EP1606231A1 - Procede de preparation de clopidogrel, ses sels et compositions pharmaceutiques - Google Patents

Procede de preparation de clopidogrel, ses sels et compositions pharmaceutiques

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Publication number
EP1606231A1
EP1606231A1 EP04705140A EP04705140A EP1606231A1 EP 1606231 A1 EP1606231 A1 EP 1606231A1 EP 04705140 A EP04705140 A EP 04705140A EP 04705140 A EP04705140 A EP 04705140A EP 1606231 A1 EP1606231 A1 EP 1606231A1
Authority
EP
European Patent Office
Prior art keywords
clopidogrel
acetate
chlorophenyl
alpha
pyridine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04705140A
Other languages
German (de)
English (en)
Inventor
Sunil Sadanand Torrent Pharmaceuticals NADKARNI
Hasmukh Mathurbhai Torrent Pharmaceuticals Patel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Torrent Pharmaceuticals Ltd
Original Assignee
Nadkarni Sunil Sadanand
Patel Hasmukh Mathurbhai
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Application filed by Nadkarni Sunil Sadanand, Patel Hasmukh Mathurbhai filed Critical Nadkarni Sunil Sadanand
Publication of EP1606231A1 publication Critical patent/EP1606231A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the invention relates to an improved and cost effective process for preparation of clopidogrel and its salts including clopidogrel bisulphate, a biologically active thiophene, preparation of pharmaceutically acceptable salts of clopidogrel and pharmaceutical compositions containing them.
  • the invention also relates to novel salts of clopidogrel, their preparation and pharmaceutical compositions comprising them.
  • Clopidogrel bisulfate (I) i.e., methyl (S)-(+)-alpha-(2-chlorophenyl)-6,7-dihydro- thieno[3,2-c]pyridine-5(4H)-acetate sulphate
  • ADP Adosine Di- Phosphate
  • Atherothrombosis can give rise to unstable angina, myocardial infarction or stroke in susceptible individuals. Platelets, which do not interact with the endothelium of normal vessels, play a central role in atherothrombosis by adhering to exposed sub-endothelial structures in damaged vessels.
  • Platelets may be activated by several substances. Among these, ADP plays an important role. ADP is present in high concentrations in the dense granules within platelets and can initiate and reinforce aggregation after secretion of these granules (George JN. Platelets. Lancet 2000 Apr. 29: 355: 1531-9). Clopidogrel bisulfate is an antiplatelet agent that selectively and irreversibly blocks ADP-induced platelet aggregation.
  • clopidogrel bisulfate is a selective and irreversible inhibitor of ADP-induced platelet aggregation (Blair Jarvis and Kerryn Simpson, Drugs 2000, Aug; 60(2): 347-377).
  • US 4,847,265 describes the process to obtain clopidogrel bisulphate (I) i.e., methyl(S)-(+)-alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine- 5(4H)-acetate sulphate, wherein methyl-alpha-(2-chlorophenyl)-6,7-dihydro- thieno[3,2-c]pyridine-5(4H)-acetate (II) is resolved by laevorotatory camphor- 10-sulfonic acid to give methyl(R)-(-)-alpha-(2-chlorophenyl)-6,7-dihydro- thieno[3,2-c]pyridine-5(4H)-acetate camphor sulfonic acid salt (III), which remains in the mother liquor and can be converted in to methyl (R)-(-)-alpha- (2-chlorophenyl)-6,7-
  • camphor sulfonic acid salt (IV) is converted into (+)- stereo isomer of (II) i.e., methyl (S)-(+)-alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate by using aqueous sodium bicarbonate in dichloromethane, which is further reacted with H 2 SO 4 in acetone to give desired product, clopidogrel bisulfate(l).
  • the resolution step being the extreme last step, all the reagents, solvents, drying agents, purification agents, utilities, manpower from the first step of the synthesis till the resolution step which are used up in the formation of discarded R-isomer (III) are wasted.
  • WO 00/27840 (Sanofi - Synthelabo) describes the racemization of undesired intermediate amide (V) i.e., (-)-[2-(2- thienyl)ethylamino] (2-chlorophenyl)acetamide.
  • the racemization process converts undesired R-isomer of amide (V) into racemic amide (VI) i.e., [2-(2- thienyl)ethylamino] (2-chlorophenyl)acetamide using base.
  • racemized amide (VI) further needs to be converted into clopidogrel bisulfate(l) by a number of reaction steps as shown in Scheme 3.
  • it requires more number of reaction steps for recycling racemic amide (VI), in order to get the final product i.e., clopidogrel bisulfate (I).
  • it requires more (a) time, (b) reagents, (c) solvents, (d) purifying agents, (e) manpower, (f) utility, which makes this recycling of undesired stereoisomer to get clopidogrel bisulfate a costlier process.
  • WO 02/059128 describes the process for the racemization of undesired R- isomer i.e., compound (V) to intermediate amide (VI) as well as undesired
  • Another object of the invention is to provide an improved process for racemization of the said R-isomer for recycling to the process for synthesis of clopidogrel
  • Yet another object of the invention is to provide an improved commercially viable and cost effective racemization process towards the synthesis of the clopidogrel or its salts, which requires minimum (a) reaction steps, (b) time, (c) reagents, (d) solvents, (e) purifying agents (f) manpower and (g) utility and also avoids hazardous reagents.
  • a further object of the invention is to reduce the time required for the preparation of the reaction intermediates.
  • a still further object of the invention is to provide a cost effective method of preparation of clopidogrel and its salts, namely clopidogrel mesylate, clopidogrel hydroiodide and clopidogrel perchlorate, and the other
  • Still another object of the invention is to provide the industrially suitable
  • Another object of the invention is to provide novel clopidogrel salts.
  • a further object of the invention is to provide pharmaceutical composition with
  • the present invention accordingly provides a process for the racemization of
  • the acid used in the step (a) is selected from the group comprising of HCI, H 2 SO 4 , CH3COOH, H 3 PO4.
  • the preferred acid is selected from HCI, H 2 SO 4 .
  • the most preferred acid is HCI.
  • the solvent used in the step (a) is selected form the group comprising of methanol, ethanol, isopropyl alcohol, n-butanol and tert-butanol.
  • the preferred solvent is isopropyl alcohol.
  • the base used in the step (b) is selected from the group comprising of sodium hydroxide, potassium hydroxide, sodium ethoxide, liquor ammonia, triethyl amine, diethyl amine and monomethyl amine.
  • the preferred base is liquor ammonia.
  • the reaction step (a) is carried out for 30 minutes to 4 hrs.
  • the reaction step (b) is carried out for 15 minutes to 45 minutes.
  • undesired R-isomer (XII) is racemized to methyl-alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate (II), which is further converted to methyl-(S)-(+)-alpha-(2-chlorophenyl)-6,7- dihydro-thieno[3,2-c]pyridine-5(4H)-acetate sulphate (I) according to a literature process (US 4,847,265) as given in Scheme -4.
  • the invention also provides an improved process for the preparation of methyl (S)-(+)-alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)- acetate (XIV) i.e. clopidfogrel or its pharmaceutically acceptable salt,
  • step (f) reacting methyl-alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c] pyridine-5(4H)-acetate acid salt (XIII) with base to produce the racemic methyl-alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)- acetate (II) for reuse in step (a).
  • the present invention further provides novel method of preparation of clopidogrel salts as shown in Scheme - 5, below, which comprises the steps of
  • camphor sulphonate camphor sulphonate
  • the solvent used for the resolution in step (b) is alkoxy substituted acyclic ethers.
  • the preferred alkoxy substituted acyclic ether used as solvent is CH 3 -O-CH 2 - CH2-O-CH2-CH2-O-CH 3 i.e., bis(2-methoxyethyl)ether (diglyme).
  • step (b) The time required for step (b) is 48 hrs.
  • the reduction of reaction time compared to prior art processes (US 4,847,265), wherein the reaction time is 72 hrs and which also requires intermittent work-up of volume reduction results in a substantial decrease in utilities, manpower and expenditure, thus making the process more convenient and economic.
  • the invention provides an improved process for the preparation of methyl (S)-(+)-alpha-(2-chlorophenyl)-6,7- dihydrothieno [3,2-c]pyridine-5(4H)-acetate (XIV), i.e., clopidogrel or its pharmaceutically acceptable salts,
  • step (b) treating the compound (Xlll-A), thus obtained from step (a) with aqueous sodium bicarbonate in methylene chloride to obtain racemic methyl-alpha-(2- chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate (II) by a method known per se;
  • the invention further provides novel clopidogrel salts and pharmaceutical
  • composition comprising them.
