ANNEXURE - environmentclearance.nic.in · M/s Novazeal Lifesciences, Plot no.806,G.I.D.C., Kerala,...

Annexures to Form – 1 & Pre Feasibility ReportProposed Project for manufacturing of bulk drugs and its intermediates of

M/s Novazeal Lifesciences, Plot no.806,G.I.D.C., Kerala, District: Ahmedabad, Gujarat.

ANNEXURE – A

DETAILS OF PRODUCTS

Sr. No. Name of Product Production[ MT/Month]

1 Chlomiphene Citrate 1

2 Oxyclozanide 15

3 Bupropione hydrochloride 5

4 Benfotiamine 1

5 n-butyl bromide And / OR

Iso propyl bromide And / OR

n-propyl bromide

306

7

8 Chlorzoxazone 10

9 Piroxicam 5

10 Nitrazepam And / OR

Diazepam10

11

12 Buclazine dihydrochloride And / OR

Meclazine dihydrochloride10

13

14 Tramadol hydrochloride 5

15 Duloxetine hydrochloride 5

16 Dapoxetine hydrochloride 5

17 Lidocaine hydrochloride 5

18 Sodium Bromide solution 5

TOTAL 112



ANNEXURE – B

DETAILS OF RAW MATERIALS CONSUMPTION

Sr.no.

Name of Raw Materials Consumption(MT/Month)

Chlomiphene Citrate 11 P-Hydroxy Benzo Phenone (PHBP) 0.53

2 DEC HCl 0.55

3 BTAC 0.04

4 MDC 1.85

5 Water 1.06

6 NaOH 0.26

7 Benzyl chloride 0.79

8 Mg Turning 0.16

9 2-Me THF 4.23

10 DIl. HCl 0.26

11 IPA 2.65

12 Con. H2SO4 0.21

13 Chloroform 3.97

14 Cl2 gas 0.13

15 Sodium Carbonate 0.95

16 Citric acid 0.35

17 Methyl Ethyl Ketone 2.91

Oxyclozanide 15

1 2,4-DCP 6.24

2 Dil.HNO3 (60%) 4.80

3 Na2S 7.38

4 Water 7.92

5 H2SO4 2.79

6 MCB 55.20

7 TCSA 9.18



8 Thionyl chloride 4.54

9 Acetone/Methanol 45.96

10 Activated carbon 0.615

Bupropione HCl 5

1 3-chloropropiophenone 3.33

2 NBS 3.93

3 PTSA 0.04

4 MDC 9.00

5 Water 3.33

6 Tert. butylamine 4.33

7 IPA 10.00

8 IPA. HCl 3.66

Benfotiamine 1

1 Thiamine Hydrochloride 0.74

2 Phosphoric Acid 0.52

3 TBA 0.96

4 Chloroform 1.67

5 Water 1.64

6 Caustic flakes 0.21

7 Benzoyl chloride 0.11

8 Con. HCl 0.16

9 Mysol 0.83

N-Butyl Bromide 30

1 N-Butanol 18.2

2 HBr/Liq.Bromine 20.0

3 H2SO4 0.45

ISO-Propyl Bromide 30

1 N-propanol 17.2


3 H2SO4 0.85

N-Propyl Bromide 30

1 N-propanol 17.15




3 H2SO4 0.85

Chlorzoxazone 10

1 4- Chloro-2-aminophenol 10.00

2 Urea 8.32

3 HCl 5.62

4 Methanol (80%) 12.50

5 MDC 5.00

6 Carbon 0.25

Piroxicam 5

1 Methyl Benzothiazine iso propyl ester 4.52 2 Amino pyridine 1.42

3 O-xylene 31.82

4 IPA 22.73

5 Carbon 0.37

Nitrazepam 10

1 Chloroacetyl chloride 4.67

2 2-amino 5-nitro benzophenone 10.08

3 Toluene 41.67

4 Ammonia 2.08

5 Methanol 52.08

6 Carbon 0.42

Diazepam 10

1 Chloroacetyl chloride 4.61

2 (5-chloro-2-methylamino)phenyl)(phenyl)methanone

10.08

3 Toluene 41.15

4 Ammonia 2.10

5 Methanol 51.44

6 Carbon 0.41

Buclazine dihydrochloride 10

1 P-chloro benzhydrylpiperizine 6.36

2 P-tert butylbenzyl chloride 4.04



3 NaOH 0.89

4 Toluene 22.22

5 Acetone 17.78

6 Carbon 0.22

7 HCl 1.56

Meclazine dihydrochloride 10

1 P-chloro benzhydrylpiperizine 6.98

2 meta methylbenzylchloride 3.41

3 NaOH 0.98

4 Toluene 24.39

5 Acetone 19.51

6 Carbon 0.24

7 HCl 1.71

Tramadol hydrochloride 5

1 Cyclohexanone 1.81

2 Formaldehyde 0.56

3 Dimethylamine 0.83

4 m-chloroanisol 2.63

5 Mg Turning 0.445

6 Toluene/THF 20.37

7 Acetone 18.52

8 Carbon 0.28

9 HCl gas 0.67

Duloxetine hydrochloride 5

1 2-acetyl thiophene 2.10

2 Formaldehyde 0.50

3 Dimethylamine 0.75

4 Toluene 8.33

5 Methanol 13.33

6 Ni cat. 0.03

7 DMSO 10.00

8 Fluro naphthalene 2.42



9 KOH 1.87

10 Acetone 16.67

11 HCl gas 0.6

Dapoxetine hydrochloride 5

1 3-chloro-1-phenylpropan-1-one 2.51

2 Methanol 11.94

3 Ni cat. 0.07

4 Alpha naphthol 2.15

5 KOH 0.84

6 Toluene 11.94

7 Methane sufonicacid 1.43

8 Diethylamine 0.67

9 Acetone 17.91

10 Carbon 0.15

11 HCl gas 0.54

Lidocaine Hydrochloride 5

1 2,6-Xylidine 2.28

2 Chloro acetyl chloride 2.11

3 Diethyl amine 1.38

4 NaOH 0.75

5 Toluene 20.75

6 Acetone 15.09

7 Carbon 0.19

8 HCl 1.32



ANNEXURE – C

DETAILS OF MANUFACTURING PROCESS

1. Clomiphene Citrate

Process:

STAGE‐I: KETO OIL FORMATION: Methylene chloride, BTAC, PHBP, Diethyl Amino Ethyl Chloride HCl, Sodium

Hydroxide and D.M. water are reacted in reaction vessel at specific temp. andtime and at different interval of time of reaction steps.

