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AMLODIPINE BESILATE

APPLICANT’S PART
(OPEN PART)

DOCUMENT NO. CPL/AD/AP/348


VERSION NO. - 05
MARCH, 2014

CADILA PHARMACEUTICALS LIMITED


294, G.I.D.C. INDUSTRIAL ESTATE
ANKLESHWAR – 393 002
GUJARAT, INDIA
Tel. No. : +91-2646-252626, 251519
Fax No. : +91-2646-250051
COMMON TECHNICAL DOCUMENT ON
AMLODIPINE BESILATE

APPLICANT’S PART

MODULE-3: QUALITY
MARCH, 2014

TABLE OF CONTENTS

SR. NO. CONTENTS PAGE NO.


3.2.S Drug Substance 1
3.2.S.1 General Information 2-4
3.2.S.1.1 Nomenclature 2
3.2.S.1.2 Structure 3
3.2.S.1.3 General properties 4
3.2.S.2 Manufacture 5-12
3.2.S.2.1 Manufacturer(s) 5
3.2.S.2.2 Description of manufacturing process and process controls 6-8
3.2.S.2.3 Control of materials 9
3.2.S.2.4 Control of critical steps and intermediates 10
3.2.S.2.5 Process validation and/or evaluation 11
3.2.S.2.6 Manufacturing process development 12
3.2.S.3 Characterization 13-39
3.2.S.3.1 Elucidation of structure and other characteristics 13-32
3.2.S.3.2 Impurities 33-39
3.2.S.4 Control of Drug Substance 40-64
3.2.S.4.1 Specification 40-42
3.2.S.4.2 Analytical procedures 43-57
3.2.S.4.3 Validation of analytical procedures 58
3.2.S.4.4 Batch analyses 59-62
3.2.S.4.5 Justification of specification 63-64
3.2.S.5 Reference Standards or Materials 65-66
3.2.S.6 Container Closure System 67-81
3.2.S.7 Stability 82-109
3.2.S.7.1 Stability summary and conclusion 82-84
3.2.S.7.2 Post-approval stability protocol and stability commitment 85-89
3.2.S.7.3 Stability data 90-109
i
COMMON TECHNICAL DOCUMENT ON
AMLODIPINE BESILATE

APPLICANT’S PART

MODULE-3: QUALITY
MARCH, 2014

TABLE OF CONTENTS

SECTION CONTENTS
ANNEX-I Analytical method validation report and chromatograms of Related
Substances by HPLC
ANNEX-II Analytical method validation report and chromatograms of Assay by
HPLC
ANNEX-III Analytical method validation report and chromatograms of Residual
Solvents by GC
ANNEX-IV Analytical method validation report and chromatograms of Forced
Degradation Study

ii
3.2.S DRUG SUBSTANCE

NAME AND ADDRESS OF MANUFACTURING SITE

CADILA PHARMACEUTICALS LTD.,


294, G.I.D.C. Industrial Estate,
Ankleshwar - 393 002,
Gujarat, INDIA.
Tel. No.: +91 -2646 -252626, 251519
Fax No.: +91 -2646 -250051
Contact Person: Mr. Rangaraju Kakarlapudi
Vice President - Quality
E-mail: k.rangaraju@cadilapharma.co.in

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This should not be reproduced in part or full with out the written permission of the company.
Page 1 of 109
3.2 BODY OF DATA
3.2.S DRUG SUBSTANCE

3.2.S.1 GENERAL INFORMATION

3.2.S.1.1 NOMENCLATURE
3.2.S.1.1.1 Recommended International Nonproprietary Name (rINN)
Amlodipine besilate

3.2.S.1.1.2 Chemical Name


3-Ethyl 5-methyl (4RS)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-6-methyl-
1, 4-dihydropyridine-3, 5-dicarboxylate benzene sulphonate.

3.2.S.1.1.3 Company or Laboratory Code


AD

3.2.S.1.1.4 Chemical Abstracts Services Registry Number


[111470-99-6]

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Page 2 of 109
3.2.S.1 GENERAL INFORMATION

3.2.S.1.2 STRUCTURE
3.2.S.1.2.1 Structural Formula:

H
H3C N NH2
O
O O CH3 SO3H
H 3C .
O H O

Cl
and enantiomer

3.2.S.1.2.2 Molecular Formula


C26H31ClN2O8S

3.2.S.1.2.3 Molecular Mass


567.1

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Page 3 of 109
3.2.S.1 GENERAL INFORMATION

3.2.S.1.3 GENERAL PROPERTIES


3.2.S.1.3.1 Description
White or almost white powder

3.2.S.1.3.2 Solubility
Slightly soluble in water, freely soluble in methanol, sparingly soluble in ethanol,
slightly soluble in 2-propanol

3.2.S.1.3.3 Therapeutic Category


Anti-hypertensive.

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Page 4 of 109
3.2.S.2 MANUFACTURE

3.2.S.2.1 MANUFACTURER
NAME AND ADDRESS OF MANUFACTURER
Please send all correspondence to the manufacturer’s address mentioned below.
CADILA PHARMACEUTICALS LTD.,
294, G.I.D.C. Industrial Estate,
Ankleshwar - 393 002,
Gujarat, INDIA.
Tel. No.: +91 -2646 -252626, 251519
Fax No.: +91 -2646 -250051
Contact Person: Mr. Rangaraju Kakarlapudi
Vice President - Quality
E-mail: k.rangaraju@cadilapharma.co.in

Note: All steps of the manufacturing process (i.e. chemical synthesis, purification,
analysis and packaging) are carried out at this manufacturing site.

