

Triphenyl Phosphine

Mol.Wt 262

Ethyl Bromide Ethyl Triphenyl Phosphonium Bromide

Mol.Wt 371

Route of synthesis for Ethyl Triphenyl Phosponium Bromide

Process Flow Diagram-



Table No. 2:- Pollution load Ethyl Triphenyl phosphonium Bromide. Effluent in m3, rest all in kgs

Stage Effluent

Solvent Residue


Gas Generated

Inorganic Salt

Organic Residue

LCOD HCOD Name Qty

I ------- ------- 13 * ----- ----- ----- ---- ---- -------- ------ M ------ ------ 962.91 ---- ------ ------- ------ ----- -------- -------

D ------- ------- 38.516 ------- ----- ------- ----- ----- ------- -----

*-Solvent Residue is recycled for product recovery and hence not HW. M-Pollution Load per Month, D- Pollution Load per Day. No pressure or exothermic reaction or runaway reaction No gas is generated during the course of Reaction.

Table No.3:- Solvent Balance of Ethyl Triphenyl phosphonium Bromide

Sr.No/ Stage

Qty in Kg/Day Name of the

solvent

Solvent Used


Fugitive loss

To waste Water

Residue

Product drying

loss

Spent Solvent

Fresh Make

Up

I Toluene 444 370.59 ------ Nil 38.48 44.40 ------ 73.408

Table No. 4 :- Matrix showing Molecular weight, Moles, molar ratio and consumption


Name of Key

RM/Solvent

Details Mol.Wt

Qty kg

Moles

Molar

Ratio

Existing Consumptio

n

Proposed Consumptio

n

Net Consumptio

n Toluene Solvent ----- ------ ----- ---- -------- 24.80 24.80

Triphenyl Phosphine

Raw Material

162 100 0.381 1 ---------- 100 100

Ethyl Bromide

Raw material

108.97

42.50

0.390 1.023 ------------- 42.50 42.50

Note: -Solvents is in terms of volume and not based on mole ratio.


Other product details and manufacturing process is attached as an Annexure.



3.5 Plant Machinery and Equipment’s-

Item No. Description Capacity Number

A Mechanical

1. Stainless Steel Reactor 2 KL 1 2. Stainless Steel Reactor 3 KL 1 3. Glass Lined Jacketed Flange Type Reactor 2 KL 1 3.1 MS Glass lined double jacketedcondenser 6 SQM 1 3.2 MS Glass lined Unjacketed Column Section NA 1 4. Centrifuge SS 316 with control panel and VFD 36 inch 1 5. Tray Dryer 48 trays 1 6. Multimill 3HP Non-GMP Model with VFD NA 1 7. Scrubber NA 1 8. Steam boiler 600 kg/hr 1 9. Chimney NA 1 10. Vacuum pump NA 1 11. Cooling tower with FRP Basin 100 TR 1 12. Chilling plant 10 TR 1 13. Condenser 10 m2 1 14. Condenser 6 m2 2 15. Condenser 4 m2 1 16. Receiver 300 liter 1 17. Receiver 200 liter 1 18. Hammer Coated Receiver 100 liter 1 19. 150 NB Column NA 1 20. 200 NB Column NA 1 21. Pipe Line NA 1 22. Hydrogenator 500 lit 1 B Instrumentation

1. pH meter 0 -14 pH 1 2. TDS meter NA 1 3. Analytical balance 1 – 200 gm 1 4. Moisture balance NA 1 5. Balance 300 Kg 1

C Zero discharge liquid plant 250 lit/hr 1

3.6 Technology Selection

1. The technology of the products is developed by the promoters and well established andhence is

aware about the sensitive points that need careful attention in advance.

2. The products are produced using a novel & eco-friendly process.

3. The process is cost effective, safe and environment friendly.

4. Solvents used are recoverable, and are so recovered.

5. The conversion to desired product is 100 % and no side reaction takes place



3.7 Raw Material for finished Product

The basic raw material for these products details are given with all reactants, solvents and work up

support chemicals, collectively for the year.

Source for Raw Material Procurement: Raw Material is easily available in the local market; some

of the raw materials will be procured from the International Market.

Mode of Transport of Raw Materials: Few of the raw materials will be transported locally like

Nearby Aurangabad, Mumbai, Pune, Hyderabad etc. and few will be imported (if required) from the

International Market.

Storage at the site: Raw materials will be stored in Storage Yard at the project site.

3.8 Availability of Resources (Water, Energy/Power Requirement)

Power: The power requirement for proposed project is 150 KVA.

Water Requirement

Total water requirement for the project shall be 42 CMD and shall be provided by MIDC,

Paithan. The treated water shall be used for plantation. The total water balance for proposed

project is presented in the table below;

Table No.3.4 :- Detailed Water Balance

Sr.

No User source Input Loss

Effluent CMD Remark

LCOD HCOD

1. Steam Boiler 10 10 ---- ------ Condensate Recycled, Bolier

blow down to ETP

2. Softener Regeneration 2 --- 2 - TO ETP for treatment

3. Manufacturing Process 10.0 0.50 --- 9.50 Evaporation

4. Cooling Tower Process 5 4 1 ----- Evaporation loss,

5. Cooling Tower Vacuum

pump

0.50 0.50 ------ ------- ---

7. Vacuum Pump process 0.5 0.30 0.2 ------ ---

8. Q.C. Lab 0.5 0.1 0.2 0.2 ---

9. Utensil Washing 0.5 0.2 0..3 - ---

10. Machinery Washing 3 0.2 2.0 0.8 ---

11. Floor Cleaning 0.5 0.1 0.4 - ---

12. Centrifuge Bag Washing 0.5 0.1 0.4 - ---

13 Scrubber 2.0 0.50 1.5 ----- --------------------------------

14 Domestic 2 0.2 1.8 - To agriculture and gardening.

15. Gardening 5 5 ---- ------- For Green Belt

Total 42 21.70 9.80 42 ----------------

Total water consumption:/ CMD 42

Loss due to consumption and evaporation: 21.70

Domestic/CMD 1.80

Process / CMD 9.50 -LCOD, 1.0 HCOD



R&D Process/ CMD 0.2 - LCOD

Other / CMD 9.80 LCOD

Total Effluent / CMD 20.50

Manpower: During Operation Phase total man power available with industry is around 10 nos.

including skilled and non-skilled.

Fuel for Boiler: Capacity of proposed boiler is 0.6 MT /hr. (Fuel required – Coal/ Briquette/

Firewood)

DG Set: DG set of capacity 80 KVA is proposed and it is used as a standby.

3.9 Quantity of waste to be generated Non-Hazardous waste details-

Sr. No. Type of waste

Quantity Kg/month

Method of Disposal

1. Canteen waste 20 Kg/month Send to Authorised vendor 2. Packaging waste 30 Kg/month Send to Authorised vendor 3. Office waste 5 Kg/Month Send to Authorised vendor 4. Polythene bag 20 Kg/Month Send to Authorised vendor 5. Broken glass 5 Kg/ Month Send to Authorised vendor 6. Corrugated boxes 100Kg/ Month Send to Authorised vendor 7 M.S. scrap 100 Kg/Month Send to Authorised vendor 8. S.S. Scrap 150Kg/ Month Send to Authorised vendor 9. Boiler Ash 250 Kg/d Sell to brick manufacturing

unit Hazardous waste details -

Sr. No. Type of waste Category Quantity Kg/month

Method of Disposal

1. Off specification products 28.4 50.0 Regular Recycler /Cement Industry

2. Discarded containers Barrels, used for HW chemicals

33.1 200.0 Sale to authorised recycler

3. Spent oil/waste/process/residues containing oil etc

5.1/5.2 50.0

Sale to authorised recycler, re-processor /cement industry/ CHWTSDF

4. ETP Sludge 34.20 50.0 CHWTSDF 5. Manufacturing 28.1 20 CHWTSDF

6. Manufacturing- Spent solvent

28.6 168.0

Sale to authorised recycler, Re-processor, Cement industry



7. Solvent Residue 20.30 269.2 CHWTSDF 8. MEE Salt 34.20 50.0 CHWTSDF 9. Carbon/ Hyflow 28.3 24.96 CHWTSDF

Hazardous waste generation due to R&D product- i. Solvent residue 20.30 50.0 CHWTSDF ii. ETP sludge 34.20 20.0 CHWTSDF iii. Spent Solvent 28.6 50 CHWTSDF

3.10 Reuse/ Recycle/ Recovery Systems proposed along with Details

1. Sewage will be treated in septic tank followed by soak pit. Overflow of soak pit shall be used for

green belt.

2. The quantity of effluent generated will be treated in Effluent treatment plant, in following stages;

3. Low polluting stream effluent will be treated in ETP (involving Primary Treatment, 2 stages

Secondary Treatment and Tertiary Treatment) and will be used for landscaping

4. High polluting stream effluent will be treated in a system comprising of Solvent stripper, MEE.

5. The treated effluent shall be used for landscaping.



Chapter 04

Site Analysis

4.1 Connectivity

This project site is at A-106/1, MIDC Paithan Industrial Area, Village: Mudhalwadi, Taluka: Paithan,

Aurangabad, Maharashtra. Pin Code: 431148. It is well connected by road, railway and airport.

Nearest highway is SH-30. The site is 36.70 km from Aurangabad Airport and 37.6 km (aerial) from

Aurangabad Railway Station. The land and infrastructure are made available by MIDC. There is

good road connectivity to Aurangabad, Ahmednagar other cities by road network. The raw material

is easily available through the easy transport via road connectivity. With all this consideration, this

site was ranked first and adopted.

4.2 Land form, Land use and Land ownership:

The total plot area is 2499 sqm. The proposed project is located at Paithan, MIDC area. Landuse is

for industrial activity only and land ownership is on MIDC & taken by proponent.

Annexure Ishow the distance between project site and Jayakwadi Dam.

Land Form: Land is on plain contour, it is flat terrain.

Land Ownership: Land ownership is with project proponents.

Existing Land use Pattern: The Land is reserved for Industrial use.

Existing Infrastructure: Project site is having existing MIDC’s infrastructure such as road,water

supply, electricity etc.

4.3 Topography

Marathwada region comprising of eight districts, viz. Aurangabad, Beed, Hingoli, Jalna,Latur,

Nanded, Osmanabad and Parbhani. The location of Marathwada is on 70 5’ – 78 5’ E longitude and

17 5’ – 20 5’ N latitude form the part of the vast Deccan plateau all of India and is one of the six

divisions of Maharashtra State.

The total area of Marathwada region is of 64,813 km. and is bounded by the Vidarbha regionon the

North, by Andhra Pradesh on the East and Southeast, by Karnataka on the South and by Western

Maharashtra on the West. The entire region is situated at an average height of about 300-650 m.

above Mean Sea Level gradually sloping from West to East, and istraversed by hill ranges

origination from the Sahyadris in the West and the Satpudas in the North.



4.4 Soil Classification

The major part of the Aurangabad district is dominated by black cotton soil or ‘Regur’formed by the

weathering of Deccan Trap Basalt. It is rich in plant nutrients such as lime, magnesia, iron and

alkalies on which cotton and dry crops like Jowar, Bazra and tur etc.flourish. It swells and becomes

sticky on watering while on drying it contracts and develops many cracks. The soil varies both in

texture and depth. In northern portion of the district the soils are shallow and relatively poor while

in south they become deep and fairly rich in nutrients.

4.5 Climate data from secondary sources

Aurangabad has a semiarid climate under the Köppen climate classification.

Temperature: Annual mean temperature in Aurangabad range from 17 to 33 °C, with the most

comfortable time to visit in the winter October to February. The highest maximum temperature

ever recorded was 46 °C (114 °F) on 25 May 1905. The lowest recorded temperature was 2 °C (36

°F) on 2 February 1911. In the cold season, the district is sometimes affected by cold waves in

association with the eastward passage of western disturbances across north India, when the

minimum temperature may drop down to about 2 °C to 4 °C (35.6 °F to 39.2 °F).

Rainfall: Most of the rainfall occurs in the monsoon season from June to September.

Thunderstorms occur between November to April. Average annual rainfall is 710 mm. The city is

often cloudy during the monsoon season and the cloud cover may remain together for days. The

daily maximum temperature in the city often drops to around 22 °C due to the cloud cover and

heavy rains.

4.6 Social Infrastructure available

Many large- and small-scale industrial units have been established in MIDC is situated in

thecommand area of MudhalwadiGrampanchayat. There are facilitates for the workers to staynear

MIDC. Aurangabad airport is located 36.70km, State highway SH-30 from project site at 0.7 km,

Railway Station is Aurangabad Railway Station at 37.06 Km. Fire station, Hospitals, Police station,

Fire station & tourist place (Paithan) is at accessible distance from the project site.



Chapter 5

Planning Brief

5.1 Planning Concept

Proposed plant will be at M/s. Quantinental Pharmachem Pvt. Ltd., MIDC Paithan. All basic

infrastructure facilities will be provided to workers and office staff & also ensure the social

development work under its Corporate Social Responsibility (CSR). All statutory requirements will

befulfill before commissioning and while operation of the plant.

5.2 Facilities

This site is inside the existing MIDC and means safe transportation, less need of utilities, less

constructing buildings and roads, less fuel, less water with optimization of infrastructure.

Government MIDC has provided all infrastructures like electrical power, continuous water supply,

internal road network, external approach road, and networking.

5.3 Land use Planning

Land is already developed for Industrial purpose. Easting Area break-up are like fooling

Total area required: - 2499 Sq.Mt Built up area for Factory shed: - 243.04 Sq.Mt Built up area for storage: - 236.04 Sq.Mt Built up area for office: - 13.36 Sq.Mt Open Space for utility: - 65.73 Sq.Mt` Other : - Open Land 1940.83 Sq.Mt

5.4 Population Projection

Total 10 persons are required for proposed unit. Local people will be preferred for jobs based on

their educational qualification, experience and capabilities.



Chapter 6

Proposed Infrastructure

6.1 Industrial area

M/s Quantinental Pharmachem Private Limited “Proposed Active Pharmaceutical Ingredients

(APIs) and API Intermediates Manufacturing” is located is in Paithan MIDC.

6.2 Residential Area

No residential area has been proposed for the project. Facility will be provided for emergency

workers only, but no one will stay in the premises.

6.3 Green Belt

Industry proposed to develop nearly 1940 sqm for green belt development by planting various

types of trees and area has also been beautified with plantation of ornamental trees

6.4 Connectivity

As the proposed site is in Paithan MIDC, it is well connected through highway & internal roads. No

new roads are proposed.

6.5 Water Management:

The water requirement is about 85.5 m3/day for Domestic, cooling, boiler and greenery and

processes. The source of water is already available MIDC and the same is adequate and satisfactory.

Project proponent not encroaching on anybody’s water source.

6.6 Sewage System/ ETP

Sewage will be treated in septic tank followed by soak pit. Overflow of soak pit shall be used for

green belt

The quantity of effluent generated will be treated in Effluent treatment plant, in following stages;

Low polluting stream effluent will be treated in ETP (involving Primary Treatment, 2 stages

Secondary Treatment and Tertiary Treatment). Treated effluent will be used for landscaping.

High polluting stream effluent will be treated in a system comprising of Solvent stripper, MEE.

Treatment Scheme-

This plant has been designed as zero liquid discharge plant. The system has been designed as single

effect evaporation system with thermo Vapour compression.

This plant comprises of single effect evaporator along with efficient Vapour-liquid separation

system. Feed will be preheated & then will enter into Evaporator. Evaporator will be provided with

thermo Vapour compression system. Concentrated effluent shall be transferred from evaporator by

circulation cum transfer pump.



