Download Proposed TOR - Environment Clearance

FORM-I
For
PROPOSED EXPANSION OF EXISTING BULK DRUGS
AND BULK DRUG INTERMEDIATES
MANUFACTURING UNIT
of
M/s. HEM-DEEP ORGANICS PVT. LTD.
Plot No. 3801/2, GIDC Estate, Ankleshwar – 393 002,
Dist. Bharuch, Gujarat, INDIA.
APPENDIX I
FORM 1
(I)
Sr.
No.
1.
2.
3.
Basic Information
Item
Details
M/s. Hem-Deep Organics Pvt. Ltd.
5(f)
Capacity of Proposed Expansion of bulk Drugs and
its intermediates: 737.5 MT/Month, Repacking:
100 MT/Month & Distillation: 200 MT/Month
4.
Name of the Project/s
S.No. in the Schedule
Proposed capacity / area / length /
tonnage to be handled/command
area/lease area/number of wells to be
drilled
New/Expansion/Modernization
Expansion
5.
Existing capacity/area etc.
Existing Capacity: 6 MT/Month
6.
7.
Category of project i.e. ‘A’ or ‘B’
Does it attract the general condition?
If yes, please specify.
Does it attract the specific condition?
If yes, please specify.
Location
Plot/Survey/Khasra No.
Village
Tehsil
District
State
Nearest railway station/airport along
with distance in kms.
Nearest
Town,
city,
District
Headquarters along with distance in
kms.
Village Panchayats, Zilla Parishad,
Municipal corporation, Local body
(Complete postal addresses with
telephone nos. to be given)
Name of the applicant
Registered address
‘A’
Yes. Located
(Ankleshwar).
N.A.
8.
9.
10.
11.
12.
13.
14.
15.
Address for correspondence:
Name
Designation (Owner/Partner/CEO)
Address
Pin Code
E-Mail
Telephone No.
in
Critically
Polluted
Area
Plot. No. 3801/2
GIDC Estate
Ankleshwar - 393 002
Bharuch
Gujarat
Nearest Railway Station: Ankleshwar = 4 km
Nearest Airport
: Surat = 70 km
Nearest Town: Ankleshwar = 4 km
Nearest District Head Quarter: Bharuch = 15 km
Notified Area Authority, Ankleshwar
M/s. Hem-Deep Organics Pvt. Ltd.
Plot. No. 3801/2, GIDC, Ankleshwar - 393 002,
Dist: Bharuch, Gujarat, INDIA.
Mr. Kamlesh Gami
Partner
M/s. Hem-Deep Organics Pvt. Ltd.
Plot. No. 6012/1, GIDC, Ankleshwar - 393 002,
Dist: Bharuch, Gujarat, INDIA.
393 002
[email protected]
Tel. : +91-2646-226676
Mob.: +91 9824014578
16.
17.
18.
19.
20.
21.
22.
23.
24.
Fax No.
Details of Alternative Sites examined,
if any location of these sites should be
shown on a topo sheet.
Interlinked Projects
Whether separate application of
interlinked
project
has
been
submitted?
If Yes, date of submission
If no., reason
Whether the proposal involves
approval/clearance under: If yes,
details of the same and their status to
be given.
(a) The Forest (Conservation) Act,
1980?
(b) The Wildlife (Protection) Act,
1972?
(c)
The C.R.Z Notification, 1991?
Whether there is any Government
order/policy relevant/relating to the
site?
Forest land involved (hectares)
Whether there is any litigation
pending against the project and/or
land in which the project is propose to
be set up?
(a) Name of the Court
(b) Case No.
(c)
Orders/directions of the Court,
if any and its relevance with the
proposed project.
-No
No
Not applicable
Not applicable
Not applicable
Not applicable as proposed expansion activity is
going to occur within GIDC, Ankleshwar.
No
No
No
(II) Activity
1. Construction, operation or decommissioning of the Project involving actions,
which will cause physical changes in the locality (topography, land use,
changes in water bodies, etc.)
Sr.
No.
Information/Checklist confirmation
1.1
Permanent or temporary change in land
No
use, land cover or topography including
increase in intensity of land use (with respect to
local land use plan)
1.2
Clearance of existing land, vegetation and
buildings?
Yes
Minor site clearance activities shall be
carried out to clear shrubs and weed.
1.3
1.4
Creation of new land uses?
Pre-construction investigations e.g. bore houses,
soil testing?
No
No
---
1.5
Construction works?
Yes
is
1.6
1.7
No
No
Yes
Approved plan for construction
attached as Annexure: 1.
is
No
--
1.10
1.11
1.12
1.13
Demolition works?
Temporary sites used for construction workers or
housing of construction workers?
Above ground buildings, structures or Earthworks
including linear structures, cut and fill or
excavations
Underground works including mining or
tunneling?
Reclamation works?
Dredging?
Offshore structures?
Production and manufacturing
Approved plan for construction
attached as Annexure: 1.
---
No
No
No
Yes
1.14
Facilities for storage of goods or materials?
Yes
1.15
Facilities for treatment or disposal of solid waste
or liquid effluents?
Yes
---List of Products is attached as Annexure:
2 and manufacturing process is attached
as Annexure: 3.
Dedicated storage area for storage of Raw
Materials and finished products, solvents,
etc. shall be provided.
Effluent Treatment Plant will be installed
to treat effluent so as to achieve the
GPCB norms.
Details of water consumption & effluent
generation with segregation of effluent
streams are attached as Annexure: 4.
Details of proposed Effluent Treatment
Plant are attached as Annexure: 5.
Details of Hazardous waste generation
and disposal is attached as Annexure: 6.
1.16
Facilities for long term housing of operational
workers?
New road, rail or sea traffic during construction
or operation?
New road, rail, air waterborne or other airports
etc?
No
1.8
1.9
1.17
1.18
Yes
/No?
Details thereof (with approximate
quantities / rates, wherever possible)
with source of information data
Proposed expansion activity is going to
occur within existing sit in GIDC estate,
Ankleshwar.
No
--
No
--
1.19
1.20
1.21
1.22
1.23
Closure or diversion of existing transport routes
or infrastructure leading to changes in traffic
movements?
New or diverted transmission lines or pipelines?
Impoundment, damming, converting,
realignment or other changes to the hydrology
of watercourses or aquifers?
Stream crossings?
Abstraction or transfers or the water form
ground or surface waters?
No
--
No
No
---
No
Yes
1.24
Changes in water bodies or the land surface
affecting drainage or run-off?
No
-No ground water shall be used. The
requirement of raw water shall be met
through GIDC Water Supply.
--
1.25
Transport of personnel or materials for
construction, operation or decommissioning?
No
--
1.26
Long-term dismantling or decommissioning or
restoration works?
Ongoing activity during decommissioning which
could have an impact on the environment?
Influx of people to an area in either temporarily
or permanently?
Introduction of alien species?
Loss of native species of genetic diversity?
Any other actions?
No
No
There is no dismantling of any sort. Not
applicable.
No Impact on the Environment
No
--
No
No
No
----
1.27
1.28
1.29
1.30
1.31
2. Use of Natural resources for construction or operation of the Project (such as land,
water, materials or energy, especially any resources which are non-renewable or in
short supply):
Sr.
No
2.1
2.2
2.3
2.4
2.5
2.6
2.7
Information/checklist confirmation
Yes/
No?
Land especially undeveloped or agriculture
land (ha)
Water (expected source & competing
users) unit: KLD
No
Yes
Minerals (MT)
Construction material -stone, aggregates,
sand / soil (expected source MT)
Forests and timber (source - MT)
No
Yes
Energy including electricity and fuels
source, competing users Unit: fuel (MT),
energy (MW)
Yes
Any other natural resources
appropriates standard units)
No
(use
No
Details there of (with approximate quantities/rates,
wherever possible) with source of information data
-Water requirement will be met through the GIDC
Water Supply. Detailed water balance is given as
Annexure – 4.
Not applicable
Company shall use Sand, stone, Cement and
Structural Steel for Construction as required.
No wood shall be used as construction material or as
a fuel.
Power required from GEB is 100 KVA (Existing)
Power required from GEB will 500 KVA (Proposed)
1 D.G. Set = 250 KVA (Proposed) (For Emergency Only)
Fuel:
Natural Gas = 10 m3/Day(Existing)
LDO = 500 Liter/Day (Existing)
Agro Waste/Briquettes = 10 MT/Day (Proposed)
HSD = 20 Liter/Hr (Proposed) (For Emergency Only)
--
3. Use, storage, transport, handling or production of substances or materials, which
could be harmful to human health or the environment or raise concerns about
actual or perceived risks to human health.
Sr.
No.
Information / Checklist confirmation
Yes/
No?
3.1
Use of substances or materials, which are hazardous
(as per MSIHC rules) to human health or the
environment (flora, fauna, and water supplies)
Yes
3.2
Changes in occurrence of disease or affect disease
vectors (e.g. insect or water borne diseases)
Affect the welfare of people e.g. by changing living
conditions?
No
3.4
Vulnerable groups of people who could be affected
by the project e.g. hospital patients, children, the
elderly etc.,
No
3.5
Any other causes
No
3.3
Details
thereof
(with
approximate
quantities / rates wherever possible) with
source of information data
Please refer Annexure : 8.
Not applicable as site is located in GIDC,
Ankleshwar.
Not applicable as site is located in GIDC,
Ankleshwar.
No
Not applicable as site is located in GIDC,
Ankleshwar.
--
4. Production of solid wastes during construction or operation or decommissioning
MT/month)
Sr.
No.
Information/Checklist confirmation
Yes/
No?
4.1
4.2
No
No
--
4.7
Spoil, overburden or mine wastes
Municipal waste (domestic and or
commercial wastes)
Hazardous wastes (as per Hazardous Waste
Management Rules)
Other industrial process wastes
Surplus product
Sewage sludge or other sludge from effluent
treatment
Construction or demolition wastes
Details thereof (with approximate
quantities / rates, wherever possible)
with source of information data
--
4.8
4.9
4.10
4.11
Redundant machinery or equipment
Contaminated soils or other materials
Agricultural wastes
Other solid wastes
4.3
4.4
4.5
4.6
Yes
Please refer Annexure: 6
Yes
No
Yes
Please refer Annexure: 6
-Please refer Annexure: 6
No
Construction waste shall be utilized for
leveling & land filling in the premises.
---Please refer Annexure: 6
No
No
No
No
5. Release of pollutants or any hazardous, toxic or noxious substances to air (Kg/hr)
Sr.
No.
Information/Checklist confirmation
Yes/
No?
5.1
Emissions from combustion of fossil fuels
From stationary or mobile sources
Emissions from production processes
Yes
5.2
Yes
Details
thereof
(with
approximate
quantities/rates, wherever possible) with
source of information data
Details of flue & process gas emission are
attached as Annexure: 7
Reactors shall be connected to common
scrubber system.
Details of emission levels from process are
attached as Annexure: 7.
5.3
Emissions from materials handling including
storage or transport
Yes
5.4
Emissions from construction
including plant and equipment
activities
No
5.5
Dust or odours from handling of materials
including construction materials, sewage and
waste
No
5.6
5.7
Emissions from incineration of waste
Emissions from burning of waste in open air
(e.g. slash materials, construction debris)
No
No
5.8
Emissions from any other sources
No
Details of Air Pollution Control measures are
attached as Annexure: 7
All liquid raw materials shall be procured in
bulk tankers and shall be transferred through
a closed circuit pipe lines by pumps.
Solid raw material shall be handled in closed
charging rooms with proper ventilation and
charged through close pipeline into reactors.
Utmost care will be taken during construction
activity and water sprinklers shall be utilized
whenever necessary.
All the waste shall be stored in designated
places and shall be transported to TSDF or
Incineration Site in their own approved closed
vehicles.
6. Generation of Noise and Vibration, and Emissions of Light and Heat:
Sr.
No.
Information/Checklist confirmation
Yes/
No?
6.1
From operation of equipment e.g. engines,
ventilation plant, crushers
Yes
6.2
From industrial or similar processes
Yes
6.3
6.4
From construction or demolition
From blasting or piling
No
No
Details there of (with approximate Quantities
/rates, wherever possible) With source of source
of information data
There are few activities due to which noise would
be generated. The equipments resulting in noise
generation are machinery of plant and Diesel
generator. Adequate noise control measures will
be provided whenever required.
Proper and timely oiling, lubrication and
preventive maintenance will be carried out for
the machineries & equipments to reduce noise
generation.
Use of PPEs like ear plugs and ear muffs will be
made compulsory near the high noise generating
machines.
Noise monitoring shall be done regularly in plant
area.
The D.G. Set will be installed in a closed room and
provided with acoustic enclosure.
The unit will carry out plantation in the proposed
greenbelt within the premises which will prevent
the noise pollution in surrounding area.
All machinery / equipment shall be well
maintained, shall have proper foundation with
anti vibrating pads wherever applicable and noise
levels will be within permissible limits.
Acoustic enclosures shall be provided for DG set.
6.5
6.6
6.7
From construction or operational traffic
From lighting or cooling systems
From any other sources
No
No
Yes
Acoustic enclosures shall be provided for DG set.
7. Risks of contamination of land or water from releases of pollutants into the
ground or into sewers, surface waters, groundwater, coastal waters or the sea:
Sr.
No
Information/Checklist confirmation
Yes/
No?
7.1
From handling, storage, use or spillage of
hazardous materials
Yes
7.2
From discharge of sewage or other
effluents to water or the land (expected
mode and place of discharge)
By deposition of pollutants emitted to air
into the land or into water
From any other sources
Is there a risk of long term build up of
pollution in the environment from these
sources?
No
7.3
7.4
7.5
Details thereof (with approximate quantities /
rates, wherever possible) with source of
information data
All the raw material shall be stored separately in
designated storage area and safely. Bund walls
shall be provided around raw materials storage
tanks for containing any liquid spillage.
Other materials shall be stored in bags / drums on
pallets with concrete flooring and no spillage is
likely to occur. Please refer Annexure : 8.
No
--
No
No
Not applicable
Full- fledged Environmental Management System
(EMS) will be installed. i.e. ETP, Air Pollution
Control systems, Hazardous Waste Handling and
Management as per norms, etc. which will
eliminates the possibility of building up of
pollution.
8. Risks of accident during construction or operation of the Project, which could
affect human health or the environment:
Sr.
No
8.1
8.2
8.3
Information/Checklist confirmation
From explosions, spillages, fires etc from
storage, handling, use or production of
hazardous substances
From any other causes
Could the project be affected by natural
disasters causing environmental damage
(e.g. floods, earthquakes, landslides,
cloudburst etc)?
Yes/
No?
Yes
No
No
Details
thereof
(with
approximate
quantities / rates, wherever possible) with
source of information data
The risk assessment will be carried out and
all mitigative measures shall be taken to
avoid accidents.
Not applicable
--
9. Factors which should be considered (such as consequential development) which
could lead to environmental effects or the potential for cumulative impacts with
other existing or planned activities in the locality
Sr.
No.
9.1
9.2
9.3
9.4
Information/Checklist confirmation
Lead to development of supporting. laities,
ancillary development or development
stimulated by the project which could have
impact on the environment e.g.:
* Supporting infrastructure (roads, power
supply, waste or waste water treatment,
etc.)
•
housing development
•
extractive industries
•
supply industries
•
other
Lead to after-use of the site, which could
have an impact on the environment
Set a precedent for later developments
Have cumulative effects due to proximity
to Other existing or planned projects with
similar effects
Yes/
No?
Yes
No
No
No
Details thereof (with approximate quantities
/ rates, wherever possible) with source of
information data
Site is located in Ankleshwar Industrial Area,
having the entire required infrastructure.
This industrial zone is having existing road
infrastructure, power supply are to be
utilized.
Local people will be employed and no housing
is required.
Please refer Annexure – 9.
-Not applicable
The ETP of the company shall be designed
such that the treated effluent conforms to
the statutory requirement.
(III) Environmental Sensitivity
Sr.
No
1
2
3
4
5
6
7
8
9
10
11
12
Information/Checklist confirmation
Name / Aerial distance (within 25 km). Proposed
Identity Project Location Boundary.
Areas protected under international conventions
No
Site is located in Ankleshwar Industrial
national or local legislation for their ecological,
Area, Tal. Ankleshwar, Dist. Bharuch,
landscape, cultural or other related value
Gujarat.
Areas which are important or sensitive for
No
Site is located in Ankleshwar Industrial
Ecological reasons - Wetlands, watercourses or
Area, Tal. Ankleshwar, Dist. Bharuch,
other water bodies, coastal zone, biospheres,
Gujarat.
mountains, forests
Areas used by protected, important or sensitive
No
Site is located in Ankleshwar Industrial
species of flora or fauna for breeding, nesting,
Area, Tal. Ankleshwar, Dist. Bharuch,
foraging, resting, over wintering, migration
Gujarat.
Inland, coastal, marine or underground waters
Yes
River Narmada: 9 Km
Amla Khadi: 5 Km
State, National boundaries
No
-Routes or facilities used by the public for to
No
Not applicable
recreation or other tourist, pilgrim areas.
Defense installations
Densely populated or built-up area
Areas occupied by sensitive man-made land
community facilities)
Areas containing important, high quality or
scarce resources (ground water resources,
surface
resources, forestry, agriculture,
fisheries, tourism, tourism, minerals)
Areas already subjected to pollution or
environmental damage. (those where existing
legal environmental standards are exceeded)
Are as susceptible to natural hazard which could
cause the project to present environmental
problems (earthquakes, subsidence ,landslides,
flooding erosion, or extreme or adverse climatic
conditions)
No
NIL
Yes
No
Bharuch city: 4 Lakh population
No
The project being in industrial area does
not affect agricultural land.
No
Site is located in Ankleshwar Industrial
Area, Tal. Ankleshwar, Dist. Bharuch,
Gujarat.
N.A.
No
I hereby given undertaking that the data and information given in the application and
enclosures are true to the best of my knowledge and belief and I am aware that if any
part of the data and information submitted is found to be false or misleading at any
stage, the project will be rejected and clearance given, if any to the project will be
revoked at our risk and cost.
Date: July 10, 2017
Place: Ankleshwar
NOTE:
1. The projects involving clearance under Coastal Regulation Zone Notification, 1991
shall submit with the application a C.R.Z. map duly demarcated by one of the
authorized agencies, showing the project activities, w.r.t. C.R.Z. (at the stage of TOR)
and the recommendations of the State Coastal Zone Management Authority (at the
stage of EC). Simultaneous action shall also be taken to obtain the requisite clearance
under the provisions of the C.R.Z. Notification, 1991 for the activities to be located in
the CRZ.
2. The projects to be located within 10 km of the National Parks, Sanctuaries, Biosphere
Reserves, Migratory Corridors of Wild Animals, the project proponent shall submit the
map duly authenticated by Chief Wildlife Warden showing these features vis-à-vis the
project location and the recommendations or comments of the Chief Wildlife Warden
thereon (at the stage of EC).
3. All correspondence with the Ministry of Environment & Forests including submission
of application for TOR/Environmental Clearance, subsequent clarifications, as may be
required from time to time, participation in the EAC Meeting on behalf of the project
proponent shall be made by the authorized signatory only. The authorized signatory
should also submit a document in support of his claim of being an authorized signatory
for the specific project.
ANNEXURES LIST:
1
Plot layout
2
List of products with production capacity and raw materials
3
Brief manufacturing process, chemical reaction and mass balance
4
Details of water consumption and waste water generation
5
Details of effluent treatment plant
6
7
Details of hazardous/solid waste generation, management and
disposal mode
Details hazardous chemical storage facility
8
Details of air pollution sources and control measures
9
Socio - Economic impacts
10
Proposed Terms Of References
11
GIDC Plot Allotment Letter & GIDC Water Supply Letter
12
Membership Certificate of CETP, ETL-Ankleshwar for disposal of
treated effluent
13
Membership Certificate of TSDF & Common Incinerator, BEILAnkleshwar
ANNEXURE-1
PLOT LAYOUT
ANNEXURE-2
LIST OF PRODUCTS WITH PRODUCTION CAPACITY (Existing and Proposed scenario)
Sr.
No.
Products
Existing
Capacity
(MT/Month)
Additional
CAS No.
Total
1
Oxyclozanide
3.5
0
3.5
2277-92-1
2
Furosemide
2.5
0
2.5
5.0
54-31-9
100
100
123-92-2
0
100
100
105-68-0
0
--------------------------------------
10
10
25
25
76824-35-6
14205-39-1
88150-62-3
93479-97-1
106649-95-0
76824-35-6
152751-57-0
845273-93-0
71550-12-4
7554-65-6
182815-44-7
93479-97-1
5579-84-0
106685-40-9
144701-48-4
175591-09-0
8068-28-8
147098-20-2
534-07-6
2114-02-5
117976-90-6
72956-09-3
169590-42-5
120202-66-6
134523-03-8
202409-33-4
137862-53-4
1197-18-8
59-30-3
189005-44-5
148553-50-8
79794-75-5
60142-96-3
54965-21-8
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
Diaminomethyleneamino (1-amino-1iminomethylene) thiomethyl thiozole
dihydrochloride [ITU]
N-Sulfomyl-3-chloropropionamide
hydrochloride[IF]
Famotidine
Fomepizole
Colsevelam hydrochloride
Glimepiride
Betahistine Dihydrochloride
Adapalene
Telmisartan
Tapentadol Hydrochloride
Colistimethate Sodium
Rusvastatin Calcium
1-3 dichloro Acetone
Gunylthiourea
Rabeprazole Sodium
Carvediol
Celecoxib
Clopidogrel Bisulfate
Atoravastatin Calcium
Etoricoxib
Valsartan
Tranexamic Acid
Folic Acid
Zolpidic Acid
Pregabaline
Chlorohexidine Base
Benzarone
Benzbromarone
Zaltoprofen
Ondansetron Hydrochloride
Miconazole Nitrate
Ecanazole Nitrate
Desloratadine
Loratidine
Gabapentine
Albendazole
39
40
41
42
43
44
45
46
47
48
49
50
51
52
(B)
60
61
62
63
64
64
Citrezine Hydrochloride
Lasamide
Pioglitazone Hydrochloride
Mesalamine
Febuxostat
Itopride Hydrochloride
Amodafinil
Quetipine Fumrate
Aripiprazole
Amlodipine Besylate
Nebivilol Hydrochloride
Sevelamer Hydrochloride
Sevelamer Carbonate
Poly Allaylamine Hydrochloride
Total (A)
Distillation of Solvent (B)
REPACKING
Benzophenone (Repacking)
Para
Cresyl
Phenyl
Acetate
(Repacking)
Poly
Allaylamine
Hydrochloride
(Repacking)
Allaylamine (Repacking)
Allaylamine
Hydrochloride
(Repacking)
Micronization of Bulk Drugs/APIs
(Famotidine,
Amlodipine,
Glibenclamide,
Sevelamer
HCl,
Glimepride, Adapalene, ITU, IF,
Colsevelam
HCl,
Furosemide,
Telmisartan,
Betahistine
Dihydrochloride, Tapentadol HCl, etc.)
Total (C)
Total (A+B+C)
--------------6.0
--
500
737.5
200.0
500
743.5
200.0
100.0
100.0
100.0
1037.5
100.0
1043.5
------
--
-6.0
83881-52-1
2736-23-4
112529-15-4
89-57-6
144060-53-7
122892-31-3
68693-11-8
111974-72-2
129722-12-9
111470-99-6
152520-56-4
106-27-4
103-45-7
122-70-3
LIST OF RAW MATERIALS AND CONSUMPTION:
Sr. No. Raw Material
1.
2.
3.
4.
5.
6.
