s- amlo besylate
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PREPARATION OF (S)- AMLODIPINE BESYLATEDr Krishna sarma pathy
The 1,4-dihydropyridine Ca+2 channel blockers are clinicallysignificant antihypertensive drugs and have been immenselyvaluable as molecular tools with which probe structural andfunctional aspects of Ca+2 channel function.The object of the invention relates is a process for the preparation of S-(-)
amlodipine (chemical name: S-(-)-2-(2-aminoethoxy)-methyl-4-(2-hlorophenyl)-3-ethoxycarbonil-5-methoxy-carbonyl-6-methyl-1,4-dihydropiridine) of theformula (I): starting from (R,S)-amlodipine by diastereomeric salt formation, in
which the (R,S)-amlodipine is reacted with 0.5-1.5 mol L-(+)-tartaric acid
(S)- AMLODIPINE BESYLATE
NAME OF THE PRODUCT:
(S)-Amlodipine Besylate
CHEMICAL NAME:
3-ethyl-5-methyl(4S)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate benzenesulphonate
THERAPEUTIC CATEGORY: Calcium channel blockerIndication: Hypertension, angina
CAS. No: 111470-99-6
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BRAND NAME: Asomex
NAME OF THE ORIGINATOR:
The development of chiral process for S-amlodipine besylate was done by thecollaborative research between NCL and Emcure
MOLECULAR FORMULA: C20H25ClN2O5.C6H6O3S
MOLECULAR WEIGHT: 567.1
PHYSICO-CHEMICAL CHARACTERISTICS:
DESCRIPTION:(S)-Amlodipine Besylate is a White or pale yellow powder
SOLUBILITY:It is slightly soluble in water & sparingly soluble in ethanol.
DESCRIPTION OF THE MANUFACTURING OF (S) - AMLODIPINE BESYLATE:
1) Stage-1: Preparation of R, S Amlodipine Base from Phthaloyl Amlodipine.2) Stage-2: Preparation of S- Amlodipine Hemitartarate DMSO Monosolvate
from RS Amlodipine base.3) Stage-3: Preparation of S- Amlodipine from of S- Amlodipine
Hemitartarate DMSO Monosolvate.4) Stage-4: Preparation of S- Amlodipine Besylate from S- Amlodipine
LAB EXPERIMENTS WITH OBSERVATIONS & FINDINGS:
EXPERIMENTSTAGES
BATCH NO BATCHSIZE
BATCHTYPE
% YIELD % PURITY MELTINGPOINT
STAGE -1ABI/STG-I/R&D/02 25 GM CRUDE 0.68% 98.83% 137-139CABI/STG-I/R&D/08 220 GM PURE 0.7% 99.66% 136-142C
STAGE-2ABI/STG-II/R&D/03 5 GM CRUDE 0.44% - 155-158CABI/STG-II/R&D/07 130 GM PURE 0.48% 99.56% 157-162C
STAGE-3ABI/STG-III/R&D/03 60 GM CRUDE 0.65% -ABI/STG-III/R&D/07 30 GM PURE 0.7% -
STAGE-4 ABI/STG-IV/R&D/02 38 GM CRUDE 0.78% 99.62% 62-65C
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ABI/STG-IV/R&D/06 20 GM PURE 1.22% 99.86% -
SELECTION OF FINAL SCHEME:
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NH2
NH2NH2
NH2
NH2
H3CO
H3CO
H3CO
M.W : 410
M.F :C20H25ClN2O5
NH
O
H3CO
H3CO
O
ClMONO METHYL AMINE
H2
Phthaloyl amlodipine
M.W : 539
M.F : C28H27CLN2O7
o o
Stage : 01
Stage : 02
D-Tartaric acid
DMSO . Hemitartrate DMSO mono -solvate
Stage : 03
MDC
NaOH
S -Amlodipine Hemitartrate
DMSO Monosolvate
S- Amlodipine
Benzene sulfonic acid
IPA
