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PREPARATION OF (S)- AMLODIPINE BESYLATE Dr Krishna sarma pathy The 1,4-dihydropyridine Ca+2 channel blockers are clinically significant antihypertensive drugs and have been immensely valuable as molecular tools with which probe structural and functional 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 the formula (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-methyl1,4dihydropyridine-3,5-dicarboxylate benzenesulphonate THERAPEUTIC CATEGORY: Calcium channel blocker Indication: Hypertension, angina 111470-99-6

CAS. No:

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BRAND NAME: NAME OF THE ORIGINATOR:

Asomex

The development of chiral process for S-amlodipine besylate was done by the collaborative research between NCL and Emcure MOLECULAR FORMULA: MOLECULAR WEIGHT: C20H25ClN2O5.C6H6O3S 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: EXPERIMENT STAGES STAGE -1 STAGE-2 STAGE-3 STAGE-4 BATCH NO ABI/STG-I/R&D/02 ABI/STG-I/R&D/08 ABI/STG-II/R&D/03 ABI/STG-II/R&D/07 ABI/STG-III/R&D/03 ABI/STG-III/R&D/07 ABI/STG-IV/R&D/02 BATCH SIZE 25 GM 220 GM 5 GM 130 GM 60 GM 30 GM 38 GM BATCH TYPE CRUDE PURE CRUDE PURE CRUDE PURE CRUDE % YIELD 0.68% 0.7% 0.44% 0.48% 0.65% 0.7% 0.78% % PURITY 98.83% 99.66% 99.56% 99.62% MELTING POINT 137-139C 136-142C 155-158C 157-162C 62-65C

drkrishnasarmapathy@yahoo.in ABI/STG-IV/R&D/06 20 GM PURE 1.22% 99.86% -

SELECTION OF FINAL SCHEME:

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ROS of S-(-) Amlodipine besylate

Stage : 01 H N O O o O Cl MONO METHYL AMINE O H3C H3CO o Cl H N O O

H3C H3CO

H2

Phthaloyl amlodipine M.W : 539 M.F : C28H27CLN2O7

R,S -Amlodipine Base M.W : 409 M.F : C20H25CLNO5

Stage : 02 H N O O o Cl D-Tartaric acid DMSO O o Cl

. Hemitartrate DMSO mono solvate

H3C H3CO

H2 H3C H3CO

H N O O

NH2

R,S -Amlodipine Base M.W : 409 M.F : C20H25CLNO5 Stage : 03 H N O O o Cl . Hemitartrate DMSO mono solvate MDC NaOH

S -Amlodipine Hemitartrate DMSO Monosolvate

H3C H3CO

NH2

H3C H3CO

H N O O o Cl

NH2

S -Amlodipine Hemitartrate DMSO Monosolvate

S- Amlodipine M.W : 410 M.F :C20H25ClN2O5

Stage : 04 H N O O o Cl Benzene sulfonic acid IPA H3C

NH2

H N O O o Cl

NH2

H3C H3CO

H3CO

. C6H5SO3H

S- Amlodipine M.W : 410 M.F :C20H25ClN2O5

S- Amlodipine Besylate M.W : 567.05 M.F :C20H25ClN2O5.C6H5O3S

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DISCUSSION ON DEVELOPMENT: Phthaloyl Amlodipine is the starting material used for the preparation of Amlodipine Besylate. This starting material failed in solubility profile and hence, Phthaloyl Amlodipine was first purified. This purification stage was performed by using solvents viz, Acetone, Toluene & methanol and ethyl acetate. SOLVENT USED FOR PURIFICATION Acetone Ethyl Acetate Toluene & Methanol BATCH NO BATCH SIZE %YIELD 93.0% 90.0% 76.0% %PURITY 99.59% 99.5% 99.69%

