Ph.D. (Pharmaceutical Sciences) Thesisshodhganga.inflibnet.ac.in/bitstream/10603/12278/17/17... · 2015-12-04 · Ph.D. (Pharmaceutical Sciences) Thesis Shri Jagdish Prasad Jhabarmal

Ph.D. (Pharmaceutical Sciences) Thesis

Shri Jagdish Prasad Jhabarmal Tibrewala

3.2. S DRUG SUBSTANCE

3.2. S.1 General Information

3.2. S.1.1 Nomenclature

INN : Tianeptine Sodium

USAN: Tianeptine Sodium

Molecular formula : C21H24ClN

CAS:—66981–73–5

ATC code: N06AX14

Chemical Name: 7-[(3–Chloro

amino]heptanoic acid S,S-dioxide

3.2. S.1.2 Structure

Chemical Structure:

Chemical Name: 7-[(3–Chloro

amino]heptanoic acid S,S-dioxide

Molecular Weight: 458.9

3.2. S.1.3 General Properties

Physico-chemical properties

1) Physical description: White or yellowish powder, very hygroscopic.

2) Solubility: Freely soluble in water, in methanol and in methylene chloride.

3) Melting point: 180°

4) Biological Activity: Selective facilitator of 5

affinity for a wide range of receptors, including 5


rasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj)

3.2. S.1 General Information

ClN2NaO4S

Chloro–6,11–dihydro–6–methyldibenzo[c,f][1,2]thiazepin

dioxide

Chloro–6,11–dihydro–6–methyldibenzo[c,f][1,2]thiazepin

dioxide

3.2. S.1.3 General Properties

chemical properties

White or yellowish powder, very hygroscopic.

Freely soluble in water, in methanol and in methylene chloride.

Selective facilitator of 5-HT uptake in vitro and in vivo has no

affinity for a wide range of receptors, including 5-HT and dopamine (IC 50 > 10

Page 1 of 22

][1,2]thiazepin–11–yl)-

][1,2]thiazepin–11–yl)-

Freely soluble in water, in methanol and in methylene chloride.

HT uptake in vitro and in vivo has no

HT and dopamine (IC 50 > 10 µ M) and


Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 2 of 22

has no effect on noradrenalin or dopamine uptake. Antidepressant, analgesic and

neuroprotective following systemic administration in vivo

3.2. S.2 Manufacture

3.2. S.2.1 Manufacturer

Address:

1 Vivan Life sciences Pvt Limited

# 502, Rutu Business Park, Besides Eastern Express Highway, Service road, Thane (w) -

400601, Mumbai, India

Tel: + 91-22-2544 4584/2544 4585

Fax: +91-22-2544 4588

E-mail: [email protected], Url: www.vivanls.com

2. Taj Pharmaceuticals Ltd.

434, Laxmi Plaza, Laxmi Industrial Estate,

New Link Road, Andheri (W),

City: Mumbai- 400 053, India

Phone: 91 -(0)22 - 26374592/93 91

(0)22 - 30601000, Fax : 91-(0)22-26341274

E-mail: [email protected]

3.2. S.2.2 Description of Manufacturing Process and Process Controls

a) Material flow route

b) Process description

Material flow route

Activity Flow Chart:

Incoming of Raw Materials (RM) and Packing Materials (PM)

Testing of RM and PM by Quality Control Department

Approval of RM and PM by Quality Control Department

Line Clearance by Quality Assurance Department

Dispensing of Raw Materials




Compounding of Raw Materials

In process testing and approval of the product by Quality Control

Release of Packaging material

Line clearance by Quality Assurance Department

In process checking by Q.A


Packing of the Product

Finished product testing and approval of the product

Dispatch of the product

Distribution of the product

Methods of Preparation

Raw Materials

1. Ethyl 7-aminoheptanoate

2. 5, 8-Dichloro-10-dioxo-11-methyldibenzo[c,f] thiazepine

3. Sodium hydroxide

Manufacturing Process

A solution of 27.6 g (0.16 mol) of freshly distilled ethyl 7-aminoheptanoate in 40 ml of

nitromethane was added all at once and with mechanical stirring to asuspension of 26.2 g

(0.08 mol) of 5,8-dichloro-10-dioxo-11-methyldibenzo[c,f]thiazepine(1,2) in 120 ml of

nitromethane.

The whole was heated to 55°C for 30 minutes, the solvent was then evaporated in vacuo and

the residue was taken up in water. The crude ester was extracted with ether After evaporation

of the ether 36 g of crude ester were obtained, and 30 g(0.065 mol) there of were treated



under reflux with a solution of 2.8 g (0.07mol) of sodium hydroxide in 35 ml of ethanol and

25 ml of water.

After one hour’s refluxing, the alcohol was evaporated in vacuo. The residue was taken up in

150 ml of water.The mixture was twice extracted with 75 ml of chloroform and the aqueous

phase was evaporated in vacuo.

The sodium salt was then dissolved in 150 ml of chloroform, the solution was dried over

sodium sulfate and the product precipitated with anhydrous ether.

The salt was filtered off, washed with ether and dried at 50°C. 13 g of sodium 7-[8-chloro-

10-dioxo-11-methyldibenzo[c,f] thiazepin-(1,2)-aminoheptanoate, melting with

decomposition at about 180°C, were obtained.

3.2. S.2.3 Control of Materials

Synthesis of Tianeptine Sodium B.P

Preparation of 7- [8-chloro-10-dioxo-11-methyldibenzo [c,f] thiazepin - (1,2) -

aminoheptanoate

Reagents and solutions used:

1. Ethyl 7-aminoheptanoate,

2. 5,8-Dichloro-10-dioxo-11-methyldibenzo[c,f] thiazepine

3. Sodium hydroxide

4. Ether

3.2.S.2.4 Controls of Critical Steps and Intermediates

1. Boiling of solution for 55°C for 30 minutes

2. Extraction of crude product with ether

3. Reflex of solvent with 2.8 g (0.07mol) of sodium hydroxide in 35 ml of ethanol and

25 ml of water.

4. Filtration of solvent and its decomposition.

3.2.S.2.5 Process Validation and/or Evaluation

Not applicable

3.2.S.2.6 Manufacturing Process Development

Not applicable



3.2.S.3 Characterisation

3.2.S.3.1 Elucidation of Structure and other Characteristics

Spectrophotometric UV – maximum at 205,270 nm;

Figure 2: UV Spectrum



Mass spectrometry

MS (70 eV) – 228, 293, 194, 213, 165 m/z

Mass spectrometry was designed to get m/z ratio in order to optimize the substances and

conformation of elucidation of drug product.

Figure 3: Mass spectrometry



NMR Spectra:

Figure 4: NMR Spectra



3.2.S.4 Control of Drug Substance

3.2.S.4.1 Specification

The drug substance is official in British pharmacopeia monograph (B.P.2012); hence its

specifications (tests and limits) are based on the pharmacopoeial tests.

Specifications have been set according to general compendial standards. All the

specifications and procedures used are Pharmacopoeial hence no Justification of

Specification is required.

Specification for Tianeptine Sodium B.P is given below:-

Table: Specification for Tianeptine Sodium B.P

TEST PARAMETER SPECIFICATION

Appearance White to yellowish powder, very hygroscopic.

Solubility Freely soluble in water, in Methanol and in Methylene chloride

Identification by:

a) IR Spectroscopy The characteristic bands obtained at the wave numbers should be specific for the functional groups.

b) Reaction of Ions It gives the reaction of sodium.

Impurity - A by GC (%) Not more than 0.1%

Related substances by HPLC (%w/w)

Impurity - B Not more than 0.1%

Impurity – C Not more than 0.1%

Impurity – D1 Not more than 0.1%

Impurity – D2 Not more than 0.1%

Impurity – E Not more than 0.1%

Any Individual unknown Impurity Not more than 0.1%

Total Impurities Not more than 0.4%

Residual solvents by GC (ppm)

Methanol Not more than 3000

Methylene chloride Not more than 600

Ethyl acetate Not more than 5000

Toluene Not more than 890

Acetone Not more than 720

Water by KF(%w/w) Not more than 5.0%

Assay by HPLC (%w/w) (on anhydrous basis)

99%-101.0%

Remarks: The Substance Conforms to EP and BP Specifications.



3.2.S.4.2 Analytical Procedures

DEFINITION

Sodium 7-[[(11RS)-3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11- yl] amino]

heptanoate S,S-dioxide.

Content: 99.0 per cent to 101.0 per cent (anhydrous substance).

CHARACTERS

Appearance: White or yellowish powder, very hygroscopic

Solubility: Freely soluble in water, in methanol and in methylene chloride

IDENTIFICATION

A. Infrared absorption spectrophotometry (2.2.24).

Comparison Ph. Eur. reference spectrum of Tianeptine Sodium B.P sodium.

B. It gives reaction (a) of sodium (2.3.1).

TESTS

Impurity A

Gas chromatography (2.2.28)

Internal standard solution Dilute 1 ml of ethyl 5-bromovalerate R in ethanol R and dilute to

100.0 ml with the same solvent. Dilute 1.0 ml of the solution to 250.0 ml with ethanol R.

Test solution Dissolve 0.1000 g of the substance to be examined in the internal standard

solution and dilute to 2.0 ml with the same solution.

Reference solution. Dissolve 10.0 mg of Tianeptine Sodium B.P impurity A CRS in the

internal standard solution and dilute to 200.0 ml with the same solution.

Column material: fused silica;

Size: l = 25 m, Ø = 0.25 mm;

Stationary phase: poly (cyanopropyl) siloxane R (film thickness 0.2 µm).

Carrier gas: helium for chromatography R.

Linear velocity: 26 cm/s.

Split ratio: 1:100.

Temperature:

Column: 150 °C;

Injection port and detector: 210 °C.

Detection Flame ionisation

Injection 1 µl

Run time Twice the retention time of ethyl 5-bromovalerate.



System suitability Reference solution:

Elution order: ethanol, ethyl 5

Resolution: minimum 10 between the peaks due to ethyl 5

Signal-to-noise ratio: minimum 20 for the peak due to impurity A.

Limit: Impurity A: not more than the area of the corresponding peak in the chromatogram

obtained with the reference solution (0.1 per cent).

Related substances

Liquid chromatography (2.2.29

Solvent mixture Mix 50 volumes of

chromatography R

Test solution Dissolve 50.0 mg of the substance to be examined in the solvent mixture and

dilute to 50.0 ml with the solvent mixture.

Reference solution (a) Dilute 1.0 ml of the test solution to 100.0 ml with the solvent

mixture. Dilute 1.0 ml of this solution to 20.0 ml with the solvent mixture.

Reference solution (b) Dissolve 20.0 mg of

suitability CRS in the solvent mixture and dilute to 200.0 ml with the solvent mixture.

Column: size: l = 0.15 m, Ø = 4.6 mm;

Stationary phase: octadecylsilyl silica gel for chromatography R

0.01 µm;

Temperature: 30 °C.

Mobile phase: mobile phase A

R1 and 47.5 volumes of a 2 g/l solution of

phosphoric acid R;

Mobile phase B: mix 20 volumes of

lauryl sulfate R, adjusted to pH 2.5 with

R1;

Flow rate 1 ml/min.

Detection Spectrophotometer at 220 nm



Reference solution:

: ethanol, ethyl 5-bromovalerate, impurity A;

: minimum 10 between the peaks due to ethyl 5-bromovalerate and impurity A;

: minimum 20 for the peak due to impurity A.

: not more than the area of the corresponding peak in the chromatogram

obtained with the reference solution (0.1 per cent).

2.2.29)

Mix 50 volumes of methanol R and 50 volumes of

Dissolve 50.0 mg of the substance to be examined in the solvent mixture and

dilute to 50.0 ml with the solvent mixture.

Dilute 1.0 ml of the test solution to 100.0 ml with the solvent

of this solution to 20.0 ml with the solvent mixture.

Dissolve 20.0 mg of sodium Tianeptine Sodium B.P for system

in the solvent mixture and dilute to 200.0 ml with the solvent mixture.