ADDRESS OF RESEARCH, DEVELOPMENT AND REGULATORY AFFAIRS DIVISION

CADILA PHARMACEUTICALS LTD.,


1389, Trasad Road
Dholka, Ahmedabad - 387 810
Gujarat, INDIA.
Tel. No.: +91-2714- 221481 / 83 / 84
Fax No.: +91 -2714- 220301
Contact Person: Dr. Arvind Mishra
Joint President - QA, QC & RA
Email: arvind.mishra@cadilapharma.co.in

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Page 5 of 109
3.2.S.2 MANUFACTURE

3.2.S.2.2 DESCRIPTION OF MANUFACTURING PROCESS AND PROCESS


CONTROLS

Reaction of ethyl-4-chloro acetoacetate with hydroxy ethyl phthalimide (HEP) in


presence of sodium hydride gives ethyl – 4 - [2- (phthalimido) ethoxy]
acetoacetate (PHEMAA).

Reaction of ethyl-4-[2-(phthalimido) ethoxy] acetoacetate (PHEMAA) with


o-chloro benzaldehyde and on further reaction with methyl-3-amino crotonate
(MAC) gives phthaloyl Amlodipine.

Phthaloyl Amlodipine is treated with mono methyl amine solution to form


Amlodipine base. Amlodipine base is treated with benzene sulphonic acid in
aqueous media to give Amlodipine besilate crude. The crude Amlodipine besilate
is purified using IPA to produce Amlodipine besilate.

Note: Detailed description of manufacturing process of Amlodipine besilate is


a confidential part of Drug Master File.

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Page 6 of 109
3.2.S.2 MANUFACTURE
ROUTE OF SYNTHESIS
O

NCH 2 CH 2OH O
NaH

O
+ Cl CH 2 C CH 2 COOC 2 H5

Hydroxy ethyl phthalimide Ethyl-4-chloro-acetoacetate


M.W. 191 M.W. 164

O
O

NCH 2 CH 2 OCH 2 C CH 2 COOC 2 H5

O
Ethyl-4-[ 2-(phthalimido)ethoxy] acetoacetate (PHEMAA)
M.W. 319
CHO O

NH2 O
Cl

+ H 3C C CH 2 COOCH 3 + NCH 2 CH 2 OCH 2 C CH 2 COOC 2 H5

O
o- Chloro benzaldehyde Methyl-3-amino crotonate Ethyl-4-[ 2-(phthalimido)ethoxy] acetoacetate (PHEMAA)
M.W. 140. 5 M.W. 115 M.W. 319

H
H 3C N N
O

O O CH3 O
H 3C
H
O O

Cl

Phthaloyl amlodipine
M.W. 537

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Page 7 of 109
3.2.S.2 MANUFACTURE

H
H 3C N N
O

O O CH3 O
H 3C
H
O O

Cl

Phthaloyl amlodipine
M.W. 537

Mono Methyl Amine


(MMA)
H
H 3C N NH2
O

O O CH3
H 3C
H
O O

Cl

Amlodipine base
M.W. 408
SO 3 H

H
H 3C N NH2
O

O O CH3 SO 3 H
H 3C
H
O O ,

Cl

AMLODIPINE BESILATE
M.W. 567

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Page 8 of 109
3.2.S.2 MANUFACTURE

3.2.S.2.3 CONTROL OF MATERIAL


Note: Control of materials of Amlodipine besilate is a confidential part of Drug
Master File.

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Page 9 of 109
3.2.S.2 MANUFACTURE

3.2.S.2.4 CONTROL OF CRITICAL STEPS AND INTERMEDIATES


Note: Control of critical steps and intermediates of Amlodipine besilate is a
confidential part of Drug Master File.

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Page 10 of 109
3.2.S.2 MANUFACTURE

3.2.S.2.5 PROCESS VALIDATION AND/OR EVALUATION


Not applicable as the process is neither aseptic nor sterilization.

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Page 11 of 109
3.2.S.2 MANUFACTURE

3.2.S.2.6 MANUFACTURING PROCESS DEVELOPMENT


Note: Manufacturing process development of Amlodipine besilate is a
confidential part of Drug Master File.

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Page 12 of 109
3.2.S.3 CHARACTERIZATION

3.2.S.3.1 ELUCIDATION OF STRUCTURE AND OTHER CHARACTERISTICS


The structure of Amlodipine besilate has been confirmed by analytical evidences
like Infra red absorption spectrum, 1H NMR spectrum, 13C NMR spectrum, Mass
spectrum and X-ray spectral analysis.
The structure of Amlodipine besilate has been elucidated on the basis of the
following spectral analysis:

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Page 13 of 109
3.2.S.3 CHARACTERIZATION

3.2.S.3.1.1 Infra-Red Spectroscopy


The Infrared absorption spectrum of Amlodipine besilate is taken in potassium
bromide dispersion of the sample. The spectrum is recorded with Shimadzu FTIR
8400 Spectrophotometer in the range of 4000 cm-1 to 400 cm-1.

H
H3C N NH2
O
O O CH3 SO3H
H 3C .
O H O

Cl
and enantiomer

The assignments of characteristic frequencies to different functional groups are as


follows:

Sr.No. Observed wave number (cm-1) Peak assignment


1AMLO070 2AMLO001
1. 615.2 615.2 C-Cl Stretching
2. 1672.1, 1697.2 1672.1, 1697.2 Two C=O Stretching

3. 2980.0 2981.0 ib i
Due to Sulphonic acid
4. 3138.0 3138.0 -NH stretching

Amlodipine besilate is identified by its characteristic infrared absorption spectrum.