Oxyclozanide
3,5,6 TCSA
MCB
Thionyl Chloride
2,4 DCAP
Sodium Bicarbonate
Acetone
Furosemide
Furfuryl Amine
Lasamide
Caustic Flake
IPA
Carbon
Acetic Acid
Diaminomethyleneamino
(1-amino-1iminomethylene)
thiomethyl
thiozole
dihydrochloride [ITU]
1,3 DCA
Guanyl Thiourea
Acetone
Catalyst
Thiourea
Acetic Acid
N-Sulfomyl-3-chloropropionamide
hydrochloride [IF]
Acrylonitrile
Hydrogen Peroxide
HCl (Gas)
Sulfamide
Acetone
Famotidine
ITU
IF
Methanol
NaOH
Water
Acetic Acid
Colsevelam hydrochloride
Monoallylamine
2,2-dimethyl-2,2-azopropane dihydrochloride
Concentrated Hydrochloric acid
Methanol
Polyallylamine
Epichlorohydrin
n-Decylchloride
Quantity
(MT/MT)
1.50
1.50
0.75
1.00
0.05
3.25
0.450
0.850
0.234
0.240
0.080
0.220
0.435
0.413
3.100
0.004
0.261
0.261
1.303
0.008
1.495
0.500
0.400
1.150
0.965
5.710
0.690
20.50
0.200
0.60
0.01
1.15
0.31
0.90
0.01
0.02
7.
8.
9.
10.
11.
12.
Trimethylammoniumhexylchloride
Sodium hydroxide
Glimepiride
3 Ethyl methyl Pyrroline
2 Phenyl ethyl isocyanate
Toluene
Chloro Sulfonic Acid
Ammonia Solution
EDC
Fomepizole
Propanaldehyde
Ethanol
Hexane
Phosphorus oxychloride
Hydrazine Hydrate
Potassium Carbonate
Carbon
Di isopropyl Ether
N,N-Dimethyl Formamide
Dichloro Methane
Betahistine Dihydrochloride
2- vinyl pyridine
Methylamine hydrochloride
Chloroform
Sodium hydroxide
Acetic Acid
IPA
IPA HCl(20%)
Adapalene
Adamentanol
Para Bromo Phenol
THF
Mg Turning
MDC
6-Bromo-2-methyl naphthoate
HCl
Telmisartan
4-Amino 3- Methylbenzoic acid
Conc. Sulphuric Acid
Liq. Ammonia
Methanol
MDC
TEA
Butryl Chloride
Sodium Bicarbonate
Sodium Sulphate
Hexane
Fuming Nitric Acid
Tapentadol Hydrochloride
0.02
0.45
0.40
0.40
0.15
1.00
3.10
0.30
1.31
0.015
0.015
3.45
1.10
0.75
0.15
0.02
0.01
0.03
0.63
0.80
0.23
0.45
0.06
0.01
1.38
0.48
0.30
0.025
0.06
0.04
0.72
1.32
1.484
1.423
2.968
0.06
0.03
0.01
1.287
0.153
0.387
0.02
4.050
13.
14.
3-methoxy propiophenone
IPA
Dimethyl Amine HCL
Paraformadehyde
Sodium Hydroxide
MDC
L (-) Dibenzoyl tartaric acid
THF
Mg Turning
Ethyl Bromide
Acetic Acid
Ammonium Solution
Ethyl Acetate
Trifluroacetic anhydride
Palladium
Acetone
HBr
IPA HCl
Colistimethate Sodium
Colistin Sulphate
Sodium Bicarbonate
Sodium Carbonate
Formaldehyde
Sodium Bisulfite
Acetic Acid
Solvent
Acetone
Methanol
Rusvastatin Calcium
4-Fluoro Benzaldehyde
4-Methyl-3-oxo-Pentatonic Acid Ethyl Ester
Potassium Hydroxide
Methyl Iodide
Methanol
5-Methyl Iso Thio Urea
2,3-Dichloro-5,6-Dicyano Benzoquinone
HMPA
MDC
Meta Chloro Peroxy Benzoic Acid
Methyl Amine
Ethanol
Methane Sulfonyl Chloride
Sodium Hydride (60%)
Di Methoxy Ethane
Hydrogen
DIBAL-H
Toluene
1.412
0.350
1.059
0.588
0.376
0.350
1.412
0.080
0.171
0.588
0.118
0.506
0.230
0.882
0.070
0.260
1.765
0.882
1.33
0.67
0.33
1.33
3.06
0.16
0.80
2.00
3.00
0.52
0.66
0.24
0.60
5.50
0.35
0.85
1.00
8.00
0.11
0.10
2.50
0.35
0.01
3.00
0.01
0.01
8.00
15.
16.
17.
18.
Methyl(3R)-3-(tert butyl dimethyl silyloxy)-5oxo-6-triphenyl phosphoranylidene hexanoate
Triethyl Amine
N,N-Dimethyl Formamide
Hydrogen Fluoride
THF
Ethyl Acetate
Diethyl Methoxy Borane
Sodium Borohydride
Calcium Chloride
1-3 dichloro Acetone
Epichlorohydrin
HCl (30%)
Sulfuric Acid (98%)
Sodium Dichromate
Gunylthiourea
Phosphorus Penta Sulphide
KOH
Dicyanadiamide
Sodium Hydro Sulphite
Rabeprazole Sodium
2,3-Lutidine
H2O2 (50%)
Nitric Acid
Acetic Acid
3-Methoxy 1-Propanol
NaOH
Toluene
DMSO
Acetic Anhydride
HCl
Thionyl Chloride
MDC
Sodium Sulphate
2-Mercaptobenzimidazole
Ammonium Hydroxide
Sodium Hypochlorite (8%)
Acetone
Sodium Hydro Sulphate
MMA
IPA
Activated Carbon
Carvediol
4-Hydroxy Carbazole
Epichlorohydrin
Hydrose
Methanol
1.45
0.15
3.00
0.05
7.50
10.50
0.20
0.01
0.13
1.302
3.125
1.862
1.562
0.827
1.000
0.909
0.181
0.460
0.330
0.380
0.060
0.430
0.155
0.012
0.010
0.390
0.200
0.530
0.370
0.100
0.530
0.125
3.270
0.100
0.120
0.100
0.150
0.100
0.447
0.790
0.116
0.067
19.
20.
21.
Ethyl Acetate
Carbon
Hyflo
Monoethylene Glycol Dimethyl Ether
2-(2-Methoxy Phenoxy) Ethyl Amine
Acetone
Potassium Carbonate
Oxalic Acid
IPA
Sodium Sulphate
Ortho Phosphoric Acid
Celecoxib
4 SPH
Dione Deri
Toluene
Carbon
Clopidogrel Bisulfate
amino(2-chlorophenyl)acetic acid
methanol
Potassium salt
MDC
Liq. ammonia
Thiophene-2-Ethanol
p-toluene sulphonyl chloride
Toluene
Sodium hydroxide
Acetonitrile
Dipotassium phosphate
Ethyl acetate
HCL
P-Formaldehyde
MDC
Liq. Ammonia
Acetone
Tartaric acid
MDC
Sodium carbonate
Acetone
Activated carbon
Sulfuric acid
Atoravastatin Calcium
Ethyl-4-Cyano-3-hydroxy butanaote
THF
Diisopropyl amine
N-Butyl Lithium
0.029
0.022
0.005
2.330
0.956
0.101
0.372
0.532
0.052
0.207
0.442
0.70
0.65
2.80
0.01
1.25
0.20
0.7
0.50
0.62
0.5
1.05
0.16
1.25
0.32
0.87
0.28
0.85
0.53
1.02
0.60
1.10
0.82
0.67
0.70
0.24
0.15
0.31
1.00
0.85
1.22
0.6
22.
23.
Tert-Butyl acetate
HCl
Ethyl Acetate
NaCl
Methanol
DEMB (50 % Soln)
Sodium Borohydride
Acetic Acid
Dimethoxy Propane
Methane Sulphonic Acid
Sodium Bicarbonate
n-Hexane
Raney Nickel
Pivalic Acid
Toluene
Activated Carbon
Methyl Tert Butyl
Etoricoxib
Acetic Acid
Acetone
Ammonia Solution
CPT-Phosphate
D M Water
Hydroxylamine Hydrochloride
Hyflow
Isopropyl Alcohol
Ketosulfone
Methanol
Potassium Tertrabutoxide (KTB)
Sodium Acetate
Sodium Hydroxide
Toluene
THF
Trifluro Acetic Acid
Activated Carbon
Hexane
Valsartan
L-Valine
Methanol
Thionyl Chloride
Toluene
DCM
NaOH
NaCL
4-Bromo Methyl 2-Cyano biphenyl
Acetonitrile
Potassium Carbonate
1.68
0.76
1.5
1.20
1.02
0.70
0.44
0.98
1.81
0.03
2.00
0.023
1.00
0.240
0.45
0.100
0.410
1.520
2.80
5.80
1.520
26.00
0.115
0.177
10.00
0.574
10.00
0.664
0.297
2.153
55.000
23.00
0.465
0.022
0.250
1.44
0.23
6.90
0.38
2.41
0.65
0.29
2.17
1.00
1.49
24.
25.
26.
27.
Oxalic Acid
o-Xylene
Valeoryl Chloride
Sodium Bicarbonate
HCl
Tributyl Tin Chloride
Calcium Hydroxide
Ethyl Acetate
Diisopropyl ether
TBAB
Tranexamic Acid
4-aminomethyl benzoic
Acid
HCl
Ruthenium
Sodium hydroxide
Methanol
Folic Acid
PABGA
TAPS
TCA
SMBS
NaHCO3
HCl 30%
NaOH
Acetic Acid
Zolpidic Acid
Toluene
Methyl Phenacyl bromide
2- Amino-5-methyl pyridine
Triethyl amine
Oxalyl chloride
Methylene Dichloride
Potassium hydroxide
Acetic acid
Hydrazine hydrate
Methanol
Pregabaline
Sodium Hydroxide
4-CMH
Liquid Bromine
Activated carbon
Hyflo
Hydrochloric acid
IPA
Morpholine
Methyl-3-Amino Crotonate : 294 Kg.
Mono Ethanol Amine
1.00
1.16
1.24
0.28
0.65
5.55
0.42
0.35
7.17
0.14
1.060
0.440
0.300
0.252
2.000
1.00
0.90
0.64
0.36
1.20
6.00
0.22
0.32
0.128
1.000
0.611
0.531
0.700
1.000
1.340
1.651
0.431
1.000
1.90
1.37
1.23
0.07
0.02
2.46
7.06
0.08
1.47
0.625
28.
29.
30.
31.
Chlorohexidine Base
Hexamethelinediamine
Butanol
Hydrochloric acid
Sodiumdicynamide
Parachloroaniline HCl
Sodium hydroxide
Methanol
Benzarone
Salicylaldehyde
Chloroacetone
Hydrazine hydrate
KOH
Methanol
MEG
Toluene
p-Anisoyl chloride
Ferric chloride
Aluminium chloride
HCl
Activated carbon
Ethyl Acetate
Benzbromarone
Salicylaldehyde
Chloroacetone
Hydrazine hydrate
KOH
Methanol
MEG
Toluene
p-Anisoyl chloride
Ferric chloride
Aluminium chloride
HCl
Activated carbon
Bromine
TEA
IPA
Zaltoprofen
2-(2-(phenylthio)-5propionylphenyl)acetic
acid
Methanol
Sulfuric Acid
Sodium Carbonate
Trimethyl Ortho
Formate
Zinc Dust
Bromine
0.30
3.51
0.63
0.46
0.85
0.21
0.12
0.98
0.87
1.075
1.300
0.200
0.05
0.150
1.32
1.00
2.475
2.25
1.25
0.158
0.670
0.600
0.730
0.880
0.100
0.600
0.140
0.900
0.680
1.680
2.540
0.07
1.190
0.690
0.200
1.414
8.485
0.141
0.263
1.232
0.061
0.919
32.
33.
34.
35.
36.
Sodium Hydroxide
Toluene
Polyphosphoric acid
EDC
Ethanol
Acetic Acid
Sodium Carbonate
Ondansetron HCL
Ondensetron Base
IPA
HCl
Miconzole Nitrate
0.778
3.242
5.657
3.536
2.823
0.894
0.258
1,3-dichloro benzene
Aluminum chloride
Chloro Acetyl Chloride
2,2’,4’ Trichloro acetophenone
0.40
0.40
0.32
0.56
NaOH
MeOH
Sodium Borohydrate
Imidazole
Toluene
2,4-DBC
Activated Charcoal
Nitric Acid
0.10
0.08
0.04
0.17
0.16
0.46
0.008
0.24
Ecanzole Nitrate
1-(2,4-Dichloro phenyl)2-(1H-Imidazol-1yl)Ethanol
Toluene
NaOH
4-Chloro benzyl Chloride
TBAB
Nitric acid
Methanol
Desloratadine
Loratidine
Methanol
KOH
MIBK
Loratidine
M-5
Sulphuric Acid
NaOH
MDC
SOCl2
DMF
AlCl3
Hyflow
Ethylene Dibromide
THF
0.90
3.54
0.21
0.80
0.20
0.35
0.50
0.02
0.20
0.30
2.95
0.30
3.93
0.45
2.90
0.90
3.25
4.00
3.31
0.13
0.72
0.63
0.23
0.9
39
Iodine
HCl
Chloroform
Hexane
Toluene
NaHCO3
Acetonitrile
Gabapentine
1-1, Cycloacetic Acid
Urea
NaOH
Xylene
Conc. HCl
Methanol
Ethyl Acetate
Albendazole
Ortho Nitro Aniline
Ammonium Thiocynate
Methanol
Chlorine Gas
Caustic Soda
N- Propanol
N-Propyl Bromide
Toluene
Sodium Hydrosulphide Diluted
Cyaanamide Solution (L-500)
Methyl Chloro Format
Acetone
Citrizine HCL
40
P-Chloro benzophenone
Methyl Alcohol
Sodium Borohydrate
Sodium Hydroxide
Toluene
Thionyl Chloride
Hydroxy Ethyl Piperazine
Sodium Hydroxide Lye
Sodium Mono Chloro Acetate
Dimethyl Formamide
Potassium Hydroxide
Acetone
Activated carbon
HCl gas
Lasamide
37.
38
41
2,4 Dichloro Benzoic acid
Chlorosulfonic acid
Ammonia
HCl
MESALMINE
POTASSIUM HYDROXIDE
0.005
1.50
1.50
2.20
1.50
1.75
0.20
1.67
1.00
0.62
0.58
2.34
0.30
0.30
1.06
1.24
0.20
0.76
0.91
0.383
0.90
0.380
4.50
0.52
0.65
0.18
1.00
1.35
0.07
0.01
0.25
0.85
0.80
2.00
0.38
0.15
0.65
0.20
0.02
0.20
0.950
4.720
0.720
1.296
2.54
2-chloro-5- nitro benzoic acid
HYDROCHLORIC ACID
SODIUM CARBONATE
RANEY NICKEL
SODIUM HYDROXIDE
HYDROCHLORIC ACID
CHARCOAL
SODIUM BICARBONATE
42
FEBUXOSTAT
Ethyl-2-(3-cyano-4-isobutoxyphenyl)-4-methyl5-thiazolecarboxylate
Methanol
Toluene
Caustic soda flakes
HCl
43
44
45
1.82
3.10
0.60
0.30
4.73
2.70
0.20
0.54
1.250
12.50
7.50
0.125
0.250
ITOPRIDE HYDROCHLORIDE
Veratric acid
Thionyl chloride
Toluene
4-[2-(Dimethylamino)
ethoxy]Benzyl amine
Caustic soda flakes
IPA
IPA HCl
Methanol
Acetone
Amrodafinil
Benzhydrolthiol
Chloroacetic Acid
Sodium Hydroxide
HCL (30%)
Acetic Acid
Hydrogen Peroxide
L(-)Phenyl Ethyl Amine
Methanol
Ammonium Solution
Carbon
Hyflow
QUETIAPINE FUMARATE
2- Amino diphenyle sulfide
Sodium Hydroxide flakes
Toluene
Phenyl chloroformate
Hydrochloric acid
Polyphospheric acid
Acetone
Dibenzo [b,f] [1,4] Thiazepin -11(1 OH)- ONE
N,N- Dimethyl ANILINE
Phosphorous oxychloride
Hydrochloric acid
0.667
0.667
3.270
0.667
0.095
2.857
0.317
0.159
0.635
2.90
1.37
0.58
0.20
6.62
0.88
0.30
0.14
0.52
0.12
0.12
1.11
0.32
6.67
1.27
0.66
8.89
3.48
0.6
0.4
0.3
0.5
Sodium Sulphate
Toluene
Triethanolamine
Hydroxy ethoxyrthyl piparazine
Sodium bicarbonate
1 N HCl
Hyflosupercel
Methanol
Fumaric acid
46
ARIPIPERAZOLE
7- Hydroxy -3,4- dihydroQuinoline
1- Bromo -4- Chloro Butane
Sodium Hydroxide
n- Propanol
Cyclohexane
Triethylamine
DCPP HCl
Methanol
47
48
49
0.1
5.2
0.4
0.4
0.1
0.1
0.0
7.7
0.2
Amlodipine Besylate
Phthaloyl Amlodipine
Mono Methyl Amine
Methanol
Ethyl Acetate
Benzene Sulfonic Acid
Carbon
NEBIVOLOL AND ITS INTERMEDIATE
Maleic Anhydride
AlCl3
EDC
Para Fluoro Anisole
HCl
Hexane
Acetic Acid
Sulphuric Acid
Pd/c
Hyflow
Sodium Borohydride
THF
MDC
Sodium Carbonate
DMSO
Oxahl Chloride
TEA
Sodium Hydride
Methanol
Benzyl Amine
Acetonitrile
Sevelamer Hydrochloride
Allylamine
2,2-Dimethyl-2,2-azopropane dihydrochloride
HCl
Epichlorhydrin
0.74
4.44
0.24
3.70
1.48
0.59
0.59
0.37
1.09
1.68
4.38
3.09
0.38
0.75
1.4
3.50
5.00
1.42
3.20
4.25
0.95
1.20
0.41
0.80
1.20
4.00
5.6
0.9
0.80
3.25
6.50
1.00
1.00
0.33
0.8
0.75
0.03
1.25
0.11
50
51
NaOH Flakes
Sevelamer Carbonate
SevelamerHCl
Caustic soda flakes
Carbon dioxide
Poly Allaylamine Hydrochloride
Allylamine
2,2-Dimethyl-2,2-azopropane dihydrochloride
HCl
0.37
1.111
0.333
0.278
0.333
0.117
0.600
ANNEXURE-3
BRIEF MANUFACTRING PROCESS, CHEMICAL REACTION AND MASS BALANCE
1. Oxyclozanide
Manufacturing Process:
3,5,6 Trichloro Salycylic acid, Thionyl chloride will be mixed with MCB and maintain for
2 hours at 75°-80°C. After TLC ok above mass will be filtered. Filtrate 2,4 Dichloro 6Amino Phenol will be mixed in solvent with MCB and will be maintain at 133°C
temperature for 2 hours. After TLC ok adjustment of pH, above mass will be filtered
and finish (crude) product will be obtained. Finish (crude), Acetone, Carbon, Hydrose
will be mixed in water. Above mass will be filtered and dried to obtain finished
product.
Mass Balance:
Water : 50
3,5,6 TC SA : 150
MC B : 3000
Thionyl Chloride : 75
REA CTION AT 80°C
40
HC L G A S
SCRUBBE R
HCl : 50
to ETL
W ater : 100
Caus tic : 48
SO 2 G A S
SCRUBBE R
30% N aHSO 3
: 188
3185
2,4 DCAP : 100
MCB : 3000
Sodium Bic arbonate
:5
S OLV ENT RE COVERY
Acetone : 12000
H ydrous : 10
S OLV ENT RE COVERY
MC B Recovered : 5850
440
Acetone Recovered : 11725
725
W ashing water
: 3500
F ILTRATI ON
W astewater to CETP (ET L) : 4000
225
W ashing water
: 800
W AS HI NG
Wastewater to C ETP (ETL) : 900
125
D RY ING
FINISHED P ROD UC T :
O XYCLOZA NIDE
: 10 0 K G .
Evaporation Loss : 25
2. Furosemide
Manufacturing Process:
Lasamide, Furfuryl Amine, Sodium Bicarbonate will be added in Reactor and reaction
will be carried out at 125°C for 4 hours. Caustic solution will be added to it and then
Hydrochloric acid will be added to adjust the pH of the reaction mass. Then separate
the org. residue and transfer remaining mass into another reactor for purification by
adding carbon followed by filtration. Then chill the purified reaction mass to 0°- 5°C
temp. Precipitation takes place and centrifuge the reaction mass followed by drying to
obtain finished product.
Mass Balance:
Furfuryl Amine : 32
Lasamide : 90
Sodium carbonate : 25
Caustic Flakes : 10
SS R EACTOR
157
FILTRATION /
SEPARATION
Furfuryl Amine
ML : 25
for Recovery
Recovered
Furfuryl Amine : 20 Kg.
&
Dist. Residue : 2.5 Kg.
132
DM Water : 200
Carbon : 1
P URIFICATION
Spent Carbon to BEIL
for Incineration : 1
332
CHILL UPTO
0°-5°C
332
CENTRI FUGE
Wastewater to CETP (ETL)
: 207
125
DRYING
FINISHED P RODUCT :
F UROSEMIDE
: 100 KG.
Note: Afore mentioned quantities are in Kg
Evaporation Loss : 25
1. Diaminomethyleneamino(1-amino-1-iminomethylene)
dihydrochloride [ITU]
thiomethyl
thiozole
Manufacturing Process:
Charge acetone into the reaction vessel. Chill acetone up to 10°C. Add slowly 1,3Dichloro acetone within 1 hour maintain temp. 10 °C. Add KI (Lot-1) at 10°C and stir
the reaction mass for 15 minutes. Add Guanyl thiourea by maintaining temp. 12 °C to
15 °C. Add KI (Lot-2) at 15 °C to 20 °C and maintain for 3 hours. Add acetic acid (glacial)
at 20°C to 25°C temp. Heat the reaction mass to 40 °C temp. Now add thiourea and
acetone under stirring at 40 °C temp. Raise the temp. of the reaction mass to 55 °C to
60 °C. Reflux the reaction mass at 55 °C to 60°C temp. for 3 hours. Cool the reaction
mass to 30 °C temp. Further cool to 20 °C temp. Centrifuge the material and wash the
wet cake with acetone. Unload the wet cake from the centrifuge. Dry the wet cake in
dryer at 95 °C to 100 °C temperature for 9 to 10 hours. Unload the dried material and
weight and packed it.
Chemical Reaction:
q
Mass Balance:
Sr.
No.
1
2
3
4
5
6
Total
Input
1,3 DCA
Guanyl Thiourea
Acetone
Catalyst
Thiourea
Acetic Acid
Quantity
(Kg)
0.435
0.413
3.100
0.004
0.261
0.261
4.474
Output
Product
Evaporation Loss
Acetone Recover
Dist. Residue
Total
Quantity
(Kg)
1.000
0.400
3.000
0.074
4.474
2. N-Sulfomyl-3-chloropropionamide hydrochloride [IF]
Manufacturing Process:
Charge Acrylonitrile into the reaction vessel. Add hydrogen peroxide (50 %) under
stirring. Chill the reaction mass to 15°C to 20°C. Purge HCl gas at 15°C to 20°C for 38 to
40 hours at the feeding rate of 0.8-1.0 Kg/hour. After completion of gas passing, degas
the reaction mass. Now Add sulfamide under stirring at RT. Cool the reaction mass to
18°C to 22°C temp. Further chill the reaction mass to 0°C to 10°C temp. Purge HCl gas
at 0°C to 10°C for 8 hours at the feeding rate of 0.8-1.0 Kg/hour. Raise the temp. of the
reaction mass to 15°C to 20°C within 2 hours with continue HCl gas passing. Raise the
temp. of the reaction mass to 50°C to 55°C within 2 to 3 hours with continue HCl gas
passing. Maintain reaction mass at 50°C to 55°C for 5 hours with continue HCl gas
passing. Degas the reaction mass for 5 hours at 50°C to 55°C temp. Cool the reaction
mass to 28°C to 32°C temp. Further cool the reaction mass to 18°C to 22°C. Centrifuge
the material and wash the wet cake with chilled acetone. Unload the wet cake and dry
the wet cake in dryer at 65°C to 70°C temp. for 5 to 6 hours. Unload the dried material
and record the weight and packed.
