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REPORT 2 TON PER MONTH

PREGABALIN MANUFACTURE

BIZOTIC LIFESCIENCE PVT. LTD. NEW KHARECHIYA, MORBI, GUJARAT

________________________________________

LACIMEHC PROTECH PVT LTD

Address: 214-216, Vinayak Complex Contact: [email protected] Manjalpur, Vadodara Tel Ph: +91 7567311166

Website: www.lacimehc.com +91 8140614866

REPORT: 2 TON PER MONTH PREGABALIN MANUFACTURE

1 | C L I E N T : B I Z O T I C L I F E S C I E N C E P V T . L T D . , M O R B I , G U J A R A T

INDEX

SL.

NO.

CONTENT

PAGE

NO.

1 INTRODUCTION 2

2 PROCESS DESCRIPTION 3

3 MATERIAL BALANCE 10

4 RAW MATERIAL REQUIREMENT 13

5 LIST OF PROPOSED EQUIPMENT AND UTILITIES 14

6 EQUIPMENT CAPACITY 16

7 WATER BALANCE 17

8 WATER CHART 18

9 AIR DETAILS 19

10 DETAILS OF PROPOSED EFFLUENT TREATMENT PLANT 20

11 BLOCK DIAGRAM OF ETP SECTION 21

12 BLOCK DIAGRAM OF PROCESS 22

13 LAYOUT DRAWING 23

14 PRODUCTION PLAN LAYOUT 24



INTRODUCTION

Pregabalin is a gamma-Aminobutyricacidanaloganticonvulsant and

analgesicused for neuropathic pain and as an add on therapy for partial

seizures with or without secondary generalization in adults.

Molecular Structure of Pregabalin is as follows:

The process of manufacture involves the following steps:

Step 1: Preparation of (3R)-3-(carbamoylmethyl )-5-methyl hexanoic

acidphenyl ethyl amine salt

Step 2: Preparation of (3R)-3-(carbamoylmethyl)-5-methyl hexanoic acid

Step 3: Preparation of (3S)-3- (Aminomethyl)-5-methylhexanoic acid (Tech.

Pregabalin)

Step 4: pH adjustment

Step 5: Purification of technical grade pregabalin

Step 1A: Preparation of unwanted isomer from MLR

Step 1B: Conversion of unwanted isomer into Racemic compound



PROCESS DESCRIPTION

STAGE 1:

Procedure :

1. Charge Chloroform into reactor.

2. Charge Methanolinto reactor.

3. Charge (±)-3-(carbamoymethyl)-5-methyl hexanoic acid into reactor.

4. Raise the temperature of the reaction mass to 50 - ⁰C.

5. Add R-(+)-1-phenyl ethyl mine to the above slurry slowly at 50 - ⁰C.

6. Maintain for 15 min at 50 - ⁰C.

7. Again add R-(+)-1-phenyl ethyl mine to reaction mass at 50 - ⁰C.

8. Check the mass, it should be clear.

9. Maintain mass for 30 min at 50 - ⁰C.

10. Stop heating and charge (3R)-(-)-3-(carbamoylmethyl)-5-methyl-hexanoic acid as a seeding

for crystallization under stirring.

11. Cool the mass slowly to 30- ⁰C.

12. Maintain under stirring for 30 min at 30 - ⁰C.

13. Centrifuge the material and wash with chloroform.

14. The wet cake is ready for next stage.



STAGE 2:

Procedure:

1. Charge water (lot-1) into reactor.

2. Charge (3R)-3-(Carbamoylmethyl)-5-methylhexanoic acidphenylethylamine salt into reactor.

3. Cool the reactio ass up to to ⁰C.

4. Adjust the mass pH to 10-11 using sodium hydroxide solution. (Dissolve sodium hydroxide in

water(Lot-2))

5. Maintain the mass for 30 min under stirring.

6. Solution should be clear.

7. Charge chloroform (lot-1) into the reactor.

8. Maintain reaction for 30 min under stirring.

9. Settle the mass for 30 min.

10. Separate the lower chloroform layer.

11. Again charge chloroform (lot-2) into the reactor.

12. Maintain reaction mass for 30 min under stirring.

13. Settle the mass for 30 min.


15. Slowly adjust the pH to 2-3 using con. HCl.

16. Maintain the mass at 10-1 ⁰C for hr.

17. Centrifuge the material.

18. Wash the material with water (lot-3).




STAGE 3:

Procedure:

1. Charge water lot-1 into the reactor.

2. Charge NaOH lot-1 into the reactor.

3. Cool the ass to to ⁰C.

4. Add chlori e gas i to the reactor slowly at to ⁰C gas purgi g .

5. After addition of gas, transfer the sodium hypochlorite solution in to the Buffer Tank.

6. Then in the same reactor, charge water lot-2 into the reactor.

7. Charge NaOH lot-2 in reactor.

8. Cool the mass to 0- ⁰C.

9. Charge (3R)-3-(Carbamoylmethyl)-5-methylhexanoic acid into reactor from Stage 2.

10. Maintain the mass for 30 min.

11. Add sodium hypochlorite solution slowly at 0 to 15 ⁰C (exothermic reaction)

12. After addition maintain mass for hr at to ⁰C.

13. Slowly raise the temperature to 50 - ⁰C.

14. Maintain the reaction mass at 50 - ⁰C for -45 min.

15. Cool the mass to 30 - ⁰C.

16. Filter the mass through hiflow bed (sparkler filter).

NaOH



STAGE 4:

1. Now, put the mass into a Mixing Vessel to adjust the mass pH 3.5 by adding 50 % H2SO4

solution at 30- ⁰C.

2. Adjust the mass pH 7-7.5 using 50 % NaOH solution at 25- ⁰C.

3. Maintain the mass at 20- ⁰C for hr.




STAGE 5:

Procedure:

1. Charge n-butenol into reactor.

2. Charge tech- pregabalin into reactor.

3. Charge water into reactor.

4. Heat the ass to 8 to 8 ⁰C.

5. Maintain for 30 min at 80 - 8 ⁰C.

6. Cool the mass slowly to 8 - ⁰C

7. Maintain mass at 8- ⁰C for hr.

8. Filter the material.

9. Dry the material at 45 - ⁰C.



STAGE 1A:

Procedure:

1. Charge MLR in to the reactor.

2. Charge sodium Hydroxide solution in to the reactor.

3. Maintain the mass for 1 hr under stirring.

4. Settle the mass for 30 mins.


6. Slowly adjust pH 2-3 using Con. Hydrochloric acid.

7. Mai tai the ass at to ⁰C for hr.





STAGE 1B:

Procedure:

1. Charge toluene into the reactor.

2. Charge unwanted isomer into reactor.

3. Charge PTSA into reactor.

4. Heat the mass to reflux temperature (110- ⁰C for hrs.


6. Slowly charge sodium hydroxide solution (dissolved sodium hydroxide in water lot-1).

7. Maintain the reaction at 60- ⁰C for -3 hrs.


9. Separate the layers.

10. Take aq. Layer in to the reactor.

11. Adjust the pH to 2-2.5 using Con. HCl.


13. Maintain mass for 1 hr at 10- ⁰C.

14. Filter the material through a centrifuge.

15. Wash the material with water (Lot-2) at 10- ⁰C.

16. Dry the material at 50- ⁰C till m/c less than 1.0%.

17. The material is ready to be recycled to Stage 1.



RAW MATERIAL REQUIREMENT

(PER MONTH CALCULATIONS)

SL.

NO.

RAW MATERIALS QUANTITY

(Kg/Month)

1 3-(Carbamoylmethyl)-5-methylhexanoic acid

i.e. P-I (C9H17O3N)

1453.31

2 ( R )-(+)-1-Phenyl ethyl amine i.e. PEA (C8H11N) 707.04

3 Chloroform (CHCl3) 27947.13

4 Methanol (CH3OH) 351.24

5 Water (H20) 38856.60

6 Sodium Hydroxide (NaOH) 4286.87

7 Conc. Hydrochloric Acid (HCl) 3763.53

8 Sulphuric Acid (H2SO4) 3500.00

9 Chlorine (Cl2) 446.54

10 n-butenol (C4H7OH) 5717.65

11 Toulene (C6H5CH3) 4685.38

12 p-Toulenesulphonic acid (PTSA)

(CH3C6H4SO3H)

90.80

TOTAL 91806.10



LIST OF PROPOSED EQUIPMENTS AND UTILITIES

PROPOSED EQUIPMENT LIST SL.

NO. AREA EQUIPMENT MOC STAGE

1 REACTION SS REACTOR SS 316 1



4 REACTION GLASS LINED REACTOR 2

5 REACTION CENTRIFUGE 1

6 REACTION CENTRIFUGE MSRL 2

7 REACTION CENTRIFUGE SS 316 4

8 REACTION MIXING VESSEL SS 316 4

9 REACTION SPARKLER FILTER SS 316 3

10 REACTION BUFFER STORAGE FOR SODIUM

HYPOCHLORIDE SS 316 3

11 PP REACTION SS REACTOR SS 316 5

12 PP REACTION CENTRIFUGE SS 316 5

13 PP REACTION TRAY DRYER SS 316 5

14 POWDER

PROCESSING ROTOCONE VACUUM DRYER SS 316

15 POWDER

PROCESSING MULTIMILL SS 316

16 POWDER

PROCESSING SHIFTER SS 316

17 RECOVERY SS REACTOR SS 316 1A

18 RECOVERY SS REACTOR SS 316 1B

19 RECOVERY GLASS LINED REACTOR 1A

20 RECOVERY GLASS LINED REACTOR 1B

21 RECOVERY CENTRIFUGE MSRL 1A

22 RECOVERY CENTRIFUGE MSRL 1B

23 RECOVERY TRAY DRYER SS 316 1B

24 RECOVERY BUFFER STORAGE FOR MLR FROM STAGE 1 SS 316 1A

25 STORAGE P-I STORAGE TANK

26 STORAGE CHLOROFORM STORAGE TANK

27 STORAGE METHANOL STORAGE TANK

28 STORAGE PHENYL ETHYL AMINE STORAGE TANK

29 STORAGE SODIUM HYDROXIDE STORAGE TANK

30 STORAGE CONC. HYDROCHLORIC ACID STORAGE

TANK

31 STORAGE SULPHURIC ACID STORAGE TANK

32 STORAGE CHLORINE STORAGE TANK



33 STORAGE CARBON DIOXIDE STORAGE TANK

34 STORAGE n-BUTENOL STORAGE TANK

35 STORAGE P-IV STORAGE TANK (FINAL PRODUCT)

36 STORAGE p-TOULENE SULPHONIC ACID STORAGE

TANK

37 STORAGE TOULENE STORAGE TANK

UTILITIES

SL. NO. NAME NO

1 HOT WATER GENERATOR 1

2 AIR DRYER + COMPRESSOR 1

3 DG SET 1

4 DM PLANT 1

5 COOLING TOWER 1

6 CHILLING PLANT 2

7 AHU 6

OTHER ROOMS IN PP AREA SL. NO. NAME NO

1 FP STORAGE ROOM 1

2 QUARRANTINE ROOM 1

3 PACKING AND LABELLING ROOM 1



EQUIPMENT CAPACITY

SUGGESTED EUIPMENT CAPACITY

SL.

NO.

EQUIPMENT STAGE CAPACITY

1 SS REACTOR 1 3 KL

2 SS REACTOR 2 3 KL

3 SS REACTOR 3 3 KL

4 GLASS LINED REACTOR 2 3 KL

5 SS REACTOR 5 3 KL

6 SS REACTOR 1 A 3 KL

7 SS REACTOR 1 B 3 KL

8 GLASS LINED REACTOR 1 A 3 KL

9 GLASS LINED REACTOR 1 B 3 KL

10 CENTRIFUGE 1

11 CENTRIFUGE 2

12 CENTRIFUGE 4

13 CENTRIFUGE 5

14 CENTRIFUGE 1 A

15 CENTRIFUGE 1 B

16 MIXING VESSEL 4 3 KL

17 AHUs 200 CFM



WATER BALANCE

WATER

CONSUMPTION

GENERATION/LOSSES ETP SECTION

SL.

NO

USERS

FRESH

WATE

R FEED

(m3/d

ay)

RECYCL

E FEED

(m3/da

y)

TOTAL

FEED

(m3/d

ay)

EVAPOR

ATION

LOSSES

(m3/da

y)

GROUN

D/SUM

P PIT

LOSSES

(m3/da

y)

EFFLUENT

GENERATI

ON TO ETP

(m3/day)

RECYCLE

@40 %

EFFLUENT

GENREAT

ION BACK

TO PLANT

(m3/day)

DISPOS

AL to

CETP

(m3/da

y)

A Domestic 1 0 1 0.03 0.2 0.77

1.27

1.91

B Industrial

1 Process 1.6 0 1.6 0.2 0

2 Washing 2 0 2 0.06 1.94

3 Boiler Feed 0.5 0 0.5 0.05 0.45

4 Cooling

Makeup

0.5 0 0.5 0.475 0.025

5 Gardening 0.5 2 2.5 2.5

6 Others

(R.O. &

Softening

Rejects)

0.5 0.5

0.815 2.7 3

TOTAL 6.6 2 8.6 6.7 3.19



WATER CHART



AIR DETAILS

Sr.

No

Stack

Attached

Fuel

used

Stack

Height (ft)

Pollution control

measure

Exit Gases

Type of

Pollutant

Flue Gas Emission

1

Hot Water

Generator to

Steam Boiler

Diesel 90

Cyclone Separator

and Scrubber

Water Vapour

+ Carbon

Dioxide

NIL



DETAILS OF PROPOSED EFFLUENT TREATMENT PLANT

The steps followed in the Effluent Treatment Plant are described below:

1. The raw effluent is being passed through the Oil & Grease Chamber for preliminary

treatment and collected in the Collection tank where chemical dosing is carried out to

neutralize the effluent.

2. The effluent from the collection tank is pumped to Primary Settling Tank (PST). The

sufficient retention time is provided in PST to settle down the coagulated mass.

3. The sludge generated from the bottom of the PST is collected in the Sludge Sump. The

filtrate from the Sludge Sump is conveyed to the Filter Press.

4. The over flow of PST is conveyed to Anaerobic Reactor for reduction of organic loading by

Anaerobic treatment.

5. From the Anaerobic Reactor the effluent is conveyed to Aeration Tank, where sufficient

retention time is provided for Biological Treatment of the Effluent.

6. The over flow of Aeration Tank is conveyed to Secondary Settling Tank for further settling

of coagulated mass. The settled biomass is recycled and excess biomass is drained to

Sludge Sump.

7. The over flow of SST is collected in the Treated Water Sump. After treated water sump,

Filter has been provided before its final discharge to CETP.



LINE DIAGRAM OF EFFLUENT TREATMENT PLANT

Sr. No. Treatment Unit No. of Units

1 Oil and Grease Tank 1

2 Collection cum Equalization Tank 1

3 Primary Settling Tank 1

4 Anaerobic Reactor 1

5 Aeration Tank 1

6 Secondary Settling Tank 1

7 Treated Water Sump 1

8 Pressure Sand Filter 1

10 Sludge Sump 2

11 Filter Press 1

SF XXX

R XXXGLR XXX D XXX

T XXXCF

XXX

SS REACTORGLASS LINED

REACTOR

SPIN DRYER

TANK CENTRIFUGE SPARKLER

FILTER

SYMBOL

T 004

T 003

T 002

BS 002

R 001T 005

R 002 R 003

GLR 001

R 004

R 006R 005

GLR 003GLR 002

T 006

BF 001

SF 001

T 010

MLR

(TO ETP)

T 012

T 013

CF

001

CF002

CF

003

CF004

CF006

DM WATER

T 011

CF005

TO

CHLOROFORM

RECOVERY

TOULENE

LAYER

TO

CHLOROFORM

RECOVERY

BLOCK DIAGRAM FOR MANUFACTURE OF PREGABALIN

T 007

MV OO1

MLR

(TO ETP)