Product in oil form is obtained after layer separation and reaction is carriedout.

After layer separation collected organic MDC is distilled out.STAGE‐II: CARBINOL FORMATION (GR) 2‐Methyl THF and Magnesium Turning are charged and stirred. Benzyl chloride is added and steam is applied. After reflux cool the mass. Keto‐Oil and 2‐ Methyl THF are added. Cooling is applied and mass is stirred. Mass is allowed to settle. Reaction mass is heated and 2‐Methyl THF is distilled out. Cooling is applied and IPA is added. Mass is filtered and centrifuged. Mother liquor is separated out.

STAGE‐III: HYDROLYSIS Carbinol and C.H2SO4 and Chloroform are added. Mixture is stirred. Mixture is used with chloroform for next step.

STAGE‐IV: CHLORINATION Mixture is cooled and liq. Chlorine is added. Mass is stirred. Sodium carbonate is added to the mass and it is stirred. Mass is allowed to settled. Layers are separated out. In lower organic layer water is added. Steam is applied and chloroform is distilled out.

STAGE‐V: CITRATE FORMATION Clomiphene base, MEK and Citric acid are added under stirring. Rection mass is cooled, stirred and filtered by centrifugation. Mother liquor is separated and product is dried.



Chemical Reaction:

(4-hydroxyphenyl)(phenyl)methanoneMolecular Weight: 198.22

O

OH

(4-(2-(diethylamino)ethoxy)phenyl)(phenyl)methanoneMolecular Weight: 297.39

O

ON

ClN . HCl

Molecular Weight: 172.10

2-chloro-N,N-diethylethanamine

(Keto Oil)


O

ON

1-(4-(2-(diethylamino)ethoxy)phenyl)-1,2-diphenylethanolMolecular Weight: 389.53

ON

OHCl


Mg-turning

Keto Oil(Carbinol)

ON

OH

(Carbinol)

Acid catalyst ON

(E)-2-(4-(1,2-diphenylvinyl)phenoxy)-N,N-diethylethanamine




ON

(Z)-2-(4-(2-chloro-1,2-diphenylvinyl)phenoxy)-N,N-diethylethanamineMolecular Weight: 405.96

ON

(E)-2-(4-(1,2-diphenylvinyl)phenoxy)-N,N-diethylethanamine


Cl

chloriation

ON

Cl

(Z)-2-(4-(2-chloro-1,2-diphenylvinyl)phenoxy)-N,N-

diethylethanamine

citric acid

ON

Cl .

HO

OOH

O OH

O

HO

(Z)-2-(4-(2-chloro-1,2-diphenylvinyl)phenoxy)-N,N-diethylethanamine 2-hydroxypropane-1,2,3-tricarboxylate




Mass Balance:

Keto oil

Hydro Product

Input : 884.05 Kg Output : 884.05 Kg

Carbinol

Clomiphene base

PHBP : 20 KgDEC HCl : 21 KgBTAC : 1.6 KgMDC : 70 LWater : 40 LNaOH : 10 Kg

Reaction vessel

Waste water : 67.6 KgMDC : 68.5 LSolvent loss : 1.5 Kg

Seperation &solvent

distillation

Benzyl chloride : 30 KgMg Turning : 6 Kg2-Me THF : 160 LWater : 60 KgDil. HCl : 10 kgIPA : 100 L

IPA reco : 95 LWaste water : 106.2 KgSolvent loss : 10 L2-Me THF : 155 L

Seperation &Solvent

Distillation &Centrifuge

Hydrolysis

Chloroform : 145 LWaste water : 74.6 Kg

Chlorination,Distilation and

Centrifuge

Pulvarising andPacking

Con. H2SO4 : 8 KgChloroform : 150 L

Cl2 gas : 4.95 KgSod. Carbonate : 36 KgWater : 33 L

Citric acid : 13.5 KgMEK : 110 L

Chlorination,Distilation and

Centrifuge

MEK : 106 LEvaporation loss : 6.7 Kg

Clomiphene citrate (37.8 kg)

Drying Loss : 10.15



2. Oxyclozanide

Process:

STEP ‐I: Nitration Reaction: Dilute nitric acid is charged and Stirred. 2,4-dichlorophenol is added under

cooling. After stirring it is filtered. The wet cake will be used in the next step without drying.

STEP‐II: Reduction Reaction: Water and sodium sulphide are stirred, heated and 2,4-dichloro-6-nitrophenol

is added. After stirring and heating at specific temp. and time MCB and sulphuric acid

are added. MCB layer containing 2,4-dichloro-6-aminophenol will be used in the next

step.Step-III [Crude Oxyclozanide] Mono Chloro Benzene, 3, 5, 6-Trichloro Salicylic Acid and Thionyl chloride are

charged, Scrubber pump is started and products are heated. Thionyl chloride is distilled out. Material is transferred into 2, 4, Di chloro – 6-

Amino phenol and Mono Chloro Benzene. HCl is scrubbed through Scrubber. After reflux, mass is cooled and filtered. Product is dried.