ABI/PUR/R&D/03 250 GM ABI/PUR/R&D/02 50 GM ABI/PUR/R&D/05 200 GM

From the above observations it can be concluded that the purification carried out by Acetone showed higher percentage of purity and yield of Phthaloyl amlodipine. The experimental preparation of S- Amlodipine Besylate comprises of 4- stages; each stage performed with a crude batch and pure batch respectively which included certain changes viz. the stage-2 of this experimentation was performed where alteration were made in the duration of the maintenance period of the reaction mass. The results of which are summarized below: STAGE-2 MAINTENANCE PERIOD (HOURS) 6 HOURS 8 HOURS 10 HOURS 16 HOURS BATCH NO ABI/STG-II/R&D/04 ABI/STG-II/R&D/01 ABI/STG-II/R&D/02 ABI/STG-II/R&D/07 BATCH SIZE 5 GM 15 GM 5 GM 130 GM % YIELD 50% 44% 54% 48% MELTING POINT 157-161C 155-158C 154-157C 156-159C

From the above results, it can be concluded that the reaction mass can be maintained for about 6-16 hours depending that the reaction has been completed or not which can be detected by TLC chromatogram. ANALYTICAL METHODS: The starting material Phthaloyl Amlodipine was tested as per inhouse specification. Amlodipine base tested as per inhouse method. (S)-Amlodipine Hemitartarate DMSO Monosolvate was tested as per (S)- Amlodipine was tested as per

drkrishnasarmapathy@yahoo.in The final product Amlodipine Besylate was tested as per E.P. Solvents used in stage-1: 1) Monomethyl amine: As per In house specification Solvents used in stage-2: 1) DMSO: 2) D-Tartaric acid: 3) Acetone: As per In house specification Solvents used in stage-3: 1) 2N NAOH: As per In house specification 2) Methylene Dichloride (MDC): As per In house specification 3) N- Hexane: As per In house specification 4) Sodium sulphate: As per In house specification Solvents used in stage-4: 1) Isopropyl Alcohol (IPA): As per In house specification 2) Benzene Sulphonic Acid: As per In house specification 3) n- hexane: As per In house specification PROCESS OPTIMIZED REPORT: Batch No: AB/STG-I/R&D/10 Batch size: 100 gm STAGE: 1 AIM: Preparation of R, S Amlodipine Base from Phthaloyl Amlodipine. REQUIREMENTS: 1) Phthaloyl Amlodipine : 100gm 2) Monomethyl Amine :400ml 3) D.M. water :1800ml PROCEDURE: S.R.NO. TIME (MINS) 1 10 TEMP. ( C) R.T OPERATIONS OBSERVATIONS

2 3 4

5 2 2

30 30 30

Arrange a 4 necked RBF with a mechanical stirrer, powder funnel with condenser, thermometer pocket & thermometer. Charge (200ml) Monomethyl Amine into the flask. Charge Phthaloyl Amlodipine Faint yellow (100gm). coloured reaction mass observed. Again charge (200ml) Yellow coloured monomethyl amine reaction mass seen.

drkrishnasarmapathy@yahoo.in 5 6 7 15 hrs 40 30 30 Maintain the raw material for 15-16 hrs at R.T. Check TLC TLC complies If TLC does not comply then stir the reaction mass for 2-3 hrs. If TLC complies, then cool the reaction mass to 0-5C. Maintain the reaction mass for 1 Off white hr reaction mass observed. Filter the material, suck dry for White powder 30 mins. & collect the filtrate obtained Then wash with chilled (1800ml) White reaction D.M. water mass observed Unload the material & White powder immediately dry it at 70-75C in obtained tray drier

8 9 10 11

1 hr 45 10 2 hrs

0-5 30 RT RT

RESULTS: 1) Wet weight of the compound: 113gm 2) Dry weight of the compound: 72gm 3) % of yield: 0.72 % 4) % of purity: 99.65 % 5) Appearance: White powder STAGE: 2 Batch No: AB/STG-II/R&D/12 Batch size: 68 gm AIM: Preparation of S- Amlodipine Hemitartarate DMSO Monosolvate from RS Amlodipine base. REQUIREMENTS: 1) RS Amlodipine base : 68gm 2) DMSO : 1020ml 3) D-Tartaric acid :12.5gm 4) Acetone :204ml PROCEDURE: S.R.NO. TIME (MINS). 1 10 TEMP. ( C) RT OPERATIONS Arrange a 4 necked RBF with a mechanical stirrer, powder funnel with condenser, thermometer pocket & OBSERVATIONS