M.W : 567.05
M.F :C20H25ClN2O5.C6H5O3S
. C6H5SO3H
. Hemitartrate DMSO
mono solvateo
M.W : 410
M.F :C20H25ClN2O5
Stage : 04
S- Amlodipine Besylate
S- Amlodipine
N
ROS of S-(-) Amlodipine besylate
H2
N
H
R,S -Amlodipine Base
oo
o
o
o
O
N
N
M.W : 409
M.F : C20H25CLNO5
N
NN
H
R,S -Amlodipine Base
H3CO
H
H
S -Amlodipine Hemitartrate
DMSO Monosolvate
H
OO
H3C
O
H
H3C
O
H
H3CO
H3C
H3C
M.W : 409
M.F : C20H25CLNO5
O
O
O
O
H3C
O
OO
O
Cl
H3COH3CO
O
O
Cl
O
O
H3C
Cl
H3C
Cl
OO
Cl
OO
ClCl
NH2
NH2NH2
NH2
NH2
H3CO
H3CO
H3CO
M.W : 410
M.F :C20H25ClN2O5
NH
O
H3CO
H3CO
O
ClMONO METHYL AMINE
H2
Phthaloyl amlodipine
M.W : 539
M.F : C28H27CLN2O7
o o
Stage : 01
Stage : 02
D-Tartaric acid
DMSO . Hemitartrate DMSO mono -solvate
Stage : 03
MDC
NaOH
S -Amlodipine Hemitartrate
DMSO Monosolvate
S- Amlodipine
Benzene sulfonic acid
IPA
M.W : 567.05
M.F :C20H25ClN2O5.C6H5O3S
. C6H5SO3H
. Hemitartrate DMSO
mono solvateo
M.W : 410
M.F :C20H25ClN2O5
Stage : 04
S- Amlodipine Besylate
S- Amlodipine
N
ROS of S-(-) Amlodipine besylate
H2
N
H
R,S -Amlodipine Base
oo
o
o
o
O
N
N
M.W : 409
M.F : C20H25CLNO5
N
NN
H
R,S -Amlodipine Base
H3CO
H
H
S -Amlodipine Hemitartrate
DMSO Monosolvate
H
OO
H3C
O
H
H3C
O
H
H3CO
H3C
H3C
M.W : 409
M.F : C20H25CLNO5
O
O
O
O
H3C
O
OO
O
Cl
H3COH3CO
O
O
Cl
O
O
H3C
Cl
H3C
Cl
OO
Cl
OO
ClCl
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DISCUSSION ON DEVELOPMENT:
Phthaloyl Amlodipine is the starting material used for the preparation ofAmlodipine Besylate. This starting material failed in solubility profile andhence, Phthaloyl Amlodipine was first purified. This purification stage wasperformed by using solvents viz, Acetone, Toluene & methanol and ethylacetate.
SOLVENT USEDFORPURIFICATION
BATCH NO BATCHSIZE
%YIELD %PURITY
Acetone ABI/PUR/R&D/03 250 GM 93.0% 99.59%Ethyl Acetate ABI/PUR/R&D/02 50 GM 90.0% 99.5%Toluene &Methanol
ABI/PUR/R&D/05 200 GM 76.0% 99.69%
From the above observations it can be concluded that the purification carriedout by Acetone showed higher percentage of purity and yield of Phthaloylamlodipine.
The experimental preparation of S- Amlodipine Besylate comprises of 4- stages;each stage performed with a crude batch and pure batch respectively whichincluded certain changes viz. the stage-2 of this experimentation was
performed where alteration were made in the duration of the maintenanceperiod of the reaction mass. The results of which are summarized below:
STAGE-2MAINTENANCEPERIOD (HOURS)
BATCH NO BATCH SIZE % YIELD MELTING POINT
6 HOURS ABI/STG-II/R&D/04 5 GM 50% 157-161C8 HOURS ABI/STG-II/R&D/01 15 GM 44% 155-158C10 HOURS ABI/STG-II/R&D/02 5 GM 54% 154-157C16 HOURS ABI/STG-II/R&D/07 130 GM 48% 156-159C
From the above results, it can be concluded that the reaction mass can bemaintained for about 6-16 hours depending that the reaction has beencompleted or not which can be detected by TLC chromatogram.
