WO1992020334A1 - Pharmaceutical composition comprising ibuprofen salt - Google Patents
Pharmaceutical composition comprising ibuprofen salt Download PDFInfo
- Publication number
- WO1992020334A1 WO1992020334A1 PCT/EP1992/001025 EP9201025W WO9220334A1 WO 1992020334 A1 WO1992020334 A1 WO 1992020334A1 EP 9201025 W EP9201025 W EP 9201025W WO 9220334 A1 WO9220334 A1 WO 9220334A1
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- WIPO (PCT)
- Prior art keywords
- sodium
- isobutylphenyl
- propionate
- water
- enantiomeric purity
- Prior art date
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Classifications
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
Definitions
- This invention relates to a salt of S(+) -ibuprofen, co its anti-inflammatory, anti-pyretic and analgesic activity, to pharmaceutical compositions containing the salt, to its use as an intermediate in a process to prepare S(+) -ibuprofen of high enantiomeric purity and to a novel form of the salt.
- ( ⁇ )-2-(4-Isobutylphenyl)propionic acid, ibuprofen is a potent and well tolerated anti-inflammatory, analgesic and anti-pyretic compound.
- the racemic mixture consists of two enantiomers, namely S(+)-2-(4- isobutylphenyDpropionic acid or S(+) -ibuprofen and R(-) -2-(4-isobutylphenyl)propionic acid or R(-)- ibuprofen. It is known that S(+) -ibuprofen is the active agent and that R(-) -ibuprofen is partially converted into S(+) -ibuprofen in humans.
- the drug has been previously marketed as the racemic mixture, however, in certain circumstances it may be advantageous to administer S(+) -ibuprofen. Problems arise, however, when attempting to formulate S(+) -ibuprofen into pharmaceutical compositions due to its low melting point of 51°C.
- DE 3922441 considers the formulation problems associated with the low melting point of S(+)-ibuprofen and proposes a solution to the problem by using the calcium salt of S(+)-ibuprofen on its own or in admixture with a compound selected from the group comprising the sodium-, potassium- or ammonium- S(+)- ibuprofen salt, ibuprofen or S-(+) -ibuprofen. It is disclosed that the pharmaceutical composition must contain the calcium salt as an essential component as alkali metal salts of S(+)-ibuprofen per se, for example the sodium salt, are too hygroscopic to allow satisfactory tabletting.
- the sodium salt of S(+)-ibuprofen has a negative optical rotation of -4.3° and is thus correctly named as S(-)sodium 2-(4-isobutylphenyl)propionate.
- compositions comprising S(-)sodium 2-(4-isobutyl- phenyl)propionate having an enantiomeric purity of at least 90%, together with a pharmaceutically acceptable carrier, with the exception of (a) compositions consisting of a solution of S(-)sodium 2-(4- isobutylphenyl) ropionate in water with no additional pharmaceutical excipient and (b) compositions comprising the calcium salt of S(+)-ibuprofen.
- S(-)sodium 2-(4-isobutylphenyl)propionate possesses a number of formulation advantages over S(+)-ibuprofen.
- S(-)sodium 2-(4-isobutylphenyl)propionate may be easily compressed into tablets even on long compressing runs during which the temperature of the tablet tooling will rise. Under similar circumstances S(+) -ibuprofen would tend to stick and generally display poor flow characteristics.
- S(-)sodium 2- (4-isobutylphenyl) - propionate may also be easily milled to the most appropriate particle size.
- the high melting point of S(-)sodium 2-(4-iso ⁇ butylphenyl)propionate allows higher temperatures to be used in drying intermediates in formulation processes, for example granules, compared to the corresponding intermediates containing S(+)- ibuprofen.
- the high melting point also gives increased physical stability to final formulations containing S(-)sodium 2-(4-isobutylphenyl)propionate during storage for example in hot climates compared to final formulations containing S(+) -ibuprofen which may deteriorate, when stored at temperatures close to the melting point of S(+)-ibuprofen.
- S(-)sodium 2-(4-isobutylphenyl)propionate has a higher water solubility than S(+) -ibuprofen and is thus very useful in the formulation of pharmaceutical compositions containing water.
- Such compositions may be formulated to have a bright, clear, aesthetically- appealing appearance.
- S(-)sodium 2-(4-isobutylphenyl)propionate will resist esterification with excipients which contain a hydroxyl group for example mono-, di-, tri- or poly-hydric alcohols.
- excipients which contain a hydroxyl group for example mono-, di-, tri- or poly-hydric alcohols.
- S(+)-ibuprofen with liquid fill excipients, for example, esterified natural vegetable oils which may contain alcohols.
- the enantiomeric purity of S(-)sodium 2-(4- isobutylphenyl) ropionate used in the pharmaceutical compositions of the invention is in the range of 90-100%.
- S(-)sodium 1-(4-isobutylphenyl)- propionate can exist in the form of a stable dihydrate which is a novel and valuable compound for use in preparing pharmaceutical compositions.
- S(-)sodium 2-(4-isobutylphenyl)propionate includes the anhydrous form and hydrated forms. Preferably the dihydrate is used.
- S(-)sodium 2-(4-isobutylphenyl)propionate dihydrate may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.
- S(-)sodium 2-(4-isobutyl ⁇ phenyl)propionate may be administered orally, rectally, parenterally or topically, preferably orally or topically.
- the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration.
- Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy.
- the compositions of the invention may contain 1-99% by weight of S(-)sodium 2- (4-isobutylphenyl)propionate.
- the compositions of the invention are generally prepared in unit dosage form.
- the unit dosage of S(-)sodium 2-(4- isobutylphenyl)propionate is in the range of 10-1200mg in a precalculated amount to provide doses which are equivalent by weight to doses of for example lOO g, 200mg, 400mg or 800mg of S(+) -ibuprofen.
- compositions for oral administration are preferred compositions of the invention and there are known pharmaceutical forms for such administration, for example tablets and capsules.