drkrishnasarmapathy@yahoo.in thermometer. Charge (340ml) DMSO in RBF Then charge RS Amlodipine base (130gm) Meanwhile prepare a solution of (12.5 gm) D-tartaric acid & DMSO (340ml) in a beaker. Mix the above solution in the reaction mass Separate the material & maintain the reaction mass for overnight at RT Filter the reaction mass & wash with (340ml) DMSO Take the slurry & give acetone washing (204ml). Then filter & dry the material.

2 3 4 5 6 7 8

5 5 5 10 10 30 30

RT RT RT 30 RT RT RT

Pale yellow coloured solution is formed Pale yellow coloured reaction mass formed

White wet cake obtained White powder obtained

RESULTS: 1) Wet weight of the compound: 33.1gm 2) Dry weight of the compound: 31.6gm 3) % of yield: 0.46% 4) % moisture content: 0.30% 5) Melting point of the compound: 158-160C 6) Appearance: White powder STAGE: 3 Batch No: AB/STG-III/R&D/08 Batch size: 30 gm AIM: Preparation of S- Amlodipine from of S- Amlodipine Hemitartarate DMSO Monosolvate. REQUIREMENTS: 1) S- Amlodipine Hemitartarate DMSO Monosolvate: 30gm 2) 2N NAOH: 300ml 3) Methylene Dichloride (MDC) : 300ml 4) N- Hexane : 215ml 5) D.M. Water: 110ml 6) Sodium sulphate: 40gm

drkrishnasarmapathy@yahoo.in PROCEDURE: S.R.NO TIME (MINS) 1 10

3 4 5 6 7 8 9

TEMP. OPERATIONS ( C) RT Arrange a 4 necked RBF with a mechanical stirrer, powder funnel with condenser, thermometer pocket & thermometer 5 RT Charge MDC in RBF (300ml) & then add SAmlodipine Hemitartarate DMSO Monosolvate (60gm) in it. Stir for 15 mins. 5 RT Charge 2N NAOH solution (300ml) & stir for 5 mins 15 RT Separate the layers 15 RT Collect the MDC layer & wash with D.M. Water (110ml) 45 RT Dry the MDC layer with sodium sulphate (40gm) 1hr 15 40 Charge MDC layer in RBF & distill mins out completely 30 RT Charge hexane (150ml) & stir for 30 mins at RT. RT Filter the reaction mass & wash with (65 ml) n-hexane

OBSERVATIONS

Clear reaction mass observed.

Clear reaction mass observed

White reaction mass observed White powder obtained

RESULTS: 1) Wet weight of the compound: 21gm 2) Dry weight of the compound: 20gm 3) % of yield: 0.7% 4) Appearance: White powder 5) Moisture content: 0.17% STAGE: 4 Batch No: AB/STG-IV/R&D/06 Batch size: 20 gm AIM: Preparation of S- Amlodipine Besylate from S- Amlodipine. REQUIREMENTS: 1) S- Amlodipine : 20gm 2) Isopropyl Alcohol (IPA) : 66ml 3) Benzene Sulphonic Acid : 7.6gm 4) D.M. Water : 286ml 5) n- hexane : 50ml

drkrishnasarmapathy@yahoo.in PROCEDURE: S.R.NO. TIME TEMP. (MINS) ( C) 1 10 RT

OPERATIONS Arrange a 4 necked RBF with a mechanical stirrer, powder funnel with condenser, thermometer pocket & thermometer Charge IPA (66ml) in RBF & then charge S- Amlodipine (20gm) into it & stir Meanwhile prepare a solution of (7.6gm) Benzene sulphonic acid in a beaker & add (16ml) D.M. Water in it. Mix benzene sulphonic acid mixture to the above reaction mass & maintain for 20-30 mins

OBSERVATIONS

2 3

10 5

34 34

25

34

5 6 7 9

15 hrs 1 hr 30 30

34 0-5 0

Charge (154ml) D.M. water & maintain overnight at RT Chill the reaction mass & Solid maintain for 1 hr at 0-5 C observed Add (33ml) D.M. Water & filter the mass Wash with (83ml) D.M. water & then wash with (50ml) nhexane. Unload the wet cake and dry it.

