13 Feb 2017 165512037CZ3OUJRNPFR PDF

5 (f) Synthetic organic Chemicals
PREPARED BY
ABC TECHNO LABS INDIA PRIVATE LIMITED, CHENNAI

NABET Accreditation: Ref: QCI website
NABET/EIA/1316/RA001
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
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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
317 Nos
Requirement
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
Site Elevation above
3 184 m
MSL
• NH 4 – 0.5 km (SSW)
• NH 46 – 3.8 km (SSE)
4 Nearest highway
• 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)
• Vanapadi – 1.38 km (NNE)
• Chettithangal – 1.5 km (NNE)
7 Nearest town/ city
• Agravaram – 2.1 km (NNW)
• Ranipet – 2.3 km (SSE)
8 Topography Plain
Archaeologically
9 Nil in 15 kmradius
important places
National parks/ Nil in 15 km radius
10
Wildlife Sanctuaries
• Vanapadi lake - 0.81 km (N)
• Thandalam lake – 0.96 km (ESE)
11 Reservoir
• Maniyampattu lake – 2.4 km (W)
• Palar river – 3.2 km ( S)
• Ammur R. F. – 4.7 km (ENE)
Reserved/ Protected
12 • TiruvallamR.F. – 5.2 km (W)
Forests
• 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
Existing Proposed
Sr. Qty Qty
Product
No
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.N Qty. Qty.(
Stage Name Inputs Outputs
o (kg/d) kg/d)
Water + Sodium
chloride179 Kg +
DM water 900 1129
25 Kg Sodium
l - Eph Base hydroxide
Preparation Caustic Soda Distilled Toluene
144 280
1. 20A Flakes recycle
l-Eph.base in
l - Eph.salt 600 680
Toluene
Toluene vapour
Toluene 473 29
loss
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
27
loss
1755 1755
DM Water 1950
Pseudo base in
Acet.Mass 725 1725
Toluene
Sod. Sulphate 490
Hydrolysis & Toluene 860 Kg + Sod. Acetate 3271.2
Basification in Aq.layer
3. 20C Toluene vapour
Caustic lye 1500 39
loss
(Water 1000 L +
NaoH
500 kgs)
5035 5035
Pseudo base in
1725 Pseudo base 440
Toluene
Sod.Sulphate49
Sod. Sulphate 490
0 Kg + Sod. 3271.
Kg + Sod. Acetate 3219
Extraction Acetate in 2
in Aq. layer
washing & Aq.layer
Solvent Toluene 817 Toluene ® 774
4. recovery 20C
Wash water
D M Water 800 800
recycle
Toluene vapour
50
loss
Base Mother
1330
liquor
6613 6613
Pseudo salt in
DM water 400 1130
Water
Hydrochloric
Bleaching 290 Charcoal 1
acid
5. 21A1
Pseudo Base 440
Chalcoal 1
1131 1131
6. Concentration Pseudo Eph.salt Rec.water ® 450
17 FEBRUARY 2017
21A2 in Water 1130 Conc. Mass 650

Water vapour loss 30
1130 1130
Crystallised
650 Pseudo 1st Crop 350
Mass
Acetone wash
Centrifuging Acetone 165.9 142.2
(Recovered & sold)
21A Acetone vapour
7. 23.7
loss
Mother liquor
300
recycle
815.9 815.9
3.5.2 Alprazolam
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
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)

Raw materials (Chemicals) Effluent to ETP Recov
By
S.N Recyl Reactant / Name of the Orga Inorga ery/ Produ Resi Lo
Fresh To Q Produ
o. Name ed Solvent Output nic nic Recycl cts due ss
Input tal ty cts
Input Imp. Imp. e
Chloroacetami
01 Acetic Acid 50.00 0 50 Reactant 26
de
water
Chloro
50Kg+HCl
02 acetyl 13.00 0 13 Reactant 107
7.0Kg+Acetic
chloride
acid50Kg
2 Amino 5
Chloro
03 20.00 0 20 Reactant
Benzopheno
ne
04 DM water 50.00 0 50 Reactant
Stage 2: NDP preparation