- tablets may be prepared by mixing S(-)sodium 2-(4-isobutylphenyl) - propionate with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example maize starch, and lubricating agents, for example magnesium stearate, and tableting the mixture by known methods.
- Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate.
- capsules for example hard or soft gelatin capsules, containing S(-)sodium 2-(4-isobutylphenyl) - propionate with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner.
- the tablets may be formulated in a manner known to those skilled in the art so as to give a controlled release of the compound of the present invention.
- Other compositions for oral administration include oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil.
- a solid composition comprises a) 10-99% S(-)sodium 2-(4-isobutylphenyl)propionate; b) 1-90% of a diluent and c) 0.1-10% of a lubricating agent, d) 0.1- 15% of a disintegrating agent and optionally e) 0.1-15% of a binder. Optionally 0.1-10% of a flow aid may be added.
- the diluent includes lactose, calcium phosphate, dextrin, microcrystalline cellulose, sucrose, starch, calcium sulphate or mixtures thereof. More preferably the diluent is lactose or calcium phosphate.
- the lubricating agent includes magnesium stearate, stearic acid, calcium stearate or mixtures thereof. More preferably the lubricating agent is magnesium stearate or stearic acid.
- the disintegrating agent includes microcrystalline cellulose, maize starch, sodium starch glycollate, low substituted hydroxypropyl cellulose, alginic acid or croscarmellose sodium or mixtures thereof.
- the binder includes polyvinyl pyrrolidone, gelatin, hydroxypropylmethyl cellulose, starch or mixtures thereof. More preferably the binder is polyvinylpyrrolidone. Suitable flow aids include talc and colloidal silicon dioxide. It will be appreciated by those skilled in the art that a particular excipient may perform more than one function for example maize starch may act as a diluent, a binder or as a disintegrating agent.
- Controlled release forms of S(-)sodium 2-(4- isobutylphenyl)propionate include rapid release formulations such as soluble granules or melt filled fast release capsules, delayed release formulations such as tablets provided with enteric coatings, for example, of cellulose acetate phthalate and, in particular, sustained release formulations. Numerous types of sustained release formulations are known to those skilled in the art.
- S(-)sodium 2-(4- isobutylphenyl)propionate may be encapsulated within a release retarding coating, for example, a copolymer of cellulose ether and acrylate, or may be bound to small particles such as, for example, ion exchange resin beads.
- S(-) sodium 2- (4- isobutylphenyl)propionate may be incorporated into a matrix containing a release retarding agent such as a hydrophilic gum e.g. xanthan gum, a cellulose derivative e.g. hydroxypropyl methylcellulose, or a polysaccharide, wax or plastics material.
- a release retarding agent such as a hydrophilic gum e.g. xanthan gum, a cellulose derivative e.g. hydroxypropyl methylcellulose, or a polysaccharide, wax or plastics material.
- Such techniques may provide sustained blood levels of S(+)-ibuprofen by controlling, for example, erosion, swelling, disintegration and dissolution of the composition within the gastrointestinal tract.
- Liquid fill compositions for example viscous liquid fills, liquid paste fills or thixotropic liquid fills are also suitable for oral administration.
- Melt filled compositions may be obtained by mixing S(-)sodium 2-(4- isobutylphenyl)propionate with certain esters of natural vegetable oil fatty acids, for example, the Gelucire
- a melt-filled capsule comprises a) 10-80% S(-)sodium 2-(4- isobutylphenyl)propionate and b) 20-90% of a fatty acid ester excipient which comprises one or more polyol esters and triglycerides of natural vegetable oil fatty acids.
- an effervescent composition comprises a) 1-50% of S(-)sodium 2-(4-isobutylphenyl)propionate and b) a pharmaceutically acceptable effervescent couple.
- a composition may be presented in the form of tablets or granules.
- the effervescent compositions additionally comprise a taste masking component for example a sweetener, a flavouring agent, arginine, sodium carbonate or sodium bicarbonate.
- compositions of the present invention comprise S (-) sodium 2- (4- isobutylphenyl)propionate as the dihydrate.
- oral liquid compositions comprise a) 0.1-10% S(-)sodium 2-(4-isobutylphenyl) ropionate b) 1- 50% of a diluent c) water to 100%.
- the .composition may contain alcohol and/or include a preservative.
- Suitable diluents include sweetening agents for example sorbitol, xylitol, sucrose, or LYCASIN® (registered trademark of Roquette) .
- Flavourings or other taste-masking agents known to those skilled in the art for example saccharin, sodium saccharin may be added.
- S(-)sodium 2-(4- isobutylphenyl)propionate in aqueous liquid compositions is particularly advantageous as it provides clear, homogeneous, bright formulations which are aesthetically appealing to the consumer in addition to the beneficial pharmacological effect provided.
- compositions for topical administration are also preferred compositions of the invention.
- S(-)sodium 2-(4-isobutylphenyl)propionate may be dispersed in a pharmaceutically acceptable cream, ointment or gel.
- a suitable cream may be prepared by incorporating S(-)sodium 2-(4-isobutylphenyl)propionate in a topical vehicle such as petrolatum and/or light liquid paraffin, dispersed in an aqueous medium using surfactants.
- An ointment may be prepared by mixing S(-)sodium 2-(4-isobutylphenyl)propionate with a topical vehicle such as a mineral oil, petrolatum and/or a wax e.g.
- a gel may be prepared by mixing S(-)sodium 2-(4-isobutylphenyl)propionate with a topical vehicle comprising a gelling agent e.g. basified Carbomer BP, in the presence of water.
- a gelling agent e.g. basified Carbomer BP
- Suitable topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally for example in a patch or poultice.
- a suitable transdermal composition may be prepared by mixing S(-)sodium 2-(4- isobutylphenyl)propionate with a topical vehicle, such as described above, together with a potential transdermal accelerant such as dimethyl sulphoxide, propylene glycol or peppermint oil.
- compositions are preferred for topical use for example compositions in the form of a cream, an ointment or a gel.
- Suitable gels comprise a) 1-15% S(-)sodium 2-(4-isobutylphenyl)propionate; b) 1-20% of a gelling agent c) 0.01-10% of a preservative and d) water to 100%.
- the gelling agent comprises 0.1-10% of a carbomer and a neutralising agent.
- a suitable cream comprises a) 1-15% S(-)sodium 2-
- Suitable oily phases comprise petrolatum and/or light liquid paraffin.
- S(-)sodium 2-(4-isobutylphenyl)- propionate may be distributed in a base comprising a) 10-40% of a self-emulsifying base b) 60-90% of water to form a cream.
- LABRAFILL and GELOT both tradenames of Gattefosse are examples of self-emulsifying bases.
- a suitable ointment comprises a) 1-15% S(-)sodium 2-(4-isobutylphenyl)propionate and b) a topical vehicle to 100%.
- Suitable topical vehicles include mineral oil, petrolatum and/or a wax.
- Compositions of the invention suitable for rectal administration are known pharmaceutical forms for such administration, for example suppositories with polyethylene glycol bases or semi-synthetic glycerides.
- composition in the form of a suppository comprises 10-30% S(-)sodium 2-(4-isobutylphenyl)- propionate and 70-90% of a carrier wherein the carrier is selected from a base which comprises polyethylene glycol or a semi-synthetic glyceride.
- compositions of the invention suitable for parenteral administration are known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.
- S(-)sodium 2-(4-isobutylphenyl)propionate in the form of particles of very small size, for example as obtained by fluid energy milling.
- the S(-)sodium 2-(4-isobutylphenyl)propionate may, if desired, be associated with other compatible pharmacologically active ingredients and/or enhancing agents.
- S(-)sodium 2-(4-isobutyl ⁇ phenyl)propionate may be combined with any ingredient commonly used in a cough or cold remedy, for example, an antihis amine, caffeine or another xanthine derivative, a cough suppressant, a decongestant, an expectorant, a muscle relaxant, or combinations thereof.
- Suitable antihistamines which are preferably non-sedating include acrivastine, astemizole, azatadine, azelastine, bromodiphenhyrdramine, brompheniramine, carbinoxamine, cetirizine, chlorpheniramine, cyproheptadine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, ebastine, ketotifen, lodoxamide, loratidine, levocubastine, mequitazine, oxatomide, phenindamine, phenyltoloxamine, pyrilamine, setastine, tazifylline, warmthlastine, terfenadine, tripelennamine or triprolidine.
- Suitable cough suppressants include caramiphen, codeine or dextromethorphan.
- Suitable deconges ta t s include seudoephedrine , phenylpropanola ine and phenylephrine.
- Suitable expectorants include guaifensin, potassium citrate, potassium guaiacolsulphonate, potassium sulphate and terpin hydrate.
- S(-)sodium 2-(4-isobutylphenyl)propionate is an anti-inflammatory, analgesic and anti-pyretic agent. It is, therefore, indicated for use in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, seronegative arthropathies, periarticular disorders and soft tissue injuries.
- S(-)sodium 2-(4- isobutylphenyl)propionate may also be used in the treatment of postoperative pain, postpartum pain, dental pain, dysmenorrhoea,headache, musculoskeletal pain or the pain or discomfort associated with the following: respiratory infections, colds or influenza, gout or morning stiffness.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising S(-)sodium 2-(4- isobutylphenyl)propionate having an enantiomeric purity of at least 90% together with a pharmaceutically acceptable carrier for use in the treatment of inflammation, pain and pyrexia.
- a pharmaceutically acceptable carrier for use in the treatment of inflammation, pain and pyrexia.
- the S(-)sodium 2-(4-isobutylphenyl)propionate in present as the dihydrate.
- the present invention provides the use of a pharmaceutical composition
- a pharmaceutical composition comprising S(-)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric purity of at least 90% together with a pharmaceutically acceptable carrier for the manufacture of a medicament for use as an antiinflammatory, analgesic and anti-pyretic agent.
- a pharmaceutically acceptable carrier for the manufacture of a medicament for use as an antiinflammatory, analgesic and anti-pyretic agent.
- the S(-)sodium 2-(4-isobutylphenyl)propionate in present as the dihydrate.
- the present invention provides a method of treating inflammation, pain and pyrexia by administration of a pharmaceutical composition comprising S(-)sodium 2-(4-isobutylphenyl)- propionate having an enantiomeric purity of at least 90% together with a pharmaceutically acceptable carrier to a mammal, e.g. a human, in need thereof.
- a pharmaceutically acceptable carrier e.g. a human
- S(-)sodium 2-(4-isobutylphenyl)propionate in present as the dihydrate.
- S(-)sodium 2-(4-isobutylphenyl)propionate may be absorbed more quickly from the gastrointestinal tract in humans than S(+)-ibuprofen thus giving therapeutically acceptable plasma levels in a shorter period of time.
- This effect offers the possibility of eliciting an onset - hastened and/or enhanced therapeutic response, by use of S(-)sodium 2-(4-isobutylphenyl)propionate compared to S(+)-ibuprofen, which is especially important in cases where analgesia is required, for example, in headache or dental pain.
- the present invention includes a method of eliciting an onset-hastened and/or enhanced analgesic response compared to the use of an equivalent dose of S(+)-ibuprofen in a mammal, e.g. a human, comprising the administration of S(-)sodium 2-(4- isobutylphenyl)propionate to a mammal in need thereof.
- S(-)sodium 2-(4-isobutylphenyl)propionate is admin- istered in solution but also when administered in other formulations, for example, solid formulations for oral use (for example tablets or capsules) or suppositories.
- the present invention provides a method of preparing a pharmaceutical composition
- a pharmaceutical composition comprising S(-) -sodium 2-(4-isobutylphenyl) ropionate together with a diluent or carrier characterised in that S(-)sodium 2-(4-isobutylphenyl)propionate dihydrate is used as the source of S(-)sodium 2-(4- isobutylphenyl)propionate.
- the present invention provides a process to prepare a pharmaceutical composition comprising S(-)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric purity of at least 90% together with a pharmaceutically acceptable carrier comprising combining S(-)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric purity of at least 90% in solid form with a pharmaceutically acceptable carrier and formulating into a dosage form.
- a preferred process for preparing a solid composition in tablet form comprises combining 10-90% of S(-)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric purity of at least 90% with 1-90% of a diluent, optionally adding other pharmaceutically acceptable excipients selected from lubricating agents, disintegrating agents, binders, flow aids, oils, fats and waxes, mixing the ingredients with one another to form a uniform mixture, and compressing the mixture thus obtained to form tablets which may be optionally coated with a film coat or a sugar-coat.
- S(-)sodium 2-(4- isobutylphenyl)propionate Processes for the preparation of S(-)sodium 2-(4- isobutylphenyl)propionate will now be described. These processes form another aspect of the present invention.
- S(-)sodium 2-(4-isobutylphenyl)propionate includes the anhydrous form and hydrated forms for example the dihydrate.
- S(-)sodium 2-(4-isobutylphenyl)propionate may be prepared by neutralising S(+)-2-(4-isobutylphenyl) propionic acid with a sodium-containing base. It would be expected that in order to prepare S(-)sodium 2-(4- isobutylphenyl)propionate in an enantiomerically pure form, for example greater than 90%, then the S(+)-2-(4- isobutylphenyl) ropionic acid employed would be required to be greater than 90%. While this procedure may be used, it is time-consuming and costly to prepare S(+)-2- (4-isobutylphenyl)propionic acid of greater than 90% enantiomeric purity.
- racemic ibuprofen is resolved using S(-)-1-phenylethylamine as described in the Journal of Pharmaceutical Sciences, 1976, page 26.
- the intermediate S(-)-1-phenylethylammonium S(+)-2-(4- isobutylphenyl)propionate salt requires several recrystallisations to raise the enantiomeric purity of the S(+) -ibuprofen produced, after hydrolysis of the salt, to above 90%.
- the amine employed is expensive and in theory the yield of S(+)-ibuprofen obtained cannot exceed 50%.
- the unwanted R(-) -ibuprofen may be racemised and the resolution procedure repeated to produce more S(+)-ibuprofen but overall the whole process is costly in terms of manpower, materials and plant equipment.
- the present invention provides a process for preparing a sodium salt of a desired enantiomer of 2- (4-isobutylphenyl)propionic acid said sodium salt having an enantiomeric purity of greater than 90% that is 90-100% comprising the steps of: a) neutralising 2- (4-isobutylphenyl)propionic acid containing 50% or more of the desired enantiomer with a sodium-containing base in the presence of a solvent system; b) crystallising to produce the solid sodium salt of the desired enantiomer; and c) separating said solid from the solvent system; and either d) recrystallising said solid or e) converting said solid into 2- (4-isobutylphenyl) propionic acid and repeating steps a, b and c.
- the 2- (4-isobutylphenyl)propionic acid used contains 70% or more of the desired enantiomer, preferably 80% or more of the desired enantiomer and more preferably 85% or more of the desired enantiomer.
- the present invention provides a process for preparing S(-) sodium 2-
- (4-isobutylphenyl)propionate having an enantiomeric purity of greater than 90% comprising the steps of: a) neutralising 2- (4-isobutylphenyl)propionic acid containing 85% or more of the S (+) -enantiomer with a sodium-containing base in the presence of a solvent system; b) crystallising to produce solid S(-)sodium 2-(4- isobutylphenyl)propionate and c) separating said solid from the solvent system.
- the S(-)sodium 2-(4-isobutylphenyl- propionate may be recrystallised.
- the S(-)sodium 2-(4-isobutylphenyl)propionate may be acidified to produce S(+) -2-(4-isobutylphenyl)propionic acid of higher enantiomeric purity than the acid used as starting material.
- the process provides S(-)sodium 2-(4- isobutylphenyl)propionate having an enantiomeric purity of greater than 95%. More preferably the process provides S(-)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric purity of greater than 98%. Most preferably the process provides S(-)sodium 2-(4- isobutylphenyl)propionate having an enantiomeric purity of greater than 99%. In an especially preferred process the enantiomeric purity is greater than 99.5% e.g. greater than 99.9%.
- the present invention provides a process for preparing S(-)sodium 2- (4-isobutylphenyl)propionate having an enantiomeric of greater than 99% comprising the steps of: a) neutralising 2-(4-isobutylphenyl)propionic acid containing 95% or more of the S(+) -enantiomer with a sodium-containing base in the presence of a solvent system; b) crystallising to produce solid S(-)sodium 2-(4- isobutylphenyl)propionate and c) separating said solid from the solvent system.
- 2-(4-Isobutylphenyl) ropionic acid containing 50% of a desired enantiomer i.e. racemic ibuprofen may be prepared by methods known to those skilled in the art.
- 2-(4-Isobutylphenyl)propionic acid containing more than 50% of a desired enantiomer for example 70%, 80%, 85%, 90%, 95% and 98% may be prepared by the partial resolution of racemic ibuprofen via salt formation with an optionally active amine for example S(-)-1-phenyl- ethylamine followed by separation and hydrolysis as is well known in the art.
- starting material for use in the process containing more than 50% of a desired enantiomer 2-(4-isobutylphenyl)propionic acid may be prepared by asymmetric synthesis using chemical techniques for example asymmetric hydrogenation, or biochemical techniques, for example stereoselective enzymatic ester hydrolysis.
- neutralisation means that substantially a molar equivalent of base is used within acceptable experimental error of around 10%. It will be appreciated by a person skilled in the art that the sodium salt of 2-(4-isobutylphenyl)propionic acid will give a pH value of greater than 7 in aqueous solution. In practice we have found that best results are achieved by neutralisation in the range 90-98% for example 96% of the calculated amount of 2-(4-isobutylphenyl)propionic acid and then measuring the pH of the solution to confirm that it is into the range of pH 8-9.9 prior to crystallisation. If necessary the pH may be adjusted to the required value by the addition of more acid or base. It will be appreciated that if the solution is heated at a pH greater than 10 for any length of time that there is a possibility of racemisation occurring.
- the formation of the sodium salt of S(+)-2-(4-iso ⁇ butylphenyl)propionic acid may be carried out in numerous ways.
- the acid is reacted with an equivalent of a sodium-containing base in a solvent system.
- Suitable sodium-containing bases are sodium hydroxide, sodium carbonate, sodium bicarbonate, a sodium alkoxide, for example sodium methoxide or sodium ethoxide, sodium hydride or sodamide.
- the sodium-containing base is sodium hydroxide or a sodium alkoxide.
- the sodium-containing base is sodium hydroxide.
- the solvent system employed depends on the sodium- containing base used and may be a single solvent or a mixture of solvents.
- the solvent system may contain water when a hydrolytically-stable, sodium-containing base is used, for example sodium hydroxide, or the solvent system may be substantially anhydrous when a hydrolytically-uns able, sodium-containing base, for example a sodium alkoxide or sodium hydride, is used.
- the purpose of the solvent system is to allow contact between the acid and sodium-containing base to permit formation of the sodium salt of the acid and to provide a medium from which this salt will crystallise or precipitate. Any solvent system in which these purposes are achieved may be used.
- the solvent system contains water.
- the solvent system employed contains water in at least twice the stoichiometric amount of the 2-(4- isobutylphenyl)propionic acid used as the starting material then the S(-)sodium 2-(4-isobutyl- phenyl)propionate initially obtained is in the dihydrate form which may be dried by heating, optionally under vacuum to produce the anhydrous form.
- the solvent system employed is anhydrous the initially formed S(-)sodium 2-(4-isobutylphenyl)propionate is anhydrous.
- Suitable solvent systems for hydrolytically-stable, sodium-containing bases are water or mixtures of water and at least one water-miscible organic solvent for example acetone or a C- j __ alcohol for example methanol, ethanol, propan-1-ol, propan-2-ol or butan-1-ol. Also suitable are mixtures of water and a partially water- miscible organic solvent for example methyl ethyl ketone.
- the solvent system comprises a mixture of water and acetone.
- the solvent system may comprise a mixture of water and a water-immiscible organic solvent in a two phase solvent system wherein the 2-(4- isobutylphenyl)propionic acid is dissolved in the organic phase and the base is dissolved in the aqueous phase.
- the mixture may be agitated for example by stirring or shaking to form the sodium salt of the acid in the aqueous layer.
- the sodium salt may be recovered from the aqueous layer, optionally after separating the two layers, by crystallisation optionally after the addition of a water miscible organic solvent, for example acetone.
- Suitable water-immiscible solvents are for example aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers or esters.
- the water immiscible solvent is toluene.
- a suitable solvent system comprises a substantially anhydrous inert organic solvent, for example toluene or methanol, which is compatible with the base employed.
- the formation of the sodium salt is carried out at a temperature in the range of 0 - 150°C, although lower temperatures may be used, preferably in the range 5 - 120°C and most preferably in the range 10 - 80°C.
- the formation of the sodium salt is carried out in the range from ambient temperature to 50°C at atmospheric pressure.
- the crystallisation of the sodium salt is carried out at a temperature in the range between the boiling point of the solvent system employed and the freezing point of the solvent system.
- the crystallisation may be carried out at a temperature in the range from -50°C to +50°C, preferably in the range -20°C to ambient temperature and most preferably from -10°C to +10°C at atmospheric pressure. It will be appreciated by those skilled in the art that the crystal size of the product obtained, may be varied by adjusting the crystallisation temperature, and by varying the rate of cooling.
- S(+)2-(4-isobutylphenyl)propionic acid is converted into the sodium salt by reaction with sodium hydroxide in the presence of a solvent system comprising a mixture of water and acetone.
- a solvent system comprising a mixture of water and acetone.
- the process is carried out in the range 0-80°C, preferably between 40°C and 60°C.
- the volume ratio of acetone to water is in the range from 50:1 to 1:10 preferably the ratio is in the range 20:1 to 1:1 and most preferably in the range 15:1 to 2:1.
- the sodium salt may be crystallised from the solvent system by methods for encouraging crystallisation known to those skilled in the art.
- the solvent system may be cooled, concentrated, seeded with the desired material or diluted with a solvent in which the sodium salt is less soluble or any combination of these methods may be employed.
- the solvent system is selected so that the sodium salt crystallises immediately after it is formed or on cooling of the solvent system.
- the crystallised sodium salt may be separated from the solvent system by methods known to those skilled in the art for example by filtration or centrifugation.
- the present invention provides a process for preparing a sodium salt of a desired enantiomer of 2- (4-isobutylphenyl)propionic acid said sodium salt having an enantiomeric purity of greater than 90% comprising the steps of: a) dissolving sodium 2 - (4-isobutylphenyl)propionate containing 50% or more of the desired enantiomer in a solvent to form a saturated solution; b) seeding said solution with the desired enantiomer of sodium 2- (4-isobutylphenyl)propionate; c) cooling said solution in a controlled manner to cause crystallisation of the solid sodium salt; d) separating said solid sodium salt from the solvent; e) repeating steps a to d until the desired level of enantiomeric purity is achieved.
- the crystallisation mother liquors which contain a higher proportion of the undesired enantiomer may be racemised by known methods, for example heating in the presence of a base e.g. sodium hydroxide, and the racemic salt obtained optionally by crystallisation or by evaporation, recycled by carrying out steps a) to e) above.