ANALYTICAL METHODS:
The starting material Phthaloyl Amlodipine was tested as per inhousespecification.Amlodipine base tested as per inhouse method.(S)-Amlodipine Hemitartarate DMSO Monosolvate was tested as per(S)- Amlodipine was tested as per
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The final product Amlodipine Besylate was tested as per E.P.
Solvents used in stage-1:
1) Monomethyl amine: As per In house specificationSolvents used in stage-2:1) DMSO:2) D-Tartaric acid:3) Acetone: As per In house specificationSolvents used in stage-3:1) 2N NAOH: As per In house specification2) Methylene Dichloride (MDC): As per In house specification3) N- Hexane: As per In house specification4) Sodium sulphate: As per In house specificationSolvents used in stage-4:
1) Isopropyl Alcohol (IPA): As per In house specification2) Benzene Sulphonic Acid: As per In house specification3) n- hexane: As per In house specification
PROCESS OPTIMIZED REPORT:
Batch No: AB/STG-I/R&D/10Batch size: 100 gmSTAGE: 1AIM: Preparation of R, S Amlodipine Base from Phthaloyl Amlodipine.
REQUIREMENTS:1) Phthaloyl Amlodipine : 100gm2) Monomethyl Amine :400ml3) D.M. water :1800ml
PROCEDURE:S.R.NO. TIME
(MINS)TEMP.( C)
OPERATIONS OBSERVATIONS
1 10 R.T
Arrange a 4 necked RBF with amechanical stirrer, powderfunnel with condenser,thermometer pocket &thermometer.
2 5 30Charge (200ml) MonomethylAmine into the flask.
3 2 30Charge Phthaloyl Amlodipine(100gm).
Faint yellowcoloured reactionmass observed.
4 2 30Again charge (200ml)monomethyl amine
Yellow colouredreaction massseen.
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5 15 hrs 30Maintain the raw material for15-16 hrs at R.T.
6 40 30 Check TLC TLC complies
7
If TLC does not comply then stirthe reaction mass for 2-3 hrs.If TLC complies, then cool thereaction mass to 0-5C.
8 1 hr 0-5Maintain the reaction mass for 1hr
Off whitereaction massobserved.
9 45 30Filter the material, suck dry for30 mins. & collect the filtrate
White powderobtained
10 10 RTThen wash with chilled (1800ml)
D.M. water
White reaction
mass observed
11 2 hrs RTUnload the material &immediately dry it at 70-75C intray drier
White powderobtained
RESULTS:1) Wet weight of the compound: 113gm2) Dry weight of the compound: 72gm3) % of yield: 0.72 %4) % of purity: 99.65 %
5) Appearance: White powder
STAGE: 2Batch No: AB/STG-II/R&D/12Batch size: 68 gmAIM: Preparation of S- Amlodipine Hemitartarate DMSO Monosolvate from RSAmlodipine base.
REQUIREMENTS:1) RS Amlodipine base : 68gm
2) DMSO : 1020ml3) D-Tartaric acid :12.5gm4) Acetone :204ml
PROCEDURE:S.R.NO. TIME
(MINS).TEMP.( C)
OPERATIONS OBSERVATIONS
1 10 RT
Arrange a 4 necked RBF witha mechanical stirrer, powderfunnel with condenser,thermometer pocket &
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thermometer.2 5 RT Charge (340ml) DMSO in RBF
3 5 RTThen charge RS Amlodipinebase (130gm)
4 5 RTMeanwhile prepare a solutionof (12.5 gm) D-tartaric acid &DMSO (340ml) in a beaker.
Pale yellowcoloured solutionis formed
5 10 30Mix the above solution in thereaction mass
Pale yellowcoloured reactionmass formed
6 10 RTSeparate the material &maintain the reaction massfor overnight at RT
7 30 RT Filter the reaction mass &wash with (340ml) DMSO White wet cakeobtained
8 30 RT
Take the slurry & giveacetone washing (204ml).Then filter & dry thematerial.
