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AssigneeSaneca Pharmaceuticals A.S.
InventorsMiroslav KAVALA, Dusan VANDÁK, Miroslav PALÍK, Ján GASPAR, Richard HERCEK
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The invention describes a method for purification of naltrexone base from reaction mixtures concentrated by evaporation and/or from mixtures containing naltrexone in the presence of other organic or inorganic substances by trituration and/or extraction and crystallization from cyclopentyl methyl ether (CPME), optionally from a mixture of cyclopentyl methyl ether and another organic solvent. Naltrexone of high purity is obtained by this method and can be used in a parenteral dosage form.
A method for the isolation or purification of naltrexone, naltrexone salts, naltrexone base, or any combination thereof, said method comprising processing said naltrexone, naltrexone salts, naltrexone base, or any combination thereof, in cyclopentyl methyl ether (CPME).
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A crystallization mixture comprising CPME and naltrexone, naltrexone salts, naltrexone base, or any combination thereof.
A trituration mixture, comprising CPME and naltrexone, naltrexone salts, naltrexone base, or any combination thereof.
The trituration mixture according to claim 23, wherein the additional solvent is methanol, ethanol, 2-propanol, n-propanol, 2-butanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, isoamyl alcohol, tert-amyl alcohol, 4-methyl-2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl isobutyl ketone, or methyl isopropyl ketone.
Dependencies are inferred from the claim text.
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With a hetero atom directly attached in position 14: oxygen atom
In which the condensed system contains two hetero rings: bridged systems
Galenical forms characterised by the site of application: injectable compositions; Intramuscular, intravenous, arterial, subcutaneous…
Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite: containing oxygen, e.g. ethers,…
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The invention is from the field of pharmaceutical manufacture. It relates to preparation and purification of naltrexone which is used as opioid analgesic antagonist.
Naltrexone, structure (1), and its salts, such as naltrexone hydrochloride, are active pharmaceutical ingredients (API) which are used particularly for reduction of psychological dependence in patients with drug addiction.
Naltrexone can be isolated or purified by crystallization or precipitation. Several methods for purification (described in the patents bellow) are known in the patent literature, using polar, non-polar, protic, as well as aprotic solvents.
This invention is defined in the patent claims.
Trituration—means stirring a compound in a solvent in the form of suspension, wherein soluble impurities remain in the solution and crystalline substance is enriched by its main poorly soluble component.
The use of cyclopentyl methyl ether for the crystallization of naltrexone base containing approx. 75% by weight provides good results (a product containing 95 to 96% by weight is obtained). In case that such quality is not sufficient, it is possible to repeat the crystallization with cyclopentyl methyl ether, wherein content of thus recrystallized product increases to 98% by weight or more. Naltrexone thus obtained has HPLC purity and content depending on the purity and the content of starting substrate, but preferably more than 93%. In the best case, optionally by repeated crystallization, a product with HPLC purity of naltrexone 99.8% and more and with the content above 99.0% by weight is obtained. For crystallization, dry or wet cyclopentyl methyl ether can be used. Crystallization yields are achieved in the range of 40 to 95%.