S L PHARMACEUTICALS F. No. 407, Mallikarjuna Residency Bramarambikanagar colony, Beeramguda, Ameenpur, Sangareddy, Telangana State.502032
Date:14.02.2018
To,
The Director and Member Secretary, State Expert Appraisal Committee (SEAC), Andhra Pradesh Pollution Control Board, Madhavadhara, VUDA Layout, Beside RTO Office, Visakhapatnam-530018.
Sir,
Sub: Proposal of New API Bulk Drugs & Intermediates Manufacturing Unit, Plot No. 160, Sy. No. 93,94,95 & 96 in APIIC, Thirumalagiri (V), Jaggaiahpet (M), Krishna District in A.P – Submission of Form-I, Pre-feasibility Report & Draft Terms of Reference for issue of Terms of Reference (TOR)-Reg.
With reference to the above subject, we are proposed to Establish API Bulk Drug & Intermediates Manufacturing Unit at Plot No. 160 in Sy. No. 93, 94, 95 & 96 of APIIC, Thirumalagiri (V), Jaggaiahpet (Municipality), Krishna District of Andhra Pradesh. Please find enclosed here with Hard & Soft copy in C.D of Basic information, Form-I duly filled & Pre-feasibility report along with all necessary annexures and Draft Terms of Reference for issue of Terms of Reference (TOR).
We request you to kindly process our application and arrange to issue Terms of Reference for our new Proposed Project.
Kindly acknowledge the receipt of the same.
Thanks & Regards,
For M/s. S L Pharmaceuticals
Authorized Signatory FORM-I APPLICATION FOR APPROVAL OF TERMS OF REFERENCE (TOR)
(New API Bulk Drugs & Intermediate Manufacturing Unit) OF M/s. S L PHARMACEUTICALS PLOT NO. 160, SY. NO. 93,94,95, & 96, APIIC, THIRUMALAGIRI (V), JAGGAIAHPET (M), KRISHNA DISTICT IN ANDHRA PRADESH
FOR OBTAINING
ENVIRONMENTAL CLEARANCE ANDHRA PRADESH POLLUTION CONTROL BOARD
Prepared by:
SAI SAHITHI ENVIRO CHEM PVT. LTD.
PLOT NO.17, SRINILAYAM, POWER NAGAR COLONY, MOOSAPET, HYDERABAD - 500018
M/s. S L Pharmaceuticals
LIST OF CONTENTS
Annexure S. No. Content Name No. Page No s 1 Form-I Applicaiton -- -- Pre-feasibility Report for API Bulk Drug & 2 Intermediate Unit. -- 1-22 3 Site Location Map I 23 4 Google Earth Map II 24 5 Site Plan III 25 6 MSME Certificate IV 26 7 List of Products V 27 8 List of Raw Material VI 28-39 Typical Process Description & Flow Chart for 9 Proposed products. VII 40-113 1) Lansoprazole 40-44 2) Losartan Potassium 45-52 3) Lisinopril 53-56 4) Levocetirizine dihydrochloride 57-63 5) Rabeprazole Sodium 64-70 6) Pantoprazole Sodium 71-76 7) Itraconazole 77-80 8) Fexofenadine Hydrochloride 81-88 9) Ciprofloxacin Hydrochloride 89-93 10) Pregabalin 94-102 11) Domperidone 103-107 12) Esomeprazole Magnesium trihydrate 108-113 10 Water Consumption Details VIII 114 11 Effluent generation Details IX 115-116 12 Solid/Hazardous Waste generation Details X 117 13 Process Emission Detials XI 118 14 Stack Emission Details XII 119-120 15 Hazardous Chemicals list XIII 121 16 Draft TOR XIV 122-124 Proposed Effluent Treatment Plant Flow 17 Diagram XV 125 M/s. S L Pharmaceuticals
18 Additonal information XVI 126-152 A. Topography Map – 10 Km radius 126 B. Project Report 127-133 C. APIIC Allotment Letter 134-139 D. List of Starting Raw Materials 140 E. Pollution Load Details 141-152
S L Pharmaceuticals APPENDIX I
FORM 1
(I) Basic information
S. No Item Details 1. Name of the project S L Pharmaceuticals API & Intermediates Manufacturing Unit 2. S. No.in the schedule 5(f) 3. Proposed capacity /area/length/tonnage API Bulk Drugs Total Production Capacity-8.5 to be handled/command area/lease area/ MT/Month number of wells to be drilled List of Products with their Production capacity are given in Executive Summary Report. Total 12 Products at any point of time Total Area: 1313.3 SMT 4. New/Expansion/Modernization New 5. Existing Capacity/Area etc. New 6. Category of Project i.e. A or B Category B 7. Does it attract the general condition? No. If yes, please specify. 8. Does it attract the specific condition? If No. yes, please specify. 9. Location Plot No.160, Sy. No. 93,94, 95 & 96, APIIC, Thirumalagiri (V), Jaggaiahpet (Municipality) Krishna District. Andhra Pradesh. 10. Nearest Railway station/airport along Railway station at Khammam is 43 KM (S), at with distance in KM. Vijayawada is 76 KM (SSW) (aerial distance) Gann avaram Airport – 98 KM (S) (aerial distance) 11. Nearest Town, City, District Jaggaiahpet – 8 Km Headquarters along with distance in Vijayawada - 79 Km KM. Kodada- 22.9 Km Khammam – 43.5 Km 12. Village Panchayats, Zilla Parishad, APIIC, Thirumalagiri (V), Municipal Corporation, Local Body Jaggaiahpet (Municipality) (Complete postal addresses with Krishna District. telephone nos. to be given) Andhra Pradesh. 13. Name of the applicant M/s. S L Pharmaceuticals Shri. M. Sreenivasa Rao Proprietor Authorized Signatory: Mr. Sreenivasa Rao 14. Registered Address M/s. S L Pharmaceuticals Flat No. 407, Mallikarjuna Residency,
1 S L Pharmaceuticals Bramarambikanagar colony, Beerumguda, Ameenpur (M), Sangareddy District, Telangana State. 15. Address for correspondence: M/s. S L Pharmaceuticals Name Shri. M. Sreenivasa Rao Designation (Owner/Partner/CEO) Proprietor Address Flat No. 407, Mallikarjuna Residency, Bramarambikanagar colony, Beerumguda, Ameenpur (M), Sangareddy District, Telangana State. Pin Code 502032 E-mail [email protected] Telephone No. 8712162360 Fax No. -
16. Details of alternative sites examined, if Not Exanimated any. Location of these sites should be shown on a topo sheet 17. Interlinked Projects Nil 18. Whether separate application of Not Applicable interlinked project has been submitted? 19. If Yes, date of submission Not Applicable 20. If no, reason Not Applicable 21. Whether the proposal involves approval/clearance under: if yes, details of the same and their status to be given. (a) The Forest (Conservation) Act, Nil 1980? (b) The Wildlife (Protection) Act, 972? (c) The C.R.Z Notification, 1991? 22. Whether there is any Government Nil Order/Policy relevant/relating to the site? 23. Forest land involved (hectares) Nil 24. Whether there is any litigation pending against the project and/or land in which the project is propose to be setup? Nil (a) Name of the court (b) Case No. (c) Orders/directions of the Court, if any and its relevance with the proposed project.
2 S L Pharmaceuticals
(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.)
S.No. Information/Checklist Yes/No Details thereof (with approximate confirmation quantities/rates, wherever possible) with source of information data 1.1 Permanent or temporary change in Yes Permanent change in the land use. land use, land cover or topography Construction of Buildings for manufacturing including increase in intensity of of Drugs & Intermediates in 1313.3 SMT land use (with respect to local land Please refer Annexure-III for Plant use plan) Layout 1.2 Clearance of existing land, Yes APIIC Land vegetation and buildings? 1.3 Creation of new land uses? Yes Construction of various blocks Buildup Area: 587.0 SMT Green Belt: 473.0 SMT Open Area: 253.3 SMT Total Area: 1313.3 SMT 1.4 Pre-construction investigations e.g. No APIIC bore houses, soil testing? 1.5 Construction works? Yes Production Block-161.0 SMT Boiler House- 25 SMT Warehouse/ Eng. Stores - 156 SMT MEE System – 50 SMT Power House / Transformer – 75 SMT Water Sump / Storage Tanks – 120 SMT Total Area: 1313.3 SMT Site Plan Enclosed (Annexure-I) 1.6 Demolition works? No No demolition work
1.7 Temporary sites used for No No temporary sites for construction works or construction works or housing of housing of construction workers construction workers? 1.8 Above ground buildings, structures Yes Waste water storage tanks 2 meters above or earthworks including linear the ground. Stacks for Boiler and DG set structures, cut and fill or excavations 1.9 Underground works including No No Mining or Tunneling Works. mining or tunneling? 1.10 Reclamation works? No No Reclamation Works 1.11 Dredging? No No Dredging Work.
3 S L Pharmaceuticals 1.12 Offshore structures? No No Offshore Works. 1.13 Production and manufacturing Yes Manufacturing Production & Process Details processes? are Enclosed (Annexure– VII) 1.14 Facilities for storage of goods or Yes A temporary shed in about 50 SMT will be materials? Constructed for storing construction materials 1.15 Facilities for treatment or disposal Yes MEE System for treatment of Liquid waste of solid waste or liquid effluents? will be installed in about 50 Sq. Meters. Schematic drawing of Effluent treatment is attached. (Annexure-XIV) 1.16 Facilities for long term housing of No No housing facilities will be provided for operational workers? operational workers. 1.17 New road, rail or sea traffic during No No construction or operation? 1.18 New road, rail, air, waterborne or No No other transport infrastructure including new or altered routes and stations, ports, airports etc? 1.19 Closure or diversion of existing No No transport routes or infrastructure leading to changes in traffic movements? 1.20 New or diverted transmission lines No No or pipelines? 1.21 Impoundment, damming, culverting, No realignment or other changes to the No hydrology of watercourses or aquifers? 1.22 Stream crossings? No No 1.23 Abstraction or transfers of water No The proposed plant shall use APIIC water from ground or surface waters? during construction and quantity required shall be 43.2 KLD during operation. The water will be drawn from ground water sources. (Annexure-VIII) 1.24 Changes in water bodies or the land No There will not be any changes in water surface affecting drainage or run- bodies or the land surface affecting drainage off? or run-off 1.25 Transport of personnel or materials Yes The construction material shall be drawn for construction, operation or from local sources within 15 Km. There is decommissioning? no transport of personnel as the construction workers shall be drawn from nearby villages. 1.26 Long-term dismantling or No No dismantling or decommissioning or decommissioning or restoration restoration works works?
4 S L Pharmaceuticals 1.27 Ongoing activity during No Not applicable decommissioning which could have an impact on the environment 1.28 Influx of people to an area in either Yes None temporarily or permanently? 1.29 Introduction of alien species? No None 1.30 Loss of native species or genetic No None diversity? 1.31 Any other actions? No Every care shall be taken to protect the ecology of the surroundings
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):
S. No Information/Checklist Yes/ Details thereof (with approximate confirmation No? quantities/rates, wherever possible) with source of information data 2.1 Land especially undeveloped or No Nil agricultural land (ha) 2.2 Water (expected source & competing Yes Source of Water – APIIC users) unit: KLD Process – 3.2 KLD Washings – 2.0 KLD Boiler Makeup – 15.0 KLD Cooling Towers Makeup – 10.0 KLD Scrubber System – 2.0 KLD R&D/QC -1.0 KLD Domestic – 5.0 KLD Green Belt- 5.0 KLD Total Water Consumption is 43.2 KLD Please Refer Annexure- VIII 2.3 Minerals (MT) No No Minerals required
2.4 Construction material – stone, Yes From the Local Sources aggregates, sand/soil (expected Approximately source (MT) Stone-20mm – 1500 M3 40mm – 700 M3 Sand – 300 M3 2.5 Forests and timber (source – MT) No No Timber will be used. 2.6 Energy including electricity and fuels Yes Electricity – From APSEB –250 KVA (source, competing users) Unit: fuel Generator: 250 KVA (MT), energy (MW) Fuel: HSD about 50 Liters per day Steam: from Boiler – 2 TPH Fuel: Coal: 6 TPD 2.7 Any other natural resources (use No None appropriate standard units)
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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.
S. No Information/Checklist confirmation Yes/ Details thereof (with approximate No? quantities/rates, wherever possible) with source of information data 3.1 Use of substances or materials, which Yes List of Hazardous Chemicals will be used in the are hazardous (as per MSIHC rules) to proposed project are Enclosed human health or the environment Please refer Annexure-XII (flora, fauna, and water supplies) 3.2 Changes in occurrence of disease or No No such occurrence envisaged, since waste water affect disease vectors (e.g. insect or generated will be treated properly and disposed as water borne diseases) per norms of PCB 3.3 Affect the welfare of people e.g. by Yes Shall increase the employment potential for locals changing living conditions? thereby effect the living conditions towards betterment 3.4 Vulnerable groups of people who No Plant boundary is more than 2 KM away from the could be affected by the project e.g. plant nerest habitation. hospital patients, children, the elderly etc., 3.5 Any other causes No Nil
4. Production of solid wastes during construction or operation or decommissioning (MT/month)
S. No Information/Checklist confirmation Yes/ Details thereof (with approximate No? quantities/rates, wherever possible) with source of information data 4.1 Spoil, overburden or mine wastes No No Spoil, overburden or mine wastes 4.2 Municipal waste (domestic and or No No Domestic waste. The Commercial waste like commercial wastes) empty cement bags and Irons scrap will be generated during construction stage. 4.3 Hazardous wastes (as per Hazardous Yes Organic Solid Waste – 121.17 Kg/Day Waste Management Rules) MEE Salts -197.07 Kg/Day Spent Carbon – 9.3 Kg/Day ETP Sludge – 50.0 Kg/Day Used Oils- 100 LPM Detoxified Container & Liners – 200 No s/Month Spent Solvents – 5 KL/Month Lead Acid Batteries - 2 No s/Annum Please refer Annexure-X 4.4 Other industrial process wastes Yes Non-Hazardous Waste Coal Ash- 2.4 TPD
6 S L Pharmaceuticals 4.5 Surplus product No Surplus production is not envisaged since production will be as per the market demand only.
4.6 Sewage sludge or other sludge from Yes Domestic Waste water will be sent to Septic tank effluent treatment followed by soak pit. Over flow will be sent to ETP. During operation: 50.0 Kg /day
4.7 Construction or demolition wastes No No Demolition waste will be generated. Construction waste such as dugout soil will be used as replenishment, Iron scrap and Empty cement bags during the construction. 4.8 Redundant machinery or equipment No None 4.9 Contaminated soils or other materials No Nil 4.10 Agricultural wastes No Not Applicable 4.11 Other solid wastes Yes Plastic & Empty drums
5. Release of pollutants or any hazardous, toxic or noxious substances to air (Kg/hr.)
S. No Information/Checklist confirmation Yes/ Details thereof (with approximate quantities/rates, No wherever possible) with source of information data 5.1 Emissions from combustion of fossil Yes No emissions during construction period. fuels from stationary or mobile sources 5.2 Emissions from production processes Yes 14.2 Kg/day from all the products Please Refer Annexure-XI 5.3 Emissions from materials handling Yes Air Pollution Equipment s will be provided. including storage or transport 5.4 Emissions from construction activities Yes Negligible quantity of fugitive dust will generate. including plant and equipment 5.5 Dust or odors from handling of No No odors from construction materials will be materials including construction released. Septic tank will be provided both during materials, sewage and waste construction and operation of the plant. Hence no odors will be released into atmosphere. 5.6 Emissions from incineration of waste No Provision of the incinerator not envisaged. 5.7 Emissions from burning of waste in No No burning activity in the site. No emissions will open air (e.g. slash materials, generate construction debris) 5.8 Emissions from any other sources No None
6. Generation of Noise and Vibration, and Emissions of Light and Heat
S. No Information/Checklist confirmation Yes/ Details thereof (with approximate quantities/rates, No? wherever possible) with source of information data 6.1 From operation of equipment e.g. Yes None.
7 S L Pharmaceuticals engines, ventilation plant, crushers Noise will generate when generator is used. 6.2 From industrial or similar processes Yes Noise from process utilities will be within the limits. About 56dB(A)
6.3 From construction or demolition Yes None, since plant size is small 6.4 From blasting or pilling No None, since no blasting or pilling during construction
6.5 From construction or operational Yes Noise will be generation traffic 6.6 From lighting or cooling systems No Negligible. 6.7 From any other sources No Nil
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
S. No Information/Checklist confirmation Yes/ Details thereof (with approximate quantities/rates, No? wherever possible) with source of information data
7.1 From handling, storage, use or No. Nil. spillage of hazardous materials Since hazardous material will be transported to production block by means of pipes, Spillage of material will not occur. Hazardous materials will be stored in drums on an elevated platform, provided with leach ate collection pits. 7.2 From discharge of sewage or other No Domestic sewage effluent will be 4.0 KLD. It will be effluents to water or the land sent to soak pit. Process effluent will be treated in (expected mode and place of MEE System followed by RO System and Permeate discharge) will be recycled within the plant 7.3 By deposition of pollutants emitted to No Stack emission is controlled by providing adequate air into the land or into water height. Fly ash will be sold to brick manufacturers. 7.4 From any other sources No Process emissions are controlled by scrubbers.
7.5 Is there a risk of long term buildup of No No risk of built up. All the pollutants will be pollutants in the environment from controlled appropriately. these sources?