Vapors from vapor liquid separator will be sent to surface condenser. This condenser shall be

cooled by cooling water. Process Condensate from evaporator as well as surface condenser shall be

taken out from surface condenser by Process Condensate Pump. Condensate generated will be

treated in Reverse osmosis plant & can be reused in the system or for tree plantation purpose.

Concentrated effluent will be dried in agitated thin film dryer to dry it further & can be disposed

further.

The system will operate under vacuum. Vacuum will be applied by using water ring vacuum pump

to remove non-condensable from the system.

System will be supplied with required sufficient panel & automation.

6.7 Air Pollution

The air pollution is mainly from emissions of air pollutants from the boiler stacks and DG set. Very

little emission from fugitive sources is also predicted. Total power requirement for proposed plant

is 150 KVA which is sourced from Maharashtra State Electricity Distribution Company Limited

(MSEDCL). The other energy source is proposed solid fuel fired boiler of 0.6 MT/day. DG SET will be

80 KVA Capacity (fuel requires HSD) is used as a stand-by source of electricity. Cyclone dust

collector is proposed to combat the emissions from the boilers before releasing into atmosphere



through a stack. Very little emission from fugitive sources is also predicted. The stack heights

areprovided as per the guidelines of CPCB.

6.8 Solid Waste Management

The main solid waste from this factory will be (a) non-hazardous and (b) hazardous from process.

a. Non-hazardous waste:

Non-Hazardous waste details- Sr. No. Type of waste Quantity Kg/month 1. Canteen waste 20 Kg/month 2. Packaging waste 30 Kg/month 3. Office waste 5 Kg/Month 4. Polythene bag 20 Kg/Month 5. Broken glass 5 Kg/ Month 6. Corrugated boxes 100Kg/ Month 7 M.S. scrap 100 Kg/Month 8. S.S. Scrap 150Kg/ Month 9. Boiler Ash 250 Kg/d Nonhazardous waste will be segregated as recyclable/ saleable.

Waste minimization at all levels for discarded products, empty containers, packing, surplus,

unloading spillages and fugitives.

The plant will produce very less amount of scrap material. All these will however be stored

carefully on raised platform, with dwarf toe-walls all around and an overhead roof. The contents

will not be stored in the factory for more than a fortnight.

b. Hazardous Waste-

Sr. No. Type of waste Category Quantity Kg/month

Method of Disposal

1. Off specification products 28.4 50.0 Regular Recycler /Cement Industry

2. Discarded containers Barrels, used for HW chemicals

33.1 200.0 Sale to authorised recycler

3. Spent oil/waste/process/residues containing oil etc

5.1/5.2 50.0

Sale to authorised recycler, re-processor /cement industry/ CHWTSDF

4. ETP Sludge 34.20 50.0 CHWTSDF 5. Manufacturing 28.1 20 CHWTSDF

6. Manufacturing- Spent solvent

28.6 168.0 Sale to authorised recycler, Re-processor, Cement industry

7. Solvent Residue 20.30 269.2 CHWTSDF



8. MEE Salt 34.20 50.0 CHWTSDF 9. Carbon/ Hyflow 28.3 24.96 CHWTSDF

Hazardous waste generation due to R&D product- iv. Solvent residue 20.30 50.0 CHWTSDF v. ETP sludge 34.20 20.0 CHWTSDF vi. Spent Solvent 28.6 50 CHWTSDF

6.9 Power Requirement & Supply/ Source

Power requirement of proposed plant is 150 KVA and will be supplied by MSEDCL. DG set

of capacity 80 KVA is also proposed for emergency backup.



Chapter 07 Rehabilitation and Resettlement (R & R Plan)

7.1 Policy to be adopted

The project site is located in MIDC area, hence there is no any kind of activity of Rehabilitation and

Resettlement has to be carried out.



Chapter 08

Project Schedule & Cost Estimates

8.1 Time schedule of the Project

M/s Quantinental Pharmachem Pvt. Ltd. is wants to commence their project within 6 to 8

Months after getting all relevant permissions and clearances.

8.2 Estimated project cost

Estimated Project Cost for the project is 404.96 Lacs;

Table 8.1: Project cost

Sr. No. Fixed Assets Proposed Amount Rs. In Lakhs

1. Land and land development 25.09

2. Building premises 78.23 3. Plant & Machinery/Equipment 170.83

5. EMP Cost (including green belt) 94.5 6. CSR 10.00

7. Other 26.31 Total 404.96

Table 8.2 Environment Management Cost

Sr. No.

Description Capital Cost (Rs. in Lakhs)

Recurring Cost per annum (Rs. in Lakhs)

1. Air Pollution Control system 21.00 1.05 2. Water Pollution Control 65.0 4.0 3. Environment monitoring and Management 1.5 0.40 4. Rain water Harvesting 1.00 0.10 5. Occupational Health 1.00 0.20 6. Green Belt 1.00 0.82 7. Solid waste management 3.00 0.50 8. Energy Saving Devices and Solar Heating System 1.00 0.10 Total 94.5 7.17



Chapter 9

Analysis of Proposal

9.1 Financial and Social Benefits

M/s Quantinental Pharmachem Pvt. Ltd. will create direct & indirect employment opportunities

to the people residing at surrounding region. The management also trying to recruit the locals by

giving them in plant training and making them permanent employee.

Different types of people are being recruited based on the basic qualification as skilled, unskilled or

semiskilled.

Considering financial point of view, proposed project helps to generated Additional government

revenues from taxes, duties and other fees. Additional benefit of the project also includes

considerable growth of the industrial and commercial activities in the state.



Annexure I:

Wild life letter



Annexure-II

Google Image



Annexure-III

Toposheet Showing Location of Project Site from Jayakwadi Dam



Annexure-IV

Proposed Master Layout Plan



Annexure-VI MIDC

Layout



Annexure-V

Detailed Manufacturing Process of the remaining products

(Product No. 4 to Product No. 23)

4. NAME OF PRODUCT: FLUCONAZOLE

Brief description of the Process: -

Crude Fluconazole is charged in water and stirred to get a homogeneous solution. To this solution

30 % hydrochloric acid is added to get a clear solution at ambient temperature. Carbon and hyflow

is added and reaction mass is stirred for 10-20 minutes. The reaction mass is filtered to separate

carbon,hyflow. To the clear solution 25 % ammonia solution is added to precipitate Fluconazole.

The product formed is centrifuge and washed with water and spin dried. The wet product is dried

in tray dryer at 100 0c to dry and pure fluconazole.

Route of Synthesis

Crude Fluconazole

1. HCl, Ammonia Crabon, Hyflow

F

F

CH2

OH

H2C NN

N

NN

N

Fluconazole

Molecular Wt. 306.7

+ NH4CL + H20

Qty/Month 475.00kg.

Batch Output 475 kg





Process Flow diagram-

Table no. 1 :- Input and output and mass Balance


Crude FLC kg 583 Product 475 Pur Fluconazole

HCl 30 % kg 570 Aq.Effluent HCOD 6458

Ammonia 25% kg 372 Carbon 48 TO CHWTSDF

Carbon kg 48 Hyflow 19 TO CHWTSDF

Hyflow kg 19 Ammoium Chloride

292 Salt formed in the purification process

Water kg 5700 ------ ------- -------

Total kg 7292 Total 7292 ----------------

Table no. 2:- Pollution load. Effluent in M3, Rest all in Kgs

Stage Effluent in Lit

Solvent Residue

in kg

Carbon In kg

Hyflow In kg

Spent Solvent

In kg

Gas generated Qty kg

Inorganic Salt

In kg

Organic Residue In kg LCOD HCOD Name Qty

I

I ------ 6750 ----------- ------- ------- ----- Nil ----- --------- ---------

M ------ 6750 ---- 48 19 ------- ------ ----- 292* --- D ------ 270 ----- 1.92 0.76 ----- ---- --- 11.68 ------

* In Organic Salt is in effluent in dissolved state. No pressure or exothermic reaction. Toxic and hazardous raw materials Gas is generated during the process of purification or manufacturing process.



Table no. 3:- Solvent Balance of Fluconazole.

Sr.No/ Stage

Qty in Kg/Day Name of the solvent

Solvent Used


Fugitive loss

Distillation Process loss

To waste Water


Product drying loss

Spent Solvent

Fresh Make Up

I

Ammonia

Solution

372 --------- ------ ------- 372 ------- ----- ---- 372

Table no. 4 :- Matrix showing Molecular weight, Moles, molar ratio and consumption

Name of Key RM/ Solvent


Moles Molar Ratio


Proposed Consumptio

n

Net Consumption

Crude FLC

Raw material

30.6 583 0.524 1 ------- 583 583

Ammonia Reagent 17 93 5.40 10.10 -------------- 372 372 Wtaer Solvent ---- 5700 ---- ---- -------- 5700 5700

Note: - Solvents is in terms of volume and not based on mole ratio. Key Raw materials are considered as they are involved to build the desired molecule



5. Name of the Product- LINEZOLID

Qty/Month 94.00kg.

Batch Output 94 kg



Brief Manufacturing Process-

Crude Linezolid is charged in a SS Reactor having previously charged Isopropanol. The reaction

mixture is heated to 40-50 0c to get a clear solution. To the hot clear solution, carbon and hyflow is

charged and the reaction mixture is further heated to reflux temperature and maintained for 1-2

hrs. The hot reaction mass is filtered through sparkler pressure filter. The filtrate is collected in a

clean SS Reactor. Isopropanol is distilled to 50 % of input and then cooled to ambient and further

cooled to 0-5 0c and maintained for 1 hr. The reaction mass is centrifuged and spin dried. Wet pure

LINEZOLID is dried in tray dryer to get dry LINEZOLID. Mother liquor is recycled.

Table No 1:- Input and output and mass Balance


Crude Linezolid kg 100 Linezolid 94 Pure Linezolid

Isopropanol kg 300 Isopropanol 150 Rec and recycled

Carbon Kg 10 Carbon 10 To- CHWTSDF

Hyflow kg 5 Hyflow 5 To CHWTSDF

-------------- kg ------- Mother liquor 156 Recycled

Total kg 415 Total 415 --------------



Route of Synthesis

O

N

F NO

NHO

N-((3-(3-fluoro-4-morpholinophenyl)-2-methyleneoxazolidin-5-yl)methyl)acetamide

Mol.Wt 335.37

O

N

F NO

NHO

N-((3-(3-fluoro-4-morpholinophenyl)-2-methyleneoxazolidin-5-yl)methyl)acetamide

1. Isopropanol2. Carbon3.Hyflow

Mol.Wt 335.37

Crude Linezolid

Process Flow Diagram-



Table No 2:- Pollution load. Effluent in m3, Rest all figs in kg.


Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic

Residue

LCOD HCOD Name Qty

I ------ ------- ----- 10 05 ----- ------ ----- ------- --------

M ------- --------- ----- 10 05 ---- ----- ---- ---- ----

D -------- ------ ------- --0.40 0,20 ----- ----- ---- ----- -----------

M- Pollution load per month,D- Pollution load per day.

No gas is produced or generated during the reaction processing.

The reaction is not exothermic or run away or pressure.

No toxic raw material is used in manufacturing process of Linezolid.

6. Product Name- TELMISARTAN

Qty/Month 400.00kg.

Batch Output 100 kg




4- Methyl –Biphenyl -2 Craboxylate is charged in solvent Ethyleen di chlorided at ambient

temperature. The reaction mass is stirred and a solution od sodium carbonate is added at ambient.

To this reaction mass N-Bromo succinamide is added and reaction mass is stirred for 1-2 hrs and

settled.

The aqueous layer is separated and subjected for succinamide recover and let to ETP for treatment.

The EDC layer containing Bromo derivative is distilled under vacuum completely. The reaction

mass is cooled to ambient and Acetone is added to the reaction mass and stirred for 10-20 minutes.

To this reaction mass is added water, pottasium hydroxide, TBAB and Benzimidazole. The total

reaction mass is heated to reflux and maintained for 4-5 hrs till completion of reaction. The

completion of reaction mass is ensured on TLC. If the reaction is complete, the reaction mass is

cooled to ambient and centrifuge. The product is washed with water, spin dried and unloaded and

wet cake at this stage is used for next stage. The wet product is charged in methanol and NaOH



solution and heated to reflux and maintained for 2 hrs. Carbon is added and refluxed further for

20-30 minutes and filtered. The clear filtrate is added acetic acid to precipitate Telmisartan. The

reaction mass is cooled to ambient and then to 0-5 0c and centrifuged and washed with water to get

acid free, spin dried and unloaded. The wet cake is dried in Tray dryer to get dry TELMISARTAN.

Table No 1.:- Input and output and mass Balance


4-Methyl Bi Phenyl-

Carboxylate

kg 98 Telmisartan 100 Final Product

EDC kg 590 EDC 580 Recovered and recycle

Sodium Crabonate kg 15 EDC 10 Distillation loss

N-Bromo Siccinamdie kg 85 Succinamide 44.20 Recovered and sale

Acetone kg 200 Spent Ml-Acetone 850 Sale to Recycler

KOH kg 92 Spent Ml

Methanol

1164,80

Sale to Recycler

Benzimidazole kg 100 Carbon 4 To CHWTSDF

TBAB kg 10 Hyflow 2 To CHWTSDF

Methanol kg 900 Aq.Effluent LCOD 800 -To ETP for treatment

NaOH kg 36 Drying loss 40 Evaporation loss during

product drying operation

Carbon kg 4 -------------- ------ -----------------

Hyflow kg 2 ------------ ------- ----------------------

A cetic acid kg 125 --------------- ------ -------------------------

Water kg 1250 --------------- ------ -----------------------

Total kg 3595 Total 3595 ----------------------



Route of Synthesis

COOCH3EDC , NaHCO3

N Br

O

O

COOCH3

4-Methyl-Biphenyl-Carboxylate

Mol.Wt 226.27

1-bromopyrrolidine-2,5-dione

Mol.Wt 178

Br

Bromo Methyl Biphenyl Carboxylate

Mol.Wt 306

COOCH3

Br

Bromo Methyl Biphenyl Carboxylate

Mol.Wt 306

+N

N

NH

N

1-methyl-2-(4-methyl-2-propyl-1H-benzo[d]imidazol-6-yl)-1H-benzo[d]imidazole

Mol.Wt 304..39

1.Acetone, KOH,TBAB

2. methanol, NaOH, Carbon,Hyflow

3,Acetic acid,Water

N

N

N

N

HOOC

TELMISARTAN Mol.Wt 514.617

NH

O

O

+



Table No 2:-Pollution load. Effluent in m3, Rest all figs in kg.


Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas Generated

Inorganic

Salt

Organic

Residue LCOD HCOD Name Qty

I 0.800 ------ ----- 4 2 2014.80 ------ ----- ------- --------

M 3.200 ------- ----- 16 8 8059.20 ---- ----

D 0.128 ------- ----- ---- 322.37 ----- ---- ----- -----

M- Pollution load per month D- Pollution load per day.