The infrared absorption spectrum analysis indicates that the spectrum is in
agreement with structure of the compound.
A typical infrared spectrum of Amlodipine besilate working standard 1AMLO070
and batch no. 2AMLO001 are given below.

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Page 14 of 109
IR Spectrum of Amlodipine besilate working standard 1AMLO070

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Page 15 of 109
IR Spectrum of Amlodipine besilate batch no. 2AMLO001

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Page 16 of 109
3.2.S.3 CHARACTERIZATION

1
H NMR Spectroscopy
The proton NMR spectrum of batch no. 9AD072 shows similar protons, which are
present in Amlodipine besilate working standard WRS/AMD/004.
1
H NMR spectra were recorded on a Bruker Avance-300 Spectrometer in DMSO
containing TMS as the internal standard. Chemical shifts are given in parts per
million (ppm) down field from TMS.

4'
5' 3'

2'
6'
1' Cl
-
4 H SO3
H3COOC 5 COOCH2CH3
14 13 10 11 12
3 1''
6 6'' 2''
+
2
H3C N CH2OCH2CH2NH3 .
1 7 8 5'' 3''
15 9
H 4''

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Page 17 of 109
3.2.S.3 CHARACTERIZATION

Sr. Chemical shift (, ppm) Multiplicity Assignments of


No. Working Standard Batch No. proton (s)
WRS/AMD/004 9AD072
1. 1.062-1.109 1.062-1.109 Triplet H-12 (3H)
2. 2.290 2.291 Singlet H-15 (3H)
3. 2.490 2.490 Broad Singlet H-1 (1H)
4. 3.099 3.100 Multiplet H-7 (2H)
5. 3.489 3.489 Singlet H-14 (3H)
6. 3.639 3.639 Multiplet H-8 (2H)
7. 3.927- 3.991 3.945-3.976 Multiplet H-9 (2H)
8. 4.533- 4.710 4.534- 4.711 Quadrate H-11 (2H)
9. 5.303 5.303 Singlet H-4 (1H)
10. 7.106-7.128 7.101-7.132 Multiplet Ar-5’ (1H)
11. 7.184-7.274 7.181-7.276 Multiplet Ar-4’,6’(2H)
12. 7.319-7.354 7.312-7.356 Multiplet Ar-3', 3”,4”,
5” (4H)
13. 7.634-7.652 7.635- 7.652 Multiplet Ar-2”, 6”-(2H)

A typical proton NMR spectrum of Amlodipine besilate working standard


WRS/AMD/004 and batch no - 9AD072. The proton NMR spectrum analysis
indicates that assignments of protons are in agreement with the structure of the
compound.

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Page 18 of 109
1
HNMR of Amlodipine besilate working standard WRS/AMD/004

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Page 19 of 109
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Page 20 of 109
1
HNMR of Amlodipine besilate batch no. 9AD072

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Page 21 of 109
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Page 22 of 109
3.2.S.3 CHARACTERIZATION
13
C NMR Spectroscopy
13
The C NMR spectrum of batch no 9AD072 shows similar carbons, which are
present in Amlodipine besilate working standard WRS/AMD/004
13
The C NMR spectra were recorded on a Bruker Avance-300 Spectrometer in
DMSO containing TMS as the internal standard. Chemical shifts are given in parts
per million (ppm) down field from TMS.
. 4'
5' 3'

2'
6'
1' Cl
-
4 H SO3
H3COOC COOCH2CH3
5
14 13 10 11 12
3 1''
6 6'' 2''
+
2
H3C N CH2OCH2CH2NH3 .
1 7 8 5'' 3''
15 9
H 4''

13
C NMR Spectra of Amlodipine besilate working standard WRS/AMD/004 is
consistent with the spectrum of batch no- 9AD072 are given below.

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Page 23 of 109
3.2.S.3 CHARACTERIZATION

Chemical Shift (ppm) Assignment Chemical Shift (ppm) Assignment


Working Batch No. Working Batch No.
Standard 9AD072 Standard 9AD072
WRS/AMD/004 WRS/AMD/004
14.102 14.105 C12 127.476 127.480 C5' &C6'
18.286 18.288 C15 127.823 127.829 C4'
36.650 36.651 C4 128.803 128.813 C3’
39.225 39.228 C9 129.013 129.015 C3” & C5”
50.563 50.565 C14 131.032 131.036 C2' & C4”
59.449 59.451 C11 131.146 131.149 C1'
66.639 66.644 C7 144.661 144.669 C2
66.721 66.725 C8 145.367 145.375 C1”
102.027 102.031 C3 145.815 145.823 C6
102.136 102.137 C5 166.311 166.314 C13
125.504 125.508 C2" & C6" 167.175 167.179 C10

13
From these assignments, we concluded that C NMR data of batch no. 9AD072
and working standard WRS/AMD/004 confirms the structure of Amlodipine
Besilate as delineated above.

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Page 24 of 109
13
C NMR of Amlodipine besilate working standard WRS/AMD/004

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Page 25 of 109
13
C NMR of Amlodipine besilate batch no. 9AD072

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Page 26 of 109
3.2.S.3 CHARACTERIZATION

Mass Spectroscopy
The Mass spectrometer used for this analysis was an applied biosystems MDC
SCIEX, QTRAP LC/MS/MS system.
The Mass spectra of Amlodipine besilate indicated a very prominent peak of pseudo
molecular ion [M ++1] at m/z 409.2 (molecular wt 567.1, where M.+= Amlodipine)
as the major component. Sample spectrum of batch no. 9AD072 and working
standard WRS/AMD/004 are attached.