White powderobtained
RESULTS:1) Wet weight of the compound: 33.1gm
2) Dry weight of the compound: 31.6gm3) % of yield: 0.46%4) % moisture content: 0.30%5) Melting point of the compound: 158-160C6) Appearance: White powder
STAGE: 3Batch No: AB/STG-III/R&D/08Batch size: 30 gmAIM: Preparation of S- Amlodipine from of S- Amlodipine Hemitartarate DMSO
Monosolvate.
REQUIREMENTS:1) S- Amlodipine Hemitartarate DMSO Monosolvate: 30gm2) 2N NAOH: 300ml3) Methylene Dichloride (MDC) : 300ml4) N- Hexane : 215ml5) D.M. Water: 110ml6) Sodium sulphate: 40gm
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PROCEDURE:S.R.NO TIME
(MINS)TEMP.( C)
OPERATIONS OBSERVATIONS
1 10 RT Arrange a 4 necked RBF with amechanical stirrer, powderfunnel with condenser,thermometer pocket &thermometer
2 5 RT Charge MDC in RBF (300ml) &then add S- AmlodipineHemitartarate DMSOMonosolvate (60gm) in it. Stir for15 mins.
Clear reactionmass observed.
3 5 RT Charge 2N NAOH solution(300ml) & stir for 5 mins
Clear reactionmass observed
4 15 RT Separate the layers5 15 RT Collect the MDC layer & wash
with D.M. Water (110ml)6 45 RT Dry the MDC layer with sodium
sulphate (40gm)7 1hr 15
mins40 Charge MDC layer in RBF & distill
out completely8 30 RT Charge hexane (150ml) & stir for
30 mins at RT.White reactionmass observed
9 RT Filter the reaction mass & washwith (65 ml) n-hexane White powderobtained
RESULTS:1) Wet weight of the compound: 21gm2) Dry weight of the compound: 20gm3) % of yield: 0.7%4) Appearance: White powder5) Moisture content: 0.17%
STAGE: 4
Batch No: AB/STG-IV/R&D/06Batch size: 20 gmAIM: Preparation of S- Amlodipine Besylate from S- Amlodipine.
REQUIREMENTS:1) S- Amlodipine : 20gm2) Isopropyl Alcohol (IPA) : 66ml3) Benzene Sulphonic Acid : 7.6gm4) D.M. Water : 286ml5) n- hexane : 50ml
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PROCEDURE:S.R.NO. TIME
(MINS)TEMP.( C)
OPERATIONS OBSERVATIONS
1 10 RT Arrange a 4 necked RBF with amechanical stirrer, powderfunnel with condenser,thermometer pocket &thermometer
2 10 34 Charge IPA (66ml) in RBF & thencharge S- Amlodipine (20gm)into it & stir
3 5 34 Meanwhile prepare a solution of(7.6gm) Benzene sulphonic acidin a beaker & add (16ml) D.M.Water in it.
Solids dissolveslowly andbecomes a clearsolution
4 25 34 Mix benzene sulphonic acidmixture to the above reactionmass & maintain for 20-30 mins
Slightlyexothermicreaction.Clear reactionmass observed.
5 15 hrs 34 Charge (154ml) D.M. water &maintain overnight at RT
6 1 hr 0-5 Chill the reaction mass &maintain for 1 hr at 0-5 C
Solid massobserved
7 30 0 Add (33ml) D.M. Water & filterthe mass9 30 Wash with (83ml) D.M. water &
then wash with (50ml) n-hexane.Unload the wet cake and dry it.
RESULTS:1) Wet weight of the compound: 34.1gm2) Dry weight of the compound: 24.5gm
3) % of yield: 1.22%4) % of purity: 99.86%5) % Moisture content: 8.2%6) Appearance: White powder
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FLOW CHART:
Collect the filtrate
Amlodipine base &DMSO
Separate the material& maintain forovernight at RT
Charge DMSO & D-tartaric acid solution
Filter & wash withDMSO
Phthaloylamlodipine & monomethyl amine
Maintain for 15-16hrs & check TLC
Cool to 0-5 & maintainfor 1 hr, filter Washwith chilled D.M.