Table No 2: -Solvent balance of Telmisartan

Sr.No/

Stage

Qty in Kg/Day

Name of

the

solvent

Qty

Used

Recovered

[Distilled]

Fugitive

loss

Distillation

Process

loss

To

waste

Water

Distillation

Residue

Product

drying

loss

Spent

Solvent

Fresh

Make

Up

I EDC 16 Nil Nil Nil 16 Nil Nil Nil 16

I Acetone 58.48 46.72 ------- 0.8 0.8 8 ----- ------ 1.12

Methanol 24 --------- 0.16 ------ 23.84 ---- --- ---- 24

Table No 3:- Matrix showing Molecular weight, Moles, molar ratio and consumption


Name of

Key RM

Details Mol.Wt Qty

kg

Moles Molar

Ratio


Proposed

Consumption

Net

Consumption

RM I Raw

material

226.37 98 0.434 1 ------------ 98 98

RM II Raw

material

304 100 0.329 0.75 -------------- 100 100



N-Bromo

Succinamide

Raw

material

178 85 .477 1.10 ------------ 85 85

EDC Solvent ---- 590 ----- ---- ------- 10 10

Acetone Solvent ----- 230 ----- ----- ------ 230 230

TBAB Catalyst 322 10 0.0310 0.07 ------- 10 10

KOH Reactant 56 92 1.64 3.785 ---------- 92 92

NaOH Recant

Methanol Solvent ----- 900 ---- ----- ------ 900 900



7. Product Name- TETRA BUTYL AMMONIUM BROMIDE

Qty/Month 130 Kg

Batch Output 130 kg



Brief manufacturing process-

Acetonitrile is charged in clean SS Reactor, followed by addition of N-Butyl Amine. The reaction

mass is stirred for 15-20 minutes and heated to reflux. N-Butyl Bromide is added slowly keeping

the temperature of the reaction mass to 65-70. The reflux is maintained for 36 hrs. Acetonitrile is

recovered completely under vacuum and Ethyl acetate is added to the reaction mass. The reaction

mass is cooled to 0-5 0c and centrifuged. The wet cake is washed with ethyl acetate. Mother liquor

is collected for recovery of ethyl acetate and recycling. Recovered Acetonitrile is stored and

recycled for next successive batches.



Route of Synthesis

Table No. 1 :- Input, output and Mass balance.

No Input Name UOM Qty Output name Qty Remark

1 Tri-n-Butyl Amine kg 100 Product TBAB 130 Product

2 N-Butyl Bromide kg 105 Acetonitrile/ N-

Butyl Bromide and

Tributyl amine

Mixture

80 Recovered and use

3 Acetonitrile kg 34 Acetonitrile 4 Distillation loss

4 Ethyl acetate kg 107 Ethyl acetate 91 Recovery and use

5 ---------------------- kg -------- Ethyl, acetate 6 Distillation loss

6 --------------------- kg ---- Product drying

loss

10 Drying Loss

--- ------------------ kg ----- Solvent Residue 25 CHWTSDF

--- Total kg 346 Total 346 ---------------

TBAB- Tetra Butyl Ammonium Bromide.



Process flow diagram-

Table No.2 :-Pollution load. Effluent in m3, rest all figs in kg.


Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic

Residue

LCOD HCOD Name Qty

I ------ ----- 25* Nil Nil --Nil-- Nil Nil Nil -------

M ------- ------ 25* Nil Nil Nil Nil Nil Nil ------

D -------- ------ 1.0* Nil Nil Nil Nil Nil Nil -------

* Solvent distillation residue is recycled as II nd crop and hence no HW



6. Toxic and hazardous raw material used 1. N- Butyl Amine and N-Butyl Bromide.



Table No.3 :- Solvent Balance of TBAB

Sr.No/

Stage

Qty in Kg/Day

Name of the

solvent

Solvent

Used

Recovered

[Distilled]

Fugitive

loss

To

waste

Water

Residue

Product

drying

loss

Spent

Solvent

Fresh

Make

Up

I Acetonitrile 34 12 ------ ------ 25 ----- ------ 22

I Ethyl acetate 107 91 ----- ----- 10 ----- 16

Table No. 4: - Matrix showing Molecular weight, Moles, molar ratio and consumption

The below figures of the respective raw material are representative of a batch. Name of Key

RM/Solvent

Details Mol.Wt Qty

kg

Moles Molar

Ratio

Existing

Consumption

Proposed

Consumption

Net

Consumption

Acetonitrile Solvnet ---- 34 ----- ---- -------- 22 22

Ethyl Acetate Solvent ---- -91 ----- ---- --------- 16 16

N-Butyl

amine

Raw

material

185.36 100 0.539 1 ------- 100 100

N-Butyl

Bromide

Raw

Material

137.02 105 0.766 1.421 -------- 105 105


Key Raw materials are considered as they are involved to build the desired molecule

.



8. Product Name- Glimepiride

Qty/Month 150.00kg. Batch Output 150 kg No of Batches/ Month 1 No of working days 25

Brief Description process: - Stage I

Stage I:- 3-Ethyl-4 methyl 1-H pyrazole and 2- Phenylethyl isocyanate, are condensed in

presence of methanol as solvent at high temperature. The resultant product as stage I is isolated by

centrifuging. The wet product is washed with methanol and spin dried. Mother liquor is recycled to

successive batches.

Route of synthesis Glimepiride stage I




Table No: - 1 Stage I:-Input, Output and Mass Balance.

Sr. No.


001 3-Ethyl-4 Methyl 2-Oxo Pyrroline

kg 70 Stage I product

130 Intermediate Glimepride

002 Phenyl Ethyl Ioscynate

kg 100 Methanol- 10 40

Distillation loss Ml recycled .

003 Methanol kg 160 Methanol 130 Recovery and use ----- -------------------- ----- ------ Methanol 20 Drying loss ----- Total kg 330- Total 330 -------------------- Stage I--- No pollution load. The reaction is dry fusion reaction and Mother Liquor is recycled

to next batch.

Brief Description of the process stage II and III-Chlorosulphonation and amidation.

Stage is I added in chlorosulphonic acid at low temperature. After complete addition, the

reaction mass is digested for 4-5 hrs and then quenched in ice water. The product is centrifuged

and washed with chilled water till the PH is neutral. The wet product is used for amidation stage.

Stage II is added in ethyl acetate in SS Reactor at ambient temperature. The reaction mass is stirred

for 20-30 minutes and slowly 20 % ammonia solution is added under stirring at ambient

temperature. After complete addition of the addition of ammonia solution, tye reaction mass is

stirred for 20-30 minutes. The reaction mass is centrifuged, the wet cake in centrifuge is washed

with water. The mother liquor is collected and ethyl acetate layer is separated. The aqueous layer is

send to ETP,ethyl acetate layer is subjected to distillation. Recovered ethylacetate is reuse. The

residue is discharged in close container and stored for HW disposal. The wet product is dried in

dryer. Dry product at stage III is further used for next stage.

Table No. 2:- Stage II/ III:-Input, Output and Mass Balance.

Sr.No Input UOM Qty Output Qty Remark 001 Stage I [Dry] kg 130 Product 146 Stage III product 002 Chlorosulphonic

acid kg 240 Aq.Effluent

HCOD PH 2 450 ETP for treatment

002 Ice Water kg 100 Ethyl acetate 100 Recovery and reuse 003 20 % Ammonia kg 577 Solvent Residue 18.80 HW Disposal 004 Ethyl acetate kg 105 Aq.Effluent

HCOD/HTDS 813.90 HCOD For Disposal,

Contains salts like Ammonium chloride and sulphate

005 water kg 295 Ethyl acetate 11.30 Solvent loss 006 Stage II kg 158 Water 65 Drying Loss ------ Total kg 1605 Total 1605 ---------------



Route of Synthesis Stage II/ III

1. Chlorosulphonic acid

2. Water

3. Ethyl acetate

4. 20 % Ammonia.

ClSO3H + H2O+ NH4OH----- NH4Cl+ [NH4]2SO4 + H20



Stage IV: Glimepiride Crude and Pure

Sulphonamide is condensed with Trans 4-Methyl Isocyanine in presence of Acetone and potassium

carbonate at reflux temperature. The resultant reaction mass is cooled and filtered on notch filter.

The wet solid is washed with acetone. The acetone washing and mother liquor is stored for further

processing. The wet product is charged in water and PH of the reaction mass adjusted to 7.0 with

acetic acid. The reaction mass is stirred at ambient and then centrifuged to get crude Glimepiride.

The crude is purified by using DMF and Methanol solvent.



Table No. 3:- Stage IV:-Input, Output and Mass Balance.

Sr. No


1 Sulphonamide Kg 146 Product 160 Crude Final Product 2 Acetone Lit 312 Acetone

Acetone 270 010

Recovery and reuse Distillation loss

3 Potassium Carbonate

Kg 146 Distillation Residue

05 HW Disposal

3 4-Methyl Isocyanate

Kg 76.47 Aq. Effluent HCOD

880.97 To ETP for treatment, contains Ammonium Acetate, acetone

4 Water kg 625 CO2 gas generation

60 Let to atmosphere

5 Acetic acid Kg 55.50 Methanol

425 Recovery and reuse

6 Methanol kg 625 Methanol 170 Spent solvent for sale

7 Carbon kg 7.00 Methanol 05 Distillation loss 8 Hylow kg 2.0 Hyfow 2 HW for disposal 9 ------------------ kg ----- Carbon 7 HW disposal ------ --------------------- kg --------- Methanol 25 Drying loss Total kg 1994.97 Total 1994.97



Stage V- Purification.

Brief Description of manufacturing process of purification

The crude Glimepiride is charged in DM/ Methanol mixture and heated to 80-90 0c to geta clear

solution. To this clear solution is added carbon and stirred for 20-30 minutes. The hot reaction

mass is filtered through filter to separate the carbon and filtrate is collected in clean Reactor. DMF

and methanol is distilled and recycled. The Reaction is cooled to ambient and water is added to the

reaction mass and stirred. To the water solution is added DIPA, stirred and separated. DIPA solvent



is sold to authorized recycler. MIBK is added, stirred and settled. The aq layer is separated and

sends to ETP for treatment. The MIBK layer is distilled to recover and recycle. The reaction mass is

cooled and centrifuged and spin dried. The wet cake from centrifuge is dried in tray dryer to get

pure Glimepiride. Centrifuge Ml is send to CHWTSDF as HW.

Table No. 4:- Input, output and mass Balance.

Sr.No Input UOM Qty Output Qty Remark 001 Stage IV GLP Crude Kg 160 Product 150 Pure Glimepride 002 DMF kg 2080 DMF 2000 Rec and Reused 003 Activated Carbon kg 16 DMF 70 Along with Effluent 004 Water kg 320 DMF 10 Process Loss 005 Methanol kg 480 Methanol 400 Rec and reused 006 MIBK kg 640 Methanol 65 Process Loss 007 Di Isopropyl Ether kg 60 Methanol 15 In aq Effluent 008 --------------- kg ---- Carbon 16 To CHWTSDF 009 ----------------- Kg ----- MIBK

MIBK MBK

518 100 20

Recover and Recycle Liquid spent as HW Drying Loss

010 ------------------ kg ----- Di Isopropyl Ether

58 To sale to Recycler

----- ---------------- Kg ---- MIBK 2 Process Loss kg ---- Di Isopropyl

Ether 2 Process Loss

kg ---- Aq. Effluent-HCOD

330 To ETP for Treatment

----- Total kg 3756 Total 3756 -----------

ROUTE of Synthesis Stage V

N

O

NH

OS

NH

O

O

NH

O

CH3

Glimeperide Crude

1. DMF/Methanol2.Carbon3.Water4.DIPE5.MIBK

N

O

NH

OS

NH

O

O

NH

O

CH3

Pure GLP Mol Wt 490



Table No.5 :- Cumulative pollution load. [Per day] of Stage I, II, III, IV and V Effluent in m3, rest all in kgs.

Stage Effluent in m3

Solvent Residue


Gas Generated

Inorganic Salt

Organic Residue

LCOD HCOD Name Qty

I ----- -------- ---------- ------ -------- ----- --------- ----- ------- ------

II / III

------- 1.263 18.80 ------- -------- ------- ------ ----- ---------- ------

IV ------ 0.880 05 7 2 ----- CO2 55.50 ------- -----

V ---- 0.330 ----- 16 ---- 100 ---- --- --- ----

M --- 2.473 23.80 23 2 100 CO2 55.50 -------- --------

D ---- 0.0989 0.952 0.92 0.08 4.0 CO2 2.22 -------- -------

M- Pollution load per month.

D- Pollution load per month

Table No. 6:- Solvent Balance of Glimepiride

Sr.No/ Stage

Qty in Kg/Day/Month Name of the solvent

Solvent Used


Fugitive loss

Distillation Process loss

To waste Water


Product drying loss

Spent Solvent

Fresh Make Up

I Methanol 1265 955 --- --- --- --- --- --- 310

II Ethyl Acetate

105 100 ----- 2 3- -18.80 ----- ---- 5

II Water 1340 ---- ----- ---- 1275 ----- 65 ---- 1340

III Acetone 312 270 ----- 10 ------ 5 ---- ----- 42

V DMF 2080 2000 80

VI DIPE 60 58 ---- 2 ---- ---- ---- ---- 2

VII MIBK 640 518 ---- 2 ----- 100 20 ----- 120

DIPE- DI ISOPROYL ETHER,DMF –DIMETHYL FORMAMIDE, MIBK- METHYL ISOBUTYL KETONE



Table No.7:- Matrix showing Molecular weight, Moles , molar ratio and consumption.

Name of Key

RM/Solvent

Details

Mol.Wt

Qty kg

Moles

Molar

Ratio

Existing Consumpti

on

Proposed Consumpti

on

Net Consumpti

on

Pyrroline Raw materi

al

125 70 0.56 1 --------- -70 70

Phenyl Isocynate

Raw materi

al

147 100 0.68 1.21 ------------ 100 100

Chlorosulphonic acid

Raw materi

al

116.50

240 2.06 1 ------------- 240 240

Ammonia Reagent

17 144.25

--8.48

4.11 ----------- 577 577

Potassium Carbonate

Reagent

138 146 1.05 1 --------- -146 146

Trans-4 Methyl Cyclohexylisocy

nate

Raw materi

al

139 76.47 0.50 0.50- --------- 76.47 76.47

Acetic acid Reagent

---- 55.50 ---- ---- ---------- 55.50 55.50

Methanol Solvent

------ 1265 -------

----- --------- 310 310

Acetone Solvent

----- 312 ----- ---- -------- 42 42

DIPE Solvent

---- 60 ----- --- ----- 60 60

MIBK Solvent

----- 640 ------ ---- ----------- 120 120

Water Solvent

---- 1340 ----- ---- ------- 1340 1340

DMF Solvent

------ 2080 ------ ---- ----- 80 80





9. Name of the Product- TRI-O- Phenyl phosphine

Qty/Month 2 MT.

Batch Output 166 kg



No of Batches/day 0.480


Ochloro Toluene is reacted with Magnesium metal in the presence of THF. The Grignard reagent so

prepared is treated with Phosphorus Tri Chloride in toluene. The resultant reaction mass is

quenched in acid water. To the reaction mass is stirred and settled. The aq layer and organic layer is

separated and washed with alike water. The solvent component containing product is treated with

carbon and filtered. The filtrate is subjected for complete solvent recovery. Isopropanol is added

and reaction mass is cooled and chilled and centrifuge to get wet TOTP, which on drying in tray

dryer gives dry TOTP. The distillate is treated with ferrous sulphate and alkali for Toluene and THF

recovery. The Recovered Toluene and THF are recycled. Solvent distillation Residue

Table No 1 :- Input and output and mass Balance for a Batch


Ortho Chloro Toluene kg 347 TOTP 166

Tetra Hydro Furan kg 69.50 THF 47 Recovered and recycled

Magnesium kg 59 Toluene 38 Recovered and recycled

Toluene kg 43 THF 5 Process Loss

Phosphorus Tri Chloride kg 114.60 Toluene 3 Process Loss

Water kg 500 Aq.Effluent PH-2 HCOD

742.50 To ETP for Treatment Contains Magnesium Chloride, Sodium Chloride

HCl 30 % kg 66 Solvent Residue 250 To CHWTSDF

Sodium Chloride kg 60.80 Carbon 10.50 To CHWTSDF

NaOH flakes kg 12 Isopropanol 80 Ml for II nd crop

Ferrous Sulphate kg 1.60 Isopropanol 2 Process Evaporation loss

Isopropyl Alcohol kg 70 Drying loss 10 Evaporation loss

Activated Carbon kg 10.50 --------------- ----- ------------------------

Total kg Total 1354 ----------------------



Rout of Synthesis for Tri O- Phenyl Phosphine

CH3

Teytra Hydro FuranCl

1-chloro-2-methylbenzene

Mol.Wt 126.58

+ Mg.