Solids dissolve slowly and becomes a clear solution Slightly exothermic reaction. Clear reaction mass observed. mass

RESULTS: 1) Wet weight of the compound: 34.1gm 2) 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

drkrishnasarmapathy@yahoo.in FLOW CHART:

Phthaloyl amlodipine & mono methyl amine

Maintain for 15-16 hrs & check TLC

Cool to 0-5 & maintain for 1 hr, filter Wash with chilled D.M.

Collect the filtrate

Unload & dry the material

Amlodipine base

Amlodipine base & DMSO

Charge DMSO & Dtartaric acid solution

Separate the material & maintain for overnight at RT

Filter & wash with DMSO

Give Acetone wash to the slurry, filter

Unload & dry the material

S- Amlodipine Hemi tartarate DMSO Monosolvate

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Charge MDC into the material, & then NaOH

Separate the layers

Collect the MDC layer with Sodium Sulphate

Distill out MDC

Charge hexane, stir for 30 mins

Filter, wash with hexane. Unload & dry the material Charge IPA & Then also add solution of Benzene Sulphonic acid & D.M. water

(S)-Amlodipine

Maintain for 30 mins.

Charge water, maintain for overnight at RT

Chill to 0-5C & maintain for 1 hr

Filter, wash with water & hexane. unload & dry the material

(S)-Amlodipine Besylate

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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. Slightly hazardous in case of skin contact (irritant), of eye contact (irritant), of inhalation. 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. Ground all equipment containing material. Do not ingest. Do not breathe dust. Wear suitable protective clothing. If ingested, seek medical advice immediately and show the container or the label. Storage: Keep container tightly closed. Keep container in a cool, wellventilated area.
3. PHYSICAL AND CHEMICAL PROPERTIES:

Physical state and appearance: Solid. (Crystalline powder.) Molecular Weight: 567.1 g/mole Color: 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 heat Polymerization: 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. Slightly hazardous in case of skin contact (irritant), of inhalation. Special Remarks on Chronic Effects on Humans: May cause adverse reproductive effects.
6. ECOLOGICAL INFORMATION:

Products of Biodegradation: Possibly hazardous short term degradation products are not likely. However, long term degradation products may arise.

drkrishnasarmapathy@yahoo.in Toxicity of the Products of Biodegradation: The products of degradation are as toxic as the product itself.
7. DISPOSAL CONSIDERATIONS:

Waste Disposal: Waste must be disposed of in accordance with federal, state and local environmental control regulations. IMPURITY PROFILE: The acceptable limits of the impurities or related substances that can be formed 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. 1. 2. 3. 4. 5. TEST Description Solubility Identification By HPLC Water Chromatographic purity by HPLC SPECIFICATION Pale yellow crystalline powder. Soluble in ethyl acetate and chloroform. The RT of major peak in sample chromatogram matches with std. chromatogram NMT 0.5 % w/w NLT 99.0 %w/w

SPECIFICATION OF MONO METHYL AMINE (MMA) (SBL/RM/STP/41) Sr. TEST

drkrishnasarmapathy@yahoo.in No. 1 2 3 4 Description Solubility Specific gravity Assay SPECIFICATION Clear colourless to light yellow liquid. Miscible in water. About 0.890 at 25C. NLT 39.0 % w/w

SPECIFICATION OF SODIUM HYDROXIDE (SBL/RM/STP/54) Sr. No. 1. 2. 3 4. 5. Description Solubility Identification Assay by Titrametric Carbonate TEST SPECIFICATION White Hygroscopic Pellets. Freely Soluble in Water and Ethanol (95%). Positive for Sodium test. NLT 98.0% w/w NMT 2.0% w/w

SPECIFICATION OF METHYLENE DICHLORIDE (MDC) (SBL/RM/STP/25) Sr. No. 1. 2. Description Miscibility TEST SPECIFICATION Clear colourless liquid. Miscible in methanol and in chloroform.