Chemical Reaction:
O
H2C
CH2CN
+
H2N
NH2
O
S
NH2
Cl CH2
CH2
C
N
(1)
(2)
(1) Acrylonitrile
(2) Sulfamide
(3) N-sulfomyl-3-chloropropionamidehydrochloride
(3)
SO 2NH2
Mass Balance:
Sr.
No.
1
2
3
4
5
6
Total
Input
Acrylonitrile
Hydrogen Peroxide
HCl (Gas)
Sulfamide
Acetone
Quantity
(Kg)
1.303
0.008
1.495
0.500
0.400
3.706
Output
Product
Evaporation Loss
Acetone Recover
CAN Recover
Dist. Residue
Dil. HCl
Total
Quantity
(Kg)
1.000
0.556
0.350
1.2907
0.050
0.46
3.706
3. Famotidine
Manufacturing Process:
STAGE-1: [FAMOTIDINE CRUDE]: Charge Methanol into the reaction vessel. Add
caustic soda flakes and reflux the reaction mass under stirring. Cool to 30°C and then
chill to 20°C to 22°C temp. Now add ITU (Diaminomethyleneamino(1-amino-1iminomethylene) thiomethyl thiozole dihydrochloride) and IF (N-Sulfomyl-3chloropropionamide hydrochloride) at 20°C to 22°C temp. Regulate the temperature to
25°C and maintain for 2 hours under stirring. Chill the reaction mass to 0°C to 5°C
22.temp. Centrifuge the slurry. Unload the wet material from the centrifuge. Charge
water into the reaction vessel and add wet cake under stirring. Stir for 30 minutes.
Centrifuge the material and wash the wet cake with water and then wash with
methanol. Load the wet cake in dryer. Dry the wet cake at 80°C to 85°C temperature
for 7 to 8 hours. Unload the dried material and weight it.
STAGE-2: [FAMOTIDINE PURE]: Charge Water & caustic soda into the reaction vessel.
Add Famotidine Crude (Stage-1) under stirring. Heat the reaction mass to 70°C to 75°C
temperature. Check the clarity of the reaction mass. It should be clear. Now prepare
the slurry of Activated carbon in water. Add activated carbon slurry into the reaction
mass at 70°C to 75°C temp. And maint. for 15 minutes. Filter the reaction mass
through pressure filter and transfer filtrate online to another reaction vessel
maintaining temperature 30°C to 40°C. Add Acetic Acid & follow out the material Now
chill the filtrate to 0°C to 5°C temp. and maintain for 30 minutes. Centrifuge the slurry
and wash the wet cake with water. Unload the wet cake and weight it. Dry the wet
cake in dryer at 75°C temperature for 5 to 6 hours. Unload the dried material and
weight it and packed it as Famotidine Pure.
Chemical Reaction:
NH
CH 2 S
NH2
C
N
NH 2
H 2N
+
2 HCl
C l CH 2
CH 2
C
N
C
SO 2 NH 2
NaOH
N
H 2N
S
(1)
(2)
NH 2
CH 2 S
CH 2
N
C
C
N
H 2N
H 2N
CH 2
SO 2 NH 2
N
S
(3)
(1) D iaminomethyleneamino(1-amino-1-iminomethylene)thiomethyl thiozole dihydrochloride
(2) N -Sulfamyl-3-chloropro pionamidine hydrochloride
(8) Famotidine
Mass Balance:
Sr.
No.
1
2
3
4
5
6
Total
Input
ITU
IF
Methanol
NaOH
Water
Acetic Acid
Quantity
(Kg)
1.150
0.965
5.710
0.690
20.50
0.200
29.215
Output
Product
Methanol Recover
Methanol Loss
Effluent
Evaporation Loss
Dist. Residue
Total
Quantity
(Kg)
1.000
5.500
0.200
22.305
0.010
0.200
29.215
4. Sevelamer HCl
Manufacturing Process:
Stage-1 Preparation of Polyallylamine Hydrochloride
Into clean reactor charge 250 Kg Hydrochloric acid at room temperature. Add 150 Kg
allylamine in 2 hrs at 5 to 10 °C. Raise the temperature 80 °C and add a solution of 2,2dimethyl-2,2-azopropane dihydrochloride (6.0 Kg in 44 Kg water) at 45 to 50 °C. Stir
the mass 30 hrs at 45 to 50 °C. Monitor the reaction performance by analytical
methods. After completion of reaction, cool the mass to 25 to 30 °C Stir for 1 hr at 25
to 30 °C. Expected weight is 450 Kg.
Stage-2 Preparation of Sevelamer
Add 150 Kg Sodium hydroxide solution (75 Kg in 75 Kg water) into 450 Kg
Polyallylamine at room temperature and stir for 30 minutes. add 22.0 Kg of
epichlorohydrin into above solution at room temperature and stir for 20 minutes. Heat
the mass at 25 to 50 °C in 10 to 20 minutes. Cool to 30 °C and stir for 30 minutes at 25
to 30 °C. Filter the slurry and wash the material and finally with 3 X 1500 Kg Water.
Collect the main and washing Mother Liquor together. Unload and dry the material at
45 to 50 °C in vacuum tray drier (VTD) till to reach the required moisture content of
the product. Expected weight is 200 Kg.
Chemical Reaction:
Stage –I (Preparation of Polyallylamine Hydrochloride):
H2C
allylamine
NH2
+
HCl
Hydrochloric acid
Polymerisation
25 to 80ºC
Water
.
.
.HCl
NH2
n
Polyallylamine Hydrochloride
Stage – 2 (Preparation of Sevelamer):
.
.HCl
.
O
NH2
Cl
n
+
Polyallylamine Hydrochloride
Hydroxide
Cross Linking
Na OH
+
Epichlorohydrin
Sodium
Water
25 to 50ºC
CH3
H3C
H2N.nHCl
HN .nHCl
a
OH
H2N .nHCl
HN .nHCl
H3C
b
Sevelamer
a, b = number of primary amine groups
c = number of cross linking groups
n = fraction of protonated amines
m = large number to indicate extended polymer network
c
m
CH3
Mass Balance:
Sr. Input
No.
1
Allylamine
2
2,2-Dimethyl-2,2azopropane
dihydrochloride
3
HCl
4
Water
5
Epichlorhydrin
6
NaOH Flakes
Total
Quantity
(Kg)
150
6
250
2119
22
75
2622
Output
Product
Effluent
Quantity
(Kg)
200
2250
Evaporation Loss
172
Total
2622
4 (a). Sevelamer Carbonate
Manufacturing Process:
• Charge Purified Water and Sevelamer Hydrochloride.
• Charge Caustic Soda flakes.
• Purge Carbon Dioxide gas.
• Filter the mass and wash with Water.
• Dry wet material to give Sevelamer Carbonate.
Chemical Reaction:
Mass Balance:
Sr. Input
No.
1
SevelamerHCl
2
Caustic soda flakes
3
Carbon dioxide
4
Water
Total
Quantity
(Kg)
1.111
0.333
0.278
37.778
39.500
Output
Product
Effluent
Quantity
(Kg)
1.000
35.556
Evaporation Loss
2.944
Total
39.500
5. Poly Allaylamine Hydrochloride
Manufacturing Process:
Into clean reactor charge 250 Kg Concentrated hydrochloric acid at room temperature.
Add 150 Kg allylamine in 2 hrs at 5 to 10 °C. Raise the temperature 80 °C and add a
solution of 2,2-dimethyl-2,2-azopropane dihydrochloride (6.0 Kg in 44 Kg water) at 45
to 50 °C. Stir the mass 30 hrs at 45 to 50 °C. Monitor the reaction performance by
analytical methods. After completion of reaction, cool the mass to 25 to 30 °C Stir for 1
hr at 25 to 30 °C. Expected weight is 450 Kg.
Chemical Reaction:
H2C
NH2
allylamine
+
HCl
Hydrochloric acid
Polymerisation
25 to 80ºC
Water
.
.HCl
.
NH2
n
Polyallylamine Hydrochloride
Mass Balance:
Sr. Input
No.
1
Allylamine
2
2,2-Dimethyl-2,2azopropane
dihydrochloride
3
HCl
4
Water
Total
Quantity
(Kg)
150
6
250
44
450
Output
Product
Total
Quantity
(Kg)
450
450
6). Fomepizole
Manufacturing Process
Stage-1 Preparation of 1, 1-Diethoxy Propane
Into reactor, charge 395 Kg Ethanol and 131 Kg Propanaldehyde at room temperature.
Heat the mass to 90ºC and reflux for 15 hrs.
Cool the mass to room temperature.
Add 390 Kg Hexane and stir for 30 minutes at room temperature. Separate the layers.
Distill out the Hexane completely at 80ºC.
Expected weight is 300 Kg
Stage-2 Preparation of Fomepizole
Into the reactor charge 233 Kg N,N-Dimethyl formamide and 300 Kg 1,1- Diethoxy
Propane at room temperature. Add 535 Kg Phosphorus oxychloride solution
(345 Kg in 190 Kg N,N-Dimethyl formamide) into the mass in 14 hrs at 90ºC. Cool to
50ºC and stir for 12 hrs.
Monitor the reaction performance by analytical methods.
After completion of reaction cool the mass to room temperature. Into the mass add
2000 Kg Water and 2680 Kg Dichloro methane and stir for 30 minutes. Separate the
layers and distill out Dichloro methane completely at below 50ºC.
Into the above mass, add 2010 Kg Dichloro methane and 110 Kg Hydrazine hydrate at
room temperature.
temperature.
Heat the mass to 100ºC reflux
for 15 hrs at the reflux
Monitor the reaction performance by analytical methods.
After
completion of reaction cool the mass to room temperature. Add 2000 Kg Water into
the mass and adjust the pH to 7.0 using Potassium carbonate solution (75 Kg in 750 Kg
Water).
Separate the layers and wash the dichloro methane layer with 1000 Kg
Water. Distill out Dichloro methane completely under vacuum at below 40ºC.
Add 425 Kg Di isopropyl ether and stir for 30 minutes at room temperature. Add 15
Kg Carbon and stir for 30 to 40 minutes at room temperature. Filter and wash with
73 Kg Di isopropyl ether.
Distill out Di isopropyl ether completely under vacuum at
below 50ºC. Release the vacuum and unload the liquid Fomepizole.
Chemical Reaction
Stage – 1 (Preparation of 1,1-Diethoxy Propane)
O
H3C
H3C
OH
H
+
Hexane / 90ºC
H3C
O
O
CH3
H3C
Ethanol
Propanaldehyde
1,1-Diethoxy Propane
Stage-2 (Preparation of Fomepizole)
H3C
O
O
CH3
Cl
Cl
P
H3C
1,1-Diethoxy Propane
O
Cl
+
Phosphorous
Oxychloride
+
H2N
NH2. H O
2
Hydrazine Hydrate
N,N-Dimethyl Formamide (DMF)
Dichloro Methane (MDC)
Water
50ºC/ 90ºC
100ºC
H
N
N
H3C
Fomepizole
Mass Balance:
Sr. Input
No.
Step-1
1
Propanaldehyde
2
Ethanol
3
Hexane
4
5
6
Total
Quantity
(Kg)
Sr. Input
No.
Step-2
1
Step-I
2
Phosphorus
oxychloride
3
Hydrazine Hydrate
4
Potassium Carbonate
5
Carbon
6
Di isopropyl Ether
7
N,N-Dimethyl
Formamide
8
Dichloro Methane
9
Water
10
Quantity
(Kg)
Output
Quantity
(Kg)
300
Product
100
345
Dichloro methane
4670
110
75
15
498
Dichloro methane loss
Dimethyl formamide
Di isopropyl ether
Di isopropyl ether loss
20
30
480
18
423
Carbon
15
4690
5750
Water
Dimethyl formamide
Dimethyl formamide
loss
Dist. Residue
Total
11
Total
131
395
390
916
12206
Output
Step-1
Ethanol Recover
Ethanol Loss
Hexane Recover
Hexane Loss
Dist. Residue
Total
Quantity
(Kg)
300
378
15
375
15
2
916
6470
383
10
10
12206
7. COLESEVELAM
Manufacturing Process
Stage-1 Preparation of Polyallylamine
Into clean reactor charge
temperature.
301 Kg Concentrated hydrochloric acid at room
Add 156 Kg Monoallylamine in 2 hrs at 5 to 10ºC.
Raise the
temperature and distill out water and excess hydrochloric acid under vacuum at below
60ºC.
Add 95 Kg Water into the mass at room temperature.
Raise the mass
temperature to 45 to 50ºC and add a solution of 2,2-dimethyl-2,2-azopropane
dihydrochloride (3 Kg in 10 Kg water) at 45 to 50ºC.
Stir the mass 30 hrs at 45 to
50ºC. Monitor the reaction performance by analytical methods. After completion of
reaction, cool the mass to 25 to 30ºC and transferred into 1354 Kg Methanol. Stir for 1
hr at 25 to 30ºC.
Filter the slurry and wash the material with 395 Kg Methanol.
Collect the main and washing Mother Liquor together. Unload and dry the material at
45 to 50ºC in vacuum tray drier (VTD) till to reach the required LOD (Loss On Drying)
of the product.
Expected weight is 245 Kg.
Stage-2 Preparation of Colesevelam
Add 200 Kg Sodium hydroxide solution (50 Kg in 150 Kg water)
into 245 Kg
Polyallylamine at room temperature and stir for 30 minutes. In a separate reactor,
add 2 Kg of Epichlorohydrin, 4 Kg n-Decylchloride and 4 Kg Trimethyl ammonium
hexylchloride into 63 Kg of above solution and at room temperature and stir for 20
minutes.
Add this solution into the above remaining mass at 25 to 50ºC in 10 to 20
minutes. Cool to 30ºC and stir for 30 minutes at 25 to 30ºC. Filter the slurry and wash
the material with 32 Kg Methanol, 100 Kg Water, 20 Kg Sodium hydroxide solution
(1Kg in 19 Kg Water) and finally with 400 Kg Water. Collect the main and washing
Mother Liquor together. Unload and dry the material at 45 to 50ºC in vacuum tray
drier (VTD) till to reach the required moisture content of the product.
Expected weight is 260 Kg.
Chemical Reaction
Stage – 1 (Preparation of Polyallylamine)
NH2
H2C
Monoallylamine
Polymerisation
+
HCl
Hydrochloric acid
45 to 50ºC
Water
.
.
.HCl
NH2
n
Polyallylamine Hydrochloride
Stage-2 (Preparation of Colsevelam HCl)
.
.HCl
.
NH2
n
+ NaOH +
Polyallylamine Hydrochloride
rochloride
O
H3C
Cl
+
Epichlorohydrin
+
n-Decyl chloride
CH3
+
N
Cl
H3C
Trimethylammoniumhexylchloride
Cross Linking
25 to 50ºC
CH3
H2C
NH
N
H3C
H2C
+
CH3
NH
CH3
O
H2C
NH2
Cl
.HCl
n
Colesevelam Hydrochloride
Mass Balance:
Sr. Input
No.
Step-1
1
Monoallylamine
2
2,2-dimethyl-2,2azopropane
dihydrochloride
3
Concentrated
Hydrochloric acid
4
Methanol
5
Water
Total
Quantity
(Kg)
Sr. Input
No.
Step-2
1
Polyallylamine
2
Epichlorohydrin
3
n-Decylchloride
4
Trimethylammoniumh
exylchloride
5
Sodium hydroxide
6
Methanol
7
Water
Total
Quantity
(Kg)
156
Output
Step-1
Methanol Recover
Quantity
(Kg)
245
1696
3
301
1749
105
2314
245
2
4
4
116
32
849
1252
Methanol Loss
52
Effluent
321
Total
2314
Output
Quantity
(Kg)
Product
Efflunet
Sodium chloride
Methanol
260
788
172
32
Total
1252
9. Glimepiride
Manufacturing Process
•
Charged 3 Ethyl 4 methyl Pyrroline and toluene is SSR. Charged slowly 2 Phenyl
Isocyante in it. Heat the RM to reflux for 2 hrs.
•
Cool and then chilled the rm. Filter the mass and dry it.
•
Charged Chloro Sulfonic Acid in Reactor at RT and chilled it. Charged Amide
derivative in above reaction mixture in chilling condition.
•
The reaction mixture was heated and stirred. The reaction mixture was very slowly
quenched in chilled ammonia solution. Filter the solid mass, wash with water and
dry it.
•
Charged EDC and above crude product in Reactor at RT. The reaction mixture was
heated and stirred the chilled to 0-5oC. Filter the solid mass under chilling condition
and dry it.
Chemical Reaction:
Mass Balance:
Sr. Input
No.
1
3 Ethyl methyl
Pyrroline
2
2 Phenyl ethyl
isocyanate
3
Toluene
4
Chloro Sulfonic Acid
5
Ammonia Solution
6
EDC
7
Water
Total
Quantity
(Kg)
0.40
Output
Quantity
(Kg)
Product
1.00
0.40
Toluene Recover
3.35
3.50
EDC Recover
Distillation + Drying
loss
Residue
Effluent
1.70
1.00
3.10
2.00
1.00
11.29
Total
0.83
0.03
4.38
11.29
10. Furosemide
Manufacturing Process:
To Furfurylamine, 2,4-Dichloro-5-Sulfamoyl Benzoic acid (Lasamide) will be added
below 60°C. Gradually, temperature of the reaction mixture, under Nitrogen
atmosphere will be raised to 117- 120°C and maintained for several hrs. The reaction
mass will be cooled and passing of Nitrogen gas will be stopped and diluted with
Isopropyl Alcohol. Subsequently the pH of reaction mass will be adjusted to highly
alkaline with solution of sodium hydroxide & cooled to 0°C for several hours. When the
crude sodium Frusemide separates out, it will be centrifuged. The sodium salt of
Frusemide will be dissolved in DM water, charcolised and filtered. pH of clear solution
will be adjusted to acidic when pure Frusemide separates out. It will be centrifuged,
washed with DM water & dried. Dried product will be milled blended, shifted and
packed.
Chemical Reaction:
Mass Balance:
Sr. Input
No.
1
Furfuryl Amine
2
Lasamide
3
Caustic Flake
4
IPA
5
Carbon
6
Water
7
Acetic Acid
8
Total
Quantity
(Kg)
1564
850
234
5920
80
7396
220
16263
Output
Product
Furfuryl Amine
Recover
Loss
Dist. Residue
Spent Carbon
Effluent
IPA Recover
IPA Loss
Total
Quantity
(Kg)
1000
1210
450
20
70
7593
5680
240
16263
11. BETAHISTINE DIHYDROCLORIDE:
Manufacturing process:
2-vinyl pyridine react with methylamine hydrochloride in presence of acetic acid to
form betahistidine Base isolated by high vacuum distillation. Betahistidine Base react
with IPA Hcl to form Betahistidine dihydrochloride.
CHEMICAL REACTION:
N
+ H3C
CH3
NH2 HCl
CH3
N
NH
Molecular Formula: C7H9N
Molecular Formula: CH6ClN
Formula Weight:
107.15306 Formula Weight:
67.51804
CH3
N
Molecular Formula: C8H12N2
Formula Weight:
136.19428
2 HCl
IPA HCl
NH
CH3
N
NH
Molecular Formula: C8H12N2
Formula Weight:
136.19428
Molecular Formula: C8H14Cl2N2
Formula Weight:
209
Mass Balance:
Sr. Input
No.
1
2
3
4
5
6
7
8
Total
2- vinyl pyridine
Methylamine hydrochloride
water
Chloroform
Sodium hydroxide
Acetic Acid
IPA
IPA HCl(20%)
Quantity (Kg)
0.63
0.80
0.31
3.13
0.45
0.06
2.50
1.38
9.25
Output
Quantity (Kg)
Product
Effluent
Chloroform Recovery
Chloroform Loss
IPA Recovery
IPA Loss
Distillation residue
1.00
2.22
2.90
0.23
2.40
0.10
0.40
Total
9.25
12. Adapalene
Manufacturing Process:
Charge THF & start nitrogen purging until water quenching. Charge Mg turnings. Heat
the mass up to reflux 60-65°C . Prepare solution of adamentanol & p- bromomphenol
in MDC inn a clean container. Add above prepared solution through the addition
funnel in 10 – 15 min at 60-65°C. Prepare solution of Adamentanol in MDC in clean
container. Add above prepared solution of in THF in 45-60 min at 60-65°C. Reflux the
reaction mass for 60 min. Cool the reaction mass. Charge MDC to the reaction mass.
Cool the reaction mass. Charge 6-Bromo-2-methyl naphthoate at 15-20°C. Maintain
the reaction mass for 30 min at 40- 45°C. Take purified water in RBF & cool it 20-25.
Prepare HCl water solution Add the HCl water solution slowly. Stir the reaction mass.
Wash with purified water. Suck dry well. Unload the material of crude stage C wet cake
& take for purification. Dry the wet cake at 70 – 75°C.
Chemical Reaction:
Step-2
Step-3
Step-4
Mass Balance:
Sr. Input
No.
1
2
3
4
5
6
7
8
Total
Adamentanol
Para Bromo Phenol
THF
Mg Turning
MDC
6-Bromo-2-methyl naphthoate
HCl
Water
Quantity (Kg)
24
15
30
3
68
36
66
350
592
Output
Product
Effluent
MDC Recovery
MDC Loss
THF Recovery
THF Loss
Distillation residue
Total
Quantity (Kg)
50
442.5
65
2
29
0.5
3
592
13. TELMISARTAN AND ITS INTERMEDIATE
Manufacturing Process:
4-Amino-3-benzoic acid is esterifies to gives methyl-4-amino-3-bezoate, which reacted
with butryl chloride to produce butyramide derivative, which nitrated with fuming
nitric acid to produced nitro derivative, which reduced in presence of Palladium on
charcoal and then hydrolyzed to gives Benzimidazole derivative. Benzimidazole is
reacted with n-methyl o-pheniline Diamine to gives condensed product, which is
reacted with bromo ester to gives telmi ester, which hydrolyzed with potassium
hydroxide to gives Telmisartan.
Chemical Reaction:
CH3
CH3
NH2
NH2
CH3OH/H2SO4
HO
H3C
O
65°C
O
O
M wt - 165
TS-1
TS-1
Yield 94 %
O
O
CH3
CH3
O
NH2
H3C
NH
H3C
O
Cl
H3C
O
TEA/MDC
0 to 5°C
Yield 96 %
O
O
M wt - 235
TS-2
O
CH3
O
NH
Fuming HNO3
CH3
NH
H3C
CH3
O
-20 to -25°C
Yield 93 %
H3C
O
CH3
NO2
O
M wt - 280
TS-3
O
NH
O
CH3
O
CH3
H3C
CH3
CH3
Pd/Charcoal
Acetic Acid
H3C
H
N
O
N
80°C
NO2
CH3
O
O
M wt - 232
TS-5
CH3
CH3
H
N
10% NaOH Sol.