CH3

MgCl

Grignard Reagent

CH3

MgClToluene/PCl3

Water/HCl

Isopropanol

P

trio-tolylphosphine

Mol.Wt 304.17



Table No. 2:- Pollution load. Effluent in m3, Rest all figs are in kg Stage Effluent in lit

Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic

Residue

LCOD HCOD Name Qty

I ----- 742.50 250 12.50 ------- ----- ------ ----- ------- 80

M 8910 -3000 150 ----- ---- ----- ---- ---- 960

D 356.40 120 6.0 ---- ----- ----- ---- ----- 38.40

Organic Residue as Mother Liquor is recycled. M- Pollution load per month, D- Pollution load per day.




Table No. 3 :- Solvent Balance of Tri-O- phenyl Phosphine.

Sr.No/

Stage

Qty in Kg/Day

Name of

the solvent

Qty

Used

Recovered

[Distilled]

Fugitive

loss

Distillation

Process

loss

To

waste

Water

Distillation

Residue

Product

drying

loss

Spent

Solvent

Fresh

Make

Up

I THF 59 47 --- 5 7 ---- --- -- 17

2 Toluene 43 38 --- 3 2 250 ---- --- 5

3 Isopropanol 70 * ------- ----- 2 ---- ---- ---- --- ------

*-Isopropanol Ml is recycled for recovery of II nd crop.





Name of

Key RM

Details Mol.

Wt

Qty kg Moles Molar

Ratio

Existing

Consumption

Proposed

Consumption

Net

Consumption

O Chloro

Toluene

Raw

material

126.58 347 2.741 1 ----------- 347 347

Magnesium Reagent 59 24 2.458 0..89 ---------- 59 59

PCl3 Raw

material

137.34 114.60 0.830 0.30 ---------- 114.60 114.60

NaoH Reagent ----- 12.50 ---- ---- ----- 12.50 12.50

Ferrois

Sulphate

Regent ----- 1.60 ------ --- ---- 1.60 1.60

Isopropanol Solvent ------ 70 ---- --- ------- 70 70

Toluene Solvent ----- 43 ----- ---- ----- 5 5

Note: - Solvents is in terms of volume and not based on mole ratio


10. Product Name- Cilnidipine Qty/Month 150.00kg.

Batch Output 30 kg




2- Methoxyethyl 3-Oxybutanone is condensed with 3-Nitrobenzaldehyde in presence of

ammonium carbonate and methanol as solvent, The reaction mass is refluxed for 2-6 hrs,

till the reaction is complete. The reaction mass is cooled to ambient and further cooled to

0-5 °c and centrifuged, washed with chilled methanol to get stage I as 2-Methoxy 3-amino-



2-enolate. The product is unloaded and dried in tray dryer to get dry stage I. Output 10.50

kg.

Route of synthesis Cilnidipine Stage I

+ Ammonium carbonate

Mol Wt 96.09

+

METHANOL

O

O

O

O

2-methoxyethyl 3-oxobutanoate

NH2

O

O

O

Mol.Wt 160.17

(Z)-2-methoxyethyl 3-aminobut-2-enoate

Mol.Wt 159.18

+ +2H2O NH3 + CO2

Mol.Wt 18 Mol.Wt 17 Mol.Wt 44

Table No 1:- Input and output and mass balance


RM I kg 11.0 Stage I 10.50 Stage I-Product

Methanol kg 150 Water 1.18 Water formed in the Reaction.

Ammonium Carbonate kg 6.30 CO2 2.90 Let to air

Ammonia 1.12 Let to Scrubber

Methanol 120 Rec and Recycled

Methanol 05 Process Loss

Solvent Residue

21.60 Send to CHWTSDF

------------------------- ------

----- Methanol 05 Drying loss

Total kg 167.30 Total 167.30 ------------------

RM I- 2-Mmethoxyethyl -3-oxybutanonoate,



Table No. 2:-Pollution load. Effluent in m3, Rest all figs in kg.


Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic


I ------ ------- 21.60 ------ ------- ----- CO2

NH3

2.90

1.12

------- -------

M ------- ------- 944.50 ----- ----- ---- CO2

NH3

14.50

5.66-

---- -------

D -------- ------ 37.78 ----- ---- ----- CO2

NH3

0.58

0.226

----- -----


1. NH3 and CO2 gas is generated during the reaction process. NHE is connected to

scrubber, while CO2 is left to air.


3. Toxic and hazardous raw material used- Nil



Table No. 3:- Solvent Balance of Stage I of Cilnidipine

Sr.

No/

Stage

Qty in Kg/Day

Name of

the

solvent

Qty

Used

Recovered

[Distilled]

Fugitive

loss

Distillation

Process

loss

To

waste

Water

Distillation

Residue

Product

drying

loss

Spent

Solvent

Fresh

Make

Up

I Methanol 30 24 Nil 1.0 --- Nil Nil Nil 6.0

Brief Manufacturing Process for Cilnidipine Stage II

Cinnamyl -3-oxobutanoate is condensed with 3-Nitro Bnezaldehyde in methanol. After reaction

completion, piperidine and 2-Methoxy ethanol is added and reaction mass is heated to reflux for 4-

5 hrs. The completion of the reaction is monitored on TLC. After completion of the reaction, the

reaction mass is cooled to ambient and water is added.

Acetic acid is added to neutral the reaction mass. The product formed is centrifuged and washed

with water, spin dried and unloaded. The wet product is dried in tray dryer to get dry CILNIDIPINE.



Route of Synthesis for Stage II-

Cilnidipine.

NH2

O

O

O

(Z)-2-methoxyethyl 3-aminobut-2-enoate

Mol.Wt 159.18

O

O O

cinnamyl 3-oxobutanoate

Mol.Wt 218.25

+

NO2

Methanol

CHO

NO2

O O

O

(2E)-cinnamyl 2-(3-nitrobenzylidene)-3-oxobutanoate

Mol.Wt-351.35

1. Piperdinne

2. Water

3.Acetic acid

NH

O2N

O

O

O

O

cinnamyl 5-(1-(2-methoxyethoxy)vinyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylate

Mol Wt 490.21



Table No. 3:- Batch Input and output and mass balance

nput UOM Qty Output Qty Remark

RM I kg 14 Stage II 30 Final Product

RMII kg 9.69 Water 10 Drying Loss

Methanol kg 100 Spent Solvent

241.20 Sale to Recycler

Piperdine kg 5 ------- ------- ------------------

RMIII kg 10.50 ------------ ------- ------------------

Acetic acid kg 5 ------- -------- ------------------

Water kg 100 ---------- ------- -------

Total kg 224.10 Total 224.10 -------------------

Table No. 4 :-Pollution load of Stage II of Cilnidipine. Effluent in m3, Rest all figs in kg.


Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic

Residue

LCOD HCOD Name Qty

I ------ ------- ----- ------ ------- 214.1 ----- ----- ------- -------

M ------- ------- ------ ----- ----- 1070.50 ------ ----- ---- -------

D -------- ------ -------- ----- ---- 42.82 ------- ----- ----- -----



Table No. 5 :-Solvent Balance of STAGE II of Cilnidipine

Sr.N

o/

Stag

e

Qty in Kg/Day

Name

of the

solven

t

Qty

Use

d

Recover

ed

[Distille

d]

Fugiti

ve

loss

Distillati

on

Process

loss

To

wast

e

Wat

er

Distillati

on

Residue

Produ

ct

dryin

g loss

Spent

Solve

nt

Fres

h

Mak

e Up

I

Methan

ol

20 ---------- Nil ----- ---- Nil Nil Nil 20

No solvent recovery, Mother liquor sale to recycler as spent solvent



Name of

Key RM

Deatils Mol.Wt Qty

kg

Moles Molar

Ratio

Existing

Consumption

Proposed

Consumption

Net

Consumption

RM1 Raw

Material

160.17 11 0.0685 1 ------- 11 11

RMII Raw

Material

218.25 14 0.0641 1 ------------ 14 14

RMII Raw

Material

153.12 9.69 0.0632 0.98 ---------- 9.69 9.69

Ammonium

Carbonate

Reagent 96 6.30 0.0656 0.95 --------------- 6.30 6.30

Methanol Solvent ------ 100 ---- --- --------- 100 100

Note: - Solvnets is in terms of volume and not based on mole ratio.




11. Product Name- Triclabendazole Qty/Month 80.00kg.

Batch Output 16 kg



Brief Manufacturing Process

3,4-Dichloro Aniline is reacted with Acetic anhydride,the acetylated product is further nitrated in

the presence of Nitric and sulphuric acid to get 3,4-Dichloro-2-Nitro phenyl acetamide. The

reaction is carried out in solvent EDC [ Ethylene di chloride]

Route of Synthesis Triclabendazole Stage-I

NH2Cl

Cl

+ [CH3CO]2 O

3,4-Dichloro Aniline

Mol.Wt---162.02

Acetic anhydride

Mol.Wt--102.

NHCOCH3Cl

Cl

+

N-(3,4-dichlorophenyl)acetamide

Mol.Wt-204

NHCOCH3Cl

Cl

N-(3,4-dichlorophenyl)acetamide

Mol.Wt-204

NHCOCH3Cl

Cl NO2

N-(4,5-dichloro-2-nitrophenyl)acetamide

Mol.Wt-249

HNO3/ H2SO4

EDC/ Water



Table No. 1:- Input and output and mass Balance Stage I Triclabendazole


3,4- Dichloro Aniline kg 10.50 Stage I 14.30 Product for next stage

Acetic anhydride kg 6.50 EDC 96 Rec and used

HNO3 Kg 4.0 EDC 0.80 Distillation loss

Sulphuric acid kg 10 Carbon Di Oxide gas

4.50 Let to air

Ethylene di chloride Kg 100 EDC 5.2 Distillation Residue

Soda Ash kg 10.80 Aq.Effleunt HCOD

421 To ETP for treatment Contains Sodium

Sulphate and acetic acid

Water kg 400 --------- ---- --------

Total kg 541.80 Total 541.80 ------------------



Table No. 2:-Pollution load. Effluent in m3, Rest all figs in kg Stage I Triclabendazole.


Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic

Residue

LCOD HCOD Name Qty

I ------ 0.421 5.20 ------ ------- ----- CO2 4.5 ------- -------

M --- 2.105 26 ---- ---- --- CO2 22.50 ---- -----

D ----- 0.0842 1.04 ----- ----- ----- CO2 0.90 ------ -----

Table No. 3:- Solvent Balance Stage I Triclabendazole

Sr.No/

Stage

Qty in Kg/Day

Name

of the

solvent

Qty

Used

Recovered

[Distilled]

Fugitive

loss

Distillation

Process

loss

To

waste

Water

Distillation

Residue

Product

drying

loss

Spent

Solvent

Fresh

Make

Up

I EDC 50 46 ---- 0.16 --- 1.04 Nil Nil 4.0

I Water 200 ---- ---- ----- 200 --- --- --- 200

Table No. 4: Matrix showing Molecular weight, Moles, molar ratio and consumption of Stage I

Triclabendazole


Name of

Key RM

Details Mol.

Wt

Qty

kg

Moles Molar

Ratio

Existing

Consumption

Proposed

Consumption

Net

Consumption

3,4-

Dichloro

Aniline

Raw

material

162.02 10.3 0.0635 1 ------ 10.30 10.30

Acetic

anhydride

Raw

material

102 6.50 0.0637 1 ------ 6.50 6.50

HNO3 Raw

material

63 4.0 0.0634 0.99 -------- 4 4

H2SO4 Raw

material

98 10 0.102 1.60 80 10 10



Soda Ash Reagent 106 10.80 0.10 0.99 ----- 10..0 10.80

Water Solvent --- 400 --- --- ---- 400 400

EDC Solvent ------ 100 ----- ------ ------ 100 100

Brief Process Description for stage II Triclabendazole

2, 3-Dichloro phenol is condensed with Stage I, in presence of potassium Carbonate, solvent DMSO

and Toluene. The reaction completion is ensured on TLC, after completion of the reaction, water is

added to the reaction. Sodium hydroxide flakes are added and the reaction mass is heated to 50 0c

and maintain for 2 hrs. After temperature maintaining, the reaction mass is cooled to ambient. The

product is centrifuged and washed with water till neutral PH, spin dried and unloaded. The wet

product is used for next stage as such. The Ml is settled and toluene is separated, distilled to get

Rec.Toluene, The residue left over is unloaded and send to CHWTSDF for disposal, The Aq .Effluent

containing the salts like KCl and NaCl is send to ETP for treatment.



Route of Synthesis

Cl

Cl

NH

NO2

O

N-(4,5-dichloro-2-nitrophenyl)acetamide

+

2,3-dichlorophenol

Mol.Wt 240 Mol.Wt-163

Cl

Cl

OH

Cl NO2

NH

O

O

ClCl

N-(5-(2,3-dichlorophenoxy)-4-chloro-2-nitrophenyl)acetamide

Mol.Wt 375

Cl NO2

NH

O

O

ClCl

NaOH , Toluene, Water

1.DMSO

2.K2CO3

N-(5-(2,3-dichlorophenoxy)-4-chloro-2-nitrophenyl)acetamide

Mol.Wt 375



Table No 5:- Input and output and mass Balance Stage II Triclabendazole


Stage I kg 14.30 Stage II 18 Used for stage III

2,3-Dichloro Phenol kg 9.40 Aq .Effluent

HCOD

845.10 To ETP for treatments contains DMSO, SODIUM Chloride, and unreacted

organics

Sodium Hydroxide kg 4.4 Toluene 144 Rec and used

Toluene kg 150 Toluene 1.20 Distillation Loss

Dimethyl sulphoxide kg 30 Solvent Residue 4.80 TO CHWTSDF disposal

Pottasium Carbonate kg 5 ------ ----- ----------

Water kg 800 ----- ---- ---------

Total kg 1013.10 Total 1013.10 -------------------------

Process Flow Diagram for Stage II- Triclabendazole



Table No. 6:-Pollution load. Effluent in m3, Rest all figs in kg Stage II Triclabendazole.


Solvent Residue


Gas Generated

Inorganic Salt

Organic Residue

LCOD HCOD Name Qty

I ------ 0.845.10 4.80 ---- ---- --- --- --- ------- ------- M --- 4.225.50 24 ----- ---- ---- --- --- ---- -----

D ----- 0.169 0.96 ----- ----- ---- ---- --- ------ -----

Table No. 7:- Solvent Balance of Stage II- Triclabendazole

Sr.No/

Stage

Qty in Kg/Day

Name of the solvent

Qty

Used

Recovered

[Distilled]

Fugitive loss

Distillation

Process loss

To waste

Water

Distillation

Residue

Product drying loss

Spent

Solvent

Fresh Make Up

II DMSO 6 ------ ---- ----- --- ---- Nil Nil 6

II Toluene 30 28.80 0.24 --- ---- 0.96 --- -- 1.20

Table No. 8: -Matrix showing Molecular weight, Moles, molar ratio and Consumption Stage II

Triclabendazole.


Name of

Key RM

Details Mol.Wt Qty

kg

Moles Molar

Ratio

Existing

Consumption

Proposed

Consumption

Net

Consumption

Stage I Raw

material

249 14.30 0.057 1 -------------- 14.30 14.30

2.3-

Dichloro

Phenol

Raw

material

163 9.40 0.057 1 ---------- 9.40 9.40

DMSO Solvent ----- 30 ---- --- ---- 30 30

K2CO3 reagent 139 5 0.036 0.63 ----------- 5 5

NaOH

flakes

Regent 40 4.40 0.11 1.92 -------- 4.4 4.4

Water Solvent ----- 800 ----- --- ------ 800 800



Route of Synthesis for Stage III/IV –Triclabendazole

Cl

Cl

O

Cl

NH2

NO2

5-(2,3-dichlorophenoxy)-4-chloro-2-nitrobenzenamine

Mol.Wt-333

Cl

Cl

O

Cl

NH2

NH2

4-(2,3-dichlorophenoxy)-5-chlorobenzene-1,2-diamine

Cl

Cl

O

Cl

N

N

S

H

Methanol/Raney Ni

Cl

Cl

O

Cl

N

N

SH

H

5-(2,3-dichlorophenoxy)-6-chloro-1H-benzo[d]imidazole-2-thiol

Water/ KOH / CS2

5-(2,3-dichlorophenoxy)-6-chloro-2-(methylthio)-1H-benzo[d]imidazole

Mol. Wt--359

DMS/Methanol

Water

Brief Process Description of Stage III/IV-Triclabendazole

Stage II is hydrogenated in presence of methanol and Raney Ni as catalyst at 40-50 °c. After

complete hydrogenation, the reaction mass is filtered and transferred to another reactor. Methanol

is distilled to half of the volume and cooled to ambient. Potassium Hydroxide flakes is added,

followed by slow addition of carbon di sulphide at ambient temperature. After complete addition of

CS2, the reaction mass temperature is raised to 50 °c and maintained for 3-4 hrs till completion of

the reaction, monitored on TLC. If the reaction is complete .methanol is distilled and water is added

to the reaction mass, stirred for ½ hr and centrifuged to get stage III. The wet material is charged to

another reactor in methanol and dimethyl sulphate is added at ambient .The reaction mass is

stirred for 2 hrs till reaction completion and centrifuged, washed with methanol, spin dried and

unloaded. The wet Triclabendazole is dried in tray dryer to get dry Triclabendazole.



Table No. 9:- Input and output and mass Balance of Stage- III Triclabendazole

Input UOM Qty Output Qty Remark Stage II Kg 17.60 Stage III 18 Used for next stage

Methanol Kg 54 Raney Ni 2 Recovered and recycle

Raney Ni 50% wet Kg 2 Methanol 25 Recovered and recycle

Carbon di sulphide Kg 4.0 Aq.Effluent HCOD


Potassium Hydroxide Kg 5.0 Hydrogen* 2M3 Excess released to air through water.

Water kg 400 -------- ---- ----------

Hydrogen Gas M3 21

Total kg 482.60 Total 482.60 -------------------

*- Hydrogen gas is not included in mass balance.



Table No. 10:- Pollution load Stage- III Triclabendazole. Effluent in m3, Rest all figs in kg


Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas Generated

Inorganic

Salt

Organic

Residue

LCOD HCOD Name Qty

III ------ -

0.4476

------ ---- ----- ----- H2 2m3 ------- -------

M ------- -2,238 ------- ---- ---- ----- H2 10 m3 ---- -------

D -------- 0.088 ----- ---- ---- ------ H2 0.4m3 ----- -----


Table No.11:- Solvent Balance of Stage- III Triclabendazole

Sr.No/

Stage

Qty in Kg/Day

Name of

the

solvent

Qty

Used

Recovered

[Distilled]

Fugitive

loss

Distillation

Process

loss

To

waste

Water

Distillation

Residue

Product

drying

loss

Spent

Solvent

Fresh

Make

Up

I Methanol 10.80 5.0 Nil --------- ----- Nil Nil Nil 8.64

Table No. 12 :- Matrix showing Molecular weight, Moles, molar ratio and Consumption of

Stage- III Triclabendazole


Name of

Key RM

Details Mol.Wt Qty

kg

Moles Molar

Ratio

Existing

Consumption

Proposed

Consumption

Net

Consumption

Stage II Raw material

332 17.60 0.0530 1 --------- 17.60 17.60

Methanol Solvent ----- 54 ---- ---- --- 29 29

Raney No Catalyst --- 2 ---- ---- --- 00 00

Water Solvent --- 400 --- --- --- 400 400

KOH Reagent 56 4 0.071 1.30 ------- 4 4

CS2 Reactant 76 5 0.065 1.03 ------- 5 5



Note:- Solvent is in terms of volume and not based on mole ratio.


Brief Process Description for Stage IV Triclabendazole:-

Triclabendazole stage III is charged in methanol and cooled to ambient. To the reaction mass is

added dimethyl sulphate at ambient. The reaction mass is stirred till reaction is complete.

Completion of reaction mass is ensured on TLC. Water is added after completion of the reaction and

pH of the reaction mass is adjusted with liquor ammonia. The reaction mass is centrifuged and

washed with water till pH-7, spin dried and unloaded. The wet Triclabendazole is dried in Tray

dryer to get dry Triclabendazole.



Table No. 13:- Batch Input and output and mass Balance of Stage IV Triclabendazole


Stage III kg 16.90 Product stage IV

16.70 Triclabendazole

Methanol kg 54 Water 15 Drying Evaporation loss

Dimethyl Sulphate kg 6.20 Aq.Effluent 550.40 To ETP for treatment

Water kg 500

Aq.Ammonia kg 5

Total kg 582.10 Total 582.10 -------------------

Table No. 14:-Pollution load of Stage IV Triclabendazole. Effluent in m3, Rest all figs in kg.


Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic


I ------ 0.550 ----- ------ ------- ----- ----- ------- -------

M ------- 2.750 ------ ----- ----- ------ ----- ---- -------

D -------- 0.11 -------- ----- ---- ------- ----- ----- -----

Table No. 15:- Solvent Balance of Stage IV Triclabendazole

Sr.No/

Stage

Qty in Kg/Day

Name of

the

solvent

Qty

Used

Recovered

[Distilled]

Fugitive

loss

Distillation

Process

loss

To

waste

Water

Distillation

Residue

Product

drying

loss

Spent

Solvent

Fresh

Make

Up

I Methanol 10.80 ---------- Nil ----- ---- Nil Nil Nil 10.80



Table No. 16 :- Matrix showing Molecular weight, Moles, molar ratio and Consumption of

Stage IV Triclabendazole,


Name of

Key RM

Details Mol.W

t

Qty

kg

Mole

s

Mola

r

Ratio

Existing

Consumptio

n

Proposed

Consumptio

n

Net

Consumptio

n

Stage III Reactan

t

345 16.9

0

0.048 1.0 ------- 16.90 16.90

Methanol Solvent ---- 54 ---- ---

DImethyl

Sulphate

Reactan

t

110 6.20 0.056 1.17 ------- 6.20 6.20

Aq.Ammoni

a

Reagent ------ 5.0 -----

Water Solvent ------- 500 --- --- --- 500 500

Note: - Solvent is in terms of volume and not based on mole ratio.


TRICLABENDAZOLE CUMULATIVE POLLUTION LOAD

Table No. 17:- Cumulative Pollution load of Stage IV Triclabendazole.

Effluent in m3, Rest all figs in kg. / Day


Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas Generated

Inorganic

Salt

Organic


I ------ 0.0842 1.04 ----- ----- ---- ---- --- --- ---

II ------- 0.169 ---- ------ ----- ---- CO2 0.90 ----- ----

III -------- 0.088 ---- ----- ---- ---- H2 0.40 m3 --- --

IV ----- 0.11 --- --- --- -- -- -- -- --

Total 0.452 1.04 --- --- --- CO2

H2

0.90

0.4 m3

------ ------



12. Name of the Product –-Voglibose Qty/Month 25.00kg.

Batch Output 5 kg



Brief Manufacturing Process for- Voglibose Charge water and Dimethyl Sulphoxide in a clean Reactor. Charge crude Voglibose under stirring.

Heat the reaction mass to reflux and maintain for 4 hrs. After reflux is over cool the reaction mass to

10 °c and maintain for 1 hr. Centrifuge the reaction mass and spin dry. Unload the wet material and

dry in a vacuum tray dryer to get dry Voglibose.

Route of Synthesis- HO

HO

HO OHOH

NH

OH

OH

5-(1,3-dihydroxypropan-2-ylamino)-1-(hydroxymethyl)cyclohexane-1,2,3,4-tetraol

Mol Wt---267.28

HO

HO

HO OHOH

NH

OH

OH

5-(1,3-dihydroxypropan-2-ylamino)-1-(hydroxymethyl)cyclohexane-1,2,3,4-tetraol

Mol Wt---267.28

1. Water2.DMSO3.Carbon



Table No. 1 :- Input and output and mass Balance for a Batch


Crude Voglibose kg 5.5 Pure Voglibose 5.00 Final Product

Water kg 5 Carbon 1.0 TO CHWTSDF

Dimethyl Sulphoxide kg 5 Aq. Effluent HCOD

9.50 To ETP for Treatment

Activated Carbon kg 1 Drying Loss 01 -

Total kg 16.50 Total 16.50 ------------------


Table No. 1:-Pollution load. Effluent in m3, Rest all figs in kg.

Stage Effluent in m3 Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas Generated

Inorganic

Salt

Organic


I ------ 9.50 ----- 01 ----- ------ ------- ------- ------- -------

M ------- -47.50 -------- 05 ----- ------- -------- ------ ---- -------

D -------- 1.90 ----- 0.20 ---- ---- ------- ------- ----- -----




1. NH3 and CO2 gas is generated during the reaction process. NHE is connected to scrubber,

while CO2 is let to air.


3. Toxic and hazardous raw material used Nil

Table No.2 :- Solvent Balance of Voglibose

Sr.No/

Stage

Qty in Kg/Day

Name of

the

solvent

Qty

Used

Recovered

[Distilled]

Fugitive

loss

Distillation

Process

loss

To

waste

Water

Distillation

Residue

Product

drying

loss

Spent

Solvent

Fresh

Make

Up

I Dimethyl

Sulphoxide

0.20 ------- Nil ------- 0.2 Nil Nil Nil 0.20



Name of

Key RM

Details Mol.Wt Qty

kg

Moles Molar

Ratio

Existing

Consumption

Proposed

Consumption

Net

Consumption

Crude

Voglibose

Raw

material

267.28 5 0.018 1 -------- 5 5

DMSO Solvent ----- -------- ------ ----- --------- 5 5

Water solvent ------ 5 --- ---- ----- 5 5





13. Product Name-Darunavir Qty/Month 100.00kg.

Batch Output 50 kg




RMI 4-Amino-N-[2R,3S] [ 3-Amino-2-hydroxyphenyl butyl] isobutyl bezenesulphonamide is

condensed in presence of methylene di chloride as solvent and 2-methyl—2-butanol with

hexahydro furan-3-ol and Disucinimidyl Carbonate. Sulphuric acid is added as a catalyst. The

reaction mass is refluxed for 10-12 hrs. Reaction completion is ensured on TLC. If the reaction is

complete, the reaction mass is cooled to ambient and water is added. The reaction mass is stirred

and settled. The aq Layer is separated and send to ETP for treatment. The organic layer having the

product is washed with water and then distilled off completely under vacuum. To the dry mass is

added cyclohexane and stirred for 10-15 minutes. Cyclohexane organic is washed with alkali

solution .The aq layer is separated and sodium sulphate is added.The reaction mass is stirred and

filtered. Activated carbon is added and the reaction mass is heated to 40-50 °c and filtered. The

clear filtrate is transferred to a clean and dry Reactor. Cyclohexane is distilled 50 % and cooled to

ambient. The product Darunavir is centrifuged and spin dried under Nitrogen blanket. The wet

product is unloaded and dried in vacuum tray dryer to get dry Darunavir. Mother liquor is distilled

off completely and residue is cooled and unloaded and send to CHWTSDF for disposal.



Route of Synthesis-

OH

N

S

CH3

CH3

O

O

NH2

H2N

4-Amino-N-(2R,3S,(3-AMINO-2-HYDROXY-PHENYL BUTYL)-N-ISOBUTYL BENZENESULPHONAMIDE

Mol.Wt-391

+O

O

OH

tetrahydro-2H-furo[2,3-b]furan-3-ol

Mol.Wt-130

1.Disucinimidyl Carbonate

2. Methylene di chloride

3.. Cyclohexane

4. Sodium sulphate

OH

NS

CH3

CH3

O

O

NH2

NH

O

OO

O

DARUNAVIR MOL.WT- 547

Table No.1 :- Input and output and mass Balance of Darunavir


RM I kg 45 Darunavir 50.5 Final Product

RMII kg 15 Aq.Effluent 250 To ETP for treatment

DIsucinimidyl Carbonate kg 29 Methylene di chloride 140 Rec and recyceld

Sulphuric acid kg 1.80 Methylene di chloride 4 Distillation loss

2-Methyl-2-butanol kg 1 Cyclohexne 85 Rec and used

Methyleen di chloride kg 150 2-Methyl-2-butanol 1 To effluent

Cyclohexane kg 100 Sodium Sulphate 1.7 To ETP for treatment



Sodium Hydroxide kg 1.9 Sodium Hydroxide 1.90 To Effluent

Sodium sulphate Kg. 1.70 Cyclohexane 2 Distillation and Process loss

Water kg 250 Activated Carbon 2 TO CHWTSDF

Activated carbon kg 2 Solvent distillation Residue

54.30 TO CHWTSDF

----------------------- kg ----- Drying loss 05 Evaporation loss

Total kg 597.40 Total 597.40



Table No. 2:-Pollution load of Darunavir. Effluent in m3, Rest all figs in kg.


Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic


I ------ 250 54.30 2 ----- ------ ---- ---- ------- -------

M ------- 500 108 4 ----- ------- ----- ----- ---- -------

D -------- 0.020 4.344 0.16 ----- ------- ------- ------- ----- -----


Table No. 3:- Solvent Balance of Darunavir

Sr.No/

Stage

Qty in Kg/Day

Name of

the solvent

Qty

Used

Recovered

[Distilled]

Fugitive

loss

Distillation

Process

loss

To

waste

Water

Distillation

Residue

Product

drying

loss

Spent

Solvent

Fresh

Make

Up

I MDCl 24 22.40 Nil 0.64 0.01 8.688 Nil Nil 1.60

I Cyclohexane 16 14.40 Nil 1.50

Table No. 4:- Matrix showing Molecular weight, Moles, molar ratio and consumption


Name of Key RM


Moles Molar Ratio



Net Consumption

RMI Reactant 391 45 0.115 1 ----------- 45 45

RMII Reactant 130 15 0.115 1 ---------- 15 15

Disu.Carbonate Catalyst 256 29 .113 0.985 -------- 29 29

Sulphuric acid Catalyst 98 1.8 ----- ---- -------- 1.8 1.8

2-Methyl-2-

Butanol

Reagent 1 ----- ---- ------- 1 1

MDC Solvent --------- 150 ----- ---- ---- 10 10



Sodium

Sulphate

Reagent ------- 1.90 ---- ---- --- 1.90 1.90

Cyclohexane Solvent ------ 100 --- -- ------- 15 15

Water solvent ------ 500 --- --- -------- 500 500

Carbon Adsorbent --- 2 ---- --- --- 2 2



14. Product Name- MONTELUKAST SODIUM Qty/Month 750.00kg.

Batch Output 75.00 kg




Intermediate I is condensed with 2-[Sulfonyl]-Ethyl Cyclopropyl acetic acid in presence of

Acetonitrile and Toluene as solvent. Di isopropyl amine is used as a catalyst. The

Montelukast base is converted to sodium salt in presence of NaoH and Methanol. The

product Montelukast sodium is centrifuged and washed with chilled methanol, spin dried

and unloaded. The wet product is dried in vacuum tray dryer.



Route of Synthesis-

HO

Cl

2-(2-(3-(3-((E)-2-(2-chloronaphthalen-7-yl)vinyl)phenyl)propyl)phenyl)propan-2-ol

OH

Mol.Wt 457

+

HO

COOH

2-(1-(hydroxymethyl)cyclopropyl)acetic acid

Mol.Wt 130

1. Tolueen, Acetonitrile

2.DiIsopropyl amine

3. NaOH , HCl , NaCl

4.Methanol5.Carbon , Water

HO

Cl

O

+

COONa

sodium 2-(1-((1-(3-((E)-2-(2-chloronaphthalen-7-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propoxy)methyl)cyclopropyl)acetate

Mol.Wt---591

Table No. 1:- Batch Input and output and mass Balance


RMI-hydroxy propyl-phenyl-2-Propanol

kg 99.40 Montelukast Sodium 75 Product

Sulphonyl methyl Cyclopropane acetic acid [

RMII ]

kg 31.71 Aq.Layer as Effluent HCOD , contains NaCl

250 To ETP for treatment.

Methano sulphonyl Chloride kg 24.87 Water formed during reaction

2.22 To waste Water

Sodium Hydroxide kg 13.62 Toluene 68.25 Rec. and used

N,N-Di isopropyl Ethyl amine

kg 0.50 Toluene Distillation loss 0.38 Distillation and Process loss

HCl 30% Kg 3.42 Toluene 0.26 To Waste Water

Sodium Chloride Kg 0.50 Toluene solvent Residue 35.00 To CHWTSDF

Acetic acid kg 1 Acetonitrile 45.00 Rec and used Toluene kg 75 Acetonitrile 0.33 Recovery process loss

Aceto Nitrile kg 65 Aceto nitrile 42.50 Solvent Residue



Methanol kg 100 Hexane

95.00

Rec and used

n-Hexane kg 130 Hexane 2.50 Distillation loss

Water kg 115 Hexane 15.0 Solvent Residue

Activated Carbon kg 01 Activated Carbon 1 To CHWTSDF as HW ----------------------------- kg ---- Sodium Chloride 13.20 To waste Water

------------------- kg ---- Drying Loss 15.38 Hexane Drying Loss

Total kg 661.02 Total 661.02 -----------



Table No. 2:-Pollution load of Montelukast Sodium.

Effluent in m3, Rest all figs in kg.


Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic


I ------ 0.250 92 1 ----- ---- ---- --- ------- -------

M ------- 2.500 920 10 ----- ----- ------- ---- ---- -------

D -------- 0.10 40.50 0.40 ----- ----- ----- --- ----- -----


Table No.3 :- Solvent Balance of Montelukast Sodium

Sr.No/ Stage


the solvent

Qty Used


Fugitive loss


loss

To waste Water


Product drying

loss

Spent Solvent

Fresh Make

Up

I Methanol 10 ---- ---- ----- 10 Nil Nil Nil 10

I Toluene 30 27 ------- 0.38 0.26 14 --- --- 3.0

I Hexane 52 37.96 ----- 1.0 --- 6.0 6.152 --- 14.40

Table No. 4:- Matrix showing Molecular weight, Moles, molar ratio and consumption of

Montelukast Sodium


Name

of

Key RM

Details Mol.Wt Qty

kg

Moles Molar

Ratio

Existing

Consumption

Proposed

Consumption

Net

Consumption

RMI Reactant 458 99.40 0.21 1 --------- 99.40 99.40

RMII Reactant 146 31.71 0.71 3.30 -------- 31.71 31.71





15. Product Name- Losartan Base

Brief Process Description -

Losartan intermediate is reacted with sodium azide in presence of Triethyl amine and Toluene as

solvent. The reaction temperature is 90-95°C and maintained for 30 hrs. The reaction completion is

ensured on TLC. If TLC is clear the reaction mass is cooled to ambient and quenched in sodium

hydroxide solution at 25-30 °c. After complete quenching the reaction mass is stirred for 10-15

minutes and settled for 20-30 minutes. The organic layer is separated and distilled to get recovered

Toluene, which is recycled. The aq layer having product is transferred to another clean Reactor and

added carbon and hyflow to it. The reaction mass is heated to 60-65 °c and maintained for 20-30

minutes. The hot reaction mass is filtered and clear filtrate is transferred to clean Reactor. The

reaction mass is cooled to ambient an d solution of sodium nitrite is added slowly at 25-30 °c, After

addition of sodium nitrite, pH of the reaction mass is adjusted to 2-3 with HCL/WATER mixture.

Sodium hydrosulphite is added, the reaction mass is stirred and PH is rechecked. The product

formed is centrifuged and washed with water to a neutral pH. The wet cake is slurried in DM water,

stirred and centrifuged. The wet cake is recharged in a Reactor having IPA, stirred and centrifuged.

The wet product is dried in Tray Dryer to get Dry Losartan K; ML is distilled to get rec.IPA. The

solvent Residue is cooled and unloaded and send to CHWTSF for disposal.

Qty/Month 975.00kg.

Batch Output 195 kg





Route of Synthesis-

CN

N

N

HO

Cl

1. Toluene

2.TEA.HCl

1. NaOH

2. Sodium NitriteN

N

HO

Cl

HN

N N

N

LOSARTAN BASE MOL.WT 422.91LOSARTN INTERMEDIATE MOL.WT 379

( 4-(2-Butyl-4-Chloro-5-hydroxy menthyl)-1

H- Imidazole-1-Yl] Biphenyl -2-Carbonate

(2-Butyl-4-chloro-1-[(2<(1H-Tetrazole-5-yl)[1,2< Biphenyl]-4ylmenthyl]-1H-Imidazole-5-methanol

SYNTHETICROUTE FOR LOSARTAN BASE

Table No.1 :- Batch Input and output and mass Balance of Losartan Base


Losartan Intermediate kg 200 Product 195 Losartan potassium

Toluene kg 344 Aq. Effluent 1900 To ETP for treatment

Sodium Azide kg 136 Toluene 340 Rec and reused

Triethyl amine kg 288 Toluene 02.0 Distillation loss

NaOH solution [ 120+ 600 watrr]

kg 720 Toluene 54 Distillation Residue

Sodium Nitrite kg 60 Toluene 02 To waste Water

Carbon kg 5 IPA 165 Rec and used

Hyflow kg 2 IPA 05 Distillation loss

Sodium hydro Sulphite kg 5 IPA 20 Solvent Residue

Water/ HCl mixture kg 400 IPA 20 Drying Loss

Water for washing and slurry

kg 350 Carbon- 5 To CHWTSDF

Isopropanol kg 200 Hyflow 2 To CHWTSDF

Total kg 2710 Total 2710 -------------------



Table No. 2:-Pollution load of Losartan Base.



Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic


I ------ 1.900 74 5 2 ----- ---- --- ------- -------

M ------- 9.500 370 25 10 ----- ------ ---- -------

D -------- 0.236 14.80 1 0.40 ------ ------ --- ----- -----




Table No.3 :- Solvent Balance of Losartan Base

Sr.No/

Stage

Qty in Kg/Day

Name

of the

solvent

Qty

Used

Recovered

[Distilled]

Fugitive

loss

Distillation

Process

loss

To

waste

Water

Distillation

Residue

Product

drying

loss

Spent

Solvent

Fresh

Make

Up

I Toluene 68.80 67.90 Nil 0.40 0.40 54 Nil Nil 0.80

I IPA 40 33 Nil 1 --- 20 4.0 ---- 7.0

Table No.4: - Matrix showing Molecular weight, Moles, molar ratio and consumption of Losartan

Base


Name of

Key RM

Details Mol.Wt Qty

kg

Moles Molar

Ratio

Existing

Consumption

Proposed

Consumption

Net

Consumption

Intermediate

I

Reactant 379 200 0.52 1 --------- 200 200

Sodium

azide

Reactant 65 136 0.47 0.92 -------- 136 136

TEA.HCl Catalyst 102 288 2.80 5.40 -------- 288 288

Sodium

Nitrite

Reactant 69 60 0.86 1.67 -------- 60 60

Water Solvent ---- 1550 ---- ---- ---- 1550 1550

Toluene Solvent ---- 344 -- -- ---- 4 4

IPA Solvent --- 200 --- --- -- 35 35





16. Product name- Sparfloxacin Qty/Month 50.00kg.




Brief Process Description-

Ethyl 1-Cyclopropyl -5, 6, 7, 8-tetra fluoro-4-0xo-1, 4-dihydro quinoline carboxylate is condensed

with Benzyl amine in presence of sodium Carbonate and toluene. The reaction is carried out at

reflux temperature. Reaction completion is ensured on TLC, after completion of the reaction, the

reaction mass is cooled and water is added. Toluene layer is separated and distilled to get

rec.Toluene which is recysled. Solvent distillation residue is unloaded and sends to CHWTSDF for

disposal. To the aq layer HCL is added, heated to reflux, maintained for 2 hr, cooled and the product

as stage I, is centrifuged and used for next stage as wet. Stage I, is charged in methanol. 2,6 –

Dimethyl piperzine is added along with N-Methyl pyrrolidine, The Reaction mass is refluxed and

maintained for 10-12 hrs. The reaction completion is ensured on TLC. After completion of reaction,

methanol and N-methyl pyrrolidine is recovered by distillation and water is added to the reaction

mass, PH of the reaction mass is adjusted to 8-9 with sodium hydroxide and reaction mass is

filtered. The filtrate is acidified with acetic acid to precipitate Sparfloxacin. The product is isolated

by centrifuging and washed with water. Wet product is unloaded and dried in Tray dryer to get dry

Sparfloxacin.



Route of Synthesis of – Sparfloxacin—Stage I

N

F

F

F

F

O

COOC2H5

ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate

Mol.Wt---329

NH2

phenylmethanamine

Mol.Wtn 107.15

+

N

F

F

NH

F

O

COOC2H5

ethyl 5-(benzylamino)-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate

Mol.Wt-416.39

+ HF

Mol.Wt-20



N

F

F

NH

F

O

COOC2H5

ethyl 5-(benzylamino)-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate

Mol.Wt-416.39

HCL

Toluene

N

F

F

NH2

F

O

COOH

+ C2H5OH

+

OH

Benzyl Alcohol

Ethyl Alcohol

Mol.Wt- 108.145-amino-1-cyclopropyl-6,7,8-trifluoro-

1,4-dihydro-4-oxoquinoline-3-carboxylic acid

Mol.Wt-298.22

Table No. 1:- Batch Input and Output and Mass Balance Stage I of Sparfloxacin


Ethyl cyclopropyl tetra fluoro-4-oxo di hydro

quinoline--- RMI

kg 18.50 Stage I 13.40 Used for next stage

Benzyl amine kg 6 Toluene 55 Rec and recycled

Hydrochloric acid kg 2 Toluene 02 Distillation loss

Toluene kg 60 Toluene 11.90 Solvent residue

Sodium carbonate kg 1.20 Toluene 0.50 To waste Water

Water kg 30 Aq.Effluent 30 To ETP for treatment

------------------- kg ----- Sodium Chloride 1.70 To waste water to ETP

------------------------- kg -------- Carbon Di Oxide 0.50 Let to air

------------------------- kg ------ HF acid 0.9 To waste water

-------------------------- kg ---- Ethanol 2.10 To waste Water

------------------- kg ---- ------- ------ -----------------

--------------------------- kg --- ------------ ----- ----------

Total kg 118 Total 118 -------------------



Table No. 2:-Pollution load of Sparfloxacin Stage I.



Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic


I ------ 0.367 11.90 ----- ---- ----- ---- --- ------- -------

M ------- 0.110 35.70 ----- ---- ----- ------ ---- -------

D -------- 0.176 1.428 ----- ----- ------ ------ --- ----- -----


Table No. 3:- Solvent Balance of Sparfloxacin Stage I

Sr.No/

Stage

Qty in Kg/Day

Name of

the

solvent

Qty

Used

Recovered

[Distilled]

Fugitive

loss

Distillation

Process

loss

To

waste

Water

Distillation

Residue

Product

drying

loss

Spent

Solvent

Fresh

Make

Up

I Toluene 7.2 6.59 --- 0.024 0.06 11.90 ---- --- 0.61

I Water 3.6 ----- ----- ----- 3.6 ---- --- --- 3.6

Table No. 4 :- Batch Input and output and mass Balance Sparfloxacin Stage II


Sparfloxacin stage I kg 13.40 Sparfloxacin 16.70 Final Product

2,6-d-Methyl Piperzine kg 5.10 Aq Water as effluent


N-Methyl Pyrrolidine kg 40 .Methanol 32 Rec and used

Methanol kg 40 Methanol 3.5 Distillation loss

Acetic acid kg 1.50 NMP 30 Rec and recycled

Sodium Hydroxide kg 1 NMP 10 To waste water

Water kg 30 Unreacted Stage I 0.730 To waste Water

------------------------- kg ---- Acetic acid 1.50 To waste water

------------------------------ kg ---- NaOH 1 To waste water

------------ ------------ kg ----- Methanol 4.5 To waste water.

------------------------ kg ----- HF 0.70 To waste water

----------------------------- kg ----- Drying Loss 0.37 Product drying loss

Total kg 131 Total 131 -----------



Route of Synthesis of Sparfloxacin Stage II

N

O

F

F

NH2

COOH

F

5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

Mol.Wt-298.06

+

NH

HN

(2R,6S)-2,6-dimethylpiperazine

Mol.Wt 114.19

1. Methanol

2.N-Methyl Pyrrolidine

N

O

F

N

NH2

COOH

FHN

5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid

mol.Wt-392.04

+ HF

Hydrofluoric acid



Table No. 1:- Pollution load of Sparfloxacin Stage II.


Stage Effluent in m3 Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas Generated Inorganic

Salt

Organic


II ------ 0.384 ----- ----- ---- ----- ---- --- ------- -------

M --- 1.152 --- --- ----- --- --- --- --- ---

D --- 0.0468 --- ---- --- --- --- --- --- --

Table No. 2:- Solvent Balance of Sparfloxacin Stage II

Sr.No/

Stage

Qty in Kg/Day

Name of

the

solvent

Qty

Used

Recovered

[Distilled]

Fugitive

loss

Distillation

Process

loss

To

waste

Water

Distillation

Residue

Product

drying

loss

Spent

Solvent

Fresh

Make

Up

II Methanol 4.80 3.84 --- 0.42 0.54 ---- --- 1.04

II Water 3.60 ---- ---- --- --- 3.56 0.044 --- 3.60



Table No.3 :- Cumulative Pollution load of Sparfloxacin Stage II.

Effluent in m3, Rest all figs in kg/Day


Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic


II ------ 0.2248 1.428 ----- ---- ----- ---- --- ------- -------

Table No. -4: - Matrix showing Molecular weight, Moles, Molar Ratio and Consumption.


Name of

Key RM

Details Mol..Wt Qty

kg

Moles Molar

Ratio

Existing

Consumption

Proposed

Consumption

Net

Consumption

Tetra

fluoro

Quinoline

Reactant 329 18.50 0.056 1 ------ 18.50 18.50

Benzyl

amine

Reactant 107 6.0 0.056 1 ------- 6 6

Sodium

Carbonate

Reagent 1.2 106 0.011 0.202 -------- 1.2 1.2

Toluene Solvent ----- --60 ---- --- ------ 2.2 2.2

Stage I Rectant 298 13.4 0.044 1 ----- 13.40 13.40

NMP solvetn ---- 40 --- -- --- 10 10

Piperzine Recatnt 114.19 5.10 0.044 1 -------- 5.1 5.1

Methanol Solvent ----- 40 ---- --- ---- 8 8

Water Solvent ----- 30 ---- --- ---- 30 30





17. Product Name- Salbutamol Sulphate

Qty/Month 2.00 MT.

Batch Output 50 kg




Benzyl Salbutamol is charged in methanol. Nitrogen is flushed and Raney Ni catalyst is charged

under Nitrogen blanket. After charging Raney Ni Catalyst, Hydrogen gas is purged and then a

pressure of 3.5 kg is maintained till reaction is complete. Reaction completion is monitored on TLC.

After completion of the reaction, hydrogen gas is released with nitrogen blanket through water.

After releasing the hydrogen gas, the reaction mass is filtered through hyflow bed and the clear

filtrate is transferred to Clean Reactor

The Raney Ni and Hyflow are removed from the filter under nitrogen and send for recovery. The

clear filtrate cooled to 0-5 °c, AR grade sulphuric acid is added and the reaction mass is stirred for

10-12 hrs. The reaction mass as Salbutamol sulphate is centrifuged and spin dried and charged in

tray dryer to get dry Salbutamol sulphate.

Route of Synthesis-

O

HO NH

OH

2-(tert-butylamino)-1-(4-(benzyloxy)-3-(hydroxymethyl)phenyl)ethanol

Mol.Wt 329.

1.Methanol

2. Raney Ni

3.H2SO4

OH

HO NH

OH

.. SO4

Salbutamol Sulpahte

Mol.Wt 337.30



Table No. 1:- Batch Input and output and mass Balance of Salbutamol Sulphate


Benzyl Salbutamol kg 66.70 Salbutamol sulphate

50 Final product

Methanol kg 416 Raney Ni 10 For recovery

Raney Ni 50 % wet kg 10 Hyflow 4 To HW for disposal

Hydrogen M3 30 Hydrogen 25 M3 Used for Reaction

Nitrogen M3 7 Hydrogen 5 M3 Released to air through water

Hyflow kg 4 Nitrogen 7.0M3 Used for Blanketing

Sulphuric acid 98 % kg 10 Toluene 18.65 Formed during the reaction in spent solvent

Methanol 300 Rec and used

Methanol 102.05 Spent for sale

Methanol loss 07..0 Distillation loss

Drying Loss 15 Product drying

Total kg 506.70 Total 506.70 ------------------

1. The reaction is pressure reaction. Hydrogen gas is used as a reactant. Excess gas is

released through water.

2. No gas is generated during the course of Reaction.



Table No.2 :-Pollution load of Salbutamol Sulphate. Effluent in m3, Rest all figs in kg.


Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic


I ------ ------ ------ 10 4 120 ---- --- ------- -------

M ------- ----- ------- 400 160 4828 ------ ---- -------

D -------- ----- ------ 16 6.40 193.12 ------ --- ----- -----


H2/N2 gas is not generated but used as reactant and blanketing, excess gas is released

through water.

Carbon is an catalyst and hence not included as HW, It is send to processing and recycled.

Table No. 3:- Solvent Balance of Salbutamol Sulphate

Sr.No/

Stage

Qty in Kg/Day

Name of

the

solvent

Qty

Used

Recovered

[Distilled]

Fugitive

loss

Distillation

Process

loss

To

waste

Water

Distillation

Residue

Product

drying

loss

Spent

Solvent

Fresh

Make

Up

I Methanol 665. 472.50 Nil 11.76 ----- --- 20 Nil 192.50


The below figures of the respective raw material are representative of a batch. Name of

Key RM

Details Mol.Wt Qty

kg

Moles Molar

Ratio

Existing

Consumption

Proposed

Consumption

Net

Consumption

Benzyl

Salbutamol

Reactant

329

66.70 0.202 1 ---- ---- ----

Methanol Solvent ----- 416 ----- ---- ---- 116 116

Raney Ni Catalyst ---- 10 --- --- ---- ---- ---

Sulphuric

acid

Reagent 98 10 0.10 0.50 ---------- 10 10





18. Product Name- Pantoprazole Sodium

Qty/Month 450.00kg.

Batch Output 150 kg




2 Chloromethyl -3, 4-dimethoxy pyridine hydrochloride is condensed in toluene and NaOH as

reagent for neutralizing hydrochloric acid formed.

After the reaction is over, water is added and reaction mass is stirred and cooled. The reaction mass

is centrifuged, washed with water and spin dried, unloaded and used for next stage.

Stage I is charged in solution sodium hypochlorite, sodium hydroxide and toluene as solvent. The

reaction mass is heated to reflux temperature and maintained for 3-5 hrs. After the reaction is

complete, the reaction mass is cooled and settled. Toluene is separated and subjected for

distillation to recovered Toluene and recycled. The solvent residue is send to CHWTSDF for

disposal. Water is added to the reaction mass and centrifuged, washed with water, spin dried and

unloaded. The wet product is charged in acetone and heated to get a clear solution. Carbon is added

and filtered through SPF [Sparkler pressure filter]. The filtrate is transferred to a clean Reactor and

cooled to ambient and then chilled to 0-5 °C, maintained for 2 hrs and centrifuged. The wet product

is unloaded and dried in tray dryer to get dry Pantoprazole sodium as final product



Route of Synthesis of Pantoprazole Sodium Stage I

N

OCH3

OCH3

CH2Cl

2-(chloromethyl)-3,4-dimethoxypyridine

Mol.Wt 224

. HCl .+

N

NH

HS

OCHF2

5-(difluoromethoxy)-1H-benzo[d]imidazole-2-thiol

Mol.Wt 216

5-(difluoromethoxy)-1H-benzo[d]imidazole-2-thiol

1. Tolueen , NaOH

2. water

N

OCH3

OCH3

.

S

HN

N

OCHF2

+2NaCl +2H2O

2-((3,4-dimethoxypyridin-2-yl)methylthio)-5-(difluoromethoxy)-1H-benzo[d]imidazole

Mol.Wt 367



Route of Synthesis of Pantoprazole Sodium Stage II

N

OCH3

OCH3

.

S

HN

N

OCHF2

2-((3,4-dimethoxypyridin-2-yl)methylthio)-5-(difluoromethoxy)-1H-benzo[d]imidazole

Mol.Wt 367

N

OCH3

OCH3

.

S

HN

N

OCHF2

1. Sodium Hypochlorite2. Toluene3.Water O

2-((3,4-dimethoxypyridin-2-yl)methylsulfinyl)-5-(difluoromethoxy)-1H-benzo[d]imidazole

Mol.Wt 383

1.Acetone

2.NaOH

N

OCH3

OCH3

.

S

N

N

OCHF2

O

Na

PENTAPRAZOLE SODIUM

MOL.WT 406

Table No.1:- Batch Input and output and mass Balance of Pantoprazole Sodium Stage I


2- Chloromethyl-3-4-dimethoxy pyridine hydrochloride

kg 94 Stage I 151 Used for Stage II

5-Difluoro methoxy-2-mercapto benzimidazole

kg 91 Sodium Chloride 48.80 To Waste Water

Sodium Hydroxide kg 34 Aq. Effluent 4890 To ETP for treatment

Water kg 4875 Toluene 346 Rec and used

Toluene kg 360 Toluene 0.9 Recovery loss

HCl kg 0.7 Toluene 3.6 To waste Water

Toluene 14.40 Solvent distillation residue contains unreacted stage I/II

Total kg 5454.70 Total 5454.70 -------



Table No. 2:-Pollution load of Pantoprazole Sodium Stage I.



Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic


I ------ 4.942.0 14.40 ---- ----- ---- ---- --- ------- -------

M ------- 14.8272 43.20 ----- ----- ----- ------ ---- -------

D -------- 0.593 1.728 ----- ------ ----- ------ --- ----- -----


Table No. 3:- Solvent Balance of Pantoprazole Sodium Stage I

Sr.No/

Stage

Qty in Kg/Day

Name

of the

solvent

Qty

Used

Recovered

or

Distilled

Fugitive

loss

Distillation

Process

loss

To

waste

Water

Distillation

Residue

Product

drying

loss

Spent

Solvent

Fresh

Make

Up

I Toluene 43.20 41.52 Nil 0.108 0.432 1.728 --- Nil 1.68

I Water 586.80 --------- ------ ------ 586 -- --- ---- 586



Table No. 4:- Batch Input and Output and Mass Balance of

Pantoprazole Sodium Stage II


Stage I kg 151 Stage II 150 Final Product

Sodium Hypochlorite 4% kg 766 Sodium Chloride 24 To waste water

Sodium Hydroxide kg 16 Effluent aq. 1193 To ETP for treatment

Toluene kg 600 Toluene 576 Recovery and use

Acetone kg 750 Toluene 1.2 Distillation loss

Carbon kg 15 Toluene 9 To waste water

Water kg 450 Solvent Residue 28.90

---------------------- Kg ------ Carbon 15 TO CHWTSDF

---------------------- Kg ------ Acetone 684 Rec and used

---------------------- Kg ------ Acetone 12 Distillation loss

---------------------- Kg ------ Acetone sol. Residue 14.10 Acetone distillation Residue

---------------------- kg ------ Acetone 15 Product drying loss

--------------------- kg ---- Carbon 15 TO CHWTSDF as HW

Total kg 2748 Total 2748



Table No. 5:-Pollution load Pantoprazole Sodium Stage II.

Effluent in m3, Rest all figs in kg. Stage II

Stag

e

Effluent in

m3

Solvent

Residu

e

Carbo

n

Hyflo

w

Spent

Solven

t

Gas

Generated

Inorgani

c

Salt

Organi

c

Residu

e LCO

D

HCO

D

Nam

e

Qt

y

I ------ 1.214 43 15 ----- ---- ---- --- ------- -------

M ----- 3.642 129 45 ----- ----- ----- ---- --- ----

D ---- 0.145 5.16 1.80 ------ ------ ----- ---- ---- ----



Table No.6 :- Solvent Balance of Pantoprazole Sodium Stage II

Sr.No/

Stage

Qty in Kg/Day

Name

of the

solvent

Qty

Used

Recovered

or

Distilled

Fugitive

loss

Distillation

Process

loss

To

waste

Water

Distillation

Residue

Product

drying

loss

Spent

Solvent

Fresh

Make

Up

II Toluene 72 69.12 ----- 1.44 1.08 3.468 ---- --- 2.88

II Acetone 90 82.08 ---- 1.44 ---- 1.692 1.80 --- 8.0

II Water 54 ------ ------ ---- 54 ---- --- ---- 54

Table No.7 :- Cumulative Pollution load of Pantoprazole Stage I/II

Stag

e

Effluent in

m3

Solvent

Residu

e

Carbo

n

Hyflo

w

Spent

Solven

t

Gas

Generated

Inorgani

c

Salt

Organi

c

Residu

e LCO

D

HCO

D

Nam

e

Qt

y

I/II ------ 0.738 6.888 1.80 ----- ---- ---- --- ------- -------



Name of Key RM

Details Mol.Wt

Qty kg

Moles

Molar

Ratio

Existing Consumptio

n

Proposed Consumptio

n

Net Consumptio

n

RM I Reactant 224 94 0.419 1.0 ---------- 94 94

RMII Reactant 216 91 0.421 1.005 ------------ 91 91

Sodium

Hydroxid

e

Reagent 40 34 0.85 2.0 ----------- 40 40

Toluene Solvent ----- 360 ---- --- ------ 14 14

Water Solvent ----- 487

5

---- --- ------ 4875 4875



Stage II Reactan

t

------ 151 ------ ----- -------- 151 151

NaOCL Reactan

t

------- 766 ------ ----- -------- 766 766

Toluene Solvent ------- 600 ------ ----- ------ 24 24

Acetone Solvent ----- 750 ---- ---- ------ 76 76



19. Product Name- Fenofibrate Qty/Month 500.00kg.

Batch Output 50 kg




STAGE 1:

Starting materials 4-chloro-4-hydroxy benzophenone,Isopropyl alcohol and Potassium

Carbonate are added into the reaction vessel and agitated until reaction is completed.

Isopropyl alcohol was added and reaction mass is filtered. The Potassium Bicarbonate and

Potassium bromide is recovered as distillation residue.

The recovered Isopropyl alcohol is used for further use after centrifuge.

STAGE 2:

Starting materials stage 1 product; Isopropyl alcohol and carbon are added into the reaction

vessel and stirred until reaction is completed.

The recovered Isopropyl alcohol is used for further use after centrifuge.



Table No. 1:- Input and output and mass Balance


Isopropyl –alpha bromoisobutyrate

Kg 41.0 Crude Fenofibrate 54.0 Final Product

4-Chloro 4- hydroxy benzophenone

Kg 73.5 Isopropyl alcohol 131 Recovered and recycled

Isopropyl alcohol Kg 162.5 Isopropyl alcohol 3.30 Evaporation Loss

Potassium Carbonate kg 27.0 Solvent distillation Residue

69.00 Unreacted RMI and II and solvent IPA as residual part.

-------------- --- ---- Potassium bi carbonate 19.50 For resale to authorized Recycler

-------------------- ----- ---- Potassium bromide 23.20 For resale to Recycler

-------------- ----- IPA in crude FENOFIBRATE

04.00 Used as such for purification

Total 304.0 304.0

Route of Synthesis-



Table No. 2:-Pollution load. Effluent in m3, Rest all figs are in kg


Solvent Residue

Carbon Hyflow

Spent Solven

t

Gas Generated

Inorganic Salt


I -- -- 4.0 -- -- -- SO2 HCl HBr

90.45 120.75 165.90

42.70 --

II -- -- 69 2.5 0.350 -- CO2 193.05 ----- -- M -- -- 730 25.0 3.50 -- SO2

HCl HBr CO2

904.5 1207.5 1659.0 1930.5

427 --

D -- -- 29.20 1.0 0.140 -- SO2 HCl HBr CO2

36.18 48.3

66.36 77.22

17.08 --

M- Pollution load per month- Pollution load per day.

The reaction is not exothermic or run away or pressure.

Table No 3: - Solvent Balance of Fenofibrate. Stage I/II

Sr.No

/

Stage

Qty in Kg/Day

Name of

the

solvent

Qty

Used

Recovered

[Distilled]

Fugitiv

e loss

Distillatio

n

Process

loss

To

wast

e

Wate

r

Dist

illat

ion

Resi

due

Produ

ct

dryin

g loss

Spen

t

Solve

nt

Fresh

Make Up

I Isopropy

l alcohol

65 52.40 ---- 1.32 -- 27.6

0

-- -- 12.60

II Isopropy

l alcohol

46.60 36.80 --- 2 -- 1.60 7.80 -- 9.80



Table No 4: - Matrix showing Molecular weight, Moles, molar ratio and consumption

Name of

Key RM

Details Mol.

Wt

Qty

kg

Moles Molar

Ratio

Existing

Consumption

Proposed

Consumptio

n

Net

Consumpt

ion

Isopropyl –alpha

bromoisobutyrate

Reactant 209.0

8

41.0 0.19 1.27 --- 410 410

4-Chloro 4-

hydroxy

benzophenone

Reactant 235.5 73.5 0.312 2.09 --- 735 735

Isopropyl alcohol Solvent 60.1 162.5 --- --- --- 310 310

Potassium

Carbonate

Reagent 139.0 27.0 0.194 1.30 --- 270 270

Crude

Fenofibrate

Reactant 360.8 54.0 0.149 1.00 --- 540 540

Isopropyl alcohol Solvent 60.1 116.5 --- -- --- 240- 240

Activated Carbon Catalyst 12.01 2.5 --- --- --- 25 25

Hyflo Filtration

Media

NA 0.35 --- --- --- 3.5 3.5

Note: - Solvents is in terms of volume and not based on mole ratio. Key Raw materials are

considered as they are involved to build the desired molecule. The above figures of the

respective raw material are representative of a batch.