8. Risk of accidents during construction or operation of the Project, which could affect human health or the environment
S. No Information/Checklist confirmation Yes/ Details thereof (with approximate quantities/rates, No wherever possible) with source of information data 8.1 From explosions, spillages, fires etc., Yes No explosions will occur during construction. from storage, handling, use or During production-operations every safety precaution
8 S L Pharmaceuticals production of hazardous substances will be followed. Reactors will be provided with rupture disks. MSDS of individual chemicals will be followed while handling, use or storage of hazardous substances 8.2 From any other causes Yes Static Electricity
8.3 Could the project be affected by No No natural disasters are envisaged, since site is in an natural disasters causing area where such occurrences do not arise environmental damage (e.g. floods, earthquakes, landslides, cloudburst etc.,)?
(II) 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
S. No Information/Checklist Yes/ Details thereof (with approximate quantities/rates, confirmation No? wherever possible) with source of information data 9.1 Lead to development of supporting Yes Supporting laities or ancillary units may come up in laities, ancillary development or the area because the present proposed project is in an development stimulated by the industrial area. project which could have impact on the environment e.g. No roads will be laid, since plant site is well connected to road. Power supply will be obtained * Supporting infrastructure from public supply and there will not be any effect on (roads, power supply, waste or waste the environment. Waste water generation from the water treatment, etc.) process is very low and waste water treatment plant will be constructed and there will not be any impact on the environment.
Housing development activity is not envisaged, since * Housing development the workers will be employed from local nearby villages.
* Extractive industries No extractive industries will come up, since proposed project is small.
* Supply industries Since proposed industry is small, no supply units will come up. All the necessary supplies will be from * Other nearby places and available abundantly. Nil. Hence there will not be any impact ion environment
9.2 Lead to after-use of the site, which No Site will be permanently used for manufacturing bulk could have an impact on the drugs only. No impact on environment environment 9.3 Set a precedent for later developments No Since area is small, there will not be much development at latter stages. Green belt development
9 S L Pharmaceuticals is envisaged. 9.4 Have cumulative effects due to No Marginal cumulative effects envisaged. proximity to other existing or planned projects with similar effects
(III) Environmental Sensitivity
S. No Areas Name/ Aerial distance (within 25 km) Proposed project Identity location boundary 1 Areas protected under international Nil None conventions, national or local legislation for their ecological, landscape, cultural or other related value 2 Areas which are important or Nil Wet lands, water bodies, coastal zones, biospheres, sensitive for ecological reasons – mountains and forests are very far. Hence Wetlands, watercourses or other environmental sensitivity will not be disturbed water bodies, coastal zone, biospheres, mountains, forests 3 Areas used by protected, important Nil There is no protected, important or sensitive of or sensitive species of flora or fauna flora, fauna for breeding, nesting, foraging over for breeding, nesting, foraging, wintering migration, since the site is away from resting, over wintering, migration such place 4 Inland, coastal, marine or Nil No inland, coastal, marine or underground waters underground waters will be affected since the proposed project site is located in an industrial area 5 State, National boundaries Yes Inter District boundaries: No interstate Boundaries North – Khammam District-32Km West – Nalgonda-30 Km East – Bay of Bengal-140Km South – Nalgonda District-30Km 6 Routes or facilities used by the No Nil public for access to recreation or other tourist, pilgrim areas 7 Defense installations No No defense establishments within the area.
8 Densely populated or built-up area No The proposed project site is located in APIIC industrial area.
9 Areas occupied by sensitive man- Nil made land uses (hospitals, schools, None within the 10Km radius from plant site places of worship, community facilities) 10 Areas containing important, high Nil quality or scarce resources (ground None
10 S L Pharmaceuticals water resources, surface resources, forestry, agriculture, fisheries, tourism, minerals) 11 Areas already subjected to pollution Nil or environmental damage. (Those None. where existing legal environmental standards are exceeded) 12 Areas susceptible to natural hazard Nil None which could cause the project to present environmental problems (earthquakes, subsidence, landslides, erosion, flooding or extreme or adverse climatic conditions)
“I hereby given undertaking that the data and information given in the application and enclosures are true to the best of my knowledge and behalf 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 give, if any to the project will be revoked at our risk and cost
Date: 13.02.2018 Place: Hyderabad
for S L Pharmaceuticals
M. Sreenivasa Rao Proprietor.
11
M/s. S L Pharmaceuticals
Pre-Feasibility Report for API Bulk Drugs & Intermediates Manufacturing Unit
1.0 Executive Summary
M/s. S L Pharmaceuticals., proposes to establish Bulk Drugs & Intermediates manufacturing Unit at Plot No. 160 in Sy. No. 93, 94, 95 & 96 of APIIC, Thirumalagiri (V), Jaggaiahpet (Municipality), Krishna District of Andhra Pradesh with an area of 1313.3 SMT.
The Industry proposes to manufacture 12 New Products along with their intermediates on Campaign basis at a single point of time based on the market demand. The Bulk Drug proposed will either be manufactured till the final stage of the product or up to the corresponding quantities of the intermediates based on the market demand with a total production capacity of 283.33 Kg/Day (8.5 MT/Month).
1.1 About the Industry:
M/s. S L Pharmaceutical., promoted by a team of professionals having rich experience in the pharmaceutical industry and clear vision and is conscious about long term sustainable value-added growth. M/s. S L Pharmaceuticals., has proposed to establish an up a medium scale Bulk Drugs & Intermediates manufacturing facility in a 1313.3 SMT site at Plot No. 160 in Sy. No. 93, 94, 95 & 96 of APIIC, Thirumalagiri (V), Jaggaiahpet (Municipality), Krishna District of Andhra Pradesh.
The Total Project investment in Land, Buildings, Plant and Machinery is approximately Rs.501.5 Lakhs (5.02 Crores). The manufacturing facility will be developed in future to meet the cGMP norms and USFDA approvable levels. However, in case further up gradation/ modernization of pollution control facilities is required, it will be undertaken in a phased manner.
Table 1: Cost of Project & Details S.No. Cost of the Project Amount Rs. In Lakhs 1 Land 46.0 2 Buildings (Civil works) 90.2 3 Plant & Machinery 365.3 Total (Project Cost) 501.5
1.2 Location of the Project:
M/s. S L Pharmaceuticals., is located at Plot No. 160 in Sy. No. 93, 94, 95 & 96 of APIIC, Thirumalagiri (V), Jaggaiahpet (Municipality), Krishna District of Andhra Pradesh. The plant area falls at the intersection of 160 54 40.2” North Latitude 80007 10.3 East Longitude. The site is
Page | 1 M/s. S L Pharmaceuticals situated at an altitude of 64-68 m above Mean Sea Level (MSL). The nearest railway station is Kondapally which is around 2.2 KM (SSW) from the plant and the major Railhead is Vijayawada. The National Highway NH-30 (Vijayawada – Mylavaram Road) is around 0.2 KM (E) and The Nearest Air Port is Vijayawada which is around 23.34 KM from the Plant.
2.0 Introduction of the Project:
M/s. S L Pharmaceuticals., proposes to establish Bulk Drugs & Intermediates manufacturing Unit at Plot No. 160 in Sy. No. 93, 94, 95 & 96 of APIIC, Thirumalagiri (V), Jaggaiahpet (Municipality), Krishna District of Andhra Pradesh.
2.1 Project Proponent:
Mr. M. Sreenivasa Rao is the Proprietor of the company. He has more than 15 years of experience in pharmaceutical industry.
2.2 Brief description of nature of the project:
M/s. S L Pharmaceuticals has proposed to manufacture 12 New Products along with their intermediates on Campaign basis at a single point of time based on the market demand. The Bulk Drug proposed will either be manufactured till the final stage of the product or up to the corresponding quantities of the intermediates based on the market demand with a total production capacity of 283.33 Kg/Day (8.5 MT/Month).
2.3 Need for the project and its importance to the country and or region:
Active Pharmaceutical Ingredients (API) or bulk drugs are the principal ingredients for finished pharmaceutical products. Intermediates are the compounds from which active pharmaceutical ingredients are prepared. APIs cannot be administered directly to the patient, and other inactive substances called excipients are added to stabilise the mixture. This end product, which includes the API and the excipient, is referred to as a formulation. Formulations are the pharmaceutical products administered to patients and can take the form of tablets, capsules, syrups, ointments, creams, injectables etc.,
The Indian pharmaceutical industry currently tops the chart amongst India s science-based industries with wide ranging capabilities in the complex field of drug manufacture and technology. A highly organized sector, the India pharmaceutical industry is estimated to be worth $ 4.5 billion, growing at about 8 to 9 percent annually. It ranks very high amongst all the third world countries, in terms of technology, quality and the vast range of medicines that are manufactured. It ranges
Page | 2 M/s. S L Pharmaceuticals from simple headache pills to sophisticated antibiotics and complex cardiac compounds, almost every type of medicine is now made in the Indian pharmaceutical industry.
The domestic market accounts for 90% of the company s total revenue and supplies its products to Leading Pharma industries of domestic and international clients.
2.4 Demands – Supply Gap:
There is a quite considerable gap between supply and demand for bulk drugs and intermediates. Very few players are in the market who can offer continuous supply. The company wants to bridge this gap between demand and supply by expanding the production capacity and thereby, making good business. Company s marketing edge comes from its direct and close contact with the customers. Their products are major strength of their customers. Each stage of their product is being monitored / checked for their quality to ensure quality product reaches their customer. They plan to launch new products every year to satisfy the need of their customers as per the market demand.
2.5 Employment Generation (Direct and Indirect) due to the project:
The Estimated employment generation for this proposed project is about Indirect -10 No s and Direct – 30 No s and the total 40 No. of Employees. Apart from this there will be significant non- estimated employment generation at the supplier firms and service industry providing services to the company. Company shall be giving preference to people from economically weaker sections for employment in various semi-skilled/ unskilled jobs there by contributing to their upliftment.
3.0 Project Description:
M/s. S L Pharmaceuticals., proposes to establish Bulk Drugs & Intermediates manufacturing Unit at Plot No. 160 in Sy. No. 93, 94, 95 & 96 of APIIC, Thirumalagiri (V), Jaggaiahpet (Municipality), Krishna District of Andhra Pradesh. The location map is shown at Figure-1.1 & 1.2
The site coordinates are
Latitude: 16o 54 40.2” N
Longitude: 80o 07 10.3” E
The site well connected to road and rail way line. No archaeological, historical sites located nearby. Therefore, the project site does not offer any negative impact on the local area as because it is located in APIIC land, but rather has a positive impact on socio economic conditions of the habitants around it. The National Highway NH-30 (Vijayawada – Mylavaram Road) is around 0.2 KM (E) and The Nearest Air Port is Vijayawada which is around 23.34 KM from the Plant.
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Figure No. 1.1: Location Map
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Figure No. 1.2 Google Earth Map Showing S L Pharmaceuticals
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4.0 About the Proposed Activity:
M/s. S L Pharmaceutical., has proposed to manufacture12 New Bulk Drugs & Intermediates on campaign basis at a single point of time based on the market demand (either Bulks or their corresponding quantities of intermediates).
The list and quantities of the proposed products are given Table 2
Table 2: List and Quantities of the Proposed Products
S.No. Name of the Product Capacity in Therapeutic Category/ Kg/Day Class 1 Lansoprazole 33.33 Anti-ulcerative 2 Losartan Potassium 33.33 Anti- hypertensive 3 Lisinopril 16.67 Anti- hypertensive 4 Levocetirizine dihydrochloride 16.67 Anti-histamine 5 Rabeprazole Sodium 33.33 Anti-ulcerative 6 Pantoprazole Sodium 33.33 Anti-ulcerative 7 Itraconazole 10.00 Anti-fungal 8 Fexofenadine Hydrochloride 33.33 Anti-histamine 9 Ciprofloxacin Hydrochloride 33.33 Anti-biotic 10 Pregabalin 6.67 Anti-convulsant 11 Domperidone 16.67 Anti-emetic 12 Esomeprazole Magnesium trihydrate 16.67 Anti-ulcerative Total 283.33
4.1 Raw material Requirement:
Bulk Drugs & Intermediate manufacturing involves the use of various chemicals and organic solvents either directly as reactant or for extraction of a product of interest from the reaction mixture. Such reactions, which are taking place under varied physical conditions like temperature and pressure lead to evaporative losses. All such losses are recovered by condensing the vapors. There would however still be some quantity of unrecovered solvents. These solvents find way out of the reactor sheds through designed vents. What do not escape could remain in the production block causing an unhealthy work-room environment. The production blocks will be provided with very efficient ventilation in order to maintain healthy workroom environment ensuring minimal
Page | 6 M/s. S L Pharmaceuticals residual solvent concentrations, which would be many times less than the threshold limits defined by OSHA.
All the Raw materials required for manufacturing of above products will be sourced from local market. The proposed products raw materials consumption details are enclosed.
4.2 Manufacturing process:
The manufacturing process of bulk drugs consists of chemical synthesis extending to stages of processing involving different type of chemical reactions. The generalized Flow Chart for bulk drug manufacturing is shown in Figure No. 2
Figure No.2: Generalized Flow Chart for Bulk Drug Manufacturing
4.3 Resource – Utilize & Recycling: 4.3.1 Water Consumption:
The total water requirement of the plant is 43.2 KLD. APIIC will provide the required quantity at the plant boundary for the construction and operation of the Proposed Plant. Water is required for Process & Washings, Utilities like Boiler, Cooling Towers, Scrubber and Domestic usage.
The water consumption details shown in below Table 3
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Table.3 Water Consumption Details
S. No. Purpose Water Consumption in KLD 1 Process 3.2 2 Washings (Reactor & Floor washings) 2.0 3 Boiler Feed 15.0 4 Cooling Towers Makeup 10.0 5 Scrubber 2.0 6 R&D/ QC 1.0 7 Domestic 5.0 8 Gardening 5.0 TOTAL 43.2
The total water requirement of the plant is 43.2 KLD, out of this 35.2 KL of Fresh water will be met form from APIIC supply and balance 8.0 KL of treated water will be recycled from MEE Condensate for Cooling towers makeup.
4.3.2 Power Requirement:
Power requirement of proposed project will be made available through APSPDCL. Total power requirement of proposed project will be 250 KVA.
The industry is proposed to install 250 KVA DG Set to meet emergency power requirement of the plant. These sets will be installed in a separate room with proper Acoustic enclosures and individual silencers so as to reduce the noise levels and proper rubber padding is also provided to curtail the vibrations.
4.3.3 Fuel Requirement:
The industry is proposed to install 2 TPH Coal fired boiler for is operated for Steam requirements of the Process, Pollution Control equipment and solvent recovery systems.
About 6.0 TPD Coal will be used as fuel at full production and about 2.4 TPD Coal Ash is generated which is sent to Brick Manufacturers. Diesel of about 50 liters/hr. will be used for 250 KVA DG Set.
4.4 Quantity of wastes to be generated: 4.4.1 Waste water generation and Utilization:
The total Effluent generation of the proposed project is 16.0 KLD. The Source of Effluent will be generated from Process & Washings, Boiler Blow down, cooling towers blow down, Scrubbers, R&D, QC and Domestic Effluent.
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Table.4 Effluent generation and Disposal Details
Effluent generation in KLD Disposal Method S.No. Purpose HTDS LTDS Total 1 Process 3.0 0.5 3.5 HTDS Effluents: 2 Washings 0.0 2.0 2.0 Stripper condensate for recovery of 3 Boiler Blow down 1.5 0.0 1.5 organic compounds will be disposal to 4 Cooling Towers Blow 0.0 2.0 2.0 cement plant. down Stripped bottom effluents to Forced 5 Scrubbers System 2.0 0.0 2.0 evaporation in MEE & ATFD. 6 R&D/ QC 0.0 1.0 1.0 Condensate from MEE & ATFD to ETP. Salts from ATFD to TSDF. RO Permeate for boiler makeup RO Reject to MEE/ ATFD. LTDS Effluents: Sent to Biological ETP. RO Permeate will be reused for Boiler makeup RO Rejects sent to MEE/ATFD. 7 Domestic 0.0 4.0 4.0 Septic Tank Followed by soak pit. Total 6.5 9.5 16.0
Table.5 Effluent Treatment Flow for as per Segregation
Effluent Characteristics Quantity Treatment Flow (KLD) Process, Boiler & Scrubber Collection » Equalization » Neutralization » Settling » HTDS/ HCOD Holding » Stream stripper » MEE along with HTDS HTDS > 5000 mg/l Effluent » Condensate to ETP (Biological Treatment) » LTDS > 5000 mg/l Condensate to ATFD.
ATFD Condensate to ETP (Biological Treatment) along 6.5 with domestic waste water (Septic tank over flow) » Pressure Sand Filter » Activated Carbon Filter » RO Treatment Plant » RO Reject to MEE.
RO Permeate & Condensate to Cooling Towers. ATFD Salts to TSDF and Stripped solvents to SPCB Authorized cement industries. Washings, Cooling Towers, Collection » Equalization » Neutralization » ETP QC / R&D LTDS/ LCOD (Biological Treatment) along with MEE condensate. 9.5 LTDS < 5000 mg/l LCOD < 5000 mg/l Domestic 4.0 Septic tank » Overflow to ETP (Biological Treatment)
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The total water requirement is about 43.2 KLD and waste water generated from the plant will be about 16.0 KLD. Out of this about 6.5 KLD will be HTDS from Process, Boiler blow down & Scrubber System and 5.5 KLD LTDS from Process, Washings, Scrubber, R&D/ QC & Cooling towers and 4.0 KLD from Domestic/ Sewage will be collected by gravity from all sources into a collection tanks (Syntex tank for 2 KL capacity for HTDS and another 2 KL capacity for LTDS with standby facility). This waste water will be pumped separately to the above ground level tank for storage and Neutralization of HTDS and LTDS effluents, then routed to “Zero Liquid Discharge” facility in the Plant Premises. All the treatment tanks will be constructed/ Installed above the ground only with water proof lining.