drkrishnasarmapathy@yahoo.in The RT of major peak in sample 3. Identification chromatogram matches with std. chromatogram 3. 4. Specific Gravity at 25C Water About 1.32 NMT 0.50 %

Sr. No. 1. 2. 3. 4. 5

SPECIFICATION OF N- HEXANE (SBL/RM/SPEC/30) TEST Description Specific Gravity at 25C Identification Water content Chromatographic purity by GC SPECIFICATION Clear, Colorless mobile Liquid. About 0.65. The RT of major peak in sample chromatogram matches with std. chromatogram . NMT 0.5 % w/w NLT 99.0 %

Sr. No.
1. 2.

SPECIFICATION OF ACETONE (SBL/RM/SPEC/11)

TEST
Description Miscibility

SPECIFICATION
Clear, Colourless Liquid. Miscible in water.

drkrishnasarmapathy@yahoo.in Identification 3. 4. 5. 6. Specific gravity at 25 C Water by KF Titrator The RT of chromatogram chromatogram. About 0.791 NMT 0.5 % w/w major peak in sample matches with std.

Chromatographic purity by NLT 99.0 % GC

Sr No. 1. 2. 3. 4. 5. 6.

SPECIFICATION OF ISOPROPYL ALCOHOL (IPA) (SBL/RM/SPEC/36) TEST Description Miscibility Identification Specific gravity Water Chromatographic by G.C SPECIFICATION Clear, Colourless Liquid. Miscible in Methanol and chloroform. The RT of major peak in sample chromatogram matches with std. chromatogram. About 0.780 at 25C NMT 0.5 % w/w NLT 99.0 %

SPECIFICATION OF SODIUM SULPHATE (SBL/RM/SPEC/57) Sr. No. 1. 2. Description Solubility TEST SPECIFICATION White to Off-white Crystalline powder. Soluble in Water.

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3. 4.

Identification Loss on drying at 130C

A) Gives the reaction of Sodium. b) Gives the reaction of Sulphates. NMT 0.5 % w/w

SPECIFICATION OF BENZENE SULPHONIC ACID Sr. No. 1. 2. 3 4. 5. Description Solubility Melting point Boiling point Assay TEST SPECIFICATION Colorless crystalline solid Soluble in water, ethanol, and insoluble in benzene & ether 45-55C 190C NLT 95.0%

SPECIFICATION OF DIMETHYL SULPHOXIDE (DMSO) Sr. No. 1. 2. 3. 4. 5. 6. Description Melting point Boiling point Water Solubility Assay TEST SPECIFICATION Clear Colorless liquid 18.5C 189C NMT 0.10% Soluble in water, alcohol & diethyl ether 99.7% minimum

SPECIFICATION OF D-TARTARIC ACID

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Sr. No. 1. 2. 3. 4. 5. 6. 7. 8. Description Solubility

TEST

SPECIFICATION White powder or white crystals Soluble in Water, alcohol, diethyl ether -12 to 12.8 NMT 0.5 % w/w NMT 0.001 % NMT 0.05% NMT 0.1% NLT 99%

Specific optical rotation Loss on drying at 130C Heavy Metals (as Pb) Sulphate Residue on Ignition Assay

SPECIFICATION OF S- AMLODIPINE BESYLATE Sr. No. 1 Description Identification (A) BY IR TEST 1. SPECIFICATION white to pale yellow powder The Infrared spectrum of sample should be concordant to that of working standard.

3 4 5 6 7 8

Related Impurities by HPLC Individual Impurity Total impurities Sulphated Ash Heavy metals Water content Specific Optical Rotation (1% Assay by HPLC (On anhydrous basis)

Not more than 0.5 % Not more than 1.0 % Not more than 0.2% w/w Not more than 25 ppm Not more than 8.0% w/w Between -24.0 and -30.0 Between 98.0 % to 102.0 % w/w

TESTING PROCEDURES:

drkrishnasarmapathy@yahoo.in REFERENCE STANDARDS: STABILITY STUDY: