5 (f) synthetic organic chemicals prepared byenvironmentclearance.nic.in/writereaddata/online/...the...

ABC TECHNO LABS INDIA PRIVATE LIMITED, CHENNAI

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5 (f) Synthetic organic Chemicals

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FEBRUARY 2017

PRE FEASIBILITY REPORT

Table of Contents

1. EXECUTIVE SUMMARY ........................................................................... 1

2. INTRODUCTION ...................................................................................... 2

2.1 Identification of the Project & Project Proponent ................................. 2

2.1.1 Project ........................................................................................ 2

2.1.2 Project Proponent ....................................................................... 2

2.2 Brief description of nature of the project ............................................. 3

2.3 Need of the project and its importance for the country ....................... 3

2.3 Demand supply gap ............................................................................ 5

2.4 Import ................................................................................................ 6

2.5 Export possibility ............................................................................... 6

2.6 Employment generation ...................................................................... 7

3. PROJECT DESCRIPTION ......................................................................... 8

3.1 Type of the project .............................................................................. 8

3.2 Location of the project ........................................................................ 8

3.3 Details of alternate site ..................................................................... 13

3.4 Size or magnitude of the operation ................................................... 13

3.5 Manufacturing Process and Material Balance ................................... 14

3.5.1 Pseudo Ephedrine HCl ............................................................... 15

3.5.2 Alprazolam ................................................................................. 18

3.5.3 Phenylepherine ........................................................................... 24

3.5.4 Triprolidine ................................................................................ 30

3.5.5 Cyclene ...................................................................................... 33

3.5.6 Bosentan .................................................................................... 37

3.5.7 Methylphenidate......................................................................... 40

3.5.8 Etafedrine HCl ............................................................................ 43

3.5.9 DL - Ritalinic acid ................................................................... 46

3.5.10 d-Ritalinic Acid HCl .................................................................. 49

3.5.11 L- oxazolidinone (Chiral) ........................................................... 51

i FEBRUARY 2017


3.5.12 DL - oxazolidinone .................................................................... 53

3.5.13 Lorazepam ................................................................................ 55

3.5.14 Amlodipine ............................................................................... 57

3.5.15 Selegeline ................................................................................. 61

3.5.16 Tranexamic acid ....................................................................... 65

3.6 Raw material requirement ................................................................ 70

3.7 Resource optimization ...................................................................... 70

3.8 Water requirement ........................................................................... 70

3.9 Quantity of waste generation (Liquid and Solid) & its management .. 74

3.9.1 Air Pollution Management .......................................................... 74

3.9.3 Noise Generation and its management ....................................... 74

3.9.4 Hazardous waste Management ................................................... 75

3.10 Power Requirement .................................................................. 75

4. SITE ANALYSIS ..................................................................................... 77

4.1 Connectivity ..................................................................................... 77

4.2 Land Form, Land use and Land ownership ....................................... 78

4.3 Topography ...................................................................................... 78

4.4 Existing Infrastructure ..................................................................... 78

4.4.1 List of Industries ........................................................................ 78

4.5 Soil Classification ............................................................................. 79

4.6 Rainfall and Climate ......................................................................... 79

4.7 Social Infrastructure ........................................................................ 79

5. PLANNING BRIEF AND INFRASTRUCTURE FOR PROPOSED PROJECT 80

5.1 Planning Concept ............................................................................. 80

5.2 Population Projection........................................................................ 80

5.3 Land Use Planning ........................................................................... 80

5.4 Assessment of Infrastructure Demand ........................................... 81

5.5 Amenities/Facilities ....................................................................... 81

6. PROPOSED INFRASTRUCTURE............................................................. 82

6.1 Industrial Area – Processing Area ..................................................... 82

6.2 Residential Area – Non Processing Area ............................................ 82

6.3 Green Belt ........................................................................................ 82

ii FEBRUARY 2017


6.4 Social Infrastructure ...................................................................... 82

6.5 Connectivity ................................................................................... 83

6.6 Drinking water Management – Source & Supply ............................... 83

6.7 Sewage Treatment System ................................................................ 83

6.8 Effluent Treatment System ............................................................... 83

6.9 Solid waste Management .................................................................. 83

6.10 Power requirement, Supply & Source ............................................. 84

6.11 Rain Water Harvesting System & Storm water management system 84

7. REHABILITATION AND RESETTLEMENT (R&R) PLAN ........................... 85

8. PROJECT SCHEDULE AND COST ESTIMATES ..................................... 85

9. ANALYSIS OF PROPOSAL (FINAL RECOMMENDATIONS) ...................... 85

List of Tables

Table 3.1 Environmental setting of the project site ...................................... 9

Table3.2 Products & their production capacity .......................................... 14

Table 3.3 Details of Hazardous waste generated ........................................ 75

Table 3.4 Details of DG Set ........................................................................ 76

Table 5. 1 Land Use Break-Up of Project Site ............................................. 81

List of Figures Figure 3.1 Location Map of Project Site ...................................................... 10

Figure 3.2 Satellite Image of the Project Site .............................................. 11

Figure 3.3 Master Layout ........................................................................... 12

Figure 3.4 Existing Water Balance ............................................................. 72

Figure 3.5 Proposed Water Balance ........................................................... 73

Figure 4.1 Site Connectivity ....................................................................... 77

iii FEBRUARY 2017


List of Annexures

Annexure – I: Land cum sale deed

Annexure – II: Raw Material Requirement

Annexure – III: Water Supply Letter from SIPCOT

Annexure – IV: Design details of Sewage Treatment Plant

Annexure –V: Design details of Effluent Treatment Plant

Annexure – VI: Green Belt Development

Annexure – VII: Consent for Establishment

Annexure VIII: Compliance to Consent

Annexure IX: Disclosure of Consultant

iv FEBRUARY 2017


1. EXECUTIVE SUMMARY

S. No. Particulars Details

1. Name of the project Proposed production of Active Pharmaceutical Ingredients by “M/s. Malladi Drugs and Pharmaceutical” in the existing plant at Plot No. 7B & 7C, SIPCOT Industrial Complex, Ranipet, Vellore district, Tamil Nadu.

2. Project Proponent M/s. Malladi Drugs and Pharmaceutical No.9 G.S.T Road ,St. Thomas Mount , Chennai -600016

3. Location of the project Plot No. 7B & 7C, SIDCO Industrial Complex, Ranipet, Vellore District-632 403

4. Co-ordinates Latitude(N) - 12°57'0.60"N Longitude(E) - 79°19'09.21"E

5. Production Capacity Production Capacity increased from 88.992 MT/month to 85.93MT/month

6. Major Raw Materials Caustic Soda, Hydrochloric Acid, Toluene, Sulphuric Acid, Methanol, Ethyl Acetate, Benzaldehyde, Heptanes , Acetic anhydride

7. Land availability 29865 Sq.m , No additional land required 8. Man Power

Requirement 317 Nos

9. Power Requirement 1450 KVA 10. Water Requirement 210 KLD to 270 KLD 11. Source of Water SIPCOT Water Supply 12. Sewage generation 8 KLD 13. Effluent Generation Zero Liquid Discharge 14. APC measures Wet scrubber, Dust collectors, Acoustic

enclosures & stacks of adequate height 15. Project Cost (Rs.) Rs. 2376.7 Lakhs

1 FEBRUARY 2017


2. INTRODUCTION

2.1 Identification of the Project & Project Proponent

M/s Malladi Drugs & Pharmaceuticals Ltd, Unit 1 is engaged in the

production of Active Pharmaceutical Ingredients for use in the

pharmaceutical industry. In view of expanding requirement and to meet

customer’s demand, the project proponent has proposed to increase the

production capacity of A.P.I.s at their factory located in SIPCOT Industrial

Area, Ranipet.

2.1.1 Project

M/s Malladi drugs and Pharmaceuticals has proposed to enhance

their production capacity of Active Pharmaceutical Ingredients at their

existing Plant located at Plot No.7B & 7C, SIPCOT Industrial Complex,

Ranipet, Tamilnadu. The existing production includes 1) Pseudo Ephedrine

HCl, 2) Alprazolam, 3) Propranolol HCl, 4) Atenolol, 5) Albendazole, 6)

Theophylline, 7) Dapsone. This proposal has been submitted for obtaining

Environmental Clearance for change in the production capacity from 88.992

MT/month to 85.93MT/month which also includes elimination of certain

Existing Products. The proposed activity will take place within the existing

factory.

2.1.2 Project Proponent

Malladi Drugs & Pharmaceuticals Ltd is one of India's most traditions

conscious and ethically sounds Pharmaceutical Company. Malladi Drugs

was founded in 1980 by late Mr. M L N Sastry, a pioneering microbiologist

with expertise in fermentation technology.

Today, Malladi is the leading manufacturer of Active Pharmaceutical

Ingredients (API) in the Cough and Cold segment along with a dominant

presence in other therapeutic segments like Anti-histamines, Anti-

convulsants, Anti-depressants and Anxiolytics (CNS) of the global

pharmaceutical industry.

2 FEBRUARY 2017


Malladi Drugs & Pharmaceuticals is having five manufacturing units

in India and one in the USA. In fact, Malladi is the only facility in the

United States of America for manufacturing Pseudoephedrine HCl. Their

manufacturing units, which are ISO 9001:2000, cGMP compliant, audited

by the USFDA, EDQM, TGA and other big Pharma Majors; establish a

benchmark for other manufacturing units in the Industry.

Malladi Drugs & Pharmaceuticals Ltd has validation capabilities

across the Product Development Cycle and facilitates quick and efficient

DMF compilation with dedicated QA and QC teams for identified projects.

Company ensures that manufacturing units are completely safe for the

environment as well as for workers. Their all units have Zero effluent

discharge and an impeccable safety record.

2.2 Brief description of nature of the project

The unit currently manufactures one product and the proponent has

planned to increase the production capacity based on market demand. The

proposed change of product in A.P.I. production will fall under Schedule 5

(f) of the EIA Notification 2006. The existing facility is located within a

notified industrial area/estate i.e. Ranipet Industrial Area, Vellore which

comes under CEPI moratorium as per CPCB hence attracts general

conditions of EIA notification 2006 & treated as Category ‘A’ project,

requires prior Environmental Clearance from the Ministry of

Environment, Forests & Climate Change (MoEFCC).

2.3 Need of the project and its importance for the country

Bulk drugs have become a part of our life for sustaining many of our

day-to-day activities, preventing and controlling diseases. Bulk drugs

manufacturing sector in India is well established and has recorded a steady

growth in the overall Indian industrial scenario. The bulk drugs and allied

industries have been amongst the fastest growing segments of the Indian

industry.

3 FEBRUARY 2017


The Indian API industry is moving at a sizzling pace and we are fast

gearing up to cash in on the bright export market prospects in next two

years. In terms of global ranking, India is now the third largest API

producers of the world just after China and Italy, and by end 2015, it is

expected to be the second largest producer after China. However, in Drug

Master File (DMF) filings India is currently ahead of China.

The API industry is poised for a bigger league in the global landscape

by 2015 due to the global drug off patent cliff. Indian API manufacturers

are likely to benefit as market dynamics undergo a major change in the

Asian subcontinent. India, Japan and China are expected to receive a

windfall of about $55-60 billion in the next two years, which is

unprecedented. As per estimates, Indian companies are expected to grab a

substantial share of the pie from the regulated markets, such as the US

and EU, which are saddled with mounting pricing pressures from low cost

providers in developing markets and backward and forward integration by

some generic companies.

The Indian pharma market is pegged approximately at Rs 1.20 lakh

crores, in which API market comprises about Rs 50, 000 - Rs 55, 000

crores. Out of 10,000 manufacturers, about 70 per cent are into drug

formulation, and the rest 30 per cent are into manufacturing APIs. Hence,

the patent expiry will provide a significant opportunity for API suppliers and

generic drugs manufacturers. It will further offer multinational pharma

companies the opportunity to outsource bulk drugs from India.

Today, the API landscape in India is quite promising due to the robust

research-based processes, low cost operations and availability of skilled

manpower. The global economic slowdown further amplified the growth

prospects of the API sectors in India, Japan and China, which on the other

hand restricted the growth in developed economies such as the US and

Europe and helped to fuel the growth in the Asian markets.

4 FEBRUARY 2017


2.3 Demand supply gap

Increasing expenditure on health: Spending on health is the main

driver of demand of pharmaceuticals. India’s private final consumption

expenditure (PFCE) on medical care and health services increased 15.4%

during FY2008 to Rs. 1,523 billion. However, in real terms, expenditure

increased 7.3% to Rs. 1,116 billion. In current prices, PFCE on medical

care and health services increased at a 5-year compound average growth

rate (CAGR) of 13.4% during FY2004-08, and at a 10-year CAGR (1998-

2008) of 17.7%.

The increasing government expenditure on health also contributes to

the demand of pharmaceutical products. The sector, by improving

indicators such as life expectancy, reduction in disease burden and child

mortality, can drive the macroeconomic growth, which will result in greater

income, consumption and investment and enhance the quality of life in

India. Estimates indicate that every Rs. 1,000 increase in per capita health

expenditure results in a 1.3% increase in life expectancy.

India’s competitive advantage lies in its lower production and research

costs, its large pool of low cost technical and scientifically trained

personnel, and the large number of US Food and Drug Administration

(FDA) certified plants. Other important factors include the popularity of

outsourcing non-critical business functions to India by MNCs, the

reintroduction of product patents for pharmaceuticals, the growing

importance of R&D related to drug discovery by Indian drug companies,

and the growing demand for generic drugs in developed markets. It is

estimated that manufacturing costs in India are between 30 to 40% lower

than those in the US and Western Europe and labour costs are one-seventh

of that in the US.

5 FEBRUARY 2017


2.4 Import

Indian pharmaceutical companies supply almost all the country's

demand for formulations and nearly 70 per cent of demand for bulk drugs.

The imports of pharmaceuticals are estimated at 10 to 12 percent of the

total market. The major suppliers are Switzerland, China, USA, Germany,

Italy, Denmark, France, and UK. Imports include raw materials and

finished products. Some major pharmaceuticals which are imported include

Provitamins and Vitamins, Cortisones, Hydrocortisone, Insulin, Penicillin,

Oestrogen, Progesterone and other hormones, Erythromycin and other

ANTIBIOTICS, Antisera & other blood fraction, and Glycosides. The imports

are from Switzerland, US and Germany primarily consist of finished

medicament in dosage forms for retail sales.

The import value of pharmaceuticals was Rs. 6,680 crore in past few

years. The imports are mainly raw materials, which account for around

70% of the imports. Imports have been growing at a CAGR of 18.4%. The

key exporting countries to India are China, Switzerland, US and Germany.

China is the largest exporter to India and accounted for 40% of the import

value in 2007-08.

(Source: Report of the Task Force, Ministry of Commerce & Industry)

2.5 Export possibility

India is currently recognized as a high-quality, low-cost skilled

producer of pharmaceuticals. It is seen not only as a manufacturing base

for Active Pharmaceutical Ingredients (APIs) and formulations, but also as

an emerging hub for biotechnology, bioinformatics, contract research,

clinical data management and clinical trials. At present, India is among the

top-20 pharmaceutical exporters world- wide and with the largest number

of US FDA inspected plants outside the USA. Various other agencies such

as Medicines and Healthcare products Regulatory Agency (MHRA) UK,

Therapeutic Goods Administration (TGA), Australia and Health Protection

Branch Canada have approved scores of plants in India. India’s exports of

6 FEBRUARY 2017


drugs and pharmaceuticals have registered strong growth during the last

few years. Exports have increased at a 5-year CAGR of 18% to around Rs.

29,100 crore in 2007-2008. India’s pharmaceutical exports are primarily to

US, Germany, Russia, UK, and Nigeria.US is the largest export market

accounting for 19% of the exports in 2007-08. India exports full basket of

pharmaceutical products comprising intermediates, APIs, Finished Dosage

Combinations (FDCs), biopharmaceuticals, vaccines, clinical services, etc.,

to various parts of the world.

2.6 Employment generation

The total direct employment potential of the proposed industry is

about 317 people. However, there are indirect employment generations due

to the project during the transportations, marketing & distribution etc.

7 FEBRUARY 2017


3. PROJECT DESCRIPTION

3.1 Type of the project

The proposed project involves the preparation of Active

Pharmaceutical Ingredients. An active ingredient (AI) is the substance of a

pharmaceutical drug that is biologically active. Terms in similar use

include: active pharmaceutical ingredient (API) and bulk active in medicine.

Some medications may contain more than one active ingredient. The

traditional word for the API is pharmacon or pharmakon which originally

denoted a magical substance or drug. A dosage form of a drug is

traditionally composed of two things: The API, which is the drug itself; and

an excipient, which is the substance of the tablet, or the liquid the API is

suspended in, or other material that is pharmaceutically inert. Drugs are

chosen primarily for their active ingredients. The main activity of the

proposed industry is manufacturing of Active Pharmaceutical Ingredients

(APIs).

It is an independent project not interlinked or interdependent project.

The proposed project of A.P.I. manufacturing plant is located in SIPCOT

Industrial Complex, Ranipet. The proposed project will utilize existing

facility with some modification.

3.2 Location of the project

The proposed activity will be carried out within the existing production

facility at Plot no. 7B & 7C, SIPCOT Industrial Complex, Ranipet – 632 403,

Vellore district, Tamil Nadu. The Environmental setting of the project site is

presented in the Table 3.1.The location map of the project area is

represented in Figure 3.1. The satellite imagery showing the project site is

given in Figure 3.2 & site layout in Figure 3.3.

8 FEBRUARY 2017


Table 3.1 Environmental setting of the project site

S. NO. PARTICULARS DETAILS 1 Site Latitude 12° 57'14.60"N 2 Site Longitude 79°19'09.21"E

3 Site Elevation above MSL

184 m

4 Nearest highway

• NH 4 – 0.5 km (SSW) • NH 46 – 3.8 km (SSE) • SH 124 A – 0.25 km (W) • Vanapadi Road – 0.75 km (E)

5 Nearest railway station Walajah Railway Station – 4.7 km (ENE) 6 Nearest airport Chennai International Airport – 90km (E)

7 Nearest town/ city

• Vanapadi – 1.38 km (NNE) • Chettithangal – 1.5 km (NNE) • Agravaram – 2.1 km (NNW) • Ranipet – 2.3 km (SSE)

8 Topography Plain

9 Archaeologically important places

Nil in 15 kmradius

10 National parks/ Wildlife Sanctuaries

Nil in 15 km radius

11 Reservoir

• Vanapadi lake - 0.81 km (N) • Thandalam lake – 0.96 km (ESE) • Maniyampattu lake – 2.4 km (W) • Palar river – 3.2 km ( S)

12 Reserved/ Protected Forests

• Ammur R. F. – 4.7 km (ENE) • TiruvallamR.F. – 5.2 km (W) • VilapakkamR.F. – 6.2 km (WSW)

13 Seismicity Zone III as per Seismic Zone Map of India 14 Defense Installations Nil in 15km radius 15 Nearest Port Chennai Port – 106 km – (NE)

9 FEBRUARY 2017


Figure 3.1 Location Map of Project Site

10 FEBRUARY 2017


Figure 3.2 Satellite Image of the Project Site

11 FEBRUARY 2017


Figure 3.3 Master Layout

12 FEBRUARY 2017


3.3 Details of alternate site

The proposed change of products will take place within the existing

facility owned & operated by M/s Malladi Drugs & Pharmaceuticals. This

site has the following advantages:

As the factory is currently in operation all infrastructural facilities are

already in place.

There is no adverse siting factor such as reclassification of land use

and pattern, R & R as the facility is located within notified Industrial

Area.

As well as the efficient functioning of any industry mainly depends on

the availability of its basic requirements viz. raw materials, fuel, power,

water, manpower etc. The industry is proposed to be established in SIPCOT

Industrial Complex, Ranipet. The choice of the land confers several

advantages, which are summarized below.

1. The land use of the site is Industrial

2. The site is well connected by roadways.

3. Water supply facility is available with SIPCOT.

4. Power will be supplied by TANGEDCO

Hence, no alternative sites were considered.

3.4 Size or magnitude of the operation

M/s Malladi Drugs & Pharmaceuticals Ltd is currently manufacturing

seven variants of A. P. I.s at the production rates detailed below. The total

proposed production capacity will be 85.83MT/month after adding, deleting

and modifying the products. Proposed project will produce A.P.Is. List of

products to be manufactured along with quantity are given in Table 3.2.

13 FEBRUARY 2017


Table3.2 Products & their production capacity

Sr. No Product

Existing Qty

Proposed Qty

Mt / M Mt / M 1 Pseudo Ephedrine Hcl 12 40 2 Alprazolam 0.12 0.1 3 Propranolol Hcl 24 0 4 Atenolol 48 0 5 Albendazole 0.18 0 6 Theophylline 3 0 7 Dapsone 1.8 0 8 Phenylepherine 0 10 9 Triprolidine 0 0.5 10 Cyclene 0 5 11 Bosentan 0 0.5 12 Methylphenidate 0 0.08 13 Eta ephedrine 0 0.05 14 DL - Ritalinic acid 0 3 15 D-Ritalinic Acid 0 0.5 16 L - Oxa 0 10 17 Dl - Oxa 0 10 18 Lorazepam 0 0.05 19 Amlodipine 0 1 20 Tranaxemic acid 0 5 21 Seligiline 0 0.05 Total 89.1 85.83

3.5 Manufacturing Process and Material Balance

The manufacturing process for each product proposed to be produced is

described with process description and material balance flow charts as given

below.

14 FEBRUARY 2017


3.5.1 Pseudo Ephedrine HCl

Manufacturing process

A. Process Description:

Pseudoephedrine is a sympathominetic amine that relieves nasal congestion

commonly associated with colds or allergies. T he stage wise production

details are described below.

Stage: 1

L-Ephedrine hydrochloride is basified with caustic solution to obtain l-

ephedrine base which is extracted with toluene to separate aqueous layer

and finally partially distilled off solvent to obtain l- ephedrine in solvent.

Stage-2

L-Ephedrine base in solvent obtained in stage-1 is added to acetic anhydride

and subsequently treated with sulphuric acid. Then toluene and acetic acid

mixture is distilled out to obtain acetyl ephedrine.

Stage-3

Acetyl ephedrine obtained in the previous stage is mixed with water, heated

to boil, basified with caustic solution in toluene medium. Then the aqueous

layer is taken for further extraction and aqueous layer is discarded. The

base in toluene medium is washed with de - mineralized water and toluene

is recovered cooled and centrifuged to obtain pseudo ephedrine base as

solid.

Stage- 4

Pseudoephedrine base is acidified with hydrochloric acid, bleached with

activated carbon and filtered to obtain filtered pseudoephedrine

hydrochloride in solution. This solution is concentrated and crystallized by

distilling off excess water, centrifuged, dried and get Pseudoephedrine

Hydrochloride.

15 FEBRUARY 2017


Process Flow Chart of Pseudo Ephedrine HCl

Material Balance S.No Stage Name Inputs Qty.

(kg/d) Outputs Qty.(kg/d)

1.

l - Eph Base Preparation

20A

DM water 900

Water + Sodium chloride179 Kg +

25 Kg Sodium hydroxide

1129

Caustic Soda Flakes 144 Distilled Toluene

recycle 280

l - Eph.salt 600 l-Eph.base in Toluene 680

Toluene 473 Toluene vapour loss 29

2117 2117

2. Acetylation l - Eph.Base in 680 Rec.acetic acid 840

16 FEBRUARY 2017


20B

Solvent (80% sold)

A. Anhydride 735 Acelytated Mass 725

Sulphuric Acid 340 Toluene ® 163.4

Toluene vapour loss 27

1755 1755

3.

Hydrolysis & Basification

20C

DM Water 1950

Acet.Mass 725 Pseudo base in Toluene 1725

Toluene 860 Sod. Sulphate 490 Kg + Sod. Acetate

in Aq.layer 3271.2

Caustic lye 1500 Toluene vapour loss 39

(Water 1000 L + NaoH

500 kgs)

5035 5035

4.