  • the present invention has the following advantages:
  • novel pharmaceutically acceptable salts namely clopidogrel mesylate (clopidogrel methane sulfonic acid salt), clopidogrel hydroiodide, clopidogrel besylate, clopidogrel oxalate clopidogrel trifluoroacetate, clopidogrel acetate, clopidogrel nitrate, clopidogre perchlorate, clopidogrel phosphonate, clopidogrel benzoate, clopidogre fumarate, clopidogrel maleate, clopidogrel citrate, clopidogrel tartrate clopidogrel benzene sulfonate, clopidogrel gentisate, clopidogrel pamoate clopidogrel palmitate, clopidogrel succinate, clopidogrel estolate, clopidogre acistrate, clopidogrel succinate
  • the solvent for the reaction to prepare pharmaceutically acceptable salt may be selected from the group comprising of alcohol, ester, ether, ketone and acetonitrile or a mixture thereof.
  • Alcohol as mentioned above, when used as reaction solvent may be selected from the group comprising of methanol, ethanol, n-propanol, isopropanol n- butanol and t-butanol.
  • Ketone when used as reaction solvent may be selected from the solvent such as acetone.
  • Ester when used as reaction solvent may be selected from the group comprising of ethyl acetate and butylacetate.
  • Ether when used as reaction solvent is tetrahydrofuran.
  • the solvent for the isolation is preferably ether.
  • the ether may be selected from the group comprising of t-butyl methyl ether and di-isopropyl ether.
  • Methyl-alpha-(2-chlorophenyl)- ⁇ ,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate (II) as received by above examples is further converted to clopidogrel bisulfate (I) by the manner known per se.
  • clopidogrel (XIV) in 500 ml of methanol was dissolved at room temperature. To it, 10 gm of acetic acid was added. The reaction mixture was refluxed for 30 hours. Methanol was distilled under vacuum at 60 to 65°C. To the residue, n-hexane was added at room temperature, stirred and then decanted n-hexane. Distilled out n-hexane completely under vacuum at 60 to 65°C to get 40 gm of clopidogrel acetate.
  • Clopidogrel hydroiodide thus produced is characterized by X-ray powder diffraction (XRPD) pattern with peaks at two-theta values (Values in parentheses indicate the lattice spacing in angstroms) at about : 3.7 ⁇ 0.2 (23.592), 4.3 ⁇ 0.2(20.441), 5.2 ⁇ 0.2(16.895), 8.7 ⁇ 0.2(10.072), 9.6 ⁇ 0.2(9.179), 11.4 ⁇ 0.2(7.693), 12.8 ⁇ 0.2(6.862), 13.8 ⁇ 0.2(6.396), 16.6 ⁇ 0.2(5.334), 17.0 ⁇ 0.2(5.191), 17.7 ⁇ 0.2(4.983), 18.0 ⁇ 0.2(4.899), 18.8 ⁇ 0.2(4.715), 19.2 ⁇ 0.2(4.596), 20.6 ⁇ 0.2(4.292) at degrees 29.
  • XRPD X-ray powder diffraction
  • Clopidogrel perchlorate thus prepared is characterized by X-ray powder diffraction (XRPD) pattern with peaks at two-theta values (Values in parentheses indicate the lattice spacing in angstroms) at about: 7.9 ⁇ 0.2 (11.059), 13.8 ⁇ 0.2(6.413), 16.3 ⁇ 0.2(5.414), 17.4 ⁇ 0.2(5.084), 17.7 ⁇ 0.2(5.006), 18.8 ⁇ 0.2(4.718), 20.2 ⁇ 0.2(4.385), 20.7 ⁇ 0.2(4.287), 21.8 ⁇ 0.2(4.059), 23.0 ⁇ 0.2(3.853), 24.1 ⁇ 0.2(3.678), 24.7 ⁇ 0.2(3.606), 25.0 ⁇ 0.2(3.550), 25.7 ⁇ 0.2(3.462), 27.8 ⁇ 0.2(3.205) degrees 2 ⁇ .
  • XRPD X-ray powder diffraction
  • clopidogrel (XIV) was reacted with 104.3183 gm of methane sulfonic acid in 1646.9 gm of methanol at 30-35°C followed by distillation of the methanol to prepare a solution of clopidogrel mesylate (645.553 gm).