Sr. No. Working Standard (WRS/AMD/004)


m/z Relative Abundance (%)
1. 409.2 (M+1) Amlodipine 100%

Sr. No. 9AD072


m/z Relative Abundance (%)
1. 409.3 (M+1) Amlodipine 100%

Mass spectrums of Amlodipine besilate working standard batch no.


WRS/AMD/004 and batch no. 9AD072 are attached.

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Page 27 of 109
Mass Spectra of Amlodipine Besilate working standard WRS/AMD/004

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Page 28 of 109
Mass spectra of Amlodipine Besilate batch no. 9AD072

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Page 29 of 109
3.2.S.3 CHARACTERIZATION

X-RAY POWDER DIFFRACTION (XRPD)


An X-ray diffraction pattern was recorded on a Philips X-ray diffractometer XRD-
pert MPD using Cu/LFF radiation (λ = 1.5406 A°) and a scan speed of 0.02. The
powder patterns were recorded under the following conditions: 40 eKV, 35mA,
angle range 2-50° 2 θ; primary slit of 5.0°, secondary slit of 0.20°.

The X-RAY Diffraction pattern of Amlodipine besilate batch no. 3AM001 is given
below.

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Page 30 of 109
X-Ray Diffractogram of Amlodipine besilate batch no. 3AM001

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Page 31 of 109
3.2.S.3 CHARACTERIZATION

3.2.S.3.1.2 POTENTIAL FOR ISOMERISM


Amlodipine besilate molecule has one chiral carbon. Due to that chirality, potential
isomer may be present. The optical rotation of Amlodipine besilate manufactured
by Cadila Pharmaceutical Ltd. shows the presence of racemic mixture.

3.2.S.3.1.3 IDENTIFICATION OF STEREOCHEMISTRY


Amlodipine besilate manufactured by Cadila Pharmaceutical Ltd. exists as a
racemic mixture.

3.2.S.3.1.4 POTENTIAL FOR FORMING POLYMORPHS


Amlodipine besilate exist in anhydrous, monohydrate and dehydrate form.
Amlodipine besilate manufactured by Cadila is anhydrous form.

Cadila has defined water content and Sulphated Ash limit as not more than 0.50 %
w/w and not more than 0.20 % w/w respectively in specification of Amlodipine
besilate drug substance as a control test for anhydrous form.

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Page 32 of 109
3.2.S.3 CHARACTERIZATION

3.2.S.3.2 IMPURITIES
3.2.S.3.2.1 FOLLOWING ARE THE POTENTIAL PROBABLE IMPURITIES IN OUR
AMLODIPINE BESILATE .
A) POSSIBLE ORGANIC IMPURITIES IN AMLODIPINE BESILATE
1. Impurities possible from starting materials:
No impurities are possible from starting materials.

2. Impurities possible from synthetic route:


Following impurities are possible from synthetic route.
a. Impurity A: 3-ethyl 5- methyl (4RS)-4-(2- chlorophenyl)-2-{[2-(1, 3-dioxo-1, 3-
dihydro-2H-isoindol-2-yl) ethoxy] methyl}-6-methyl-1, 4-dihydropyridine-3, 5-
dicarboxylate.
b. Impurity B: 3-ethyl 5- methyl (4RS)-4-(2- chlorophenyl)-6-methyl-2-[[2-[[2-
(methylcarbamoyl) benzoyl] amino]-ethoxy] methyl-1, 4-dihydropyridine-3, 5-
dicarboxylate
c. Impurity C: Ethyl methyl (4RS)-2, 6-bis [(2-aminoethoxy) methyl]-4-(2-
chlorophenyl)-1, 4-dihydropyridine-3, 5-dicarboxylate.
d. Impurity E: Diethyl (4RS)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl) -6-
methyl-1, 4-dihydropyridine-3,5-dicarboxylate
e. Impurity F: Dimethyl (4RS)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl) -6-
methyl-1,4-dihydropyridine-3,5-dicarboxylate

3. Impurities possible from side reaction/ Degradation:


Impurity D: 3-ethyl, 5-methyl-2-[(2-aminoethoxy) methyl}-4-(2-chlorophenyl)-6-
methyl pyridine -3, 5- dicarboxylate. (Impurity A as per USP Monograph)

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Page 33 of 109
3.2.S.3 CHARACTERIZATION

B) INORGANIC IMPURITY
1. Catalysts and Reagents
No catalysts are used in the manufacturing process of Amlodipine Besilate.

2. Other Inorganic Impurity


Cadila has incorporated the test for Sulphated Ash with limit not more than 0.20 %
w/w in the specification of Amlodipine besilate to control the inorganic impurities.

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Page 34 of 109
3.2.S.3 CHARACTERIZATION

3.2.S.3.2.2 DISCUSSION OF SYNTHETIC PROCESS WITH REGARD TO


IMPURITIES:
1) Impurities possible from synthetic route:
a. Impurity A:
Chemical Name: 3-ethyl 5- methyl (4RS)-4-(2- chlorophenyl)-2-{[2-(1, 3-dioxo-1,
3-dihydro-2H-isoindol-2-yl) ethoxy] methyl}-6-methyl-1, 4-dihydropyridine-3, 5-
dicarboxylate.
Structure:

O
H
H3C N N
O
O CH3 O
O
H3 C
O H O
Cl
and enantiomer

b. Impurity B:
Chemical Name: 3-ethyl 5- methyl (4RS)-4-(2- chlorophenyl)-6-methyl-2-[[2-[[2-
(methylcarbamoyl) benzoyl] amino]-ethoxy] methyl-1, 4-dihydropyridine-3, 5-
dicarboxylate.
Structure:
O