REACTION AREA PP REACTION AREA

POWDER PROCESSING AREA

MM 001RCVD001

SH

001

MLR

(TO ETP)

MLR

(TO ETP)

MLR

(TO ETP)

MM XXXRCVDXXX

SH

XXX

SHIFTER MULTIMILL ROTO-CONE

VACUUM DRYER

SL. NO. EQUIPMENTTAG NO.AREA

9

2

3

4

5

6

7

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

8

1 REACTION

PP

PP

PP RCVD 001

MM 001

SH 001

ROTOCONE VACUUM DRYER

MULTIMILL

SHIFTER

PP-REACTION

PP-REACTION

PP-REACTION

REACTION

REACTION

REACTION

REACTION

REACTION

REACTION

REACTION

REACTION

RECOVERY

RECOVERY

RECOVERY

RECOVERY

RECOVERY

RECOVERY

RECOVERY

RECOVERY

TRAY DRYER (STAGE 5)

CENTRIFUGE (STAGE 5)

SS REACTOR (STAGE 5)

SPARKLER FILTER (STAGE 3)

MIXING VESSEL (STAGE 4)




GLASS LINED REACTOR (STAGE 2)


CENTRIFUGE (STAGE 2) [MOC: MSRL]


SS REACTOR (STAGE 1A)

SS REACTOR (STAGE 1B)

GLASS LINED REACTOR (STAGE 1A)

GLASS LINED REACTOR (STAGE 1 B)

BUFFER STORAGE FOR MLR FROM STAGE 1 (STAGE 1A)

TRAY DRYER (STAGE 1B)

CENTRIFUGE (STAGE 1B) [MOC: MSRL]

CENTRIFUGE (STAGE 1A) [MOC: MSRL]

MV XXX

MIXING VESSEL

R 001

R 002

R 003

GLR 001

CF 001

CF 002

CF 003

MV 001

SF 001

R 004

CF 004

TD 001

R 005

R 006

GLR 002

GLR 003

CF 005

CF 006

TD 002

BS 002

T 001

T 002

T 003

T 004

T 005

T 006

T 007

T 008

T 009

T 010

26

27

28

34

33

32

31

30

29

STORAGE

STORAGE

STORAGE

STORAGE

STORAGE

STORAGE

STORAGE

STORAGE

STORAGE

STORAGE

T 008

T 009

REACTION BUFFER STORAGE FOR SODIUM HYPOCHLORIDE (STAGE 3)BS 001

D 001

D 002

[ TO

BUTENOL

RECOVERY]

T 01135 STORAGE

T 01236 STORAGE

T 001

T 01337 STORAGE

P-I STORAGE TANK

CHLOROFORM STORAGE TANK

METHANOL STORAGE TANK

PHENYL ETHYL AMINE STORAGE TANK

SODIUM HYDROXIDE STORAGE TANK

CONC. HYDROCHLORIC ACID STORAGE TANK

SULPHURIC ACID STORAGE TANK

CHLORINE STORAGE TANK

CARBON DIOXIDE STORAGE TANK

n-BUTENOL STORAGE TANK

P-IV STORAGE TANK (FINAL PRODUCT)

p-TOULENE SULPHONIC ACID STORAGE TANK

TOULENE STORAGE TANK

BS XXX

BUFFER STORAGE

NOTE:

1) FOR STAGE 3, WE FIRST MAKE SODIUM

HYPOCHLORIDE IN R 003, TRANSFER IT TO THE BUFFER

STORAGE BS 002, THEN WE USE THE SAME REACTOR R

003 FOR MAKING TECH PREGABALIN AND THE

TRANSFER THE MATERIAL TO SPARKLER FILTER SF 001.

2) LATER IN STAGE 4, WE HAVE REPLACED THE

REACTOR WITH A MIXING VESSEL, MS 001 IN WHICH

ADDITION OF SULPHURIC ACID IS DONE.

3) FOR SEPARATION OF CHLOROFORM AND PEA FROM

CHLOROFORM LAYER OF STAGE 1A GLR 002, WE CAN

USE SAME SSR/GLR AS STAGE 1A

9000

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report -...

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