For National Authority Use Only: Supriya Lifescience LTD., Mumbai, INDIA

Supriya Lifescience Ltd.
, Mumbai, INDIA
Applicant Part
Name of Company For National Authority
Supriya Lifescience Ltd., Mumbai, INDIA Use Only
Name of Active Ingredient
Chlorpheniramine Maleate USP
3.2. S.3.2 Impurities

3.2. S.3.2.1 Potential impurities
Following possible potential impurities in the Chlorpheniramine Maleate:
[A] Impurities arising out of starting materials and Intermediates:

1. 2-(4-chlorophenyl)-4-(dimethylamino)-2-[2-(dimethylamino) ethyl] butanenitrile.
*
(Diamine analog)/**Impurity A
2. N-pyridin-2-ylpyridin-2-amine ( 2,2’-dipyridylamine).
*(Chlorpheniramine Related Compound B)/**Impurity B
3. (3RS)-3-(4-chlorophenyl) -N-methyl-3-(pyridin-2-yl) propan-1-amine.
*(Chlorpheniramine Related Compound C)/**Impurity C
4. (2RS)-2-(4-chlorophenyl)-4-(dimethylamino)-2-(pyridin-2-yl) butanenitrile.
*(Chlorpheniramine Nitrile)/**Impurity D
[B] Degradation Impurities:

Not Available
[C] Potential Genotoxic Impurity

1. Dimethyl amino ethyl chloride hydrochloride
[D] Inorganic Impurities:

Residue on Ignition
[E] Impurities arising out of solvents used in the process:
1. Isopropanol
2. Methanol
3. O-xylene
Note: *USP monograph impurity identification names.
**
EP monograph impurity identification names.
Corporate Office: 207/208, Udyog Bhavan, Sonawala Road, Goregaon (East), Maharashtra,
MUMBAI - 400 063. INDIA
Page 40
Supriya Lifescience Ltd., Mumbai, INDIA
Applicant Part
3.2. S.3.2.2 Detail description of Potential impurities
Name: 2-(4-chlorophenyl)-4-(dimethylamino)-2-[2-(dimethylamino) ethyl] butanenitrile.

Identity: Diamine analog/Impurity A
Property of Impurity:
Molecular Formula = C16 H24 Cl N3
Formula Weight = 293.835
Composition = C (65.40%) H (8.23%) Cl(12.07%) N (14.30%)
Nominal Mass = 293 Da
Average Mass = 293.840921 Da
Structure:
Cl
CN
H3C
N
CH3
N CH3
H3C
2-(4-chlorophenyl)-4-(dimethylamino)-2-[2-(dimethylamino) ethyl] butanenitrile
Explanation for formation:

While following Stage II of the manufacturing process if some very small quantity of p-
chlorophenylacetonitrile remains unreacted, then the molecule of N-(2-chloroethyl)-N, N-
dimethylamine can react with p-chlorophenylacetonitrile in the presence of sodamide giving very
small quantity of “Diamine analog/Impurity A”.
Page 41
Applicant Part
Name: N-(pyridin-2-yl)pyridin-2-amine (2,2’-dipyridylamine)

Identity: Chlorpheniramine related Compound B/Impurity B
Molecular Formula = C10 H9 N3
Composition = C (70.16%) H (5.30%) N (24.54%)
Structure:
N NH
N-(pyridin-2-yl)pyridin-2-amine(2,2’-dipyridylamine)
It is known that 2-Aminopyridine can be prepared from Pyridine & Sodamide.

In our synthesis if a very small quantity of pyridine is present in 2-chloropyridine, it may form 2-
Aminopyridine which may further react with 2-chlorpyridine in presence of sodamide giving very
minor impurity of “Chlorpheniramine related Compound B/Impurity B”.
Page 42
Applicant Part
Name: (3RS)-3-(4-chlorophenyl) -N-methyl-3-(pyridin-2-yl) propan-1-aimne.

