WO2008108639A1 - Formes co-cristallines de carbamazépine - Google Patents

Formes co-cristallines de carbamazépine Download PDF

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Publication number
WO2008108639A1
WO2008108639A1 PCT/NL2008/000076 NL2008000076W WO2008108639A1 WO 2008108639 A1 WO2008108639 A1 WO 2008108639A1 NL 2008000076 W NL2008000076 W NL 2008000076W WO 2008108639 A1 WO2008108639 A1 WO 2008108639A1
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WIPO (PCT)
Prior art keywords
crystal
carbamazepine
glycolamide
lactamide
api
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PCT/NL2008/000076
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English (en)
Inventor
Erik-Jan Ras
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Avantium Holding B.V.
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Application filed by Avantium Holding B.V. filed Critical Avantium Holding B.V.
Publication of WO2008108639A1 publication Critical patent/WO2008108639A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
    • C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
    • C07D223/26—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a double bond between positions 10 and 11
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • the present invention relates to novel crystalline forms of carbamazepine, in particular a co-crystal of carbamazepine with glycolamide, methods for the preparation and the formulation and application in the field of medicine, in particular medicines used for psychiatric disorders.
  • Carbamazepine or 5-carbamoyl-5H-dibenz (b, f)azepine (or 5H- dibenz(b, f) azepine-5-carboxamide or N-carbamoyliminostilbene), is an iminostilbene derivative.
  • Carbamazepine has anticonvulsant properties, which have been found useful in the treatment of psychomotor epilepsy and as an adjunct in the treatment of partial epilepsies, when administered in conjunction with other anticonvulsant drugs to prevent the possible generalisation of the epileptic discharge.
  • a mild psychotropic effect has been observed in some patients, which seems related to the effect of the carbamazepine in psychomotor or temporal lobe epilepsy.
  • carbamazepine is used in various psychiatric disorders such as bipolar disorder, depression, cocaine addiction, alcohol addiction, opiate addiction, nicotine addiction, other obsessive compulsive disorders, cardiovascular disease and neurological disorders such as chronic pain states and headaches .
  • Carbamazepine relieves or diminishes the pain associated with trigeminal neuralgia often within 24 to 48 hours.
  • Carbamazepine given as a monotherapy or in combination with lithium or neuroleptics has been found useful in the treatment of acute mania and the prophylactic treatment of bipolar (manic- depressive) disorders.
  • Carbamazepine is a poorly water-soluble drug (0.11 gr/L at 25 degrees Celsius, i.e. HO ppm) .
  • Pharmacokinetic studies have shown it to be slowly and erratically absorbed from the gastro-intestinal tract when administered in tablet form.
  • Carbamazepine is used for systemic applications, which have many disadvantages such as ' the need for high dosages (The regular dosage for an adult is 800-1200 mg per day, but in different cases it comes up to 1600 mg) , toxicity to the organs like liver and others, side effects at unaffected tissues and long-lasting results. Carbamazepine may cause adverse haematological effects, neuropathy and hypersensitivity syndrome including dermatitis. The enhancement of its solubility leading to higher bioavailability may be crucial in decreasing the dosage and the side effects.
  • Currently research is directed towards the provision of forms that overcome disadvantages of carbamazepine, such a its variable dissolution rate (currently strongly depending on pH fluctuations in the stomach etc.) .
  • APIs Active pharmaceutical ingredients in pharmaceutical compositions can be prepared in a variety of different forms.
  • Such APIs can be prepared so as to have a variety of different chemical forms including chemical derivatives or salts.
  • Such APIs can also be prepared to have different physical forms.
  • the APIs may be amorphous, may have different crystalline polymorphs, or may exist in different solvation or hydration states.
  • crystalline polymorphs typically have different solubility's from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph.
  • compositions can also differ in properties such as shelf-life, bioavailability, morphology, vapour pressure, density, colour, and compressibility. Accordingly, variation of the crystalline state of an API is one of many ways in which to modulate the physical properties thereof .
  • a co-crystal form of an API is particularly advantageous where the original API is insoluble or sparingly soluble in water.
  • co-crystal properties conferred upon the API are also useful because the bioavailability of the API can be improved and the plasma concentration and/or serum concentration of the API can be improved. This is particularly advantageous for orally- administrable formulations.
  • the dose response of the API can be improved, for example by increasing the maximum attainable response and/or increasing the potency of the API by increasing the biological activity per dosing equivalent.
  • Typical notation for a co- crystal of an API and a co-crystal former is API : co-crystal former, the : depicting the existence of a co-crystal structure, as opposed to the generally used period (.) for salts and solvates.
  • APIs that have improved properties formulations. Specifically, it is desirable to identify improved forms of APIs that exhibit significantly improved properties including increased aqueous solubility and stability. Further, it is desirable to improve the processability, or preparation of pharmaceutical formulations. For example, needle-like crystal forms or habits of APIs can cause aggregation, even in compositions where the API is mixed with other substances, such that a non- uniform mixture is obtained. It is also desirable to increase or decrease the dissolution rate of API-containing pharmaceutical compositions in water, increase or decrease the bioavailability of orally-administered compositions, and provide a more rapid or more delayed onset to therapeutic effect.
  • the improved properties discussed above can be altered in a way which is most beneficial to a specific API for a specific therapeutic effect. See for the effect of various crystal forms of carbamazepine on formulation behaviour and stability for instance Otsuka et al . in Chem. Pharm. Bull. 47(6), 852-856, 1999.
  • a co-crystal is commonly defined as a crystalline material comprised of two or more unique solids at room temperature, i.e. 20- 25 degrees Celsius, each containing distinctive physical characteristics, such as structure, melting point and heats of fusion with the exception that, if specifically stated, the API may be a liquid at room temperature.
  • the co-crystals of the present invention comprise a co-crystal former that is preferably H-bonded to an API, but other interactions such as pi-stacking, guest-host complexation, Van Der Waals interactions etc. also may play a role in the formation of co-crystals.
  • the co- crystal former may be bonded directly to the API or may be bonded to an additional molecule which is bound to the API.
  • the additional molecule may be bonded to the API or bound ionically or covalently to the API.
  • the additional molecule could also be a different API .
  • Solvates of API compounds that do not further comprise a co-crystal former are not co-crystals according to the present invention.
  • the co-crystals may however, include one or more solvate molecules in the crystalline lattice. That is, solvates of co-crystals, or a co-crystal further comprising a solvent or compound that is a liquid at room temperature, is included in the present invention.
  • the co-crystals may also be a co-crystal between a co-crystal former and a salt of an API, but the API and the co- crystal former of the present invention are constructed or bonded together, preferably through hydrogen bonds.
  • Other modes of molecular recognition may also be present including, pi-stacking, guest-host complexation and Van Der Waals interactions.
  • hydrogen-bonding is the dominant interaction in the formation of the co-crystal, (and a preferred interaction according to the present invention) whereby a non-covalent bond is formed between a hydrogen bond donor of one of the moieties and a hydrogen bond acceptor of the other.
  • Hydrogen bonding can result in several different intermolecular configurations. For example, hydrogen bonds can result in the formation of dimers, linear chains, or cyclic structures.
  • An alternative embodiment provides for a co-crystal wherein the co- crystal former is a second API. In another embodiment, the co-crystal former is not an API. In another embodiment the co-crystal comprises two co-crystal formers.
  • the chemical and physical properties of an API in the form of a co- crystal may be compared to a reference compound that is the same API in a different form.
  • the reference compound may be specified as a free form, or more specifically, a free acid, free base, or zwitterion,- a salt, or more specifically for example, an inorganic base addition salt such as sodium, potassium, lithium, calcium, magnesium, ammonium, aluminium salts or organic base addition salts, or an inorganic acid addition salts such as HBr, HCl, sulfuric, nitric, or phosphoric acid addition salts or an organic acid addition salt such as acetic, propionic, pyruvic, maleic, succinic, malic, malonic, fumaric, tartaric, citric, benzoic, methanesulfonic, ethanesulfonic, stearic or lactic acid addition salt ; an anhydrate or hydrate of a free form or salt, or more specifically, for example, morpholine, and N-ethylpiperidine) .
  • an inorganic base addition salt such as sodium, potassium, lithium, calcium, magnesium, ammonium, aluminiu
  • the ratio of API to co-crystal former may be stoichiometric or non-stoichiometric according to the present invention. For example, 1:1, 1.5 : 1,1 : 1.5, 2: 1 and 1: 2 ratios of API : co-crystal former are acceptable .
  • the co-crystals were prepared by (wet) grinding.
  • a carbamazepine :aspirine co-crystal has been described by Zaworotko and co-workers in J. Amer. Chem.. Soc, 127, 16802-16803, 2005.
  • the present invention now provides for a novel crystalline form of carbamazepine.
  • the form according to the invention has a higher dissolution rate, which results in increased bioavailability, lower dosage and significant improvement of pharmacokinetic profiles and hence provides a solution to the problems with carbamazepine outlined above.
  • Figure IA illustrates the X-Ray Powder Diffraction patterns of glycolamide, carbamazepine and the co-crystal of carbamazepine :glycolamide as obtained from ethylacetate and form acetonitrile.
  • Figure IB illustrates the DSC pattern of glycolamide, carbamazepine and the co-crystal.
  • Figure 2A illustrates the X-Ray Powder Diffraction patterns of lactamide, carbamazepine and the co-crystal of carbamazepine: lactamide as obtained from ethylacetate and form acetonitrile .
  • Figure 2B illustrates the DSC pattern of lactamide, carbamazepine and the co-crystal.
  • Figure 3 illustrates a comparison between the dissolution rate of carbamazepine and carbamazepine: glycolamide co-crystal
  • Figure 4 demonstrates the difference in solubility at 50% and 90% dissolution.
  • Figure 5 shows some results from determination of the thermodynamic solubility of the co-crystal in comparison with carbamazepine.
  • Rl and/or R2 can independently be selected from the group consisting of H, C1-C6 (cyclo) alkyl, C1-C6 (cyclo) alkenyl, C5-C6 aromates such as cyclopentadienyl and benzene.
  • the carbon atoms in Rl and/or R2 can be independently substituted, for instance with halogen, hydroxy, nitro, nitrile and or amine groups.
  • the present invention provides a carbamazepine:glycolamide co-crystal, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably four X-ray powder diffraction peaks selected from the group consisting of 6.3, 15,6; 16.3 and 26.8 degrees two-theta +/- 0.3 degrees two-theta.
  • the co-crystal is preferably a crystalline co-crystal.
  • the co-crystal of the present invention can be further characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four X-ray powder diffraction peaks selected from the group consisting of 8.8; 13.3; 18.2; 19.2; 20.0; 20.5; 22.0; 22.8; 23.8; 24.4; 29.0; and 29.5 degrees two-theta +/- 0.3 degrees two-theta.
  • at least five, preferably at least six and, in an increasingly preferred order, at least seven, eight, nine, ten or eleven peaks are selected from this group.
  • the co-crystal can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
  • the co-crystal can be characterised by an XRPD substantially according to Fig IA.
  • the co-crystal can be characterised by an DSC substantially according to Fig IB.
  • the co-crystal of the present invention can be characterised by DSC with a characterising peak at 147 0 C. From the comparison with known XRPD data for two dihydrates and a monohydrate in the CSD, analysis, it is concluded that the solid co- crystal of the invention is anhydrous.
  • the present invention in one aspect relates to a method for the preparation of the co-crystal of carbamazepine:glycolamide comprising the steps of dissolving equimolar amounts of carbamazepine and glycolamide in acetonitrile, warming the mixture and crystallising carbamazepine : glycolamide by cooling the mixture.
  • the present invention further relates to a method for the preparation of the co-crystal of carbamazepine: glycolamide comprising the steps of dissolving equimolar amounts of carbamazepine and glycolamide in ethylacetate, warming the mixture and crystallising carbamazepine : glycolamide by cooling the mixture.
  • Crystalline carbamazepine lactamide co-crystal:
  • the present invention provides a carbamazepine : lactamide co-crystal, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably four X-ray powder diffraction peaks selected from the group consisting of 7.9, 8.6, 15.8, 19.5, 21.0, 22.7, 24.3 and 26.8 degrees two-theta +/- 0.3 degrees two-theta.
  • the co-crystal is preferably a crystalline co-crystal.
  • the co-crystal can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
  • the co-crystal can be characterised by an XRPD substantially according to Fig 2A.
  • the co-crystal can be characterised by an DSC substantially according to Fig 2B.
  • the co-crystal of the present invention can be characterised by DSC with a characterising peak at 121 0 C.
  • the present invention in one aspect relates to a method for the preparation of the co-crystal of carbamazepine : lactamide comprising the steps of dissolving equimolar amounts of carbamazepine and lactamide in acetonitrile, warming the mixture and crystallising carbamazepine : lactamide by cooling the mixture.
  • the co-crystals of the present invention is in a substantially pure form, preferably substantially free from other amorphous, crystalline and/or polymorphic forms.
  • substantially pure relates to at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the pure compound.
  • substantially free from other amorphous, crystalline and/or polymorphic forms means that no more than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% of these other amorphous, crystalline and/or polymorphic forms are present in the form according to the invention.
  • the present invention further relates to pharmaceutical formulations comprising the novel (crystalline form) of the carbamazepine :glycolamide and/or the carbamazepine : lactamide co- crystal .
  • compositions of the present invention contain the crystalline form according to the present invention, such as the co-crystal as disclosed herein.
  • the invention also provides pharmaceutical compositions comprising the crystal form according to the present invention.
  • Pharmaceutical formulations of the present invention contains the crystal form according to the present invention as active ingredient, optionally in a mixture with other crystal form(s) .
  • the pharmaceutical formulations according to the invention may further comprise, in addition to the co-crystal former, additional pharmaceutical active ingredients.
  • the pharmaceutical formulations of the present invention may contain one or more excipients. Excipients are added to the formulation for a variety of purposes.
  • Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle.
  • Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel (R) ) , micro fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit (R) ) , potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
  • microcrystalline cellulose e.g. Avicel (R)
  • micro fine cellulose lactose
  • lactose starch
  • pregelatinized starch calcium carbonate, calcium sul
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. Carbopol) , carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel (R) ) , hydroxypropyl methyl cellulose (e.g.
  • Methocel (R) liquid glucose, magnesium aluminium silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon(R) , Plasdone (R) ) , pregelatinized starch, sodium alginate and starch.
  • povidone e.g. Kollidon(R) , Plasdone (R)
  • pregelatinized starch sodium alginate and starch.
  • the dissolution rate of ⁇ a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-SoI(R), Primellose (R) ) , colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon(R), Polyplasdone (R) ) , guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab(R)) and starch.
  • alginic acid include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-SoI(R), Primellose (R) ) , colloidal silicon dioxide, croscarmellose sodium
  • Glidants can be added to improve the flowability of a non- compacted solid composition and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
  • a dosage form such as a tablet
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
  • Flavouring agents and flavour enhancers make the dosage form more palatable to the patient.
  • Common flavouring agents and flavour enhancers for pharmaceutical products include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
  • Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level .
  • liquid pharmaceutical compositions of the present invention the crystalline forms according to the present invention and any other solid excipients are suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerine.
  • a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerine.
  • Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatine, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
  • Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth- feel of the product and/or coat the lining of the gastrointestinal tract.
  • Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatine guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
  • Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
  • a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient (s) in an amount of, for example, 0.01 to 10% w/w (including active ingredient (s) in a range between 0.1% and 5% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 3% w/w and most preferably 0.5 to 2% w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogues .
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent) , it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
  • the emulsifier (s) with or without stabiliser (s) make up the emulsifying wax, and the wax together with the oil and fat make up the emulsifying ointment base which forms the oily dispersed phase of the cream formulations .
  • Emulgents and emulsion stabilisers suitable for use in the formulation of the present invention include Tween8 60, Spans 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers .
  • Straight or branched chain, mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters . These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • a suitable carrier especially an aqueous solvent for the active ingredient.
  • the active ingredient is suitably present in such formulations in a concentration of 0.01 to 20%, in some embodiments 0.1 to 10%, and in others about 1.0% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis, such as gelatine and glycerine, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for nasal or inhalational administration wherein the carrier is a solid include a powder having a particle size for example in the range 1 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc) .
  • Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents. Inhalational therapy is readily administered by metered dose inhalers .
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate .
  • the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous) , inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral .
  • the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts. Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs.
  • the dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
  • the shell may be made from gelatine and optionally contain a plasticizer such as glycerine and sorbitol, and an opacifying agent or colorant.
  • compositions and dosage forms may be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tabletted/compressed, or other excipients may be added prior to tabletting, such as a glidant and/or a lubricant .
  • a tabletting composition may be prepared conventionally by dry blending.
  • the blended composition of the actives and excipients maybe compacted into a slug or a sheet and then comminuted into compacted granules .
  • the compacted granules may subsequently be compressed into a tablet.
  • a blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
  • Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
  • a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
  • the crystalline forms according to the present invention can be formulated for administration to a mammal, preferably a human, via injection.
  • the crystalline forms according to the present invention may be formulated, for example, as a viscous liquid solution or suspension, preferably a clear solution, for injection.
  • the formulation may contain solvents. Among considerations for such solvent include the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability) , fluidity, boiling point, miscibility and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP and Castor oil USP. Additional substances may be added to the formulation such as buffers, solubilizers, antioxidants, among others. Allen et al . , Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th Ed, 2004.
  • the present invention also provides pharmaceutical formulations comprising the crystalline form according to the present invention, optionally in combination with other polymorphic forms or co-crystals, to be used in a method of treatment of a mammal, preferably a human, in need thereof.
  • a pharmaceutical composition of the present invention comprises co-crystal of carbamazepine and glycolamide and/or of carbamazepine and lactamide.
  • the crystalline form according to the present invention may be used in a method of treatment of a mammal comprising administering to a mammal suffering from the ailments described herein before a therapeutically effective amount of such pharmaceutical composition.
  • the invention further relates to the use of the crystalline form of the invention for the preparation of a medicament for the treatment of the ailments described herein before, in particular HIV.
  • XRPD patterns were obtained using a T2 high-throughput XRPD set-up by Avantium technologies, The Netherlands. The plates were mounted on a
  • Bruker GADDS diffractometer equipped with a Hi-Star area detector.
  • the XRPD platform was calibrated using Silver Behenate for the long d-spacings and Corundum for the short d-spacings.
  • Data collection was carried out at room temperature using monochromatic CuK (alpha) radiation in the two-theta region between 1.5 ° and 41.5 °.
  • the diffraction pattern of each well is collected in two two-theta ranges (1.5 ° ⁇ 2 ⁇ ⁇ 21.5 ° for the first frame, and 19.5 ° ⁇ 2 ⁇ ⁇ 41.5 ° for the second) with an exposure time of 120 s for each frame.
  • XRPD data are collected with a variance of about 0.3 degrees two-theta, preferable about 0.2 degrees, more preferably 0.1 degrees, even more preferable 0.05 degrees. This has consequences for when X-ray peaks are considered overlapping.
  • TGA/SDTA851e Monitoring of the sample weight, during heating in a TGA/SDTA851e instrument (Mettler-Toledo GmbH, Switzerland), resulted in a weight vs. temperature curve.
  • the TGA/SDTA851e was calibrated for temperature with indium and aluminium. Samples were weighed into 100 microliter aluminium crucibles and sealed. The seals were pin-holed and the crucibles heated in the TGA from 25 0 C to 300 0 C at a heating rate of 20°C/min. Dry N 2 gas is used for purging. Melting point determinations based on DSC have a variability of +/- 2.0 degrees Celsius, preferably 1.0 degrees Celsius.
  • Prom acetonitrile A small quantity, about 60 mg of the starting material was placed in a HPLC vial. The solvent acetonitrile was added in small amounts to the vial containing the dry starting material at room temperature to a total volume of 1000 microliter and a concentration of about 60 mg/ml . The vial was shaken and the qualitative solubility was assessed visually. The solution was heated and maintained at 60 0 C for 16 hours minutes. Subsequently, the solution was cooled at a rate of 0.1 °C/ min. Crystalline material started to form at 32 °C. The resulting solid was analysed by X-ray powder diffraction, DSC and identified as a carbamazepine :glycolamide co-crystal.
  • a small quantity, about 60 mg of the starting material was placed in a HPLC vial .
  • the solvent ethylacetate was added in small amounts to the vial containing the dry starting material at room temperature to a total volume of 1000 microliter and a concentration of about 60 mg/ml.
  • the vial was shaken and the qualitative solubility was assessed visually.
  • the solution was heated and maintained at 60 °C for 16 hours minutes. Subsequently, the solution was cooled at a rate of 0.1 0 C/ min. Crystalline material started to form at 32 0 C.
  • the resulting solid form was analysed by X-ray powder diffraction, DSC and identified as carbamazepine :glycolamide co-crystal.
  • a small quantity, about 60 mg of the starting material was placed in a HPLC vial.
  • the solvent acetonitrile was added in small amounts to the vial containing the dry starting material at room temperature to a total volume of 1000 microliter and a concentration of about 60 mg/ml.
  • the vial was shaken and the qualitative solubility was assessed visually.
  • the solution was heated and maintained at 60 °C for 16 hours minutes. Subsequently, the solution was cooled at a rate of 0.1 0 C/ min. Crystalline material started to form at 32 0 C.
  • the resulting solid was analysed by X-ray powder diffraction, DSC and identified as a carbamazepine: lactamide co-crystal.
  • UV absorption at 284 nm was used to determine the amount of carbamazepine dissolved.
  • Figure 4 shows some graphical representations of the obtained dissolution data.