S. Fres Reactant By
Recy Name of the Orga ery/ Produ Resi
No h Tot / Qt Inorgani Produ Loss
Name cled Output nic Recycl cts due
. Inpu al Solvent y c Imp. cts
Input Imp. e
t
Chloroaceta 26.0
0 26 Reactant NDP 19.5
01 mide 0
144. 14
Methanol 0 Solvent Methanol Loss 10.4
02 0 4
32.5 32. water
Hexamine 0 Reactant 100.5
03 0 5 50Kg+HCl
20 FEBRUARY 2017
50.50Kg
Ammonium 11.5 11. Recovered
0 Reactant 133.6
04 carbonate 0 5 Methanol
50.0 Recovered
DM water 0 50 Reactant 18.7
05 0 Toluene
20.0
Toluene 0 20 Solvent Toluene Loss 1.3
06 0
Stage 3: Thione Preparation

Raw materials (Chemicals) Effluent to ETP Reco
Recy Reacta By
S.N Name of the Orga Inorga very/ Prod Resi Los
Fresh cled nt / Qt Prod
o. Name Total Output nic nic Recy uct due s
Input Inpu Solvent y uct
Imp. Imp. cle
t
Reactan
01 NDP 19.50 0 19.50 Thione 16.5
t
02 Acetonitrile 92.00 0 92 Solvent Acetonitrile 88
Posporuspe Reactan
03 12.00 0 12 Acetonitrile Loss 4
nta sulphide t
water100Kg+Phos
Sodium Reactan perousSulphides+
04 15.50 0 15.5 130.5
bicarbonate t Sodium bi
carbonate
100.0 Reactan
05 DM water 0 100
0 t
Stage 4: Inter Preparation

Reacta By
S.N Recyc Name of the Q Orga Inorg ery/ Produ Resi
Fresh Tot nt / Produ Loss
o. Name led Output t nic anic Recycl cts due
Input al Solvent cts
Input y Imp. Imp. e
01 Thione 16.50 0 16. Reactan Inter 15
21 FEBRUARY 2017
5 t
Hydrazine Reactan
02 18.00 0 18 IPA 130.8
Hydrate t
Isopropyl 141.0 14
03 0 Solvent IPA Loss 10.2
alcohol 0 1
water100Kg+Hy
04 Toluene 39.00 0 39 Solvent drogen 119.5
sulphide19.5Kg
DM 100.0 10 Reactan
05 0 Toluene 36.5
Water 0 0 t
Ethyl
06 52.00 0 52 Solvent Toluene Loss 2.5
Acetate
07 Acetone 10.00 0 10 Solvent Ethylacetate 52
Acetone 9
Acetone Loss 1
Stage 5: Crude Alprazolam Preparation
Raw materials (Chemicals) Reacta Effluent to ETP Recover By
S.No Name of the Produc Residu Los
Nam Fresh Recycle Tota nt / Qt Organi Inorgan y/ Produc
. Output ts e s
e Input d Input l Solvent y c Imp. ic Imp. Recycle ts
15.0 Reactan Crude
01 Inter 15.00 0 12.5
0 t Alprazolam
Xylen 127.5 127.
02 0 Solvent Xylene 125
e 0 5
Xylene Loss 2.5
Crude ML 2.5
Stage 6: Purification
Raw materials (Chemicals) Effluent to ETP Recove
Fres Reactan Name of By
S.N Recyc Orga Inorga ry/ Produ Resid
h Tot t/ the Q Produ Loss
o. Name led nic nic Recycl cts ue
Inpu al Solvent Output ty cts
Input Imp. Imp. e
t
22 FEBRUARY 2017
Crude 12. Alprazola

01 12.5 0 Reactant 10
Alprazolam 5 m
02 Methanol 98.0 0 98 Solvent Methanol 90.9
Activated Methanol
03 0.50 0 0.5 Reactant 7.1
charcoal Loss
Spent
3
Charcoal
23 FEBRUARY 2017
3.5.3 Phenylepherine
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
Qty in
Qty in
S.NO Input Output Kg/Bat
Kg/Batch
ch
01 MAAP sulphate 320 dl-Phenylephrine Base 215
Palladium
02 DM Water 760 12
catalyst(Recycle)
dl-Phenylephrine Base
03 Palladium catalyst 9 1070
ML(Recycle)
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

dl-Phenylephrine
01 1070 dl-Phenylephrine Base 23
Base ML(Recycle)
02 DM Water 150 365
ML(Recycle)
03 Methanol 60 Ammonium Sulphate 120
Water+Methanol
04 Liquor ammonia 35 75
recovered
Methanol distillation
05 Dil Sulphuric acid 20 7
loss
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
Qty in Qty in
S.NO Input Output
Kg/day Kg/day
dl-Phenylephrine d-Phenylephrine
500 437.5
Base bitartarate
l-Phenylephrine
01 Tartaric acid 500 1750
bitartarate ML(Recycle)
02 Iso Propyl alcohol 938.125
03 DM Water 250
Total 2188.125 Total 2187.5
Stage II no ETP Load.
Stage – III-9C
Qty in Qty in
S.NO Input Output
kg/day kg/day
l-Phenylephrine
01 1750 l-Phenylephrine base 225
bitartarate ML
l-Phenylephrine base
02 DM Water 725 1625
ML(Recycle)
03 Activated carbon 3 Distilled IPA 967.5
04 Liquor ammonia 368.75 IPA Distillation loss 29
Total 2846.75 Total 2846.5
9CM
l-Phenylephrine dl-Phenylephrine
01 1625 81.25
base ML(Recycle) Base
dl-Phenylephrine
02 DM Water 62.5 1756.25
Base ML(Recycle)
03 Liquor ammonia 150
9AM 1837.5 1837.5
26 FEBRUARY 2017
dl-Phenylephrine dl-Phenylephrine
01 1756 38
Base ML(Recycle) Base
dl-Phenylephrine
02 DM Water 231 500
Base ML(Recycle)
03 Methanol 125 Ammonium Tartarate 231
Water+Methanol
04 Liquor ammonia 63 156
recovered
Dil Sulphuric Methanol distillation
05 44 13
acid loss
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
Qty in Qty in
S.NO Input Output
kg/day kg/day
d-
01 Phenylephrine 400 d-Phenylephrine base 170
bitartarate
d-Phenylephrine base
02 DM Water 580 1160
ML(Recycle)
Liquor
03 350
ammonia
Total 1330 Total 1330
d-
Phenylephrine
01 1160 dl-Phenylephrine Base 29
Base
ML(Recycle)
02 DM Water 143 274
ML(Recycle)
03 Methanol 69 Ammonium Tartarate 200
Liquor
04 57 Water+Methanol recovered 109
ammonia
Dil Sulphuric
05 29 Methanol distillation loss 17
acid
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
Qty in Qty in
S.NO Input Output
kg/day kg/day
d-Phenylephrine
base
02 Aceticanhdride 1280 2100
ML(Recycle)
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
l-Phenylephrine
01 2099.5 dl-Phenylephrine Base 77.35
Base ML(Recycle)
02 DM Water 276.25 751
ML(Recycle)
03 Methanol 154.7 Ammonium Sulphate 232
04 Liquor ammonia 88.4 Water+Methanol recovered 155
Dil Sulphuric
05 55.25 Methanol distillation loss 22
acid
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
Qty in Qty in
S.NO Input Output
kg/day kg/day
01 l-Phenylephrine base 320 l-Phenylephrine base 250
02 Iso Propyl alcohol 1260 1730
ML(Recycle)
03 DM Water 420 Iso propyl alcohol loss 20
Stage VI no ETP Load.
Stage – VII 9G
Qty in Qty in
S.NO Input Output
kg/day kg/day
l-Phenylephrine
base
02 DM Water 1100 1878
ML(Recycle)
Dil. Sulphuric
03 380 Activated carbon 5
acid
28 FEBRUARY 2017
l-Phenylephrine
01 Base 1878 l-Phenylephrine Base 60
ML(Recycle)
02 DM Water 240 530
ML(Recycle)
03 Methanol 130 Ammonium Sulphate 230
04 Liquor ammonia 70 Water+Methanol recovered 150
Dil Sulphuric
05 52 Methanol distillation loss 20
acid
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
Qty in Qty in
S.NO Input Output
kg/day kg/day
l-Phenylephrine
01 400 l-Phenylephrine HCl Crude 380
base
l-Phenylephrine HCl Crude
02 DM Water 125 625
ML(Recycle)
03 HCl 250 Water Recovered 375
Activated
04 7.5 Water distillation loss 37.5
carbon
Activated carbon+Hyflow
05 Hyflow supercell 0 9
supercell
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

Qty in Qty in ETP
S.NO Input Output
kg/day kg/day Load
l-Phenylephrine
01 340 l-Phenylephrine HCl 260
HCl Crude
l-Phenylephrine HCl
02 Activated carbon 1.5 565
ML(Recycle)
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
Process Flow chart of Triprolidine
31 FEBRUARY 2017
Material balance
Stage I
Raw material Qty in Qty in

S.No. Product Output
Input kg kg
1 Triprolidine inter 160 Triprolidine oxalate 110
Water447.9Kg+Ammonium
2 Sulphuric acid 704 1396.1
Sulphate948.2Kg
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. Raw material Qty in Product Qty in

No. Input kg Output kg
Triprolidine
1 110 TriprolidineHCl.Crude 90
oxalate
Water403.5Kg+Ammonium
2 D M Water 420 494.6
Oxalate91.1Kg
n-Hexane
3 Ammonia 25 316.3
recovered(Recycle)
4 n-Hexane 329.4 n-Hexane distillation loss 13.1
5 Hydrochloric acid 36.0 Unreacted Residue 40
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.N Wate Inorgan Organ
o. INPUT OUTPUT r ic ic
Uni
Name of Chemicals t Qty Name of Product Qty
1 N-BENZYLE EHANOLAMINE kg 400 CRUDE TBC 315.0
RECOVERED
3034.1
2 TOLUENE kg 3096 TOLUENE(RECYCLE)
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
PARA TOLUENE SULPHONIC
160.2
8 ACID kg 200 EA layer ( Recycle)
34 FEBRUARY 2017
9 Ethyl acetate 178

HCl 150
Sulphuric acid 500
10 DM water 600
1437 14373.
TOTAL 3 TOTAL 35 7332 1068 0
Stage III (Pure TBC)

Sl.No Inorgani Organi
. INPUT OUTPUT Water c c
Uni
CRUDE TETRA PURE TETRA BENZYL
1 BENZENE CYCLEN kg 300 CYCLEN 130
RECOVERED ETHYL
2 ETHYL ACETATE kg 3000 ACETATE (R) 2900
3 CALCIUM CHLORIDE kg 37.5 RESIDUE 150 150
ETHYL ACETATE
DISTILLATION LOSS 57.5
Calcium Chloride layer 100 100
3337.
TOTAL 5 TOTAL 3337.5 0 100 150
Stage IV (Crude Cyclene)
Sl.No Wate Inorgani Organi
. INPUT OUTPUT r c c
Uni
1 PURE TETRA kg 200 CRUDE CYCLEN 120
35 FEBRUARY 2017
BENZYLE CYCLEN
2 DM WATER kg 600 TOLUENE(RECYCLE) 50
PALLADIUM CARBON
3 HYDROCHLORIC ACID kg 90 (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
1181.5 1181.28562
TOTAL 1 TOTAL 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
Qty Qty
S.No Input Output
in Kg in Kg
ChloroSulfonamide
01 BP-Dichloro 28 50
(Dry)
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
Qty in Qty in
S.No Input Output
Kg/day Kg/day
ChloroSulfonamide 50 Distilled Ethylene 56
01
(Dry) glycol
02 Ethylene glycol 839 Mother liquor( MEG) 800
03 DM Water 30 Vapour loss 33
Caustic soda 30 Bosantan sodium salt 60
04
crude
Total 949 Total 949
Stage - III
Qty Qty
S.No Input Output
in Kg in Kg
Bosantan sodium salt 60 Bosantan sodium salt 38
01
crude pure
02 Seed 1 Mother liquor( ACE ) 720
03 ACE mixture 705 Vapour loss 8
Total 766 Total 766
Stage – IV
Qty Qty
S.No Input Output
in Kg in Kg
Bosantan sodium salt Bosantan monohydrate
01 38 35
pure
02 Acetone 395 Distilled acetone 195
Mother liquor
03 DM water 73 220
( Water+Acetone )
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
Process Flow chart of Methylphenidate
41 FEBRUARY 2017
Material Balance
Stage -61A
Total Total
S.N Quanti Quanti
Input Qty in Output Loss Qty
o. ty ty
kg in kg
Threo- Crude
1 100.0 85 Kg 85
Ritalinic acid 100 Kg Methylphenidate
0
HCl HCl
Methylphenidate
21 Kg 21.00
HCl (as residue)
Recovered 211.0
2 Methanol 247 Kg 277 211 Kg
methanol 0
Consumption of 12.5
12.50
methanol Kg
Evaporation loss 47.5
47.50
of methaol Kg
HCl
Hydrochloric 118.0 14.5
3 118 Kg consumption for 14.50
acid 35% 0 Kg
reaction
26.8
Evaporation loss 26.80
Kg
Sulphuric 122.7 122.7
4 46 Kg 46.00 Mother liquor
acid Kg 0
541.0 541.
Total Total
0 00
Stage - 61B
S. Total Total
No Input Qty Qty in Output Qty Loss Qty in
. kg kg
Crude Pure
100 80
1 Methylphenida 100 Methylphenidate 80
Kg Kg
te HCl HCl
Methylphenidate 18
18
HCl (residue) Kg
Activated 387
2 1 Kg 1 Distilled water 387
Carbon Kg
50
Evaporation loss 50
Kg
Mother liquor + 60
3 Hyflowsupercel 1 Kg 1 60
Acetone wash Kg
Evaporation loss 8 Kg 8
435 2.0
4 Water 435 Spent carbon 2
Kg Kg
70 2.0
5 Acetone 70 Spent Hyflow 2
Kg Kg
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. Qty in Qty in
Stage Name Inputs Outputs
No kg kg
Water +
Sodium
chloride 179
DM water 900 1129
Kg + 25 Kg
1. l - Eph Base Sodium
Preparation hydroxide
28A Distilled
Caustic Soda
144 Toluene 280
Flakes
recycle
l-Eph.base in
l - Eph.salt 600 680
Toluene
Toluene
Toluene 473 29
vapour loss
2117 2117
l Ephedrine base 200
Etafedrine 230
Acetonitrile 825.3
base crude
Sodium carbonate Recovered 786
160
(Anhydrous) Acetonitrile
Ethyl 250
l-Ephedrine base Ethyl bromide 240
bromide salt
2. to Etafedrine Recovered 645
base crude DM water 420
Toluene
28B Toluene 688 Vapour loss 672
Caustic soda
40
flakes
Sodium sulphate
10
(anhydrous)
2583.3 2583
Etafedrine
Etafedrine base
base 1st
crude
300 fraction 40
Etafedrine
base Main
fraction 260
300 300
4. Etafedrine
Etafedrine base 220
HCl 220
Etafedrine base
Recovered
to Etafedrine HCl
Hydrochloric acid 115 Isopropyl
28D
alcohol 397.5
Mother
Activated carbon 1
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 OUTPUT Quantity loss Total qty
in kg in kg in kg
1 alpha-Phenyl-
2-piperidyl
115.5 Material 100.485 100.485
acetamide
(erythro rich)
2 Potassium Mother
144.375 544.005 77.385 621.39
hydroxide 85% liquor
3 Water 462
Total 721.875 Total 721.875
47 FEBRUARY 2017
Stage - 51B
S.N Input Total Output Quanti loss Total
o qty in ty in qty in
kg kg kg
1 Stage -51A 100.4 Stage - 51B 116.5 116.56
2 Water 246.1 HCl crude 14.16 16.9 31.15
during reaction
3 Hydrochloric 45.22 Distilled water 220.0 24.1 244.18
acid 35%
4 Isopropyl 157.7 Isopropyl 127.6 30.1 157.76
alcohol alcohol
5 Dichlorometha 1396.74 Dichlorometha 743.5 653. 1396.74
ne ne 1
6 Total 1946.39 Total 1946.39
Stage - 51C
S.No Input Total Output quantity loss Total
qty in qty in
kg kg
Stage -
1 Stage - 51B 116.563 90.44 90.44
51C
Hydrochloric
2 316.47 HCl gas 16.6801 93.833 110.51
acid 35%
Distilled
3 Water 1004.77 1060.02 150.72 1210.74
water
Mother
Isopropyl
4 78.878 liquor + 62.7923 16.07 78.866
alcohol
IPA wash
Residue 26.1217 26.12
Total 1516.68 Total 1516.67
Stage - 51D
S.No Input Total Output Quantity loss Total
qty in in kg qty in
kg kg
1 Stage -
90.436 Stage - 51D 58.78 58.784
51C
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 Mother liquor
70.993 56.523 14.470 70.993
alcohol + IPA wash
Residue 31.653 31.653
Total 345.015 Total 345.015
48 FEBRUARY 2017
Stage - 53A
S.No Input Total Output Quantity loss Total
qty in in kg qty in
kg kg
1 Stage - 51D 58.78 Stage - 53A 50.025 50.025
2 Ammonia
DM water 352.70 4.232 0.411 4.644
complex
3 Ammonia Mother
45.85 361.520 41.149 402.668
hydroxide10% liquor
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.N Qty in
o Input Qty in kg Output kg
1. DM water 400 Material 36.25
2. Methanol+Water
Methanol
450 ML 980
3. Methanol Vapour
dl-threo-Ritalinic acid
25 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
STAGE 68C
S.N Qty in Qty in
o Input kg Output 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. Spent
Stir, settle & layer separation
carbon 2
6. Add HCl solution (DM water + Distilled
HCl) 10.2 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
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
Qty Total
S.N Stage Qty
Inputs in kg Qty in Outputs
o Name in kg
kg
DM water 3.25 975 Wet 270
Toluene 5.83 1749 Recovered Toluene 1200
Recovered Toluene +
01. 63A l-PPA 300 300 1400
Ethanol
Caustic
- 100 n-Heptane ML 2800
solution
NaCl 0.08 24 Aq.layer 1100
Sodium
0.17 51 Vapour loss 142
sulphate
Hyflow - 2 Solid waste 70
DEC 0.76 228
Sodium
- 25
ethoxide
Toluene 3.63 1089
DM water
0 750
wash
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
Stage Qty in Qty in