  • the sample of the solution was analyzed for the content of clopidogrel mesylate % w/w. The analysis indicated that clopidogrel mesylate was present in 69.68% w/w in methanol.
  • clopidogrel (XIV) was reacted with 20.27 gm of 55% hydriodic acid in 300 ml of diethyl ether at 0-5°C to produce 35.0 gm of clopidogrel hydriodide (50.07%).
  • clopidogrel (XIV) was reacted with 14.81 gm of concentrated nitric acid in 2.5 lit of diethyl ether at 0-5°C to produce 32.0 gm of clopidogrel nitrate (53.52%).
  • the new salts of instant invention can be prepared from any salt / form disclosed in the literature or by using the salts mentioned in the instant invention, preferably, the new salts can be prepared, using clopidogrel perchlorate obtained in the above example. This is especially to achieve the higher purity / assay levels of the newly formed salt including the known salt such as bisulfate, hydrochloride, hydrobromide, taurocholate etc., which in turn are obtained from the higher purity / assay of clopidogrel perchlorate.
  • Pharmaceutical Compositions including the known salt such as bisulfate, hydrochloride, hydrobromide, taurocholate etc.
  • compositions with novel salts of the invention as active ingredient may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels or aqueous or oily solutions or suspensions), for administration by inhalation (for example as finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, or intramuscular dosing or as a suppository (for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elix
  • compositions according to the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions can be prepared from active ingredient, wherein the active ingredient is in a pure form or can also be in a solution form of desired concentration.
  • the solution form can be in various organic solvents or mixtures thereof.
  • Organic solvents can be selected from the group comprising of alcohols, halogenated solvents, ethers, amides, esters, ketones, hydrogenated solvents, acetonitrile, nitromethane and the like.
  • alcohols, halogenated solvents, ethers and amides that can be used are given below:
  • Halogenated Solvents Dichloromethane, Chloroform, Ethylenedichloride and the like
  • the active ingredients either in solid or solution form can be converted into pharmaceutical composition, wherein depending on the process of preparation of pharmaceutical composition, the solvent associated with Active Pharmaceutical Ingredient can be optionally removed before or during the process.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include for example, inert diluents such as lactose, spray dried anhydrous lactose, mannitol, spray dried mannitol, microcrystalline cellulose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch, hydroxy propyl cellulose (Klucel LF RTM), sodium starch glycolate, cross povidone, cross carmellose sodium or alginic acid; binding agents such as starch, povidone, hydroxypropylcellulose, hydroxypropyl methylcellulose, gelatin, pregelatinised starch, lubricating agents such as magnesium stearate, stearic acid or talc, hydrogenated castor oil, colloidal silicon dioxide, preservative agents such as ethyl or propyl p- hydroxybenzoate, and anti-oxidants, such as ascorbic acid, citric acid and other organic acids, butylated hydroxyanisole
  • the granules for the tablet can be prepared by using high or low shear granulator or fluid bed processor.
  • the granules or pellets can also be prepared in extruders, merumeriser, rotor or wurster equipment.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract like enteric coating comprising polymers like cellulose acetate pthalate, hydroxypropyl methylcellulose pthalate, methacrylic acid copolymer type A, B or C (Eudragit L, Eudragit S or Eudragit L 30 D 55) , or to improve their stability and/or appearance, in either case, using conventional coating, agents and procedures well known in the art.
  • the tablets may be coated with composition comprising polymers like ethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, Eudragit E 100 and combinations thereof in order to provide protection to the tablet core from the moisture.
  • the tablets can be moisture protected by suitable excipients by making tablet in tablet where these excipients are present in outer coat.
  • compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, the capsule can filled with granules or pellets.
  • Compositions for oral use may be in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil or can be filled as such.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid) colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharin or aspartame).
  • preservatives such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid) colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharin or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those sets as above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally occurring gums such as gum acacia or gum tragacanth, naturally occurring phosphatides such as soya bean, lecithin, an esters, or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may be also contain sweetening, flavouring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose and may also contain a demulcent, preservative, flavouring and/or coloring agent.
  • the pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile or solvent, for example a solution in 1 ,2-butanediol.
  • Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • Topical formulations such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art.
  • Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • the amount of active ingredients that can be combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • the compounds of the present invention may also be administered by controlled release means or delivery devices that are well known to those of ordinary skill in the art, such as those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809;
  • compositions can be used to provide slow or controlled release of one or more of the active ingredients therein using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems multiple layer coatings, microparticles, liposomes, microspheres, or like, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein may be readily selected for use with the pharmaceutical compositions of the invention.
  • single unit dosage forms suitable for oral administration such as tablets, capsules, gelcaps, caplets, and the like, that are adapted for controlled-release are encompassed by the present invention.
  • the salts of the present invention particularly clopidogrel hydroiodide and clopidogrel mesylate exhibit excellent flowability properties, as indicated by their low values of angle of repose and high values of tapped density. Tapped density is of great importance when one considers the high dose capsule product or the homogeneity of a low-dose formulation in which there are large differences in drug and excipient densities.
  • Tapped density is determined by the following procedure.
  • Tapped density for clopidogrel hydroiodide is 0.991 g/ml, which is higher than that of clopidogrel bisulphate i.e. 0.834 g/ml.
  • Good flowability properties are essential for an efficient tabletting operation.
  • a good flow of the powder or granulation to be compressed is necessary to assure efficient mixing and acceptable weight uniformity for the compressed tablets.
  • Pharmaceutical powders have angle-of-repose values varying from 25 to 45°, with lower values indicating better flow characteristics. The angle of repose is determined by the following procedure.
  • a dry stainless steel funnel of length 14.0 cm, stem length of 8.0 cm, internal diameter 7.5 cm and an internal diameter of outflow opening of 0.8 cm.
  • the angle of repose was calculated from the value of tan using the tangent table/scientific calculator.
  • the angle of repose for clopidogrel bisulphate is found to be 22.73°, which is less than 25°.
  • the angle of repose for clopidogrel hydroiodide is found to be 28.56°.
  • the solubility of the mesylate and hydroiodide salt is significantly better than that of the bisulphate salt (the solubility for the mesylate, hydroiodide and bisulphate being 204.17 mg/dl, 62.77 mg/dl and 30.68 mg/dl respectively). From the data available it is expected that the mesylate and hydroiodide salt will be more soluble than the bisulphate salt at the relevant human gastric pH (pH 1.2 - 1.8).
  • the dissolution and dissolution rate are related to the solubility.
  • One can increase the absorption rate by increasing the dissolution rate (Notari. R Absorption of Drugs from Gastrointestinal Tract in Biopharmaceutics and Clinical Pharmacokinetics and Introduction, 4 th Edition, Marcel Decker, New York). Therefore, drug dissolution in aqueous media being a significant contributor in its oral absorption; drugs with greater solubility and dissolution have less chance of oral drug absorption problems.
  • the mesylate and the hydroiodide salts which are highly soluble at a pH of 1.2 will be more rapidly and completely absorbed in the stomach and the upper Gl tract as compared to the bisulphate salt.
  • Excipients lactose, microcrystalline cellulose, starch, povidone, magnesium stearate.
  • Excipients magnesium stearate, corn starch, gum Arabic, shellac, white sugar, glucose, white wax, carnauba wax, paraffin, new cochinealin
  • Active ingredient equivalent to 75 mg base; isotonic solvent sufficient to make 3 ml
  • Active ingredient equivalent to 75 mg base; Semi-synthetic triglycerides sufficient to make 1 suppository.
  • Excipients polyethylene glycol, mentha oil, mono and di-glycerides, gelatin, sorbitol, glycerin, methyl paraben, propyl paraben, sodium lauryl sulphate.
  • Preparatory examples for pharmaceutical formulations of clopidogrel salts are given below.
  • the granules were sized and mixed with 1.84 %w/w polyethylene glycol 6000, 0.92% w/w hydrogenated castor oil (Boricin Pharma, RTM), 0.92 %w/w colloidal silicon dioxide, 2.39 %w ⁇ w lactose anhydrous (Pharmatose DCL 21 , RTM), 0.92 %w/w magnesium stearate, and 1.84 %w/w talc. This mixture was compressed to 544 mg weight tablets having a diameter of 11.11 mm. Results of various tests are given in Table 1.
  • the granules were sized and mixed with 1.84 %w/w polyethylene glycol 6000, 0.92% w/w hydrogenated castor oil (Boricin Pharma), 0.92 %w/w colloidal silicon dioxide, 2.39 %w/w lactose anhydrous (Pharmatose DCL 21 ), 0.92 %w/w magnesium stearate, and 1.84 %w/w talc. This mixture was compressed to 544 mg weight tablets having a diameter of 11.11 mm. Result of various tests are given in Table 2.