Identity: Chlorpheniramine related Compound C/Impurity C
Composition = C (69.09%) H (6.57%) Cl (13.60%) N (10.74%)
Structure:
Cl
and enantiomer
H
N
H
N
H3C
(3RS)-3-(4-chlorophenyl) -N-methyl-3-(pyridin-2-yl) propan-1-aimne.
In our synthesis of Chlorpheniramine Maleate one of the raw material is N,N-Dimethylaminoethyl

Chloride Hydrochloride. In case this raw material contains a minute quantity of N-Methylaminoethyl
chloride Hydrochloride as on impurity, it will be carried forward & appear as an “Chlorpheniramine
related Compound C/Impurity C” in Chlorpheniramine Maleate.
*Note: Impurity C is directly procured from edqm.
Page 43
Applicant Part
Name: (2RS)-2-(4-chlorophenyl)-4-(dimethylamino)-2-(pyridin-2-yl) butanenitrile

Identity: Chlorpheniramine Nitrile/Impurity D
Composition = C (68.11%) H (6.05%) Cl (11.83%) N (14.02%)
Structure:
Cl
N
and enantiomer
CH3
N
H3C
(2RS)-2-(4-chlorophenyl)-4-(dimethylamino)-2-(pyridin-2-yl) butanenitrile
This product is synthesized in stage II of our manufacturing process. It has been named as ‘Cyano
Base’. This product is further decyanated using potassium hydroxide as described in stage III.
During the process of Decyanation if a minute quantity of Cyanobase remains unreacted, then this
“Chlorpheniramine nitrile/Impurity D” can arise in the final product.
Page 44
Applicant Part
3.2.S.3.2.3 Limits of impurities and residual solvents
HPLC studies were carried out to determine the impurities in our manufactured Chlorpheniramine
Maleate. It was found in these studies that impurity arises from the starting materials or intermediates
were present in the final products. Based on these studies we have determined the impurity profile of
our manufactured Chlorpheniramine Maleate as follows:
[A] Organic Impurites & Process Impurities
Diamine analog/Impurity A NMT 0.2 % w/w

Chlorpheniramine Related Compound B/Impurity B NMT 0.1 % w/w
Chlorpheniramine Related Compound C/Impurity C NMT 0.1 % w/w
Chlorpheniramine nitrile/Impurity D NMT 0.1 % w/w
Any other unspecified impurity NMT 0.10 % w/w
Total impurities: NMT 0.5 % w/w
[B] Inorganic Impurities:
Residue on Ignition NMT 0.2 % w/w
[C] Potential Genotoxic Impurity

Dimethyl amino ethyl chloride hydrochloride NMT 37.5 ppm
[D] Impurities arising out of solvents used in the process:
Methanol: NMT 3000 ppm

Isopropanol: NMT 5000 ppm
O-xylene: NMT 2170 ppm
**Benzene: NMT 2 ppm
Page 45
Applicant Part
3.2. S.4 Control of drug substance
3.2.S.4.1 Specification (USP current edition + In- House)
Specification is attached in Annexure-IV
Page 46
Applicant Part
Annexure-IV
Page 47
Supriya Lifescience Limited
FlNISI-IEDPRODUCT SI'ECIlTICATIONS
CI-ILORPHENIRAMINIi:MALEATli:
Specification No.
Effective Date 06110120 15 Review Date 05110120 18
SLL/FPSP/C/USP/003 -09,
Supersedes Revision No. 10
Ei'i'ective date: 29/07/20 15
Molkcular Formula : C 61-11&IN2 .C41-1404
Molecular Weight : 390.86
Chemical Name : 2-Pyridinepropanamine, y-(4-chloropheny1)-N,N-dimethyl-,(2)-2-

butenedioate (1 :1)
CAS Registry
Category : Histamine HI-receptor antag0nist;antihistamine.
Structure
Storage condition : Preserve in tight, light-resistant containers.
QC/078/F02-00 / Effective date: 10/08/2014 Page 1 of 3

FINISIIED I'liODUCT Sl'ECIFICATIONS
CIILOlII'I-1ENIlWMINE MALEATE
I Specification No. I SLL/FPSP/C/US1)/003 I Standard I US1) I
I Effective Date 1 Review Date
SLL/FPSP/C/USP/003-09,
Supersedes Revision No. 10
Effective date: 29/07/20 15
Tests Specifications
1. Description White crystalline powder, Odourless.
2. Solubility Freely soluble in water; soluble in alcohol and in
1 I chloroforin.
3. pFI(1.0 %,w/v solution in water) 4.0 to 5.0
4. Identification
i. Test A: By IR The infrared absorption spectrum of sample is
concordant with infra-red absorption spectrunl of
Chlorpheniramine maleate working standard.
ii. Test B: by HPLC The retention times of the inaleic acid and
chlorpheniramine peaks of the sample solution
correspoild to those of the standard solution, as obtained
in the Assay test.
Assay by HPLC on dried basis
5. NLT 9gm0and NMT 02.0
(%-,
6. 1 Residue on ignition (%, w/w) 1 NMT 0.2
7. Organic Impurities by HPLC (%)
i. Diamine analog; I NMT 0.2
1 ii. Chlorphenaramine related
compound B
1 NMT 0.1 I
iii. Chlorpheilaramine related
NMT 0.1
compound C
iv. Chlorphenaramine nitrile NMT 0.1
v. Any other unspecified
NMT 0.10
impurity
vi. Total Impurities NMT 0.5
Optical rotation @ 20 "C (1 00
8' -O. to +O.
mglrnl solution in water) ( O )
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FINISEIEI) PliOUUCT SI'ECIFICATIONS