NHCH3
H H
H3C N N
O
O CH 3 O
O
H3 C
O H O
Cl
and enantiomer

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3.2.S.3 CHARACTERIZATION

c. Impurity-C: Ethyl methyl (4RS)-2, 6-bis [(2-aminoethoxy) methyl]-4-(2-


chlorophenyl)-1, 4-dihydropyridine-3, 5-dicarboxylate. (As per Ph. Eur.
Monograph)
Structure:
H
H2N N NH2
O O

O O CH3
H3C H
O O
Cl
and enantiomer

d. Impurity E:
Chemical Name: Diethyl (4RS)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl) -
6-methyl-1,4-dihydropyridine-3,5-dicarboxylate.
Structure:

H
H3C N NH2
O

C2H5 O O C2H5

O H O
Cl
and enantiom er

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e. Impurity F:
Chemical Name: Dimethyl (4RS)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)
-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate.
Structure:

H
H3C N NH 2
O

CH 3O O CH 3

O H O
Cl
and enantiomer

2) Impurities possible from side reaction/ degradation:


a) Impurity D: (Impurity A as per USP)
Chemical Name: 3-ethyl, 5-methyl -2- [(2-aminoethoxy) methyl} -4- (2-
chlorophenyl) -6- methyl pyridine -3, 5- dicarboxylate.
Structure:
H3C N NH2
O
O CH3
O
H3C
O H O
Cl

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3.2.S.3 CHARACTERIZATION

3.2.S.3.2.3 IMPURITY PROFILE OF AMLODIPINE BESILATE :


Determination of impurities present in Amlodipine besilate manufactured by Cadila
Pharmaceutical Limited has been conducted; the level of impurities meets the Ph.
Eur. requirements. Details of method validation provided in 3.2.S.4.3.1 as Annex-I.
To support this, batch analysis data along with specification limits stated in Ph. Eur.
is presented below for three consecutive batches of Amlodipine besilate
manufactured by Cadila Pharmaceutical limited, Ankleshwar, Gujarat, INDIA.
The impurity profile along with the specification limits for three batches are
presented in table-1.
Table -1: Impurity Profile
Impurity levels observes
Impurity Specification
0AD018 0AD019 0AD020
Related Substances (BY HPLC)
Impurity D NMT 0.30% BDL BDL BDL
Impurity A NMT 0.15% BDL BDL BDL
Impurity E NMT 0.15% BDL BDL BDL
Impurity F NMT 0.15% 0.05 % 0.05 % 0.07 %
Unspecified impurity NMT 0.10% BDL 0.01 % 0.01 %
Total Impurities NMT 0.80% 0.05 % 0.07 % 0.09 %

BDL: Below Detection Limit, NMT: Not More Than

From the above results, it is evident that Cadila’s Amlodipine besilate is meeting
the predefined specification.
None of the individual impurity was observed to be greater than 0.10 %. Therefore,
no characterization study of impurities was carried out.

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3.2.S.3 CHARACTERIZATION

3.2.S.3.2.4 RESIDUAL SOLVENTS:


None of the class 1 solvents are used in the manufacturing process of
Amlodipine besilate. Isopropyl Alcohol, Methanol and Toluene are used in the
manufacturing process of Amlodipine besilate. Based on batch analysis, these
solvents may appear in the finished product. Hence these solvents are included
in the final product specifications and tested using in-house validated analytical
methods. These solvents are controlled as per in-house limits (below ICH
limits).
The In-House limits and class of the solvents as per ICH are provided below.
Name of the Class of In-House Limits ICH Limits
Solvents Solvent
Isopropyl Alcohol 3 NMT 2000 ppm NMT 5000 ppm
Methanol 2 NMT 2000 ppm NMT 3000 ppm
Toluene 2 NMT 800 ppm NMT 890 ppm

Commercial batches of Amlodipine besilate were analysed using In-House


validated analytical method. The analytical results of the residual solvent
analysis for three consecutive batches are provided in Table – 2.
Table – 2: Residual Solvents

Name of the Observed (in ppm)


Specification
Solvents 0AD018 0AD019 0AD020
Isopropyl alcohol NMT 2000ppm 30 ppm 50 ppm 19 ppm
Methanol NMT 2000ppm BDL 13 ppm 154 ppm
Less than Less than
Toluene NMT 800ppm 1 ppm
1 ppm 1 ppm
NMT- Not More Than, BDL - Below Detection limit
Based on the batch analysis results, it has been observed that all the solvents are
coming well within the specified limits.

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3.2.S.4 CONTROL OF DRUG SUBSTANCE

3.2.S.4.1 SPECIFICATION
Finished drug substance specification for ‘Amlodipine besilate’ is provided in this
section.

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3.2.S.4 CONTROL OF DRUG SUBSTANCE

3.2.S.4.2 ANALYTICAL PROCEDURES


Analytical procedures for the finished drug substance of ‘Amlodipine besilate’ are
provided in this section.

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3.2.S.4 CONTROL OF DRUG SUBSTANCE
3.2.S.4.3 VALIDATION OF ANALYTICAL PROCEDURES
3.2.S.4.3.1 RELATED SUBSTANCES
The analytical procedure used for detection of related substances is EP method.
This method is validated for attributes Specificity, Limit of Detection, Limit of
Quantitation and Linearity. The method validation report for the mentioned related
substance method is provided as ANNEX-I.

3.2.S.4.3.2 ASSAY
The analytical procedure used for detection of assay of Amlodipine Besilate is EP
method. This method is validated for attributes Specificity and Linearity. The
method validation report for the mentioned assay method is provided as ANNEX-
II.

3.2.S.4.3.3 RESIDUAL SOLVENTS


A suitable in-house GC method was developed for determination of solvents in
‘Amlodipine besilate’. Further, it was validated for specificity, precision, limit of
detection, limit of quantitation (LOQ), precision at LOQ level, linearity, accuracy
(recovery study), robustness & ruggedness proved that the method is capable to
resolve all residual solvents in the product.

Validation report and its supporting chromatograms are provided as ANNEX- III.

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3.2.S.4 CONTROL OF DRUG SUBSTANCE

3.2.S.4.4 BATCH ANALYSIS


The batches of Amlodipine besilate, manufactured as per the procedure described
in this section, have been analyzed as per the specification and test method provided
in section 3.2.S.4.1 & 3.2.S.4.2. The certificates of analysis of the following three
batches are provided in this section.

Assay (Not less


than 97.0%w/w
Batch
Date and not more
Batch No. Manufacturing Site size
of Mfg. than 102.0% )
(Kg)
(On anhydrous
basis)
March,
0AD018 261.20 99.1 % w/w
CADILA PHARMACEUTICALS LTD. 2010
294, G.I.D.C. Industrial Estate
March,
0AD019 262.10 99.7 % w/w
Ankleshwar - 393002 2010
Gujarat, INDIA
April,
0AD020 261.0 99.2 % w/w
2010

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3.2.S.4 CONTROL OF DRUG SUBSTANCE
3.2.S.4.5 JUSTIFICATION OF SPECIFICATION
List of all the tests along with specifications and justifications and references is
given below.
1. Characters
Specification : Appearance: White or almost white powder.
Justification : As per Ph. Eur. monograph.
Specification : Solubility: Slightly soluble in water, freely soluble in methanol,
sparingly soluble in ethanol, slightly soluble in 2-propanol.
Justification : As per Ph. Eur. monograph.

2. Identification (By IR)


Specification : The infrared absorption spectrum of the substance being
examined in mulls should be concordant with the spectrum
obtained from Amlodipine besilate working standard.
Justification : As per Ph. Eur. monograph.

3. Optical rotation at 589 nm (1 % solution in Methanol)


Specification : Between –0.10° and +0.10°
Justification : As per Ph. Eur. monograph.

4. Related substances (By HPLC)


Specification
- Impurity D : Not more than 0.30 %
- Impurity A : Not more than 0.15 %
- Impurity E : Not more than 0.15%
- Impurity F : Not more than 0.15%
- Unspecified impurity : Not more than 0.10%
- Total impurities : Not more than 0.80%
Justification : As per Ph. Eur. monograph.

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5. Water content (By KF)
Specification : Not more than 0.50 % w/w
Justification : As per Ph. Eur. monograph.

6. Sulphated Ash
Specification : Not more than 0.20 % w/w
Justification : As per Ph. Eur. monograph.

7. Assay (By HPLC)


Specification : It should contain not less than 97.0 % w/w and not more than
102.0 % w/w of C26H31ClN2O8S, calculated on anhydrous basis.
Justification : As per Ph. Eur. monograph.

Additional Test

8. Residual Solvents (By GC)


Specification : Isopropyl alcohol : Not More Than 2000 ppm
: Methanol : Not More Than 2000 ppm
: Toluene : Not More Than 800 ppm
Justification Limits for the solvents are based on the ICH guideline and on
historical data of the laboratory batches

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3.2.S.5 REFERENCE STANDARDS OR MATERIALS

3.2.S.5.1 Primary standard and evaluation of working standard


Amlodipine besilate manufactured at Ankleshwar site is compared with the most
recent reference standard provided by Ph. Eur. commission Amlodipine besilate
CRS Batch No: 4.0. Working reference standard of Amlodipine besilate:
WRS/AMD/010 is prepared from one of the production batch. This working
reference standard is evaluated with the monographs of Ph. Eur. reference standard
(batch no. 4.0) with respect to IR Spectrum, Ph. Eur. monograph specification and
in-house specification.

Reference standard : Amlodipine besilate CRS Batch No.: 4.0


Working Reference standard : WRS/AMD/010

Working reference standard WRS/AMD/010 is analyzed for following tests as per


Ph. Eur. monograph and in-house specification, in comparison with CRS Batch No.:
4.0.

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3.2.S.6 CONTAINER CLOSURE SYSTEM

This section describes the acceptance criteria for the Packaging Materials used in
the packing of the Amlodipine besilate, also includes packaging and labeling
procedures for finished product

Primary packing material and material of construction


Transparent double polyethylene bags being used as the primary packing materials
for packing of Amlodipine besilate are made up of food grade LDPE (Low density
polyethylene).

Secondary packing material and material of construction


Fiber drum is used as the secondary packaging material for Amlodipine besilate.
The drum is made up of fiberboard, one end sealed with rust proof metal ring and a
lid and other end open having lid & rust proof metal ring

PACKAGING AND LABELING PROCEDURE


Written procedures are employed to ensure the quality and purity of bulk drugs and
to ensure that the correct labels are affixed on the containers. Any labeling or
packaging material should meet appropriate specifications. The materials that do
not meet such specifications shall be rejected to prevent their use in operations for
which they are unsuitable.
Records are maintained for shipment of labeling and packaging material, indicating
examination and status of acceptance or rejection.
Labels of material for each different drug are stored separately under lock and key.
Outdated labels and packaging materials are destroyed as per Standard Operating
Procedure.