- a base e.g. sodium hydroxide
- racemic sodium 2- (4-isobutylphenyl) - propionate is used in the process. It may be prepared by hydrolysis of an ester of 2- (4-isobutylphenyl) - propionic acid or by hydrolysis of 2- (4-isobutylphenyl) - propionitrile or by hydrolysis of a 2- (4-isobutylphenyl) propionamide derivative or by other methods known to those skilled in the art.
- any solvent or mixture of solvents in which sodium 2- (4-isobutylphenyl)propionate is soluble and from which the salt may be recovered by ' crystallisation, may be employed.
- a mixture of water and a partially water miscible organic solvent for example methyl ethyl ketone may be used.
- the solvent is a mixture of water and at least one water-miscible solvent selected from acetone or a C ⁇ _ alcohol for example methanol, ethanol, propan-1-ol, propan-2-ol or butan-1-ol.
- the solvent comprises a mixture of water and acetone.
- the S(-)sodium 2-(4-isobutylphenyl)propionate obtained by any of the above processes may be acidified to produce S(+)-ibuprofen having an increased enantiomeric purity compared to that of the 2-(4-isobutylphenyl)-propionic acid used initially.
- This process is commercially extremely useful since S(+) -ibuprofen may be prepared by resolution of the racemic acid as described earlier or by asymmetric synthesis using chemical techniques, for example asymmetric hydrogenation, or biochemical techniques, for example stereoselective enzymatic ester hydrolysis.
- the final purification step is often a problem if the enantiomeric purity of the material obtained is not of the required standard.
- an expensive resolution would have been required to upgrade the enantiomeric purity to an acceptable level,for example to greater than 99% purity.
- the process herein described provides a cheap and efficient method of increasing the enantiomeric purity of S(+)-ibuprofen to produce S(+)-ibuprofen of 99% or greater enantiomeric purity.
- R(-)-ibuprofen may be increased by conversion into R(+)sodium 2-(4-isobutylphenyl)- propionate using the same process.
- the present invention provides S(-)sodium 2-(4-isobutylphenyl)propionate dihydrate having an enantiomeric purity of at least 90%.
- the enantiomeric purity of the S(-)sodium 2- (4-isobutyl-phenyl)propionate dihydrate is greater than 95% (that is 95-100%) , more preferably the enantiomeric purity is greater than 98% and most preferably the enantiomeric purity of the S(-)sodium 2- (4- isobutylphenyl)propionate dihydrate is greater than 99%.
- the enantiomeric purity of the S(-)sodium 2- (4-isobutylphenyl)propionate dihydrate is greater than 99.5% e.g. greater than 99.9%.
- a particularly preferred embodiment of the present invention comprises solid S(-)sodium 2-(4-isobutylphenyl)propionate dihydrate in which two molecules of water are present for each molecule of S(-)sodium 2-(4-isobutylphenyl)propionate.
- the present invention provides S(-)sodium 2-(4-isobutylphenyl)propionate for use in the treatment of inflammation, pain and pyrexia.
- the sample of R(-)-2-(4-isobutylphenyl)propionic acid used as a starting material was prepared by resolving racemic ibuprofen using R(+) -1-phenylethyl- amine in a similar manner to that described in J. Chromato ⁇ raphv 99, (1974), p.541-551.
- the enantiomeric purity of samples of S(-)sodium 2-(4-isobutylphenyl)propionate was determined as follows.
- the S(-)sodium 2-(4-isobutylphenyl)propionate was acidified with 5 M hydrochloric acid and the mixture extracted with ether.
- the combined ether extracts were washed with water, dried and evaporated to give S(+)2- (4-isobutylphenyl)propionic acid.
- the acetone mother liquors (1570 kg) were treated with hydrochloric acid (5 1, SG 1.17) and water (300 1) and heated to 70°C where acetone (1393 kg) was recovered by distillation.
- Water (300 1) was added to the residue and a water/acetone azeotrope (107 kg) was removed by distillation at 100°C.
- the aqueous residues were cooled to 57°C and then hydrochloric acid (5 1, SG 1.17) and toluene (150 1) were added.
- the aqueous phase was removed by separation and the toluene phase was washed with water (300 1) at 60°C.
- Hydrochloric acid (76 1, SG 1.18) was added over 15 minutes to a mixture of S(-) sodium 2- (4-isobutyl ⁇ phenyl)propionate (203 kg, enantiomeric purity 99.4%), water (450 ml) and heptane (159 1) .
- the aqueous phase was removed by separation and the heptane solution was washed with de-ionised water (2 x 200 1) at 30°C.
- the heptane solution was filtered and added to chilled heptane (159 1) over approximately 1.75 h.
- Tablets are prepared from the following ingredients:
- the drug is granulated with an aqueous solution of methocel.
- the dried granules are blended with the lactose, croscarmellose sodium, hydroxypropyl cellulose and magnesium stearate.
- the blend is compressed and then coated using an aqueous solution of the film- coating ingredients.
- Example 13 (Tablet) m tablet % w w
- the drug, tricalcium phosphate and macrocrystalline cellulose are granulated with a solution of polyvinylpyrrolidone in alcohol.
- the granules are dried and blended with croscarmellose sodium and magnesium
- the drug and a portion of the maize starch are granulated with a portion of the maize starch as a gel.
- the mixture is dried and blended with the remaining maize starch and is compressed.
- the cores are sugar- coated by serial application of varnish, build-up, smoothing and colouring syrups.
- the tablets are polished with carnauba wax.
- GELUCIRE 44/14 ' 340 68.0 GELUCIRE 44/14 ' 340 68.0 (GELUCIRE is the trademark of Gattefosse)
- Example 16 (Suppository; mq/suppository % w/w
- the drug is dispersed in a mixture of the molten carriers.
- the mixture is poured into cavities to give a suppository of 2.1g.