H
H
N
O
CH3
N
H3C
O
N
CH3
Methanol
O
Yield 86 %
M wt - 218
TS-6
O
Polyphospheric Acid
CH3
H
N
140 to 145°C
CH3
CH3
H
N
N
N
H
O
N
N
CH3
NH2
O
NH
CH3
Yield 96 %
M wt - 304
TS-7
CH3
Mass Balance:
Qty (Kg)
INPUT
Raw material
3.53
1.484
Methanol
4-Amino 3-Methylbenzoic acid
1.423
Conc. Sulphuric acid
2.968
Liq. NH3
9.410
Total
OUTPUT
Material
Qty(Kg)
TS-01
ML to ETP
7.574
Output
Loss
Qty (Kg)
1.53
5.670
INPUT
Raw material
TS-1
MDC
OUTPUT
Material
Qty(Kg)
TS-02
Soduim Sulpahte
Aqs. Layer
1.314
1.287
0.153
0.387
12.240
5.094
TEA
Butryl chloride
Sodium Bicarbonate
Sodium Sulphate
Water
Hexane
Recovered MDC+Hexane
ML to ETP
27.675
Total
Output
0.387
12.240
6.084
7.705
Loss
Qty (Kg)
0.90
4.050
0.090
9.000
14.040
INPUT
Raw material
TS-2
Fuming Nitric acid
Sodium Bicarbonate
DM Water
Total
1.53
0.31
OUTPUT
Material
0.90
0.359
Qty(Kg)
TS-03
ML to ETP
12.748
Output
Loss
1.00
0.292
14) Tapentadol Hydrochloride
Manufacturing Process:
• Charge isopropyl alcohol, 3-methoxy propiophenone, dimethyl amine
hydrochloride, Paraformaldehyde. Heat the reaction mass. Maintain the reaction
mass and distill out isopropyl alcohol. Charge Purified water and sodium hydroxide.
• Charge dichloromethane and separate out layers. Charge dichloromethane layer
into the reactor and distill out dichloromethane. Charge IPA and charge L (-)
Dibenzoyl tartaric acid. Maintain the reaction mass and filter it. Charge Purified
water and above wet cake.
• Charge sodium carbonate and Dichloromethane. Separate out layers. Charge
dichloromethane layer into the reactor and distill out dichloromethane and charge
Tetrahydrofuran. Charge magnesium turning and ethyl acetate. Maintain the
reaction mass and distill out Tetrahydrofuran. Charge Purified water and Acetic
acid. Add ammonium solution and Dichloromethane. Stir the reaction mass and
separate out layers. Charge Product layer into a reactor and distill out
dichloromethane. Charge Ethyl acetate into the above reactor and cool the
reaction mass. Charge Trifluoroacetic anhydride and maintain the reaction mass.
Unload the reaction mass.
• Charge palladium and apply hydrogen pressure. Maintain the reaction mass. Filter
the reaction mass and collect filtrate. Charge hydrobromic acid into the reaction
mass. Heat the reaction mass and maintain the reaction mass charge ammonia
solution and ethyl acetate. Separate out layers. Distill out ethyl acetate and charge
Isopropyl alcohol. Add IPA HCl. Maintain the reaction mass. Centrifuge the reaction
mass.Dry it to give Tapentadol Hydrochloride.
Chemical Reaction:
Mass Balance:
Sr.
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Total
Input
3-methoxy propiophenone
IPA
Dimethyl Amine HCL
Paraformadehyde
Sodium Hydroxide
MDC
L (-) Dibenzoyl tartaric acid
THF
Mg Turning
Ethyl Bromide
Acetic Acid
Ammonium Solution
Ethyl Acetate
Trifluroacetic anhydride
Palladium
Acetone
HBr
IPA HCl
Water
Quantity (Kg)
1.412
7.530
1.059
0.588
0.376
10.00
1.412
3.530
0.171
0.588
0.118
0.506
5.883
0.882
0.070
6.470
1.765
0.882
17.647
60.889
Output
Quantity (Kg)
Product
IPA Recover
IPA Loss
MDC Recover
MDC Loss
THF Recover
THF Loss
Ethyl Acetate Rec.
Ethyl Acetate Loss
Palladium Recover
Palladium Loss
Acetone Recover
Acetone Loss
Effluent
Dist. Residue
Process Waste
Loss
1.00
7.15
0.35
9.60
0.35
3.42
0.08
5.65
0.23
0.06
0.01
6.21
0.26
25.827
0.407
0.235
0.05
Total
60.889
15. Colistimethate Sodium
Manufacturing Process:
Stage 1:
Take Colistin sulphate and water. Filter and remove insoluble material. Charge sodium
bi carbonate solution. Add sodium carbonate for adjusting pH. Get white precipitation.
Add 400 ml sodium bi carbonates solution. Add dematerialized water and adjust pH by
adding sodium carbonate. Continue stirring 2 hours. Filter the reaction mass under
nitrogen gas. Unloaded wet cake and charge dematerialized water. Add slowly sodium
bi sulfite solution for adjust pH. Maintain 1 hour. Add remaining solution in reaction
mass for pH. Stirring for 2 hours. Add acetic acid. Adjust pH. Stir for 1 hour. Add
industrial solvent. Start a zeotropic distillation. Strip out 2 times from industrial
solvents. Thick slurry mass is obtained. Add acetone for make free flowing slurry.
Maintain 6 hours. Filter and unload wet cake. Dry under vacuum.
Final Stage:
Take crude stage-1 and methanol, add industrial solvent. Filter with flow bed. Wash
with methanol. Distill out methanol under vacuum. Add Industrial solvent under
stirring and get uniform slurry. Distill out methanol under vacuum. After complete
distillation, add industrial solvent and maintain for 2 hours at 25 to 30oC temperature.
Filter and wash with Industrial solvent. Dry under vacuum at 25 to 30 oC temperature
for 4 hours. After drying continue 6 hours on 45 to 60oC temperature. Getting final
material.
Chemical Reaction:
Mass Balance:
Sr.
No.
Step-I
1
2
3
4
5
6
7
8
9
Total
Step-II
9
10
11
12
13
Total
Input
Colistin Sulphate
Sodium Bicarbonate
Sodium Carbonate
Formaldehyde
Sodium Bisulfite
Acetic Acid
Solvent
Acetone
Water
Step-I
Methanol
Water
Quantity (Kg)
Output
Quantity (Kg)
100
50
25
100
230
12
2100
3400
3000
9017
Step-I
Solvent Recover
Solvent Loss
Acetone Recover
Acetone Loss
Dist. Residue
Effluent
Drying Loss
155
2015
85
3230
170
50
3227
85
Total
9017
155
5800
1340
Product
Methanol Recover
Methanol Loss
Effluent
Solid Waste
Total
75
5510
250
1430
30
7295
7295
16. Chlorohexidine Base
Manufacturing process:
First charge the Hexamethelinediamine and butanol then added concentrated
hydrochloric acid and sodiumdicyamide into the reactor Heat the mass and distill out
water then reflux at desire temperature, cool and charged parachloroaniline and
reflux.
Charge Sodium hydroxide flaks and water then separated the layers, Chilled the
Organic phase and centrifuge.
Wet material further subjected to purification in methanol, chill, and centrifuge
followed by washing with methanol and dried it.
CHEMICAL REACTION:
NH2
H2N
Hexametheline diamine
+
2 HCl
Hydrochloric acid
M.W.116.2
M.F. C6H16N2
M.W.36.5
M.F. HCl
[1 Eq.]
[2 Eq.]
NH2.HCl
HCl. H2N
Hexametheline diamine dihydrochloride
M.W.189.2
M.F. C6H18N2Cl2
[1 Eq.]
N
NH2 HCl
+
HCl H2N
Hexametheline diamine dihydrochloride
2 Na N
N
M.W.189.2
M.F. C6H18N2Cl2
Sodiumdicynamide
M.W.89.03
M.F. C2N3Na
[1 Eq.]
[2 Eq.]
N
HN
HN
NH
NH
NH
NH
1,1'-hexane-1,6-diylbis(3-cyanoguanidine)
[1Eq.]
2 NaCl
Sodium chloride
N
M.W.250.3
M.F. C10H18N8
+
M.W.58.2
M.F. NaCl
[2Eq.]
NH2
N
HN
HN
NH
+
NH
NH
Cl
NH
N
Parachloroaniline Hydrochloride
1,1'-hexane-1,6-diylbis(3-cyanoguanidine)
M.W.164
M.W.250.3
M.F.C10H18N8
M.F.C6H7NCl2
[2Eq]
[1Eq]
Cl
HCl
2
NH
NH
NH
NH
NH
NH
NH
NH
.
2HCl
NH
Chlorhexidine dihydrochloride
NH
Cl
M.W.578.4
2NaOH
Sodium hydroxide
M.F.C22H32Cl4N10
[1Eq]
M.W.40
[2Eq]
Cl
NH
NH
NH
NH
NH
NH
NH
NH
NH
Chlorhexidine Base
NH
Cl
M.W.505.4
M.F.C22H30Cl2N10
[1Eq]
+
+
2H2O
water
2NaCl
Sodium chloride
M.W.18
M.W.58.5
[2Eq]
[2Eq]
MASS BALANCE:
Sr.
No.
Input
1
2
3
4
5
6
7
Hexamethelinediamine
Butanol
Hydrochloric acid
Sodiumdicynamide
Parachloroaniline HCl
Sodium hydroxide
8
Methanol
Total
Water
Quantity
(Kg)
100
1170
210
153.40
283.30
70
870
830
3686.7
Output
Effluent
Residue
Butanol Recover
Butanol Loss
Methanol
Methanol Loss
Chlorhexidine
base
Total
Quantity
(Kg)
1250
103.70
1117
53
793
37
333
3686.7
17. Benzarone
Manufacturing Process:
Stage-1: [BZN-A]
Charge Methanol, Potassium hydroxide and Salicylaldehyde into the reactor. Apply
steam to achieve temperature 70°C. Maintain and reflux for 30 minutes. Cool the
reaction mass to 28°C to 32°C. Chill the reaction mass to 15°C to 20°C. Start addition of
Chloroacetone and maintain temperature 15°C to 20°C. Apply steam in the jacket of
reactor to achieve temperature 80°C. Reflux for 3 hours at 80°C. Cool the reaction
mass to achieve temperature 50°C. Filter the material & separate the potassium
chloride cake & ML. Wash the cake with Methanol. Transfer the filtrate material to
reactor. Apply steam and distil out Methanol till 80°C. Cool the reaction mass to
achieve the temp. 40°C. Charge Monoethylene glycol in reactor through vacuum.
Charge Hydrazine hydrate (80%) through vacuum. Apply steam to achieve the
temperature 120°C. Cool the reaction mass to achieve temperature 30°C to 35°C. Start
addition of Potassium hydroxide at 30°C to 40°C. Apply steam to achieve the temp.
120°C. Maintain and reflux for 3 hours. After reflux stop applying steam and cool the
reaction mass to achieve the temperature 100°C. Apply steam in the bottom of reactor
and start steam distillation. Distillate & Separate Aqueous layer / Organic layer in HDPE
tank. Transfer the organic material from HDPE tank to HDPE container as finished
product BZN-A.
Stage-2: [BZN-B]
Charge Toluene in reactor. Charge BZN-A. Apply steam and start distillation to remove
water from the reaction mass azeotropically till 115-118 °C. Cool the reaction mass to
achieve room temperature. Charge p-Anisoyl chloride. Chill the reaction mass to
achieve temperature 0°C to –5°C. Add slowly Ferric chloride between 0°C to 5°C in 3.0
– 5.0 hours. Stir and maintain 0 to 5°C for 30 minutes. Cool the reaction mass to 25°C
to 30°C. Stir and maintain temperature 25°C to 30°C for 5 hours. Cool the reaction
mass to 0°C – 5°C. Charge Water with maintaining temperature between 0°C-10°C. Stir
the reaction mass for 30 minutes at 0°C - 5°C. Cool to 25°C – 30°C. Filter the material.
Collect the filtrate in HDPE tank. Wash the cake with Toluene. Charge filtrate material
into reactor and stir for 30 minutes. Settle for 30 minutes. Separate Aqueous layer &
Organic layer in separate HDPE tank respectively. Charge Aqueous layer and Toluene
into reactor. Stir for 30 minutes. Settle for 30 minutes. Charge organic layer into
reactor. Charge Hydrochloric acid. Stir for 30 minutes. Settle for 30 minutes. Collect
Aqueous layer in HDPE tank. Charge Hydrochloric acid. Stir for 30 minutes. Settle for 30
minutes. Collect Aqueous layer in HDPE tank. Start distillation upto 115°C-118°C &
distil out toluene. Cool the reaction mass to achieve 25°C-30°C. Charge Aluminium
chloride under stirring. Raise the temp. to 50°C - 55°C. Stir and maintain reaction mass
for 5 hours at 50°C - 55°C. Cool the reaction mass to 30°C. Quench the mass in
previously ready 20 slab ice + Hydrochloric acid. Keep temperature below 5°C during
quenching. Stir for 1 hour at 0 to 5° C for complete solidification of material. Centrifuge
the Material at 0°C to 5°C and wash the cake with chilled water (0-10°C) till pH of ML is
3 to 4. Weigh the wet cake. Charge Toluene in reactor. Charge wet cake in reactor
under stirring. Apply steam to achieve temperature 100°C to get clear solution. Start
azeotropic distillation. Take Toluene in HDPE tank and add Activated carbon [B] and
stir it manually with SS rod to make slurry. Charge Activated carbon slurry into the
reaction mass. Stir for 30 minutes at 100°C. Filter the reaction mass through pressure
filter. Charge the filtered mater ial in reactor. Chill the filtered material to 5°C. Stir and
maintain the temperature for 1 hour at 0°C-5°C. Centrifuge the chilled mass and wash
the cake with chilled Toluene. Weigh the wet cake. Load the wet material in dryer and
dry the material at 60°-70°C for 4 hours. Unload the dried material and pack as BZN-B.
Stage-3: [BZN-P]
Charge Ethyl acetate in reactor. Charge BZN-B in reactor. Raise the temperature of the
reaction mass to 75°C to 80°C for 30 minutes. Cool the reaction mass to 20°C to 25°C.
Stop cooling and chilled the reaction mass to 0°C to 5°C. Maintain the temperature 0°C
to 5°C for 1.0 hour. Centrifuge the material. Weigh the wet cake. Charge Ethyl acetate
in reactor. Add wet cake in reactor under constant stirring. Heat the reaction mass up
to 750C - 800C. Add slurry of Activated carbon [B] in Ethyl acetate in reactor. Reflux
the reaction mass for 30 minutes at 750C to 800C. Filter reaction mass through
pressure filter. Transfer the filtrate on line to the reactor. Heat the filtrate at 75°C80°C. Distil out Ethyl acetate (70% of total quantity of Ethyl acetate used) from
reaction mass at 75°C- 80°C. Cool the reaction mass to 30°C ± 2°C. Further, cool the
reaction mass to 20°C ± 2°C. Chill the reaction mass to 0°C ± 5°C. Maintain the reaction
mass at 0°C ± 5°C for 1.00 hour. Centrifuge the Material. Wash the cake with Ethyl
acetate. Weigh the wet cake and record the gross weight, tare weight and total
weight. Ensure cleanliness and dryness status of Dryer. Dry the wet cake in dryer at
65°C ± 2°C. Unload the dry material and pack as BENZARONE.
Chemical Reaction:
Mass Balance:
Sr.
Step-I
1
2
3
4
5
6
7
8
Total
Step-II
1
2
3
4
5
6
7
8
9
Total
Step-III
1
2
3
4
Total
Input
Salicylaldehyde
Chloroacetone
Hydrazine hydrate
KOH
Methanol
MEG
Quantity (Kg)
0.980
0.870
1.075
1.300
3.100
2.150
Step-II
Ethyl Acetate
Activated Carbon
Quantity (Kg)
Step-I
Methanol
Methanol Loss
MEG recover
MEG Loss
Dist. Residue
Effluent
1.100
2.900
0.200
2.100
0.050
0.020
1.930
KCl Cake
Total
1.175
9.475
1.100
5.650
1.320
1.000
2.475
2.250
1.250
10.00
1.600
26.645
Step-II
Toluene Recover
Toluene Loss
Dist. Residue
Spent Carbon
Solid Waste
Effluent
Loss
1.330
5.300
0.15
0.015
0.100
0.050
19.05
0.665
Total
26.645
1.330
3.170
0.100
Product
Ethyl Acetate
Ethyl Acetate Loss
Spent Carbon
Total
1.000
3.011
0.158
0.100
4.600
9.475
Step-I
Toluene
p-Anisoyl chloride
Ferric chloride
Aluminium chloride
HCl
Activated carbon
Ice
Water
Output
4.600
18. BENZBROMARONE
Manufacturing Process
(a) Manufacturing Process:
Stage-1: [BZB-1]
Charge Methanol, Potassium hydroxide and Salicylaldehyde into the reactor. Apply
steam to achieve temperature 70°C. Maintain and reflux for 30 minutes. Cool the
reaction mass to 28°C to 32°C. Chill the reaction mass to 15°C to 20°C. Start addition of
Chloroacetone and maintain temperature 15°C to 20°C. Apply steam in the jacket of
reactor to achieve temperature 80°C. Reflux for 3 hours at 80°C. Cool the reaction
mass to achieve temperature 50°C. Filter the material & separate the potassium
chloride cake & ML. Wash the cake with Methanol. Transfer the filtrate material to
reactor. Apply steam and distil out Methanol till 80°C. Cool the reaction mass to
achieve the temp. 40°C. Charge Monoethylene glycol in reactor through vacuum.
Charge Hydrazine hydrate (80%) through vacuum. Apply steam to achieve the
temperature 120°C. Cool the reaction mass to achieve temperature 30°C to 35°C. Start
addition of Potassium hydroxide at 30°C to 40°C. Apply steam to achieve the temp.
120°C. Maintain and reflux for 3 hours. After reflux stop applying steam and cool the
reaction mass to achieve the temperature 100°C. Apply steam in the bottom of reactor
and start steam distillation. Distillate & Separate Aqueous layer / Organic layer in HDPE
tank. Transfer the organic material from HDPE tank to HDPE container as finished
product BZB-1.
Stage-2: [BZB-2]
Charge Toluene in reactor. Charge BZB-1. Apply steam and start distillation to remove
water from the reaction mass azeotropically till 115-118 °C. Cool the reaction mass to
achieve room temperature. Charge p-Anisoyl chloride. Chill the reaction mass to
achieve temperature 0°C to –5°C. Add slowly Ferric chloride between 0°C to 5°C in 3.0
– 5.0 hours. Stir and maintain 0 to 5°C for 30 minutes. Cool the reaction mass to 25°C
to 30°C. Stir and maintain temperature 25°C to 30°C for 5 hours. Cool the reaction
mass to 0°C – 5°C. Charge Water with maintaining temperature between 0°C-10°C. Stir
the reaction mass for 30 minutes at 0°C - 5°C. Cool to 25°C – 30°C. Filter the material.
Collect the filtrate in HDPE tank. Wash the cake with Toluene. Charge filtrate material
into reactor and
stir for 30 minutes. Settle for 30 minutes. Separate Aqueous layer & Organic layer in
separate HDPE tank respectively. Charge Aqueous layer and Toluene into reactor. Stir
for 30 minutes. Settle for 30 minutes. Charge organic layer into reactor. Charge
Hydrochloric acid. Stir for 30 minutes. Settle for 30 minutes. Collect Aqueous layer in
HDPE tank. Charge Hydrochloric acid. Stir for 30 minutes. Settle for 30 minutes. Collect
Aqueous layer in HDPE tank. Start distillation upto 115°C-118°C & distil out toluene.
Cool the reaction mass to achieve 25°C-30°C. Charge Aluminium chloride under
stirring. Raise the temp. to 50°C - 55°C. Stir and maintain reaction mass for 5 hours at
50°C - 55°C. Cool the reaction mass to 30°C. Quench the mass in previously ready 20
slab ice + Hydrochloric acid. Keep temperature below 5°C during quenching. Stir for 1
hour at 0 to 5° C for complete solidification of material. Centrifuge the Material at 0°C
to 5°C and wash the cake with
chilled water (0-10°C) till pH of ML is 3 to 4. Weigh the wet cake. Charge Toluene in
reactor. Charge wet cake in reactor under stirring. Apply steam to achieve temperature
100°C to get clear solution. Start azeotropic distillation. Take Toluene in HDPE tank and
add Activated carbon [B] and stir it manually with SS rod to make slurry. Charge
Activated carbon slurry into the reaction mass. Stir for 30 minutes at 100°C. Filter the
reaction mass through pressure filter. Charge the filtered material in reactor. Chill the
filtered material to 5°C. Stir and maintain the temperature for 1 hour at 0°C-5°C.
Centrifuge the chilled mass and wash the cake with chilled Toluene. Weigh the wet
cake. Load the wet material in dryer and dry the material at 60°-70°C for 4 hours.
Unload the dried material and pack as BZB-2.
Chemical Reaction:
Stage-3: [BZB-3]
Charge Methanol (Lot-I) in reactor. Chill the Methanol up to 0°C – 5°C. Add Bromine
under constant agitation, and maintain the solution at 0°C – 5°C. Charge Methanol
(Lot-II) inanother reactor and Stir it for 15 minutes. Add BZB-2 under constant stirring.
Agitate thereaction mass to get clear solution. Add Triethylamine in the reaction mass
at 25°C. Cool the reaction mass up to 18°C ± 2°C. Chill the reaction mass up to 0°C 5°C. Add dilute solution of Bromine from first reactor at 0°C-5°C within 10.0 to 15.0
hrs. Slowly heat the reaction mass up to 20°C to 25°C and maintain for 4.0 hours.
Centrifuge the Material and wash wet cake with Methanol (Lot-III). Unload the wet
material from the Centrifuge. Charge Water in Reactor and add above wet cake under
stirring at room temperature. Centrifuge the Material and wash wet cake with
Methanol (Lot-IV). Dry the wet cake in dryer at 60°C to 70°C temperature for 8.0 to
10.0 hrs. Weigh the dry material and affix the
label as BZB-3.
Stage-4: [BZB]
Charge Isopropanol (Lot-I) in SS Reactor. Add BZB-3 under constant stirring. Stir
reaction mass for 30 minutes. Heat the reaction mass up to 800C - 820C. Reflux the
reaction mass for one Hour at 800C - 820C. Add slurry of Activated carbon [A] in
reaction mass at 80°C – 82°C. [Prepare the Slurry of Activated carbon [A] in 25 L of
Isopropanol (Lot-II)] Stir reaction mass for 30 minutes. Filter the reaction mass from SS
Reactor and transfer the filtrate into the Glass lined reactor. Slowly cool the filtrate to
30°C ± 2°C and then further cool to 20°C ± 2°C. Centrifuge the Material and wash wet
cake with Isopropanol (Lot-IV). Dry the wet cake in dryer at 55°C to 60°C temperature
for 5 to 6 hours. Weigh the dry product, affix the label as BENZBROMARONE.
Mass Balance:
Sr.
Step-I
1
2
3
4
5
6
7
8
Total
Step-II
1
2
3
4
5
6
7
8
Total
Step-III
1
2
3
4
5
Total
Step-IV
1
2
3
4
Total
Input
Salicylaldehyde
Chloroacetone
Hydrazine hydrate
KOH
Methanol
MEG
Quantity (Kg)
0.670
0.600
0.730
0.880
2.100
1.460
Output
Quantity (Kg)
Step-I
Methanol
Methanol Loss
MEG recover
MEG Loss
Dist. Residue
Effluent
0.750
2.000
0.100
1.400
0.060
0.010
1.230
6.440
KCl Cake
Total
0.800
6.440
Step-I
Toluene
p-Anisoyl chloride
Ferric chloride
Aluminium chloride
HCl
Activated carbon
Water
0.750
6.140
0.900
0.680
1.680
2.540
0.070
8.10
20.860
Step-II
Toluene Recover
Toluene Loss
Dist. Residue
Spent Carbon
Solid Waste
Effluent
Loss
Total
0.900
6.000
0.140
0.010
0.060
0.030
13.220
0.500
20.860
Step-II
Methanol
Bromine
TEA
Water
0.900
4.000
1.190
0.690
4.500
11.280
Step-III
Methanol Recover
Methanol Loss
Effluent
Loss
Total
1.200
3.800
0.200
4.97
1.110
11.280
Step-III
IPA
Activated Carbon
1.200
5.300
0.120
Product
IPA Recover
IPA Loss
Spent Carbon
Total
1.000
5.100
0.200
0.320
6.620
6.620
19. Carvedilol
Manufacturing process
Guiacol is condensed with Ethylene Dichloride to give 2-(2-Methoxyphenoxy)ethyl
Chloride(CV-1). CV-1 is reacted with Pthalimide to give 2-(2-methoxyphenoxy) ethyl
phthalimide (CV-2). Dephthaloylation and treatment with HCl gives 2-(2methoxyphenoxy) ethyl amine hydrochloride(CV-3 HCl) , which is further basified to
give 2-(2-methoxyphenoxy)ethyl Amine (CV-3).