  • the granules are sized and mixed with 1.84 %w/w polyethylene glycol 6000, 0.92% w/w hydrogenated castor oil (Boricin Pharma), 0.92 %w/w colloidal silicon dioxide, 2.39 %w/w lactose anhydrous (Pharmatose DCL 21 ), 0.92 %w/w magnesium stearate, and 1.84 %w/w talc. This mixture was compressed to 544 mg weight tablets having a diameter of 11.11 mm. Result of various tests are given in Table 3
  • the tablets prepared in example 21 were film-coated with coating suspension prepared using composition given below.
  • the film coating was performed using perforated coating pan apparatus.
  • the approximate weight gain of the tablets was 5%w/w.
  • the tablets prepared in example 21 were film-coated with coating suspension prepared using composition given below.
  • the film coating was performed using perforated coating pan apparatus.
  • the approximate weight gain of the tablets was 3%w/w.
  • the tablets prepared in example 21 were film-coated with coating suspension prepared using composition given below.
  • the approximate weight gain of the tablets was 3%w/w.
  • the granules prepared in example 21 were filled in hard gelatin capsules.
  • the fill weight of the capsule was 544 mg.
  • Part A- 26.81 %w/w of hydrated silica and 20.24%w/w lactose anhydrous (Pharmatose DCL 21 ) were mixed and the mixture was granulated with 44.69 %w/w clopidogrel mesylate (69.68%w/w solution in methanol) and then dried.
  • the granules are sized and mixed with 2.29 %w/w cross povidone (Polyplasdone XL 10), 4.59% w/w hydrogenated castor oil (Boricin Pharma), 0.46 %w/w lake of amaranth, and 0.92 %w/w talc. This mixture was compressed to 218 mg weight tablets having a diameter of 8.51 mm.
  • Tablet in tablet compression The tablets compressed in part A and powder mixture prepared in part B were utilized to prepare tablet in tablet in which the powder mixture prepared in part B formed the outer portion or coating and the tablet prepared in part A formed the core.
  • the total weight of the tablet was 800 mg and the tablet diameter was 12.7 mm.
  • the tablets prepared in example 26 (part A) were film-coated with coating suspension prepared using composition given in example 23.
  • the film coating was performed using perforated coating pan apparatus.
  • the approximate weight gain of the tablets was 3%w/w.
  • the core tablets prepared in example 28 were compression coated with granules mixture ( 582 mg average wt)having following composition :
  • Lactose anhydrous (Pharmatose DCL-21 ) 48,72 Mannitol (Pearlitol SD-200) 48,72
  • microcrystalline cellulose Avicel PH-112
  • 17.27 % w/w mannitol Pearlitol SD-200
  • 37.23% w/w lactose anhydrous Pharmatose DCL-21
  • 2.39% w/w cross povidone Polyplasdone XL-10
  • 17.90% w/w clopidogrel mesylate 69.68% w/w solution in methanol
  • the granules were sized through appropriate sieves and mixed with 1.84% w/w of hydrogenated castor oil (Boricin Pharma), 1.84% w/w of polyethylene glycol 6000, 0.92% w/w of colloidal silicon dioxide, 2.39% w/w of cross povidone (Polyplasdone XL-10) and 1.86 % w/w of talc.
  • This mixture was compressed to 544 mg tablets having a diameter of 11.11 mm.
  • the compressed tablets were film coated with coating suspension prepared using composition given below. The film coating was performed by using perforated coating pan apparatus. The approximate weight gain of the tablets was 4 % w/w.
  • the granules were sized through appropriate sieves and mixed with 1.84% w/w of hydrogenated castor oil (Boricin Pharma), 1.84% w/w of polyethylene glycol 6000, 0.92% w/w of colloidal silicon dioxide, 2.39% w/w of cross povidone (Polyplasdone XL-10) and 1.85 % w/w of talc. This mixture was compressed to 544 mg tablets having a diameter of 11.11 mm.
  • the compressed tablets were film coated with coating suspension prepared using composition given below.
  • the film coating was performed by using perforated coating pan apparatus.
  • the approximate weight gain of the tablets was 3.67%.
  • Titanium dioxide 0,50
  • the mixed blend was compressed into tablets of 270 mg weight on Rotary tablet KORSCH machine using 12/32" Standard Concave punches.