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3.2.S.6 CONTAINER CLOSURE SYSTEM

Label issuance
Strict control is exercised over labels issued for use. Exact number of labels,
sufficient for the number of containers to be labeled and one specimen label are
issued for each batch. Labeling materials issued for a batch, are carefully examined
for identity and conformity to the labels specified in Master/Batch Process Records.
Only one batch is labeled at a time.

Packaging and Labeling Methodology


Empty clean, dry fiber drums, clean, dry and food grade inner clear transparent and
double polyethylene bags are weighed for tare weight. Material is filled in double
polyethylene bags lined fiber drums to give required net weight. The bags are tied
with PVC strip inter locking system. Drums are closed and sealed with a seal
bearing Company's monogram with a specified number. Drums are also affixed
with the labels containing details like product name, manufacturing lic. no, batch
no. / lot no., manufacturing date, re-test date, gross weight, tare weight, net weight,
storage conditions and address of the manufacturer. Packing material specifications
and test methods for primary and secondary packing materials are attached in this
section.

Drug product Inspection


Packed and labeled products are examined by Quality Assurance to provide
assurance that the containers have correct labels and packed as per requirements.
Results of these examinations are recorded in the Batch Process Records.

STORAGE CONDITIONS
Store in tightly closed container.

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PACKING MATERIAL SPECIFICATIONS
Specifications and test methods of packing materials together with Food grade
certificate are provided in this section.

Sr. No. Name of the Packing Material Size


1. Polyethylene Transparent Bags 28" x 46"
2. Fiber Drum 16" x 30"

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3.2.S.6 CONTAINER CLOSURE SYSTEM

SPECIMEN PRODUCT LABEL

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3.2.S.7 STABILITY

3.2.S.7.1 STABILITY SUMMARY AND CONCLUSION


Stability studies have been initiated at our location Dholka, Ahmedabad, INDIA.

The following tests are performed during stability:-


Description, Identification (by IR), Water (By KF), Optical Rotation, Related
substance and Assay.
For all the tests the same methods are used for release and stability study.

OBSERVATIONS
There are no significant changes observed in the physical and chemical properties
during accelerated and long-term stability studies.

Physical Form (Description)


There is no significant change observed in description of the drug substance
during accelerated and long-term storage conditions. It implies that the material is
stable in physical form.

Identification (By IR)


IR spectrum of the sample is concordant with that of working standard during
accelerated and long-term storage conditions.

Water (By KF) (Not More Than 0.50 %w/w)


No significant change is observed during the accelerated and long term storage
conditions.

Optical Rotation (-0.10º to +0.10º)


There is no significant change in the optical rotation observed compared to initial
value in all the batches. All the results are within the acceptance limits.

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3.2.S.7 STABILITY

Related substances (By HPLC)

Impurity D (Not More Than 0.30%)


There are no significant changes observed during the stability studies of accelerated
and long-term stability conditions. All the results are within the acceptance limits.

Impurity A (Not More Than 0.15%)


There are no significant changes observed during the stability studies of accelerated
and long-term stability conditions. All the results are within the acceptance limits.

Impurity E (Not More Than 0.15%)


There are no significant changes observed during the stability studies of accelerated
and long-term stability conditions. All the results are within the acceptance limits.

Impurity F (Not More Than 0.15%)


There are no significant changes observed during the stability studies of accelerated
and long-term stability conditions. All the results are within the acceptance limits.

Unspecified Impurity (Not More Than 0.10%)


There are no significant changes observed during the stability studies of accelerated
and long-term stability conditions. All the results are within the acceptance limits.

Total Impurities (Not More Than 0.80%)


There are no significant changes observed during the stability studies of accelerated
and long-term stability conditions. The level of total impurities is well within the
acceptance limits.

Assay
It contains not less than 97.0 % w/w and not more than 102.0 % w/w. All the values
are within the specified limits. All results are within the acceptance limits.

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CONCLUSIONS
Based on 60 month stability study data, Cadila propose the expiry date for
Amlodipine besilate to be 5 years when stored under recommended storage
conditions as given on the product label, “Store in tightly closed container”

Annually one batch of product will be placed for long-term stability, if a batch is
manufactured that year.

FORCED DEGRADATION
Forced degradation studies is carried out for Amlodipine Besilate under stress
conditions of Acid, Alkali, Oxidation, water, heat and Sunlight. From the results of
3-point peak purity of degradations.
Validation report and its supporting chromatograms are provided as ANNEX-IV.

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3.2.S.7 STABILITY
3.2.S.7.2 POST-APPROVAL STABILITY PROTOCOL & STABILITY
COMMITMENT
The stability study of Amlodipine besilate has been initiated at our location in
Dholka, Ahmedabad, INDIA.
PURPOSE
To carry out accelerated & Long-term stability studies of Amlodipine besilate to
determine re-test date of the active pharmaceutical ingredient.

Name of Product : Amlodipine besilate


Product Code : AD
Manufacturing Information : Commercial batches / lots

Batch No. Manufactured By Manufacturing Batch size Date of Mfg.


Site (kg)
6AD031 115.0 Sep., 2006
6AD032 114.9 Sep., 2006
6AD033 115.0 Sep., 2006
8AD001 132.3 Jan, 2007
Cadila Pharmaceuticals Ltd
9AD001 113.50 Jan, 2009
294, G.I.D.C. Industrial Estate,
0AD001 261.50 Jan, 2010
Ankleshwar-393002. Gujarat, INDIA
1AD001 262.10 Jan, 2011
2AD001 265.10 Jan, 2012
13AD001 265.10 Jan, 2013
14AD001 264.50 Jan, 2014

Note: Batch no: 6AD031, 6AD032, 6AD033 upto 36 months stability data station
was analyzed as per old specification and from 48 months onwards stability data
station has been analyzed as per current specification.