Step-IV [Oxyclozanide] Acetone, Crude Oxyclozanide and Activated Carbon are added Mass is refluxed, heated and stirred. The reaction mass is stirred and filtered in hyflow bed to remove charcoal. Mass is chilled, stirred and filtered. Mass is washed in chilled acetone and dried.



Chemical Reaction:

O2N

Cl

OHCl

2,4-dichloro-6-nitrophenol


H2N

Cl

OHCl

2,4-dichloro-6-aminophenol


Na2SMolecular Weight: 78.04

OH

OHO

Cl

Cl Cl

3,5,6-trichlorosalicylic acid

SOCl2OH

OCl

Cl

Cl Cl

H2N

Cl

OHCl

+OH

OCl

Cl

Cl Cl

HOO

Cl Cl

Cl

NH

Cl

OHCl

2,3,5-trichloro-N-(3,5-dichloro-2-hydroxyphenyl)-6-hydroxybenzamide

O2N

Cl

OHCl

Cl

OHCl HNO3

+ H2O

2,4-dichlorophenol 2,4-dichloro-6-nitrophenol

water

Molecular Weight: 163.00 Molecular Weight: 208.00

H2O +++ Na2S2O3

H2SO4

Na2SO4 H2O

MW-158 MW-142

++ HCl SO2

2,3,5-trichloro-6-hydroxybenzoyl chlorideMolecular Weight: 259.90

2-amino-4,6-dichlorophenol


Molecular Weight:178.02


(Oxyclozanide)

MCB

130 0C



63

18



Mass Balance:

Oxyclozanide : 250 KgInput : 2410.7 Kg Output : 2410.7 Kg

2,4 - DCNP

2,4 - DCAP

Acid chloride

Oxyclozanide crude

Rec. Acetone/Methanol :730 LSolvent loss : 20 LResidue : 16 Kg

2,4-DCP : 104 KgDil.HNO3(60%) : 80 KgMCB : 100 L

Reaction vessel

Waste water : 70 KgMCB reco : 95 LLoss : 5 L

Nitration &Filtration

Na2S : 123 KgWater : 132 LH2SO4 : 43.5 KgMCB : 410 L

Waste water : 160 LReduction

SO2 gas : 40.75 KgHCl : 46.5 Kg

Chlorination

MCB reco : 780 LDistilled residue : 15 KgEvaporation loss : 25 LWaste water : 100.5 L

Condensation,Centrifuge and

Distillation

Chilling and Centrifuge

TCSA :153.5 KgThionyl chloride : 75.75 KgMCB :410 L

Acetone/Methanol :766 LActivated carbon :10 Kg

Filter Spent carbon : 10 Kg

Drying Loss : 47



3. Bupropione Hydrochloride

Process:

Step‐I: Preparation of 2-bromo-1-(3-chlorophenyl)propan-1-one: 3‐Chloropropiophenone ,PTSA are charged and stirred. NBS is charged and

mass is heated. After cooling MDC and DM water are charged. Mass is stirred and organic layers are separated out.

Step‐II: Preparation of 2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one In organic layer tert. Butyl amine is charged and product is heated to reflux. DM water is charged. Layers are separated and aqueous layer is extracted with MDC. Both Organic layers are distilled out under vacuum. Product is obtained as

Oil.Step‐III: Preparation of Bupropion hydrochloride: IPA is added in Base oil. Mass is cooled and IPA,HCl is added in it. Mass is hold, filtered and washed with chilled IPA. Mass is dried under vaccum.



Chemical Reaction:

Cl

CH3

O

1-(3-chlorophenyl)propan-1-one


Cl

CH3

O

Br

2-bromo-1-(3-chlorophenyl)propan-1-one


NBS

Cl

CH3

O

Br

2-bromo-1-(3-chlorophenyl)propan-1-one


Cl

CH3

O

HN

2-(ter t-butylamino)-1-(3-chlorophenyl)propan-1-one


Tert.butylamine

Cl

CH3

O

HN

2-(tert -butylamino)-1-(3-chlorophenyl)propan-1-one


IPA.HCl

Cl

CH3

O

HNHCl

2-(tert -butylamino)-1-(3-chlorophenyl)propan-1-onehydrochloride


Bupropion Hydrochloride



Mass Balance:

Bupropione HCl : 150 Kg

m-chloro-bromo-propiophenone in MDC

Bupropion base

Input : 1129.2 Kg Input : 1129.2 Kg

3-chloropropiophenone:100KgNBS : 118 KgPTSA : 1.2 KgMDC : 200 LWater : 50 L

Reaction vessel

Waste water : 103.2 LBromination &

SolventDistilation

Tert. Butyl Amine : 130 KgMDC : 70 LWater : 50 Kg

MDC : 260 LEvaporation loss : 10 LWaste water : 178 L

Amination &Solvent

Distillation

IPA : 390 LEvaporation loss : 15 LResidue : 5 Kg

CentrifugeIPA : 300 LIPA. HCl : 110 L

Pulvarising andPacking

Drying Loss : 18 L



4. Benfotiamine

Process:

Step‐I: Preparation of thiamine monophosphate(TMP): Poly Phosphoric Acid is added at room temperature and it is cooled. Thiamine Hydrochloride is added and it is stirred. Mass is heated, condensed

and water is added at same temp. for hydrolysis of product. Mass is cooled. Tributylamine is added and stirred. Chloroform is added and it is stirred. After stirring reaction mass is allow to settle and aq. and organic layer is

separated out.The aq. Layer distilled out the under vacuum. After centrifugation and drying product is obtained.