Simultaneously 1,3 Cyclohexandione is reacted with phenyl hydrazine to give 1,3
cyclohexandione mono phenyl hydrazone (CV-4). CV-4 was cyclized under acidic
conditions to give 1,2,3,4-tetrahydrocarbazol-4-one(CV-5). Catalytic aromatization of
CV-5 gives 4-hydroxy-9-(H) carbazole (CV-6). CV-6 is further reacted with
Epichlorohydrin to give 4-oxyranylmethoxy-9-(H)-carbazole(CV-7).
CV-7 and CV-3 are then reacted together to give crude CV-8. It is then purified to get
Carvedilol.
Chemical Reaction:
Synthetic Route of Carvedilol
O
O
N
H
CV 7
O
Dioxane
NH 2
OCH 3
CV 3
Toluene:Cyclohexane:Ethyl acetate (60:19:21)
OH
O
O
NH
H 3 CO
N
H
Carvedilol (CV )
Mass Balance
20. ZALTOPROFEN
a) Manufacturing Process
Stage-1: Charge Methanol, 2-(2-(phenylthio)-5-propionylphenyl)acetic acid and
Sulfuric acid. Heat reaction mixture for 65 oC for 5 hours. After completion distill out
methanol cool reaction mixture and add toluene and water. Separate layers. Wash
organic layer with Sodium Carbonate solution. Evaporate organic layer under vacuum.
To the reaction mass charge Trimethylorthoformate, Zinc dust and heat at 50
oC.Charge bromine slowly. Upon completion cool the reaction mass and charge zinc
dust. Heat reaction mass at 100 oC. Upon completion cool reaction mass and charge
DM water and toluene. Separate layers. Wash organic layer with 20 % Sodium
hydroxide solution. Acidify aqueous layer with dilute sulfuric acid. Cool reaction
mixture to and filter slurry yield 5-(1-Carboxyethyl)-2- (phenylthio)phenylacetic acid.
Stage-2: Polyphosphoric acid is charged in reactor, followed by 5-(1- Carboxyethyl)-2(phenylthio)phenylacetic acid. Charge Ethylene Dichloride and heat reaction mass to
reflux at 83-85 oC for 30 minutes. Distill out Ethylene Dichloride. Reflux reaction mass
for more 2 hours. After completion of reaction cool reaction mass to room
temperature and quench the reaction mass in water. Heat reaction mass to 68-72 oC
for 30 minutes. Separate layers and cool organic layer at 0-5 oC for 2 hours. Filter the
product.
Stage-3: Charge water and Ethanol in reactor and stir for 30 minutes. Charge
Zaltoprofen crude at room temperature. Charge sodium carbonate solution slowly and
stir for 1 hour. Neutralize reaction mass with Acetic acid. Filter the reaction mass and
transfer filtrate to reactor. Charge more acetic acid and stir for 1 hour. Filter product
and wash with DM water.
Chemical Reaction:
Mass Balance:
Sr.
Input
No.
Step-I
1
2-(2-(phenylthio)-5propionylphenyl)acetic
acid
2
Methanol
3
Sulfuric Acid
4
Sodium Carbonate
5
Trimethyl Ortho
Formate
6
Zinc Dust
7
Bromine
8
Sodium Hydroxide
9
Toluene
10
Water
Total
Step-II
11
Step-I
12
Polyphosphoric acid
13
EDC
14
Water
15
Total
Step-III
16
Zaltoprofen Crude
17
Ethanol
18
Acetic Acid
19
Sodium Carbonate
20
Water
21
22
23
Total
Quantity (Kg)
Output
Quantity (Kg)
1.414
Step-I
1.414
8.485
0.141
0.263
Methanol Rec
Methanol Loss
Toluene Rec.
7.828
0.657
3.939
1.232
Toluene Loss
0.303
0.061
0.919
0.778
3.242
11.101
28.636
Effluent
Dist. Residue
14.162
0.333
Total
28.636
1.414
5.657
3.536
4.167
Step-II
EDC Recover
EDC Loss
Effluent
Dist. Residue
Total
1.197
3.384
0.152
9.874
0.167
14.774
Zalttoprofen
Ethanol Rec.
Ethanol Loss
Acetic Acid Rec.
Acetic Acid Loss
Effluent
Dist. Residue
CO2
Total
1.000
2.677
0.101
0.808
0.035
4.153
0.322
0.086
9.182
14.774
1.197
2.823
0.894
0.258
4.010
9.182
21. ONDANSENTRONE HYDROCHLORIDE
Manufacturing Process:
Stage 1: In a GLR, charge Iso Propyl Alcohol and Ondensetron Base. Heat up to 800C,
add water 10% and Hydrochloric Acid 35%. Check clarity and check for pH 2, if Ok,
filter the material through Sparkler Filter.
Stage 2: In a GLR Collect filtrate and check its moisture and pH, if ok chill up to 50 C
maintain for 5 hrs. Centrifuge the material. Unload and Dry Ondensentron
Hydrochloride. Collect ML for recovery.
Stage 3 (IPA Recovery): In a SSR, take ML of centrifuge and add caustic to obtain pH
9.0 and distilled out IPA completely. Charge water and cool to room temperature.
Centrifuge the material and dry it. Recovered Ondansetron Base is used in Stage – I for
next batch and ML is sent to ETP.
Chemical Reaction
Material Balance
Sr.
No.
1
2
3
4
Total
Input
Ondensetron Base
IPA
Water
HCl
Quantity (Kg)
90.91
354.54
136.36
21.45
603.26
Output
Quantity (Kg)
Ondensetron HCl
Crop Base II
Effluent
100.00
35.09
468.17
Total
603.26
22. Miconazole Nitrate and its intermediates:
Manufacturing process and Chemical Reaction:
Step-I
2,2’,4’ Trichloro acetophenone
A charge 1,3-dichloro benzene100 Kg and chloroacetyl chloride 80 Kg and aluminum chloride
100Kg at A RT, Stir 30min. then stir 8 hour ,then cool to RT then dumping ice 400 kg
,centrifuge wash with 10 lit water , the wet cake:-170 Kg, Dry 65-700C Output dry :-140Kg
O
Cl
Cl
Cl
+
Cl
O
Cl
AlCl 3
Cl
Cl
Step -II
A charge Step -1 140 Kg and Add 180 kg of methyl alcohol and 25 liters of water at 20-250C.
Added a solution of 10 Kg. of sodium borohydride in 20 kg water and 1kg sodium hydroxide to
the above reaction mixture slowly at 20-250C in 5 hours. Allowed the reaction mixture
temperature to 25-300C. Recovery of Methyl alcohol, Stirred the reaction mixture for 6 hours
at 25-300C.add water 200kg, Filtered the precipitated solid and Centrifuge. Wet cake 160Kg,
Output dry: - 140 Kg
HO
O
Cl
Cl
Cl
Cl
NaBH
Cl
4
Cl
Step -III
Step-2 140Kg was dissolved in toluene 360Kg. and Imidazole 43 Kg was added at 20-25° C.
add caustic soda 25Kg , The temperature was raised to 50-55° C. and stirred for 3-5 hours, then
cooled to 25-30° C. Reaction mass added into cold-water 200 lit. Reaction mixture was
extracted and organic layer concentrated under reduced pressure to provide thick Filtered the
precipitated solid and Centrifuge. Wet cake 160Kg, Output dry: - 150 Kg
HO
Cl
H
N
Cl
OH
Cl
+
N
N
N
Cl
Cl
Step -IV
Step-3 150Kg was dissolved in toluene 450Kg..add caustic soda 25Kg , The temperature was
raised to 50-55° C. and add slowly 2,4-Dichloro benzyl chloride 115 Kg was added 5-6 hrs and
stirred for 3-5 hours, then cooled to 25-30° C. Reaction mass added into cold-water 200 lit.
Reaction mixture was extracted and organic layer concentrated under reduced pressure to
provide thick Filtered the precipitated solid and Centrifuge. Wet cake 250Kg, Output dry :- 225
Kg
Cl
Cl
N
N
N
Cl
Cl
Cl
O
+
OH
N
Cl
Cl
Cl
Cl
Step -V
A charge step-4 base 225 Kg and 390Kg Methyl alcohol at a RT , Then heat to clear solution
temp 50-550C, then add activated charcoal 2kg stir 1 hour, filter then cool to RT, Then add
Nitric acid 60 Kg heat to 550C, then cool to RT then child to 5-100C 1hour maintain. Then
centrifuge wash to Methyl alcohol 10 lit, wet cake 275kg, Dry:- 250Kg
Cl
Cl
N
Cl
N
N
O
+
Cl
HNO3
. HNO3
Cl
Cl
]
N
O
Cl
Cl
MATERIAL BALANCE:
Sr.
Material Input
No.
Step-1
Qty
(Kg)
Material Output
Qty
(Kg)
Drying Loss
Effluent
2,2’,4’ Trichloro
acetophenone
30
510
140
1
2
3
1,3-dichloro benzene
Aluminum chloride
Chloro Acetyl Chloride
100
100
80
4
Ice Water
Total
400
680
Total
680
140
Effluent
213
NaOH
MeOH
Sodium Borohydrate
Water
Total
2
200
11
200
553
Resue
Drying Loss
Product
180
20
140
Total
553
Step-2
Imidazole
Toluene
Caustic Soda
Water
140
43
360
25
200
Total
768
Effluent
Drying Loss
Re Use toluene
Loss toluene
Bottom
Product
Total
240
15
330
30
3
150
768
Step-3
2,4-DBC
Toluene
Caustic Soda
Water
150
115
450
25
200
Total
940
Drying Loss
Re Use toluene
Loss toluene
Bottom
Effluent
Product
Total
25
400
50
10
230
225
940
Step-4
MeOH
Activated Charcoal
Nitric Acid
225
400
2
60
Total
687
Waste Charcoal
Drying Loss
Re Use MeOH
Loss MeOH
Bottom
Product
Total
4
25
360
40
8
250
687
Step-2
1
2,2’,4’ Trichloro acetophenone
2
3
4
5
Step-3
1
2
3
4
5
Step-4
Step-5
23. Ecanazole Nitrate
Manufacturing Process:
Miconazole base is synthesized from the reaction of 1-(2, 4-Dichloro phenyl)-2-(1HImidazol-1yl) Ethanol and 4-Chloro benzyl chloride in presence of sodium hydroxide
and Tetrabutyl ammonium bromide as a catalyst and toluene as a solvent. The
Miconazole Base treat with Nitric acid as in presence of Toluene give Nitrate salt of
Miconazole
Chemical Reaction
N
Cl
N
Cl
N
HO
N
Cl
+ NaOH
+
O
Toluene,TBAB
Cl
Cl
+
Na Cl
+ H2O
M.Wt.:58.44 MWt: 18.01
M.Wt: 40.00
Cl
M.Wt.: 195.03
Cl
Cl
M.Wt.: 381.68
Toluene
M.Wt.:257.11
N
N
HNO3
O
Cl
M.Wt.: 63.01
HNO3
Cl
M.Wt.: 444.69
Mass Balance
INPUTS for 100.0 Kgs
RM
1-(2,4-Dichloro phenyl)2-(1H-Imidazol-1yl)Ethanol
Toluene
NaOH
4-Chloro benzyl Chloride
TBAB
Nitric acid
Methanol
D.M.water
Activated Carbon
Total
Out Puts
Product & By Product &
waste
QTY
80.0
Econazole Nitrate
100.0
300.0
35.0
50.0
2.0
20.0
30.0
200.0
1.0
718.0
Toluene
Activated Carbon
Residue
Water
280.0
1.0
1.0
336.0.
QTY (Kg)
Total
718.0
24. ROSUVASTATIN CALCIUM
Manufacturing Process:
Step-I
4-Fluoro-Benzadehyde reacts with 4-Methyl-3-oxo-pentanoic acid ethyl ester in
presence of Base to give Stage-1 as product.
Step-II
Sage-1 product reacts with S-Methyl iso thio urea and 2, 3Dichloro-5, 6-dicyano benzo
quinone in presence of HMPA to give stage-2 as product.
Step-III
Stage-2 product reacts with meta-chloro peroxy benzoic acid to give Stage-4 as
product and Meta chloro benzoic acid as by-product.
Stage-4
Stage-3 product reacts with methyl amine in presence of Ethanol s solvent media to
give Stage-4 as product.
Stage-5
Stage-4 product reacts with Methane sulfonyl chloride in presence of Sodium hydride
as catalyst to give Stage-5 as product.
Stage-6
Stage-5 product undergoes reduction and oxidation in presence of Hydrogen gas to
give Stage-6 as product.
Stage-7
Stage-6 product reacts with methyl (3R)-3-(ert-butyldimethylsilyloxy)-5-oxo-6triphenylphosphoranylidene hexanoate.
Stage-8
Stage-7 product reacts with Hydrogen fluoride in presence of Acetonitrile as solvent
media to give Stage-8 as product.
Stage-9
Stage-8 product reacts with Sodium Boro hydride undergoes hydrogenation to give
Sage-9 as product.
Stage-10
Stage-9 product reacts with Calcium chloride undergoes saponification to give
Rosuvastatin Calcium as product.
Chemical Reaction:
Mass Balance
25. Desloratadine
Manufacturing Process:
Loratidine is refluxed with Methanol. The Material is then extracted in MIBK after
Methanol removal. The product is then crystallized after distillation of MIBK to give
Desloratidine.
Chemical Reaction:
Mass Balance:
26. LORATADINE AND ITS INTERMEDIATE
Manufacturing Process:
M-5 is reacted with Sulphuric acid and quenched to give M-6. M-6 is then chlorinated
using Thionyl chloride and AlCl3 catalyst to give M-7. M-7 is then reacted with Grignard
reagent and then acidified to give M-8. M-8 is then acidified and quenched to give
Loratidine Crude. The crude is then purified first using Acetonitrile. The product is
further purified using Ethyl acetate. Pure Loratidine is obtained by one more
purification in Acetonitrile.
Chemical Reaction:
Mass Balance:
Sr.
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Particular
M-5
Sulphuric Acid
NaOH
MDC
Water
SOCl2
DMF
AlCl3
Hyflow
Ethylene Dibromide
THF
Iodine
HCl
Chloroform
Hexane
Toluene
NaHCO3
Acetonitrile
Total
Input Qty
(kg)
5.8
1.8
6.5
161.04
25
6.63
0.27
1.45
1.26
0.47
36
0.01
3.1
62.3
4.5
58.72
3.36
7.88
386.09
Particular
MDC Recovered
MDC Loss
THF Recovered
THF Loss
Chloroform Recovered
Chloroform Loss
Toluene Recovered
Toluene Loss
Acetonitrile Recovered
Acetonitrile Loss
Loratidine
Effluent to ETP
Solid to Incinerator
Residue to Incinerator
Spent Sulphuric Acid
Total
Output Qty
(kg)
154.6
6.44
34.84
1.16
59.5
2.8
57.5
1.22
7.56
0.32
2.00
35.5
0.55
9
13.1
386.09
27. Gabapentine
Manufacturing Process:
Step-I
1,1-cyclodiacetic acid is condensed with urea in xylene. After completion,
product is isolated by adjusting its pH with HCl to give stage-I.
Stage 2:
Stage-1 undergoes hoffman reduction with sodium hypochloride followed
by cyclisation to give stage-II.
Stage 3:
Stage-II is converted into its hydrochloride salt with concentrate HCl.
The product (Stage-III) is isolated by cooling the reaction mixture.
Stage 4:
Hydrochloride salt of stage-III is converted into gabapentin monohydrate
by treatment with caustic solution.
The product crystallises during caustic addition.
Stage 5:
Gabapentin monohydrate is dehydrated with methanol to get clear solution. It is
treated with activated carbon and filtered. Gabapentin is isolated by cencentrating
followed by cooling of reaction mixture. Product is filtered, washed and dried.
Chemical Reaction:
Mass Balance:
28. ALBENDAZOLE
Manufacturing Process:
1. Charge Methanol, Ortho nitro aniline , Ammonium Thiocynate and cool to
0oC.Add Chlorine marinating temp between 0-5 oC ,then charge water and stirr
for 1 hrs, centrifuge at R.T and wash with water to PH neutral.
2. Charge water , N-propanol ,charge STEP-1.Start addition of caustic lye slowly
below 40 oC and heat to 50 oC . Maintain temp between 40-50 oC for 1/2 hrs
and charge n- Propyl Bromide maintain the temperature at 50 oC . Maintain 4
Hrs at 62-65 oC .Distilled water Heat to 90 oC . Charge NACL while stirring.
Settle & separate organic layer (TOP)
3. Charge STEP-2 with methanol stirring 15 minutes and heat to 50 oC . Start
addition of NAHS slowly lot wise. Temp rises from 50 to 70 oC. Complete
addition of NAHS from 60 -65 oC . Reflux 6-8 Hrs at 80-85 oC .
4. Start methanol recovery at temp 90 oC . Charge water and heat upto 85-90oC .
Settle RM for 1 Hrs. Separate RM for 1 hrs , Separate Aqueous layer from
bottom .Collect the top organic layer in Drums. Distilled out organic layer under
vacuum I st cut removed upto temp 100 oC then distilled out product at temp
upto 210 oC out product at temp upto 210 oC .
5. Charge water and cool to 8-10 oC . Charge Hydrogen Cynamide solution. Start
simultaneous addition of MCF and Caustic lye slowly below 20 oC and PH should
be 6-8 . Complete the addition below 20 oC. Stirring 1/2 Hrs. Check the absence
of unreacted Hydrogen Cynamide.
6. Charge water , HCL , PART A, ,acetone and start addition of PART B. Heat to 65
o
C . continue to reflux RM at 80-85 oC for 1HRs. Check PH of RM .It should be
4.00 to 6.0. Centrifuge Reaction mass at 80-85oC . Wash cake with Hot Water ,
Then wash with Methanol and again wash with Acetone to get the pure
Albendazole.
Chemical Reaction:
Chemical reaction of ALBENDAZOLE
STEP-1
NH4SCN
Chlorine Gas
NH4CL+H
CL
Methanol
Ortho Nitro Aniline
MOL WT :- 138.12
Ammonium
Thiocynate
MOL WT ::
76.122
5-THIOCYNO-2NITRO
ANILINEMOL WT :-195.1985
NAOH
CH3CH2CH2Br
Methanol
Step-2
INTERMIDIATE
5-THIOCYNO-2NITRO ANILINEMOL
WT :- 195.1985
STEP -3 & 4
3,4
DIAMINOPROPYL
THIO ANILINE (A)
STEP-2
+ NABR
+NACN
2-NITRO 4
PROPYL THIO
ANILINE
NAHS
MEOH
Caustic Soda,
Sodium
Hydrosulphide,
TOLUENE,
Carbon,
EDTA, SODIUM
META
BISULPHITE,
Acetone
METHANOL
HCL 30%
1,2-DIAMINE5-PROPYL
THIO
BENZENE
STEP -5 PART (B)
(CYANAMIDE
COMPLEX WITH
CYANAMIDE
SOLUTION)
NAOH
NC-NHCOOCH3
CAUSTIC SODA
METHYL CYNO
ESTER ( CYNO
COMPOUND )
CH2N2
CYANAMIDESOLUTI
ON (L-500)
METHYL
CHLORO
FORMAT
+HCL+
NAOH
STEP-6
NC-NH
NHCOOCH3
1,2-DIAMINE-5PROPYL THIO
BENZENE
CONDENSATION
(A+B)=C
METHYL CYNO
ESTER (CYNO
COMPOUND)
METHANOL
ACETONE
ALBENDAZOLE
Input
(in Kgs)
MATERIAL OUTPUT
1000
CRUDE 5-THIOCYNO-2NITRO ANILINE
HCL
NH4CL
METHANOL
ML TO ETP
Total Output
MATERIAL BALANCE
Sr
No.
MATERIAL INPUT
STEP-1
Ortho Nitro Aniline
1
2
4
5
6
1
2
3
4
5
6
7
1
2
3
4
5
6
Ammonium Thiocynate
Methanol
Chlorine Gas
WATER
Total Input
1168
5520
720
1000
9408
STEP 2
step-1
Caustic Soda
N- Propanol
N-Propyl Bromide
1400
860
3600
850
Toluene
METHANOL
3600
3500
ML TO ETP
NaBr
STEP-2 OUTPUT
RECOVERED
METHANOL
LOSS
RECOVERED TOLUENE
Sodium Hydrosulphide DILUTED
TOTAL
STEP -3
CYAANAMIDE SOLUTION (L-500)
(L
4200
18010
LOSS TOLUENE
TOTAL
CAUSTIC SODA
METHYL CHLORO FORMAT
STEP 2
ACETONE
WATER
TOTAL
495
742
608
1400
2520
800
6565
Output
(in Kgs)
1400
888
600
5520
1000
9408
8910
600
1400
3325
175
3420
180
18010
RECOVERD ACETONE
LOSS ACETONE
ML TO ETP
RESIDUE
OUTPUT QTY ABZ
2344
176
3000
105
940
TOTAL
6565
30. Cetrazine diHCl and its intermediates:
Manufacturing Process and Chemical Reaction:
Step-I
P-chlorobenzophenone
A charge chlorobenzene 100 Kg and Benzoile chloride 125 Kg and Aluminum chloride4 1kg
at A RT, Then heat to 70-75 oC Stir 30min. Add Ice 120 kg then stir 1 hour , add slowly sodium
hydroxide 35kg Stir 30min. , then centrifuge wet cake 175Kg. Dry Output 145.
O
STEP-1
Cl
+
O
Cl
+
NaCl
Cl
Step-II
4-Chloro benzhydrol
A charge p-chloro benzophenone 100 Kg and add methyl alcohol 135 Kg and sodium boro
hydrate 7 Kg and caustic soda 1Kg at A RT, Stir 30min. Heat to reflux temp 600C ,Then add
100lit water cool to RT , wet cake 120 Kg, Dry 60-700C Out put dry :-100Kg
STEP-2
OH
O
Cl
Cl
Step-III
N- (4-chloro benzhydrol),N-(2-hydroxy ethyl) piperazine
A charge 4-chloro benzhydrol 100 Kg and add toluen 235 Kg and thionyl chloride 85 Kg
and scrubber caustic soda lye 200Kg and 100kg water at A RT, Stir 30min. Heat to reflux temp
600C ,Then add 80kg 2-hydroxy ethyl piperazine Stir 30min. Heat to reflux temp 600C ,then
recovery of toluene, then add 100 lit Water then stir 1 hour , cool to RT ,centrifuge, the wet
cake 120 Kg, Dry 60-700C Output dry :-100Kg
STEP-3
OH
N
H
N
OH
Cl
N
+
N
OH
Cl
Cl
Cl
Step-IV
Cetrazine Base
A charge N- (4-chloro benzhydrol),N-(2-hydroxy ethyl) piperazine100 Kg and add Sodium
mono chloro acetic acid 38 Kgand Dimethyl formamide 185 Kg and Caustic potash 65 Kg at a
RT, Stir 30min. Heat to temp 600C ,Then cool to 5 0C Stir 30min.add water 300kg ,centrifuge ,
the wet cake;-112 Kg, Dry 50-550C Output dry :-100Kg.
STEP-4
OH
OH
O
N
N
Cl
N
+
O
O
N
+ NaCl
Na
Cl
Cl
Step-V
Cetrazine Di HCl API
A charge Cetrazine base 100 Kg and acetone 400kg at a RT , Then heat to clear solution
temp 65-700C, then add activated charcoal 2kg stir 1 hour, filter and cool to RT, then child to 5100C 1hour maintain. Then start HCl gas 20kg pursing solid product isolated then check pH
acidic , centrifuge, wet cake146 kg, Dry 110Kg
STEP-5
OH
O
O
O
N
OH
N
O
N
N
+
HCl
.