HTDS Effluent will be sent to MEE System with Stripper column followed by ATFD. The Condensate from MEE System & LTDS Effluents will be sent to Biological ETP. After Pretreatment effluent will be Sent to E- RO System. After RO Treatment, permeate will be reused for Cooling Towers makeup and rejection will be back to the MEE System. The MEE Salts generation from ATFD, which will be collected and sent to TSDF, Parawada for safe disposal.
HTDS concentration will be more than 5,000 mg/l TDS and Above 5,000 mg/l of COD. LTDS concentration will be < 5,000 mg/l of TDS and < 5,000 mg/l of COD.
Domestic Effluent will be sent to Septic tank followed by Soak pit.
4.4.2 Description of Waste Water Treatment System:
The Effluent management system is developed to ensure “Zero Liquid Discharge” Waste water from each production block is segregated into two streams HTDS & LTDS. The treatment system adopted by the industry consists of the following systems. a) HTDS Effluent:
The treatment system consists of Equalization cum Neutralization, settling tanks, Stripper (2 KL), Multiple Effect Evaporator (20 KL MEE), Agitated Thin Film Drier (2 KL ATFD). The Organic distillate from the stripper is sent to incinerator for the Thermal Destruction and aqueous bottom is sent to MEE followed by ATFD. Condensate from MEE and ATFD are sent to secondary RO Plant for further treatment. RO Permeate will be used for Cooling towers make up and Rejection will be sent to MEE. MEE Salts will be disposed to TSDF for further treatment and disposal.
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Figure No.3 HTDS Effluent Treatment Flow Diagram
HTDS & HCOD from HTDS = 6.5 KLD Process (6.5 KLD)
COLLECTION Steam Condenser
EQUALIZATION & Stripper Column Organic distillate NEUTRALIZATION (2 KL) to Incinerator
6.5 + 7.5 (RO Reject) = 14.0
MULFIPLE EFFECT EVAPORATOR (20 KL) 6.0 KLD
Recycle Water CONDENSATE Collection Sump (90%) ATFD (2 KL)
ETP (20 KL) Sludge to (Biological Treatment) TSDF 6.0 + 9.5 (LTDS) = 15.5 KLD b) LTDS Effluent:
The LTDS Effluent will be generated from Process washings, Floor washing, cooling towers blow down are subjected to Biological treatment (20 KL) followed by Reverse Osmosis System (10 KL). RO Permeate will be used for Cooling towers and Boiler. RO Rejects are subjected to MEE. c) Primary Treatment:
The Effluents are sent to Equalization Tanks for dilution of Process Effluent for better treatment. The Effluent is thoroughly mixed with the help of Air (Aeration) to get a constant composition of
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Effluent. The Effluent pH is checked for Acidic (or) Basic media to Neutralized with C.S Lye (or) Hydrochloric Acid to Adjust pH of 7.0 to 7.5
The Neutralized effluent is pumped to primary setting tank where settled solids are removed. The clarified effluent is sent to secondary treatment and settled sludge from primary settling tank is sent to sludge drying beds/decanter centrifuge to collect the dry sludge for disposal to TSDF. d) Secondary Treatment: The secondary treatment is a biological activated sludge process. A two-stage activated sludge process is adopted.
Stage-1 The clarified effluent water after primary treatment is introduced into aeration tank where aerobic bacterial culture is maintained in suspension and also referred as mixed liquor suspended solids (MLSS). The aerobic environment in the reactor is achieved by the use of mechanical surface aerators and Praxair pure oxygen mix flow-v system. Which is also, serves the reactor contents in a completely mixed regime with proper D.O. Level. The Effluent from the aeration tank is passed into a primary clarifier where the activated sludge is separated from the treated waste water. A portion of the settled activated of MLSS and MLVSS in aeration tank. The overflow from the clarifier is sending to second stage of activated sludge process called oxidation ditches.
Stage-2 There are three oxidation ditches with surface aerator operated in series and connected an in Aeration tank. The treatment process involved in the ditches is as same in aeration tank. The overflow from the ditches is connected to the secondary clarifier and collected in treated effluent collection sump. e) Tertiary Treatment: The treated effluent collected from activated sludge process is sent to primary RO Plant of capacity 40KL and 55-45% of water is recovered and collected in recycle water sump. Reject water from primary R.O. Plant are sent to MEE, treated effluent from recycle water sump is further purified in secondary R.O Plant to recover 75-85% pure and hardness free water used for boiler feed along with return steam condensate water. Some part of the recycle water is used for cooling towers make up and general purpose. The details of existing facilities are presented below.
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Figure No.5 LTDS Effluent Treatment Flow Diagram
LTDS EFFLUENT (9.5 KLD) LTDS = 9.5 KLD
COLLECTION Primary Settling Aeration Tank Tank
Oil & Grease Trap Primary Clarifier
EQUALIZATION & NEUTRALIZATION Chlorination
Sludge ETP Secondary Clarifier (20 KL) drying beds
9.5 (LTDS) + 6.0 (Condensate) = 15.5 KLD Sand Filter & Carbon Filter
9.5 + 6.0 = 15.5 KLD RO PLANT Permeate (10 KL) (50%) 7.5 KLD CT Make up 8.0 KLD Rejection (50%) MEE
4.5 Solid Waste Generation:
Solid waste is generated from Process where Organic solid waste and isolated Inorganic salts are produced; Pollution control facilities like Neutralization tanks where sludge will be generated; Stores where waste paper, cartons, wooden crates, plastic bags etc., are generated. The Organic residue from the process will be sent to TSDF for incineration. Inorganic salts, sludge from Neutralization tanks will be collected and disposed-off to TSDF for secured land fill. Wastes from stores will be segregated and disposed-off to the authorized agents as scrap.
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4.5.1 Process: a) Process residues mainly consists of organic residues which are collected and stored for disposal to TSDF / Authorized Parties for Incineration / Recovery
b) Inorganic solid wastes from process are disposed-off to TSDF after isolating and drying it. These salts are collected in bags and stored on a dedicated raised platform under a shed prior to disposal to TSDF.
Table 6: Solid Waste generation from the Plant and Method of Disposal S.No. Description Quantity Method of Disposal 1 Organic Solid Waste 121.17 Kg/Day Sent to TSDF/Cement Industries 2 MEE Salts 197.07 Kg/Day Sent to TSDF 3 Inorganic Solid Waste 13.33 Kg/Day Sent to TSDF/Cement Industries 4 Spent Carbon 9.3 Kg/Day Sent to TSDF/Cement Industries 5 ETP Sludge 50.0 Kg/Day Sent to TSDF
Solid waste will be segregated, detoxified and collected in HDPE Drums/ Bags and will be stored in the Covered and raised Platform with Leachete collection System.
4.5.2 Stores
a) The solid waste generated in the form of empty drums, containers/liners, HDPE liners etc., will be disposed-off to the Authorized parties identified by APPCB.
b) Other paper waste will be disposed-off to scrap venders.
c) Metal scrap disposed-off to the scrap vendors.
4.5.3 Other Hazardous By-products / wastes
Table 7: Hazardous by – Products / Waste generation from the Plant
S. No Description Quantity Mode of Disposal 1 Waste Oils & Grease 100 LPM APPCB Authorized Agencies for Reprocessing/Recycling 2 Detoxified Containers & 200 No s/Month After Detoxification sent back to Container Liners suppliers/APPCB Authorized Parties 3 Used Lead Acid Batteries 2 No s/Annum Send back to suppliers for buyback of New Batteries 4 Spent Solvents 5 KL/Month Recycle within the Premises 5 Coal Ash 2.4 TPD Disposed to Brick Manufacturers
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Container & Container liners will be detoxified at the specified covered platform with dyke walls and the wash waste water is routed to LTDS collection tank. 4.6 Gaseous Emissions
4.6.1 Process Emissions
Manufacturing of Bulk Drugs could result in gaseous emissions. Proposed gaseous emissions, quantity and handling methods are given in following tables.
Table 8: Process Emission Details
S.No. Name of the Gas Quantity Disposal Method Kg/Day 1 Hydrogen chloride 2.5 Scrubbed by using chilled water/ Caustic lye solution 2 Sulfur dioxide 2.0 Scrubbed by using Caustic Lye Solution 3 Carbon dioxide 8.5 Dispersed into Atmosphere 4 Hydrogen 1.3 Diffused with flame arrestor Total 14.3
Table 9: Scrubber System Details All the scrubbers are 2 stages Scrubbers.
Evacuation Capacity 750 M3/Hr at Room Temperature Acid Fume Capacity 25 Kg/Hr Scrubbing Media Caustic Solution/Chilled water MOC PP + FRP, Body made of 3mm PP and 5mm FRP Packing s 12mm Honeycomb Packing s in PVC Operating Temperature Less than 350C Blower Capacity 750 M3/Hr,2HP Motor
The Industry has been provided 1 No s of two stage scrubbers & 1 No s of Single Stage Scrubber to the process vents and control the process emissions.
4.6.2 Boiler The industry proposed to install 1 No. of Coal fired Boiler of Capacity 2.0 TPH is operated for Steam requirements of the Process, Pollution Control equipment and solvent recovery systems. The Coal fired boiler will be attached with Cyclone Separator with Bag Filter to Control the SPM
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Emissions. Stack height 30 Mtrs has been provided to disperse the emissions in the form of SPM, SO2 and NOx. The emissions are regularly analyzed on monthly basis by recognized laboratories.
About 6.0 TPD Coal will be used as fuel at full production and about 2.4 TPD Coal Ash is generated which is sent to Brick Manufacturers.
Fugitive dust will be controlled by adopting dust extraction and dust suppression measures and development of green belt along the periphery of the proposed Boiler area.
Table 10: Stack Emission Details of Boiler
Units 2.0 TPH Coal Fired Particulars Boiler Type of Fuel -- Indian Coal Coal Consumption TPD 6.0 Ash Content % 40 Sulphur Content % 0.8 Nitrogen Content % 1.07 No. of Stacks No 1 Height of the Stack m 30 Diameter of Stack M 0.60 Temperature of Flue Gas oC 110 Velocity of Flue Gas m/s 8.5 Particulate Matter at outlet of Bag filter gm/sec 0.27 (Based on 115 mg/Nm3 at outlet) Sulphur dioxide emission gm/sec 1.15 Oxides of Nitrogen emission gm/sec 1.54
4.6.3 D.G. Set The industry proposes to install 1 Nos of Silent D.G. Sets with capacities of 250 KVA. These D.G. Sets will be installed to provide standby Power Supply in case of failure of supply by A.P.C.P.D.C through APIIC. These sets will be installed in a separate room with proper Acoustic enclosures and individual silencers so as to reduce the noise levels and proper rubber padding is also provided to curtail the vibrations. About 50 Ltrs/hr. of Diesel will be used for the two D.G. Sets.
The Emissions from the D.G Set are very nominal as it is operated on an average only for 3 to 4 hours a day.
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Table 11: Stack Emission Details of D.G. Set
Capacity Emission Emission Emission Stack Flue Gas Stack Flue gas
In KVA of SPM, in Of SO2 in of NOx dia. Temp. in Height Velocity Mg/Nm3 Mg/Nm3 in In m OC in (m) In m/sec. Mg/Nm3
250 KVA 70.0 135.0 160.0 0.30 220 10 12.5
4.6.4 Fugitive Emissions The Solvents will be transferred in a closed system. Solvent recovery facility like distillation column will be provided for efficient recovery above 95 % Purity. The evaporation losses in solvents will be control by various measures like.
a) Chilled Water/Brine circulation will be carried out to effectively reduce the solvent losses into the atmosphere. b) Transfer of solvents using pumps instead of manual handling. c) Vent condensers to the storage tanks etc., d) Closed centrifuges will be used due to which solvent losses will be reduced drastically. e) Installation of secondary condensers will further reduce the solvent losses during operations. f) The height of the solvent receiver tank vent is above production block roof level and the diameter is 20mm. The maximum solvent loss is 3-7% depending on the boiling point of the solvent.
4.7 Noise Levels
The main source of noise is D.G Set. These D.G Sets are silent powers and installed in a separate room with silencers and acoustic enclosures for reduction of the Noise levels. The operator will be provided with ear plugs. Proper rubber padding will be provided to avoid vibrations.
5.0 Storage and Handling of Hazardous Raw materials
Details of Storage and Handling of Hazardous Raw materials will be as per the safety guideline and MSDS.
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6.0 General Safety Measures a) All the personnel at the plant will be made aware about the manufacturing process and details of the products, their proximity of its exposure and risks associated with them b) Personnel engaged in handling of hazardous chemicals will be trained to respond in an unlikely event of emergency c) Safe work practices will be developed to provide for the control of hazardous during operation and maintenance d) Firefighting facilities will be provided at the plant, including dry chemical powder type, water CO2 type, mechanical foam type, CO2 type of fire extinguishers and sand bucket. Personnel will be trained to combat the fire in various hazardous chemicals e) The Firefighting system and equipment will be tested and maintained as per relevant standards f) The required PPE s for each area/ operation should be identified and the necessary PPE s like Helmets, Goggles, Hand gloves, Mask, PVC Suit, Self-containing Breathing apparatus, safety belts, ear muff and plug etc., will be provided to the personnel. 6.1 Safety Precautions a) The unit will provide special precautions for storage and handling of Chemicals within the premises b) Acid storage tanks will be placed into the separate storage area within the premises with all sign boards stating the proximity of danger to the personnel c) The proper collection system will be provided for the leakage and spillage collection of both the acids by preparing dyke wall and acid proof RRC Flooring with spillage collection tank and will be transferred to the emergency storage tank. d) Proper vent will be provided to each storage tank. Moreover, weather shed and water sprinkling system will be provided. 7.0 Site Analysis: 7.1 Connectivity: M/s. S L Pharmaceuticals., is having well developed roads and Railway connections for transpiration of raw materials and finished products. The nearest habitation from the site is Kattubadipalem at a distance of 1.19 KM-NE The nearest railway station is Kondapalli Railway station at a distance of 2.2 KMs- SSW from the site. The nearest Airport is Vijayawada Airport at a distance of 28.4 KMs – SE at Gannavaram. The nearest road ways National Highway No. 30 (Vijayawada – Mylavaram Road) - 0.2 KM – E
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7.2 Land from, Land use and Land ownership:
M/s. S L Pharmaceuticals., proposes to establish Bulk Drugs & Intermediates manufacturing Unit at Plot No. 160 in Sy. No. 23, 24, 93 & 96 of APIIC, Tirumalagiri (V), Jaggayyapet (Municipality), Krishna District of Andhra Pradesh with an area of 1313.3 SMT.
7.3 Soil classification:
The district is mainly covered by three types of Red loamy soils, Sandy soils, Black soils.
7.4 Climate data from secondary sources:
Annual Temperature Maximum: 38oC
Annual Temperature Minimum: 20oC
Normal Annual Rainfall: 1011 mm
7.5 Social Infrastructure Available:
Well developed social infrastructure facilities are available at nearby Habitations.
8.0 Planning Brief:
The proposed activities will be started after getting statutory clearance from related departments. The project will be completed within two years. Further proposed project activities will take care of all the rules and regulation of statutory authority and provide the control measure and devices to achieve the standard norms.
9.0 Greenbelt Development 9.1 Objective The purpose of a green belt around the plant site is to capture the fugitive emissions, attenuate the noise generated and improve the aesthetics. Table 12: Break up of Plant Area
S. No. Description Area in SMT
1 Buildup Area 537.0 2 Open Area & Roads / Parking Area 228.3 3 ETP & MEE System 75.0 4 Green Belt (33.52%) 473.0 Total 1313.3
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The proposed green belt at the project site will form a barrier between the plant and the surroundings. Open spaces, where tree plantation may not be possible, will be covered with shrubs and grass to prevent erosion of topsoil. Adequate attention has been paid to plantation of trees, their maintenance and protection.
9.2 Plant Species for Green Belt A wide range of plant species will be planted in and around the premises to help capture the fugitive emissions and noise levels from the plant premises. This wide range covers plants of Fast growing type
With thick canopy cover Perennial green nature Native origin A large leaf area index
A specialist in horticulture may be appointed to identify any other native species and also supervise greenbelt development.
9.3 Design of Green Belt As far as possible the following guidelines will be considered in proposed green belt development. Shrubs and trees will be planted in encircling rows around the project site.
The short trees (< 10m height) will be planted in the first two rows (towards plant side) of the green belt. The tall trees (>10m height) will be planted in the outer three rows (away from plant side).
Planting of trees in each row will be in staggered orientation. In the front row, shrubs consisting of Callistemon, Procopius etc. will be grown. Since the trunks of the tall trees are generally devoid of foliage, it will be useful to have shrubs in front of the trees so as to give coverage to this portion. The spacing between the trees will be maintained slightly less than the normal spaces, so that the trees may grow vertically and slightly increase the effective height of the green belt. 10.0 Public Relations: M/s. S L Pharmaceuticals., will maintain very good Public Relations with one and all and will continue to do so in future.
11.0 Handling of Raw materials and Finished materials The Industry is proposed to store the raw materials (maximum fifteen days storage capacity). These raw materials and finished goods will be stored in the ware house as per safety norms.
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12.0 Hazardous Chemicals, waste and Risk Assessment
Bulk Drugs & Intermediates manufacturing industry has to handle many such chemicals that are hazardous in nature. Once these chemicals are used for some reactions, some hazardous wastes are generated. The Industry will provide special training to the workers handling hazardous chemicals / Wastes. The industry will engage safety consultants to prepare a risk assessment and suggest safe handling and safe storage of Hazardous waste for the proposed project. Only highly trained personal protective equipment s will be allowed to handle such chemicals or waste under strict super vision
10.0 Recycle / Reuse
All efforts will be made by the industry to carryout R&D on the isolated by-products / wastes to recycle / reuse wherever possible. However, R&D is a continuous process, where improvements in the processes adopted by the industry, waste minimization etc. can be worked out as the project progresses.
11.0 Post Project Monitoring a) Air Environment:
Schemes for monitoring stack and ambient air quality shall be adopted. The ambient air quality monitoring the ground level concentrations and fugitive emissions as per CPCB/APPCB guidelines. Regular monitoring of ground level concentrations of SPM, RPM, SO2, and NOx will be carried out. b) Noise Environment: Monitoring of the noise levels and exposure is essential to assess the effectiveness of Environmental Management Plan implemented to reduce noise levels. Audiometric tests should be conducted periodically for the employees working close to the high noise sources c) Water Environment:
Daily analysis of Effluent of waste water treatment plant is recommended. Sampling and analysis of waste water from individual treatment unit for relevant parameters depending on type of treatment facility provided be carried out once a week. Methods of sample collection and preservation should be as per prescribed methods of APPCB, CPCB and Mo EF.
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12.0 Conclusion
M/s. SL Pharmaceuticals., has proposes to manufacture 12 New Products along with their intermediates on Campaign basis at a single point of time based on the market demand. The Bulk Drug proposed will either be manufactured till the final stage of the product or up to the corresponding quantities of the intermediates based on the market demand with a total production capacity of 283.33 Kg/Day (8.5 MT/Month).
The Industry will be fully equipped with all the pollution control facilities to handle the pollution load generated due to its proposed operations. As per the requirement the industry will also provide the ETP- “Zero Liquid Discharge “facility with primary (equalization and neutralization) , secondary (Stripper with MEE, ATFD & Biological Treatment) and Tertiary treatment (RO System) for treating its Low TDS effluent and HTDS effluents for further treatment and permeate will be reused. The industry has been entered agreement with TSDF for disposal of Solid waste. The Coal fired boiler will be equipped with Cyclone separator followed by Bag Filters and a Stack of 30 m height. D.G. Sets will be attached with acoustic enclosures and install in a separate room for controlling the noise levels.
In view of the above, it is requested to kindly issue the (TOR) Terms of Reference for manufacturing new Bulk Drugs and Intermediates Unit.
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M/s. S L Pharmaceuticals Annexure-V
LIST OF PRODUCTS
S.No. Name of the Product Capacity in Kg/Day 1 Lansoprazole 33.33 2 Losartan Potassium 33.33 3 Lisinopril 16.67 4 Levocetirizine dihydrochloride 16.67 5 Rabeprazole Sodium 33.33 6 Pantoprazole Sodium 33.33 7 Itraconazole 10.00 8 Fexofenadine Hydrochloride 33.33 9 Ciprofloxacin 33.33 10 Pregabalin 6.67 11 Domperidone 16.67 12 Esomeprazole Magnesium trihydrate 16.67 Total 283.33
Total proposed production capacity is 283.33 Kg/Day i.e., 8.5 MT/Month
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M/s. S L Pharmaceuticals Annexure-VI
PRODUCT: LANSOPRAZOLE LIST OF RAW MATERIALS
Consumption of Consumption of Raw Material/ Raw Material/ S.No. Name of the Raw Material Batch Day 2-(Chloromethyl)-3-methyl-4-trifluoro 90.0 30.0 1 ethoxy pyridine 2 1H-benzo[d]imidazole-2-thiol 60.0 20.0 3 Sodium hydroxide 30.0 10.0 4 MDC 920.0 306.7 5 Hexane 500.0 166.7 6 Sodium hypochlorite solution 250.0 83.3
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PRODUCT: LOSARTAN POTASSIUM LIST OF RAW MATERIALS
Consumption of Consumption of Raw Material/ Raw Material/ S.No. Name of the Raw Material Batch Day 1 Tolyl Benzonitrile 120.0 20.0 2 n-Bromo Succinimide 111.0 18.5 3 Toluene 2300.0 383.3 2-n-Butyl-4-chloro-5-hydroxymethyl 112.0 18.7 4 imidazole 5 Sodium hydroxide 60.0 10.0 6 Methanol 1300.0 216.7 7 Sodium Azide 50.0 8.3 8 Hydrochloric Acid (30%) 124.0 20.7 9 Potassium Hydroxide 28.0 4.7 10 Acetic Acid 6.0 1.0 11 Acetone 700.0 116.7 12 Activated Carbon 16.0 2.7
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PRODUCT: LISINOPRIL LIST OF RAW MATERIALS
Consumption of Consumption of Raw Material/ Raw Material/ S.No. Name of the Raw Material Batch Day N-(2,6-Diamino-hexanoyl)-pyrrolidine- 50.0 8.3 1 2-carboxylic acid 2 2-Oxo-4-Phenyl Butyric acid 70.0 11.7 3 5% Palladium Carbon 12.0 2.0 4 Hydrogen gas 2.0 0.3 5 Sodium hydroxide 30.0 5.0 6 Methanol 500.0 83.3
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PRODUCT: LEVOCETRIZINE DIHYDROCHLORIDE LIST OF RAW MATERIALS
Consumption of Consumption of Raw Material/ Raw Material/ S.No. Name of the Raw Material Batch Day 1-[(4-Chlorophenyl) phenylmethyl] 45.0 7.5 1 piperazine 2 Toluene 1000.0 166.7 3 2-Chloroethanol 23.0 3.8 4 Triethyl amine 25.0 4.2 5 Sodium Carbonate 12.0 2.0 6 Sodium-2-chloro acetate 35.0 5.8 7 Potassium Hydroxide 25.0 4.2 8 Dimethylformamide 150.0 25.0 9 Hydrochloric Acid (35%) 20.0 3.3 11 Acetone 300.0 50.0 12 Hydrogen chloride gas 10.0 1.7 13 Activated Carbon 5.0 0.8
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PRODUCT: RABEPRAZOLE SODIUM LIST OF RAW MATERIALS
Consumption of Consumption of Raw Material/ Raw Material/ S.No. Name of the Raw Material Batch Day 2-(Chloromethyl)-4-(3- 80.0 26.7 1 methoxypropoxy)-3-methylpyridine 2 1H-benzo[d]imidazole-2-thiol 53.0 17.7 3 Sodium hydroxide 36.0 12.0 4 MDC 500.0 166.7 5 Hexane 400.0 133.3 6 Sodium hypochlorite solution 100.0 33.3 7 Methanol 180.0 60.0
Page | 32 M/s. S L Pharmaceuticals Annexure-VI
PRODUCT: PANTOPRAZOLE SODIUM LIST OF RAW MATERIALS
Consumption of Consumption of Raw Material/ Raw Material/ S.No. Name of the Raw Material Batch Day 1 2-(Chlormethyl)-3,4-dimethoxy pyridine 70.0 23.3 5-(difluoromethoxy)-1H-benzimidazole- 80.0 26.7 2 2-thiol 3 Sodium hydroxide 39.0 13.0 4 MDC 900.0 300.0 5 Sodium hypochlorite solution 100.0 33.3 6 Ammonium sulphate 30.0 10.0 7 Acetone 200.0 66.7 8 Sodium Thiosulphate 12.0 4.0
Page | 33 M/s. S L Pharmaceuticals Annexure-VI
PRODUCT: ITRACONAZOLE LIST OF RAW MATERIALS
Consumption of Consumption of Raw Material/ Raw Material/ S.No. Name of the Raw Material Batch Day 2-sec-Butyl-4-{4-[4-(4-hydroxy-phenyl)- piperazin-1-yl]-phenyl}-2,4-dihydro- 94.5 6.3 1 [1,2,4] triazol-3-one (IT-VII) Cis-2- [(2, 4 – dichlorophenyl)-2 - (1H- 1,2,4 Triazole -1-yl Methyl) 1,3 99.0 6.6 Dioxalane -4- yl] -methyl -methane 2 sulphonate (IT-IX) 3 Dimethyl formamide 800.0 53.3 4 Methanol 900.0 60.0 5 Potassium hydroxide 15.0 1.0 6 Activated carbon 12.0 0.8
Page | 34 M/s. S L Pharmaceuticals Annexure-VI
PRODUCT: FEXOFENADINE HYDROCHLORIDE LIST OF RAW MATERIALS
Consumption of Consumption of Raw Material/ Raw Material/ S.No. Name of the Raw Material Batch Day Methyl 2-[4-(4-chlorobutanoyl) 128.5 21.4 1 phenyl]-2-methylpropanoate 2 Sodium bicarbonate 38.2 6.4 3 Azacyclonol 121.5 20.3 4 Methyl Isobutyl Ketone 64.0 10.7 5 Ethyl Acetate 1500.0 250.0 6 Sodium Borohydride 15.5 2.6 7 Sodium hydroxide 16.3 2.7 8 Acetic Acid 49.2 8.2 9 Activated Carbon 20.0 3.3 10 Methanol 1714.0 285.7 11 Hydrochloric Acid 14.8 2.5 12 Isopropyl Alcohol 1715.0 285.8
Page | 35 M/s. S L Pharmaceuticals Annexure-VI
PRODUCT: CIPROFLOXACIN HYDROCHLORIDE LIST OF RAW MATERIALS
Consumption of Consumption of Raw Material/ Raw Material/ S.No. Name of the Raw Material Batch Day 1 Q Acid 94.0 31.3 2 Piperazine 65.5 21.8 3 Hydrochloric Acid (35%) 10.0 3.3 4 Acetic Acid 21.5 7.2 5 Ammonium Hydroxide (25%) 50.0 16.7 6 Activated Carbon 4.0 1.3 7 EDTA 1.0 0.3 8 Hyflow 1.0 0.3 9 Methanol 476.0 158.7 10 Hydrochloric Acid 36.0 12.0
Page | 36 M/s. S L Pharmaceuticals Annexure-VI
PRODUCT: PREGABALIN LIST OF RAW MATERIALS
Consumption of Consumption of Raw Material/ Raw Material/ S.No. Name of the Raw Material Batch Day 1 Isovaleraldehyde 98.0 13.1 2 Diethyl Malonate 185.0 24.7 3 Acetic Acid 125.0 16.7 4 n-Hexane 555.0 74.0 5 Potassium Cyanide 63.0 8.4 6 Ethanol 225.0 30.0 7 Methanol 220.0 29.3 8 Potassium Hydroxide 55.0 7.3 9 Raney Nickel 30.0 4.0 10 Isopropyl Alcohol 1870.0 249.3 11 Hydrogen gas 5.0 0.7 12 (S)-Mandelic Acid 120.0 16.0 13 Tetrahydrofuran 900.0 120.0
Page | 37 M/s. S L Pharmaceuticals Annexure-VI
PRODUCT: DOMPERIDONE LIST OF RAW MATERIALS
Consumption of Consumption of Raw Material/ Raw Material/ S.No. Name of the Raw Material Batch Day 1-(3-(4-(4-chloro-2-nitrophenylamino) piperidin-1-yl) propyl)-1H- 140.0 23.3 1 benzo[d]imidazol-2(3H)-one 2 Methanol 870.0 145.0 3 Raney nickel 15.0 2.5 4 Hydrogen gas 3.5 0.6 5 Diethyl carbonate 40.0 6.7
Page | 38 M/s. S L Pharmaceuticals Annexure-VI
PRODUCT: ESOMEPRAZOLE MAGNESIUM TRIHYDRATE LIST OF RAW MATERIALS
Consumption of Consumption of Raw Material/ Raw Material/ S.No. Name of the Raw Material Batch Day 5-Methoxy-2-[[(3, 5-dimethyl-4-methoxy pyridine -2-yl) methyl] thio]-1H- 319.0 21.3 1 benzimidazole (Omeprazole sulphide) 2 Toluene 2597.0 173.1 3 Diethyl tartrate 200.0 13.3 4 Titaniumisopropoxide 17.0 1.1 5 Diisopropyl ethylamine (DIPEA) 18.0 1.2 6 Cumene hydroperoxide 150.0 10.0 7 Potassium hydroxide 163.0 10.9 8 Sodium sulphate 50.0 3.3 9 Methanol 1283.0 85.5 10 MDC 875.0 58.3 11 Acetic Acid 51.0 3.4 12 Magnesium chloride 87.0 5.8
Page | 39
M/s. S L Pharmaceuticals Annexure-VII
LANSOPRAZOLE
Process Description:
Stage-I:
2-(Chloromethyl)-3-methyl-4-trifluoro ethoxy pyridine reacts with 1H-benzo[d] imidazole-2-thiol in the presence of Sodium hydroxide in Methylene dichloride, Hexane and water solvent media to get 2-((3-methyl-4-(2,2,2-trifluoroethoxy) pyridine-2-yl) methylthio)-1H-benzo[d]imidazole.
Stage-II:
2-((3-methyl-4-(2,2,2-trifluoroethoxy) pyridine-2-yl) methylthio)-1H-benzo[d]imidazole reacts with Sodium hypochlorite solution in the presence of Methylene dichloride and Hexane solvent media to obtain Lansoprazole.
Page | 40 M/s. S L Pharmaceuticals Annexure-VII
LANSOPRAZOLE
Route of Synthesis:
Stage-I
F F O H Cl N F + HS + NaOH N N
2-(Chloromethyl)-3-methyl-4-trifluoro 1H-benzo[d] imidazole-2-thiol Sodium hydroxide ethoxy pyridine C7H6N2S 40.0 C9H9ClF3NO Mol. Wt.: 150.20 Mol. Wt.: 239.62
MDC, Hexane
F HN F O N S F NaCl + + H2O N
2-((3-methyl-4-(2,2,2-trifluoroethoxy) pyridine-2-yl) methylthio) Sodium chloride Water -1H-benzo[d]imidazole
58.44 18.02 C16H14F3N3OS Mol. Wt.: 353.36
Page | 41 M/s. S L Pharmaceuticals Annexure-VII
Stage-II
F HN F O N S MDC F + NaOCl N Hexane
2-((3-methyl-4-(2,2,2-trifluoroethoxy) pyridine-2-yl) methylthio)-1H- Sodium hypochlorite benzo[d]imidazole 74.44 C16H14F3N3OS Mol. Wt.: 353.36
F HN F O N S F + NaCl N O
Sodium chloride Lansoprazole
C16H14F3N3O2S 58.44 Mol. Wt.: 369.36
Page | 42 M/s. S L Pharmaceuticals Annexure-VII
LANSOPRAZOLE
Flow Chart:
2-(Chloromethyl)-3-methyl -4-trifluoro ethoxy pyridine Solvent Recovery 1H-benzo[d]imidazole- Evaporation Loss 2-thiol Stage-I Effluent Sodium hydroxide Organic Residue MDC Hexane Water
Stage-I Solvent Recovery Sodium hypochlorite Evaporation Loss Stage-II solution Effluent MDC Organic Residue Hexane Water
Lansoprazole
Page | 43 M/s. S L Pharmaceuticals Annexure-VII
LANSOPRAZOLE
Material balance Material balance of Lansoprazole Stage-I Batch Size: 100.0 Kg Name of the input Quantity Name of the out put Quantity In Kg In Kg 2-(Chloromethyl)-3-methyl-4- 90.0 Stage-I 120.0 trifluoro ethoxy pyridine 1H-benzo[d]imidazole-2-thiol 60.0 Recovery Sodium hydroxide 30.0 MDC Recovery 470.0 MDC 500.0 MDC Loss 27.0 Hexane 300.0 Hexane Recovery 280.0 Water 420.0 Hexane Loss 18.0 Effluent 469.3 (Water-420, gen. water-6.8, Sodium chloride-21.9, Sodium hydroxide-15, Hexane-2, Organic compound-3.6) Organic Residue 15.7 (Unreacted Organic impurities- 12.7, MDC-3) Total 1400.0 Total 1400.0
Material balance of Lansoprazole Stage-II Batch Size: 100.0 Kg Name of the input Quantity Name of the out put Quantity In Kg In Kg Stage-I 120.0 Lansoprazole 100.0 Sodium hypochlorite solution 250.0 Recovery MDC 420.0 MDC Recovery 386.0 Hexane 200.0 MDC Loss 32.0 Water 300.0 Hexane Recovery 184.0 Hexane Loss 14.0 Effluent 546.6 (Water-300, water from Sodium hypochlorite-220, Sodium chloride-19.6, Sodium hypochlorite-5, Hexane-2) Organic Residue 27.4 (Unreacted organic impurities- 25.4, MDC-2) Total 1290.0 Total 1290.0
Page | 44 M/s. S L Pharmaceuticals Annexure-VII
LOSARTAN POTASSIUM
Process Description:
Stage-I: Tolyl Benzonitrile is reacted with n-Bromo Succinimide in Toluene to produce Stage-I (Bromo) Compound. Stage-II: Stage-I Compound is reacted with imidazole derivative in the presence of Sodium Hydroxide in Methanol solvent media to get imidazole compound. Stage-III: Stage-III Compound is reacted with Sodium Azide and Hydrochloric Acid in Toluene and Methanol to get Losartan Base as a Stage-III compound. Stage-IV: Losartan Base is treated with Potassium Hydroxide in the presence of Methanol, Toluene and Acetone solvent media to get Losartan Potassium.
Page | 45 M/s. S L Pharmaceuticals Annexure-VII
LOSARTAN POTASSIUM
Route of Synthesis:
Stage-I: Br
O O
+ H N + Br N CN CN
O O
Tolyl Benzonitrile N-Bromo Succinimide Stage-I (Bromo Compound) Succinimide C H N C H NO 14 11 C4H4BrNO2 C14H10BrN 4 5 2 Mol. Wt.: 193.24 Mol. Wt.: 177.98 Mol. Wt.: 272.14 Mol. Wt.: 99.09
Page | 46 M/s. S L Pharmaceuticals Annexure-VII
Stage-II:
Br
Cl
N + NaOH CN + N H OH
Stage-I (Bromo Compound) 2-n-Butyl-4-chloro-5-hydroxymethyl imidazole Sodium hydroxide
C H BrN 14 10 C8H13ClN2O HNaO Mol. Wt.: 272.14 Mol. Wt.: 188.65 Mol. Wt.: 40.0 Cl
N
N OH
CN
+ NaBr + H2O
4'-(2-Butyl-4-chloro-5-hydroxymethyl-imidazol-1-ylmethyl)- Sodium Bromide Water biphenyl-2-carbonitrile 102.89 18.02 C22H22ClN3O Mol. Wt.: 379.88
Page | 47 M/s. S L Pharmaceuticals Annexure-VII
Stage-III:
Cl
N
N OH
CN + NaN3 + HCl
4'-(2-Butyl-4-chloro-5-hydroxymethyl-imidazol-1- Sodium Azide Hydrochloric Acid ylmethyl)-biphenyl-2-carbonitrile 65.01 36.46 C22H22ClN3O Mol. Wt.: 379.88
Cl
N
N N NH OH N N
+ NaCl
Sodium Chloride LOSARTAN BASE 58.44 C22H23ClN6O Mol. Wt.: 422.91
Page | 48 M/s. S L Pharmaceuticals Annexure-VII
Stage-IV:
Cl
N
N N NH OH N N
+ KOH
Potassium Hydroxide LOSARTAN BASE HKO C22H23ClN6O Mol. Wt.: 422.91 Mol. Wt.: 56.11
Cl
N K+ - N N N OH N N
+ H2O
LOSARTAN POTASSIUM Water
C22H22ClKN6O 18.02 Mol. Wt.: 461.00
Page | 49 M/s. S L Pharmaceuticals Annexure-VII
LOSARTAN POTASSIUM
Flow Chart:
Tolyl Benzonitrile Succinimide Toluene Recovery n-Bromo Succinimide Stage-I Toluene Evaporation Loss Organic Residue
Stage-I 2-n-Butyl-4-chloro-5-hydroxy Methanol Recovery methyl imidazole Stage-II Evaporation Loss Sodium hydroxide Effluent Methanol Organic Residue DM Water
Stage-II Sodium Azide Toluene Recovery Hydrochloric Acid (30%) Methanol Recovery Toluene Stage-III Evaporation Loss Methanol Effluent Sodium Hydroxide Organic Residue DM Water
Losartan Base Potassium Hydroxide Methanol Sol.Recovery Sodium Hydroxide Evaporation Loss Acetic Acid Stage-IV Effluent Toluene Organic Residue Acetone Spent Carbon Activated Carbon DM Water
Losartan Potassium
Page | 50 M/s. S L Pharmaceuticals Annexure-VII
LOSARTAN POTASSIUM
Material Balance:
Material balance of Losartan Potassium Stage-I Batch Size: 200.0Kg Name of the input Quantity Name of the out put Quantity In Kg In Kg Tolyl Benzonitrile 120.0 Stage-I 160.0 n-Bromo Succinimide 111.0 Toluene Recovery 470.0 Toluene 500.0 Toluene Loss 25.0 Organic Residue 76.0 (Unreacted Organic impurities- 9.4, Toluene-5, Succinimide-61.6) Total Input 731.0 Total Output 731.0
Material balance of Losartan Potassium Stage-II Batch Size: 200.0Kg Name of the input Quantity Name of the out put Quantity In Kg In Kg Stage-I 160.0 Stage-II 200.0 2-n-Butyl-4-chloro-5- 112.0 Methanol Recovery 554.0 hydroxymethyl imidazole Sodium hydroxide 40.0 Methanol Loss 30.0 Methanol 600.0 Effluent 897.6 DM Water 800.0 (Water-800, gen. water-10.6, Sodium Bromide-60.6, Sodium hydroxide-16.4, Methanol-10) Organic Residue 30.4 (Organic impurities-24.4, Methanol-6) Total Input 1712.0 Total Output 1712.0
Page | 51 M/s. S L Pharmaceuticals Annexure-VII
Material balance of Losartan Potassium Stage-III Batch Size: 200.0Kg Name of the input Quantity Name of the out put Quantity In Kg In Kg Stage-II 200.0 Losartan Base 200.0 Sodium Azide 50.0 Toluene Recovery 752.0 Hydrochloric Acid (30%) 124.0 Toluene Loss 32.0 Toluene 800.0 Methanol Recovery 186.0 Methanol 200.0 Methanol Loss 10.0 Sodium Hydroxide 10.0 Effluent 865.4 DM Water 700.0 (Water-700, gen. water-4.4, Sodium chloride-59.8, Methanol- 4, Hydrochloric Acid-10.4, Water from Hydrochloric Acid-86.8) Organic Residue 38.6 (Organic impurities-22.6, Toluene-16) Total Input 2084.0 Total Output 2084.0
Material balance of Losartan Potassium Stage-IV Batch Size: 200.0Kg Name of the input Quantity Name of the out put Quantity In Kg In Kg Losartan Base 200.0 Losartan Potassium 200.0 Potassium Hydroxide 28.0 Methanol Recovery 465.0 Methanol 500.0 Methanol Loss 25.0 Sodium Hydroxide 10.0 Toluene Recovery 940.0 Acetic Acid 6.0 Toluene Loss 40.0 Toluene 1000.0 Acetone Recovery 651.0 Acetone 700.0 Acetone Loss 35.0 Activated Carbon 16.0 Effluent 343.0 DM Water 300.0 (Water-300, gen. water-10.4, Potassium Acetate-2.4, Sodium Acetate-6.2, Methanol-10, Sodium hydroxide-7, Acetone-7) Spent Carbon 16.0 Organic Residue 45.0 (Organic impurities-18, Toluene- 20, Acetone-7) Total Input 2760.0 Total Output 2760.0
Page | 52 M/s. S L Pharmaceuticals Annexure-VII
LISINOPRIL
Process Description: Stage-I: N-(2,6-Diamino-hexanoyl)-pyrrolidine-2-carboxylicacid Hydrogenated with 5% Palladium Carbon Catalyst & Water. The mass is further treated with 2-Oxo-4-Phenyl Butyric Acid and Sodium Hydroxide. The resultant mass is crystalized from Methanol to get Lisinopril.
Page | 53 M/s. S L Pharmaceuticals Annexure-VII
LISINOPRIL
Route of Synthesis: Stage-I:
NH2
O NH2 O
O N OH + + H2 HO
O
2-Oxo-4-Phenyl Butyric Acid 1-(2,6-Diamino-hexanoyl)-pyrrolidine- Hydrogen 2-carboxylic acid H C H O C H N O 2 10 10 3 11 21 3 3 Mol. Wt.: 2.02 Mol. Wt.: 178.18 Mol. Wt.: 243.30
Pd/C NH 2 NaOH/ Methanol
O OH
O N H O N + H2O OH
(2S)-1-[(2S)-6-amino-2-[[(1S)-1-carboxy-3-phenylpropyl] Water amino]hexanoyl]pyrrolidine-2-carboxylic acid Mol. Wt.: 18.02 (Lisinopril)
C21H31N3O5 Mol. Wt.: 405.49
Page | 54 M/s. S L Pharmaceuticals Annexure-VII
LISINOPRIL
Flow Chart:
N-(2,6-Diamino-hexanoyl)- Solvent Recovery pyrrolidine-2-carboxylic acid Evaporation Loss 2-Oxo-4-Phenyl Butyric acid Effluent 5% Palladium Carbon Stage-I Organic Residue Hydrogen gas Palladium carbon Sodium hydroxide Process Emission Methanol Water
Lisinopril
Page | 55 M/s. S L Pharmaceuticals Annexure-VII
LISINOPRIL
Material Balance:
Material balance of Lisinopril Stage-I Batch Size: 100.0Kg Name of the input Quantity Name of the out put Quantity In Kg In Kg N-(2,6-Diamino-hexanoyl)- 50.0 Lisinopril 100.0 pyrrolidine-2-carboxylic acid 2-Oxo-4-Phenyl Butyric acid 70.0 Solvent Recovery 5% Palladium Carbon 12.0 Methanol Recovery 470.0 Hydrogen gas 2.0 Methanol Loss 23.0 Sodium hydroxide 30.0 Palladium Carbon Reuse 12.0 Methanol 500.0 Effluent 441.7 (Water-400, Sodium hydroxide- Water 400.0 30, gen. water-5, Methanol-5, Organic compound-1.7) Organic Residue 15.8 (Unreacted Organic impurities- 13.8, Methanol-2) Process Emission 1.5 (Hydrogen) Total 1064.0 Total 1064.0
Page | 56 M/s. SL Pharmaceuticals Annexure-VII
LEVOCETRIZINE DIHYDROCHLORIDE
Stage-I
1-[(4-Chlorophenyl) phenylmethyl] piperazine react with 2-Chloro ethanol in presence of Triethyl amine, Sodium bicarbonate in Toluene Solvent media to get 4-Chloro benzhydryl piperazine ethanol as Stage-I Intermediate.
Stage-II
4-Chloro benzhydryl piperazine ethanol (Stage-I) further react with Sodium monochloroacetate in presence of Potassium Hydroxide and Hydrochloric Acid in Dimethyl formamide and Toluene Solvent media to get Levocetirizine Base.
Stage-III
Levocetirizine Base treated with Hydrochloric Acid in the presence of Acetone Solvent media to get Levocetirizine Dihydrochloride.
Page | 57 M/s. SL Pharmaceuticals Annexure-VII
LEVOCETRIZINE DIHYDROCHLORIDE
Route of Synthesis:
Stage-I
Cl NH
N Cl + + (C H ) N OH 2 5 3
1-[(4-Chloro-phenyl)-phenyl-methyl]-piperazine 2-Chloroethanol Triethylamine
C H N C17H19ClN2 C2H5ClO 6 15 Mol. Wt.: 286.80 Mol. Wt.: 80.51 Mol. Wt.: 101.19
Cl OH N
N
+ (C2H5)3N.HCl
2-{4-[(4-Chloro-phenyl)-phenyl-methyl] Triethylamine Hydrochloride -piperazin-1-yl}-ethanol
C19H23ClN2O C6H16ClN Mol. Wt.: 330.85 Mol. Wt.: 137.65
Page | 58 M/s. SL Pharmaceuticals Annexure-VII
Stage-II
Cl OH N N O + Cl + KOH + HCl ONa
Hydrochloric 2-{4-[(4-Chloro-phenyl)-phenyl-methyl]- Sodium Monochloro Potassium Acid piperazin-1-yl}-ethanol acetate Hydroxide
C19H23ClN2O C2H2ClNaO2 HKO ClH Mol. Wt.: 330.85 Mol. Wt.: 116.48 Mol. Wt.: 56.11 Mol. Wt.: 36.46
Cl O COOH N N
KCl + + NaCl + H2O
Levocetirizine Base Potassium Chloride Sodium Chloride Water
ClK C21H25ClN2O3 ClNa H2O Mol. Wt.: 388.89 Mol. Wt.: 74.55 Mol. Wt.: 58.44 Mol. Wt.: 18.02
Page | 59 M/s. SL Pharmaceuticals Annexure-VII
Stage-III
Cl O COOH N N Acetone + 2 HCl
Levocetirizine Base Hydrochloric Acid
C21H25ClN2O3 ClH Mol. Wt.: 388.89 Mol. Wt.: 36.46
Cl O COOH N N 2 HCl
Levocetirizine Dihydrochloride
C21H27Cl3N2O3 Mol. Wt.: 461.81
Page | 60 M/s. SL Pharmaceuticals Annexure-VII
LEVOCETRIZINE DIHYDROCHLORIDE
Flow Chart:
1-[(4-Chlorophenyl) phenyl methyl] piperazine Solvent Recovery Toluene Evaporation Loss 2-Chloroethanol Stage-I Effluent Triethyl amine Organic Residue Sodium Carbonate Water
Stage-I Sodium-2-chloro acetate Solvent Recovery Potassium Hydroxide Evaporation Loss Dimethylformamide Stage-II Effluent Hydrochloric Acid (35%) Organic Residue Toluene Water
Solvent Recovery Levocetirizine Base Evaporation Loss Acetone Organic Residue Hydrogen chloride gas Stage-III Spent Carbon Activated Carbon Process Emission
Levocetirizine Dihydrochloride
Page | 61 M/s. SL Pharmaceuticals Annexure-VII
LEVOCETRIZINE DIHYDROCHLORIDE
Material Balance:
Material balance of Levocetirizine Dihydrochloride Stage-I Batch Size: 50.0Kg Name of the input Quantity in Name of the out put Quantity Kg In Kg 1-[(4-Chlorophenyl) phenylmethyl] 45.0 Stage-I 48.0 piperazine Toluene 500.0 Solvent Recovery 2-Chloroethanol 23.0 Toluene Recovery 472.0 Triethyl amine 25.0 Toluene Loss 25.0 Sodium Carbonate 12.0 Effluent 853.0 Water 800.0 (Water 800, Triethylamine hydrochloride-21.6, Triethylamine-9, Sodium bicarbonate-12, 2-Chloroethanol- 10.4) Organic Residue 7.0 (Unreacted Organic impurities-4, Toluene-3) Total 1405.0 Total 1405.0
Material balance of Levocetirizine Dihydrochloride Stage-II Batch Size: 50.0Kg Name of the input Quantity in Name of the out put Quantity Kg In Kg Stage-I 48.0 Levocetirizine Base 45.0 Sodium-2-chloro acetate 35.0 Solvent Recovery Potassium Hydroxide 25.0 Toluene Recovery 470.0 Dimethylformamide 150.0 Toluene Loss 25.0 Hydrochloric Acid (35%) 20.0 DMF Recovery 130.0 Toluene 500.0 DMF Loss 10.0 Water 850.0 Effluent 931.4 (Water- 850, gen. water-2.6, Potassium Chloride -10.8, Sodium Chloride- 8.5, Sodium-2- chloro acetate- 18, Potassium Hydroxide -16.8, Dimethylformamide- 10, Hydrochloric Acid-1.7, water from HCl-13) Organic Residue 16.6 (Unreacted Organic Impurities 11.6, Toluene 5) Total 1628.0 Total 1628.0
Page | 62 M/s. SL Pharmaceuticals Annexure-VII
Material balance of Levocetirizine Dihydrochloride Stage-III Batch Size: 50.0Kg Name of the input Quantity in Name of the out put Quantity Kg In Kg Levocetirizine Base 45.0 Levocetirizine Dihydrochloride 50.0 Acetone 300.0 Acetone Recovery 270.0 Hydrogen chloride gas 18.0 Acetone Loss 28.0 Activated Carbon 5.0 Spent Carbon 5.0 Organic Residue 5.5 (Unreacted Organic impurities- 3.5, Acetone-2) Process Emission 9.5 (Hydrogen chloride) Total 368.0 Total 368.0
Page | 63 M/s. S L Pharmaceuticals Annexure-VII
RABEPRAZOLE SODIUM
Process Description: Stage-I: 2-(Chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine reacts with 1H-benzo[d]imidazole-2- thiol in the presence of Sodium hydroxide in Methylene dichloride and Hexane and Water media to get 2-((4-(3-methoxypropoxy)-3-methylpyridin-2-yl) methylthio)-1H-benzo[d]imidazole.
Stage-II: 2-((4-(3-methoxypropoxy)-3-methylpyridin-2-yl) methylthio)-1H-benzo[d]imidazole reacts with Sodium hypochlorite solution in Methylene dichloride and Hexane solvent media to gives Rabeprazole Base. Which is further reacts with Sodium Hydroxide in the presence of Methanol solvent media to get Rabeprazole Sodium as final product.
Page | 64 M/s. S L Pharmaceuticals Annexure-VII
RABEPRAZOLE SODIUM
Route of Synthesis: Stage-I:
O O
N
+ HS + NaOH Cl N N H
2-(Chloromethyl)-4-(3-methoxypropoxy)-3- 1H-benzo[d]imidazole-2-thiol Sodium hydroxide methylpyridine C7H6N2S 40.0 C11H16ClNO2 Mol. Wt.: 150.20 Mol. Wt.: 229.70
MDC, Hexane
H N O
S
N O + NaCl + H2O N
2-((4-(3-methoxypropoxy)-3-methylpyridin-2-yl) SodiumChloride Water methylthio)-1H-benzo[d]imidazole 58.44 18.02 C18H21N3O2S Mol. Wt.: 343.44
Page | 65 M/s. S L Pharmaceuticals Annexure-VII
Stage-II
H N O
S + NaOCl N O
N
2-((4-(3-methoxypropoxy)-3-methylpyridin-2-yl) Sodium hypochlorite methylthio)-1H-benzo[d]imidazole 74.44 C18H21N3O2S Mol. Wt.: 343.44
MDC, Hexane
H N O O
S + NaCl N O
N
Sodium chloride Rabeprazole base
58.44 C18H21N3O3S Mol. Wt.: 359.44
Page | 66 M/s. S L Pharmaceuticals Annexure-VII
Step-B
H N O O
S + NaOH N O
N
Sodium hydroxide Rabeprazole base
40.0 C18H21N3O3S Mol. Wt.: 359.44
Methanol
O
N O + H2O S N
N- O
Na+
sodium;2-[[4-(3-methoxypropoxy)-3-methylpyridin-2-yl] Water methylsulfinyl]benzimidazol-1-ide Mol. Wt.: 18.02 (Rabeprzole Sodium)
C18H20N3NaO3S Mol. Wt.: 381.42
Page | 67 M/s. S L Pharmaceuticals Annexure-VII
RABEPRAZOLE SODIUM
Flow chart:
2-(Chloromethyl)-4-(3- methoxypropoxy)-3- methylpyridine Solvent Recovery 1H-benzo[d]imidazole Evaporation Loss -2-thiol Stage-I Effluent Sodium hydroxide Organic Residue MDC Hexane Water
Stage-I Sodium hypochlorite solution Solvent Recovery MDC Evaporation Loss Stage-II Hexane Effluent Sodium hydroxide Organic Residue Methanol Water
Rabeprazole Sodium
Page | 68 M/s. S L Pharmaceuticals Annexure-VII
RABEPRAZOLE SODIUM
Material Balance:
Material balance of Rabeprazole Sodium Stage-I Batch Size: 100.0Kg Name of the input Quantity Name of the out put Quantity In Kg In Kg 2-(Chloromethyl)-4-(3- 80.0 Stage-I 100.0 methoxypropoxy)-3- methylpyridine 1H-benzo[d]imidazole-2-thiol 53.0 Recovery Sodium hydroxide 20.0 MDC Recovery 270.0 MDC 300.0 MDC Loss 27.0 Hexane 200.0 Hexane Recovery 186.0 Water 300.0 Hexane Loss 12.0 Effluent 335.4 (Water-300, gen. water-6.3, Sodium chloride-20.4, Sodium hydroxide-6, Hexane-2, Organic compound-0.7) Organic Residue 22.6 (Unreacted Organic impurities- 19.6, MDC-3) Total 953.0 Total 953.0
Page | 69 M/s. S L Pharmaceuticals Annexure-VII
Material balance of Rabeprazole Sodium Stage-II Batch Size: 100.0Kg Name of the input Quantity Name of the out put Quantity In Kg In Kg Stage-I 100.0 Rabeprazole Sodium 100.0 Sodium hypochlorite solution 100.0 Recovery MDC 500.0 MDC Recovery 460.0 Hexane 200.0 MDC Loss 37.0 Sodium hydroxide 16.0 Hexane Recovery 186.0 Methanol 180.0 Hexane Loss 14.0 Water 300.0 Methanol Recovery 165.0 Methanol Loss 12.0 Effluent 407.8 (Water-300, water from sodium hypochlorite-76, Sodium chloride-17, gen. water-5.2, Sodium hypochlorite-2.3, Sodium hydroxide-4.3, Methanol-3) Organic Residue 14.2 (Unreacted organic impurities- 11.2, MDC-3) Total 1396.0 Total 1396.0
Page | 70 M/s. S L Pharmaceuticals Annexure-VII
PANTOPRAZOLE SODIUM
Process Description:
Stage-I:
2-(Chlormethyl)-3,4-dimethoxypyridine is reacts with 5-(difluoromethoxy)-1H-benzi midazole-2- thiol in presence of C S lye, water and Chloroform to form 5 -(difluoromethoxy) -2-{[(3,4- dimethoxypyridin-2-yl) methyl] thio}-1H-benzimidazole (Stage-I)
Stage-II:
5-(difluoromethoxy)-2-{[(3,4-dimethoxypyridin-2-yl) methyl] thio}-1H-benzimidazole (Stage-I) reacts with sodium hypo solution in presence of dichloromethane, C.S. Flakes, ammonium chloride, acetone, carbon, water to form Sodium 5-(difluoromethoxy)-2- {[(3, 4-dimethoxypyridin- 2-yl) methyl] sulfinyl} benzimidazole-1-ide (or) Pantoprazole Sodium.
Page | 71 M/s. S L Pharmaceuticals Annexure-VII
PANTOPRAZOLE SODIUM
Route of Synthesis:
Stage-I:
O
O H N F + NaOH + HS N N O F
Cl 2-(Chlormethyl)-3,4-dimethoxy 5-Difluoromethoxy Sodium Hydroxide pyridine 2-mercapto Benzimidazole C H ClNO 8 10 2 C8H6F2N2OS NaOH Mol. Wt.: 187.62 Mol. Wt.: 216.21 Mol. Wt.: 40.00
Chloroform Water
OCH3
OCH3 H N F S + NaCl + H2O N N O F
5 -(difluoromethoxy) -2-{[(3,4-dimethoxypyridin- Sodium Chloride Water 2-yl)methyl]thio}-1H-benzimidazole (Stage-I)
C16H15F2N3O3S 58.44 18.02 Mol. Wt.: 367.37
Page | 72 M/s. S L Pharmaceuticals Annexure-VII
Stage-II
Step-A
OMe
OMe H N F S + NaOCl + NaOH N N O F
5-Difluoromethoxy-2-(((3,4-dimethoxy-2- Sodium Hypochlorite Sodium pyridinyl)methyl)thio)-1H-benzimidazole (Stage-I) Hydroxide 40.0 C16H15F2N3O3S 74.44 Mol. Wt.: 367.37
OMe +Na OMe O N- F S + NaCl + H2O N N O F
Pantoprazole Sodium SodiumChloride Water
C H F N NaO S 16 14 2 3 4 58.44 18.02 Mol. Wt.: 405.35
Page | 73 M/s. S L Pharmaceuticals Annexure-VII
PANTOPRAZOLE SODIUM
Flow Chart:
2-(Chlormethyl)-3,4-dimethoxy pyridine Solvent Recovery 5-(difluoromethoxy)-1H- Evaporation Loss benzimidazole-2-thiol Effluent Stage-I Sodium hydroxide Organic Residue MDC Water
Sodium hypochlorite solution Ammonium sulphate Solvent Recovery MDC Evaporation Loss Acetone Stage-II Effluent Sodium hydroxide Organic Residue Sodium Thiosulphate Inorganic Waste Water
Pantoprazole Sodium
Page | 74 M/s. S L Pharmaceuticals Annexure-VII
PANTOPRAZOLE SODIUM
Material Balance:
Material balance of Pantoprazole Sodium Stage-I Batch Size: 100.0Kg Name of the input Quantity Name of the out put Quantity In Kg In Kg 2-(Chlormethyl)-3,4-dimethoxy 70.0 Stage-I 100.0 pyridine 5-(difluoromethoxy)-1H- 80.0 Recovery benzimidazole-2-thiol Sodium hydroxide 25.0 MDC Recovery 368.0 MDC 400.0 MDC Loss 30.0 Water 500.0 Effluent 540.5 (Water-500, Sodium Chloride- 21.3, gen. water-6.7, Sodium hydroxide-10, Organic compound-2.5) Organic Residue 36.5 (Unreacted Organic impurities- 34.5, MDC-2) Total 1075.0 Total 1075.0
Page | 75 M/s. S L Pharmaceuticals Annexure-VII
Material balance of Pantoprazole Sodium Stage-II Batch Size: 100.0Kg Name of the input Quantity Name of the out put Quantity In Kg In Kg Stage-I 100.0 Pantoprazole Sodium 100.0 Sodium hypochlorite solution 100.0 Recovery Ammonium sulphate 30.0 MDC Recovery 460.0 MDC 500.0 MDC Loss 37.0 Acetone 200.0 Acetone Recovery 186.0 Sodium hydroxide 14.0 Acetone Loss 12.0 Sodium Thiosulphate 12.0 Effluent 417.5 (Water-300, Sodium chloride- 15.7, gen. water-4.8, water from Water 300.0 Sodium hypochlorite-80, Sodium thiosulphate-12, NaOH-3, Acetone-2) Inorganic Solid waste 30.0 (Ammonium sulphate) Organic Residue 13.5 (Unreacted organic impurities- 10.5, Acetone-3) Total 1256.0 Total 1256.0
Page | 76 M/s. S L Pharmaceuticals Annexure-VII
ITRACONAZOLE
Process Description: Stage-I 2-sec-Butyl-4-{4-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-phenyl}-2,4-dihydro- [1,2,4] triazol-3- one (IT-VII) reacts with Cis-2-[(2, 4 – dichlorophenyl)-2 - (1H- 1,2,4 Triazole -1-yl Methyl) 1,3 Dioxalane -4- yl] -methyl -methane sulphonate (IT-IX) in presence of Potassium Hydroxide in DMF Solvent media to get Itraconazole tech, this tech purification with Methanol Solvents media to get pure Itraconazole Pharma.
Page | 77 M/s. S L Pharmaceuticals Annexure-VII
ITRACONAZOLE Route of Synthesis: Stage-I: N
N N
Cl O N
N O O Cl S + O O HO O N N
N
2-sec-Butyl-4-{4-[4-(4-hydroxy-phenyl)-piperazin-1-yl]- cis-[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl phenyl}-2,4-dihydro- [1,2,4] triazol-3-one methyl)-1,3-dioxolan-4-yl] methyl methane sulfonate
C22H27N5O2 C14H15Cl2N3O5S Mol. Wt.: 393.48 Mol. Wt.: 408.26 + KOH Potassium hydroxide 56.11 Cl Cl
O O O N O N N N N N N
N
Itraconazole Pharma
C35H38Cl2N8O4 Mol. Wt.: 705.63
+ CH3KO3S + H2O
Potassium methane sulfonate Water
134.2 18.02
Page | 78 M/s. S L Pharmaceuticals Annexure-VII
ITRACONAZOLE
Flow Chart:
2-sec-Butyl-4-{4-[4-(4- hydroxy-phenyl)- piperazin-1-yl]-phenyl} -2,4-dihydro- [1,2,4] triazol-3-one (IT-VII) Cis-2- [(2, 4 - dichlorophenyl) Solvent Recovery -2 - (1H- 1,2,4 Triazole - Evaporation Loss 1-yl Methyl) 1,3- Stage-I Effluent Dioxalane -4- yl] - Organic Residue methyl -methane Spent Carbon sulphonate (IT-IX) Dimethyl formamide Methanol Potassium hydroxide Activated carbon Water
Itraconazole
Page | 79 M/s. S L Pharmaceuticals Annexure-VII
ITRACONAZOLE
Material Balance: Material Balance of Itraconazole Stage-I Batch Size: 150 Kg Quantity Quantity Name of the Input Name of the Input in Kg in Kg 2-sec-Butyl-4-{4-[4-(4-hydroxy- 94.5 Itraconazole pharma 150.0 phenyl)-piperazin-1-yl]-phenyl}- 2,4-dihydro- [1,2,4] triazol-3-one (IT-VII) Cis-2- [(2, 4 – dichlorophenyl)-2 - 99.0 Solvent Recovery (1H- 1,2,4 Triazole -1-yl Methyl) 1,3 Dioxalane -4- yl] -methyl - methane sulphonate (IT-IX) Dimethyl formamide 800.0 DMF Recovery 753.0 Methanol 900.0 DMF Loss 37.0 Potassium hydroxide 15.0 Methanol Recovery 860.0 Activated carbon 12.0 Methanol Loss 30.0 Water 1125.0 Effluent 1180.0 (Water-1125, gen. water-4.3, Methanol-10, DMF-7, Potassium hydroxide-1.5, Potassium Methane Sulfonate-32.2) Organic residue 23.5 (Unreacted Organic impurities-20.5, DMF-3) Spent carbon 12.0 Total 3045.5 Total 3045.5
Page | 80 M/s. S L Pharmaceuticals Annexure-VII
FEXOFENADINE HYDROCHLORIDE
Process Description:
Stage-I:
Condensation of Methyl 2-[4-(4-chlorobutanoyl) phenyl]-2-methylpropanoate with Azacyclonol in presence of Sodium bicarbonate, Ethyl Acetate and Methyl Isobutyl Ketone (MIBK) solvent media to gives Stage-I.
Stage-II:
Reduction of Stage-I Compound with Sodium borohydride in the presence of Sodium hydroxide, Acetic Acid and Methanol followed by hydrolysis to gives Fexofenadine Base as Stage-II.
Stage-III:
Fexofenadine Base further reacts with Hydrochloric acid for salt formation with Isopropyl Alcohol Solvent media to gives Fexofenadine Hydrochloride.
Page | 81 M/s. S L Pharmaceuticals Annexure-VII
FEXOFENADINE HYDROCHLORIDE
Route of Synthesis:
Stage-I:
Cl
+ HN + NaHCO3 O OH O O
methyl 2-[4-(4-chlorobutanoyl) phenyl] Azacyclonol Sodium -2-methylpropanoate bicarbonate C18H21NO C15H19ClO3 Mol. Wt.: 267.37 84.01 Mol. Wt.: 282.76
MIBK Ethyl Acetate Water
N OH
+ NaCl
O O O
2-(4-{4-[4-(Hydroxy-diphenyl-methyl)-piperidin-1-yl]-butyryl}-phenyl) Sodium Chloride -2-methyl-propionic acid methyl ester 58.44 C33H39NO4 Mol. Wt.: 513.67 H O + CO2 + 2
44.01 18.02
Page | 82 M/s. S L Pharmaceuticals Annexure-VII
Stage-II:
N OH
+ NaBH + CH COOH + 4 H O O 4 3 2 O O
2-(4-{4-[4-(Hydroxy-diphenyl-methyl)-piperidin-1-yl]-butyryl} Sodium Acetic Acid Water -phenyl)-2-methyl-propionic acid methyl ester borohydride
C H NO 33 39 4 37.83 60.05 72.08 Mol. Wt.: 513.67
Methanol, Water
N OH
O HO O
+ CH3OH + CH3COONa + H3BO3
(Fexofenadine Base) Methanol Sodium Acetate Boric Acid
C32H37NO4 Mol. Wt.: 499.64 32.04 82.03 61.83
+ 4 H2
Hydrogen 4X2.02=8.08
Page | 83 M/s. S L Pharmaceuticals Annexure-VII
Stage-III:
N OH
+ HCl
O HO O
2-(4-{4-[4-(Hydroxy-diphenyl-methyl)-piperidin-1-yl]-butyryl}-phenyl)-2- Hydrochloric Acid methyl-propionic acid Mol. Wt.: 36.46 (Fexofenadine Base)
C32H37NO4 Mol. Wt.: 499.64
IPA
N OH Cl H
O HO O
Fexofenadine Hydrochloride
C32H38ClNO4 Mol. Wt.: 536.10
Page | 84 M/s. S L Pharmaceuticals Annexure-VII
FEXOFENADINE HYDROCHLORIDE
Flow Chart:
Methyl 2-[4-(4-chlorobutanoyl) phenyl]-2-methylpropanoate Solvent Recvoery Evaporation Loss Sodium bicarbonate Stage-I Azacyclonol Effluent Methyl Isobutyl Ketone Organic Residue Ethyl Acetate Process Emission DM Water
Stage-II Sodium Borohydride Solvent Recvoery Sodium hydroxide Evaporation Loss Acetic Acid Stage-II Effluent Activated Carbon Spent Carbon Methanol Organic Residue Water Process Emission
Fexofenadine Base Solvent Recovery Hydrochloric Acid Stage-III Evaporation Loss Isopropyl Alcohol Organic Residue
Fexofenadine Hydrochloride
Page | 85 M/s. S L Pharmaceuticals Annexure-VII
FEXOFENADINE HYDROCHLORIDE
Material Balance:
Material Balance of Fexofenadine Hydrochloride Stage-I Batch Size:200 Kg Quantity Quantity in Name of the Input Name of the Output in Kg Kg Methyl 2-[4-(4-chlorobutanoyl) Stage-I phenyl]-2-methylpropanoate 128.5 210.0 Sodium bicarbonate 38.2 Solvent Recovery Azacyclonol 121.5 Ethyl Acetate Recovery 1423.0 Methyl Isobutyl Ketone 64.0 Loss of Solvent on Recovery 75.0 Ethyl Acetate 1500.0 Effluent 1384.7 DM Water 1286.0 Water to Effluent 1286.0 Sodium Chloride 26.5 Water generation from 8.2 reaction MIBK 64.0
Organic Residue 25.5 Unreacted Organic 23.5 impurities Ethyl Acetate 2.0
Process Emission 20.0 Carbon dioxide 20.0
TOTAL 3138.2 TOTAL 3138.2
Page | 86 M/s. S L Pharmaceuticals Annexure-VII
Material Balance of Fexofenadine Hydrochloride Stage-II Batch Size:200 Kg Quantity Quantity in Name of the Input Name of the Output in Kg Kg Stage-II 210.0 Fexofenadine Base 203.6 Sodium Borohydride 15.5 Solvent Recovery Sodium hydroxide 16.3 Methanol 1628.0 Acetic Acid 49.2 Loss of Solvent on Recovery 86.0 Activated Carbon 20.0 Effluent 1584.0
Methanol 1714.0 Water to Effluent 1470.5 Water 1500.0 Boric Acid 25.3 Sodium Acetate 67.0 Water generation 7.5 Methanol generation 13.0 Organic compound 0.7 Spent Carbon 20.0 Process Emission 3.4 Hydrogen 3.4 TOTAL 3525.0 TOTAL 3525.0
Page | 87 M/s. S L Pharmaceuticals Annexure-VII
Material Balance of Fexofenadine Hydrochloride Stage-III Batch Size:200 Kg Quantity Quantity in Name of the Input Name of the Output in Kg Kg Fexofenadine Base 203.6 Fexofenadine Hydrochloride 200.0 Hydrochloric Acid 20.0 Solvent Recovery Isopropyl Alcohol 1715.0 IPA Recovery 1590.0 IPA Loss 120.0 Organic Residue 23.4 Unreacted Organic 18.4 impurities IPA 5.0 Process Emission 5.2
Hydrogen Chloride 5.2 TOTAL 1938.6 TOTAL 1938.6
Page | 88 M/s. S L Pharmaceuticals Annexure-VII
CIPROFLOXACIN HYDROCHLORIDE
Process Description:
Stage-I: Q Acid reacts with Piperazine in the presence of Hydrochloric Acid, Acetic Acid and Ammonium Hydroxide, Methanol Solvent media to get Stage-I Compound. Which is further purification with Activated Carbon to get pure Ciprofloxacin Base Compound. Stage-II: Ciprofloxacin Base reacts with Hydrochloric Acid in the presence of Methanol Solvent media to produce Ciprofloxacin Hydrochloride as final Product.
Page | 89 M/s. S L Pharmaceuticals Annexure-VII
CIPROFLOXACIN HYDROCHLORIDE
Route of Synthesis: Stage-I: O O
F OH
Methanol HN Cl N + 2 NH
7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- Piperazine quinoline-3-carboxylic acid C4H10N2 2X86.14=172.28 (Q-ACID)
C13H9ClFNO3 Mol. Wt.: 281.67
O O
F OH
HN N N + NH Cl H HN
Ciprofloxacin Base Piperazine Hydrochloride
C17H18FN3O3 C4H11ClN2 Mol. Wt.: 331.34 Mol. Wt.: 122.60
Page | 90 M/s. S L Pharmaceuticals Annexure-VII
Stage-II
O O
F OH
N N H O + HCl + 2 HN
Ciprofloxacin Base Hydrochloric Acid Water
C17H18FN3O3 Mol. Wt.: 36.46 Mol. Wt.: 18.02 Mol. Wt.: 331.34
O O
F OH
Cl O N N H H H
HN
Ciprofloxacin Hydrochloride
C17H21ClFN3O4 Mol. Wt.: 385.82
Page | 91 M/s. S L Pharmaceuticals Annexure-VII
CIPROFLOXACIN HYDROCHLORIDE
Flow Chart:
Q Acid Piperazine Hydrochloric Acid (35%) Methanol Recovery Acetic Acid Loss of Methanol Ammonium Hydroxide (25%) Stage-I Piperazine CF Ml's for sale Activated Carbon Spent Carbon EDTA Hyflow Hyflow Methanol DM Water
Ciprofloxacin Base Pure Methanol Recovery (470 + 370) Loss of Methanol Hydrochloric Acid Stage-II Effluent to ETP Methanol Organic Residue DM Water
Ciprofloxacin Hydrochloride
Page | 92 M/s. S L Pharmaceuticals Annexure-VII
CIPROFLOXACIN HYDROCHLORIDE Material Balance: Material Balance of Ciprofloxacin Hydrochloride Stage-I BatchSize:100.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Q Acid 94.0 Ciprofloxacin Base Pure (94 + 74) 168.0 Piperazine 65.5 Methanol Recovery 110.0 Hydrochloric Acid (35%) 10.0 Methanol Loss 10.0 Acetic Acid Send to Authorized Parties 587.0 21.5 (Piperazine CF ML s) (Piperazine Hydrochloride-52.4, Ammonium Acetate-27.7, gen water- 6.4, EDTA-1, Water from Ammonium Hydroxide (25%) 50.0 Ammonium Hydroxide-37.5, Organic compound-16.5, Water from Hydrochloric Acid-6.5, Water-439) Activated Carbon 4.0 Spent Carbon & Hyflow 5.0 EDTA 1.0 Hyflow 1.0 Methanol 120.0 Water 513.0 Total 880.0 Total 880.0
Material Balance of Ciprofloxacin Hydrochloride Stage-II BatchSize:100.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Ciprofloxacin Base Pure (94+ 74) 168.0 Ciprofloxacin Hydrochloride 100.0 Hydrochloric Acid 36.0 Solvent Recovery Methanol 356.0 Methanol Recovery 330.0 Water 435.0 Methanol Loss 18.0 Effluent 534.5 (Water-429.5, Hydrochloric Acid-2.6, Methanol-5, Water from Hydrochloric Acid-23.4, Water from Base Pure-74) Organic Residue 12.5 (Unreacted Organic Impurities-9.5, Methanol-3) Total 995.0 Total 995.0
Page | 93 M/s. S L Pharmaceuticals Annexure-VII
PREGABALIN
Process Description Stage-I:
Condensation of Isovalderaldehyde with Diethyl malonate in presence of di-n-propyl amine and glacial acetic acid to give 2-carbethoxy-5-methylhex-2-enoic acid ethyl ester. Stage-II:
Reaction of 2-Carbethoxy-5-methylhex-2-enoic acid ethyl ester with potassium cyanide and ethanol to give 2-Carbethoxy-3-cyano-5-methylhexanoic acid ethyl ester. Stage-III:
Hydrolysis of 2-Carbethoxy-3-cyano-5-methylhexanoic acid ethyl ester using potassium hydroxide and Methanol and Reduction of cyano group to amine by adding sponge nickel, water and ethanol to same reaction mass and followed by Decarboxylation in acetic acid to give (±)-3-(Amino methyl)-5-methylhexanoic acid. Stage-IV:
Resolution of (±)-3-(Amino methyl)-5-methylhexanoic acid using (S)-Mandelic acid in 3% v/v water in Isopropyl alcohol to give (S)-3-(Amino methyl)-5-methylhexanoic acid (S)-Mandelic acid Salt. Stage-V:
Hydrolysis of (S)-3-(Amino methyl)-5-methylhexanoic acid, (S)-Mandelic acid Salt in mixture of tetrahydrofuran and water to give solid which is recrystallized in mixture of isopropyl alcohol and water to give pure (S)-3-(Amino methyl)-5-methylhexanoic acid (Pregabalin).
Page | 94 M/s. S L Pharmaceuticals Annexure-VII
PREGABALIN
Route of Synthesis: Stage-I
O O H3C O O
H3C O H C O CH + H3C O O CH3 3 3 CH3 CH3 O Isovaleraldehyde Diethyl Malonate Stage-I Compound
C5H10O C7H12O4 C12H20O4 Mol. Wt.: 86.13 Mol. Wt.: 160.17 Mol. Wt.: 228.28
+ H2O
Water Mol. Wt.: 18.02 Stage-II
H3C O O
H3C O CH3 + KCN + CH3COOH
CH3 O
Stage-I Compound Potassium Cyanide Acetic Acid
C12H20O4 CKN C2H4O2 Mol. Wt.: 228.28 Mol. Wt.: 65.12 Mol. Wt.: 60.05
H3C O O
H C O CH 3 3 + CH3COOK
CH3 O N
Stage-2 Compound Potassium Acetate C H KO C13H21NO4 2 3 2 Mol. Wt.: 255.31 Mol. Wt.: 98.14
Page | 95 M/s. S L Pharmaceuticals Annexure-VII
Stage-III
H3C O O
H3C O CH3 H O + 2 KOH + 2H2 + 2CH3COOH + 2
CH3 O N
Stage-2 Compound Potassium Hydroxide Hydrogen Acetic Acid Water
C13H21NO4 Mol. Wt.: 255.31 56.11 2.02 60.05 18.02
H3C OH
+ 2 C2H5OH + 2 CH3COOK + CO2
CH3 O NH2
Stage-3 Compound Ethanol Potassium Acetate Carbon dioxide
C8H17NO2 Mol. Wt.: 159.23 46.07 98.14 44.01
Page | 96 M/s. S L Pharmaceuticals Annexure-VII
Stage-IV
OH NH2 CH3 COOH COOH + H3C
Stage-3 Compound (S)-Mandelic Acid C H NO 8 17 2 C8H8O3 Mol. Wt.: 159.23 Mol. Wt.: 152.15
OH OH + + NH3 NH3 CH CH3 - 3 -OOC OOC 1/2 1/2 COOH + COOH H3C H3C
Stage-4 Compound R(-)-Isomer
C16H25NO5 C16H25NO5 Mol. Wt.: 311.37 Mol. Wt.: 311.37
Page | 97 M/s. S L Pharmaceuticals Annexure-VII
Stage-V: OH NH + 2 NH3 CH - 3 CH3 OOC 1/2 COOH COOH H3C H3C
Stage-4 Compound Pregabalin
C16H25NO5 C8H17NO2 Mol. Wt.: 311.37 Mol. Wt.: 159.23
OH
COOH +
S-Mandelic Acid
C8H8O3 Mol. Wt.: 152.15
Page | 98 M/s. S L Pharmaceuticals Annexure-VII
PREGABALIN Flow Chart:
Isovaleraldehyde Sol.Recovery Diethyl Malonate Evaporation Loss Acetic Acid Stage-I Effluent n-Hexane Organic Residue Water
Stage-1 Sol.Recovery Potassium Cyanide Evaporation Loss Ethanol Stage-II Effluent n-Hexane Organic Residue Acetic Acid Water
Stage-2 Sol.Recovery Methanol Evaporation Loss Potassium Hydroxide Effluent Raney Nickel Stage-III Inorganic Solid Waste Acetic Acid Process Emissions Isopropyl Alcohol Hydrogen Gas Water
Sol.Recovery Stage-3 Evaporation Loss Isopropyl Alcohol Stage-IV Effluent (S)-Mandelic Acid Organic Residue Water
Stage-4 Sol.Recovery Tetrahydrofuran Evaporation Loss Stage-V Isopropyl Alcohol Effluent Water
Pregabalin
Page | 99 M/s. S L Pharmaceuticals Annexure-VII
PREGABALIN Material Balance:
Material Balance of Pregabalin Stage-I BatchSize:50.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Isovaleraldehyde 98.0 Stage-I 221.0 Diethyl Malonate 185.0 Recovery Acetic Acid 5.0 n-Hexane Recovery 167.5 n-Hexane 180.0 n-Hexane Loss 9.0 DM Water 700.0 Effluent 730.0 (Water-700, gen. water-20.5, Acetic Acid-5, Diethyl malonate-2.7, Organic compound-1.8) Organic Residue 40.5 (Organic Impurities-37, n-Hexane- 3.5) Total Input 1168.0 Total Output 1168.0
Material Balance of Pregabalin Stage-II BatchSize:50.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-I 221.0 Stage-II 225.0 Potassium Cyanide 63.0 Recovery Ethanol 225.0 Ethanol Recovery 209.0 n-Hexane 375.0 Ethanol Loss 11.0 Acetic Acid 60.0 n-Hexane Recovery 349.0 DM Water 850.0 n-Hexane Loss 19.0 Effluent Water 952.0 (Water-850, Potassium Acetate-95, Ethanol-5, Acetic Acid-2) Organic Residue 29.0 (Organic Impurities-22, n-Hexnae-7) Total Input 1794.0 Total Output 1794.0
Page | 100 M/s. S L Pharmaceuticals Annexure-VII
Material Balance of Pregabalin Stage-III BatchSize:50.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-II 225.0 Stage-III 120.0 Methanol 220.0 Recovery Potassium Hydroxide 55.0 Methanol + Ethanol Recovery 269.5 Raney Nickel 30.0 Methanol + Ethanol Loss 11.0 Acetic Acid 60.0 Isopropyl Alcohol Recovery 325.5 Isopropyl Alcohol 350.0 Isopropyl Alcohol Loss 17.5 Hydrogen gas 5.0 Raneyl Nickel Reuse 30.0 DM Water 900.0 Effluent Water 1031.2 (Water-884, gen. water-1.8, Potassium Acetate-96.3, Ethanol- 16.2, Acetic Acid-1.1, Methanol- 4.5, IPA-7, Organic compound- 20.3) Process Emission 40.3 (Carbon Dioxide-38.8, Hydrogen- 1.5) Total Input 1845.0 Total Output 1845.0
Material Balance of Pregabalin Stage-IV BatchSize:50.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-III 120.0 Stage-IV 110.0 Isopropyl Alcohol 960.0 Recovery (S)-Mandelic Acid 120.0 Isopropyl Alcohol Recovery 893.0 DM Water 950.0 Isopropyl Alcohol Loss 48.0 Effluent Water 956.3 (Water-950, IPA-2, Mandelic Acid- 4.3) (R)-Isomer for Reuse 110.0 Organic Residue 32.7 (Organic Impurities-14.7, IPA-18) Total Input 2150.0 Total Output 2150.0
Page | 101 M/s. S L Pharmaceuticals Annexure-VII
Material Balance of Pregabalin Stage-V BatchSize:50.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-IV 110.0 Pregabalin 50.0 Tetrahydrofuran 900.0 Recovery Isopropyl Alcohol 560.0 THF Recovery 846.0 DM Water 500.0 THF Loss 45.0 IPA Recovery 526.0 IPA Loss 28.0 Effluent Water 575.0 (Water-500, Mandelic Acid-53.7, IPA-6, Tetrahydrofuran-9, Organic compound-6.3) Total Input 2070.0 Total Output 2270.0
Page | 102 M/s. S L Pharmaceuticals Annexure-VII
DOMPERIDONE
Process Description:
Stage-I: 1-(3-(4-(4-chloro-2-nitrophenylamino) piperidin-1-yl) propyl)-1H-benzo[d]imidazol-2(3H)-one on catalytic reduction in Methanol in the presence of Raney-Nickel as a catalyst under hydrogen mild pressure followed by solvent distillation and isolation in methanol gave the 1-(3-(4-(2-amino- 4-chlorophenylamino) piperidin-1-yl) propyl)-1H-benzo[d]imidazol-2(3H)-one.
Stage-II: 1-(3-(4-(2-amino-4-chlorophenylamino) piperidin-1-yl) propyl)-1H-benzo[d]imidazol-2(3H)-one reacts with Diethyl carbonate in Methanol to form 5-chloro-1-(1-(3-(2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl) propyl) piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Domperidone)
Page | 103 M/s. S L Pharmaceuticals Annexure-VII
DOMPERIDONE
Route of Synthesis: Stage-I:
O O- N+ H N O NH
N N Cl + 3 H2
1-(3-(4-(4-chloro-2-nitrophenylamino) piperidin-1-yl) Hydrogen propyl)-1H-benzo[d]imidazol-2(3H)-one 2X2.02=6.06 C21H24ClN5O3 Mol. Wt.: 429.90 Raney nickel
Cl
H2N
N
N N H + 2 H2O
N O H
1-(3-(4-(2-amino-4-chlorophenylamino) piperidin-1-yl) Water propyl)-1H-benzo[d]imidazol-2(3H)-one
2X18.02=36.04 C21H26ClN5O Mol. Wt.: 399.92
Page | 104 M/s. S L Pharmaceuticals Annexure-VII
Stage-II:
Cl
H2N
N O
N N H + O O
N O H
1-(3-(4-(2-amino-4-chlorophenylamino) piperidin-1-yl) Diethylcarbonate propyl)-1H-benzo[d]imidazol-2(3H)-one
C5H10O3 C21H26ClN5O Mol. Wt.: 118.13 Mol. Wt.: 399.92
Cl
Methanol
N N HN
O N + HO O N H
6-chloro-3-[1-[3-(2-oxo-3H-benzimidazol-1-yl)propyl] 2-Propanol piperidin-4-yl]-1H-benzimidazol-2-one C3H8O (Domperidone) Mol. Wt.: 60.10
C22H24ClN5O2 Mol. Wt.: 425.91 + CH3OH
Methanol
32.04
Page | 105 M/s. S L Pharmaceuticals Annexure-VII
DOMPERIDONE
Flow Chart:
1-(3-(4-(4-chloro-2-nitrophenyl amino) piperidin-1-yl) propyl) Solvent Recovery -1H-benzo[d]imidazol- Evaporation Loss 2(3H)-one Effluent Stage-I Methanol Organic Residue Raney nickel Process Emission Hydrogen gas Water
Solvent Recovery Diethyl carbonate Evaporation Loss Methanol Stage-II Effluent Water Organic Residue
Domperidone
Page | 106 M/s. S L Pharmaceuticals Annexure-VII
DOMPERIDONE
Material Balance:
Material balance of Domperidone Stage-I Batch Size: 100.0Kg Name of the input Quantity Name of the out put Quantity In Kg In Kg 1-(3-(4-(4-chloro-2- 140.0 Stage-I 112.0 nitrophenylamino) piperidin-1-yl) propyl)-1H-benzo[d]imidazol- 2(3H)-one Methanol 420.0 Recovery Raney nickel 15.0 Methanol Recovery 390.0 Hydrogen gas 3.5 Methanol Loss 23.0 Water 500.0 Raney nickel Reuse 15.0 Effluent 516.8 (Water-500, gen. water-11.8, Methanol-5) Organic Residue 20.2 (Unreacted organic imputies-18.2, Methanol-2) Process Emission 1.5 (Hydrogen) Total 1078.5 Total 1078.5
Material balance of Domperidone Stage-II Batch Size: 100.0Kg Name of the input Quantity Name of the out put Quantity In Kg In Kg Stage-I 112.0 Domperidone 100.0 Diethyl carbonate 40.0 Recovery Methanol 450.0 Methanol Recovery 427.0 Water 450.0 Methanol Loss 20.0 Effluent 482.7 (Water-450, Diethyl carbonate-7, 2-Propanol-16.7, Methanol-9) Organic Residue 22.3 (Unreacted organic impurities- 19.3, Methanol-3) Total 1052.0 Total 1052.0
Page | 107 M/s. S L Pharmaceuticals Annexure-VII
ESOMEPRAZOLE MAGNESIUM TRIHYDRATE
Process Description: Stage-I: 6-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl) methylthio)-1H-benzo[d]imidazole reacts with Potassium hydroxide in the presence of Diethyl tartrate, Titanium isopropaxide, DIPEA, Cumene hydroperoxide and Methanol, MDC Solvent media to gives Potassium salt of 5-methoxy- 2-((S)-(4-methoxy-3,5-dimethylpyridin-2-yl) methyl sulfinyl)-2,3-dihydrobenzo [d] imidazole-1- ide (Stage-I). Stage-II: Stage-I Compound reacts with Magnesium chloride in the presence of water media to obtain Esomeprazole Magnesium trihydrate.
Page | 108 M/s. S L Pharmaceuticals Annexure-VII
ESOMEPRAZOLE MAGNESIUM TRIHYDRATE
Route of Synthesis: Stage-I:
H O N O S O OH N + 3 KOH + N
6-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl) Potassium Cumene methylthio)-1H-benzo[d]imidazole Hydroxide hydroperoxide
C17H19N3O2S 2X56.1=168.3 C9H12O2 Mol. Wt.: 329.42 Mol. Wt.: 152.19
O OH + O Titanium isopropaxide O DIPEA, MDC, HO O Methanol Diethyl tartrate
C8H14O6 Mol. Wt.: 206.19 O K+ O- O N OH O S N O + + O N- O O + K -O K+
potassium;5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2- Cumene Potassium diethyl yl)methylsulfinyl]benzimidazol-1-ide hydroxide tartrate (Stage-I) C9H12O C8H12K2O6 Mol. Wt.: 136.19 Mol. Wt.: 282.37 C17H18KN3O3S Mol. Wt.: 383.51
+ 3 H2O
Water
3X18.02=54.06
Page | 109 M/s. S L Pharmaceuticals Annexure-VII
Stage-II:
O
O N
2 S N + MgCl2 + 3H2O N- O
K+
potassium;5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2- Magnesium chloride Water yl)methylsulfinyl]benzimidazol-1-ide
(Stage-I) 95.2 3X18 =54.0
C17H18KN3O3S 2X 383.5 = 767.0
Water
O Mg2+
O N + S N 2 KCl 3H2O N- O 2 Potassium chloride Esomeprazole Magnesium Trihydrate
C34H36MgN6O6S2 3H2O 2X74.55=149.1
M.Wt.767.2
Page | 110 M/s. S L Pharmaceuticals Annexure-VII
ESOMEPRAZOLE MAGNESIUM TRIHYDRATE
Flow Chart:
5-Methoxy-2-[[(3, 5-dimethyl- 4-methoxy pyridine-2-yl) methyl] thio]-1H- benzimidazole (Omeprazole sulphide) Solvent Recovery Toluene Evaporation Loss Effluent Diethyl tartrate Stage-I Titaniumisopropoxide Organic Residue Diisopropyl ethylamine Inorganic waste Cumene hydroperoxide Potassium hydroxide Sodium sulphate Methanol MDC Acetic Acid Water
Magnesium chloride Effluent Water Stage-II
Esomeprazole Magnesium Trihydrate
Page | 111 M/s. S L Pharmaceuticals Annexure-VII
ESOMEPRAZOLE MAGNESIUM TRIHYDRATE
Material Balance: Material balance of Esomeprazole Magnesium Trihydrate Stage-I Batch Size: 250.0Kg Name of the input Quantity Name of the out put Quantity in Kg In Kg 5-Methoxy-2-[[(3, 5-dimethyl-4- 319.0 Stage-I 319.0 methoxy pyridine-2-yl) methyl] thio]-1H-benzimidazole (Omeprazole sulphide) Toluene 2597.0 Recovery Diethyl tartrate 200.0 Toluene Recovery 2520.0 Titaniumisopropoxide 17.0 Toluene Loss 70.0 Diisopropyl ethylamine (DIPEA) 18.0 Methanol Recovery 1218.0 Cumene hydroperoxide 150.0 Methanol Loss 50.0 Potassium hydroxide 163.0 MDC Recovery 800.0 Sodium sulphate 50.0 MDC Loss 75.0 Methanol 1283.0 Effluent 4163.6 MDC 875.0 (Water-3600, gen. water-52.3, DIPEA-18, Titanium isopropoxide- 17, Cumene hydroxide-132, Potassium diethyltartrate-273.7, Acetic Acid-51, Cumene hydroperoxide-2.6, Toluene-2, Methanol-15) Acetic Acid 51.0 Organic Residue 57.4 Water 3600.0 (Unreacted Organic impurities-52.4, Toluene-5) Inorganic Solid Waste 50.0 (Sodium sulphate) Total 9323.0 Total 9323.0
Page | 112 M/s. S L Pharmaceuticals Annexure-VII
Material balance of Esomeprazole Magnesium Trihydrate Stage-II Batch Size: 250.0Kg Name of the input Quantity Name of the out put Quantity in Kg In Kg Stage-I 319.0 Esomeprazole Magnesium 250.0 Trihydrate Magnesium chloride 87.0 Effluent 1304.0 Water 1200.0 (Water-1177.5, Potassium chloride-62, Magnesium chloride- 47.5, Organic compound-17) Organic Residue 52.0 (Unreacted Organic impurities-52) Total 1606.0 Total 1606.0
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M/s. S L Pharmaceuticals Annexure-VIII
WATER CONSUMPTION DETAILS
S. No. Purpose Water Consumption in KLD 1 Process 3.2 2 Washings (Reactor & Floor washings) 2.0 3 Boiler Feed 15.0 4 Cooling Towers Makeup 10.0 5 Scrubber 2.0 6 R&D/ QC 1.0 7 Domestic 5.0 8 Gardening 5.0 TOTAL 43.2
Note: The total water requirement of the plant is 43.2 KLD, out of this 35.2 KL of Fresh water will be met form from APIIC supply and balance 8.0 KL of treated water will be recycled from MEE Condensate for Cooling towers makeup.
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M/s. S L Pharmaceuticals Annexure-IX
EFFLUENT GENERATION – METHOD OF DISPOSAL
Effluent generation in KLD Disposal Method S.No. Purpose HTDS LTDS Total 1 Process 3.0 0.5 3.5 HTDS Effluents: 2 Washings 0.0 2.0 2.0 Stripper condensate for recovery of 3 Boiler Blow down 1.5 0.0 1.5 organic compounds will be disposal to 4 Cooling Towers Blow 0.0 2.0 2.0 cement plant. down Stripped bottom effluents to Forced 5 Scrubbers System 2.0 0.0 2.0 evaporation in MEE & ATFD. 6 R&D/ QC 0.0 1.0 1.0 Condensate from MEE & ATFD to ETP. Salts from ATFD to TSDF. RO Permeate for boiler makeup RO Reject to MEE/ ATFD. LTDS Effluents: Sent to Biological ETP. RO Permeate will be reused for Boiler makeup RO Rejects sent to MEE/ATFD. 7 Domestic 0.0 4.0 4.0 Septic Tank Followed by soak pit. Total 6.5 9.5 16.0
Page | 114 M/s. S L Pharmaceuticals Annexure-IX
EFFLUENT TREATMENT FLOW FOR AS PER SEGREGATION
Effluent Characteristics Quantity Treatment Flow (KLD) Process, Boiler & Scrubber Collection » Equalization » Neutralization » Settling » HTDS/ HCOD Holding » Stream stripper » MEE along with HTDS HTDS > 5000 mg/l Effluent » Condensate to ETP (Biological Treatment) » LTDS > 5000 mg/l Condensate to ATFD.
ATFD Condensate to ETP (Biological Treatment) along 6.5 with domestic waste water (Septic tank over flow) » Pressure Sand Filter » Activated Carbon Filter » RO Treatment Plant » RO Reject to MEE.
RO Permeate & Condensate to Cooling Towers. ATFD Salts to TSDF and Stripped solvents to SPCB Authorized cement industries. Washings, Cooling Towers, Collection » Equalization » Neutralization » ETP QC / R&D LTDS/ LCOD (Biological Treatment) along with MEE condensate. 9.5 LTDS < 5000 mg/l LCOD < 5000 mg/l Domestic 4.0 Septic tank » Overflow to ETP (Biological Treatment)
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M/s. S L Pharmaceuticals Annexure-X
SOLID/ HAZARDOUS WASTE GENERATION – DISPOSAL OPTION
S.No. Description Quantity Method of Disposal 1 Organic Solid Waste 121.17 Kg/Day Sent to TSDF/Cement Industries 2 MEE Salts 197.07 Kg/Day Sent to TSDF 3 Inorganic Solid Waste 13.33 Kg/Day Sent to TSDF/Cement Industries 4 Spent Carbon 9.3 Kg/Day Sent to TSDF/Cement Industries 5 ETP Sludge 50.0 Kg/Day Sent to TSDF 6 Waste Oils & Grease 100 LPM APPCB Authorized Agencies for Reprocessing/Recycling 7 Detoxified Containers & 200 No s/Month After Detoxification sent back to Container Liners suppliers/APPCB Authorized Parties 8 Used Lead Acid Batteries 2 No s/Annum Send back to suppliers for buyback of New Batteries 9 Spent Solvents 5 KL/Month Recycle within the Premises 10 Coal Ash 2.4 TPD Disposed to Brick Manufacturers
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M/s. S L Pharmaceuticals Annexure-XI
PROCESS EMISSION AND METHOD OF DISPOSAL
S.No. Name of the Gas Quantity Disposal Method Kg/Day 1 Hydrogen chloride 2.5 Scrubbed by using chilled water/ Caustic lye solution 2 Sulfur dioxide 2.0 Scrubbed by using Caustic Lye Solution 3 Carbon dioxide 8.5 Dispersed into Atmosphere 4 Hydrogen 1.3 Diffused with flame arrestor Total 14.3
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M/s. S L Pharmaceuticals Annexure-XII
STACK EMISSION DETAILS OF BOILER
Units 2.0 TPH Coal Fired Particulars Boiler Type of Fuel -- Indian Coal Coal Consumption TPD 6.0 Ash Content % 40 Sulphur Content % 0.8 Nitrogen Content % 1.07 No. of Stacks No 1 Height of the Stack m 30 Diameter of Stack M 0.60 Temperature of Flue Gas oC 110 Velocity of Flue Gas m/s 8.5 Particulate Matter at outlet of Bag filter gm/sec 0.27 (Based on 115 mg/Nm3 at outlet) Sulphur dioxide emission gm/sec 1.15 Oxides of Nitrogen emission gm/sec 1.54
Page | 119 M/s. S L Pharmaceuticals Annexure-XII
STACK EMISSION DETAILS OF D.G. SET
Capacity Emission Emission Emission Stack Flue Gas Stack Flue gas
In KVA of SPM, in Of SO2 in of NOx dia. Temp. in Height Velocity Mg/Nm3 Mg/Nm3 in In m OC in (m) In m/sec. Mg/Nm3
250 KVA 70.0 135.0 160.0 0.30 220 10 12.5
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M/s. S L Pharmaceuticals Annexure-XIII
LIST OF HAZARDOUS CHEMICALS LIST
S.No. Name of the Hazardous Chemical 1 Sodium hydroxide 2 Methylene dichloride 3 Hexane 4 Sodium hypochlorite solution 5 Tolyl Benzonitrile 6 n-Bromo Succinimide 7 Toluene 8 Sodium Azide 9 Hydrochloric Acid 10 Potassium Hydroxide 11 Acetic Acid 12 Acetone 13 5% Palladium Carbon 14 Hydrogen gas 15 1H-benzo[d]imidazole-2-thiol 16 Sodium Thiosulphate 17 Sodium Borohydride 18 Isopropyl Alcohol 19 Piperazine 20 Ammonium Hydroxide 21 Potassium Cyanide 22 Ethanol 23 Raney Nickel 24 (S)-Mandelic Acid 25 Methanol 26 Tetrahydrofuran 27 Diethyl tartrate 28 Cumene hydroperoxide 29 Magnesium chloride 30 Titaniumisopropoxide
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M/s. S L Pharmaceuticals Annexure-XIV
DRAFT TERMS OF REFERENCE
Objective Preparation of Environmental Impact Assessment Report (EIA) based on one season (Three Months) data, which would be used as management planning tool for better Environmental Management by suggesting control measures to avoid pollution problems arising out of the project. The report will include a detailed environmental management plan (EMP). The study will be carried out incorporating all the details and requirements of Andhra Pradesh State Pollution Control (APPCB) and Ministry of Environment & Forests (MoEF) as per their requirements. Meteorological Information The micro climatic parameters will be recorded using automatic / manual weather station for the study period. Wind speed, wind direction and relative humidity will be recorded on hourly basis. Minimum & Maximum temperatures will be recorded during the study period. Other required data like seasonal wind patterns, cloud cover; etc will be collected from the concerned government departments. The collected data will be further processed and interpreted in the report for assessment of the study area. Air Environment Ambient Air Quality assessment will be carried out through a scientifically designed monitoring network for one season (Three Months) as part of EIA report. The important parameters that will be monitored are Suspended particulate matter (SPM) Sulfur Dioxide (SO2), nitrogen oxides (NOX). Carbon Monoxide (CO) content will be collected near the plant site. The monitoring at each location will be carried out for eight days in a month. The analyses values will be further processed using the latest software to represent the values as per the requirements of the statutory bodies. Noise Environment Noise levels in the study area shall be monitored at requisite locations using the latest equipment. The sampling locations will cover the project site and sensitive, habituated areas such as hospitals, roads, and residential areas. The noise levels will be collected hourly for one day at each location and the collected data will be processed further to arrive at the noise equivalents, which can be used as the baseline noise levels. Water Environment Composite of 3 water samples from surface and ground will be collected and tested as per IS: 2488 (Part 1-5) method for the assessment of the water quality in the study area. Existing data of the study area will be collected from Government departments and will be incorporated in the report. The samples will be analyzed for some specific parameters as per the IS 10500 standards and other relevant standards. Water consumption and wastewater discharge will be assessed. Impact on Water environment and mitigation measures will be included in the EIA report. Page | 122 M/s. S L Pharmaceuticals Annexure-XIV
Land Environment Composite of 3 Soil samples at each location will be collected and analyzed for physical and chemical parameters. Information on Topography, Geology and hydro geological features of the study area will be collected from secondary sources. Cropping pattern shall form a part of the report.
Flora and Fauna studies Forests, wild life, flora and fauna information form a part of this study. Though most of the data will be based on the information collected from the secondary data available with government authorities, a part of the information collection is supplemented with on filed surveys. Socio-Economic Information Population, human health, occupational patterns, housing, land holding, business activity, employment and income forms a part of this survey. Amenities survey like education, medical facilities, water supply, sanitation, marketing facilities, Transport, roads, banks, post offices also will be collected through secondary data Project Environ details This information forms the first part of the report which would cover review of process design, pollution control facilities from the details provided by you. Suggestion to minimize impacts shall form a part of the environmental management plan. Greenbelt development post project monitoring etc. are also covered in the EMP. Prediction of Impacts Recourse will be taken to use the state of the art mathematical dispersion models for prediction of air quality levels due to stack emission. The models used will be the most advanced and a combination of USEPA ISC3 and Industrial Sources complex. Isopleths will be drawn using advanced graphics packages. Noise prediction shall be carried out with homogenous dispersion equation in loss free environment. This is the most accepted mode. Predictions shall be carried out with the most acceptable procedures. Stacks connected to Boiler, DG Sets will be assessed. Apart from these stacks, all process emissions will be estimated from the proposed products. All major noise generating areas like DG Sets and Production blocks will be assessed for noise. Water consumption and wastewater discharge will be estimated. Impact on Water environment and mitigation measures will be included in the report. Solid waste quantification and disposal method will form a part of report
Page | 123 M/s. S L Pharmaceuticals Annexure-XIV
Environment Management Plan An environment management plan to mitigate any adverse impact will be prepared after evaluation of the environment. This will also include greenbelt development plan and plant species to be used for greenbelt. Details covered will be encompassing post project monitoring requirements, equipment and manpower requirements. It will also include the statutory obligations to be fulfilled by the proponent. Monitoring Plan Having identified the significant environmental impact that is likely to arise as a result of the proposed project, the project team will prepare a monitoring plan. The monitoring plan will identify parameters and frequency of monitoring Risk assessment and management Plan
The risk assessment and management plan will be prepared based on the maximum storage capacity of the chemicals, solvents stored at plant after plant commences the operations. The methodology to be adopted for the preparation of Risk assessment is as per the statutory guidelines provided by the Ministry of Environment and Forests, Government of India. The following methods would be applied for conducting the Risk assessment.
Hazard identification: Identification of major hazardous units, Fire Explosion and Toxicity index, Visualization of maximum credible accident scenarios.
Maximum Credible accident analyses to identify models for analysis, hazard and operability studies.
Consequence Analysis to quantify the effects.
Estimation of individual risk and Group Risk.
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