= 4.6 mm;

Stationary phase: octadecylsilyl silica gel for chromatography R (3 µm) with a pore size of

Mobile phase: mobile phase A: mix 21 volumes of methanol R1, 31.5 volumes of

and 47.5 volumes of a 2 g/l solution of sodium lauryl sulfate R, adjusted to pH 2.5 with

: mix 20 volumes of methanol R1, 20 volumes of a 2 g/l solution of

, adjusted to pH 2.5 with phosphoric acid R and 60 volumes of

Spectrophotometer at 220 nm

Page 10 of 22

bromovalerate and impurity A;

: not more than the area of the corresponding peak in the chromatogram

and 50 volumes of water for

Dissolve 50.0 mg of the substance to be examined in the solvent mixture and

Dilute 1.0 ml of the test solution to 100.0 ml with the solvent

of this solution to 20.0 ml with the solvent mixture.

sodium Tianeptine Sodium B.P for system

in the solvent mixture and dilute to 200.0 ml with the solvent mixture.

(3 µm) with a pore size of

, 31.5 volumes of acetonitrile

, adjusted to pH 2.5 with

, 20 volumes of a 2 g/l solution of sodium

and 60 volumes of acetonitrile



Injection 10 µl

Relative retention With reference to Tianeptine Sodium B.P (retention time = about 30

min): impurity C = about 0.4; impurity D1 = about 0.6;

= about 1.1; impurity B = about 1.7.

System suitability Reference solution (b):

Resolution: minimum 2.5 between the peaks due to Tianeptine Sodium B.P and impurity E.

Limits: Any impurity: not more than twice the area of the principal peak in the chromatogram

obtained with reference solution (a) (0.1 per cent);

Total: not more than 8 times the area of the principal peak in the chromatogram obtained with

reference solution (a) (0.4 per cen

Disregard limit: area of the principal peak in the chromatogram obtained with reference

solution (a) (0.05 per cent).

Water (2.5.12)

Maximum 5.0 per cent, determined on 0.100 g

ASSAY

Dissolve 0.165 g in 50 ml of

determining the end-point potentiometrically

1 ml of 0.1 M perchloric acid

STORAGE

In an airtight container

IMPURITIES

A. Br-[CH2]6-CO-O-C2H5: ethyl 7

B. R = H, R′ = [CH2]6-COdibenzo[c,f][1,2] thiazepin -11



With reference to Tianeptine Sodium B.P (retention time = about 30

min): impurity C = about 0.4; impurity D1 = about 0.6; impurity D2 = about 0.8; impurity E

= about 1.1; impurity B = about 1.7.

Reference solution (b):

: minimum 2.5 between the peaks due to Tianeptine Sodium B.P and impurity E.

: not more than twice the area of the principal peak in the chromatogram

obtained with reference solution (a) (0.1 per cent);

: not more than 8 times the area of the principal peak in the chromatogram obtained with

reference solution (a) (0.4 per cent);

: area of the principal peak in the chromatogram obtained with reference

Maximum 5.0 per cent, determined on 0.100 g

Dissolve 0.165 g in 50 ml of anhydrous acetic acid R. Titrate with 0.1 M perchloric acid,

point potentiometrically (2.2.20).

0.1 M perchloric acid is equivalent to 22.95 mg of C21H24ClN2NaO

: ethyl 7-bromoheptanoate,

CO-O-C2H5: ethyl 7-[[(11RS)-3-chloro-6-methyl11-yl]amino]heptanoate S,S-dioxide,

Page 11 of 22

With reference to Tianeptine Sodium B.P (retention time = about 30

impurity D2 = about 0.8; impurity E

: minimum 2.5 between the peaks due to Tianeptine Sodium B.P and impurity E.

: not more than twice the area of the principal peak in the chromatogram

: not more than 8 times the area of the principal peak in the chromatogram obtained with

: area of the principal peak in the chromatogram obtained with reference

0.1 M perchloric acid,

NaO4S.

methyl-6,11- dihydro



E. R = R′ = [CH2]6-CO2H: 7,7

thiazepin-11-yl]imino]diheptanoic acid

C. X = O: 3-chloro-6-methyldibenzo[

D. X = N-[CH2]6-CO2H: 7

ylidene]amino]heptanoic acid S,S

Refer to “Annexure 3” for Certificate of Analysis of Tianeptine sodium BP

3.2. S.4.3 Validation of Analytical Procedures

(Not Applicable)

Our Substance is present in official monograph B.P. 201

Procedures (tests and limits) are based on the pharmacopoeia tests

Validation of Analytical Procedures.

3.2.S.4.4 Batch Analyses

Table: Test and specification of Batches of

Tests Checking Time (Months)

Description White to yellowish powder,very hygroscopic

Identification Positive with Test A and B Ethyl acetate(ppm) NMT 5000Water by KF (%w/w) NMT 5.0%

Individual impurity: Not more than 0.1%

Total Impurities NMT0.4%Assay (on anhydrous basis)

99.00%anhydrous substance)

3.2.S.4.5 Justification of Specification

Table 13: Justification of Specification



H: 7,7′-[[(11RS)-3-chloro-6-methyl-6,11-dihydrodibenzo[

yl]imino]diheptanoic acid S,S-dioxide,

methyldibenzo[c,f][1,2]thiazepin-11(6H)-one S,S-dioxide,

H: 7-[[(11RS)-3-chloro-6-methyldibenzo[c,f][1,2]thiazepin

ylidene]amino]heptanoic acid S,S-dioxide.

to “Annexure 3” for Certificate of Analysis of Tianeptine sodium BP

3.2. S.4.3 Validation of Analytical Procedures

Our Substance is present in official monograph B.P. 2012. Hence its Validation of Analytical

(tests and limits) are based on the pharmacopoeia tests. So there is no need of

Validation of Analytical Procedures.

: Test and specification of Batches of Tianeptine Sodium B.P.

Specification Analysis ResultsBP/BPA_001/D/10/023

BP/BPA_001/D/10/024

White to yellowish powder,very hygroscopic

Off white powder

Off white powder

Positive with Test A and B Positive Positive NMT 5000 102 NMT 5.0% 2.81%

Not more than 0.1% 0.080% 0.078%

NMT0.4% 0.231% 0.232%99.00%-101.0% (on anhydrous substance)

100.87% 100.88%

3.2.S.4.5 Justification of Specification

Table 13: Justification of Specification

Page 12 of 22

dihydrodibenzo[c,f] [1,2]

dioxide,

][1,2]thiazepin-11(6H)-

to “Annexure 3” for Certificate of Analysis of Tianeptine sodium BP

Validation of Analytical

. So there is no need of

Analysis Results BP/BPA_001/

D/10/024BP/BPA_001

/D/10/025 Off white powder

Off white powder

Positive Positive 101 107

2.78% 2.94%

0.078% 0.081%

0.232% 0.231% 100.88% 100.91%



TEST ITEM SPECIFICATION REFERENCE

Appearance White to yellowish powder, very hygroscopic.

B.P.

Solubility Freely soluble in water and methanol B.P.

Identification Reaction positive B.P.

Related substance Individual impurity: Not more than 0.1%

B.P.

Total impurities: Not more than 0.4% B.P.

Methanol Not more than 0.3% B.P.

Dichloromethane Not more than 0.06% B.P.

Ethyl acetate Not more than 0.5% B.P.

Water Not more than 5.0% B.P.

Assay (on anhydrous basis)

99%-101.0% B.P.

Our Substance is present in official monograph B.P. 2012. Hence its tests and limits are based

on the monograph in Ph.Eur and BP. So there is no need for the Justification of Specification.

3.2.S.5 Reference Standards or Materials

Given below are the details of working standard used for analyzing the samples of Capsules

and API.

Name Batch no. Assay Tianeptine Sodium BP BP/BPA_001/D/10/025 99.65% w/w

TEST STANDARD RESULT Description White to yellowish

powder, very hygroscopic. Off-white powder, hygroscopic

Identification Should Be Complies Complies

Water NMT 5.0%W/W 0.55%

Assay NLT 99.00% and NMT 101.00 % W/W (O.A.B)

99.65% w/w

Refer to “Annexure 2” for Certificate of Analysis.

3.2.S.6 Container Closure System

Containers for Bulk Drug Products

A container closure system for bulk drug products is used for storage prior to packaging or

for shipment to repackages or contract packagers. In all cases, the container closure system

should adequately protect the dosage form and should be constructed of materials that are



compatible and safe. Container closure systems for on-site storage have generally been

considered a CGMP issue under 21 CFR 211.65. However, if a firm plans to hold bulk drug

products in storage, then the container closure system and the maximum storage time should

be described and justified in the application. In addition, stability data should be provided to

demonstrate that extended storage in the described containers does not adversely affect the

dosage form. Even when the storage time before packaging will be short, a firm should use a

container closure system that provides adequate protection and that is manufactured from

materials that are compatible and safe for the intended use (see section III.B).

The container closure system is adequate to protect the dosage form, be constructed with

materials that are compatible with product being stored, and be safe for the intended use. The

protective properties of the shipping container are verified by the practice of including annual

batches of the packaged product in post approval stability studies. A container closure system

specifically intended for the transportation of a large volume of drug product to a repackage

(section II.C.3), whether for a solid or liquid dosage form, is considered a market package.

The package meets the same requirements for protection, compatibility, and safety as a

smaller market package; should be included in 24 the stability studies for application

approval and in the long term stability protocol. The length of time that the dosage form will

spend in the bulk container may be a factor in determining the level of detail of the

supporting information.

Packaging and storage: To be stored at room temperature. Preserve in tight containers.

Store the dry powder at controlled room temperature. in a well-closed container. Tianeptine

Sodium B.P is packaged in a light resistant cardboard container Package 10 kg/drum,

according to customers. The container closure system for storage or shipment of a Tianeptine

Sodium B.P drug substance is typically a drum with double LDPE liners that are usually heat

sealed or closed with a twist tie. A desiccant is to be placed between the bags. The drum

provides protection from light and mechanical strength to protect the liner during shipment

and handling. The majority of the protection from air and moisture is provided by the liner.

Labels on the drum show the following information:

Name and address of company

Name of the product

Retest date

Drum No.

Manufacturing date



Expiration date

Gross weight

Net weight

Storage: Preserve in tight containers. Store below 25°C. Protect from light and moisture.

3.2.S.7 Stability

3.2.S.7.1 Stability Summary and Conclusions

Substance : Tianeptine Sodium B.P

Shelf-life : Tianeptine Sodium B.P, is stable at least 2 Years from the date

of manufacture.

Proposed expiry : 24 months

Storage : Store below 25°C. Protect from light and moisture.

Stability studies : Accelerated stability study at 40°C and Long term stability

study at 250C are carried out and stability data are attached.

PACKING CONDITION

Tianeptine Sodium B.P is packaged in a light resistant cardboard container Package 10

kg/drum, or according to customers.



3.2.S.7.3 Stability Data

Table: 15: Stability Study Report (Long Term Stability)

AT 25°C ± 2°C, 60% ± 5% RH; Batch No: BP/BPA_001/D/10/023 Tests Specification Analysis Results

Checking Time (Months) 0 M 3M 6M 9M 12M 18M 24M

Description White to yellowish

powder,very hygroscopic

Off

white

powder

Off

white

powder

Off white

powder

Off

white

powder

Off white

powder

Off

white

powder

Off white

powder

Identification Positive with Test A and B Positive Positive Positive Positive Positive Positive Positive

Ethyl acetate(ppm) NMT 5000 102 102 105 109 111 112 116

Water by KF (%w/w) NMT 5.0% 2.81% 2.85% 2.87% 2.88% 2.92% 2.97% 3.91%

Individual impurity: Not more than 0.1% 0.080% 0.081% 0.083% 0.083% 0.084% 0.085% 0.087%

Total Impurities NMT 0.4% 0.231% 0.233% 0.233% 0.234% 0.235% 0.236% 0.238%

Assay (on anhydrous

basis)

99.00%-101.0% (on

anhydrous substance)

100.87% 100.78% 100.67% 100.51% 100.29% 99.89% 99.43%

Remarks: The Tianeptine Sodium B.P is stable for 24 months when kept at the conditions 25°C ± 2°C, 60% ± 5% RH.

