Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-11-04
2001-01-09
Fonda, Kathleen K. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S018100, C536S018500, C514S027000
Reexamination Certificate
active
06172206
ABSTRACT:
The invention relates to a new crystalline form of morphine-6-glucuronide (M6G), known as Form A, its use and a process for preparing it.
Morphine-6-glucuronide, a metabolite of morphine, has a powerful analgesic effect.
The preparation of morphine-6-glucuronide by K{overscore (o)}nigs-Knorr Synthesis has already been described by H. Yoshimura et al. (Chem. Pharm. Bull. 1968, 16, 2114-2119 and Tetrahedron Letters 1968, 4, 483-486), P. A. Carrupt et al. (J. Med. Chem. 1991, 34, 1272-1275) and C. Lacy et al. (Tetrahedron Letters 1995, 36, 22, 3939-3950).
F. Scheinmann et al. (EP 597915) describe the preparation thereof using the imidate method (cf. Fischer et al., J. Org. Chem. 1984, 49, 4988), which is supposed to result in reduced contamination with heavy metals.
A. Mertz et al. (WO 93/05057) describe the synthesis of morphine glucuronides from morphine and protected halogenated glucuronic acid esters with subsequent hydrolysis with alkali metal salts.
In addition, morphine-6-glucuronide has been prepared by selective enzyme-catalysed hydrolysis of morphine-3,6-diglucuronide (R. T. Brown et al., Tetrahedron Letters 1995, 36, 1117-1120).
The methods of purifying and totally removing inorganic contaminants described consist of column chromatography (C. Lacy et al.) and recrystallisation from alcohol/water mixtures (H. Yoshimura et al., P. A. Carrupt et al.).
As a result of the methods of production mentioned above, morphine-6-glucuronide is obtained in the form of crystalline compounds which form stable solvates with the solvents used in purification (methanol, ethanol, dioxan or acetonitrile). Since the recrystallisations described correspond rather to a precipitation process (the addition of alcohol reduces the polarity of the aqueous solution and leads to crystallisation), there is only a limited removal of inorganic salts as they also crystallise out.
The solvent forms thus obtained are very hygroscopic and absorb up to 20% water. However, on account of their high content of residual solvent—up to several percent by weight—the solvates are unsuitable for pharmaceutical use, particularly when the solvents in question are toxic solvents such as methanol, dioxan or acetonitrile.
There is therefore a need to produce morphine-6-glucuronide in a solvent-free crystalline form. This solvent-free form of morphine-6-glucuronide should be superior to the solvent forms in its purity, stability and physical/chemical properties. Moreover, the method of producing morphine-6-glucuronide should also be feasible on an industrial scale. In particular, the solvent used should be water.
It has now been found, unexpectedly, that morphine-6-glucuronide can be produced in a new crystalline form having improved properties by a method of preparation which conforms to the requirements described above. According to the invention, therefore, morphine-6-glucuronide is prepared in a new crystalline form which is known as Form A. It has been found that, in spite of its excellent solubility in water, morphine-6-glucuronide can be crystallised from water under certain conditions. Form A thus produced has lower heavy metal residues and organic impurities such as solvent residues and related organic substances, compared with solvent-containing forms, it is more stable and is easier to handle owing to its lower hygroscopicity and water adsorption.
REFERENCES:
patent: 5621087 (1997-04-01), Scheinmann et al.
patent: 5977326 (1999-11-01), Scheinmann et al.
patent: 6046313 (2000-04-01), Scheinmann et al.
patent: WO 93 05057 (1993-03-01), None
Oguri et al. Chem. Pharm. Bull. 1970, 18(1), 209-210.
Yoshimura et al. Tetrahedron Letters 1968, (4), 483-6.
Chem. Pharm. Bull., vol. 16, 1968, pp. 2114-19, XP002024005, Yoshimura et al.: “Metabolism of Drugs. LX. The Synthesis of Codeine and Morphine Glucuronides” cited in the application (see the whole document).
Franzmair Rudolph
Koch Andreas
Rovensky Franz
Schneider Herwig
Bacon & Thomas
CeNeS Ltd.
Fonda Kathleen K.
LandOfFree
Crystalline form of morphine-6-glucuronide does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Crystalline form of morphine-6-glucuronide, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Crystalline form of morphine-6-glucuronide will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2463846