  • Coating The compressed tablets were film coated with coating suspension prepared using composition given in example 31. The film coating was performed using perforated coating pan apparatus. The approximate weight gain of the tablets was 3.70 % w/w. Results of various tests are given in Table 10.
  • the compressed tablets were film coated with coating suspension prepared using composition given in example 31.
  • the approximate weight gain of the tablets was 4.44 % w/w.
  • the compressed tablets were film coated with coating suspension prepared using composition given in example 31.
  • the approximate weight gain of the tablets was 3.2 % w/w. Results of various tests for uncoated tablets are given in table 12.
  • the granules were dried and mixed with 36.08% w/w of clopidogrel mesylate, 2.40% w/w of cross povidone (Polyplasdone XL-10 ), 1.85% w/w of polyethylene glycol (PEG-6000), 0.92% w/w of hydrogenated castor oil (Boricin Pharma), 0.74 w/w of colloidal silicon dioxide and 1.85% w/w of talc & 0.92% w/w of magnesium stearate were sifted through appropriate sieve and then mixed.
  • the mixed blend was compressed into tablets of 270 mg weight on Rotary tablet KORSCH machine using 12/32" Standard Concave punches.
  • the granules were dried and mixed with 32.69% w/w of clopidogrel mesylate, f
  • the mixed blend was compressed into tablets of 270 mg weight on Rotary tablet KORSCH machine using 12/32" Standard Concave punches. Disintegration time of the tablet is 1 - 2 minutes.
  • the compressed tablets were film coated with coating suspension prepared using composition given in example 31.
  • the approximate weight gain of the tablets was 3.2 % w/w.
  • the results of various tests are given in Table 20.
  • the tablets prepared in example 42 & example 43 were film coated with coating suspension prepared using composition given below.
  • the film coating was performed using perforated coating pan apparatus.
  • the approximate weight gain of the tablet was 3 % w/w.

Abstract

La présente invention concerne un procédé amélioré de racémisation de méthyl (R)-(-) alpha-(2-chlorophényl)-6,7-dihydro-thiéno[3,2-c]pyridine-5(4H)-acétate, d'un stéréoisomère formé lors de la synthèse de clopidogrel, à savoir, méthyl (S)-(+)-alpha- (2-chlorophényl)-6,7-dihydro-thiéno[3,2-c]pyridine-5(4H)-acétate ou ses sels. Cette invention a aussi trait à un procédé amélioré de production de clopidogrel ou de ses sels acceptables pharmaceutiquement, ainsi qu'à de nouveaux sels de clopidogrel et à des compositions pharmaceutiques les contenant.
EP04705140A 2003-02-03 2004-01-26 Procede de preparation de clopidogrel, ses sels et compositions pharmaceutiques Withdrawn EP1606231A1 (fr)

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Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004106344A2 (fr) 2003-04-25 2004-12-09 Cadila Healthcare Limited Sels de clopidogrel et procede de preparation
GB0325603D0 (en) * 2003-11-03 2003-12-10 Sandoz Ag Organic compounds
EP1713812A1 (fr) * 2004-01-13 2006-10-25 Zentiva, a.s. Nouvelles formes cristallines d'hydrobromure de clopidogrel et leurs procedes de preparation
WO2005070464A2 (fr) * 2004-01-21 2005-08-04 Biofarma Ilac Sanayi Ve Ticaret A.S. Formulation de comprimes de bisulfate de clopidogrel
US7446200B2 (en) 2004-10-04 2008-11-04 Usv, Ltd. Rapid resolution process of clopidogrel base and a process for preparation of clopidogrel bisulfate polymorph-form I
CZ20041048A3 (cs) * 2004-10-18 2005-11-16 Zentiva, A. S Způsob výroby klopidogrelu