2HCl
Cl
Cl
MATERIAL BALANCE:
Material Input
Step-1
Chloro Benzene
Benzoile Chloride
Aluminium Chloride
Sodium Hydroxide
Ice
Water
Total
Qty(Kg)
100
125
1
35
220
10
491
Material Output
Qty(Kg)
Effluent
Drying Loss
P-Chloro benzophenone
316
30
145
Total
491
Step-2
P-Chloro benzophenone
Methyl Alcohol
Sodium Borohydrate
Sodium Hydroxide
Water
Total
Step-3
100
135
7
1
100
343
Effluent
Drying Loss
4-Chloro Benzhydrol
243
345
100
Total
343
4-Chloro Benzhydrol
Toluene
Thionyl Chloride
Hydroxy Ethyl Piperazine
Sodium Hydroxide Lye
Water
100
235
85
80
200
200
230
315
20
215
20
100
Total
Step-4
900
Effluent
Scrubber waste water
Drying Loss
Reuse Toluene
Loss Toluene
N-(4-Chloro Benzhydrol),N-(2Hydroxy Ethyl)Piperazine
Total
N-(4-Chloro Benzhydrol),N-(2Hydroxy Ethyl)Piperazine
Sodium Mono Chloro Acetate
Dimethyl Formamide
Potassium Hydroxide
Water
Total
Step-5
100
Effluent
418
38
185
65
300
538
Cetrazine Base
120
Total
538
Acetone
Activated carbon
HCl gas
Cetrazine Base
400
2
20
100
Total
522
Waste Carbon
Reuse Acetone
Loss Acetone
Drying Loss
Bottam
Cetrazine Dihydrochloride
Total
2
340
36
30
4
110
522
900
31. Lasamide
Manufacturing Process:
2,4 Dichloro Benzoic acid is reacted with Chlorosulfonic acid(CSA) at elevated
temperature. The product formed is isolated by quenching in ice water, the product is
filtered and subjected to ammoniation to get Lasamide.
Chemical Reaction:
C7H4Cl2O2 + 2ClSO3H
2,4 Dichloro Benzoic acid CSA
C7H3Cl3O4S + H2SO4 + HCl
2,4 Dichloro Benzoic acid Sulfonyl Chloride
C7H3Cl3O4S + 3NH3
C7H8Cl2N2O4S + NH4Cl
C7H8Cl2N2O4S + HCl
C7H5Cl2NO4S + NH4Cl
Mass Balance:
Input
2,4 Dichloro Benzoic acid
Chlorosulfonic acid
Ammonia
HCl
Water
Total
Qty. (kg)
950
4720
720
1296
2320
10006
Output
Product
Effluent
Dil. Sulphuric Acid
Dil. HCl
Ammonium Chloride
Total
Qty. (kg)
1000
1810
1316
4150
1730
10006
32. PIOGLITAZONE HYDROCHLORIDE
Process Description
5-Ethyl-2-(2-(4- Nitro phenoxy)ethyl)pyridine (EPNB) is hydrogenated in presence of palladium
catalyst to produce PGL-I, which is further diazotized using sodium nitrite solution in water to get
diazotized PGL-I. It is further reacted with hydrogen bromide and methyl acrylate in presence of
copper oxide (I) to get PGL-II.
PGL-II is cyclized using thiourea and sodium acetate in methanol to give PGL-III (5-({4-[2-(5ethylpyridin-2-yl) ethoxy]benzyl}-2-imino-1,3-thiazolidin-4-one).
PGL-III is reacted with hydrochloric acid in water to give PGL-IV ((5-({4-[2-(5-ethylpyridin-2-yl)
ethoxy]benzyl}-1,3-thiazolidin-2,4-dione).
PGL-IV is purified in DMF and water mixture to get PGL-V (pure Pioglitazone).
PGL-V is isolated as a hydrochloride salt using concentrated Hydrochloride acid in ethanol water
mixture as a solvent to get Pioglitazone hydrochloride.
Chemical Equation
Stage IA- Preparation of PGL-I
NO 2
H3C
+
N
3 H2
O
Hydrogen gas
5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine
MW = 2.0
MW = 272.3
EPNB
Palladium carbon
NH2
H3C
+
2 H2O
O
N
4-[2-(5-ethylpyridin-2-yl)ethoxy]aniline
MW = 242.3
PGL-I
MW = 18
Stage IB- Preparation of PGL-II
NH2
H3C
N
O
+
O
NaNO
4-[2-(5-ethylpyridin-2-yl)ethoxy]aniline
+
2
Sodium nitrite
MW= 242.3
PGL-I
+
2 HBr
H2C
O
Hydrobromic Acid
MW= 69
CH3
Methyl acrylate
MW= 81
MW= 86.08
Copper oxide(I)
O
H3C
N
+
CH3
O
B
+
NaBr
+
N2
2H 2 O
r
O
m e th y l 2 - b ro m o - 3 - {4 - [2 (5 - e th y lp y rid in - 2 - y l)e th o x y ]p h e n y l}p ro p a n o a te
Sodium bromide
MW = 392.28
Nitrogen gas
MW = 103
Water
MW = 28
MW = 18
P G L - II
Stage IC- Preparation of PGL-III
O
H3C
CH3
O
Br
S
+
+
H2N
N
O
methyl2-bromo-3-{4-[2-
H3C
ONa
O
NH2
(5-ethyl pyri di n-2-yl)ethoxy]phenyl}propanoate
Thiourea
MW= 392.28
Sodium Acetate
MW= 76.1
MW= 82.03
PGL-II
H3C
N
O
O
5 - { 4 - [ 2 - ( 5 - e t h y l p y r i d i n - 2 - y l) e t h o x y ]
benzyl}-2-imino-1,3-thiazolidin-4-o
ne
MW= 355.4
PGL-III
Stage II- Preparation of PGL-IV
S
NH
H3C
+
N
H
+
2 HCl
O
2
+
KHCO
3
N
H
O
O
5-{4-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl} 2-im ino- 1,3-thiazolidin- 4-one
MW= 355.4
Potassium Bicarbonate
MW= 36.46
MW = 18
MW= 100.11
PGL-III
S
NH
+
N
+
NaBr
H
Sodium Bromide
O
N
O
O
N
H
MW= 103
+
Acetic Acid
CH 3 OH
NH 4 Cl
+
CO 2
MW= 32.0
KCl
Potassiumchloride
MW= 53.5
+
Methanol
MW= 60.0
AmmoniumChloride
5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,
3-thiazolidine-2,4-dione
MW= 356.43
+
OH
O
S
H3C
H3C
MW= 74.5
+
H2O
PGL-IV
Carbondioxide
MW= 44
MW= 18
Stage III- Preparation of PGL-V
S
S
O
H3C
N
O
O
O
H3C
DMF
N
H
N
O
O
5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,
3-thiazolidine-2,4-dione
5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,
3-thiazolidine-2,4-dione
MW= 356.43
MW= 356.43
PGL-IV
PGL-V
Stage IV- Preparation of Pioglitazone Hydrochloride
S
O
H3C
N
N
O
O
HCl
+
H
Hydrochloride
5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,
3-thiazolidine-2,4-dione
MW= 356.43
PGL-V
MW=36.5
S
O
H3C
N
O
HCl
O
MW= 392.89
Pioglitazone Hydrochloride
N
H
N
H
Mass Balance:
S tep-1 - PZ1 PR EPARA TION
I NP UT :
Raw Material
ME P
Met hanol
PFA
Fo rmi c
Charc oal
Total
I NP UT :
Raw Material
Mas s
In put , Kg s
4.86
1.35
1.8 4
0.2 5
0.0 1
8.31
OUTP UT :
Prod uct
Mas s
Total
In put , Kg s
8.31
Distillation
Total
Output, Kgs
8.31
Reaction
( 8 days)
8.31
8.31
OUTP UT :
Prod uct
P2 1
MEP
Methanol
Loss Met hanol
Residue to I nc. *
Total
Output, Kgs
1.08
3.45
0.56
0.79
2.43
8.31
OUTP UT :
Prod uct
Mas s
Output, Kgs
6.54
S tep2 - PZ 2 PR EPA RATION
I NP UT :
Raw Material
P2 1
In put , Kg s
1.08
Toluene
TE A
MSC
Total
I NP UT :
Raw Material
Water
Mas s
Total
3.71
0.84
0.91
6.54
In put , Kg s
10. 80
6.54
17.340
Reaction
Total
Water Washing
6.54
OUTP UT :
Prod uct
Ma ss
Aqueons Layer t o ETP *
Total
Output, Kgs
6.3 3
11.01
17.340
OUTP UT :
Prod uct
Mas s
Output, Kgs
12.45
S tep 3 - PZ3 PR EPARA TI ON
I NP UT :
Raw Material
PZ 2
I PA
H2O
In put , Kg s
6.33
3.41
0.29
4OH benzal dehyde
K 2 CO 3
Total
I NP UT :
Raw Material
Mas s
Water
Toluene
Total
I NP UT :
Raw Material
Mas s
NaOH
H2O
Total
Reaction
1.00
1.42
12. 45
In put , Kg s
12. 45
10. 80
2.06
25. 31
In put , Kg s
8.710
0.36
8.39
17. 46
Total
Water Washing
OUTP UT :
Prod uct
Aqueous t o ETP *
Mas s
12.45
Output, Kgs
16.60
8.71
Total
Cau stic Wash in g
OUTP UT :
Prod uct
Aqueous t o ETP *
Mas s
Total
25.31
Output, Kgs
8.75
8.71
17.46
S tep 4 - PZ 4 PR EPARA TI ON
I NP UT :
Raw Material
H2O
Acet ic Aci d
Thio Urea
Total
1.25
0.96
7.02
I NP UT :
Raw Material
Mas s
Water
Total
In put , Kg s
6.780
0.960
7.740
I NP UT :
Raw Material
Wet Cake
In put , Kg s
1.47
Total
OUTP UT :
Prod uct
Ev aporation Los s
In put , Kg s
4.81
1.47
Reaction
Filtration
D rying
Output, Kgs
0.24
Mas s
6.78
Total
7.02
OUTP UT :
Prod uct
ML t o E TP *
Wet Cake
Total
Output, Kgs
6.27
1.47
7.740
OUTP UT :
Prod uct
Vapours
Dry Cake
Total
Output, Kgs
0.22
1.25
1.47
S tep 5- PZ 5 PREPARATI ON
I NP UT :
Raw Material
Mas s
Met hanol
In put , Kg s
8.71
18. 73
Total
I NP UT :
Raw Material
Mas s
P Z4
P iperidue
Total
D is tillation
27. 44
In put , Kg s
21. 67
1.25
0.28
23. 20
OUTP UT :
Prod uct
Mas s
Output, Kgs
23.20
Total
23.20
OUTP UT :
In put , Kg s
23 .2 0
2.39
0.57
Total
I NP UT :
Raw Material
Wet Cake
Output, Kgs
4.44
1.33
21.67
27.44
Reaction
I NP UT :
Raw Material
Ma ss
Water
Met hanol
OUTP UT :
Prod uct
Toluene R ec.
D ist illation Loss
Mas s
Total
Filtration & Solv en t
Recov ery
26. 16
In put , Kg s
1.44
Total
Prod uct
Loss
MeOH Rec .
Wet Cake
R eidue t o I nc *
Total
Drying
1.44
Output, Kgs
9.86
13.51
1.44
1.35
26.16
OUTP UT :
Prod uct
Vapours Loss
D ry Cak e
Total
Output, Kgs
0.21
1.23
1.44
OUTP UT :
Prod uct
Mas s
Output, Kgs
27.97
S tep 6- PZ6 PR EPA RATI ON
I NP UT :
Raw Material
PZ5
THF
DMG
Cobalt ous Ch.
NaOH
Na BH4
DMF
Water
Total
In put , Kg s
1 .23
3.73
0.16
0.01
0.10
0.26
3.28
19. 20
27. 97
I NP UT :
Raw Material
Ma ss
E thyl Acet ate
In put , Kg s
27 .9 7
16. 60
Total
Reaction
Total
Extraction & S olv en t
recovery
44. 57
I NP UT :
Raw Material
Mas s
Ac etic Acid
Total
In put , Kg s
36. 27
2.58
38. 85
I NP UT :
Raw Material
Mas s
I PA
Total
In put , Kg s
38 .8 5
0.98
39. 83
I NP UT :
Raw Material
Wet Cake
In put , Kg s
1.38
Total
Precip itation
OUTP UT :
Prod uct
EA Rec .
Mas s
Loss
R esidue to I nc *
Total
Output, Kgs
8.30
36.27
0.88
0.88
44.57
OUTP UT :
Prod uct
Mas s
Output, Kgs
38.85
Total
Fitration
Drying
1.38
27.97
38.85
OUTP UT :
Prod uct
ML t o E TP *
Wet Cake
Total
Output, Kgs
38.45
1.38
39.83
OUTP UT :
Prod uct
D ry Cak e
Vapour
Total
Output, Kgs
1.1 1
0.27
1.38
OUTP UT :
Prod uct
Mas s
Output, Kgs
8.06
S tep 7- PZ HCl PR EPARA TI ON
I NP UT :
Raw Material
P Z6
Met hanol
HCL
Carbon
Total
I NP UT :
Raw Material
Ma ss
Hyf low
Total
In put , Kg s
1.11
6.07
0.85
0.03
8.06
In put , Kg s
8 .06
0.01
8.07
Reaction
Total
OUTP UT :
Prod uct
S park ler
Filtration
C ake t o I nc in. *
Filt erate
Total
8.06
Output, Kgs
0.05
8.02
8.07
Sparkler
Filtration
INPUT :
Raw Material
Filterate
Total
INPUT :
Raw Material
Mass
MeOH Wash
Total
INPUT :
Raw Material
Wet Cake
Input , Kgs
8.02
Total
Output, Kgs
3.30
0.33
4.39
8.02
Centrifuge & Solvent
Recovery
OUTPUT :
Product
MeOH Rec. .
Loss
Residue t o I nc. *
Wet Cake
Total
Output, Kgs
1.71
1.87
0.43
1.20
5.21
Drying
OUTPUT :
Product
Vapour
Dry Cake
Total
Output, Kgs
0.18
1.02
1.20
Sifte r & Mic ronisation
OUTPUT :
Product
Loss
PZ Pure
Total
Output, Kgs
0.02
1.00
1.02
8.02
Input , Kgs
4.39
0.82
5.21
Input , Kgs
1.20
Total
INPUT :
Raw Material
Dry Cake
Crystallisation
OUTPUT :
Product
Dis tillat ion
Dis tillat ion Los s
Mass
Total
1.20
Input , Kgs
1.02
1.02
33. MESALMINE
Brief Manufacturing Process:
STEP 1
Preparation of 2-Hydroxy-5-Nitro Benzoic Acid
With Nitration of Ortho Chloro Toluene receive the Ortho Chloro Benzoic Acid again the
nitration of the Ortho Chloro Benzoic Acid we will receive the 2-chloro-5- nitro benzoic acid.
To a stirred solution of potassium hydroxide (70 kg, 1250 mol) and water (250 l) was added 2chloro-5- nitro benzoic acid (50 kg ,248 mol) over a period of 20 minutes between 25 to 30 0C in
an autoclave. The reaction mixture was heated to 125-130oC , stirred At the same temperature
for 5 hours under 2.5 kg /cm2. The reaction mass was cooled to 25 oC and acidify to PH 1.0-2.0
using hydrochloric acid (85 L) , stirred for 1 hour. The precipitated solid was filtered and washed
with water (150 L) , and the cake slurried in water (300 L) at 30 Oc for 1 hour, filtered, washed
with water ( 150 L) and dried at 65 oC for 10 hours to afford product 43.5 kg
yield :- 43.5 kg (96 % ) purity :- 99.87 %
1H NMR ( 400 MHZ, DMSO): DELTA 11.2 (s,1H), 8.5 (m,2H), 7.3 ( s ,1H),5.2 (s,1H).MS m/z 183;
Anal Calcd.for C7H5NO5
STEP 2
Preparation of 5-amino-2-hydroxy benzoic acid
2-Hydroxy-5-Nitro Benzoic Acid (40 kg,218 mol) was added slowly to a stirred mixture of water
(320 L ) and sodium carbonate (16.3 kg, 153 mol) . stirred for 30 minutes and the mass ph
maintained between 8.0 and 9.5 . 10 % Raney Nickel (8 L) along with water (80 L) was added to
the above solution. The resultant mixture( 130 L) was added to the mass at 25oC , Stirred for 30
minutes . The catalyst was filtered through celite , and washed with water (80L) . the solution was
acidified to Ph 2.5-3.0 with hydrochloric acid (33L) and stirred for 1 hour. The obtained compound
was filtered , washed with water (40 L ). To the solution of wet cake and water (560 l ) and
hydrochloric acid (41 L) . active charcoal (2.8 kg) was added, and the contents were heated to 70
o
C , maintained at the same temperature for 2 hours. Filtered the total solution through celite,
washed with water (28 L) . Active charcoal (2.8 kg) was added to the filtrate, stirred at a
temperature of 70 oC for 2 hours, filtered through celite and washed with water (28L) . to the
obtained filtrate, Ph was adjusted to 3.0-3.5 with aq.sodium bicarbonate solution (15 L ) , stirred
for 1 hour, filtered the solid and washed with water (42 L), dried the solid at 80 OC for 9 hours to
give the product as off white colored p
powder.
Yield :- 27.5 kg (82 % ) Purity : -(99.9%)
(99.9%)
CHEMICAL REACTION
2-chloro-5- nitro benzoic
acid
2-Hydroxy-5-Nitro
Nitro Benzoic Acid
KOH
+
→
+
HYDROCHLORIC ACID
2-Hydroxy-5-Nitro
Benzoic Acid
Sodium carbonate+
MESALAMINE
CAS number :- 89-57-6
Formula :- C7H7NO3
Raney nickel +
→
Sodium hydroxide +
(5-amino-2-hydroxy
hydroxy benzoic acid)
+ Hydrochloric acid +
Charcoal +
sodium bicarbonate
MATERIAL BALANCE
Sr. MATERIAL INPUT
No.
STEP 1
1
2
3
4
POTASSIUM HYDROXIDE
2-chloro-5- nitro benzoic acid
HYDROCHLORIC ACID
WATER
TOTAL
STEP 2
1 step 1 crude
INPUT IN
KG
KG
70.00
MATERIAL OUTPUT
OUTPUT IN
KG
crude
43.5
50.00
WATER
150
85.00
HCL
74
150.00
SOLID WASTE
87
355.00
43.50
354.5
2
3
4
5
6
7
SODIUM CARBONATE
RANEY NICKEL
SODIUM HYDROXIDE
HYDROCHLORIC ACID
CHARCOAL
SODIUM BICARBONATE
TOTAL
16.30
16.9
130.00
SODIUM CARBONATE
RANEY NICKEL
SODIUM HYDROXIDE
74.00
WATER
110
5.60
mesalamine crude
27.5
TOTAL
292.4
8.00
8
130
15.00
292.4
33. RABEPRAZOLE SODIUM
Manufacturing Process:
Stage-1
2, 3-Lutidine is reacted with Hydrogen Peroxide in presence of Acetic Acid to give N-Oxide it
further reacts with Nitration mixture (Nitric Acid + Sulfuric Acid) to give Stage-1
Stage-2
Stage-1 is reacted with 3-Methoxy-1-Propanol and Sodium Hydroxide to get Stage-2 Compound
Stage-3
Stage-2 Compound is reacted with Acetic Anhydride, Sodium Hydroxide and
Hydrochloric Acid to get Stage-3 Compound
Stage-4
Stage-3 Compound is reacted with Thionyl Chloride, 2Mercapto benzimidazole and sodium
hydroxide in the presence of MDC as a solvent media to give tage-4 as product.
Stage-5
Stage-4 Compound is reacted with Sodium Hypochlorite to get Rabeprazole Base
Stage-6
Stage-5 reacts with Sodium hydroxide to get Rabeprazole Sodium
Chemical Reaction:
Mass Balance:
34. FEBUXOSTAT
Process Description:
Ethyl-2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate (NV07-3) is hydrolyzed with sodium
hydroxide solution in isopropyl alcohol to furnish the product. The pH is adjusted with hydrochloric acid and
solid is separated by filtration as Febuxostat crude.
Febuxostat (crude) is dissolved in acetone and charcoalized. After filtration, acetone is distilled out and solid
is filtered to give Febuxostat.
Chemical Equation
Mass Balance:
Sr.
No.
1
2
3
4
5
6
7
8
Particular
Ethyl-2-(3-cyano-4isobutoxyphenyl)-4-methyl-5thiazolecarboxylate
Methanol
Toluene
Caustic soda flakes
HCl
Water
Total
Input Qty
(kg)
1.250
12.50
7.50
0.125
0.250
5.000
26.625
Particular
Product
Methanol Recover
Methanol Loss
Toluene Recover
Toluene Loss
Effluent
Dist. Residue
Loss
Total
Output Qty
(kg)
1
12.00
0.50
7.25
0.25
4.375
0.750
0.500
26.625
35. ITOPRIDE HYDROCHLORIDE
Process Description
Verateric acid and Thionyl Chloride is reacted in toluene medium. At the end of the reaction any excess of
thionyl chloride is removed by purging nitrogen in the solution. The crude VC (Vertroyl Chloride) obtained is
used as such in the next step.
ITO ((2-[4 - aminomethyl) phenoxy] N,N-dimethyl ethanamine) is reacted with VC solution. The crude
product is isolated by removal of the solvent.
Crude product (Itopride Base) is treated with carbon in hot acetone. After removal of carbon, addition of
acetone HCl leads to formation of the Itopride HCl.
Chemical Equation
Mass Balance:
Sr.
No.
1
2
3
4
5
6
7
8
9
10
Particular
Veratric acid
Thionyl chloride
Toluene
4-[2-(Dimethylamino)
ethoxy]Benzyl amine
Caustic soda flakes
IPA
IPA HCl
Methanol
Acetone
Water
Total
Input Qty
(kg)
0.667
0.667
3.270
0.667
0.095
2.857
0.317
0.159
0.635
8.095
17.429
Particular
Product
Toluene Recover
Toluene Loss
IPA Recover
Output Qty
(kg)
1
3.111
0.159
2.794
IPA Loss
Dist. Residue
Effluent
HCl Gas
SO2 Gas
0.063
0.467
9.445
0.147
0.234
Total
17.42
36. Celecoxib
Manufacturing Process:
•
Charged water in Reactor at RT. Charged 4 SPH and Dione Deri in Reactor. The reaction
mixture was heated and stirred well. Cool the RM and Filter the Product.
•
Charged Toluene and wet cake in above reactor again. Heat the RM and stir well for
several time. The organic layer were washed with water add Activated carbon at stirred
under heating.
•
Filter the RM with Sparkler. The filtrate was cooled. The separated solid was filtered and
dried
Chemical Reaction:
Mass Balance:
Sr. Input
No.
1
4 SPH
2
Dione Deri
3
Toluene
4
Carbon
5
Water
6
Total
Quantity (Kg)
Output
Quantity (Kg)
0.70
0.65
2.80
0.01
1.60
Final Product
Toluene (Recd)
Distillation + Drying Loss
Residue
Carbon Waste
Effluent
1.00
2.65
0.19
0.03
0.02
1.88
5.77
Total
5.77
37. CLOPIDOGREL BISULPHATE
Manufacturing Process:
STAGE 1:
• Starting materials amino(2-chlorophenyl)acetic acid ,methanol, Sulfuric acid are added into
the reaction vessel and agitated until reaction is completed.
•
Methanol is recovered from the reaction mass by distillation and some of the same is lost as
vapor during the operation.
•
Water and Dichloro methane are added into the reaction mass and adjust PH to neutral
with liquor ammonia.
•
Two layers namely MDC layer and aqueous layer are obtained.
•
Aqueous layer is sent to ETP.
