annexure-i list of products sr. name of product quantity...

Aventon Pharmalabs 1

Annexure-I

List of Products

Sr.

No.

Name of product Quantity

MT/Month

1 Pregabalin 2

2 Telmisartan

3 Ondansetron HCl

4 Bupropioon hydrochloride

5 Celecoxib

6 Febuxostat

7 Lidocaine base/HCl 25

8 Diclofenac sodium / potassium/ diethylamine

9 Aceclofenac

Total 27

List of Raw Materials

Sr.

No.

Name of Raw Materials Quantity

(MT/MT)

1. Pregabalin

Isoveraldehyde 1.200

Ethyl cyano acetate 1.560

Di-n-propyl amine 0.025

n-Hexane 0.092

Diethyl malonate 2.120

Urea 0.860

Sodium hydroxide 1.352

Activated charcoal 0.040

Chloroform 1.24

Methanol 0.244

R-(+I-(a)-phenyl ethyl amine 0.820

Hydrochloric acid 0.600

Liquid Bromine 0.980

Hyflow powder 0.012


Sr.

No.


(MT/MT)

2. Telmisartan

Bibenzimidazole 0.840

Bromo methyl ester 0.848


Dimethyl Formamide 0.220

Acetone 0.068

Potassium hydroxide 0.340

Acetic acid 2.120

Methanol 0.720

Activated carbon 0.060

Celite 0.040

3. Ondansetron HCl

1,2,3,9-tetrahydro-4H-carbozole-4-one 0.920

Methylene dichloride 1.70


Dimethyl formamide 0.360

Tarta butyl ammonium bromide 0.004

Morpholine 0.080

p-formaldehyde 0.140

Toluene 0.920

2-methyl imidazole 0.360

Isopropyl alcohol 1.920


Activated charcoal 0.020

Hyflow powder 0.004

4. Bupropioon hydrochloride

3 Chloropropiopenon 0.020

Bromine 0.004

Isopropyl Alcohol HCl 0.060

Sodium Chloride 0.700


Sr.

No.


(MT/MT)

Sodium Thiosulphate 0.960

T-Butyl Amine 0.060

Toluene 0.200

Methanol 0.140

Activated Carbon 3.340

Celite 3.000

IPA 0.140

5. Celecoxib

4-Methyl acetophenone 0.260

Sodium methoxide 0.360

Ethyl triflouroacetate 0.620


Toluene 0.780

Isopropyl alcohol 0.100

4-Hydrozino benzene sulfonamide HCl 1.000

Methanol 0.160

Carbon 0.012

Celite 0.040

6. Febuxostat

Ethyl cyano methyl thio 1.180

NaOH 0.180

HCl 0.480

IPA 0.180

Acetone 0.300


Celite 0.040

7. Lidocaine base/HCl

2,6 Xylidine 0.330

Chloro acetyl chloride 0.435

k2CO3 0.490


Sr.

No.


(MT/MT)

Acetone 0.130

Diethyl Amine 0.440

NaOH 0.100

HCl 1.000

Carbon 0.010

Celite 0.005

8. Diclofenac sodium / potassium/ diethylamine

2,6 Dichloro sodium phenol 0.605

Potassium carbonate 0.275

Mono methyl chloro acethyl 0.440

Toluene 0.020

Aniline 0.350

Sodium methoxide 0.155

Chloro acethyl chloride 0.405

AlCl3 0.710

NaOH 0.250

Activated Charcoal 0.007

9. Aceclofenac

Chloro acetyl chloride 0.695

T-Butanol 0.332

N N Di methyl aniline 0.070

HCl 0.120

Soda ash 0.045

Diclofenac sodium 2.215

Toluene 0.090


Celite 0.003

NaOH 0.280


Annexure-II

Manufacturing Process, chemical reaction & Mass Balance

1. Pregabalin

Manufacturing Process:

Ethyl cyano acetate was first condensed with isoveraldehyde to give the

unsaturated ester micheak addition of diethyl malonate followed by acid-

induced decarboxylation gave glutaric acid which was then converted to

the amide acid via the anhydride intermediate.

Acid can be resolved with (R) - methyl benzyl amine to give the chiral

acid in 98%. Hoffmann reaction rearrangement of amide gave Pregabalin

in good yield.