(M. Khanna) (Vishal)

ANALYSED BY CHECKED BY




AT 25°C ± 2°C, 60% ± 5% RH; Batch No: BP/BPA_001/D/10/024;

Tests Specification Analysis Results




Off

white

powder

Off

white

powder

Off white

powder

Off

white

powder

Off white

powder

Off white

powder

Off

white

powder



Water by KF (%w/w) NMT 5.0% 2.78% 2.80% 2.85% 2.87% 2.91% 2.98% 3.88%


Total Impurities NMT0.4% 0.232% 0.233% 0.234% 0.235% 0.235% 0.237% 0.238%

Assay (on anhydrous

basis)

99.00%-101.0% (on

anhydrous substance) 100.88% 100.76% 100.68% 100.58% 100.49% 100.34% 99.33%

Remarks: The Tianeptine Sodium B.P is stable for at least 24 months when kept at the conditions 25°C ± 2°C, 60% ± 5% RH.






AT 25°C ± 2°C, 60% ± 5% RH; Batch No: BP/BPA_001/D/10/025;





Off

white

powder

Off

white

powder

Off white

powder

Off

white

powder

Off white

powder

Off white

powder

Off

white

powder



Water by KF (%w/w) NMT 5.0% 2.94% 2.97% 2.99% 3.12% 3.22% 3.25% 3.82%


Total Impurities NMT0.4% 0.231% 0.232% 0.234% 0.236% 0.237% 0.238% 0.239%

Assay (on anhydrous

basis)

99.00%-101.0% (on

anhydrous substance) 100.91% 100.87% 100.75% 100.64% 100.53% 100.31% 99.21%






Table: 18 Stability Study Report (Under Accelerated Conditions)

AT 40°C ± 2°C, 75% ± 5% RH; Batch No: BP/BPA_001/D/10/023


Checking Time (Months) 0 M 3M 6M

Description White to yellowish powder,very hygroscopic Off white

powder

Off white

powder

Off white

powder

Identification Positive with Test A and B Positive Positive Positive

Ethyl acetate(ppm) NMT 5000 102 107 109

Water by KF (%w/w) NMT 5.0% 2.81% 2.95% 3.67%

Individual impurity: Not more than 0.1% 0.080% 0.083% 0.084%

Total Impurities NMT0.4% 0.231% 0.233% 0.237%

Assay (on anhydrous

basis)

99.00%-101.0% (on anhydrous substance) 100.87% 100.26% 99.22%


A(M. Khanna) (Vishal)









powder

Off white

powder

Off white

powder



Water by KF (%w/w) NMT 5.0% 2.78% 2.94% 3.66%



Assay (on anhydrous basis) 99.00%-101.0% (on anhydrous substance) 100.88% 100.25% 99.23%











powder

Off white

powder

Off white

powder



Water by KF (%w/w) NMT 5.0% 2.94% 2.97% 2.99%



Assay (on anhydrous basis) 99.00%-101.0% (on anhydrous substance) 100.91% 100.24% 99.31%



ANALYSED BY CHECKED



METHOD OF STUDY

Conditions for stability study:

For accelerated stability study: For accelerated studies of the product are kept in humidity

chamber:

At 40°C ±2°C and RH 75% ±5%

For long term stability study: At 25°C ±2°C and RH 60% ±5%

Testing Intervals for stability study:

For accelerated stability study:

The stored samples are withdrawn at predetermined intervals the intervals are as follows: 0

month, 3 months and 6 months

For long term stability study:

The stored samples are withdrawn at predetermined intervals the intervals are as follows:

0 month, 3 month, 6 months,9 months,12 months,18 months and 24 months

Conclusion:

The stability data demonstrates that all lots of the substance Tianeptine Sodium B.P remained

within specifications at all times during the study, under natural (long term) temperature and

relative humidity conditions indicated above.

Based on the above, we conclude that the substance Tianeptine Sodium B.P stable within the

period of 24 months.

The above study was performed at Vivan Life sciences Ltd.under the supervision of our

analyst manager.

Documents

Ph.D. (Pharmaceutical Sciences) Thesisshodhganga.inflibnet.ac.in/bitstream/10603/12278/17/17... · 2015-12-04 · Ph.D. (Pharmaceutical Sciences) Thesis Shri Jagdish Prasad Jhabarmal