20. Product Name- Clopidogrel Hydrogen Sulphate Qty/Month 175.00kg.




Brief Process Description- In clean Reactor Acetone is charged at ambient. Clopidogrel base is charged at ambient under

stirring. The reaction mass stirred and ensured a clear solution, if not add additional Acetone to

have clear solution. The reaction mass is cooled below 10 °C and slow sulphuric acid is added. After

complete addition, the reaction mass temperature is maintained below 20 0c and then centrifuged.



The wet cake is washed with chilled Acetone and unloaded. The wet product as Clopidogrel

Hydrogen Sulphate is dried to get dry Clopidogrel Hydrogen Sulphate.

Route of Synthesis-

N

Cl

+

S

O OCH3

methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate

Mol.Wt 321.82

1.Acetone

2.H2SO4

N

ClS

O OCH3

. HSO4

CLOPIDOGREL HYDROGEN SUPLphate MOL.WT 419

Table No 1:- Batch Input and output and mass Balance Clopidogrel Hydrogen Sulphate


Clopidogrel Base kg 68.50 Clopidogrel Sulphate 87.50 Final Product Acetone kg 350 Acetone 330 Rec and Recycled

Sulphuric acid Kg 20.50 Acetone 2.5 Process Loss -------------------- kg ---- Solvent Residue 9.0 Recycled

------------------------- kg ---- Drying Loss 10 Drying Operation

Total kg 439 Total 439



Table No.2 :--Pollution load of Clopidogrel Hydrogen Sulphate.



Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic

Residue

LCOD HCOD Name Qty

I ------ ------ ------ ---- ----- ---- ---- --- ------- -------

M ---- ----- ------ ----- ----- ----- ------ ----- ---- ------

D ------ ------- ------- ----- ---- ----- ----- ---- ---- ------


All operations are in solvent. The solvent residue is recycled and hence no pollution of any kind

as mentioned different heads.

Table No. 3:- Solvent Balance of Clopidogrel Hydrogen Sulphate

Sr.No/ Stage


solvent

Qty Used

Recovered or

Distilled

Fugitive loss


loss

To waste Water


Product drying

loss

Spent Solvent

Fresh Make

Up

I Acetone 56 26.40 ----- 0.20 ---- 9 0.80 --- 29.60



Table No.4 :- Matrix showing Molecular weight, Moles, molar ratio and consumption




21. Product Name- Rosuvastatin Calcium

Qty/Month 500.00kg.

Batch Output 100 kg




Rosuvastatin intermediate as acid is charged in methanol at ambient under stirring in clean

Reactor. Sodium Hydroxide flakes are added to the reaction mass and heated to reflux .Reflux is

maintained for 2-4 hrs till complete conversion to sodium salt is over. The reaction mass is cooled

to ambient and calcium acetate is added, the reaction mass is stirred for 10-15 minutes and heated

to 50-55 °C and maintained for 1 hr. The reaction mass is cooled to ambient and filtered .The solid

salt of sodium acetate is separated and sold to recycler. The clear filtrate is transferred to another

reactor and distilled of completely, the reaction mass is cooled water is added followed by MTBE.

The reaction mixture is stirred and settled. The aq layer is send to ETP and MTBE organic layer

having product is transferred to another Reactor and, Carbon is added and heated to 55-60 °C. The

hot filtrate is filtered and the clear filtrate is transferred to another clean Reactor and chilled to 0-5

°C and maintained for 2 hrs at 0-5 °C. The product is centrifuged and spin dried. The mother liquor

is distilled to get rec. MTBE for recycling. The solvent residue left behind is unloaded and send to

CHWTSDF for disposal.

Name of Key RM


Moles Molar Ratio



Net Consumption

Clop Base

Reactant 321 68.50 0.21 - ------ 58.50 68.50

Acetone Solvent ------ 350 ---- --- --------------- 20 20 Sulphuric

Acid Reagent 98 20 0.20 0.97 ----- 20 20



Route of Synthesis of Rosuvastatin Calcium

F

N

NN

S

OO

OH

O

1(3R,6S,6E)-3,5-DIHydroxy-7-[4-(4-Fluorophenyl)-6-(1-methyl ethyl)-2[methyl, methyl sulphonyl) amino]-5- pyrimidyl]-6-methylhepteneoate

Mol.wt 481

OH OH

1. NaOH , CALCIUM ACETATE, METHANOL , MTBE

CARBON, HYFLOW, WATERF

N

NN

S

OO

OCa

O

Mol.wt 522

OH OH

ROSUVASTATIN CALCIUM

Table No. 1:- Batch Input and output and mass Balance of Rosuvastatin Calcium


Rosuvastatin Intermediate I

kg 116.70 Rosuvastatin Calcium 100 Final Product

Sodium Hydroxide kg 9.40 Sodium Acetate 18.50 Sale to Recycler

Calcium acetate kg 18.60 Methanol 550 Rec and recycled

Methanol kg 600 Methanol 10 Distillation loss

MTBE kg 500 Methanol 40 To waste water

Activated Carbon kg 5 MTBE 440 Recovered and used

Hflow kg 2.50 MTBE 05 Distillation loss

Water kg 500 MTBE 20 Product drying loss

-------------------- kg ------ MTBE 05 To Waste Water

-------------------------- kg ----- Aq. Effluent 500 To ETP for treatment

--------------------------- kg ------ MTBE solvent Residue 56.20 Distillation Residue



----------------------- kg ----- Carbon 5 To CHWRSDF

---------------------- kg ----- Hyflow 2.50 TO CHWTSDF

Total kg 1752.20 Total 1752.20 --------

MTBE- Methyl tertiary butyl ether.



Table No.2 :-Pollution load of Rosuvastatin Calcium


Stage Effluent in

m3

Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic


I ------ 0.545 56.20 5 2.5 ---- ------ ----- 18.50 -------

M ---- 2.725 281 25 12.50 ----- ----- ----- 92.50 ------

D ------ 0.109 11.24 1 0.50 ----- ------ ------ 3.70 ------


Table No 3:- Solvent Balance of Rosuvastatin Calcium

Sr.No/ Stage


the solvent

Qty Used

Recovered or

Distilled

Fugitive loss


loss

To waste Water


Product drying

loss

Spent Solvent

Fresh Make

Up

I Methanol 120 110 ------ 2 8 --- --- --- 10

I MTBE 100 88 ------- 1 1 11.24 4 ---- 12

Table No.4 :- Matrix showing Molecular weight, Moles, molar ratio and consumption


Name of Key RM

Details Mol.Wt Qty kg Moles Molar Ratio



Net Consumption

Rosuvastatin

RM1

Reactant 481 116.70 0.242 1 ---------- 116.70 116.70

Cal Acetate Reactant 99 18.60 0.18 0.71 ----------- 18.60 18.60

NaOH Reagent 40 9.40 0.235 0.896 ------- 9.40 9.40

Methanol Solvent ---- 600 --- --- ------ 50 50

MTBE Solvent ---- 500 --- --- --- 60 60





22. Product Name- Domperidone Qty/Month 100.00kg.

Batch Output 50 kg



Brief Process Description for – Domperidone

3-Chloro Phenyl Bnezimidazole is condensed with Chloro phenyl benzo imidazole one in presence

of sodium carbonate and methyl isobutyl ketone at reflux temperature. The reflux is maintained for

5-8 hrs, till completion of the reaction. The reaction completion is ensured on TLC. If the reaction is

complete, the reaction mass is cooled to ambient and water is added, stirred and settled. Aq.Layer is

separated and sends to ETP for treatment. The organic layer containing product Domeperidone is

cooled to ambient and then to 0-5 °c, stirred for 2 hrs and centrifuged. The wet product is dried in

tray dryer to get dry Domeperidone.



Route of Synthesis of Domperidone

N

HN

O

NH

Cl

5-chloro-1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

Ml.Wt 251.70

+

N

HN

O

Cl

1-(3-chloropropyl)-1H-benzo[d]imidazol-2(3H)-one

Mol.Wt 210.06

1. MIBK , SODIUM CARBONATE, WATER

N

HN

O

N

Cl

N NH

O

1-(3-(4-(6-chloro-1,2-dihydro-2-oxobenzo[d]imidazol-3-yl)piperidin-1-yl)propyl)-1H-benzo[d]imidazol-2(3H)-one

DOMEPERIDOBE MOL.WT 425.91.

Table No. 1:- Batch Input and output and mass Balance of Domperidone


Chloro Phenyl Benzimidazole RMI

kg 51 Product Domperidone 50 Final Product

3-Chloro Phenyl benzo imidazole one RMII

kg 31.1 0 Carbon di oxide 2.60 Let to Atmosphere

Methyl Isobutyl Ketone kg 250 Aq.Effluent HCOD 246..75 To ETP for treatment

Sodium Carbonate kg 6 Sodium Chloride formed 6.85 To waste water

Water kg 220 MIBK 230 Rec and recycled

--------------------------- kg ----- MIBK 1.9 Distillation loss

------------------ kg ----- MIBK 10 Solvent dis.Residue

-------------------------- kg ----- MIBK 10. Product drying loss

Total kg 558.10 Total 558.1 -----------



Table No.2 :-Pollution load of Domperidone

Effluent in m3, Rest all figs in kg


Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic


I ------ 0.2536 10 ------ ----- ---- CO2 2.60 ------- -------

M ---- 0.50720 -20 ----- ----- ----- CO2 5.20 ---- ------

D ------ 0.020 0.80 ----- ---- ----- CO2 0.208 ---- ------


Table No.3 :- Solvent Balance of Domperidone

Sr.No/ Stage


solvent

Qty Used

Recovered or

Distilled

Fugitive loss


loss

To waste Water


Product drying

loss

Spent Solvent

Fresh Make

Up

I MIBK 20 18.40 ----- 0.152 ----- 0.80 0.80 --- 1.6





Name of

Key RM

Details Mol.Wt Qty

kg

Moles Molar

Ratio

Existing

Consumption

Proposed

Consumption

Net

Consumption

RMI Reactant 251.70 51 0.202 1 ------- 51 51

RMII Reactant 210.06 31.1 0.148 0.732 ---------- 31.1 31.1

Sodium

Carbonate

Reagent 106 6 0.05 0.280 ---------- 06 06

MIBK Solvent ----- 250 ----- ---- ----------- 30 30

Water Solvent ---- 220 --- ---- -------- 220 220





23. Product Name- Nebivolol Intermediate Qty/Month 350.00kg.

Batch Output 125 kg

No of Batches/ Month 2.8


Brief Process Description for – Nebivolol Intermediate Stage I

[6-Fluoro 3, 4 Dihydro Piperdine Methanone is treated with vitride 4 % solution in toluene at

reflux temperature. The resultant reaction mass is quenched in HCl / Water mixture. The reaction

mass after quenching is stirred and settled. The toluene layer is washed with water and then

distilled to get a residual mass, which is cooled and unloaded; this residual mass is used for next

stage.

Stage II

The residual mass as stage I is charged in DMSO. Trimethy sulfonium iodide is charged and the

reaction mass is heated to 50-60 °C and maintained for 4 hrs. Reacting completion is ensured on

TLC. If the reaction is complete, the reaction mass is cooled to ambient and quenched in water. The

product of stage II is extracted in n-hexane. The aq layer is let to ETP and hexane layer containing

product is distilled to 80 % and then cooled to ambient and chilled further to 0-5°C and centrifuged

under nitrogen blanket to get stage II- Nebivolol intermediate. The wet product is dried in tray

dryer to dry product.



Route of Synthesis of Nebivolol Intermediate Stage I

O

F

N

O

(6-fluoro-3,4-dihydro-2H-chromen-2-yl)(piperidin-1-yl)methanone

Mol. Wt-263.31

+

Vitride

Mol.Wt 202

[ Sodium -Bis [ 2-methoxyethoxy] Aluminium hydride

HCl / Water

O

F

O

6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde

Mol/. wt 180

Route of Synthesis of Nebivolol Intermediate Stage II

O

F

O

6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde

Mol/. wt 180

+TRIMETHYL SULPHONIUM HYDRIDE

Mol. Wt 220

1. KOH

2.DMSO

3. HEXANE

O

F

+

O

6-fluoro-3,4-dihydro-2-(oxiran-2-yl)-2H-chromene

Mol. Wt--154



Table No.1 :- Batch Input and output and mass Balance Intermediate Stage I of Nebivolol


6-Fluoro 3,4-dihydro methanone RMI

kg 250 Liquid reaction mass

170 Used for stage II

Vitride 192 Aq.Layer 722 To ETP for treatment

Toluene kg 300 Toluene 745 Rec and used

Tolueen in Vitride kg 450 Toluene 05 Distillation loss

HCL 30 kg 50 ------------------- ------ --------------

Water kg 400 ------------------ ----- --------------------

Total kg 1642 Total 1642 --------------

Table No. 2:-Pollution load of Nebivolol Intermediate Stage I



Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic


I ------ 0.722 ------ ---- ----- ---- ---- --- ------- -------

M ---- 2.021 ------ ----- ----- ----- ------ ----- ---- ------

D ------ 0.080 ------- ----- ---- ----- ----- ---- ---- ------



Table No. 3:- Batch Input and output and mass Balance of Nebivolol Intermediate Stage II


Stage I Residue kg 170 Nabivolo Int I 125 Used for stage II

Trimethyl Sulfonium Iodide kg 183 Aq.Effluent 600 To ETP for Recycling

KOH kg 46 DMSO 200 To waste Water

DMSO kg 200 Hexane 160 Rec and used

Water kg 400 Hexane 10 Distillation loss

Hexane kg 200 Solvent Residue 84 TO CHWTSDF

------------------------- kg ----- Drying Loss 20 Evaporation loss

Total kg 1199 Total 1199 ------------

Table No. 4:-Pollution load of Nebivolol Intermediate Stage II.

Effluent in m3, Rest all figs in kg


Solvent Residue


Gas Generated

Inorganic Salt


II ------ 0.800 84 ---- ----- ---- ---- --- ------- ------- M ------- 2.24 235.20 ----- ----- ----- ------ ---- -------

D -------- 0.0896 9.408 ----- ------ ----- ------ --- ----- -----




Table No. :- Solvent Balance of Nebivolol Intermediate Stage II

Sr.No/ Stage


solvent

Qty Used

Recovered or

Distilled

Fugitive loss


loss

To waste Water


Product drying

loss

Spent Solvent

Fresh Make

Up

I Toluene 84 83.44 ----- 2.11 ---- --- --- --- .065

I DMSO 22.40 ------ ------ ------- 22.40 ----- --- --- 200

I/II Water 89.60 ------ ----- ---- 89.60 --- --- --- 89.60

II Hexane 22.40 17.92 ------ 1.12 ----- 9.40 2.24 4.48

Table No. :- Cumulative Pollution Load of Nebivolol Intermediate Stage II

Effluent in M3, Rest all in kgs


Solvent

Residue

Carbon Hyflow Spent

Solvent

Gas

Generated

Inorganic

Salt

Organic


I/II ------ 0.169 9.408 ---- ----- ---- ---- --- ------- -------

Table No. :- Matrix showing Molecular weight, Moles, molar ratio and consumption


Name of

Key RM

Details Mol.Wt Qty

kg

Moles Molar

Ratio

Existing

Consumption

Proposed

Consumption

Net

Consumption

RMI Reactant 263 250 0.95 1 ------ 250 250

Vitride Reactant 202 192 0.95 1 --------------- 192 192

Toluene Solvent ---- 750 ----- ---- ----- 5 5

Stage I Reactant 180 170 0.944 ------ ----------- 170 170

KOH Reagent 56 46 0.82 0.87 ----- 46 46

DMSO Solvent ------ 200 ---- ---- ----- 200 200

Water Solvent ----- 800 ---- --- -------- 800 800

Hexane Solvent ----- 200 --- --- ----- 40 40



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