  • Buffers - water (undetermined pH)

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Abstract

La présente invention concerne une forme co-cristalline atypique d'un co-cristal de carbamazépine : glycolamide et d'un co-cristal de carbamazépine : lactamide. L'invention concerne en outre des procédés pour la préparation d'un co-cristal de carbamazépine : glycolamide et/ou de carbamazépine : lactamide, ainsi que leur utilisation dans des applications pharmaceutiques, en particulier dans des médicaments pour le traitement de l'épilepsie, du trouble bipolaire, de la schizophrénie et/ou de la névralgie faciale. La forme co-cristalline de carbamazépine : glycolamide et/ou de carbamazépine : lactamide peut être utilisée en combinaison avec d'autres médicaments.
PCT/NL2008/000076 2007-03-08 2008-03-07 Formes co-cristallines de carbamazépine WO2008108639A1 (fr)

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WO2013153059A1 (fr) 2012-04-11 2013-10-17 Politecnico Di Milano Co-cristaux de butylcarbamate de 3-iodopropynyle
WO2013170972A1 (fr) * 2012-05-18 2013-11-21 Grünenthal GmbH Composition pharmaceutique comprenant de la (1r,4r)-6'-fluoro-n,n-diméthyl-4-phényl-4',9'-dihydro-3'h-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine et un anticonvulsivant
US9320725B2 (en) 2012-05-18 2016-04-26 Gruenenthal Gmbh Pharmaceutical composition comprising (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine and a gabapentinoid
US10328055B2 (en) 2012-05-18 2019-06-25 Gruenenthal Gmbh Pharmaceutical composition comprising (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indo]-4-amine and antidepressants
CN113214209A (zh) * 2020-02-04 2021-08-06 中国医学科学院药物研究所 橙皮素与卡马西平共晶物及制备方法和其组合物与用途
CN114199852A (zh) * 2021-12-07 2022-03-18 天津大学 一种药物共晶性能的表征方法

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WO2013153059A1 (fr) 2012-04-11 2013-10-17 Politecnico Di Milano Co-cristaux de butylcarbamate de 3-iodopropynyle
AU2013262078B2 (en) * 2012-05-18 2017-10-26 Grünenthal GmbH Pharmaceutical composition comprising (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano [3,4,b]indol]-4-amine and an anticonvulsant
CN104284656A (zh) * 2012-05-18 2015-01-14 格吕伦塔尔有限公司 包含(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氢-3’H-螺[环己烷-1,1’-吡喃并[3,4,b]吲哚]-4-胺和抗惊厥剂的药物组合物
US9320725B2 (en) 2012-05-18 2016-04-26 Gruenenthal Gmbh Pharmaceutical composition comprising (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine and a gabapentinoid
US9345689B2 (en) 2012-05-18 2016-05-24 Gruenenthal Gmbh Pharmaceutical composition comprising (1r,4r)-6′-fluoro-N, N-dimethyl-4-phenyl-4,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine and an anticonvulsant
US9629825B2 (en) 2012-05-18 2017-04-25 Gruenenthal Gmbh Pharmaceutical composition comprising (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine and a gabapentinoid
WO2013170972A1 (fr) * 2012-05-18 2013-11-21 Grünenthal GmbH Composition pharmaceutique comprenant de la (1r,4r)-6'-fluoro-n,n-diméthyl-4-phényl-4',9'-dihydro-3'h-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine et un anticonvulsivant
EA029767B1 (ru) * 2012-05-18 2018-05-31 Грюненталь Гмбх ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, СОДЕРЖАЩАЯ (1r,4r)-6'-ФТОР-N,N-ДИМЕТИЛ-4-ФЕНИЛ-4',9'-ДИГИДРО -3'H-СПИРО[ЦИКЛОГЕКСАН-1,1'-ПИРАНО[3,4,b]ИНДОЛ]-4-АМИН И АНТИКОНВУЛЬСАНТ
US10328055B2 (en) 2012-05-18 2019-06-25 Gruenenthal Gmbh Pharmaceutical composition comprising (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indo]-4-amine and antidepressants
CN113214209A (zh) * 2020-02-04 2021-08-06 中国医学科学院药物研究所 橙皮素与卡马西平共晶物及制备方法和其组合物与用途
CN113214209B (zh) * 2020-02-04 2024-03-26 中国医学科学院药物研究所 橙皮素与卡马西平共晶物及制备方法和其组合物与用途
CN114199852A (zh) * 2021-12-07 2022-03-18 天津大学 一种药物共晶性能的表征方法
CN114199852B (zh) * 2021-12-07 2024-03-01 天津大学 一种药物共晶性能的表征方法

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