Chemical reaction:


Mass balance:


IN PUT Kg Kg OUT PUT

Isoveraldehyde 300 427 Hexane recovery

Ethyl cyano acetate 390 25 Di-n-propyl amine

Di-n-propyl amine 25 60 Effluent (ML)

n-Hexane 450 138 Residue

515 Stage-1A Mass

Diethyl malonate 530 144 CO2

188 Effluent (ML)

172 Residue

541 Stage-1B Mass

Urea 215 163 CO2 & NH3 to scrubber

Sodium hydroxide 45 817 Effluent (ML)

Water 750 5 Residue

Activated charcoal 5

571 Stage-1C Mass

Chloroform 5100 4790 Chloroform recovery

Methanol 61 678 Residue

R-(+I-(a)-phenyl ethyl amine 205

469 Stage-II Mass

Hydrochloric acid 150 723 Effluent (ML)

Water 300

Sodium hydroxide 170

366 Stage-III Mass

Liquid Bromine 245

Sodium hydroxide 123 65 CO2

Activated charcoal 5 601 Effluent (ML)

Hyflow powder 3

Water 300

126 Drying Loss

250 Pregabalin-Product

Total 9372 9372

Dryer

Stage-3 Condensation

Hydrolysis


& filteration

Mass balance of Pregabalin

Stage-1 A

Condensation

Hydrolysis

Stage-1 B

Condensation

Hydrolysis

Stage-1 C Condensation

Hydrolysis


Hydrolysis

2. Telmisartan


Bibenzimidazole & bromomethyl ester is condensed in presence of sodium

methoxide in DMF to give Telmi-I (Methyl 4’-[[4-Methyl-1H benzimidazol-

2-yl)-2-propyl-1H-benzimidazole-1-yl] methyl] biphenyl 2-carboxylate).

Telmi-I is hydrolyzed using potassium hydroxide in methanol & water

mixture to give Telmisartan.

Chemical reaction:

Stage I- Preparation of Telmi-I


Stage II


Mass balance:


Bibenzimidazole 210 1035 Dimethyl formamide

Bromo methyl ester 212 315 Acetone

Sodium hydroxide 40 170 Organic Residue

Dimethyl formamide 1090 1480 Effluent (ML)

Acetone 332

Water 1340

294 Rection mass

Potassium hydroxide 85

Acetic acid 530 3540 Methanol

Methanol 3720 225 Residue

Activated carbon 15 2755 Effluent (ML)

Celite 10 35 Spent carbon

Water 2305

84 Drying Loss

250 Telmisartan-Product

Total 9889 9889

Mass balance of Telmisartan

Stage-I Reaction

Stage-2 Reaction &

filteration

Dryer


3. Ondansetron HCl


1,2,3,9-tetrahydro-4H-carbazole is reacted with 2-methyl imidazole in

presence of hydrochloric acid and isopropyl alcohol to obtain Ondansetron

hydrochloride.

Chemical reaction:

Mass balance:



1145 Methylene dichloride recovery

630 Effluent (ML)

Methylene dichloride 1570 75 Residue

Sodium hydroxide 45

Water 120

Dimethyl formamide 90

Tarta butyl ammonium bromide 1

206 Stage I Mass

Morpholine 20 915 Toluene Recovery

p-formaldehyde 35 425 Effluent (ML)

Toluene 1145 120 Residue

2-methyl imidazole 90

Water 215

251 Stage II Mass

Isopropyl alcohol 1215 735 Isopropyl alcohol recovery

Water 965 1317 Effluent (ML)

Hydrochloric acid 85 10 Used carbon

Activated charcoal 5 130 Residue

Hyflow powder 1

80 Drying Loss

250 Ondansetron HCl - Product

Total 5832 5832

Dryer

Stage-III

Purification/Cry

stallization/

centrifuge

Mass balance of Ondansetron HCl

Stage-I

Methylation

Stage-II Manichh

Reaction

1,2,3,9-tetrahydro-4H-carbozole-4-

one230

4. Bupropioon hydrochloride


Stage-1

3΄Chloropropiophenone and Bromine are reacted in water as a solvent

media and progress of the reaction is monitored on HPLC.