Unload & dry thematerial
Unload & dry thematerial
S- Amlodipine Hemi -tartarate DMSO
Give Acetone washto the slurry, filter
Amlodipine base
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Collect the MDC layerwith Sodium Sulphate
Distill out MDC
Charge hexane,
stir for 30 mins
Filter, wash withhexane. Unload &dry the material
(S)-Amlodipine
Charge IPA & Then alsoadd solution of BenzeneSulphonic acid & D.M.water
Charge water, maintainfor overnight at RT
Chill to 0-5C &maintain for 1 hr
Filter, wash with water& hexane. unload &dry the material
(S)-Amlodipine Besylate
Charge MDC into thematerial, & then NaOH
Separate the layers
Maintain for 30 mins.
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STORAGE CONDITIONS:
Ref: ScienceLab.com
In an air tight container, protected from light.
SAFETY DATA SHEET OF THE PRODUCT:Ref: ScienceLab.com
1. HAZARDS IDENTIFICATION:
Potential Acute Health Effects: Hazardous in case of ingestion. Slightlyhazardous in case of skin contact (irritant), of eye contact (irritant), ofinhalation.
Potential Chronic Health Effects:Repeated or prolonged exposure is not known to aggravate medical condition.
2. HANDLING AND STORAGE:
Precautions: Keep away from heat. Keep away from sources of ignition. Groundall equipment containing material. Do not ingest. Do not breathe dust. Wearsuitable protective clothing. If ingested, seek medical advice immediately andshow the container or the label.Storage: Keep container tightly closed. Keep container in a cool, well-ventilated area.
3. PHYSICAL AND CHEMICAL PROPERTIES:Physical state and appearance: Solid. (Crystalline powder.)Molecular Weight: 567.1 g/moleColor: White.Solubility: Slightly soluble in cold water. Sparingly soluble in ethanol.
4. STABILITY AND REACTIVE DATA:
Stability: The product is stable.Conditions of Instability: Excess heatPolymerization: Will not occur.
5. TOXICOLOGICAL INFORMATION:Routes of Entry: Inhalation, Ingestion.Toxicity to Animals: Acute oral toxicity (LD50): 37 mg/kg [Mouse].Other Toxic Effects on Humans: Hazardous in case of ingestion. Slightlyhazardous in case of skin contact (irritant), of inhalation.Special Remarks on Chronic Effects on Humans: May cause adverse reproductiveeffects.
6. ECOLOGICAL INFORMATION:
Products of Biodegradation: Possibly hazardous short term degradationproducts are not likely. However, long term degradation products may arise.
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Toxicity of the Products of Biodegradation: The products of degradation are astoxic as the product itself.
7. DISPOSAL CONSIDERATIONS:Waste Disposal: Waste must be disposed of in accordance with federal, stateand local environmental control regulations.
IMPURITY PROFILE:
The acceptable limits of the impurities or related substances that can beformed during the reaction are as under:Related Impurities by HPLC:Individual Impurity: Not more than 0.5 %
Total impurities: Not more than 1.0 %
SPECIFICATIONS:
SPECIFICATION OF PHTHALOYL AMLODIPINE (SBL/RM/STP/ 49)
Sr. No. TEST SPECIFICATION
1. Description Pale yellow crystalline powder.
2. Solubility Soluble in ethyl acetate and chloroform.
3. Identification By HPLC The RT of major peak in sample chromatogrammatches with std. chromatogram
4. Water NMT 0.5 % w/w
5.Chromatographic purityby HPLC
NLT 99.0 %w/w
SPECIFICATION OF MONO METHYL AMINE (MMA) (SBL/RM/STP/41)Sr. TEST
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No. SPECIFICATION
1Description Clear colourless to light yellow liquid.
2 Solubility Miscible in water.
3 Specific gravity About 0.890 at 25C.
4 Assay NLT 39.0 % w/w
SPECIFICATION OF SODIUM HYDROXIDE (SBL/RM/STP/54)
Sr. No. TEST SPECIFICATION
1. Description White Hygroscopic Pellets.
2. Solubility Freely Soluble in Water and Ethanol (95%).
3 Identification Positive for Sodium test.
4. Assay by Titrametric NLT 98.0% w/w
5. Carbonate NMT 2.0% w/w
SPECIFICATION OF METHYLENE DICHLORIDE (MDC) (SBL/RM/STP/25)
Sr. No. TEST SPECIFICATION
1. Description Clear colourless liquid.
2. Miscibility Miscible in methanol and in chloroform.
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3. Identification
The RT of major peak in sample
chromatogram matches with std.
chromatogram
3. Specific Gravity at 25C About 1.32
4. Water NMT 0.50 %
SPECIFICATION OF N- HEXANE (SBL/RM/SPEC/30)Sr.