•
MDC (Dichloro methane) layer is then distilled to recover MDC wherein vapor loss occurs
during the operation.
•
Stage 1 product is further isolated by continuing distillation.
STAGE 2:
• Starting materials thiophene-2-ethanol, toluene, p – toluene sulphonyl chloride, water,
sodium hydroxide solution are added into the reaction vessel and stirred until reaction is
completed.
•
Two layers toluene layer and aqueous layer are obtained. Aqueous layer is further sent to
ETP.
•
Toluene layer is then distilled to recover toluene wherein vapor loss occurs during the
operation.
•
Stage 2 product is further isolated by continuing distillation.
STAGE 3:
• Starting materials Stage 1 product, stage 2 product, acetonitrile, dipotassium phosphate are
added into the reactor and stirred until the reaction is completed.
•
Acetonitrile is recovered from the reaction mass by distillation and some of the same is lost
as vapor during the operation.
•
Ethyl acetate is added into to the reaction mass and agitated to clear solution.
•
Further water is added to obtain layer separation.
•
Two layes namely ethyl acetate layer and water layer are obtained. And water layer is sent
to ETP.
•
Further conc. Hydrochloric acid is added to the ethyl acetate layer for precipitation and then
filtered through centrifugal filter.
•
The wet cake so obtained is dried to obtain final product.
•
Filtrate is then distilled to obtain ethyl acetate and remaining effluent is sent to ETP.
STAGE 4:
• Starting materials couple ester, water, paraformaldehyde is charged into the reaction vessel
and is agitated.
•
Further dichloro methane and water are added to the reaction mass and then adjust PH
acidic with liquor ammonia.
•
Namely MDC layer and water layer are obtained.
•
Water layer is sent to the ETP.
•
MDC layer is then distilled to recover MDC. Wherein vapor loss occurs during the operation.
•
Stage 1 product is further isolated by continuing distillation.
STAGE 5:
• Starting raw materials stage 4 product, acetone, Tartaric Acid are charged into the reaction
vessel and are stirred for longer time.
•
Entire mass is then filtered by centrifugal filter and wet cake so obtained is dried to obtain
dry cake..
•
The filtrate is sent for solvent recovery.
•
Water and dichloro methane are charged into the reaction vessel & then dry cake obtained
is charged.
•
Further PH is adjust to alkaline by sodium carbonate solution to obtain layer separation.
•
Namely MDC layer & water layer are obtained.
•
Water layer is sent to ETP.MDC layer is then distilled to recover MDC wherein vapor loss
occurs during the operation.
•
Stage 2 products are further isolated by continuing distillation.
STAGE 6[Final]:
• Stage 2 product, acetone, activated carbon are charged into the reaction vessel and entire
mass of the reaction vessel is filtered through the neutch filter.
•
Further con. Sulfuric acid is added slowly to the reaction mass for crystallization.
•
It is further filter through centrifugal filter.
•
The wet cake so obtained is dried to obtain final product.
•
The filtrate is used in next batch for obtaining second crop.
•
The dried product is finally packed.
CHEMICAL REACTION:
STAGE 1:
O
OH
O
Cl
O
Cl
CH3
Methanol/H2SO4
NH2
NH2
amino(2-chlorophenyl)acetic acid
methyl amino(2-chlorophenyl)acetate
STAGE 2:
CH3
S
Thiophene-2-Ethanol
OH
+
O
S
Cl
O
para toluene sulphonyl chloride
O
H3C
S
O
O
S
Chloro phenyl glycine methyl ester tartarate salt
STAGE 3:
O
O
Cl
O
CH3
H3C
S
+
NH2
O
O
S
2-(2-thienyl)ethyl 4-methylbenzenesulphonate
methyl amino(2-chlorophenyl)acetate
Ethyl acetate/HCL
Cl
O
NH
O
.HCL
H3C
S
methyl (2R)-(2-chlorophenyl){[2-(2-thienyl)ehtyl]amino}acetate hydrochloride
STAGE -4 :
Cl
Cl
O
P-Formaldehyde
O
N
NH
O
O
H3C
H3C
S
S
methyl (2-chlorophenyl)(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate
stage 3
STAGE – 5 :
Cl
O
Cl
Tartaric Acid
O
N
N
O
H3C
S
Stage 4
STAGE – 6:
Material Balance:
O
S
H3C
methyl (2R)-(2-chlorophenyl)(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)ethanoate
Qty
(in kg)
Sr.
No.
1.25
1
Recovered Methanol
3.75
3.95
0.7
5.30
4.98
0.62
16.80
2
3
4
5
6
Loss Methanol
Recovered MDC
Loss MDC
ML to ETP
Stage 1 Output
TOTAL
0.20
4.48
0.5
6.87
1.00
16.80
STAGE 2
Thiophene-2-Ethanol
p-toluene sulphonyl chloride
Toluene
Water
Sodium hydroxide
0.5
1.05
3.12
4.5
1.25
1
2
3
4
5
Recovered Toluene
Loss Toluene
ML to ETP
Stage 2 Output
Residue
2.93
0.16
6.30
1.00
0.03
TOTAL
10.42
TOTAL
10.42
STAGE 3
Stage 1
Stage 2
Acetonitrile
Dipotassium phosphate
Ethyl acetate
water
HCL
TOTAL
1.25
1.00
6.30
0.87
5.60
2.00
0.85
17.87
1
2
3
4
5
6
7
Recovered Acetonitrile
Loss Acetonitrile
Recovered Ethyl acetate
Loss Ethyl acetate
ML to ETP
Residue
Stage 3 Output
TOTAL
5.98
0.32
5.26
0.28
4.97
0.06
1.00
17.87
STAGE 4
Stage 3
Water
P-Formaldehyde
MDC
Liq. Ammonia
1.50
12.00
0.53
11.9
0.60
1
2
3
4
Recovered MDC
Loss MDC
ML to ETP
Stage 4 product
10.71
1.19
13.53
1.10
Sr.
Material Input
No.
STAGE 1
1 amino(2-chlorophenyl)acetic
acid
2 methanol
3 Potassium salt
4 Water
5 MDC
6 Liq. ammonia
TOTAL
1
2
3
4
5
1
2
3
4
5
6
7
1
2
3
4
5
Material Output
Qty
(in kg)
1
2
3
4
5
6
1
2
3
4
TOTAL
STAGE 5
Stage 4
Acetone
Tartaric acid
Water
MDC
Sodium carbonate
TOTAL
26.53
1.10
11.00
0.82
2.70
6.65
0.70
22.97
STAGE 6
Stage 5
Acetone
Activated carbon
Sulfuric acid
1.00
4.74
0.15
0.31
TOTAL
6.20
TOTAL
26.53
1
2
3
4
5
6
Recovered Acetone
Loss Acetone
Recovered MDC
Loss MDC
ML to ETP
Stage 5 Output
TOTAL
9.90
1.10
5.98
0.67
4.32
1.00
22.97
1
2
3
4
Recovered Acetone
Loss Acetone
Spent carbon
Stage 6 Output
4.50
0.24
0.46
1.00
TOTAL
6.20
38. AMRODAFINIL
Manufacturing Process
The manufacturing process for the above mentioned products involves chemical synthesis
utilizing mainly organic chemicals as raw materials in batch process. These batch processes are
used to produce active pharma ingredients with unique physical and pharmacological
properties. Typically, a series of chemical reactions are performed in multi-purpose reactors
and the products are isolated by extraction, crystallization and filtration. The finished products
are usually dried, and milled.
Chemical Reaction:
Mass Balance:
39. QUETIAPINE FUMARATE:
Manufacturing Process:
Quetiapine stage-1 & 2
2-Amino dimethyl sulfide reacts with phenylchloro formate to give carbamate product which
cyclize in the presence of phosphoric acid to give quetiapine stage 1 & 2.
Quetiapine stage-F
Quetiapinefumarate stage – 2 reacts with N,N-Dimethyl aniline in presence of phosphorous
oxychloride will further reacts with 1-hydroxy ethoxy ethyl piperazine using triethanolamine as
catalyst in toluene as media.
Finally product will be isolated by distillation of toluene and addition of Methanol and fumaric
acid solution to form Quetiapine fumarate.
CHEMICAL REACTION:
O
NH2
Cl
Phenyl chloroformate
Molecular Formula:C7H5ClO2
Formula Weight:156.57
2-(phenylsulfanyl)aniline
Molecular Formula = C12H11NS
Formula Weight = 201.29
H
N
O
+
S
O
S
Quetiapine stage-1 & 2
Molecular Formula = C13H9NOS
Formula Weight = 227.28166
OH
+
+
Phenol
Molecular Formula:C6H6O
Formula Weight:94.11
HCl
Hydrochloric acid
Molecular Formula:HCl
Formula Weight:36.5
MASS BALANCE:
Input
2- Amino diphenyle sulfide
Sodium Hydroxide flakes
Process water
Toluene
Phenyl chloroformate
Hydrochloric acid
Polyphospheric acid
Acetone
Total
Ton
1.11
0.32
7.80
6.67
1.27
0.66
8.89
3.48
30.19
Output
Air Waste
Aqueous waste
Toluene Recovery
Toluene Loss
Acetone Recovery
Acetone Loss
distillation residue
Product
Total
Ton
0.06
19.99
6.33
0.33
3.33
0.14
0.33
1.00
30.19
MASS BALANCE :
Input
Dibenzo [b,f] [1,4] Thiazepin -11(1 OH)- ONE
N,N- Dimethyl ANILINE
Phosphorous oxychloride
Hydrochloric acid
Sodium Sulphate
Process water
Toluene
Triethanolamine
Hydroxy ethoxyrthyl piparazine
Sodium bicarbonate
1 N HCl
Hyflosupercel
Methanol
Fumaric acid
Total
Ton
0.6
0.4
0.3
0.5
0.1
6.5
5.2
0.4
0.4
0.1
0.1
0.0
7.7
0.2
22.6
Output
Air Waste
Aqueous waste
Toluene Recovery
Toluene Loss
Methanol Recovery
Methanol Loss
distillation residue
Spent hyflow
Product
Ton
0.03
8.42
4.90
0.26
7.43
0.31
0.19
0.03
1.00
Total
22.6
40. ATORVASTATIN
Manufacturing Process:
Stage: 1 Preparation of (5R)-1,1-Dimethylethyl 6-Cyano-5hydroxy 3-oxo-hexanoate (ATVS1) (R)4Cyano-3-hydroxy butyric acid, ethyl ester is reacted with tert butyl acetate in the presence of
LDA at low temp to get ATVS1.
Stage: 2 Preparation of [R-(R*, R*)]-1, 1-Dimethylethyl 6-Cyano-3, 5-dihydroxy hexonate
(ATVS2), ATVS1 is reacted with Sodium Borohydride in THF and MeOH in the presence of
Diethyl Methoxy Borane. After completion of reaction, reaction mass is quenched with acetic
acid. After work up affords ATVS2.
Stage: 3 Preparation of (4R-Cis)-1, 1-Dimethylethyl 6-Cyanomethyl-2, 2-dimethyl-1, 3-dioxane4-acetate (ATVS3), ATVS2 is reacted with Acetone in presence of Methane Sulphonic Acid using
2,2- Di Methoxy propane. And then it is neutralized with 5% NaHCO3 solution then extracted
with Ethyl Acetate. After distillation of Ethyl Acetate MeOH & Water to get ATVS3.
Stage: 4 Preparation of (4R-Cis)-1,1-Dimethylethyl 6-(2-amino ethyl)-2,2-dimethyl-1, 3dioxane-4-acetate (ATVS4), ATVS3 is reduced with Methanolic Ammonia in presence of
Raney Nickel and Hydrogen gas, then catalyst is filtered off and the filtrate is concentrated
to give oily mass ATVS4.
Stage: 5 Preparation of [R-(R*, R*)]-2(4-Fluorophenyl)-β, 8-dioxane-5-(1-methylethyl)-3phenyl-4-[(phenyl amino)Carbonyl]-1H-Pyrrol-1tert –butyl heptanoic ester (ATV8), ATVS4 is
condensed with (+) 4-fluoro-α-2-methyl-1-oxopropyl]χ-oxo-N-β- Diphenyl-benzene butane
amide in presence of Pivalic acid using Toluene, Heptane and THF at. After completion of
reaction work up is done with 0.1N NaOH & 0.1N HCl. Organic layer is evaporated which is
crystallized in IPA and Water to get ATV8.
Stage: 6 Preparation of Atorvastatin Calcium
Acidic and basic hydrolysis of ATV8 with HCl and NaOH gives sodium salt of Atorvastatin,
which is treated with Aqs Calcium Acetate to give Atorvastatin Calcium in Aqs Methanol.
CHEMICAL REACTION
MATERIAL BALANCE
Sr.
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Particular
Ethyl-4-Cyano-3-hydroxy butanaote
THF
Diisopropyl amine
N-Butyl Lithium
Tert-Butyl acetate
HCl
Ethyl Acetate
NaCl
Methanol
DEMB (50 % Soln)
Sodium Borohydride
Acetic Acid
Dimethoxy Propane
Methane Sulphonic Acid
Sodium Bicarbonate
n-Hexane
DM Water
18
19
20
21
22
Raney Nickel
Pivalic Acid
Toluene
Activated Carbon
Methyl Tert Butyl
Total
Input Qty
(kg)
1.00
17.567
1.22
13.60
1.68
0.76
31.57
1.20
25.243
0.70
0.44
0.98
1.81
0.03
2.00
5.20
22.38
Sr.
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1.00
0.240
9.379
0.100
7.410
18
19
145.496
Particular
Output Qty
(kg)
Product
1.85
THF Recovered
17.04
THF Loss
0.527
N-Butyl Lithium Recovery
12.92
N-Butyl Lithium Loss
0.68
H2 gas
0.09
Spent Catalyst
1.5
Spent Carbon
0.05
Ethyl Acetate Recovered
30.94
Ethyl Acetate Loss
0.63
Methanol Recovered
24.61
Methanol Loss
0.63
n-Hexane Recovered
5.12
n-Hexane Loss
0.08
Toluene Recovered
9.19
Toluene Loss
0.189
Methyl
Tert
Butyl
7.04
Recovered
Methyl Tert Butyl Loss
0.37
Effluent
32.04
Total
145.496
41. ARIPIPERAZOLE:
Manufacturing Process:
Stage-1
7-HDQ react with 1-bromo-4-chlorobutane to form 7-(4-chlorobutoxy)-3,4-dihydroquinoline-2one.
Stage-2
Stage-1 react with DCCPP hydrochloride in presence of TEA and TBAB to form Aripiperazole
crude.
Stage-Final
Aripiperazole crude purify by usingAcetonitrile and isobutanol to form pure Aripiperazole.
CHEMICAL REACTION:
Cl
Na
+
O
N
H
OH
Cl
OH
O
N
H
O
Br
Molecular Formula: C9H11NO2
Formula Weight:
165.18914
Molecular Formula: C4H8BrCl
Formula Weight:
171.46332
Molecular Formula: C13H18ClNO2
Formula Weight:
O
Cl
Cl
O
N
H
O
H
N
O
Cl
+
255.74052
TEA
N
N
H
N
HCl
N
Molecular Formula: C13H18ClNO2
Molecular Formula: C10H13Cl3N2
Formula Weight:
Formula Weight:
255.74052
Cl
267.58262
Cl
Molecular Formula: C23H29Cl2N3O2
O
O
H
N
Formula Weight:
450.40126
H
N
O
O
N
Purification
N
N
N
Cl
Cl
Cl
Molecular Formula: C23H29Cl2N3O2
Molecular Formula: C23H29Cl2N3O2
Cl
Molecular Formula: C23H29Cl2N3O2
Formula Weight:
450.40126
MASS BALANCE:
Input
7- Hydroxy -3,4- dihydroQuinoline
1- Bromo -4- Chloro Butane
Ton
0.74
4.44
Sodium Hydroxide
0.24
n- Propanol
Cyclohexane
Process water
Triethylamine
DCPP HCl
Methanol
3.70
1.48
9.26
0.59
0.59
0.37
Total
21.43
Output
Air Waste
Aqueous waste
1- Bromo -4- Chloro Butane
Recovery
1- Bromo -4- Chloro Butane Loss
n-Propanol Recovery
n-Propanol Loss
Cyclohexane Recovery
Cyclohexane Loss
Methanol Recovery
Methanol Loss
distillation residue
Product
Total
Ton
0.06
10.22
4.22
0.22
3.56
0.15
1.44
0.04
0.36
0.01
0.15
1.00
21.43
42. AMLODIPINE BESYLATE
Manufacturing Process:
STAGE 1
•
Charge Methanol, Phthaloyl Amlodipine and Mono Methyl amine in Reactor. Heat the
reaction mass under stirring for several times.After completion of the reaction, Solvent
was removed under vacuum to get crude material
•
The solid was treated with water under stirring and heating. Cool the rm and filter the
solid. The crude solids are washed with water. Dry the product to give White to off
white solid
STAGE 2
•
Charge Ethyl acetate and step 1 and in Reactor. Charge Benzene Sulfonic acid solution in
ethyl acetate in above RM. Heat the mass. Heat the reaction mass under stirring for
several time.
•
After completion of the reaction, Solvent was removed under vacuum to get crude
material. The solid was treated with methanol under stirring and heating. Cool the rm
and filter the solid. The crude solids are washed with methanol. Dry the product to give
White to off white solid
Chemical Reaction:
Mass Balance:
Sr. Input
No.
1
Phthaloyl Amlodipine
2
Mono Methyl Amine
3
Methanol
4
Ethyl Acetate
5
Benzene Sulfonic Acid
6
Carbon
7
Water
Total
Quantity (Kg)
Output
Quantity (Kg)
1.09
1.68
4.38
3.09
0.38
0.75
8.80
Final Product
Methanol
Ethyl Acetate
Residue
Drying + Distillation loss
Effluent
Carbon waste
1.00
4.18
2.80
0.11
0.58
10.68
0.14
20.17
Total
20.17
43. NEBIVOLOL AND ITS INTERMEDIATE
Manufacturing Process:
PFA is condensed with Maleic anhydride in presence of AlCl3 and Dichloro ethane solvent to
give NB-1. NB-1 is then cyclized to give NB-2. NB-2 is reduced to NB-3 using Palladium charcoal
catalyst. NB-3 is reduced using sodium Borohydride to give NB-4. NB-4 is reduced to give NB-5.
NB-5 is epoxydised using dimethyl sulphoxide in presence of MDC to give NB-6. NB-6 is
condensed with Benzyl Amine in presence of Methanol to give NB-7. NB-7 is debenzoylated
with Ammonium formate and palladium charcoal to give NB-8. NB-8 is then condensed with HCl
to give Nebivilol Hydrochloride.
Chemical Reaction:
Mass Balance:
Sr.
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Particular
Maleic Anhydride
AlCl3
EDC
Para Fluoro Anisole
HCl
Hexane
Acetic Acid
Sulphuric Acid
Pd/c
Hyflow
Sodium Borohydride
THF
MDC
Sodium Carbonate
DMSO
Oxahl Chloride
TEA
Sodium Hydride
Methanol
Benzyl Amine
Acetonitrile
Water
Total
Input Qty
(kg)
2.8
7.73
302.38
2.91
6.63
115.84
1.7
2.36
0.82
1.63
2.31
112.51
232.34
1.78
42.99
6.54
12.98
1.96
36.05
0.66
16.31
30.9
942.13
Sr.
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Particular
Product
Effluent to ETP
Spent Pd/c
EDC Recovered
EDC Loss
Hexane Recovered
Hexane Loss
THF Recovered
THF Loss
MDC Recovered
MDC Loss
DMSO Recovered
DMSO Loss
Residue
HCl 30%
Total
Output Qty
(kg)
2.00
44.5
0.7
296.3
6.08
110.51
5.33
109.0
3.51
225.36
6.98
41.9
1.09
1
57.04
942.13
44. ETORICOXIB
Manufacturing Process
Ketosulfone is reacted with CPT-Phosphate in presence of Potassium tert-Butoxide in Tetra hydrofurane to
give Etoricoxib crude .Etoricoxib crude recrystallized from IPA-Hexane to give Etoricoxib
Chemical Reaction
Stage-I: Preparation 2-chloro malonaldehyde from sodium salt of 2-chloromalonaldehyde
Stage-II: Preparation 3-amino-2- chloroacrolien from 2-chloro-malonaldehyde
Stage-III: Preparation of Etoricoxib hydrochloride
Stage-IV: Preparation of Etoricoxib (API)
Material Balance
Sr.
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Input
Acetic Acid
Acetone
Ammonia Solution
CPT-Phosphate
D M Water
Hydroxylamine Hydrochloride
Hyflow
Isopropyl Alcohol
Ketosulfone
Methanol
Potassium Tertrabutoxide (KTB)
Sodium Acetate
Sodium Hydroxide
Toluene
THF
Trifluro Acetic Acid
Activated Carbon
Hexane
Total
Qty
(kg)
1.520
2.80
5.80
1.520
26.00
0.115
0.177
10.00
0.574
10.00
0.664
0.297
2.153
55.000
23.00
0.465
0.022
0.250
139.357
Output
Etoricoxib
Acetone Recovery
Acetone Recovery Loss
Isopropyl Alcohol Recovery
Isopropyl Alcohol Recovery
Loss
Methanol Recovery
Methanol Recovery Loss
Toluene Recovery
Toluene Recovery Loss
Qty
(kg)
1
2.657
0.124
9.500
0.450
9.65
0.35
53.5
1.25
Aqueous Effluent
Spent Carbon
Dist. Residue
THF Recover
THF Loss
37.054
0.022
0.5
22
0.8
Total
139.357
45. VALSARTAN
Manufacturing Process
There are following steps involved in the synthesis of Valsartan.
Step - 1: - Preparation of L- METHYL VALINATE
L- Valine is treated with methanol in presence of Thionyl chloride to get L- Valine methyl ester which was
then neutralized with alkali solution to get L-methyl valinate.
Step - 2: - Preparation of VALSARTAN OXALATE
L- Methyl valinate is condensed with 4- bromo methyl -2 - cyano biphenyl in presence of potassium
carbonate which was then treated with oxalic acid to isolate the Valsartan oxalate.
Step - 3-A: - Preparation of VALEROYL VALSARTAN
The Valsartan oxalate is condensed with Valeroyl chloride in presence of potassium, Carbonate in o- xylene
to get Valeroyl Valsartan.
Step - 3-B and 3-C: - Preparation of CRUDE VALSARTAN
The cyano group of Valeroyl Valsartan is cyclized in presence of tri butyl tin chloride and sodium azide in oxylene at reflux to get methyl Valsartan. The methyl Valsartan is then hydrolyzed with sodium hydroxide
and isolated with dichloromethane and cyclohexane to get crude Valsartan.
Step - 4:- Preparation of VALSARTAN CALCIUM
The crude Valsartan is treated with calcium hydroxide in acetone and D I water and filtered to obtained
calcium salt of Valsartan.
Step - 5- Preparation of VALSARTAN
Valsartan calcium salt is treated with hydrochloric acid in ethyl acetate and water. The ethyl acetate layer is
treated with diisopropyl ether to obtain the pure Valsartan.
Chemical Reaction
Material Balance
46. Tranexamic Acid
Manufacturing Process:
• In to an Auto clave charge 4-amino methyl benzoic acid.
• Charge Aq. solution of Sodium hydroxide.
• Charge ruthenium and apply hydrogen pressure.
• Heat it and maintain it.
• Filter the reaction mass and collect filtrate.
• Charge Hydrochloric Acid to adjust pH.
• Distill out water.
• Charge methanol and water.
• Maintain it.
• Filter it.
• Dry to give Tranexamic Acid.
Chemical Reaction:
Material Balance
Sr. Input
No.