After the completion of the reaction the mass is treated with sodium

Thiosulphate solution and the subjected to work up. The organic layer

containing product is then again reacted with tertiary butyl amine and

again the reaction is monitored on HPLC.

After the completion of reaction excess of the tertiary butyl amine is

distilled off and the residual mass is then washed with water, precipitated

with IPA HCL and centrifuged.

This is stage-1 which is further used after analysis.

Stage-2

Bupropion Hydrochloride Stage-I is dissolved in methanol, purified by

means of Charcoalisation followed by filtration & finally crystallized in

Isopropanol to yield pure Bupropion Hydrochloride.

Chemical reaction:


Mass balance:


3 Chloropropiopenon 170 350 T-Butyl Amine Recovery

Bromine 175 1020 Mixture of IPA & Toluene


Isopropyl Alcohol HCl 240 95 Residue

Sodium Chloride 170

Sodium Thiosulphate 15

T-Butyl Amine 365Toluene 835

311 Bupropion HCl Stage-1

Methanol 750 715 Methanol recovery

Activated Carbon 15 35 Carbon + Celite

Celite 4 715 Iso Propyl Alcohol Recovery

IPA 750 65 Residue

50 Drying Loss

250 Bupropion Hydrochloride

Total 5169 5169

Mass balance of Bupropion Hydrochloride

Bromination

Filteration

Dryer

5. Celecoxib


Cele-1 is prepared from 4-Methyl acetophenone and ethyltrifluoroacetate

in toluene using sodium methoxide as a base. To slurry of sodium

methoxide in toluene 4-Methyl acetophenone is added slowly and stirred.

Then ethyltrifluroacetate is added slowly.

Reaction mass is heated and stirred to complete the reaction. After

completion of reaction, reaction is cooled and quenched with water. pH is


made acidic by adding concentrated HCl and product is extracted in

toluene.

Toluene layer is concentration to give oil, which is taken in isopropanol,

and water is added to obtain Cele-1 in solid form. Cele-1 is filtrated

washed with water and dried.

Cele-1 and 4-Hydrazino benzene sulfonamide HCl are taken in ethanol

and refluxed. After completion of reaction, reaction mass is cooled and

filtered to remove excess unreacted 4-Hydrazino benzene sulfonamide.

Water is added to ethanol filtrate to precipitate the product. Product is

filtrated and dried to get Celecoxib Crude.

Celecoxib pure is obtained from Celecoxib crude by crystallization in

toluene. Celecoxib crude is dissolved in toluene and charcolized with

activated carbon. Then reaction mass is cooled and ethanol is added to it.

Reaction mass is filtered through celite bed followed by filtration.

Filtrate is heated to distill out ethanol. The reaction mass is cooled and

stirred. Product is filtrated and wet solid is again crystallized with toluene

to give pure Celecoxib.

Chemical reaction:

Step I= Preparation of Cele-1:

Step-II= Preparation of Celecoxib crude:

Step-III= Preparation of Celecoxib:


Mass balance:


4-Methyl acetophenone 140

Sodium methoxide 90

Ethyl triflouroacetate 205 1410 Effluent (ML)

Hydrochloric acid 210

Toluene 425

Isopropyl alcohol 430

Water 1140

175 Celecoxib-I4-Hydrozino benzene sulfonamide HCl 250 1630 Effluent (ML)

Water 1482 885 Methanol

Methanol 925

317 Celecoxib crude

Carbon 3 20 Spent Carbon + Celite

Celite 10 710 Toluene

Toluene 745 55 Residue

40 Drying Loss

250 Celecoxib-Product

Total 6055 6055

Dryer

Mass balance of Celecoxib

Reaction

Reaction

Filteration

Mixture of solvent (IPA, Toluene,

Ethanol, Methanol)1055

6. Febuxostat


Ethyl-2(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate

(NV07-3) is hydrolyzed with sodium hydroxide solution in isopropyl

alcohol to furnish the product. The pH is adjusted with hydrochloric acid

and solid is separated by filtration as Febuxostat crude.

Febuxostat (crude) is dissolved in acetone and charcoalized. After

filtration, acetone is distilled out and solid is filtered to give Febuxostat.

