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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
Ph.D. (Pharmaceutical Sciences) Thesis
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
Ph.D. (Pharmaceutical Sciences) Thesis
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
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 3 of 22
Line Clearance by Quality Assurance Department
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
Line Clearance by Quality Assurance Department
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
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 4 of 22
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
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 5 of 22
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
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 6 of 22
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
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 7 of 22
NMR Spectra:
Figure 4: NMR Spectra
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 8 of 22
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.
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 9 of 22
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.
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala
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
Ph.D. (Pharmaceutical Sciences) Thesis
rasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj)
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
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala
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
Ph.D. (Pharmaceutical Sciences) Thesis
rasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj)
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
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala
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
Ph.D. (Pharmaceutical Sciences) Thesis
rasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj)
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%
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 13 of 22
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
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 14 of 22
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
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 15 of 22
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.
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 16 of 22
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
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 17 of 22
Table: 16: Stability Study Report (Long Term Stability)
AT 25°C ± 2°C, 60% ± 5% RH; Batch No: BP/BPA_001/D/10/024;
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 101 101 107 111 113 114 116
Water by KF (%w/w) NMT 5.0% 2.78% 2.80% 2.85% 2.87% 2.91% 2.98% 3.88%
Individual impurity: Not more than 0.1% 0.078% 0.078% 0.079% 0.081% 0.081% 0.083% 0.085%
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.
(M. Khanna) (Vishal)
ANALYSED BY CHECKED BY
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 18 of 22
Table: 17: Stability Study Report (Long Term Stability)
AT 25°C ± 2°C, 60% ± 5% RH; Batch No: BP/BPA_001/D/10/025;
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 107 106 109 111 113 117 119
Water by KF (%w/w) NMT 5.0% 2.94% 2.97% 2.99% 3.12% 3.22% 3.25% 3.82%
Individual impurity: Not more than 0.1% 0.081% 0.081% 0.082% 0.083% 0.083% 0.085% 0.086%
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%
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.
(M. Khanna) (Vishal)
ANALYSED BY CHECKED BY
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 19 of 22
Table: 18 Stability Study Report (Under Accelerated Conditions)
AT 40°C ± 2°C, 75% ± 5% RH; Batch No: BP/BPA_001/D/10/023
Tests Specification Analysis Results
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%
Remarks: The Tianeptine Sodium B.P is stable for at least 6 months when kept at the conditions 40°C ± 2°C, 75% ± 5% RH.
A(M. Khanna) (Vishal)
ANALYSED BY CHECKED BY
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 20 of 22
Table: 19 Stability Study Report (Under Accelerated Conditions)
AT 40°C ± 2°C, 75% ± 5% RH; Batch No: BP/BPA_001/D/10/024
Tests Specification Analysis Results
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 101 105 111
Water by KF (%w/w) NMT 5.0% 2.78% 2.94% 3.66%
Individual impurity: Not more than 0.1% 0.078% 0.081% 0.083%
Total Impurities NMT0.4% 0.232% 0.234% 0.237%
Assay (on anhydrous basis) 99.00%-101.0% (on anhydrous substance) 100.88% 100.25% 99.23%
Remarks: The Tianeptine Sodium B.P is stable for at least 6 months when kept at the conditions 40°C ± 2°C, 75% ± 5% RH.
(M. Khanna) (Vishal)
ANALYSED BY CHECKED BY
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 21 of 22
Table: 20 Stability Study Report (Under Accelerated Conditions)
AT 40°C ± 2°C, 75% ± 5% RH; Batch No: BP/BPA_001/D/10/025
Tests Specification Analysis Results
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 107 106 109
Water by KF (%w/w) NMT 5.0% 2.94% 2.97% 2.99%
Individual impurity: Not more than 0.1% 0.081% 0.081% 0.082%
Total Impurities NMT0.4% 0.231% 0.234% 0.238%
Assay (on anhydrous basis) 99.00%-101.0% (on anhydrous substance) 100.91% 100.24% 99.31%
Remarks: The Tianeptine Sodium B.P is stable for at least 36 months when kept at the conditions 40°C ± 2°C, 75% ± 5% RH.
(M. Khanna) (Vishal)
ANALYSED BY CHECKED
Ph.D. (Pharmaceutical Sciences) Thesis
Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 22 of 22
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.