Extraction washing &

Solvent recovery 20C

Pseudo base in Toluene 1725 Pseudo base 440

Sod.Sulphate490 Kg + Sod. Acetate in Aq.layer

3271.2

Sod. Sulphate 490 Kg + Sod. Acetate

in Aq. layer 3219

Toluene 817 Toluene ® 774

D M Water 800 Wash water recycle 800

Toluene vapour loss 50

Base Mother liquor 1330

6613 6613

5. Bleaching

21A1

DM water 400 Pseudo salt in Water 1130

Hydrochloric acid 290 Charcoal 1

Pseudo Base 440

Chalcoal 1

1131 1131

6. Concentration Pseudo Eph.salt Rec.water ® 450

17 FEBRUARY 2017


3.5.2 Alprazolam

Manufacturing process A. Process Description:

Alprazolam is anxiolytic, a short-acting drug of the benzodiazepine class

used to treat moderate to severe anxiety disorders, panic attacks, and as an

adjunctive treatment for anxiety associated with clinical depression. The

stage wise preparation details are listed below.

Stage- 1

2 Amino 5 chloro benzophenone, chloro acetyl chloride and acetic acid are

charged into a glass lined reactor to get chloroacetamide 5 chloro

benzophenone.

Stage- 2

The isolated chloroacetamide compound is charged into a stainless steel

reactor along with hexamine, ammonium carbonate and methanol refluxed

for sufficient time to get dimethyl diazepem.

Stage- 3

This is taken into a stainless steel reactor and polysulphide i.e.

phosphorous pentasulphide, sodium bicarbonate and acetonitrile are

charged. On completion of the reaction sulphadiazepam is obtained.

Stage- 4

21A2

in Water 1130 Conc. Mass 650

Water vapour loss 30

1130 1130

7.

Centrifuging 21A

Crystallised Mass 650 Pseudo 1st Crop 350

Acetone 165.9 Acetone wash (Recovered & sold) 142.2

Acetone vapour loss 23.7

Mother liquor recycle 300

815.9 815.9

18 FEBRUARY 2017


This sulpha diazepam, Acetyhydrazide compound and iso propyl alcohol are

charged into a stainless steel reactor and refluxed to get alprazolam

intermediate.

Stage- 5

The alprazolam intermediate is refluxed with xylene to get alprazolam crude.

This crude is dissolved with methanol, bleached with carbon, filtered

through hyflow bed, concentrated, cooled and centrifuged to get alprazolam.

Process Flow Chart of Alprazolam

19 FEBRUARY 2017


Material Balance for Alprazolam

Stage 1: Chloroacetamide preparation

Input Material (kg/d) Output Materials (kg/d)

S.No.

Raw materials (Chemicals) Reactant /

Solvent Name of the

Output

Effluent to ETP Recovery/

Recycle

Products

By Produ

cts

Residue

Loss Name Fresh

Input

Recyled

Input

Total

Qty

Organic

Imp.

Inorganic

Imp.

01 Acetic Acid 50.00 0 50 Reactant Chloroacetamide 26

02 Chloro acetyl

chloride 13.00 0 13 Reactant

water 50Kg+HCl

7.0Kg+Acetic acid50Kg

107

03

2 Amino 5 Chloro

Benzophenone

20.00 0 20 Reactant

04 DM water 50.00 0 50 Reactant

Stage 2: NDP preparation


S.No.

Raw materials (Chemicals) Reactant

/ Solvent

Name of the Output


Recycle

Products

By Produ

cts

Residue Loss

Name

Fresh

Input

Recycled

Input

Total

Qty

Organic

Imp.

Inorganic Imp.

01 Chloroaceta

mide 26.0

0 0 26 Reactant NDP 19.5

02 Methanol 144.0 0 14

4 Solvent Methanol Loss 10.4

03 Hexamine 32.50 0 32.

5 Reactant water 50Kg+HCl 100.5

20 FEBRUARY 2017


50.50Kg

04 Ammonium carbonate

11.50 0 11.

5 Reactant Recovered Methanol 133.6

05 DM water 50.00 0 50 Reactant Recovered

Toluene 18.7

06 Toluene 20.00 0 20 Solvent Toluene Loss 1.3

Stage 3: Thione Preparation


S.No.

Raw materials (Chemicals) Reacta

nt / Solvent

Name of the Output

Effluent to ETP Recovery/ Recycle

Product

By Product

Residue

Loss Name Fresh

Input

Recycled Inpu

t

Total Qty

Organic

Imp.

Inorganic

Imp.

01 NDP 19.50 0 19.50 Reactant Thione 16.5

02 Acetonitrile 92.00 0 92 Solvent Acetonitrile 88 03 Posporuspe

nta sulphide 12.00 0 12 Reactant Acetonitrile Loss 4

04 Sodium bicarbonate 15.50 0 15.5 Reactan

t

water100Kg+PhosperousSulphides+

Sodium bi carbonate

130.5

05 DM water 100.00 0 100 Reactan

t Stage 4: Inter Preparation


S.No.


Solvent

Name of the Output


Recycle

Products

By Produ

cts

Residue Loss

Name Fresh Input

Recycled

Input

Total

Qty

Organic

Imp.

Inorganic Imp.

01 Thione 16.50 0 16. Reactan Inter 15

21 FEBRUARY 2017


5 t

02 Hydrazine Hydrate 18.00 0 18 Reactan

t I P A 130.8

03 Isopropyl alcohol

141.00 0 14

1 Solvent IPA Loss 10.2

04 Toluene 39.00 0 39 Solvent water100Kg+Hy

drogen sulphide19.5Kg 119.5

05 D M Water

100.00 0 10

0 Reactan

t Toluene 36.5

06 Ethyl Acetate 52.00 0 52 Solvent Toluene Loss 2.5

07 Acetone 10.00 0 10 Solvent Ethylacetate 52 Acetone 9 Acetone Loss 1

Stage 5: Crude Alprazolam Preparation Input Material (kg/d) Output Materials (kg/d)

S.No.


Solvent

Name of the Output


Recycle

Products

By Produc

ts

Residue

Loss Nam

e Fresh Input

Recycled Input

Total

Qty

Organic Imp.

Inorganic Imp.

01 Inter 15.00 0 15.00

Reactant

Crude Alprazolam 12.5

02 Xylene

127.50 0 127.

5 Solvent Xylene 125

Xylene Loss 2.5

Crude ML 2.5 Stage 6: Purification Input Material (kg/d) Output Materials (kg/d)

S.No.

Raw materials (Chemicals) Reactan

t / Solvent

Name of the

Output


Recycle

Products

By Produ

cts

Residue Loss

Name

Fresh

Input

Recycled

Input

Total

Qty

Organic

Imp.

Inorganic

Imp.

22 FEBRUARY 2017


01 Crude

Alprazolam 12.5 0 12.5 Reactant Alprazola

m 10 02 Methanol 98.0 0 98 Solvent Methanol 90.9 03 Activated

charcoal 0.50 0 0.5 Reactant Methanol Loss 7.1

Spent

Charcoal 3

23 FEBRUARY 2017


3.5.3 Phenylepherine

Manufacturing process Process Description

l- Phenylephrine hydrochloride is a mydriatic and a decongestant.

Phenylephrine is a α-adrenergic receptor agonist used as an agent to dilate

the pupil and to increase blood pressure. Phenylephrine has recently been

marketed as a substitute for pseudoephedrine. The following lists the

various stages in the synthesis of l- Phenylephrine hydrochloride.

Stage 1:

The alpha-methyl-m-hydroxyacteophenone sulphate undergoes

hydrogenation in the presence of palladium on carbon catalyst to produce

dl-phenylephrine base.

Stage 2:

The dl-phenylephrine base further undergoes resolution by using tartaric

acid to obtain d-phenylephrine bitartrate as a solid and l-phenylephrine

bitartrate as liquid.

Stage 3:

L-phenylephrinebitartrate further basified with ammonia solution and

centrifuged to get l-phenylephrine base.

Stage 4:

D-phenylephrinebitartrate further basified with ammonia solution and

centrifuged to get d-phenylephrine base.

Stage 5:

D-phenylephrine base undergoes inversion by adding acetic anhydride and

H2SO4 to produce l-phenylephrine base.

Stage 6:

The l-phenylephrine base obtained is treated with hydrochloric acid to

produce l- phenylephrine hydrochloride.

24 FEBRUARY 2017


Figure No: 3. 1process flow chart of Phenylepherine

Material Balance Stage - I Hydrogenation- 9A

S.NO Input Qty in Kg/Batch Output

Qty in Kg/Bat

ch 01 MAAP sulphate 320 dl-Phenylephrine Base 215

02 DM Water 760 Palladium catalyst(Recycle) 12

03 Palladium catalyst 9 dl-Phenylephrine Base ML(Recycle) 1070

04 Hydrogen in m3 0 Activated carbon 4 05 Activated carbon 2 06 Liquor ammonia 210 0 0

25 FEBRUARY 2017


9AM Total 1301 Total 1301

01 dl-Phenylephrine Base ML(Recycle) 1070 dl-Phenylephrine Base 23

02 DM Water 150 dl-Phenylephrine Base ML(Recycle) 365

03 Methanol 60 Ammonium Sulphate 120

04 Liquor ammonia 35 Water+Methanol recovered 75

05 Dil Sulphuric acid 20 Methanol distillation loss 7

Water 745

1335 1335

Stage I The ETP Load (kg) 745

Stage I ETP Load for 10 MT (kg) 40230

Stage I Ammonium sulphate (kg) 120

Stage I Ammonium sulphate for 10 MT (kg) 6480

Stage II-9B

S.NO Input Qty in Kg/day Output Qty in

Kg/day

dl-Phenylephrine

Base 500 d-Phenylephrine bitartarate 437.5

01 Tartaric acid 500 l-Phenylephrine bitartarate ML(Recycle) 1750

02 Iso Propyl alcohol 938.125 03 DM Water 250 Total 2188.125 Total 2187.5

Stage II no ETP Load. Stage – III-9C

S.NO Input Qty in kg/day Output Qty in

kg/day

01 l-Phenylephrine bitartarate ML 1750 l-Phenylephrine base 225

02 DM Water 725 l-Phenylephrine base ML(Recycle) 1625

03 Activated carbon 3 Distilled IPA 967.5 04 Liquor ammonia 368.75 IPA Distillation loss 29

Total 2846.75 Total 2846.5 9CM 01 l-Phenylephrine

base ML(Recycle) 1625 dl-Phenylephrine Base 81.25

02 DM Water 62.5 dl-Phenylephrine Base ML(Recycle) 1756.25

03 Liquor ammonia 150 9AM 1837.5 1837.5

26 FEBRUARY 2017


01 dl-Phenylephrine Base ML(Recycle) 1756 dl-Phenylephrine

Base 38


03 Methanol 125 Ammonium Tartarate 231


05 Dil Sulphuric acid 44 Methanol distillation

loss 13

Water 1281

2218.75 2218.75

Stage III The ETP Load (kg) 1281

Stage III ETP Load for 10 MT (kg) 43562.5

Stage III Ammonium Tartarate (kg) 231.25

Stage III Ammonium Tartarate for 10 MT(kg) 7862.5

Stage – IV 9D


kg/day

01 d-

Phenylephrine bitartarate

400 d-Phenylephrine base 170

02 DM Water 580 d-Phenylephrine base ML(Recycle) 1160

03 Liquor ammonia 350

Total 1330 Total 1330

01

d-Phenylephrine

Base ML(Recycle)

1160 dl-Phenylephrine Base 29


03 Methanol 69 Ammonium Tartarate 200



Water 829

1457 1457

Stage IV The ETP Load (kg) 828.7

Stage IV ETP Load for 10 MT(kg) 30661.0

Stage IV Ammonium Tartarate (kg) 200.0

Stage IV Ammonium Tartarate for 10 MT(kg) 7400.9

Stage –V-9E

27 FEBRUARY 2017



kg/day

01 d-Phenylephrine base 320 l-Phenylephrine base 309

02 Aceticanhdride 1280 l-Phenylephrine base ML(Recycle) 2100

03 Sulphuric acid 219.5 Acetic acid(85%) Sale 1432 04 DM Water 1680 Acetic acid Distillation loss 56 05 Activated carbon 3 Activated carbon 6.5 06 Liquor ammonia 400 Total 3903 Total 3903

01 l-Phenylephrine Base ML(Recycle) 2099.5 dl-Phenylephrine Base 77.35

02 DM Water 276.25 dl-Phenylephrine Base ML(Recycle) 751

03 Methanol 154.7 Ammonium Sulphate 232 04 Liquor ammonia 88.4 Water+Methanol recovered 155

05 Dil Sulphuric acid 55.25 Methanol distillation loss 22

Water 1437

2674.1 2674.1

Stage V The ETP Load (kg) 1436.5

Stage V ETP Load for 10 MT (kg) 25857

Stage V Ammonium sulphate (kg) 232.05

Stage V Ammonium sulphate for 10 MT is(kg) 4176.9

Stage – VI- 9F


kg/day 01 l-Phenylephrine base 320 l-Phenylephrine base 250

02 Iso Propyl alcohol 1260 l-Phenylephrine base ML(Recycle) 1730

03 DM Water 420 Iso propyl alcohol loss 20


Stage VI no ETP Load. Stage – VII 9G


kg/day

01 l-Phenylephrine base 400 l-Phenylephrine base 380

02 DM Water 1100 l-Phenylephrine base ML(Recycle) 1878

03 Dil. Sulphuric acid 380 Activated carbon 5

28 FEBRUARY 2017


04 Activated carbon 3 05 Liquor ammonia 380 Total 2263 Total 2263

01 l-Phenylephrine

Base ML(Recycle)

1878 l-Phenylephrine Base 60


03 Methanol 130 Ammonium Sulphate 230 04 Liquor ammonia 70 Water+Methanol recovered 150


Water 1380

2370 2370

Stage VII The ETP Load (kg) 1380

Stage VII ETP Load for 10 MT (kg) 38640

Stage VII Ammonium sulphate (kg) 230

Stage VII Ammonium sulphate for 10 MT(kg) 6440

Stage – VIII-9H


kg/day

01 l-Phenylephrine base 400 l-Phenylephrine HCl Crude 380

02 DM Water 125 l-Phenylephrine HCl Crude ML(Recycle) 625

03 HCl 250 Water Recovered 375

04 Activated carbon 7.5 Water distillation loss 37.5

05 Hyflow supercell 0 Activated carbon+Hyflow supercell 9

IPA 325 Methanol 320 Total 1428 Total 1426.5

Stage VIII The ETP Load is 375 Stage VIII ETP Load for 10 MT is 9750

Stage –IX- 10A


kg/day ETP Load

01 l-Phenylephrine HCl Crude 340 l-Phenylephrine HCl 260

02 Activated carbon 1.5 l-Phenylephrine HCl ML(Recycle) 565

03 Hyflow supercell 0 Activated carbon 3.5 04 IPA 240 Hyflow supercell 0

29 FEBRUARY 2017


05 Methanol 248 Total 829.5 Total 829 Stage IX no ETP Load.

3.5.4 Triprolidine

Process Description

Triprolidine hydrochloride is used to combat the symptoms associated with

allergies and is sometimes combined with other cold medications designed

to provide general relief for flu-like symptoms. The stages involved in the

production are given below.

Stage –1 - Triprolidine Oxalate preparation

The Triprolidine inter is treated with sulphuric acid and extracted n-hexane.

The resultant reaction mixture is further treated with methanol and oxalic

acid to obtain Triprolidine oxalate.

Stage –2 - Triprolidine Hydrochloride preparation

The Triprolidine oxalate is treated with ammonia and extracted by using n-

hexane the resultant reaction mixture is treated with IPA HCL to obtain

triprolidine crude. The Triprolidine crude recrystallised in water and further

treated with acetone to obtain Triprolidine hydrochloride.

30 FEBRUARY 2017

http://en.wikipedia.org/wiki/Allergy

http://en.wikipedia.org/wiki/Common_cold

http://en.wikipedia.org/wiki/Influenza


Process Flow chart of Triprolidine

31 FEBRUARY 2017


Material balance

Stage I

S.No. Raw material Input

Qty in kg Product Output Qty in

kg 1 Triprolidine inter 160 Triprolidine oxalate 110

2 Sulphuric acid 704 Water447.9Kg+Ammonium Sulphate948.2Kg 1396.1

3 D M Water 176 Hexane recovered (Recycle) 823.7 4 Ammonia 340 Hexane distillation loss 19.8 5 Formic acid 32 Methanol recovered 586 6 Hexane 843.5 Methanol distillation loss 15.82 7 Methanol 601.9 Unreacted mass to recycle 80 8 Oxalic acid 160 Recovered IPA 282.9 9 Activated carbon 14 IPA distillation loss 15.7 10 Isopropyl Alcohol 298.6 Total:- 3330 3330

Stage II

S. No.

Raw material Input

Qty in kg

Product Output

Qty in kg

1 Triprolidine oxalate 110 TriprolidineHCl.Crude 90

2 D M Water 420 Water403.5Kg+Ammonium Oxalate91.1Kg 494.6

3 Ammonia 25 n-Hexane recovered(Recycle) 316.3

4 n-Hexane 329.4 n-Hexane distillation loss 13.1 5 Hydrochloric acid 36.0 Unreacted Residue 40 6 Activated carbon 2 7 Acetone 31.6 Total:- 954 954

Stage III

S.No. Input Qty in kg Output Qtyinkg

1 TriprolidineHCl.Crude 90 Pure Triprolidine HCl 50 2 D M Water 70 Water 25

Water loss 5

Mother liquor(Recycle) 80

Total 160 160

32 FEBRUARY 2017


3.5.5 Cyclene

Manufacturing Process This is an intermediate to make MRI contrast agent. Detailed here

below are the various stages involved in the manufacture of cyclene.

STAGE -1 - Hydrogenation

Benzaldehyde is hydrogenated in presence of ethanolamine and

isopropyl alcohol (IPA) as medium to form n-benzyl ethanolamine. Recovered

IPA & unreacted mixture are recovered by distillation and reused for the

next batch.

STAGE -2 - Cylization

n-benzyl ethanolamine is treated with sulphuric acid in toluene

medium and diluted with water and then neutralised with sodium hydroxide

and distilled. During distillation n-benzylaziridine is obtained. This is

treated with methanol and para toluene sulphonic acid and neutralised with

sodium hydroxide and centrifuged to get crude tetra benzyl cyclene. This is

further purified with ethyl acetate and gets Tetra benzyl cyclene.

STAGE -3 - Hydrogenation

Pure tetra benzyl cyclene is dissolved in water and treated with

hydrochloric acid and hydrogenated in presence of Palladium on carbon

catalysts. The hydrogenated mass is neutralised with sodium hydroxide and

centrifuged to get crude cyclene. Crude cyclene is recrystallised with water

and get Cyclene.

33 FEBRUARY 2017


Material Balance

Stage – I

Sl.No. INPUT OUTPUT Water Inorganic Organic Name of Chemicals Unit Qty Name of Product Qty 1 BENZALDEHYDE kg 210 NBEA 305 2 MONO ETHANOLAMINE kg 122 Rec IPA 500.045 3 ISO PROPYL ALCOHOL kg 510.25 Caustic residue to ETP 70 70 4 PALLADIUM kg 0.42 PALLADIUM (Recycle) 0.357 5 SODIUM HYDROXIDE kg 50 Vapour loss 17.268 TOTAL 892.67 TOTAL 892.67 0 70 0

Stage – II Sl.No. INPUT OUTPUT

Water

Inorganic

Organic

Name of Chemicals Uni

t Qty Name of Product Qty 1 N-BENZYLE EHANOLAMINE kg 400 CRUDE TBC 315.0

2 TOLUENE kg 3096 RECOVERED TOLUENE(RECYCLE) 3034.1

3 SULPHURIC ACID kg 392 TOLUENE LOSS 61.9 4 Raw water kg 5200 Aziridine layer to ETP 3300.0 2640 660.0 5 SODIUM HYDROXIDE kg 600 METHANOL recovered 2334.2 6 Water for caustic soln ppn 600 Methanol loss 68.0 7 METHANOL kg 2457 Lees 5100.0 4692 408.0

8 PARA TOLUENE SULPHONIC ACID kg 200 EA layer ( Recycle) 160.2

34 FEBRUARY 2017


9 Ethyl acetate 178 HCl 150 Sulphuric acid 500

10 DM water 600

TOTAL 1437

3 TOTAL 14373.

35 7332 1068 0

Stage III (Pure TBC) Sl.No

. INPUT OUTPUT Water Inorgani

c Organi

c


t Qty Name of Product Qty

1 CRUDE TETRA BENZENE CYCLEN kg 300

PURE TETRA BENZYL CYCLEN 130

2 ETHYL ACETATE kg 3000 RECOVERED ETHYL ACETATE (R) 2900

3 CALCIUM CHLORIDE kg 37.5 RESIDUE 150 150

ETHYL ACETATE DISTILLATION LOSS 57.5

Calcium Chloride layer 100 100

TOTAL 3337.

5 TOTAL 3337.5 0 100 150 Stage IV (Crude Cyclene)

Sl.No. INPUT OUTPUT

Water

Inorganic

Organic


t Qty Name of Product Qty 1 PURE TETRA kg 200 CRUDE CYCLEN 120

35 FEBRUARY 2017


BENZYLE CYCLEN

2 DM WATER kg 600 TOLUENE(RECYCLE) 50

3 HYDROCHLORIC ACID kg 90 PALLADIUM CARBON (RECYCLE) 1.285625

4 PALLADIUM CARBON kg 1.5125 Crude cyclen ML 465

465.0 5 CAUSTIC SODA kg 140 Distilled water to ETP 540 540.0 6 Water for caustic ppn kg 150 Distillation loss 5

TOTAL 1181.5

1 TOTAL 1181.28562

5 540 465 0

Stage V (Pure Cyclene) Sl.No. INPUT OUTPUT Water Inorganic Organic

Name of Chemicals Unit Qty Name of Product Qty 1 CRUDE CYCLEN kg 240 CYCLEN 108 2 DM WATER kg 314.4 WATER+SODIUM CHLORIDE 444 444 3 HYFLOW kg 1 HYFLOW RECOVERED (SALE) 2 2 4 CARBON kg 1 CARBON RECOVERED (WET) 2 2

TOTAL 556.4 TOTAL 556 0 444 4

36 FEBRUARY 2017


3.5.6 Bosentan

Process description

BP-Di chloro to ChloroSulfonamide (CSA) (Stage - I):

BP –Dichloro (BipyrimidinDichloro), TBBSA (4-Tert-Butylbenzene

sulphonamide), Potassium carbonate and TBAB (Tetra Butyl Ammonium

Bromide) mix in toluene then Heat the mass & maintain the mass at reflux

by eliminating the water through dean stark. After completion of reaction

cool and centrifuge mass to get ChloroSulfonamide (CSA).

Chloro Sulfonamide (CSA) to Bosentan Sodium salt crude to Bosentan

sodium salt pure (Stage - II):

Chloro Sulfonamide (CSA) is mixed with Ethylene Glycol, Sodium Hydroxide

flakes, DM water mixture and heat the mass. After completion of reaction

cool the mass and centrifuge to Bosentan sodium salt crude. This crude

material treated with ACE mixture to get Bosentan sodium salt pure.

Crystallization of Bosentan Monohydrate (Stage - III), Drying and

sieving (Stage-IV):

Bosentan Sodium salt pure dried material treated with Hydrochloric acid

(~30%) in acetone medium then separates the sodium salt by filtration. Then

distill out the solvent and add DM water. Cool the mass and centrifuge to

get Bosentan Monohydrate wet material. Dry the material under reduced

pressure to get Bosentan Monohydrate.

37 FEBRUARY 2017


Process Flow Chart of Bosantan

38 FEBRUARY 2017


Material balance Stage - I

S.No Input Qty in Kg Output Qty

in Kg

01 BP-Dichloro 28 ChloroSulfonamide (Dry) 50

02 Toluene 457 water 10 03 TBBSA 19 Mother liquor( Toluene) 422 04 Potassium carbonate 13 Vapour loss 36 05 TBAB 1 Total 518 Total 518

Stage - II

S.No Input Qty in Kg/day Output Qty in

Kg/day

01 ChloroSulfonamide (Dry)

50 Distilled Ethylene glycol

56

02 Ethylene glycol 839 Mother liquor( MEG) 800 03 DM Water 30 Vapour loss 33

04 Caustic soda 30 Bosantan sodium salt crude

60

Total 949 Total 949

Stage - III


in Kg

01 Bosantan sodium salt crude

60 Bosantan sodium salt pure

38

02 Seed 1 Mother liquor( ACE ) 720 03 ACE mixture 705 Vapour loss 8 Total 766 Total 766

Stage – IV


in Kg

01 Bosantan sodium salt pure 38 Bosantan monohydrate 35

02 Acetone 395 Distilled acetone 195

03 DM water 73 Mother liquor ( Water+Acetone ) 220

04 HCL 8 Vapour loss 50 05 Sodium chloride salt 15 Total 515 Total 515

39 FEBRUARY 2017


3.5.7 Methylphenidate

Process Description

Methyl phenidate is a prescriptionstimulant commonly used to treat

Attention-Deficit Hyperactivity Disorder (ADHD). It is also one of the primary

drugs used to treat the daytime drowsiness symptoms of narcolepsy and

chronic fatigue syndrome. The drug is used to treat cancer-related fatigue.

Methanol and threo-ritalinic acid and methanol are charged, stirred

and heated. Then hydrochloric acid gas is passed. The mass is heated and

distilled off methanol partially, cooled to 0°C and centrifuged to get crude

methylphenidate hydrochloride. Then the crude is re crystallised with DM

water and centrifuged washed with acetone to get methylphenidate

hydrochloride. The wet methylphenidate hydrochloride is dried.

40 FEBRUARY 2017

http://en.wikipedia.org/wiki/Medical_prescription



http://en.wikipedia.org/wiki/Attention-deficit_hyperactivity_disorder

http://en.wikipedia.org/wiki/Drug

http://en.wikipedia.org/wiki/Drowsiness

http://en.wikipedia.org/wiki/Narcolepsy

http://en.wikipedia.org/wiki/Chronic_fatigue_syndrome


Process Flow chart of Methylphenidate

41 FEBRUARY 2017


Material Balance

Stage -61A

S.No. Input Quanti

ty

Total Qty in

kg Output Quanti

ty Loss Total Qty

in kg

1

Threo-Ritalinic acid

HCl 100 Kg 100.0

0

Crude Methylphenidate

HCl

85 Kg

85

Methylphenidate HCl (as residue) 21 Kg 21.00

2 Methanol 247 Kg 277 Recovered methanol 211 Kg 211.0

0

Consumption of

methanol 12.5 Kg 12.50

Evaporation loss of methaol 47.5

Kg 47.50

3 Hydrochloric acid 35% 118 Kg 118.0

0

HCl consumption for

reaction 14.5

Kg 14.50

Evaporation loss 26.8 Kg 26.80

4 Sulphuric acid 46 Kg 46.00 Mother liquor 122.7

Kg 122.70

Total 541.00 Total 541.

00 Stage - 61B

S.No.

Input Qty Total Qty in

kg Output Qty Loss

Total Qty in

kg

1 Crude

Methylphenidate HCl

100 Kg 100

Pure Methylphenidate

HCl

80 Kg 80

Methylphenidate

HCl (residue) 18 Kg 18

2 Activated Carbon 1 Kg 1 Distilled water 387

Kg 387

Evaporation loss 50 Kg 50

3 Hyflowsupercel 1 Kg 1 Mother liquor + Acetone wash

60 Kg 60

Evaporation loss 8 Kg 8

4 Water 435 Kg 435 Spent carbon 2.0

Kg 2

5 Acetone 70 Kg 70 Spent Hyflow 2.0

Kg 2

Total 607 Total 607

42 FEBRUARY 2017


3.5.8 Etafedrine HCl

Process Description

Stage-1: Preparation of l - Ephedrine base

l-Ephedrine HCl is basified with caustic solution to convert l-Ephedrine

Base and extracted with toluene. The toluene layer is washed with DM water

to remove any inorganic salts present. The combined aqueous layer is

extracted with Toluene. The aqueous layer is transferred to ETP. The

combined toluene extract is again washed with DM water and Toluene is

distilled out to get l-Ephedrine Base.

Stage -2: Preparation of Etafedrine base

l-Ephedrine base is charging into Acetonitrile, sodium carbonate and ethyl

bromide charged into the l - Ephedrine Base solution. Heat the mass to

reflux then cooling and filtration. Charge water and Toluene into the mixture

and adjust the pH with caustic soda Separate the toluene layer and distilled

out toluene to get Etafedrine base.

Stage -3: Etafedrine base to Etafedrine HCl

Charge IPA, Etafedrine base and adjust the pH with HCl. Bleached with

activated carbon, and filter. Filtrate mass is concentrated and charged IPA,

cooled and centrifuged to get Etafedrine HCl.

43 FEBRUARY 2017


Process flow chart of Etafedrine HCl

44 FEBRUARY 2017


Material balance S.No Stage Name Inputs Qty in

kg Outputs Qty in kg

1.

l - Eph Base Preparation

28A

DM water 900

Water + Sodium

chloride 179 Kg + 25 Kg

Sodium hydroxide

1129

Caustic Soda Flakes 144

Distilled Toluene recycle

280

l - Eph.salt 600 l-Eph.base in Toluene 680

Toluene 473 Toluene vapour loss 29

2117 2117

2.

l-Ephedrine base to Etafedrine base crude

28B

l Ephedrine base 200

Acetonitrile 825.3 Etafedrine base crude

230

Sodium carbonate (Anhydrous) 160 Recovered

Acetonitrile 786

Ethyl bromide 240 Ethyl bromide salt

250

DM water 420 Recovered Toluene

645

Toluene 688 Vapour loss 672 Caustic soda

flakes 40

Sodium sulphate (anhydrous) 10

2583.3 2583

Etafedrine base crude 300

Etafedrine base 1st fraction 40

Etafedrine base Main fraction 260

300 300 4.

Etafedrine base to Etafedrine HCl

28D

Etafedrine base 220 Etafedrine HCl 220

Hydrochloric acid 115 Recovered Isopropyl alcohol 397.5

Activated carbon 1 Mother Liquor 795

45 FEBRUARY 2017


Isopropyl alcohol 1311.75 Acetone wash 47.7

DM water 100 Vapour loss 343 Acetone 55.65

1803.4 1803

3.5.9 DL - Ritalinic acid

Process description

Stage - 1: α- Phenyl-2-piperidyl acetamide (erythro rich) to α- Phenyl-2-

piperidyl acetamide (threo rich):

α- Phenyl-2-piperidyl acetamide containing rich of erythro form is treated

with alkaline solution at elevated temperature and centrifuge to get threo

rich α- Phenyl-2-piperidyl acetamide.

Stage - 2: α- Phenyl-2-piperidyl acetamide (threo rich) to α- Phenyl-2-

piperidyl acetamide HCl (threo pure):

α- Phenyl-2-piperidyl acetamide (threo rich) is converted into HCl salt using

dilute HCl acid. This salt is purified with dichloromethane

Stage - 3: α- Phenyl-2-piperidyl acetamide HCl (threo pure) to dl - Ritalinic

acid HCl crude:

α- Phenyl-2-piperidyl acetamide HCl (threo) is hydrolysed with HCl at

elevated temperature and centrifuge to get dl - Ritalinic acid HCl (crude).

Stage - 4: dl - Ritalinic acid hydrochloride crude to dl - Ritalinic acid HCl

dl - Ritalinic acid HCl crude is purified with isopropyl alcohol and centrifuge

to get dl - Ritalinic acid HCl.

46 FEBRUARY 2017


Process flow chart of dl-Ritalinic Acid HCl

Material Balance Stage - 51A

S.No INPUT Total qty in kg

OUTPUT Quantity in kg

loss Total qty in kg

1 alpha-Phenyl-2-piperidyl acetamide (erythro rich)

115.5 Material 100.485 100.485

2 Potassium hydroxide 85%

144.375 Mother liquor

544.005 77.385 621.39

3 Water 462 Total 721.875 Total 721.875

47 FEBRUARY 2017


Stage - 51B

S.No

Input Total qty in kg

Output Quantity in kg


1 Stage -51A 100.4 Stage - 51B 116.5 116.56

2 Water 246.1 HCl crude during reaction

14.16 16.9 31.15

3 Hydrochloric acid 35%

45.22 Distilled water 220.0 24.1 244.18

4 Isopropyl alcohol

157.7 Isopropyl alcohol

127.6 30.1 157.76

5 Dichloromethane

1396.74 Dichloromethane

743.5 653.1

1396.74

6 Total 1946.39 Total 1946.39

Stage - 51C S.No Input Total

qty in kg

Output quantity loss Total qty in kg

1 Stage - 51B 116.563 Stage - 51C 90.44 90.44

2 Hydrochloric acid 35% 316.47 HCl gas 16.6801 93.833 110.51

3 Water 1004.77 Distilled water 1060.02 150.72 1210.74

4 Isopropyl alcohol 78.878

Mother liquor + IPA wash

62.7923 16.07 78.866

Residue 26.1217 26.12 Total 1516.68 Total 1516.67

Stage - 51D S.No Input Total

qty in kg



1 Stage - 51C 90.436 Stage - 51D 58.78 58.784

2 Water 180.87 A.Carbon 2.261 0.452 2.713 3 A.Carbon 2.71 Distilled water 149.220 31.653 180.873 4 Isopropyl

alcohol 70.993 Mother liquor + IPA wash 56.523 14.470 70.993

Residue 31.653 31.653 Total 345.015 Total 345.015

48 FEBRUARY 2017


Stage - 53A

S.No Input Total qty in kg



1 Stage - 51D 58.78 Stage - 53A 50.025 50.025

2 DM water 352.70

Ammonia

complex 4.232 0.411 4.644

3 Ammonia

hydroxide10% 45.85

Mother

liquor 361.520 41.149 402.668

Total 457.337 Total 457.337

3.5.10 d-Ritalinic Acid HCl

Process description

Stage - 1: d-threo-Ritalinic acid. DBTA complex crude:

Charge Methanol, DM water and dl-threo-Ritalinic acid into reactor. add

dissolved (+)-Dibenzoyl-D-tartaric acid monohydrate (DBTA) in methanol

solution in to mixture, heat the mass and filter the through filter press. Cool

the mass and centrifuge to get d-threo-Ritalinic Acid DBTA complex crude.

Stage - 2: Purification of d-threo-Ritalinic acid. DBTA complex Crude:

Charge Methanol, DM water and d-threo-Ritalinic acid DBTA complex crude

into reactor. heat the mass to dissolve completely. Cool the mass and

Centrifuge to get d-threo-Ritalinic acid DBTA complex pure.

Stage - 3: Preparation of d-threo-Ritalinic acid HCl:

Charge MIBK, DM water and d-threo-Ritalinic acid DBTA complex pure into

reactor. Cool the mass and adjust the pH by using HCl. Separate the

aqueous and MIBK layer and extracted with 10% HCl solution. filtered the

mass. Concentrated the aqueous layer completely. Add IPA and

concentrated under vacuum to remove the traces of water. Add IPA and

heat to dissolve, cool the mass and centrifuge to get d-threo-Ritalinic HCl.

49 FEBRUARY 2017


Process flow chart of d-Ritalinic Acid HCl

Material balance STAGE 68A

S.No Input Qty in kg Output

Qty in kg

1. DM water 400 Material 36.25 2.

Methanol 450

Methanol+Water ML 980

3. dl-threo-Ritalinic acid

25 Methanol Vapour loss 29.25

50 FEBRUARY 2017


4. Methanol 75 5. (+)-Dibenzoyl-D-

tartaric acid monohydrate 45.5

6. DM water + MeOH 50 Total 1045.5 Total 1045.5

STAGE 68B

S.No Input Qty in kg Output Qty in kg 1. DM water 78 Wet material 40.8 2. Methanol 103.31 Methanol +Water Ml 170 3. DBTA complex crude 36.25 Methaol Vapour loss 6.76 Total 217.56 Total 217.56

STAGE 68C S.No Input

Qty in kg Output

Qty in kg

1. DM water 50 MIBK Layer 66 2. MIBK 69.4 MIBK Loss 3.4 3. Add HCl solution 8 MIBK Layer 30 4. Charge MIBK to Aqueous layer 32 MIBK Loss 4 5.

Stir, settle & layer separation

Spent carbon 2

6. Add HCl solution (DM water + HCl) 10.2

Distilled water 50

7. Charge Activated carbon 1 Distilled IPA 18 8. Distill under vacuum (60%)

IPA loss 5

9. Charge IPA (2 times) 20 Wet Material 13.2 10. Charge IPA 20 IPA ML 19 Total 210.6 Total 210.6

3.5.11 L- oxazolidinone (Chiral)

Process description

Charge DM water, (1R, 2S)-Norephedrine hydrochloride and basified with

caustic solution, extract in Toluene and partially toluene is distilled to

reduced the moisture, Further it was treated with diethyl carbonate and

sodium ethoxide in ethanol.

51 FEBRUARY 2017


The resultant mass was heated to reflux and maintained the reflux condition

by removing the ethanol and toluene azeotrope. Cool the mass, washed with

water to remove the inorganic and further it is crystallized by adding

heptane. Centrifuge the mass to get (4S, 5R)-4-Methyl-5-phenyl-2-

oxazolidinone.

Process flow chart

Process flow chart of L- oxazolidinone (Chiral)

52 FEBRUARY 2017


Material balance

S.No

Stage Name Inputs

Qty in kg

Total Qty in

kg Outputs Qty

in kg

01.

63A

DM water 3.25 975 Wet 270 Toluene 5.83 1749 Recovered Toluene 1200

l-PPA 300 300 Recovered Toluene + Ethanol 1400

Caustic solution - 100 n-Heptane ML 2800

NaCl 0.08 24 Aq.layer 1100 Sodium sulphate 0.17 51 Vapour loss 142

Hyflow - 2 Solid waste 70 DEC 0.76 228

Sodium ethoxide - 25

Toluene 3.63 1089 DM water

wash 0 750

n-Heptane 5.63 1689 6982 6982

3.5.12 DL - oxazolidinone

Process description

Dl-Phenylpropanolamine HCl is basified with caustic solution, extracted in

Toluene and partially toluene is distilled to reduce the moisture content.

Further, it is treated with diethyl carbonate and sodium ethoxide in ethanol.

The resultant mass is heated to reflux and maintain the reflux condition by

removing the ethanol and toluene azeotrope, Cool the mass, washed with

water to remove the inorganic and further it is crystallized by adding

heptane. Centrifuge the mass to get 4-Methyl-5-phenyl-2-oxazolidinone

Crude (wet)

4-Methyl-5-phenyl-2-oxazolidinone crude is dissolved in water and heat the

mass. Cool and centrifuge to get 4-Methyl-5-phenyl-2-oxazolidinone.

53 FEBRUARY 2017


Process flow chart of dl - oxazolidinone

Material balance

S.No Stage Name Input Qty in

kg Output Qty in kg

1.

62A

DM water 755 Wet 300

Toluene 3050 Recovered Toluene 2300

l-PPA 300 Recovered Toluene + Ethanol

900

Caustic solution 100 n-Heptane ML 2800 NaCl 111 Aq.layer 966 DEC 228 Water wash 300

Sodium ethoxide 37 Vapour loss 133

54 FEBRUARY 2017


Toluene 400

DM water wash 291 n-Heptane 2427

2.

62C

Water- I purification 1200 1200

Water- II Purification 1200 1200

Total 10099 10099

3.5.13 Lorazepam

Process description

Lorazepam is a benzodiazepine drug with short to medium duration of

action with five intrinsic benzodiazepine effects: anxiolytic, sedative /

hypnotic, anticonvulsant and muscle relaxant, to different extents. It is a

powerful anxiolytic. It is a unique benzodiazepine used as an adjunct

antiemetic in chemotherapy. Lorazepam's principal use has been in treating

the symptom of anxiety but it has a relatively high addictive potential. Given

below are the various stages in the preparation of this chemical.

STAGE – 1

Lactam is treated with acetic acid and acetic anhydride to get Acetyllorazepam.

STAGE – 2

Acetyllorazepam is further basified with caustic solution to get Lorazepam crude.

STAGE – 3 & 4

Crude Lorazepam is purified with acetonitrile and cyclohexane to get pure Lorazepam.

55 FEBRUARY 2017

http://en.wikipedia.org/wiki/Benzodiazepine

http://en.wikipedia.org/wiki/Anxiolytic

http://en.wikipedia.org/wiki/Sedative

http://en.wikipedia.org/wiki/Hypnotic

http://en.wikipedia.org/wiki/Anticonvulsant

http://en.wikipedia.org/wiki/Muscle_relaxant

http://en.wikipedia.org/wiki/Anxiolytic

http://en.wikipedia.org/wiki/Antiemetic


Process flow chart of Lorazepam

Material Balance Stage – I

S. No Input Qty in Kg Output Qty in

Kg 01 Acetic acid 120 Acetyl Lorazepam 48.0 02 Lactem 40 Mother liquor 225 03 Acetic anhydride 43 Vapour loss 24 04 Methanol 94

05

Total 297 Total 297

Stage – II


Kg 01 Methanol 301.5 Lorazepam crude 15.8 02 67A material 17.5 Mother liquor 550 03 Caustic soln 4.6 Vapour loss 22 04 Acetic acid 5.8 Spent carbon 2.50 05 DM water 259.5 06 Activated carbon 1.1 Total 590 Total 590

56 FEBRUARY 2017


Stage – III


Kg 01 Acetonitrile 200 Lorazepam 22 02 67B material 20 Mother liquor 175 03 Vapour loss 23 Total 220 Total 220

Stage – IV


Kg 03 Cyclohexane 242 Lorazepam 19.5 04 67C material 15 Distillout 75.0 05 Mother liquor 140 Vapour loss 22 Total 257 Total 257

3.5.14 Amlodipine

Process Description

Amlodipine is a medication used to treat high blood pressure and coronary

artery disease. While calcium channel blockers are not typically

recommended in heart failure, Amlodipine may be used if other medications

are not sufficient for high blood pressure or heart related chest pain

STAGE 1

Phthalic anhydride is reacted with Mono ethanol amine in Toluene medium

and water removed by azotropic distillation. Filter the mass to get N-(2-

Hydroxyethyl) phthalimide crude. Then water slurry done and dried to get N-

(2-Hydroxyethyl) phthalimide pure.

STAGE 2

N-(2-Hydroxyethyl) phthalimide pure is reacted Ethyl 4 chloro acetoacetate

with sodium hydride in toluene medium. Then the acetic acid and water

added to separate the salts to extract the Ethyl, 4-{2-(Phthalimido) ethoxy}

acetoacetate) in toluene medium.

57 FEBRUARY 2017

https://en.wikipedia.org/wiki/Hypertension

https://en.wikipedia.org/wiki/Coronary_artery_disease



https://en.wikipedia.org/wiki/Calcium_channel_blockers

https://en.wikipedia.org/wiki/Heart_failure

https://en.wikipedia.org/wiki/Angina


STAGE 3

Ethyl, 4-{2-(Phthalimido) ethoxy} acetoacetate) organic layer is reacted with

Piperidine, Acetic acid and Ortho chloro benzaldehyde. After that toluene

refluxed up to reaction completion then toluene recovered entirely. Water

wash the mass and treated with Acetic acid and 3-Methyl amino crotonate.

Cool the mass to get Phthalimido Amlodipine crude. This crude purified with

Ethyl Acetate and dry the material to get Phthalimido Amlodipine pure.

STAGE 4

Phthalimido Amlodipine pure is treated with 40% MMA and temperature

maintained for 24 hrs to get Amlodipine base crude. After that his crude

slurry with DM water to purify the material. Amlodipine base dissolved in

DM water and Acetic acid then filtered and basified with MMA after

Methanol addition. Filter the mass to get Amlodipine base then it is dried.

STAGE 5

Amlodipine Base is reacted with Benzene sulphonic acid in Isopropyl alcohol

to get Amlodipine Besilate crude. Then the crude dissolved in Dm water +IPA

mixture and filtered in hot condition. Petroleum ether is added to precipitate

the material in solvent medium. Cool the mass to get Amlodipine Besilate.

Then it is dried.

58 FEBRUARY 2017


Process Flow chart of Amlodipine

Material Balance

Stage – I

S.NO Input Qty in Kg Output Qty in

Kg

01 Pthaleic Anhydride 450 N-(2-Hydroxyethyl) phthalimide 500

59 FEBRUARY 2017


02 Mono Ethanol Amine 190 Toluene recovered - Reuse 1750

03 Toluene 3150 Water ML 9050 04 DM Water 6150 Toluene residue 50

05 DM Water (Toluene Purification) 1433 Toluene loss 23

06 07 Total 11373 Total 11373

Stage – II


Kg

01 N-(2-Hydroxyethyl) phthalimide 200

Ethyl, 4-{2-(Phthalimido) ethoxy} acetoacetate) (Organic layer)

2030

02 Sodium hydride 100 Water wash - layer 4000 03 Ethyl 4 Chloro acetate 188 Toluene residue 50 04 Acetic acid 473 Toluene vapour loss 17 05 Toluene 1446 06 DM Water 2000

07 DM Water (Toluene Purification) 1675

08 Sodium carbonate (Toluene Purification) 15


Stage – III


Kg

01 Ethyl, 4-{2-(Phthalimido) ethoxy} acetoacetate) (Organic layer)

2030 Pthalimido Amlodipine 205

02 Piperidine 12 Water + acetic acid ML 2890 03 Acetic Acid 1057 Organic residue 22

04 Ortho Chloro Benzaldehyde

140 Recovered Toluene 1500

05 DM Water 800 Toluene loss 8

06 3 Methyl Amino crotonate

186

07 Ethyl Acetate 400 Total 4625 Total 4625

60 FEBRUARY 2017


Stage – IV


Kg 01 Pthalimido Amlodipine 356 Amlodipine Base 210

02 Acetic ACid 49 Water based ML ( water +methanol) 6350

03 Methanol 577 MMA Based ML 2150 04 MMA 40 % 2250 Spent Hyflo 6 05 EDTA 13 Water vapour loss 32 06 Hyflo 3 07 DM Water 5500 Total 8748 Total 8748

Stage – V


Kg 01 Amlodipine Base 175 Amlodipine Besilate 210 02 Benzene Sulfonic Acid 70 IPA ML 1385 03 Petrolem Ether 405 IPA + Ether ML 1190 04 IPA 2115 Vapour loss 16 05 DM Water 36 06 07 Total 2801 Total 2801

3.5.15 Selegeline

Process Description

Stage - I

Charge chloroform, d-Ephedrine HCl in to Round bottom flask and raised

the temperature add thionyl chloride and stir. Add benzene to slurry the

mass, centrifuge, wash with acetone and dry the material to get Chloro d-

Ephedrine HCl

Stage - II

Charge DM water, Chloro d-Ephedrine HCl and activated carbon bleach and

filter. Charge filtrate and 5% Palladium on BaSo4 in to hydrogenator and

pass hydrogenation to complete the reaction. Filter the mass.

61 FEBRUARY 2017


Stage - III

Charge filtrate and adjust pH by using lye solution. Start steam distillation

and extract with benzene. Distil out benzene atmospherically followed by

vacuum distillationto get desoxy base.

Stage - IV

Charge desoxy base, acetone, potassium carbonate, potassium iodide and

Propargyl chloride heat the mass to 50°C and stir. Cool the mass and filter,

wash with acetone. Charge the filtrate and distil out acetone atmospherically

and vacuum to get Crude Selegeline Base.

Stage - V

Charge Crude Selegeline base and fractional distillation to be carried out to

get pure Selegeline base.

Stage - VI

Charge Pure Selegeline base, acetone and add IPA/HCl to adjust pH,

centrifuge and wash with acetone to get Selegeline HCl.

62 FEBRUARY 2017


Process Flow for Selegeline

63 FEBRUARY 2017


Material Balance

Stage – I Stage Name Inputs Kgs Outputs Kgs

Chloro d-Ephedrine

d-Ephedrine HCl 5.00

Chloro d-Ephedrine HCl 5.00

HCl Preparation

Chloroform

9.37

Chloro d-Ephedrine ML 10.21Kg+ Chloroform9.37Kg

14.58

Thionyl chloride 5.21 Benzene recovered 10.83 Benzene 11.25 Acetone recovered 6.04 Acetone 6.25 Acetone Loss 0.21 Benzene Loss 0.42 37.08 37.08

Stage – II Stage Name Inputs Kgs Outputs Kgs

Hydrogenation DM water 12.51 Desoxy base 2.08

Chloro d-

Ephedrine HCl 4.17 Recovered Benzene 33.36

Activated carbon 0.07 Benzene Loss 2.78

Palladium

Catalyst on BaSo4 0.42

Palladium Catalyst on BaSo4 (recycle)

0.42

H2 Cylinders

Cu.M 2.78 Sodium Sulphate 0.34

N2 Cylinders

Cu.M 0.69 Activated carbon 0.07

Caustic Soda

flakes 6.95

water12.51Kg+HCl 9.04Kg

21.55

Stage – III Stage Name Inputs Kgs Outputs Kgs Selegeline

base preparation

Deoxy base 2.08 Selegiline Base 1.56

Acetone 18.22 Recovered Acetone 16.92

Propyl chloride 1.30 Recovered Benzene 26.03

Potassium Carbonate

1.93 Acetone Loss 1.30

Potassium Iodide 2.29 Benzene Loss 1.30

Sodium Sulphate 0.65

Potassium Carbonate

1.93

DM water 7.81 Potassium Iodide 2.29

64 FEBRUARY 2017


Stage – IV

Stage Name Inputs Kgs Outputs Kgs

Crude Selegeline HCl preparation

Selegiline base 1.56 Selegiline HCl Crude 1.25 Acetone 10.93 Selegiline HCl Crude

ML(recycle) 1.87

IPA/HCl 1.56 Acetone recovered 10.15 Acetone Loss 0.78 14.05

14.05

Stage – V Stage Name Inputs Kgs Outputs Kgs

Selegeline HCl preparation

Selegiline HCl Crude

1.25 Selegiline HCl 1.00

Acetone 8.75 Acetone recovered 8.12 IPA 3.12 Acetone Loss 0.63 Activated carbon 0.13 Selegilline HCl

ML(recycle) 3.50

13.25 13.25

3.5.16 Tranexamic acid

Tranexamic acid is frequently used following major trauma. Tranexamic acid

is used to prevent and treat blood loss in a variety of situations, such as

dental procedures for hemophiliacs, heavy menstrual bleeding, and

surgeries with high risk of blood loss

Stage 1

Mono-chloro benzene & Benzoyl peroxide is treated with p-Toluic acid and

pass the chlorine gas in to the mixture. Then water distilled out and cools to

get 4-(chloromethyl) benzoic acid

Stage 2

4-(chloromethyl) benzoic acid is treated with DM water, Ammonium bi

carbonate and Ammonia solution. Then treated with activated carbon. Water

distilled out and cool to get p-(aminomethyl) benzoic acid [PAMBA].

Stage 3 p-(aminomethyl) benzoic acid [PAMBA] is dissolved in Dilute Sulphuric acid

then Hydrogenation done by using Platinum oxide catalyst. Then reaction

65 FEBRUARY 2017


mass treated with sodium hydroxide and water washings. Distilled out the

water and precipitated in Acetone. Cool and get Tranexamic acid cis/trans

mixture.

Stage 4

Tranexamic acid cis/trans mixture is dissolved in Dilute Sulphuric acid

then Hydrogenation done by using Platinum oxide catalyst. Then reaction

mass treated with barium sulphate and water washings. Distilled out the

water and precipitated in Acetone. Cool and get Tranexamic acid Crude.

Stage 5

Tranexamic acid crude is dissolved in DM water then Activated carbon

treated to improve the colour. Then it is precipitated in Acetone solvent after

water removal. Cool and get Tranexamic acid.

66 FEBRUARY 2017


Process Flow chart of Tranexamic acid

67 FEBRUARY 2017


Material Balance Stage I: Preparation of 4-(chloromethyl)benzoic acid

In put Out put

S.No

Name of the raw material

Qty in Kg

S.No Description

Qty in Kg

Loss

Total

1 P-Toluic acid 300 1 4-(chloromethyl) benzoic acid (Stage-I)

330 - 330

2 Chlorine gas 450 2 Un-reacted Chlorine gas ( Scrubbed by alkali water )

- 294 294

3 Benzoyl peroxide

4 3 HCl gas ( Scrubbed by alkali water )

80 80

4 Chlorobenzene

1554 4 Chloro benzene 1476 78 1554

5 DM water 500 5 Water washings 360 145 505 6 Residue 45 45 Total 280

8 Total 221

1 597 280

8

Stage II: Preparation of p-(aminomethyl)benzoic acid (PAMBA)

In put Out put

S.No


Qty in Kg

S.No Description

Qty in Kg

Loss

Total

1 4-(chloromethyl) benzoic acid (Stage-I)

250 1 p-(aminomethyl) benzoic acid (PAMBA) (Stage-I)

130 130

2 Ammonium bi-carbonate

411.3

2 Mother liquor* 1015

1015

3 Aqueous ammonia

751.7

3 Ammonia gas 138 138

4 Activated carbon

5 4 Distillate 2000

2000

5 Hyflo 10 5 Spent Carbon 7 7 6 DM water 1875 Hyflo (Spent) 15 15 Total 3305 Total 316

7 138 330

5

68 FEBRUARY 2017


Stage III: Preparation of Tranexamic acid cis/trans mixture

In put Out put

S.No


Qty in Kg

S.No Description Qty

in Kg Loss Total

1 p-(aminomethyl) benzoic acid (PAMBA) (Stage-II)

25 1 Tranexamic acid mixture cis/trans (Stage-III)

24 24

2 Platinum oxide

1.25 2 Platinum oxide 1.24 1.24

3 Sulphuric acid

20 3 Calcium sulfate 27.8 27.8

4 Calcium hydroxide

15.5 4 Hyflo (Spent) 15 15

5 Acetone 78.25

5 Acetone 70 8.25 78.25

6 DM water 500 6 Water 503.71

503.71

7 Hyflo 10 Total 650 Total 625.

75 24.2

5 650

Stage IV: Preparation of Tranexamic acid Crude

In put Out put

S.No


Qty in Kg

S.No

Descriptio

n

Qty in Kg

Loss Total

1 Tranexamic acid mixture cis/trans (Stage-III)

100 1 Tranexamic acid Crude (Stage-IV)

80 80

2 Barium Hydroxide

310 2 Barium sulfate

229.3 229.3

3 Sulphuric acid 96.3 3 Hyflo (Spent)

115 115

4 Acetone 235.7 4 Acetone 225 10.7 235.7

5 DM water 1600 5 Water 1757 1757 6 Hyflo 75 Total 2417 Total 2346.

3 70.

7 2417

69 FEBRUARY 2017


Stage V: Preparation of Tranexamic acid

In put Out put

S.No Name of the raw material

Qty in Kg

S.No

Descriptio

n

Qty in Kg

Loss

Total

1 Tranexamic acid Crude (Stage-IV)

100 1 Tranexamic acid (Stage-V)

60 60

2 Acetone 786 2 Acetone 726 60 786 3 Activated carbon 2 3 Spent

Carbon 4 4

4 Hyflo 10 4 Hyflo (Spent)

18 18

5 DM water 1000 5 Water 950 50 1000

6 Residue 30 30 Total 1898 Total 161

2 286 189

8

3.6 Raw material requirement

The raw materials required for the production in each stage & mode of

transportation of the raw materials is given in Annexure - II

3.7 Resource optimization

In the proposed expansion project every effort will put to recycle/reuse

the wastewater and reduce fresh water requirement.

3.8 Water requirement

The total water requirement of the existing plant is about 210 KLD

and it will be increased to 270 KLD after the proposed change of product.

The total water requirement of the plant will be sourced from SIPCOT water

supply scheme. M/s. MDPL already have a permission letter from SIPCOT

for supplying water. The copy of the supply of water is enclosed in

Annexure III. The water balance diagram showing source, water

requirement and waste water generation & usage of treated water during

70 FEBRUARY 2017


existing and proposed process is shown in Figure 3.4 and Figure 3.5

respectively.

71 FEBRUARY 2017


Figure 3.4 Existing Water Balance

140

40

210 KLD

78

30 1.5 Blow down

44 4.5

11 Effluent

0.4 Vapor loss

(water) in vacuum

0.6 T (Salt)

9.5

15

5

10

Condensate - 14

3.9

COOLING TOWER

BOILER

PROCESS / UTILITY

PROCESS

COMMUNITY SUPPLY

DOMESTIC SEWAGE TREATMENT PLANT 10 KLD

GARDENING

EFFLUENT TREATMENT PLANT

72 FEBRUARY 2017


Figure 3.5 Proposed Water Balance

73 FEBRUARY 2017


3.9 Quantity of waste generation (Liquid and Solid) & its management

In the process along with the products, different waste materials will

also be generated. These waste materials mainly include dust emissions and

solid wastes from the utilities.

3.9.1 Air Pollution Management

The major air pollution sources from the industry are DG set and

boiler apart from the process sections. These sources are provided with

stacks of adequate height so as to disperse the emanating flue gases

containing SPM, oxides of sulfur and nitrogen without affecting the ground

level concentrations are proposed to the process section with adequate stack

height as per the regulatory requirements.

3.9.2 Wastewater Generation and disposal measures

3.9.2.1 Domestic Waste water generation, treatment & disposal

The quantity of wastewater generated from domestic activities during

operation phase will be treated in the Wastewater treatment plant of

capacity 10 KLD. The treated wastewater will be reused for green belt

development. The treatment scheme has been designed to treat the

wastewater and reuse the treated water for green belt development. The

details of sewage treatment Plant is given in Annexure IV.

3.9.2.2 Trade Effluent generation, treatment & disposal

The main sources of effluent are process washings, boiler blow down,

cooling tower blow down and water treatment plant regeneration. The

effluent generated will be treated in the existing ETP. The details of Effluent

treatment Plant is given in Annexure V

3.9.3 Noise Generation and its management

The major source of noise pollution in the industry is the DG set for

which acoustic enclosure is proposed. Also ambient noise levels will be

74 FEBRUARY 2017


ensured within the ambient standards by inbuilt design of mechanical

equipment and building apart from vegetation (tree plantations) along the

periphery and at various locations within the industry premises.

3.9.4 Hazardous waste Management

The hazardous waste generated during manufacturing various

products are given in below in Table 3.3.

Table 3.3 Details of Hazardous waste generated

S.No Products HTDS Inorganic Organic By Product

1 Pseudo Ephedrine Hcl 10.62 1.69 0.00 2.04 2 Cyclene 35.95 8.02 0.71 0.00 3 Phenyl Epherine 5.99 1.05 0.03 0.87 4 l - Oxa 1.48 0.18 0.10 0.00 5 dl - oxa 2.86 0.41 0.00 0.00 6 Methyl phenindate 0.02 0.00 0.01 0.00 7 dl - Ritalinic acid 5.25 1.66 0.60 0.00 8 d- Ritalinic acid 0.92 0.00 0.00 0.00 9 Bosentan 0.00 0.00 1.03 0.00 10 Tripolidine 0.29 0.35 0.02 0.00 11 Etaephedrine 0.01 0.00 0.00 0.00 12 Alprazolam 0.29 0.04 0.00 0.00 13 Amlodipine Besilate 0.91 0.93 2.26 0.00 14 Lorazepam 0.00 0.00 0.08 0.00 15 Selegeline HCl 0.00 0.05 0.05 0.00 Total 64.59 14.39 4.89 2.91

3.10 Power Requirement

The total power requirement of project is increased from 1100 KVA to

1450 KVA. Existing power requirement is available from TNEB (Tamil Nadu

Electricity Board) and power required for proposed expansion will also be

sourced from TNEB. Two DG sets having capacity of 500 KVA (existing) and

75 FEBRUARY 2017


one DG set of 750 KVA (proposed) will be used as back-up power supply.

Details of DG set are given in Table 3.4

Table 3.4 Details of DG Set

S.No DG set Details Existing Proposed 1 Capacity 500+500KVA 750 KVA 2 Type of Fuel Diesel Diesel

3 MOC of the stack M.S M.S

4 Diameter of the stack 150 mm 150 mm 5 Height of the stack 3 M 3 M 6 Fuel consumption 3.15 L/unit 3.15 L/unit

76 FEBRUARY 2017


4. SITE ANALYSIS


facility at Plot No.7B & 7C, SIPCOT Industrial Complex, Ranipet – 632 403,

Vellore district, Tamil Nadu.

4.1 Connectivity

The project site is well connected with other parts of country through

Road, Rail and Air. The nearest highway of the project site is NH-40 (NW)

that connects Kurnool - Ranipet and also well connected to SH 124 A (N)

connecting Ranipet to Ponnai road.

Figure 4.1 Site Connectivity

77 FEBRUARY 2017


4.2 Land Form, Land use and Land ownership


facility at plot no.7B & 7C, SIPCOT Industrial Complex, Ranipet – 632 403,

Vellore district, Tamil Nadu. The land use classification of the project site is

Industrial use. The entire land area belongs to the company and land

ownership documents are enclosed as Annexure I.

4.3 Topography

M/s Malladi Drugs & Pharmaceuticals Ltd, is located at latitude of

12°57'14.60"N& Longitude 79°19'09.21"E at an elevation of 184 m above

MSL. The proposed change of expansion will be carried out within the

existing industrial site is topographically plan without any undulations.

4.4 Existing Infrastructure

The list of existing infrastructure at the project site is

1. Water supply from SIPCOT

2. Power supply from TANGEDCO

3. Existing storm water drainage system

4.4.1 List of Industries

The site is located within the SIPCOT industrial complex, Ranipet. List of some major industries are listed below.

Ultramarine & pigments limited

Om Sakthi Chemicals

Pallava Chemicals P Ltd

Ramnath Chemicals p Ltd

S.R.S Leathers

Kausik Chemicals Ltd,

Kaushik Leather Pvt Ltd

Balaji Oil Industries Pvt Ltd

Murali Krishna Engg Works

Pneumatic Atomising Mills Pvt Ltd,

78 FEBRUARY 2017


4.5 Soil Classification

Vellore district can be classified into two major physiographic

division’s viz., i) Hilly terrain in the eastern and south western parts and I i)

Plain regions in the eastern part. The soil has been classified into 1) Sandy

soil 2) Sandy loam 3) Red loam 4) Clay 5) Clayey loam and 6) Black cotton

soils. The red loamy soils are generally observed at the highest elevations

whereas the black cotton soils invariably occupy the valley areas. Other

types of soils are found at Intermediate elevations. Vellore district is

underlain by geological formations ranging in age from Archaean to Recent.

4.6 Rainfall and Climate

Vellore district receives rainfall from both southwest and northeast

monsoons. The annual normal rainfall (1901-80) for the district is 949.8

mm. The contribution of southwest monsoon ranges from 45 to 52 percent,

whereas it ranges from 30-43 percent due to northeast monsoon. The

district enjoys a tropical climate. The highest temperatures are recorded

during May and June. The mean daily minimum and maximum temperature

are 18.2 to 36.8° C. The relative humidity ranges from 37 to 85 percent.

4.7 Social Infrastructure

Infrastructure is the basic physical and organizational structures

needed for the operation of a society or enterprise or the services and

facilities necessary for an economy to function. The term typically refers to

the technical structures that support a society, such as roads, water supply,

sewers, electrical grids, telecommunications and so forth and can be defined

as "the physical components of interrelated systems providing commodities

and services essential to enable, sustain, or enhance societal living

conditions.

Viewed functionally, infrastructure facilitates the production of goods

and services, and also the distribution of finished products to markets, as

well as basic social services such as schools and hospitals; for example,

roads enable the transport of raw materials to a factory.

79 FEBRUARY 2017


5. PLANNING BRIEF AND INFRASTRUCTURE FOR PROPOSED

PROJECT

5.1 Planning Concept

M/s Malladi drugs and Pharmaceuticals has proposed to enhance

their production capacity of Active Pharmaceutical Ingredients at their

existing Plant located at Plot No.7B & 7C, SIPCOT Industrial Complex,

Ranipet, Tamilnadu. The facility has proposed the production of API from

88.992 MT/month to 85.83 MT/month which also includes elimination of

certain Existing Products.

The necessary infrastructure in terms of land, power, water and

personnel are readily available. It is only an Expansion of the existing

operation. The existing Sewage Treatment Plant has adequate capacity to

handle extra quantity of sewage, if any. There will be no significant adverse

impact on the environment due to the project; rather many beneficial

impacts are estimated. There is no adverse factor such as reclassification of

land use and pattern, displacement etc.

5.2 Population Projection

The total existing direct employment potential of the industry is about

317 people. However, there are indirect employment generations due to the

project during the transportations, marketing & distribution etc. Hence no

major population is expected to rise in the region.

5.3 Land Use Planning

The proposed project will be facilitated within the existing land of

Malladi Drugs unit - 3. The land use of the site is General Industrial use

zone. The land use break-up showing the proposed activities is given in

Table 5.1. All required amenities and facilities are available in the plant

itself. The total area of the facility is 2.98 hectares. The major usage of the

existing unit is as follows.

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Table 5. 1 Land Use Break-Up of Project Site

5.4 Assessment of Infrastructure Demand

Adequate physical and social facilities are available in this area.

5.5 Amenities/Facilities

All infrastructure facilities such as education, health facilities and

other social facilities are adequate at district headquarter which site makes

the region adequate in amenities.

Sr. No. Land use details Existing

(Sq m) Proposed

(Sq m) Total (Sq m)

% of total plot area

1 Process area 6013.5 0 6013.5 20.13 2 Utility, E.B area 989.1 0 989.1 3.31 3 Laboratory area 284.8 0 284.8 0.95 4 Storage area 1386.7 0 1386.7 4.64

5 Admin block, Canteen, Security cabin 447.2 0 447.2 1.50

6 Effluent treatment plant 120.7 0 120.7 0.40 7 Approach roads 13755 0 13755 46.06 8 Green belt 2146.9 0 2146.9 7.188 9 Vehicle parking 60 0 60 0.20 10 Total Open Space 4661.1 0 4661.1 11.77

TOTAL 29865 0 29865 100.0

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6. PROPOSED INFRASTRUCTURE

6.1 Industrial Area – Processing Area

The land available and earmarked for the proposed expansion project is

categorized as Industrial use. The total land available under the ownership

of the promoter is 2.98 hectares. The proposed activities will be carried out

within the above area which is sufficient for the planned activities. The site

will be facilitated only for the manufacturing of various synthetic chemicals

for the application in the pharmaceutical Industry.

6.2 Residential Area – Non Processing Area

No residential classified area will utilized for the proposed expansion

project. No housing or non-processing area is proposed in this project.

6.3 Green Belt

The factory has a total of 0.2147 hectares as green belt out of a total area of

2.98 ha. To achieve the mandatory requirement of 33% of green belt

requirement by CPCB / MoEF green belt area of 10027 Sq.m or 1.0027

hectares is given outside the premises in company land. The survey No of

land is 263, 264, & 265. Survey was conducted to obtain the knowledge on

existing flora within the factory premises. Adequate no of trees, bushes,

shrubs will be planted based on the site conditions. The green belt layout

has been enclosed in Annexure VI

6.4 Social Infrastructure

Infrastructure is the basic physical and organizational structures

needed for the operation of a society or enterprise or the services and

facilities necessary for an economy to function. The proposed expansion of

the project enables, sustain, or enhance societal living conditions of the

workers family. Adequate capacity of social Infrastructure facilitates the

production of goods and services, and also the distribution of finished

products to markets, as well as basic social services such as schools and

82 FEBRUARY 2017


hospitals water supply, etc. is available in the region to manage the current

expansion proposal.

6.5 Connectivity

The project site is well connected with other parts of country through

Road, Rail and Air. The nearest highway of the project site is NH-40 (NW)

that connects Kurnool - Ranipet and also well connected to SH 124 A (N)

connecting Ranipet to Ponnai road.

6.6 Drinking water Management – Source & Supply

Drinking water requirement will be met by supply from SIPCOT water

supply scheme after required treatment.

6.7 Sewage Treatment System

After proposed expansion the total sewage generation will be 8KLD.

Sewage Treatment Plant of 10 KLD will be provided to treat the sewage water

and treated water will be used for green belt development. Adequate capacity

of sewerage systems is provided taking in to consideration the total no of

people that will be employed and the expected floating population on any

day at site. Details of Sewage Treatment Plant given in Annexure IV

6.8 Effluent Treatment System

The generated trade effluents will be treated in Effluent Treatment

Plant of 180 KLD capacity using Zero Liquid Discharge.

Effluent treatment plant consist of stages

1. Pre Treatment

2. Double Effect Evaporation plant

3. Crystallizers

6.9 Solid waste Management

The generated solid wastes will be properly collected and managed as

given in the Section 3.9.4.

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6.10 Power requirement, Supply & Source

The total power requirement of project is increased from 1100 KVA to

1450 KVA. Existing power requirement is available from TNEB (Tamil Nadu

Electricity Board) and power required for proposed expansion will also be

sourced from TNEB. Two DG sets having capacity of 500 KVA (existing) and

one DG set of 750 KVA (proposed) will be used as back-up power supply.

6.11 Rain Water Harvesting System & Storm water management system

A rainwater harvesting system comprises components of various

stages – transporting rainwater through pipes or drains, filtration, and

tanks for ground water recharge. As the proposed facility will comprise only

the roof top rain water for ground water recharge. The runoff from the first

spell of rain carries a relatively larger amount of pollutants from the air and

catchments surface so the system will be provided with a filtration pit

consists of the layers of sand, gravel and pebbles of relevant sizes to remove

the removable impurities from the runoff water from the roof top.

Three Nos of percolation pits located inside our premises. This pits

details given below.

1. In-front of Q.AQ.C building – 3 x 5 M – 1 No

2. In front of New Admin Office – 1 x 15M – 1 No

3. Adjacent to Boiler house – 2 x 15 M – 1 No

Figure 6.1 Rainwater Harvesting Pits

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7. REHABILITATION AND RESETTLEMENT (R&R) PLAN

The increase in the product capacity will be carried out within the existing

plant of Malladi Drugs and Pharmaceuticals Unit 3. No home outstees /land

outstees are expected & hence no rehabilitation plan is envisaged.

8. PROJECT SCHEDULE AND COST ESTIMATES

The proposed expansion project will be implemented immediately after

obtaining EC from SEIAA. The implementation period of the expansion

project is six months from date of implementation to achieve the significant

production with new equipments. The total cost of proposed expansion

project is estimated as Rs. 23.76 Crores as detailed below.

9. ANALYSIS OF PROPOSAL (FINAL RECOMMENDATIONS)

The project is well conceived as horizontal integration efforts and effectively

planned by one of the leading Pharmaceutical Industry in India. The API

landscape in India is quite promising due to the robust research-based

processes, low cost operations and availability of skilled manpower. By

adding more advanced technologies and cost effective production

techniques, M/s MDPL will achieve cost competitiveness over other players

in this field.

85 FEBRUARY 2017

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