Chemical reaction:

Stage I-Preparation of Febuxosfat Crude:-


Stage II - Purification of Febuxostat:-

Mass balance:


Ethyl cyano methyl thio 295 835 IPA

NaOH 45 45 Residue

HCl 120 3055 Effluent (ML)

IPA 880

Water 2900

305 Febuxostate crude

Acetone 1245 1170 Acetone

Activated Carbon 15 40 Spent Carbon + Celite

Celite 10 60 Residue

55 Drying Loss

250 Febuxostate

Total 5510 5510

Mass balance of Febuxostate

Hydrolysis

Purification

Dryer

7. Lidocaine base/HCl


2,6-Xylidine is reacted with CAC in the presence of acetone to get Chloro

acetamides.

CAX is reacted with Diethylamine in presence of NaoH with exotherm to

get Lidocain Base.

Lidocine base is purified with Activated charcoal in the presence of

Toluene.


Lidocain base is reacted with HCl in acetone to get Lidocaine HCl.

Chemical reaction:

CH3

NH2

CH3

+ C2H

2Cl

2O

CH3

CH3

NHCOCH2Cl

+ HCl

2,6-Xylidine

121.2 gm/Mol 112.94 gm/Mol

N-Chloroacetyl 2,6-Xylidine (CAX)

197.5 gm/Mol

36.5 gm/Mol

NHCOCH2Cl

CH3

CH3

(CAX)

197.5 gm/Mol

+ 1/2 C

4H

11N

DEA

73.14 gm/Mol

CH3

CH3

NH

Lidocine Base C14

H22

N2O

234.34 gm/Mol

IPA HCl

CH3

NH

CH3

Lidocine HCl

C14

H22

N2O.HCl.H

2O

288.81 gm/Mol

O

NCH

3

CH3

N

CH3

CH3

O. HCl. H

2O

Mass balance:



2,6 Xylidine 330 2730 Effluent (ML)

Chloro acethyl Chloride 435 470 Acetone

K2CO3 490 45 Residue

Acetone 495

Water 1985

490 Chloro Acetamide

Diethyl Amine 1710 1270 Diethyl Amine


NaOH 100

1150 Lidocaine Base Crude

Acetone 2000 1895 Acetone

HCl 1000 775 Effluent (ML)

Carbon 10 25 Carbon + Celite

Celite 5 125 Residue

345 Drying Loss

1000 Lidocaine Base/ HCl

Total 9540 9540

Reaction-3

Mass balance of Lidocaine Base/HCl

Reaction-1

Reaction-2

Dryer

8. Diclofenac sodium / potassium/ Diethylamine


2,6-Diclorophenol is dehydrated by using Potsaaium Carbonate in the

presence of Toluene then reacted with MMCA and SMO in presence of

Aniline.

2, 6-Dichlorophenylamine is dehydrated in Toluene then reacted with CAC

to get N-Choloroacetyl 2,6-dichlorophenyl. N-Chloroacetyl 2,6-

dichlorophenyl is heated in the presence of catalyst AICI3 and quenched

to get N-chlorophenyl Indolinone.

N-chlorophenyl Indolinone is hydrolyzed by NAOH/KOH to get crude

Diclofenac Sodium or Potassium.

Diclofenac crude is purified by activated carbon and crystallized to get

pure Diclofenac.

Diclofenac pure is acidify with Acetic acid then reacted with Diethylamine

in presence of Acetone to give Diclofenac Diethylmine.

Chemical reaction:


Mass balance:


2,6 Dichloro sodium phenol 605 70 CO2

Potassium carbonate 275 385 Toluene Recover

Mono methyl chloro acethyl 440 22 Residue

Toluene 405 865 Effluent (ML)

Water 790

823 2,6 Dichloro Phenoxy Ethyle

Aniline 350 225 Effluent (ML)

Sodium methoxide 155

833 Chloro diphenyl amine

Chloro acethyl chloride 405 105 HCl gas

1133 N chloro acethyl dichloro diphenyl amine

AlCl3 710

NaOH 250 2790 ML of AlCl3

Activated Charcoal 7 3340 Effluent (ML)

Water 4215

Ice 625

430 Drying loss

1000 Diclofenac Sodium-Product

Total 9232 9232

Dryer

Mass balance of Diclofenac Sodium

Reaction-1

Reaction-2

Reaction-3

Reaction-4

9. Aceclofenac


The mixture of N, N Dimethyl Aniline and t-Butanol is reacted with Chloro

acetyl chloride in controlled temperature followed by Hydrochloric acid

and Soda Ash wash.

