Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-12-15
2003-09-23
Peselev, Elli (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
Reexamination Certificate
active
06624292
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to methods for making polymorphic Form II of clarithromycin via slurrying polymorphic Form I of clarithromycin in water.
By slurrying in water, clarithromycin Form I can be converted to clarithromycin Form II. The invention also relates to clarithromycin Form II prepared by slurrying polymorphic Form I in water and pharmaceutical compositions containing the same.
BACKGROUND OF THE INVENTION
6-O-methyl erythromycin A (clarithromycin) is a semisynthetic macrolide antibiotic related to erythromycin A. Clarithromycin exhibits excellent antibacterial activity against gram-positive bacteria, some gram-negative bacteria, anaerobic bacteria, Mycoplasma, and Chlamydia. It is stable under acidic conditions and is efficacious when administered orally. Clarithromycin is useful therapy for infections of the upper respiratory tract in children and adults. Clarithromycin is stable under acidic conditions and is efficacious when administered orally.
The chemical structure of clarithromycin is:
Several crystal forms of clarithromycin and/or solvates of clarithromycin, “Form 0,” “Form I”, and “Form II” have been identified as indicated in U.S. Pat. No. 5,945,405. The crystal form of clarithromycin is typically identified by the powder x-ray diffraction patterns. Different crystalline forms of clarithromycin may have different thermal stability, cost of preparation, dissolution characteristics and bioavailability.
Various methods of preparing clarithromycin described in the patent literature have been reported to result in different forms of clarithromycin. Purification of crude clarithromycin has been reported to convert one form of clarithromycin to another form. For example, methods in which the compound is purified by recrystallization from ethanol, have been reported to result in the initial formation of Form 0 solvate (see U.S. Pat. No. 5,945,405) or in the initial formation of Form I (See U.S. Pat. No. 5,858,986). The Form 0 solvate may be used as a therapeutic agent, as described in U.S. Pat. No. 5,945,405. The '405 patent discloses that the Form 0 solvate may be converted to the non-solvated Form I by removing the solvent by drying at a temperature of from about 0° C. to about 50° C. Another form, Form II, is reported to be relatively thermodynamically stable compared to Form I. The clarithromycin currently marketed in the United States under the trademark Biaxin® is formulated using Form II.
Several methods of converting clarithromycin Form 0 or Form I to Form II have been described. One such method, as described in U.S. Pat. No. 4,945,405 and U.S. Pat. No. 5,858,986, is to heat Form 0 under vacuum at a temperature of between about 70° C. and 110° C. According to this patent, the Form 0 solvate first converts to Form I clarithromycin and then to Form II. This method is described in U.S. Pat. No. 4,945,405 and U.S. Pat. No. 5,858,986. However, this vacuum drying step of converting Form 0 to Form II is expensive in both energy and material handling. Clarithromycin Form II has been reported to be formed when Form I is crystallized from various solvents, including ethanol and water (U.S. Pat. No. 5,844,105).
SUMMARY OF THE INVENTION
The invention relates to methods for making polymorphic forms of clarithromycin via slurrying clarithromycin Form I in water. By slurrying in water, clarithromycin Form I can be converted to clarithromycin Form II. The invention also relates clarithromycin form II formed by this slurrying process and pharmaceutical compositions containing the same.
The present invention relates to a process for converting clarithromycin Form I to clarithromycin Form II, which includes slurrying clarithromycin Form I in water. The present invention also relates to processes for the preparation of clarithromycin Form II by converting erythromycin A to clarithromycin and thereafter, converting clarithromycin Form I to clarithromycin Form II by slurrying.
DETAILED DESCRIPTION OF THE INVENTION
We have found that clarithromycin Form I undergoes transformation to Form II by simply slurrying the Form I clarithromycin with water. The present process for converting clarithromycin Form I to Form II is simpler and less expensive than previously described methods of converting Form I to Form II, which require for example, the use of organic solvents such as ethanol.