- Example 18 (Effervescent granule)
- Example 19 (Cold relief tablet) mq/tablet % w/w
- the sodium salt of S(+)-ibuprofen, tricalcium phos ⁇ phate, microcrystalline cellulose and croscarmellose sodium are granulated with a solution of polyvinyl ⁇ pyrrolidone in alcohol.
- the dried granules are blended with the pseudoephedrine hydrochloride and magnesium stearate. The blend is compressed and the cores film- coated using an aqueous solution of the film-former.
- Carbopol 980 NF (1) 2.0 polyethylene glycol 300 10.0
- CARBOPOL is the registered trademark of B.F. Goodrich.
- the polyethylene glycol was mixed with about 25% of the required purified water and the Carbopol® dispersed in this mixture. About 56% of the required purified water was added with rapid stirring until the CARBOPOL® was well dispersed and appeared hydrated.
- the sodium hydroxide was dissolved in a minimum of purified water and added to the bulk with stirring.
- the S(+)-ibuprofen sodium salt dihydrate was dissolved in a mixture of phenoxyethanol, propylene glycol and remaining purified water and added to the Carbopol® gel with rapid stirring.
- Polyethylene glycol, phenoxyethanol and propylene glycol are added to a portion of water and mixed.
- the drug is added and then the carboxamer is dispersed.
- the carboxamer is gelled by addition of triethanolamine in the remaining water.
- Example 22 (Sustained Release Tablet) .
- the sodium salt and a portion of the xanthan gum are granulated with a solution of the polyvinylpyrrolidone in isopropanol.
- the other ingredients and the remainder of the xanthan gum are blended into the mixture which is then compressed into tablets.
- the tablets may optionally be film-coated.
- LYCASIN® 80/55 (1) 40.0 glycerin 20.0 domiphen bromide 0.005 alcohol 96% 2.0 purified water to 100
- LYCASIN is the registered trademark of Roquette.
- the LYCASIN® and glycerin were mixed together.
- the domiphen bromide was dissolved in the alcohol.
- the sodium salt was added to this alcoholic solution along with sufficient purified water to produce a solution.
- the aqueous alcoholic solution was added to the LYCASIN®/glycerin mixture and mixed well.
- Optional flavourings may be added to the above formulation.
- the xylitol is dissolved in half of the water, the xanthan gum is dispersed and allowed to hydrate, then the glycerin, the sodium salt of S-(+) -ibuprofen, the domiphen bromide and the saccharin sodium are added.
- the menthol and flavour are dissolved in alcohol and added to bulk. Water is added to make up the volume.
- LYCASIN® 80/55 (1) 40.0 glycerin 20.0 domiphen bromide 0.005 alcohol 96% 2.0 purified water to 100
- LYCASIN is the registered trademark of Roquette.
- the LYCASIN® and glycerin were mixed together and diluted with a suitable volume of water.
- the sodium salt was dispersed and dissolved in the mixture.
- the domiphen bromide was dissolved in the alcohol and this solution added slowly with stirring to the bulk.
- the formulation was made up to volume and mixed well.
- Optional flavourings may be added to the formulation.
- LYCASIN® 40 glycerin 20 domiphen bromide 0.005 flavour 0.2 alcohol 96% 2.0 purified water to 100
- the powders were sieved through a 30 mesh sieve and blended together, then filled into sachets containing 2000mg of powder.
- Optional flavourings may be added to the above mixture.
- hot water 70°C or greater
- a clear solution is produced which can be drunk by the patient.
- base S-(+)-ibuprofen produced an unpalatable oily layer on the surface of the hot water.
- the ingredients are dry blended together and packed into sachets.
- S(-)sodium 2 (4-isobutylphenyl) - propionate dihydrate may be replaced by the anhydrous form or other hydrated forms.
- the pressure at which the tablets were compressed is indicated in the table below.
- the hardness of the resultant tablets was measured.
- the disintegration time was measured by the method of the British Pharmacopoeia 1980 and the dissolution time was measured using Apparatus 2 described in US Pharmacopeia XXII, section 711, pl578, with 900ml of a phosphate buffer of the pH's indicated and a paddle speed of 50 revolutions per minute.
- Tablet A gave harder tablets than comparative Tablet A when compressed at the same pressure, and that Tablet A had a longer disintegration time and comparable dissolution at pH 7.2 but superior dissolution at pH 6.0.
- the povidone was dissolved in a mixture of isopropanol and water (1:1 parts by volume).
- the S(-) sodium 2-(4-isobutylphenyl)propionate dihydrate was blended with the tricalcium phosphate, microcrystalline cellulose and croscarmellose sodium and then granulated with the solution of povidone.
- the granules were dried, sized, blended with the stearic acid and then compressed into tablets (Tablet B) .
- the dissolution time of the resultant tablets was measured at pH 6 using the method described in Example 30.
- T ⁇ time taken for 50% of active ingredient to be released
- Tgg time taken for 80% of active ingredient to be released
- Tablet B shows a superior dissolution performance compared with comparative Example B.