Distilled out the product to get the T-Butyl Chloro Acetate.


T-Butyl Chloro Acetate is reacted with Diclofenac Sodium in presence of

TBAB followed by Formic acid give the Aceclofenac Crude.

Aceclofenac crude is purified with activated carbon in the presence of

Toluene.

Chemical reaction:


Mass balance:



Chloro acetyl chloride 695 1095 N.N. Dimethylaniline HCl

T-Butanol 495 2025 Effluent (ML)

N N Di methyl aniline 805

HCl 120

Soda ash 45

Water 2010

1045 T-Butyl Chloro Acetate

Diclofenac sodium 2215 1650 Toluene

Toluene 1740 70 Distillation Residue

Water 2045 1460 Process Residue

2430 Effluent (ML)

1420 Aceclofenac Crude

Formic acid 1530 163 T-Butanol

Water 60 35 Used carbon + celite

Activated Carbon 25 1530 Formic acid

Celite 3

330 Drying loss

1000 Aceclofenac-Product

Total 11788 11788

N.N. Dimethylaniline HCl 1095 735 N,N dimethylbenzeneamine

NaOH 280 795 Effluent (ML)

Water 155

Total 1530 1530

Mass balance of Acectofenac

Reaction vessel

Filtration

Purification

N,N dimethyl

amine recovery

Dryer


Annexure-III

Water consumption & wastewater generation

Sr.

No.

Name of Product Water

Consumption Lit/Day

W/W

Generation

Lit/Day

1. Pregabalin 432 764

Telmisartan 1166 1355

Ondansetron HCl 416 759

Bupropioon hydrochloride 537 599

Celecoxib 839 972

Febuxostat 928 977

2. Lidocaine base/HCl 2965 4365

Diclofenac sodium / potassium/

diethylamine

5630 4430

Aceclofenac 4270 5250

Sr.

No.

Break up Water

Consumption

Lit/Day

w/w

Generation

Lit/Day

I Domestic 2000 1700

II Gardening 7500 -

III Industrial

(a) Process 6800 6600

(b) Scrubber 1000 1000

(c) Washing 4000 4000

(d) Cooling 8000 2500

(e) Boiler 5000 500

(f) Water treatment 2000 2000

Total Industrial 26800 16600

Total (I + II + III) 36300 18300

Less Recycle 16000 -

Actual fresh water

requirements

20300 --


Annexure-IV

Details of Air Emission

Sr.

No.

Stack attached

to

Stack

Height

in m

Fuel

Used

Fuel

consumption

rate

APC

measure

Pollutant

1 Steam Boiler (2

T/hr)

21 Agro

waste

6.0 TPD Cyclone

followed by

bag-filter

PM<150 mg/NM3

SO2<100 ppm

NOx<50 ppm 2 Thermic fluid

heater (2 lac

Kcal/hr)

Agro

waste

1.5 TPD

3 DG Set (100 kVA) 11 HSD 30 lit/hr --


Annexure-V

Details of Hazardous Generation and Disposal

Sr.

No.

Type of

Solid Waste

Schedule Quantity

MTPM

Disposal method

1 ETP Waste

MEE Salt

34.3 10.000

3.125

13.125

Collection, storage & disposal at

TSDF site approved by GPCB.

2 Process/

distillation

residue

29.1 /

20.3

30

MT/month

Collection, storage & disposal at

CHWIF or co-processing.

3 Used

Lubricating

Oil

5.1 0.2 Kl/year Collection, storage & use within

premises as lubricant/sell to

registered recycler.

4 Discarded

containers/

barrels/

liners

33.3 Barrels-

1000

nos./month

Liner-100

kg/month

Collection, storage and reuse for

packing of products or disposal

by selling to approved recycler or

traders.

annexure-i list of products sr. name of product quantity...

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