1 CHLORI'I-IENIRAMINE MALEATE I
ISpecification No. Standard1 I USl'
I Effective Date I Review Di~te
Supersedes
S.No. 1 Tests
SLL/FPSP/C/USP/003-09,
Effective date: 29/07/20 15
Revision No.
Specifications
10
I
Loss on drying @105"C for 3 NMT 0.5
9+
hours (%, wlw)
10. 1 Additional Test
lo. 1 Residual solvents by GC-HS (pprn)
1 i. Methanol 1 NMT 3000
1 ii. Isopropyl alcohol NMT 5000
1 iii. o-Xylene NMT 2170
* 10.2 1 Bulk density (g1mL)
I
i. Density (as is) For information
ii. Density (tapped) For information
* 10.3 Sieve Test For information
* 10.4 1 Particle size distribution I For information
** 10.5 1 Microbial limits (CFUlg)
1 Total aerobic microbial count NMT 1000
ii Total yeast & mould count NMT 10
iii I Pathogens:
a. Escherichia coli Should be absent
b. Salmonella Should be absent
1 c. Pseudomonas aeruginosa Should be absent
1 d. Staphyloccocus auereus Should be absent
Where: NMT - Not more than
* - These tests shall be carried out when specific requirement only. --7
** - This test shall be carried out when specific requirement I lStbatch of
every month
\
QC/078/F02-00 /Effective date: 10/08/2014 Page 3 of 3

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3.2. S.3.2 Impurities

[A] Impurities arising out of starting materials and Intermediates:

[B] Degradation Impurities:

[C] Potential Genotoxic Impurity

[D] Inorganic Impurities:

[E] Impurities arising out of solvents used in the process:

3.2. S.3.2.2 Detail description of Potential impurities

Name: 2-(4-chlorophenyl)-4-(dimethylamino)-2-[2-(dimethylamino) ethyl] butanenitrile.

2-(4-chlorophenyl)-4-(dimethylamino)-2-[2-(dimethylamino) ethyl] butanenitrile

Explanation for formation:

Name: N-(pyridin-2-yl)pyridin-2-amine (2,2’-dipyridylamine)

Explanation for formation:

It is known that 2-Aminopyridine can be prepared from Pyridine & Sodamide.

Name: (3RS)-3-(4-chlorophenyl) -N-methyl-3-(pyridin-2-yl) propan-1-aimne.

(3RS)-3-(4-chlorophenyl) -N-methyl-3-(pyridin-2-yl) propan-1-aimne.

Explanation for formation:

In our synthesis of Chlorpheniramine Maleate one of the raw material is N,N-Dimethylaminoethyl

*Note: Impurity C is directly procured from edqm.

Name: (2RS)-2-(4-chlorophenyl)-4-(dimethylamino)-2-(pyridin-2-yl) butanenitrile

Explanation for formation:

3.2.S.3.2.3 Limits of impurities and residual solvents

Diamine analog/Impurity A NMT 0.2 % w/w

[B] Inorganic Impurities:

Residue on Ignition NMT 0.2 % w/w

[C] Potential Genotoxic Impurity

[D] Impurities arising out of solvents used in the process:

Methanol: NMT 3000 ppm

3.2. S.4 Control of drug substance

3.2.S.4.1 Specification (USP current edition + In- House)

Specification is attached in Annexure-IV

Molkcular Formula : C 61-11&IN2 .C41-1404

Molecular Weight : 390.86

Chemical Name : 2-Pyridinepropanamine, y-(4-chloropheny1)-N,N-dimethyl-,(2)-2-

Category : Histamine HI-receptor antag0nist;antihistamine.

Storage condition : Preserve in tight, light-resistant containers.

QC/078/F02-00 / Effective date: 10/08/2014 Page 1 of 3

5.h ll:"$,,i 5--.,:-;$....-..

FINISEIEI) PliOUUCT SI'ECIFICATIONS

QC/078/F02-00 /Effective date: 10/08/2014 Page 3 of 3

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