Form II prepared by this process can be formulated into pharmaceutical compositions that include a therapeutically effective amount of clarithromycin Form II and one or more pharmaceutically acceptable carriers. Those pharmaceutical compositions can be administered as a therapeutically effective antibiotic. Each of these aspects of the present invention is described in further detail below.
The terms “6-O-methylerythromycin A” and “clarithromycin” are used interchangeably herein and are meant to include clarithromycin in any crystalline form or mixtures thereof, as well as amorphous solids, syrups, or semisolids comprising 6-O-methylerythromycin A in any state of purity, unless specified otherwise, or as the context requires.
The term “Form I” is used herein to mean the crystal Form I of clarithromycin. Form I has been characterized by 2-theta angle positions in the powder x-ray diffraction pattern of 5.2±0.2, 6.7±0.2, 10.2°±0.2, 12.3±0.2, 14.2°±0.2, 15.4°±0.2, 15.7°±0.2, and 16.4±0.2. Form I has also been characterized by an exothermic transition at 132.2° C. by differential scanning calorimetry, and by endothermic peaks at 223.4° C., and 283.3° C., followed by an exothermic peak at 306.9° C.
The term “Form II” is used herein to mean the crystal Form II of clarithromycin. Form II has been characterized by 2-theta angle positions in the powder x-ray diffraction pattern of 8.5°±0.2, 9.5±0.2, 10.8°±0.2, 11.5±0.2, 11.9±0.2, 12.4±0.2, 13.7°±0.2, 14.1°±0.2, 15.2±0.2, 16.5±0.2, 16.9°±0.2, 17.3°±0.2, 18.1±0.2, 18.4°±0.2, 19.0°±0.2, 19.9±0.2, and 20.5±0.2 Form II has also been characterized by melting at 223.4° C., and by an endothermic peak at 283.3° C. by differential scanning calorimetry.
The term “Form 0” is used herein to mean the crystal Form 0 or Form 0 solvate of 6-O-methylerythromycin A. Form 0 solvate is characterized by 2-theta angle positions in the powder x-ray diffraction pattern of 4.6°±0.2, 6.5°±0.2, 7.6°±0.2, 9.2°±0.2, 10.2°±0.2, 11.0°±0.2, 11.6°±0.2, 12.5°±0.2, 13.8°±0.2, 14.8°±0.2, 17.0°±0.2, 18.2°±0.2, 18.9°±0.2 and 19.5°±0.2. This pattern may be somewhat varied depending on the solvent. For example a Form 0 ethanolate may be characterized by 2-theta angle positions of 4.7°±0.2, 6.60°±0.2, 7.7°±0.2, 9.3°±0.2, 10.4°±0.2, 11.1°±0.2, 11.9°±0.2, 12.7°±0.2, 13.9°±0.2, 15.0°±0.2, 17.2°±0.2, 18.5°±0.2, 19.1°±0.2, 19.7°±0.2, 23.1°±0.2 and 24.0°±0.2.
Formation of Clarithromycin Form II
The present invention relates to processes for converting clarithromycin Form I to clarithromycin Form II, which include slurrying clarithromycin Form I with water. The present invention also relates to a process of preparing clarithromycin Form II from erythromycin A, which includes slurrying clarithromycin Form I in water. In one embodiment, this method includes first converting erythromycin A to clarithromycin and thereafter slurrying clarithromycin Form I with water to form clarithromycin Form II. There are several methods by which clarithromycin may be formed from erythromycin A, as described further below. In certain of these methods, the initial form of clarithromycin that is formed is Form I. In other methods, the initial form of clarithromycin that is formed is not Form I, but rather another form that is subsequently converted to Form I.
As used herein, the terms “slurrying” and “slurried” are intended to i
Avrutov Ilya
Lifshitz Igor
Masarwa Basem
Schwartz Edi
Peselev Elli
Teva Pharmaceutical Industries Ltd.
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