S- Amlo Besylate

7/22/2019 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


H3CO

H

H


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


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


oo

o

o

o

O

N

N

M.W : 409

M.F : C20H25CLNO5

N

NN

H


H3CO

H

H


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


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


(MINS).TEMP.( C)


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.


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)


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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(MINS)TEMP.( C)


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)


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)


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)


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


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)


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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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


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:

Documents

S- Amlo Besylate