No.TEST SPECIFICATION
1. Description Clear, Colorless mobile Liquid.
2. Specific Gravity at 25C About 0.65.
3. Identification The RT of major peak in sample chromatogrammatches with std. chromatogram .
4. Water content NMT 0.5 % w/w
5 Chromatographic purity
by GCNLT 99.0 %
SPECIFICATION OF ACETONE (SBL/RM/SPEC/11)
Sr.No.
TEST SPECIFICATION
1.Description
Clear, Colourless Liquid.
2.Miscibility
Miscible in water.
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3.
Identification The RT of major peak in samplechromatogram matches with std.chromatogram.
4.Specific gravity at 25 C
About 0.791
5.Water by KF Titrator
NMT 0.5 % w/w
6.Chromatographic purity by
GCNLT 99.0 %
SPECIFICATION OF ISOPROPYL ALCOHOL (IPA) (SBL/RM/SPEC/36)Sr
No.TEST SPECIFICATION
1. Description Clear, Colourless Liquid.
2. Miscibility Miscible in Methanol and chloroform.
3. IdentificationThe RT of major peak in sample chromatogram matches
with std. chromatogram.4. Specific gravity About 0.780 at 25C
5. Water NMT 0.5 % w/w
6.Chromatographic
by G.C
NLT 99.0 %
SPECIFICATION OF SODIUM SULPHATE (SBL/RM/SPEC/57)
Sr. No. TEST SPECIFICATION
1. Description White to Off-white Crystalline powder.
2. Solubility Soluble in Water.
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3. IdentificationA) Gives the reaction of Sodium.
b) Gives the reaction of Sulphates.
4. Loss on drying at 130C NMT 0.5 % w/w
SPECIFICATION OF BENZENE SULPHONIC ACID
Sr. No. TEST SPECIFICATION
1. Description Colorless crystalline solid
2. SolubilitySoluble in water, ethanol, and insoluble inbenzene & ether
3 Melting point 45-55C
4. Boiling point 190C
5. Assay NLT 95.0%
SPECIFICATION OF DIMETHYL SULPHOXIDE (DMSO)
Sr. No. TEST SPECIFICATION
1. Description Clear Colorless liquid
2. Melting point 18.5C
3. Boiling point 189C
4. Water NMT 0.10%
5. Solubility Soluble in water, alcohol & diethyl ether
6. Assay 99.7% minimum
SPECIFICATION OF D-TARTARIC ACID
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Sr. No. TEST SPECIFICATION
1. Description White powder or white crystals
2. Solubility Soluble in Water, alcohol, diethyl ether
3. Specific optical rotation -12 to 12.8
4. Loss on drying at 130C NMT 0.5 % w/w
5. Heavy Metals (as Pb) NMT 0.001 %
6. Sulphate NMT 0.05%
7. Residue on Ignition NMT 0.1%
8. Assay NLT 99%
SPECIFICATION OF S- AMLODIPINE BESYLATE
Sr. No. TEST SPECIFICATION
1 Descriptionwhite to pale yellow powder
2
Identification(A) BY IR The Infrared spectrum of sample should be
concordant to that of working standard.
3Related Impurities by HPLCIndividual ImpurityTotal impurities
Not more than 0.5 %Not more than 1.0 %
4 Sulphated AshNot more than 0.2% w/w
5Heavy metals Not more than 25 ppm
6
Water content Not more than 8.0% w/w
7Specific Optical Rotation(1%
Between -24.0 and -30.0
8Assay by HPLC(On anhydrous basis)
Between 98.0 % to 102.0 % w/w
TESTING PROCEDURES:
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REFERENCE STANDARDS:
STABILITY STUDY:
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