AU2005327776A1 (en) * 2005-02-15 2006-08-24 Usv Limited Rapid resolution process for clopidogrel base and a process for preparation of Clopidogrel bisulfate polymorph - Form I
TW200640932A (en) * 2005-02-24 2006-12-01 Teva Pharma Clopidogrel base suitable for pharmaceutical formulation and preparation thereof
CZ299213B6 (cs) * 2005-03-08 2008-05-21 Zentiva, A. S Zpusob racemizace R(-) izomeru methylesteru kyseliny (2-chlorfenyl)-6,7-dihydro-thieno[3,2-c]pyridin-5(4H)-octové
CN101237868A (zh) * 2005-06-13 2008-08-06 伊兰制药国际有限公司 纳米粒氯吡格雷和阿司匹林组合制剂
DE202005013839U1 (de) * 2005-09-01 2005-10-27 Helm Ag Pharmazeutische Formulierung für Salze monobasischer Säuren mit Clopidogrel
WO2007054968A2 (fr) * 2005-09-20 2007-05-18 Torrent Pahrmaceuticals Limited Compositions pharmaceutiques atypiques de mesylate de clopidogrel
DE102005060690B4 (de) * 2005-12-15 2008-09-25 Capsulution Nanoscience Ag Salze von Clopidogrel mit Polyanionen und ihre Verwendung zur Herstellung pharmazeutischer Formulierungen
CZ298349B6 (cs) * 2006-03-09 2007-09-05 Zentiva, A. S Farmaceutická kompozice clopidogrelu hydrogenbromidu
JP2009532462A (ja) * 2006-04-05 2009-09-10 カディラ・ヘルスケア・リミテッド 調節放出クロピドグレル製剤
DK2064217T3 (da) 2006-09-04 2011-05-09 Ranbaxy Lab Ltd Forbedret fremgangsmåde til fremstilling af clopidogrel og dets farmaceutisk acceptable salte
BRPI0803101A2 (pt) * 2007-04-18 2014-04-22 Teva Pharma Processos melhores para preparação de clopidogrel
EP2148655B1 (fr) * 2007-04-20 2013-02-27 Wockhardt Limited Compositions pharmaceutiques de clopidogrel
EP2107061A1 (fr) * 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation de clopidogrel enrichi optiquement
WO2009133455A2 (fr) * 2008-05-01 2009-11-05 Cadila Healthcare Limited Composition pharmaceutique de clopidogrel
KR100990949B1 (ko) 2008-06-09 2010-10-29 엔자이텍 주식회사 클로피도그렐 및 그의 유도체의 제조방법
FR2932387B1 (fr) 2008-06-16 2010-09-17 Cll Pharma Composition orale contenant un agent anti-plaquettaire de la famille des thienopyridines sous forme de base.
WO2010009745A1 (fr) * 2008-07-25 2010-01-28 Pharmathen S.A. Forme galénique orale solide contenant l’agent anti-plaquettaire clopidogrel et son procédé de préparation
CN101591346B (zh) * 2009-07-03 2014-10-29 北京华禧联合科技发展有限公司 硫酸氢氯吡格雷有关物质b的合成方法
CN104045652A (zh) * 2014-07-09 2014-09-17 沈健芬 一种氯吡格雷中间体的制备方法
CN104193762B (zh) * 2014-08-04 2017-02-15 浙江车头制药股份有限公司 一种制备苯磺酸氯吡格雷晶型ⅲ的方法
CN104211714B (zh) * 2014-08-14 2016-09-14 广东东阳光药业有限公司 一种血小板聚集抑制剂的制备方法
CN110627808B (zh) * 2018-06-21 2022-04-01 江苏同禾药业有限公司 一种硫酸氢氯吡格雷拆分母液的回收处理工艺

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2530247B1 (fr) * 1982-07-13 1986-05-16 Sanofi Sa Nouveaux derives de la thieno (3, 2-c) pyridine, leur procede de preparation et leur application therapeutique
FR2623810B2 (fr) * 1987-02-17 1992-01-24 Sanofi Sa Sels de l'alpha-(tetrahydro-4,5,6,7 thieno(3,2-c) pyridyl-5) (chloro-2 phenyl) -acetate de methyle dextrogyre et compositions pharmaceutiques en contenant
FR2652575B1 (fr) * 1989-09-29 1992-01-24 Sanofi Sa Procede de preparation d'acides alpha-bromo phenylacetiques.
FR2664596B1 (fr) * 1990-07-10 1994-06-10 Sanofi Sa Procede de preparation d'un derive n-phenylacetique de tetrahydrothieno [3,2-c] pyridine et son intermediaire de synthese.
HU226421B1 (en) * 1998-11-09 2008-12-29 Sanofi Aventis Process for racemizing optically active 2-(2-chlorophenyl)-2-(2-(2-thienyl)-ethylamino)-acetamides
CN100338068C (zh) * 2001-01-24 2007-09-19 卡地拉健康护理有限公司 制备氯吡格雷的方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004074215A1 *

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