S.No Input Output
Name kg kg
1. 62A DM water 755 Wet 300
Recovered
Toluene 3050 2300
Toluene
Recovered
l-PPA 300 Toluene + 900
Ethanol
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
Water- I
1200 1200
2. 62C purification
Water- II
1200 1200
Purification
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
Process flow chart of Lorazepam
Material Balance
Stage – I
Qty in Qty in
S. No Input Output
Kg 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
Qty in Qty in
S. No Input Output
Kg 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
Qty in Qty in
S. No Input Output
Kg Kg
01 Acetonitrile 200 Lorazepam 22
02 67B material 20 Mother liquor 175
03 Vapour loss 23
Total 220 Total 220
Stage – IV
Qty in Qty in
S. No Input Output
Kg 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
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
Qty in Qty in
S.NO Input Output
Kg Kg
Pthaleic Anhydride N-(2-Hydroxyethyl)
01 450 500
phthalimide
59 FEBRUARY 2017
Mono Ethanol Amine Toluene recovered -

02 190 1750
Reuse
03 Toluene 3150 Water ML 9050
04 DM Water 6150 Toluene residue 50
DM Water (Toluene Toluene loss
05 1433 23
Purification)
06
07
Stage – II
Qty Qty in
S.NO Input Output
in Kg Kg
Ethyl, 4-{2-
N-(2-Hydroxyethyl) (Phthalimido) ethoxy}
01 200 2030
phthalimide acetoacetate) (Organic
layer)
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
DM Water (Toluene
07 1675
Purification)
Sodium carbonate
08 15
(Toluene Purification)
Stage – III
Qty Qty in
S.NO Input Output
in Kg Kg
Ethyl, 4-{2-(Phthalimido) 2030 Pthalimido Amlodipine 205
01 ethoxy} acetoacetate)
(Organic layer)
02 Piperidine 12 Water + acetic acid ML 2890
03 Acetic Acid 1057 Organic residue 22
Ortho Chloro 140 Recovered Toluene 1500
04
Benzaldehyde
05 DM Water 800 Toluene loss 8
3 Methyl Amino 186
06
crotonate
07 Ethyl Acetate 400
60 FEBRUARY 2017
Stage – IV
Qty Qty in
S.NO Input Output
in Kg Kg
01 Pthalimido Amlodipine 356 Amlodipine Base 210
Water based ML (
02 Acetic ACid 49 6350
water +methanol)
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
Stage – V
Qty Qty in
S.NO Input Output
in Kg 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
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- d-Ephedrine HCl Chloro d-Ephedrine
5.00
Ephedrine 5.00 HCl
Chloroform Chloro d-Ephedrine
HCl
ML 10.21Kg+ 14.58
Preparation
9.37 Chloroform9.37Kg
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
Hydrogenation DM water 12.51 Desoxy base 2.08
Chloro d-
4.17 Recovered Benzene 33.36
Ephedrine HCl
Activated carbon 0.07 Benzene Loss 2.78
Palladium Palladium Catalyst
0.42 0.42
Catalyst on BaSo4 on BaSo4 (recycle)
H2 Cylinders
2.78 Sodium Sulphate 0.34
Cu.M
N2 Cylinders
0.69 Activated carbon 0.07
Cu.M
Caustic Soda water12.51Kg+HCl
6.95 21.55
flakes 9.04Kg
Stage – III
Selegeline Deoxy base 2.08 Selegiline Base 1.56
base
Acetone 18.22 Recovered Acetone 16.92
preparation
Propyl chloride 1.30 Recovered Benzene 26.03
Potassium
1.93 Acetone Loss 1.30
Carbonate
Potassium Iodide 2.29 Benzene Loss 1.30
Potassium
Sodium Sulphate 0.65 1.93
Carbonate
DM water 7.81 Potassium Iodide 2.29
64 FEBRUARY 2017
Stage – IV
Selegiline base 1.56 Selegiline HCl Crude 1.25
Acetone 10.93 Selegiline HCl Crude 1.87
Crude Selegeline ML(recycle)
HCl preparation IPA/HCl 1.56 Acetone recovered 10.15
Acetone Loss 0.78
14.05 14.05
Stage – V
Selegiline HCl 1.25 Selegiline HCl 1.00
Crude
Selegeline HCl Acetone 8.75 Acetone recovered 8.12
preparation IPA 3.12 Acetone Loss 0.63
Activated carbon 0.13 Selegilline HCl 3.50
ML(recycle)
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
Qty Qty
S.N Name of the S.N Los Tota
in Description in
o raw material o s l
Kg Kg
1 P-Toluic acid 300 1 4-(chloromethyl) 330 - 330
benzoic acid (Stage-
I)
2 Chlorine gas 450 2 Un-reacted Chlorine - 294 294
gas ( Scrubbed by
alkali water )
3 Benzoyl 4 3 HCl gas ( Scrubbed 80 80
peroxide by alkali water )
4 Chlorobenzen 1554 4 Chloro benzene 1476 78 1554
e
5 DM water 500 5 Water washings 360 145 505
6 Residue 45 45
Total 280 Total 221 597 280
8 1 8
Stage II: Preparation of p-(aminomethyl)benzoic acid

(PAMBA)
In put Out put
Qty
S.N Name of the Qty S.N Los Tot
Description in
o raw material in Kg o s al
Kg
1 4- 250 1 p-(aminomethyl) 130 130
(chloromethyl) benzoic acid
benzoic acid (PAMBA) (Stage-I)
(Stage-I)
2 Ammonium bi- 411. 2 Mother liquor* 101 101
carbonate 3 5 5
3 Aqueous 751. 3 Ammonia gas 138 138
ammonia 7
4 Activated 5 4 Distillate 200 200
carbon 0 0
5 Hyflo 10 5 Spent Carbon 7 7
6 DM water 1875 Hyflo (Spent) 15 15
Total 3305 Total 316 138 330
7 5
68 FEBRUARY 2017
Stage III: Preparation of Tranexamic acid cis/trans

mixture
In put Out put

Qty
S.N Name of the S.N Qty
in Description Loss Total
o raw material o in Kg
Kg
1 p- 25 1 Tranexamic acid 24 24
(aminomethyl mixture cis/trans
) benzoic acid (Stage-III)
(PAMBA)
(Stage-II)
2 Platinum 1.25 2 Platinum oxide 1.24 1.24
oxide
3 Sulphuric 20 3 Calcium sulfate 27.8 27.8
acid
4 Calcium 15.5 4 Hyflo (Spent) 15 15
hydroxide
5 Acetone 78.2 5 Acetone 70 8.25 78.2
5 5
6 DM water 500 6 Water 503.7 503.
1 71
7 Hyflo 10
Total 650 Total 625. 24.2 650
75 5
Stage IV: Preparation of Tranexamic acid Crude

In put Out put
S.N Name of the raw Qty S.N Qty in Los
Descriptio Total
o material in Kg o Kg s
n
1 Tranexamic acid 100 1 Tranexamic 80 80
mixture cis/trans acid Crude
(Stage-III) (Stage-IV)
2 Barium 310 2 Barium 229.3 229.
Hydroxide sulfate 3
3 Sulphuric acid 96.3 3 Hyflo 115 115
(Spent)
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. 70. 2417
3 7
69 FEBRUARY 2017
Stage V: Preparation of Tranexamic

acid
In put Out put
Qty
Name of the raw Qty in S.N Los Tota
S.No Descriptio in
material Kg o s l
n Kg
1 Tranexamic acid 100 1 Tranexami 60 60
Crude (Stage-IV) c acid
(Stage-V)
2 Acetone 786 2 Acetone 726 60 786
3 Activated carbon 2 3 Spent 4 4
Carbon
4 Hyflo 10 4 Hyflo 18 18
(Spent)
5 DM water 1000 5 Water 950 50 100
0
6 Residue 30 30
Total 1898 Total 161 286 189
2 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
140
COOLING
TOWER
40
78
BOILER PROCESS
0.4
30 Vapor loss
1.5 Blow down
Condensate - 14 (water) in vacuum
44
4.5
10 9.5
210 KLD PROCESS / EFFLUENT TREATMENT PLANT
UTILITY 11 0.6 T
Effluent (Salt)
5 3.9
DOMESTIC SEWAGE TREATMENT GARDENING
PLANT 10 KLD
15
COMMUNITY
SUPPLY
Figure 3.4 Existing Water Balance
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 3M 3M
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.
80 FEBRUARY 2017
Table 5. 1 Land Use Break-Up of Project Site
Sr. Existing Proposed Total % of total

Land use details
No. (Sq m) (Sq m) (Sq m) 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
Admin block, Canteen,
5 447.2 0 447.2 1.50
Security cabin
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
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.
81 FEBRUARY 2017
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.
83 FEBRUARY 2017
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
84 FEBRUARY 2017
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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5 (f) Synthetic organic Chemicals

ABC TECHNO LABS INDIA PRIVATE LIMITED, CHENNAI

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

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

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

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

iii FEBRUARY 2017

S. No. Particulars Details

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

M/s Malladi drugs and Pharmaceuticals has proposed to enhance

2.1.2 Project Proponent

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

Today, Malladi is the leading manufacturer of Active Pharmaceutical

Malladi Drugs & Pharmaceuticals is having five manufacturing units

Malladi Drugs & Pharmaceuticals Ltd has validation capabilities

2.2 Brief description of nature of the project

The Indian pharma market is pegged approximately at Rs 1.20 lakh

2.3 Demand supply gap

Increasing expenditure on health: Spending on health is the main

The increasing government expenditure on health also contributes to

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

Indian pharmaceutical companies supply almost all the country's

2.5 Export possibility

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

2.6 Employment generation

The total direct employment potential of the proposed industry is

3.1 Type of the project

The proposed project involves the preparation of Active

It is an independent project not interlinked or interdependent project.

3.2 Location of the project

Table 3.1 Environmental setting of the project site

S. NO. PARTICULARS DETAILS

Figure 3.1 Location Map of Project Site

Figure 3.2 Satellite Image of the Project Site

Figure 3.3 Master Layout

3.3 Details of alternate site

 As the factory is currently in operation all infrastructural facilities are

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

1. The land use of the site is Industrial

3.4 Size or magnitude of the operation

M/s Malladi Drugs & Pharmaceuticals Ltd is currently manufacturing

Table3.2 Products & their production capacity

3.5 Manufacturing Process and Material Balance

The manufacturing process for each product proposed to be produced is

3.5.1 Pseudo Ephedrine HCl

Pseudoephedrine is a sympathominetic amine that relieves nasal congestion

Process Flow Chart of Pseudo Ephedrine HCl

20B Solvent (80% sold)

21A2 in Water 1130 Conc. Mass 650

Process Flow Chart of Alprazolam

Material Balance for Alprazolam

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

Stage 2: NDP preparation

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

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

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

Crude 12. Alprazola

Figure No: 3. 1process flow chart of Phenylepherine

9AM Total 1301 Total 1301

Stage V The ETP Load (kg) 1436.5

Stage –IX- 10A

Triprolidine hydrochloride is used to combat the symptoms associated with

Stage –1 - Triprolidine Oxalate preparation