Abstract
Description
Claims
Priority Applications (23)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU9303220A HU219242B (en) | 1991-05-13 | 1992-05-04 | S(+)-ibuprofen sodium salt dihydrate, pharmaceutical composition comprising this compound and process for production of them |
CA002102530A CA2102530C (en) | 1991-05-13 | 1992-05-04 | Therapeutic agent |
CS932405A CZ281717B6 (en) | 1991-05-13 | 1992-05-04 | S(-)-sodium-2-(4-isobutylphenyl)propionate-dihydrate of high enantiomeric purity, process of its preparation and pharmaceutical compositions containing thereof |
DK92909270T DK0584108T3 (en) | 1991-05-13 | 1992-05-04 | A pharmaceutical composition comprising ibuprofen salt |
DE69231359T DE69231359T2 (en) | 1991-05-13 | 1992-05-04 | PHARMACEUTICAL COMPOSITION CONTAINING IBUPROFEN SALT |
RU93058389/14A RU2145219C1 (en) | 1991-05-13 | 1992-05-04 | Pharmaceutical composition containing (s)-(-)-2-(4-isobutyl- -phenyl)-propionate sodium, method of synthesis of 2-(4- -isobutylphenyl)-propionic acid sodium salt enantiomer, (s)-(-)-2-(4-isobutylphenyl)-propionate sodium dihydrate |
EP92909270A EP0584108B1 (en) | 1991-05-13 | 1992-05-04 | Pharmaceutical composition comprising ibuprofen salt |
GEAP19921627A GEP20002013B (en) | 1991-05-13 | 1992-05-04 | Therapeutical Means |
US08/137,092 US6525214B1 (en) | 1991-05-13 | 1992-05-04 | Therapeutic agent |
AT92909270T ATE195417T1 (en) | 1991-05-13 | 1992-05-04 | PHARMACEUTICAL COMPOSITION CONTAINING IBUPROFEN SALT |
UA93004002A UA34430C2 (en) | 1991-05-13 | 1992-05-04 | S(-)sodium2-(4-isobutyl-phenyl)propionate dihydrate useful for treatment of inflammation, ache and hyperthermia, a pharmaceutical composition based thereon and a process for preparation of s(-)sodium2-(4-isobutyl- phenyl)propionate |
SK1259-93A SK279279B6 (en) | 1991-05-13 | 1992-05-04 | S(-)-sodium-2-(4-isobutylphenyl)propionate-dihydrate of high enantiomeric purity, method of its preparation and pharmaceutical agents containing thereof |
JP50855292A JP3326174B2 (en) | 1991-05-13 | 1992-05-04 | Remedies |
PL92301289A PL170135B1 (en) | 1991-06-05 | 1992-05-04 | Method of obtaining a sodium salt of 2-(4-isobutylophenyl)propionic acid enantiomer |
AU16711/92A AU658415B2 (en) | 1991-05-13 | 1992-05-04 | Pharmaceutical composition comprising ibuprofen salt |
KR1019930703409A KR100198044B1 (en) | 1991-05-13 | 1992-05-04 | Pharmaceutical composition comprising ibuprofen salt |
RO93-01512A RO118371B1 (en) | 1991-05-13 | 1992-05-04 | Pharmaceutical composition containing a sodium salt of s(-)ibuprofen |
FI934964A FI109994B (en) | 1991-05-13 | 1993-11-10 | Process for the preparation of S (-) sodium 2- (4-isobutylphenyl) propionate |
BG98214A BG61676B1 (en) | 1991-05-13 | 1993-11-11 | Pharmaceutical composition, containing salt of ibuprophene |
NO933740A NO304678B1 (en) | 1991-05-13 | 1993-11-12 | S (-) Sodium 2- (4-isobutylphenyl) propionate of high purity and therapeutic preparations containing this |
US08557565 US5696165B1 (en) | 1991-05-13 | 1995-11-14 | Composition of s(-) sodium ibuprofen |
NO982500A NO305696B1 (en) | 1991-05-13 | 1998-06-02 | Process for the preparation of S (-) sodium 2- (4-isobutylphenyl) propionate with high enantiomeric purity |
GR20000402469T GR3034780T3 (en) | 1991-05-13 | 2000-11-08 | Pharmaceutical composition comprising ibuprofen salt. |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB919110342A GB9110342D0 (en) | 1991-05-13 | 1991-05-13 | Therapeutic agent |
GB9110342.4 | 1991-05-13 | ||
GB9112058.4 | 1991-06-05 | ||
GB919112058A GB9112058D0 (en) | 1991-06-05 | 1991-06-05 | Therapeutic agent |
Publications (1)
Publication Number | Publication Date |
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WO1992020334A1 true WO1992020334A1 (en) | 1992-11-26 |
Family
ID=26298899
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1992/001025 WO1992020334A1 (en) | 1991-05-13 | 1992-05-04 | Pharmaceutical composition comprising ibuprofen salt |
Country Status (32)
Country | Link |
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US (3) | US6525214B1 (en) |
EP (1) | EP0584108B1 (en) |
JP (1) | JP3326174B2 (en) |
KR (1) | KR100198044B1 (en) |
CN (1) | CN1068305C (en) |
AT (1) | ATE195417T1 (en) |
AU (1) | AU658415B2 (en) |
BG (1) | BG61676B1 (en) |
CA (1) | CA2102530C (en) |
CZ (1) | CZ281717B6 (en) |
DE (1) | DE69231359T2 (en) |
DK (1) | DK0584108T3 (en) |
EG (1) | EG20309A (en) |
ES (1) | ES2148175T3 (en) |
FI (1) | FI109994B (en) |
GE (1) | GEP20002013B (en) |
GR (1) | GR3034780T3 (en) |
HU (1) | HU219242B (en) |
IE (1) | IE921393A1 (en) |
IL (1) | IL101818A (en) |
MX (1) | MX9202215A (en) |
MY (1) | MY110267A (en) |
NO (2) | NO304678B1 (en) |
NZ (1) | NZ242640A (en) |
PT (1) | PT100476B (en) |
RO (1) | RO118371B1 (en) |
RU (1) | RU2145219C1 (en) |
SK (1) | SK279279B6 (en) |
TW (1) | TW304940B (en) |
UA (1) | UA34430C2 (en) |
WO (1) | WO1992020334A1 (en) |
YU (1) | YU48928B (en) |
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WO2011005478A3 (en) * | 2009-06-22 | 2011-11-17 | Wyeth Llc | Sodium ibuprofen tablets and methods of manufacturing pharmaceutical compositions including sodium ibuprofen |
AU2010270976B2 (en) * | 2009-06-22 | 2014-03-20 | Pf Consumer Healthcare 1 Llc | Sodium ibuprofen tablets and methods of manufacturing pharmaceutical compositions including sodium ibuprofen |
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