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Batch no: 8AD001 upto 24 months stability data station was analyzed as per old
specification and 36 months onwards stability data station has been analyzed as per
current specification.

3.2.S.7 STABILITY

Batch no: 9AD001 upto 12 months stability data station was analyzed as per old
specification and 18 months onwards stability data station has been analyzed as per
current specification.
Batch no: 0AD001 initial stability data station was analyzed as per old specification
and 3 months onwards stability data station has been analyzed as per current
specification.
Batch no: 1AD001, 2AD001, 13AD001 & 14AD001 all stability data stations are
analyzed as per current specification.

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3.2.S.7 STABILITY

Study Required

Type of the study Conditions Study duration


(in months)
Accelerated 40°C±2°C; 75%±5%RH 6 months
Long term 25°C±2°C; 60%±5%RH 60 months

Product Stability Details


Description of the Product
Amlodipine besilate is white or almost white powder.
Packing Details
Adequate samples are drawn and packed for stability studies. Stability samples are
packed in transparent double polyethylene bags and kept in fiber drums, which are
similar to the packing of the finished product container for commercial purpose.

Packaging Information
Name: Amlodipine besilate
Batch No: 6AD031, 6AD032, 6AD033, 8AD001, 9AD001,
0AD001, 1AD001, 2AD001,13AD001 & 14AD001.

Storage Conditions :
Type of the Study Conditions
Accelerated 40°C±2°C; 75%±5%RH
Long-term 25°C±2°C; 60%±5%RH

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3.2.S.7 STABILITY
Test Parameters & Acceptance Criteria
Test Parameters Acceptance Criteria
Description White or almost white powder.

Identification The IR absorption spectrum of the substance being


examined in mulls should be concordant with the
spectrum obtained from Amlodipine besilate working
standard.
Optical Rotation -0.10 º to + 0.10 º
Water (By KF) Not more than 0.50% w/w
Related Substances (By
HPLC)
- Impurity D Not more than 0.30%
- Impurity A Not more than 0.15%
- Impurity E Not more than 0.15%
- Impurity F Not more than 0.15%
- Unspecified Not more than 0.10%
impurity
- Total impurities Not more than 0.80%
Assay Not less than 97.0 % w/w and Not more than 102.0 %
w/w

Testing time Points: As per sampling schedule.


Analysis Period: Analysis of the sample will be done within ±2 days
for accelerated study and ±5 days for Long-term
study after withdrawal of the sample.

Sampling Schedule
Accelerated Stability Study
Initial, 1 month, 2 months, 3 months and 6 months.
Long-term Stability Study
Initial, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 36
months, 48 months and 60 months.
Reason for Stability Study
To propose and establish re-test date and storage conditions.

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3.2.S.7 STABILITY

STABILITY COMMITMENT
The stability program will be continued till the end of proposed period unless a
significant change is observed during Long-term stability study. Re-test period will
be extended based on the results of Long-term stability study.

A minimum of one commercial batch will be added every year to on going stability
study for long-term conditions.

In case of major change in the synthetic route / final purification / change in


equipment, and / or manufacturing site, fresh batches will be subjected to
Accelerated study and Long-term stability study.

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3.2.S.7 STABILITY
3.2.S.7.3 STABILITY DATA
The stability data reports of Amlodipine besilate for accelerated and long-term
conditions for the following batches are provided.

Batch Nos. 6AD031


6AD032
6AD033
8AD001
9AD001
0AD001
1AD001
2AD001
13AD001 &
14AD001

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ABBREVIATIONS

Sr. No. Abbreviation Expansion

o
1. C Degree Centigrade
2. % Percentage
3. µ Micron
4. µL/µl Microlitre
5. µm Micrometer
6. IR Infra-Red
7. A.R. No. Analytical Report Number
8. API Active Pharmaceutical Ingredient
9. Dec December
10. cm Centimeter
11. COA Certificate of Analysis
12. CPL Cadila Pharmaceuticals Limited
13. AM/AD Amlodipine Besilate
14. DMF Drug Master File
15. TIR Test Information Report
16. Exp. Date Expiry Date
17. FPS Finished Product Specification
18. FPT Finished Product Test method
19. g/cc Gram per centimeter cube
20. g/l Gram/ liter
21. GIDC Gujarat Industrial Development Corporation
1
22. H NMR Proton Nuclear Magnetic Resonance
23. GMP Good Manufacturing Practice
24. HPLC High performance liquid chromatography
25. Hrs Hours
26. HSS Head Space Sampler
27. ND Not Detected
28. Inj. Injector
29. Jul. July
30. KF Karl Fisher
31. Km Kilometer
32. GC Gas Chromatography
33. Ltd. Limited

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ABBREVIATIONS

Sr. No. Abbreviation Expansion

34. M Months
35. L Liter
36. Kg Kilogram
37. mg Milligram
38. Min Minutes
39. ml Milliliter
40. ml/min. Milliliter/minute
41. mm Millimeter
42. Mol. Wt. Molecular weight
43. mol/L Moles/liter
44. N Normal
45. BDL Below Detection Limit
46. NLT Not Less Than
47. nm Nanometer
48. NMR Nuclear Magnetic Resonance
49. NMT Not More Than
50. No. Number
51. PMS Packing Material Specification
52. ppm Parts Per Million
53. R&D Research And Development
54. RH Relative Humidity
55. RM Raw Material
56. RT Room Temperature
57. SBU Strategic business unit
58. TLC Thin Layer Chromatography
59. WRS Working Standard
60. USP United States Pharmacopoeia

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