1 4-aminomethyl benzoic
Acid
2 HCl
3 Ruthenium
Qty
(kg)
1.060
Product
Qty
(kg)
1.000
0.440
0.300
Ruthenium Recover
Methanol Recover
0.292
1.950
Sodium hydroxide
Methanol
Water
Total
0.252
2.000
7.800
11.852
Loss
Effluent
Dist. Residue
Total
0.050
8.51
0.050
11.852
4
5
6
Output
47. GUANYL THIOUREA
Manufacturing Process:
Charge water and dicynadiamide at room temperature. Charge phosphourous penta sulphide and sodium
hydro sulphite at room temperature. heat it to 45 °c to 55 °c and maintain the temperature till reaction
complite. Cool and centrifuge. Wet cake dry in dryer and pack. Mother liquor is di – potassium phosphate
which is selling in liquid form.
Chemical Reaction:
NH
H2N C N C
H2N
N + P2S5
H
2H3PO4 + KOH + H2O
S
C N C NH2 + 2H3PO4 + 4H2S + KOH + H2O
HN H
POTASSIUM SULPHATE
Material Balance
Sr. Input
No.
1 Phosphorus Penta Sulphide
2 KOH
3 Dicyanadiamide
Qty
(kg)
182
220
200
Sodium Hydro Sulphite
Water
Total
40
300
942
4
5
Output
Product
Di Potassium Phosphate
Drying Loss
Qty
(kg)
220
384
15
HCl Gas
323
Total
942
48. 1,3 DI CHLORO ACETONE
Manufacturing Process:
Stage-I
Add Epichlorohydrin (500 kg) in Glass Line Reactor and cool to 0'C to 5"C
5"C.'
Now addn 30% HCl(1200kg )within i0to12hrs
0to12hrs when temperature is between 0'C to 5"C'
After this separate the 20% solution of Spent Hydrochloric Acid (Qty: 12) kg) and
organic layer containing 1,3-Dichloro-2--Prolmnol (480.0 kg)
Stage-II
480 kg) and Sodium Dichromate solution (1500
Now charge 1,3.Dichloro-2.Propanol (480
kg) 1 in Glass Line Reactor and Cool to 10"C - 18"C
Then slowly add 70% solution of Sulphuric Acid (1000kg) within 10 to 15 hrs when
temperature is 10"C to 18"C.
After this add DM water (500 kg)
g) and Cool to 10"C'
Transfer reaction mass is centrifuge
fuge to separate mother liquor containing 1 &12%
solution of Basic chromium sulphate (3046 kg) and crude 1,3 Dichloroacetone (434 kg).
Take crude 1,3-Dichloroacetone
Dichloroacetone in Glass Line Reactor and heat to 50"c to separate
lower layer containing product 1,3-Dichloroacetone
Dichloroacetone (384 kg) and acidic waste water (50
kg)'
Keep 1,3 Dichloroacetone in clean HDPE carboy and cool it to soc for 5-6 hrs for solidification.
Chemical Reaction:
Mass Balance:
Sr. Input
No.
1 Epichlorohydrin
2 HCl (30%)
3 Sulfuric Acid (98%)
4
5
Sodium Dichromate
Water
Total
Qty
(kg)
500
1200
715
600
1685
4700
Output
Product
Dil. HCl
Basic Chromic Sulphate
Qty
(kg)
384
1220
3046
Effluent
50
Total
4700
49. FOLIC ACID
Manufacturing Process:
Step-I
PABGA, TAPS and TCA are charged in to a reactor containing sufficient water and are stirred maintaining
required pH. The technical folic acid formed is subjected to the next stage.
Step-II
The technical folic acid is treated with acid and is passed through filter press and the solid so obtained is
taken for the next stage.
Step-III
The crude folic acid is dissolved in alkaline solution and is filtered through leaf filter. The folic acid filtrate is
treated with acid and the solid so obtained is subjected to centrifugation.
Chemical Reaction:
o
OH
CH2
H
CO2H
N
O +
CO2H + C
NH2
NH2
H
CH2
H
O
O
N
CO2H
N
N
NH2
H
CO2H
N
N
H
N
H
NH2
N
H2SO4
N
NH2
Mass Balance:
Sr. Input
No.
1 PABGA
2 TAPS
3 TCA
Qty
(kg)
50
45
32
4
5
6
7
8
9
10
18
60
580
300
11
16
SMBS
NaHCO3
water
HCl 30%
NaOH
Acetic Acid
Total
1112
Output
Product
Solid Waste
Gas Emission
Qty
(kg)
50
93
45
Drying Loss
Effluent
300
624
Total
1112
50. ZOLPIDIC ACID
Manufacturing Process:
Stage 01
Reactor is charged with toluene, 4-methylphenacyl bromide, 2-amino-5-methyl pyridine and tri ethyl amine
and maintained at temp 15-20 0C for 6 hrs. After completion of the reaction, filter the mass, collect the solid
cake and wash the solid with water. Obtain stage 01 product as wet cake which is dried to afford stage 01
product.
Stage 02
Stage 01 product is reacted with, Oxaloyl chloride in presence of MDC as a solvent and TEA as a organic
base at RT temp for 3hrs followed by addition of KOH solution. Then increase the temp of reaction mass up
to 80 0C and simultaneously distill MDC. After complete removal of MDC cool the reaction mass to 60 0C
and add hydrazine hydrate and reflux for 16 hrs. Cool the reaction mass and add KOH. Further increase
temp up to 130 and remove water. Cool the reaction mass and filter; acidify the filtrate with acetic acid.
Collect Crude Zolpidic acid and crystallize in methanol. Dry the product in hot air oven to afford Zolpidic
acid.
Chemical Reaction:
1. Route of Synthesis
Stage – 1: Preparation of Stage 01
O
Br
H 3C
+
N
+
N
N(C 2 H 5 ) 3
Toluene
CH 3
N
H 3C
NH 2
+
N(C 2 H 5 ) 3 . HBr
H 2O
2 - Amino - 5 - methyl pyridine
Triethyl amine
181.9
18
4 - Methyl Phenacyl bromide
2 - (4 - methylphenyl) - 6 - methyl imidazo[1,2 -a] - pyridine
C 6 H 15 N
C 6H 8N 2
C 9 H 9 BrO
C 15 H 14 N 2
+
CH 3
212.9
108
101
222
Stage – 2: Preparation of Zolpidic acid
Cl
O
N
MDC
N
++
(C 2 H 5 )3 N 2 KOH
N
2 x 56 H C
H3C
3
Cl
O
2 - (4 - methylphenyl) - 6 - methyl imidazo[1,2 -a] - pyridine
CH3
C 15 H 14 N 2
O
O
Oxalyl chloride 101
C 2 Cl 2 O 2
222
CH3
N
+
137.5
O
C 17 H 13 KN 2 O 3
+ KCl
74.5
332
N
N
CH 3
N
+
H 3C
H 2N
NH 2
CH 3
N
H 3C
O
O
O
N
K
K
H 2N
O
32
CH 3
N
+ 2 KOH
H 3C
K
346
CH 3
N
Methanol
H 3C
O
2 x 56
O
C 17 H 15 KN 4 O 2
18
N
N
O
H 2O
346
332
N
+
O
C 17 H 15 KN 4 O 2
N 2H 4
C 17 H 13 KN 2 O 3
H2N
18
(C 2H 5) 3 N.HCl
K
127
+ H2O
+
3 CH 3 COOH
Acetic acid
3 x 60
OH
C 17 H 16 N 2 O 2
Zolpidic acid
280
+
N2
+
2 H 2O
28
2 x 18
3 CH 3 COOK
3 x 98
Mass Balance:
Sr.
No.
Input
QTY (Kg)
Output
QTY (Kg)
Toluene
1750
Stage 01
350
350
Recovered toluene
1665
214
Aqueous effluent 1
2485
Step-I
1
2
3
Methyl Phenacyl
bromide
2- Amino-5-methyl
pyridine
4
Triethyl amine
186
Solvent loss
85
5
Water
2100
Distillation residue
15
4600
Total
4600
Total
Step-II
1
Stage 01
350
Zolpidic acid
350
2
Oxalyl chloride
245
Recovered MDC
1680
3
Methylene Dichloride
2100
Recovered methanol
3150
4
Potassium hydroxide
469
Aqueous effluent 2
8423
5
Water
7000
Solvent loss
770
6
Acetic acid
578
Distillation residue
20
7
Hydrazine hydrate
151
8
Methanol
3500
Total
14393
Total
14393
51. PREGABALIN
Manufacturing Process
Sodium Hydroxide solution in Process water is chilled at 0-10°C and then charge R-(-)-3-(Carbamoylmethyl)5-methylhexanoic acid [R-(-)-CMH]. Addition of liquid Bromine is done at 0-5°C then raise the temperature
of the reaction mass up to 30-35°C. After reaction monitoring, raise the temperature of the reaction mass
to 55-60°C and apply carbon treatment. The clear filtrate is then received in another reactor. Excess water
is distilled off from the reaction mass. The reaction mixture is acidified with concentrated Hydrochloric acid.
Reaction mass is then up to 80-85°C and after that gradual cooling to 25-30°C. The material is centrifuged
after maintaining of the reaction mass at 25-30°C for 4-6 hrs.
The dry material is then charged in IPA and raises the temperature to 80-85°C. Add DM water to reaction
mass at 80-85°C. Filter the clear reaction mass and chill it to 8-12°C. The material is then centrifuged and
dried in under vacuum.
Chemical Reaction
Material Balance
Stage - 1
Sr.
No.
1
Raw Material
Process water
Sodium Hydroxide
4-CMH
Liquid Bromine
Activated carbon
Hyflo
Hydrochloric acid
Total
2
3
4
5
6
7
Quantity Kgs
2590.0
347.2
250.0
224.0
12.5
3.0
450.0
3877
Out Put
Quantity Kgs
Spent carbon and
hyflo
Spent ML
Loss on drying
Out Put
Total
28.0
3623.7
62.5
162.5
3877
Stage - 2
Sr.
No.
1
2
3
Raw
Material
Pregabalin
(Stage-I)
IPA
DM water
Total
Quantity Kgs
215.0
1290.0
860.0
2365
Out Put
Spent ML
Loss o Drying
Out Put
Total
Quantity Kgs
2150.00
32.2
182.8
2365
ANNEXURE-4
WATER CONSUMPTION AND WASTE WATER GENERATION (EXISTING AND PROPOSED)
Sr.
Usage
Water Consumption
(m3/Day)
No.
Existing
1.
Waste Water Generation (m3/Day)
Total after
Existing
Total after
proposed
proposed
expansion
expansion
Industrial
Process
2.43
30
2.95
24.0
Boiler
2.5
15
0.25
0.5
Cooling
3.0
15
Nil
0.5
Washing
3.0
5.0
3.0
5.0
10.93
65.0
6.2
30.0
Total (Industrial)
2.
Domestic
1.0
2.0
1.0
2.0
3.
Gardening
--
5.0
--
--
11.93
72.0
7.2
32.0
Total
Note:
Existing:
• Domestic effluent is disposed though septic tank & soak pit system.
• Industrial effluent is collected in effluent collection tank and finally sent to CETP of ETL for final
treatment and disposal.
Proposed:
• Domestic effluent will be disposed though septic tank & soak pit system.
• Industrial effluent (low COD = 25 KL/day) will be given primary treatment and then sent to CETP of M/s.
ETL for treatment and disposal. Industrial effluent (high COD = 5 KL/day) will be given primary
treatment and then sent to common MEE of M/s. ETL for treatment and disposal.
WATER BALANCE DIAGRAM
Raw Water: 72 KL/Day from GIDC
Domestic
2 KL/Day
2 KL/Day
Soak Pit &
Septic tank
Process
30 KL/Day
24 KL/Day
Cooling Tower
15 KL/Day
0.5 KL/Day
Boiler
15 KL/Day
0.5 KL/Day
ETP: 30 KL/Day (Low COD + High COD Stream)
Final treated effluent to
CETP for further Treatment
Washing
5 KL/Day
5 KL/Day
Gardening
5 KL/Day
Annexure -5
Effluent Treatment Plant (ETP) DETAILS:
Existing:
M/s. Hem-Deep Organics Pvt. Ltd. has two (02 nos.) collection tank for high COD and Low COD effluent
stream. Raw effluent from plant separates as high COD and Low COD stream and collects in concern
collection tank where it neutralizes and get settles. Neutralized high COD effluent then sends to common
MEE facility of M/s. ETL, Ankleshwar for further treatment and final disposal whereas low COD sends to
CETP operates by M/s. ETL, Ankleshwar for further treatment and final disposal.
ETP Units Name & Size:
Sr. No.
Unit Name
1
Collection Tank-1
2
Collection Tank-2
3
Collection Tank-3
Size (m x m x m)
4.5 x 2.5 x 4.0
10.0 KL
10.0 KL
Proposed:
Stream I (Low COD & TDS Stream)
First all non-toxic and biodegradable streams (low & medium COD& TDS) of wastewater shall pass through
Screen Chamber (SC-01) where floating material shall be removed with help of Screen (S-01). Then effluent
shall be passed through Oil & Grease Removal Tank (OGRT-01). Automatic mechanical Oil Skimmer shall be
provided in the OGRT to remove floating oil and grease from the wastewater to Oil & Grease Collection
Tank (OGCT-01). Then effluent shall be collected in Collection cum Equalization tank-1 (CET-01). Pipe grid is
provided at bottom of the CET-01 to keep all suspended solids in suspension and to provide proper mixing.
2 nos. of Air Blowers (1W+1 stand-by) shall supply air through to pipe grid.
Then after, equalized wastewater shall be pumped to Neutralization Tank-1 (NT-01) where the continuous
addition and stirring of Caustic solution is done to maintain neutral pH of wastewater from Caustic Dosing
Tanks (CDT-01) as per requirement by gravity. Then after, neutralized wastewater shall go to Flash Mixer-1
(FM-01) by gravity. Alum and Polyelectrolyte shall be dosed from Alum Dosing Tank (ADT-01) and
Polyelectrolyte Dosing Tank (PEDT-01) respectively by gravity into FM-1 to carry out coagulation by using a
Flash Mixer. Then after, coagulated wastewater shall be settled in Primary Clarifier (PCF-01).Treated
effluent will be sent to CETP for further treatment.
SIZE OF TANKS (Stream I): 25 KL/day
S.N.
Name of unit
No
.
MOC/ Remark
Stream I (Low COD & TDS Stream)
1
Screen Chamber (SC-01)
[0.6x0.5x1 depth]
1
RCC M25+A/A Bk.
Lining
2
1
RCC M25+A/A Bk.
Lining
Collection cum Equalization
Tank-1 (CET-01)
Size (m x m x m)
[2.5x2.5x 6 depth]
3
4
5
Neutralization Tank (NT-01)
Flash Mixer-1 (FM-01)
Primary Clarifier (PCL-01)
RCC M25
PCC
PP
MSEP
SS
=
=
=
=
=
[2.5x2.5x 6 depth]
1.5 x 1.5 x (2.0 LD +1.0
FB)
[2.5x2.5x 6 Height]
REINFORCED CEMENT CONCRETE (M 25 GRADE)
PLAIN CEMENT CONCRETE
POLYPROPELENE
MILD STEEL EPOXY PAINTED
STAINLESS STEEL
1
1
RCC M25+A/A Bk.
Lining
RCC M25
1
RCC M25
BLOCK DIAGRAM FOR EFFLUENT TREATMENT PLANT (Stream -I)
Screen Chamber
Oil & Grease
Trap
Collection cum
equalization
tank
Neutralization
tank
Primary Settling
tank
CETP
EXPECTED CHARACTERISTIC OF EFFLUENT (STREAM-I)
Sr.
No.
Category of Wastewater
Before Treatment
After Treatment
1
pH
3.5-6.5
6.5-8.5
2
COD (mg/L)
3,200
2,500
3
BOD3 (mg/L)
1,250
800
4
Ammonical Nitrogen (mg/L)
50
40
EXPECTED CHARACTERISTIC OF EFFLUENT (STREAM-II)
Sr.
No.
Category of Wastewater
Before Treatment
1
pH
2-10
2
COD (mg/L)
55,000
3
BOD3 (mg/L)
12,000
4
TDS (mg/L)
40,000
5
Ammonical Nitrogen (mg/L)
200
Stream-2: High COD & High TDS: 5 KL/day
High COD & High TDS effluent will be neutralized in tank and neutralized effluent will be sent to common MEE for
further treatment & disposal.
ANNEXURE: 6
DETAILS OF HAZARDOUS/SOLID WASTE GENERATION, MANAGEMENT AND DISPOSAL
Sr.
Hazardous/Solid
Category
Quantity
Mode Of Disposal
No. Waste
Existing
Total after
proposed
expansion
1
Discarded HDPE
33.1
200 Nos./ Year 1000
Collection,
Storage,
Drums/Bags
(4 MT/Year)
Transportation
and
sell
to
Nos./Month
Register Re-processors after
decontamination.
2
Used / Spent Oil
5.1
5.0 Lit/Year
10 Lit/Month
Collection,
Storage,
Transportation and sell to
registered recycler.
Collection, Storage, Transportation
3
ETP Sludge
35.3
-5 MT/Month
4
Distillation
Residue
28.1
750
Kg/ Month
10 MT/Month
5
Spent Carbon
28.2
150 Kg/ Month 2 MT/Month
6
HCL 30 %
C15
2.0 MT/Month
7
Spent Catalyst
28.3
--
100 MT/Month
2 MT/Month
8
Inorganic Salt
28.1
--
20 MT/Month
9
Organic
Waste
28.1
--
25 MT/Month
Process
and sent to common TSDF of M/s.
BEIL.
Collection, Storage, Transportation
and sent for co-processing in
cement industries or sent to
common incineration at BEIL.
Collection, Storage, Transportation
and sent for co-processing in
cement industries or sent to
common incineration at BEIL.
Collection, Storage, Transportation
and sell to end user.
Collection,
Transportation
regenerator
and
Storage,
sent to
Collection, Storage, Transportation
and sent to common TSDF at BEIL.
Collection, Storage, Transportation
and sent for co-processing in
cement industries or sent to
common incineration at BEIL.
ANNEXURE: 7
DETAILS OF FLUE & PROCESS GAS EMISSION AND CONTROL MEASURES
Sr.
No.
Source
Emission
of
Existing
1
Non IBR Boiler
(Capacity: 0.6TPH)
2
Process
(Reactor)
Vent
Stack/Vent
(meter)
Height Diameter
Fuel name &
Quantity use
Type of
Emission
APCE
SPM
SO2
NOx
--
SO2
HCl
HBr
Two Stage Alkali
scrubber
SPM
SO2
NOx
SPM
SO2
NOx
SPM
SO2
NOx
--
12
0.1
10
0.1
Natural Gas =
10 Sm3/Day or
LDO =
500 Lit/Day
--
0.2
Natural Gas =
Total Proposed
TOTAL PROPOSED EXPANSION
Flue Gas Emission
1
Boiler (Existing)
15.0
(Capacity: 0.6TPH)
3
300 Sm /Day
2
Boiler (Proposed)
(Capacity: 2.0 TPH)
30
0.5
Agro waste = 8
MT/Day
3
Thermic
fluid
heater (Proposed)
(Capacity: 4 Lakh
KCal/Hr.)
D. G. Set
30
0.5
Agro waste – 2
MT/Day
11
0.1
HSD
SPM
SO2
NOx
--
11
0.2
--
Two Stage Water &
Caustic scrubber
11
0.2
--
Cl2
NH3
HCl
HCl
SO2
4
Process Gas Emission
5
Process
Vent
(Reactor Vessel)
(Existing)
6
Process
Vent
(Reactor Vessel)
(Proposed)
Multicyclone
separator with bag
filter
Multicyclone
separator with bag
filter
Two Stage Water &
Caustic scrubber
ANNEXURE: 8
DETAILS HAZARDOUS CHEMICAL STORAGE FACILITY
Sr.
No.
Name of the
Hazardous
Substance
Maximum
Storage
Mode of
Storage
Actual
Storage
1
Methanol
20 MT
Tank
20 MT x 1
State &
Operating
pressure &
temperature
NTP
Possible type of
Hazards
2
EDC/MDC
20 MT
Tank
20 MT x 1
NTP
3
DMF
10 MT
Tank
20 MT x 1
NTP
4
Toluene
20 MT
Tank
20 MT x 1
NTP
Flammable/
Toxic
Flammable/
Toxic
Flammable/
Toxic
Flammable
5
Acetone
20 MT
Tank
20 MT x 1
NTP
Flammable
6
Ethyl Acetate
20 MT
Tank
20 MT x 1
NTP
Flammable
7
IPA
20 MT
Tank
20 MT x 1
NTP
Flammable
8
HCL
5 MT
Tank
5 MT x 1
NTP
Corrosive
9
H2SO4
5 MT
Tank
5 MT x 1
NTP
Corrosive
ANNEXURE 9
SOCIO - ECONOMIC IMPACTS
1) EMPLOYMENT OPPORTUNITIES
The manpower requirement for the proposed project is expected to generate some permanent
jobs and secondary jobs for the operation and maintenance of plant. This will increase direct /
indirect employment opportunities and ancillary business development to some extent for the
local population. This phase is expected to create a beneficial impact on the local socio-economic
environment.
2) INDUSTRIES
Required raw materials and skilled and unskilled laborers will be utilized maximum from the local
area. The increasing industrial activity will boost the commercial and economical status of the
locality, to some extent.
3) PUBLIC HEALTH
The company regularly examines, inspects and tests its emission from sources to make sure that
the emission is below the permissible limit. Hence, there will not be any significant change in the
status of sanitation and the community health of the area, as sufficient measures have been
taken and proposed under the EMP.
4) TRANSPORTATION AND COMMUNICATION
Since the existing factory is having proper linkage for the transport and communication, the
development of this project will not cause any additional impact.
In brief, as a result of the proposed project there will be no adverse impact on sanitation,
communication and community health, as sufficient measures have been proposed to be taken
under the EMP. The proposed project is not expected to make any significant change in the
existing status of the socio - economic environment of this region.
ANNEXURE – 10
PROPOSED DRAFT TERMS OF REFERENCE
1.
•
•
•
•
•
•
•
•
•
•
Project Description
Justification of project.
Promoters and their back ground
Project site location along with site map of 5 km area and site details providing
industries, surface water bodies, forests etc.
Project cost
Project location and Plant layout.
Water source and utilization including proposed water balance.
Product spectrum (proposed products along with production capacity) and process
List of hazardous chemicals.
Mass balance of each product
Storage and Transportation of raw materials and products.
various
2. Description of the Environment and Baseline Data Collection
• Micrometeorological data for wind speed, direction, temperature, humidity and rainfall in 5 km
area.
• Existing environmental status Vis a Vis air, water, noise, soil in 5 km area from the project site.
For SPM, RSPM, SO2, NOx.
• Ground water quality at 5 locations within 5 km.
• Complete water balance
3. Socio Economic Data
• Existing socio-economic status, land use pattern and infrastructure facilities available in the study
area were surveyed.
4. Impacts Identification And Mitigatory Measures
• Identification of impacting activities from the proposed project during construction and
operational phase.
• Impact on air and mitigation measures including green belt
• Impact on water environment and mitigation measures
• Soil pollution source and mitigation measures
• Noise generation and control.
• Solid waste quantification and disposal.
5.
•
•
•
Environmental Management Plan
Details of pollution control measures
Environment management team
Proposed schedule for environmental monitoring including post project
6.
•
•
•
Risk Assessment
Objectives and methodology of risk assessment
Details on storage facilities
Process safety, transportation, fire fighting systems, safety features and emergency capabilities to
be adopted.
• Identification of hazards
• Consequence analysis through occurrence & evaluation of incidents
• Disaster Management Plan.
7. Information for Control of Fugitive Emissions
8. Post Project Monitoring Plan for Air, Water, Soil and Noise.
9. Information on Rain Water Harvesting
10. Green Belt Development plan
ANNEXURE – 11
GIDC Plot Transfer Letter & GIDC Water Supply Letter
ANNEXURE – 12
Membership Certificate of CETP, ETL-Ankleshwar for disposal of treated effluent
ANNEXURE – 13
Membership Certificate of TSDF & Common Incinerator for disposal of Hazardous waste