Step‐II: Preparation Of Benfotiamine‐Condensation Reaction Thiamine Monophosphate Chloride and water are stirred. After cooling NaOH solution is added. Mass is stirred. Benzoyl Chloride is added and mass is stirred. After completion of reaction

Conc. HCl is added and mass is stirred. After centrifugation Mysol is added in mass and it is heated to reflux. Product is chiiled, stirred and centrifuged. Mysol is taken for distillation and product is dried.

Chemical reaction:

OHNH2

N+

S

N

N

Cl-

H Cl

thiamine hydrochloride


+ PO

HOOH

OH

phosphoric acid


NH2

N+

S

N

N

Cl-

PO

O

OH

OH

thiamine monophosphate chloride


(TMP)

NH2

N+

S

N

N

Cl-

PO

O

OH

OH

thiamine monophosphate chloride


(TMP)

+O

Clbenzoyl chloride

Aq.NaOH OS

OP

O

OH

HON

O

N

N

NH2

S-[2-{[(4-Amino-2-methylpyrimidin-5-yl)methyl](formyl)amino}-5-(phosphonooxy)pent-2-en-3-yl] benzenecarbothioate


(Benfotiamine)



Mass Balance:

DryingLoss : 32

Benfotiamine : 168 Kg

Thiamine monophosphate chloride

Input : 1148.7 Kg Input : 1148.7 Kg

Pulvarising &Packing

Thiamine Hydrochloride:125KgPoly Phosphoric Acid: 87.5 KgTBA : 161 KgChloroform : 280 KgWater : 125 Kg

Reaction vessel

Couplingreaction

Mysol : 137 KgWaste water : 216.78 LLoss : 3 kgResidue : 5 Kg

Condensation &hydrolysis

Water : 150 KgCaustic flakes : 34.78 KgBenzoyl chloride : 18 KgCon. HCl : 27.5 KgMysol : 140 kg

Waste water : 300 KgChloroform : 270 KgLoss : 10 KgResidue : 7 Kg



5. N-Butyl Bromide

Process:

N-Butanol, HBr/Liq.Bromine and H2SO4 are processed and N-butyl bromide isobtained.

Chemical reaction:

CH3-(CH2)3-OH + HBr + H2SO4 CH3-(CH2)3-Br + H2O

Mass Balance:

Reaction &Distillation

N-Butanol : 1.0HBr/Liq.Bromine : 1.100H2SO4 : 0.025

Waste water : 0.225Losses : 0.250

Input : 2.125 Kg Output : 2.125 KgN-Butyl Bromide : 1.65 Kg



6. Iso-propyl Bromide

Process:

N-propanol, HBr/Liq.Bromine and H2SO4 are processed and Iso-propylbromide is obtained.

Chemical reaction:

Mass Balance:

CH3-CH-CH3 + HBr / Br2 + H2SO4

OH

CH3-CH-CH3 + H2O

Br

Reaction &Distillation

N-propanol : 1.0HBr/Liq.Bromine : 1.14H2SO4 : 0.050

Waste water : 0.19Losses : 0.25

Input : 2.19 Kg Output : 2.19 KgIso-propyl Bromide : 1.75Kg



7. N-Propyl Bromide

Process:

N-propanol, HBr/Liq.Bromine and H2SO4 are processed and N-propyl bromideis obtained.

Chemical reaction:

Mass Balance:

CH3-(CH2)2-OH + HBr / Br2 + H2SO4 CH3-(CH2)2-Br + H2O

N-Propyl Bromide : 1.75Kg

Reaction &distillation

N-propanol 1.0HBr/Liq.Bromine 1.14H2SO4 0.050

Waste water 0.410Losses 0.250

Input : 2.19 Kg Output : 2.19 KgKg



8. Chloroxazone

Process:

4 –CAP and HCl are charged and stirred. Urea is added and heated forreflux.

After cooling the product it is centrifuged and filtered. Methanol is charged in wet cake and it is stirred. After heating carbon is added. Mass is filtered, centrifuged and dried.

Chemical reaction:

OH

NH2Cl

4-Chloro 2-amino Phenol

143

+H2N

ONH2

urea

60

30% HCl

Cl NH

OO

Chlorzoxazone

169

MeOH



Mass Balance:

Input : 1668 Kg Input : 1668 Kg

Chloroxazone crude

4-CAP : 400 KgUrea : 333 KgHCl : 225 KgMDC : 200 Kg

Reaction vessel

Water effluent : 650 KgCentrifuge

Methanol : 500 KgCarbon : 10 Kg

Solid waste : 10 KgS. S. ReactorReflux and filter

Rec. Methanol : 480 LLoss : 15 LResidue : 5 Kg

Centrifuge /Chilling

Chloroxazone : 400 Kg

Pulvarising andpacking

Drying Loss : 108



9. Piroxicam

Process:

O-xylene , 2 Amino pyridine, Methyl Benzothiazine and ISO propyl ester arecharged and heated.

O-xylene is distilled out by vaccum. IPA is added in wet cake with stirring. It is heated for reflux and after it carbon is added and refluxed. After cooling mass is filtered, centrifuged and dried.

Chemical reaction:

SN

O

O

OH

OO

4-Hydroxy2-methyl-2H-1,2,benzo

thiazine-3-isopropylcarboxylate,1-1-dioxide (ester)

+ NNH2

2-Amino Pyridine

Xylene

SN

OOH

OO

NNH

Piroxicam

+ OH

propan-2-ol

60

331297

94



Mass Balance:

O-xylene : 1000 Kg

IPA : 100 Kg

IPA : 100 Kg

Piroxicam Crude

Piroxicam : 330 KgInput : 4016 Kg put : 4016 Kg

Methyl BenzothiazineIsopropylester : 297 Kg

2 Amino pyridine : 94 Kgo-xylene : 1100 Kg

Reaction vessel

o-xylene Rec. : 1998 LSolvent loss : 102 L

Centrifuge

IPA : 1300 KgCarbon : 25 Kg

Solid waste : 25 KgS. S. Reactor

Reflux and Filter

Centrifuge /Chilling

Rec. IPA : 1430 KgLoss : 55Residue : 15 Kg

Pulvarising andpacking

Drying Loss : 61



10. Nitrazepam

Process:

5-Nitro 2-Amino Benzophenone ( Nitro amino Ketone) is reacted with chloroacetyl chloride in toluene by refluxing and Nitro chloro intermediate isobtained. HCl generated is scrubbed in the scrubbing system.

After the reaction the mass is cooled and centrifuged. Wet cake is taken fornext step.

Toluene layer is distilled to recover solvent. Wet cake is dissolved in Methanol and Nitro chloro intermediate is obtained. The Nitro chloro intermediate is reacted with ammonia in solvent methanol by

refluxing and cooled and filtered. The resultant filtrate is concentrated 50% torecover solvent (which is recycled).

The concentrated mass is cooled and Nitrazepam crystals are obtained.These crystals are centifuged and pure Nitrazepam is dried.

The mother liquor from the centrifuge is sent for recovery of solvent to recovermethanol. The last portion of solvent distilling is methanolic water which issent as effluent.

The residual mass remaining as undistilled is taken as Haz waste.



Chemical reaction:

O

NH2

N+O

O-

5-nitro 2-aminobenzophenone

Cl

OCl+

N

HN

O2N

Oammonia51

TolueneMethanol

Nitrazepam

242112

H2O

18

+

O

NH

N+O

O-

OCl

Nitro chloro intermediate318.5

281



Mass Balance:

HCl gas 36 Kg scrubber

Nitrazepam : 240 Kg

Nitrochloro intermediate

Input : 2664 Kg Output : 2664 Kg

Chloroacetylchloride : 112 Kg2-amino 5-Nitrobenzophenone242 KgToluene : 1000 L

Reaction vessel

Rec. Toluene : 955 LSolvent loss : 40 LResidue ; 5 Kg

Centrifuge

Ammonia : 50 KgMethanol : 1250 L

S. S. Reactor

Waste water : 128 LMethanol recovery : 1190 LMethanol loss : 55 LResi. : 5 Kg

Filter-Nutch

Spent carbon : 10 KgS. S. ReactorStir & Filter

Carbon : 10 Kg




11. Diazepam

Process:

2-MethylAmino 5-Chloro Benzophenone (Chloro Methylamino Ketone) isreacted with chloro acetyl chloride in toluene to get Di chloro intermediate.

HCl generated is scrubbed in the scrubbing system. After the reaction themass is cooled, centrifuged and product is dried. Mother liquor is sent forrecovery of solvent toluene.

The Di Chloro intermediate is reacted with ammonia in solvent methanol atspecific temp.and cooled to isolate by product Ammonium chloride which isremoved by filtration. The resultant filtrate is concentrated to recover solvent(which is recycled).

The concentrated mass is cooled and centrifuged and the pure Diazepam isdried.

The mother liquor from the centrifuge is sent to recover methanol. The lastportion of solvent is methanolic water which is sent as effluent.

The residual mass as undistilled is taken as Haz waste.

Chemical reaction

O

NH

ClCl

OCl+

N

N

Cl

Oammonia51

TolueneMethanol

Diazepam

245112

H2O18

+

O

N

Cl

OCl

Nitro chloro intermediate322.5

284

(5-chloro-2-(methylamino)phenyl)(phenyl)methanone

2-chloroacetyl chloride



Mass Balance:

\

HCl gas 36 Kg Scrubber

Dichloro intermediate

Diazepam : 243kgInput : 2668 Kg Output : 2668 Kg

Chloroacetylchloride : 112 Kg(5-chloro-2-(methylamino)phenyl)(phenyl)methanone :245 KgToluene : 1000 L

Reaction vessel

Rec. Toluene : 960 LSolvent loss : 40 L

Centrifuge

Ammonia : 51 KgMethanol : 1250 L

S. S. Reactor

Waste water : 95 KgMethanol recovery : 1195 LMethanol loss : 55 L

Filter-Nutch

Spent carbon : 10 KgS. S. ReactorStir & FilterCarbon : 10 Kg


Drying Loss : 34



12. Buclazine dihydrochloride

Process:

This involves 2 steps:1st step Para chloro benzhydryl piperazine is dissolved in solvent Toluene and reacted

with p-Tertiary buthyl benzyl chloride in presence of base Sodium hydroxide. After the reaction is complete, the mass is cooled and filtered. The clear filtrate concentrated to get Buclazine base as thick liquid. The recovered toluene solvent is purified and reused.

2nd step The Buclazine base is dissolved in Acetone, charcoalised and filtered. The filtrate is treated with HCl gas and the resultant reaction mass is cooled

and dihydrochloride salt of Buclazine base separates out by centrifuging anddried.

The mother liquor is sent for recovery of solvent Acetone which is re used. The residual mass remaining as undistilled is taken as Haz waste.

Chemical reaction:

NNH

Cl

4-Chloro benzhydryl piperazine

+

Cl

4-tbutylbenzyl chloride

NaOH

Toluene

40

286 182

NN

Cl

Buclizine Base

NaCl H2O

++58 1

8

Step-1

Step-2

NN

Cl

Buclizine Base

NN

Cl .2HCl

Buclizine dihydrochloride

432

432505

Acetone

2HCl

73



Mass Balance:

Buclazine dihydrochloride450.0kgs


Drying Loss : 63

Buclazine base

P-chloro benzhydryl piperazine: 286 KgP-tert butyl benzyl chloride :182 KgNaOH : 40 KgToluene :1000 L

Reaction vessel

Waste water : 65 KgFilter

Carbon : 10 KgAcetone : 800 L

Distillation

S. S. Reactor

Spent Carbon : 10 KgS. S. Reactor

Stir & Filter

Chilling and CentrifugeRec. Acetone : 765 LSolvent loss : 30 LResidue : 5 Kg

Toluene : 950 LSolvent loss : 50 L

HCl : 70 Kg



13. Meclazine dihydrochloride

Process:

This involves 2 steps:1st step Para chloro benzhydryl piperazine is dissolved in solvent Toluene and reacted

with m-Methyl benyl chloride in presence of base Sodium hydroxide. After the reaction is complete, the mass is cooled and filtered. The filtrate is concentrated to get Meclazine base as thick liquid. The recovered toluene solvent is purified and reused.

2nd step The Meclazine base is dissolved in Acetone, add carbon and filtered. The

clear filtrate is treated with HCl, refluxed and diydrochloride salt of Meclazinebase separates out. This Meclazine dihydrochloride is isolated by centrifugingand dried.

The mother liquor is sent for recovery of solvent which is re used.

Chemical reaction:

NNH

Cl

4-Chloro benzhydryl piperazine

+

Cl

meta methylbenzylchloride

NaOH

Toluene

40

286 140

NN

Cl

Meclizine Base

NaCl H2O++58 18

Step-1

Step-2

NN

Cl

Meclizine Base

NN

Cl .2HCl

Meclizine dihydrochloride

390

390463

Acetone

2HCl

73



Mass Balance:

P-chloro benzhydrylpiperizine: 286 Kgmeta methylbenzylchloride: 140 KgNaOH: 40 KgToluene: 1000 L

Reaction vessel

Waste water: 85 LReflux, Coolingand Filter


Distillation

S. S. Reactor

Spent carbon :10 KgS. S. ReactorStir & Filter

Chilling and CentrifugeAcetone : 770 LSolvent loss : 30 L

Toluene : 950 LSolvent loss : 50 L

HCl : 70 Kg

Meclazine Base

Meclazine dihydrochloride410.0 Kgs

Input : 2346 Kg Input : 2346 Kg

Drying Loss : 41



14. Tramadol HCl

Process:

This involves 3 steps.1st step Cyclohexanone is reacted with Formaldehyde and Dimethylamine in Solvent

Toluene. After the reaction is complete the mass is quenched with water andcooled and Dimethyl amino methyl cyclohexanone crystals obtained. It isisolated by centrifuging and dried.

The Mother liquor is separated and distilled to get pure Toluene which isrecycled.

2nd step 2-Dimethylaminomethyl cyclohexanone is dissolved in Toluene and stirred

with Magnessium filings and treated with solution of Meta bromo anisole inTHF solvent. After it the mass is quenched with water.

Layers were separated and top organic layer is distilled to recover Toluene . The concentrated mass is intermediate Tramadol Base which is immediately

dissolved in Acetone and taken for next step. Both recovered solvents are purified and reused.

3rd step The Tramadol Base in acetone is charcoaled. After filtration and cooling HCl gas is passed and after reaction it is stirred. After centrifuging and drying Tramadol hydrochloride separates out . The mother liquor is sent for recovery of solvent Acetone which is reused.



Chemical reaction:

O

cyclohexanone

98

CH2O

formaldehyde

HN

dimethyl amine

Toluene

30 45

O

N

2-((dimethylamino)methyl)cyclohexanone

H2O

water

Step-1

Step-2

O

2-((dimethylamino)methyl)cyclohexanone

+ + +

+

O

Cl

Toluene/THF

Mg

142155

O

OH N

m-chloroanisol Tramadol Base

MgCl+

60

263

Step-3

Acetone

O

OH N

Tramadol Hydrchloride299.5

O

OH N

Tramadol Base263

HCl

36.5.HCl

15518



Mass Balance:

Drying Loss : 28

Cyclohexanone : 98 KgFormaldehyde : 30 KgDimethylamine : 45 KgWater : 100 L

Reaction vessel

2-dimethylaminomethylCyclo hexanone

Waste water : 125 KgReflux, Centifuge

& Drying

m-chloroanisol : 142Mg Turning : 24 KgToluene/THF : 1100/30 LWater : 60 Kg

Rec. Toluene : 1075 LLoss : 25 LWaste water : 112 Kg

Seperation &Solvent

Distillation

Spent carbon : 15 KgStirr and Filter

Rec Acetone : 955 LSolvent loss : 45 LCentrifuge

Acetone : 1000 LCarbon : 15 Kg

HCl gas : 36 Kg

Tramadol hydrochloride:270 Kg


Tramadol base



15. Duloxetine HCl

Process:

This involves 4 steps:

1st step 2- Acetyl thiophene is mixed with Formaldehyde and Dimethylamine in

Solvent Toluene. The reaction is carried out. After the reaction is complete the mass is quenched with water and Keto

intermediate is formed. This is isolated by centrifuging and solid is dried andtaken for next step.

The Mother liquor containing toluene is sent for recovery of solvent which isreused.

2nd step The keto intermediate is dissolved in Methanol and reduced by hydrogen

using Ni catalyst. The mass is filtered. The filtrate is concentrated and hydroxy intermediate is

obtained which is dissolved in DMSO and taken for 3rd step. The solvent issent for recovery and reuse. The catalyst is used in next step.

3rd step The hydroxy intermediate solution in DMSO is heated and condensed with

Fluoro naphthalene using base KOH so Ether intermediate is obtained afterwork up with water and extraction with Toluene.

4th step The Ether intermediate from above in toluene is reacted with KOH. The mass is worked up with water and organic layer is concentrated by

distillation under vacuum and Duloxetine base is obtained. The recovered toluene is purified and reused. Benzoic acid is recovered. The Duloxetine base is dissolved in Acetone, charcoaled and filtered. The

filtrate is treated with HCl and Duloxetine Hydrochloride is obtained aftercentrifugation and drying.

The mother liquor is sent for recovery of solvent Acetone which is recycled.



Chemical reaction:

126

CH2O

formaldehyde

HN

dimethyl amine

Toluene

30 45Keto intermediate

H2O

water

+ + +

+

DMSO

KOH

2

HydrogenHydroxy intermediate

185

183 18

SO

2-Acetyl thiophene

SO

N

3-(dimethylamino)-1-(thiophen-2-yl)propan-1-one

Keto intermediate

+

183

SO

NH2

SOH

N

step-1

step-3Hydroxy intermediate

185

SOH

N

F

1-fluoronaphthalene146

Methanol

Catstep-2

56S

O

N

Ether intermediate311

+ KF + H2O

water

1858

SO

N


Toluene

KOHstep-4

56

SO

HN


Acetone

HCl 36KOCH3+

70

SO

HN

.HCl

DuloxetineHydrochloride

333



Mass Balance:

Mass Balance:

Methanol : 765 LSolvent loss : 35 LNi cat. : 2 Kg (recycle)

DMSO : 575 LLoss : 25 L

2-acetyl thiophene : 126 KgFormaldehyde : 30 KgDimethylamine : 45 KgToluene : 500 LWater : 150 L

Reaction vessel

Waste water : 168 KgRec Toluene : 450 LToluene loss : 50 L

Centrifuge

Methanol : 800 LNi cat. : 2 Kg

Filter &Distillation

Heating, Reflux,Condensation

&Distillation

Waste water : 213 LLayer separation

Chilling & Centrifuge

DMSO : 600 LFluro naphthalene: 145 KgKOH : 56 Kg

Toluene : 1000 LWater : 150 L

KOH : 56 Kgwater : 150 L

Reaction, LayerSeparation

& Distillation

Waste water : 210 KgToluene : 960 LLoss : 40 L

Recover acetone : 955 LSolvent loss : 45 L

Acetone : 1000 LHCl gas : 36 Kg

Duloxetine HCl300kg

Keto intermediate

Hydroxy intermediate

Duloxetine base

Input : 4846 Kg Output : 4846 KgKg

Ether intermediate

Drying Loss : 53



16. Dapoxetine Hydrochloride

Process:

This involves 3 steps:

1st step 3-Chloro propio phenone is reduced with Hydrogen in presence of Catalyst Ni

in Methanol solvent to get hydroxy intermediate (3-chloro 1- phenyl propanol). After completion of reaction the mass is filtered to remove catalyst (which is

reused), and the clear filtrate is concentrated to recover solvent. Therecovered Methanol is purified and reused.

The mass is quenched with water and solid Hydroxy compound is isolated bycooling and centrifuging. The wet product is taken for next step.

2nd step The Hydroxy intermediate is dissolved in Toluene and Alfa naphthol solid is

added. After heating and cooling, obtained Hydroxy Naphthyl Ether intermediate

mass is cooled and quenched with water. Layers were separated and top organic layer containing the Ether

intermediate which is taken for the next step.3rd step After drying it is treated with Methane sulfonic acid then stirred with Dimethyl

amine. After heating Dapoxetine base is formed. The mass is quenched with water

and top toluene Organic layer is separated. This layer is concentrated bydistillation under vacuum, to get viscous liquid Dapoxetine base.

Recovered solvent toluene is reused. This base is dissolved in acetone and treated with HCl gas, to get Dapoxetine

Hydrochloride. After Stirring, centrifuging and drying product is obtained. The mother liquor is sent for recovering Solvent acetone which is reused.



Chemical reaction:

O

Cl

3-chloro-1-phenylpropan-1-one

OH

ClH2

Methanolstep-1

3-chloro-1-phenylpropan-1-ol

168 170

OH

Cl

3-chloro-1-phenylpropan-1-ol170

+

OH

144alpa naphthol

Toluene

KOHstep-2

56 OH

O

Hydroxy NaphthylEther

278

KCl H2O

1874

OH

O

Hydroxy NaphthylEther

278

SO OOH

Methanesulfonic acid

+ Toluenestep-3

HN

dimethylamine

45

N

O

Dapoxetine base

30596

H2SO4 CH498 16

AcetoneHCl 36

N

O

.HCl

Dapoxetine hydrochloride

341



Mass Balance:

3-chloro-1-phenylpropan-1-one :168 KgMethanol : 800 LNi cat. : 5 Kg

Reaction, Filterand Distillaton

Waste water : 300 LCentrifuge

Toluene : 800 Lalpha naphthol : 144 KgKOH : 56 KgWater : 300 L

Waste water : 377 LHeating, Cooling

& Layerseparation

Aq. waste : 393 KgToluene : 765 LLoss : 35 L

Reaction & Layerseparation and

Distillation

Methane sufonic Acid : 96 KgDimethylamine : 45 KgWater : 300 L

Spent carbon : 10 KgFilter

Methanol : 760 LLoss : 40 LNi cat. : 5 Kg(recycle)


Dapoxetine HCl : 335 Kg

Chilling & Centrifuge

HydroxyIntermediate

Water : 300 L

Ether Intermediate intoluene

Acetone : 1150 LLoss : 50 LHCl gas : 36 Kg

Dapoxetine base


Drying Loss : 40



17. Lidocaine hydrochloride

Process:

This involves 2 steps.1st step 2,6-Xylidine is added. After cooling Chloro acetyl chloride is added and

stirred. After Centrifugation the cake is washed with chilled Toluene and dried it. The recovered solvent is purified and reused.

2nd step In reactor dry Stage-I material, Toluene, and Diethylamine is added. It is

stirred and heated. After completion of reaction Sodium hydroxide solution isadded.

After Centrifugation the product is washed with cold Water. The wet cakewhich is lidocaine base is dried and pulverized.

Lidocaine base is taken in acetone and filtered after addition of carbon. Thendry HCl gas is purged to the reaction mass and it is chilled and filtered.

The mother liquor is sent for recovery of solvent which is re used.

Chemical reaction:

AcetoneHCl 36

.HCl

Lidocaine hydrochloride

270

NH2

Cl

OCl+

O

Cl

HN

2,6-xylidine Chloro acetylchloride

121112

step-1

Toluene

197

+ HCl

36

O

Cl

HN

197

+ NH

diethylamine73

2-chloro-N-(2,6-dimethylphenyl)acetamide

2-chloro-N-(2,6-dimethylphenyl)acetamide step-2

Toluene

O

NHN + NaCl

58

Lidocaine base

234

O

NHN

NaOH

40

+ H2O

18



Mass Balance:

HCl gas : 36 Kg2,6-xylidine :121 KgChloro acetyl chloride :112 KgToluene :500 L

Reaction vessel

Toluene Recover : 475 LLoss : 25 L

Centrifuge andDrying


Centrifuge andDrying

S. S. Reactor

Spent carbon : 10 KgS. S. ReactorStir & Filter

Centrifuge and Chilling

Lidocaine hydrochloride265.0 Kg

Toluene Recover : 575 LSolvent loss : 25 LWaste water : 269 L

Dry HCl gas : 70 Kg

Toluene : 600 Ldiethylamine : 73 KgNaOH : 40 KgWater : 200 L

Acetone recover : 760 LSolvent loss : 40 L

Lidocaine Base

Amide derivatives


Drying Loss : 46

Annexures to Form – 1 & Pre Feasibility ReportProposed Project for manufacturing of bulk drugs and its intermediates ofM/s Novazeal Lifesciences, Plot no.806,G.I.D.C., Kerala, District: Ahmedabad, Gujarat

ANNEXURE – D

DETAILS OF WATER CONSUMPTION AND WASTE WATER GENERATION

DETAILS OF WATER CONSUMPTION :

Sr. no. PURPOSE Consumption, KL/day

1. Domestic 1.5

2. Industrial

a. Process 1.7

b. Boiler make up 10.0

c. Cooling make up 3.0

d. Washing water 0.5

e. Any other –ScrubbingGardening

0.20.5

TOTAL [2] 15.9

TOTAL [1+2] 17.4


DETAILS OF WASTE WATER GENERATION :

Sr. no. PURPOSE Generation, KL/day

1. Domestic 1.2

2. Industrial

a. Process 3.4

b. Boiler blow down 0.5

c. Cooling bleed off 0.02

d. Washing water 0.5

e. Any other –ScrubbingGardening

0.20.0

TOTAL [2] 4.62

TOTAL [1+2] 5.82


DETAILS OF EFFLUENT TREATMENT PLANT

For the proposed project, the sources of waste water will be from process,

washing water, scrubbing and Utilities.

The generated waste water will be collected in the collection cum equalization

tank. Then it will be neutralized if required in the neutralizer tank.

Then the neutralized effluent will be filtered and stored in the holding tank.

The neutralized effluent will be sent to Common MEE system after meeting

with the inlet norms.

CollectioncumEqualizationtank

Wastewater

Neutralizertank Filtration Final

holding tank

ETPsludge

CMEE


ANNEXURE – E

DETAILS OF HAZARDOUS WASTE GENERATION AND ITS DISPOSAL

Sr.No.

Name ofHazardous

Waste

Category asper HWM

Rules,2016

Quantity/ year

Mode of Disposal

1. Discarded

containers /

barrels / liners

33.1 5 MT Collection, Storage,

transportation and sold out

to Registered Recyclers.

2. Used Oil 5.1 0.3 MT Collection, Storage,


to Registered Recyclers.

3. Spent Solvent 20.2 Max.

300 MT

Recycled and Reused back

in next batch.

4. Distillation

Residue

20.3 Max.

8 MT

Collection, Storage,

transportation and sent to

CHWIF.

5. Inorganic Acid

HCl

B-15 12-15 MT Collection, storage,


to the authorized person.

6. ETP sludge 35.3 12 MT Collection, Storage,

transportation and sent to

secured land fill site.


M/s Novazeal Lifesciences, Plot no.806,G.I.D.C., Kerala, District: Ahmedabad, Gujarat

ANNEXURE – F

DETAILS OF AIR POLLUTION CONTROL MEASURES

DETAILS OF FLUE GAS EMISSION

Sr.No.

StackAttached

to

Capacity Name of fuel& its

consumption

StackHeight

Air pollutionControlSystem

Parameters

1. Steamboiler[ 2 nos.]

1 T/hr.[each]

Coal / Agrowaste

@ 0.8 T/hr11 m

Multicyclone, bagfilter followed

by waterscrubber

PM < 150mg/Nm3SO2 < 100 ppmNOx< 50 ppm

2. D. G. set 10 KVA Diesel@ 7.5 L/hr.

6 m --- PM < 150mg/Nm3SO2 < 100 ppmNOx< 50 ppm

DETAILS OF PROCESS GAS EMISSION :

Sr.No.

Stack Attachedto

StackHeight

Air pollution ControlSystem

Parameters

1. Reactors 11 m Water scrubber

followed by Caustic

Scrubber

HCl<20 mg/Nm3

Cl2< 09 mg/Nm3

SO2< 40 mg/Nm3

NOx< 25 mg/Nm3


ANNEXURE – G

PLANT LAY OUT

GIDC ROAD

Proposed Storage area

Utilityarea

Office

Parking

Proposed

plant area

GreenSpace

ProposedETP area

Proposedhazardous

wastestorage area

OPEN AREA

ANNEXURE - environmentclearance.nic.in · M/s Novazeal Lifesciences, Plot no.806,G.I.D.C., Kerala,...

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