Processes for preparing clarithromycin polymorphs and novel...

Details Processes for preparing clarithromycin polymorphs and novel... Processes for preparing clarithromycin polymorphs and novel...

2000-12-15

2003-07-29

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007200

Reexamination Certificate

active

06599884

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to methods for making polymorphic Form II of clarithromycin via slurrying polymorphic Form 0 of clarithromycin in water. The invention also relates to methods for making polymorphic Form IV of clarithromycin.
By slurrying in water, clarithromycin Form 0 can be converted to clarithromycin Form II. Under different conditions, a novel polymorphic form of clarithromycin, designated Form IV can be formed. The invention relates to the use of clarithromycin polymorphs so formed in pharmaceutical compositions; and to methods of using them.
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 0 in water. By slurrying in water, clarithromycin Form 0 can be converted to clarithromycin Form II.
Under different conditions, a novel polymorphic form of clarithromycin, designated Form IV, can be formed. Such conditions for example, include precipitation from aqueous ethanol at neutralization of the salt of clarithromycin with formic acid by sodium hydroxide at low temperature.
The invention relates to the use of clarithromycin polymorphs so formed in pharmaceutical compositions; and to methods of using them.
The present invention relates to a process for converting clarithromycin Form 0 to clarithromycin Form II, which includes slurrying clarithromycin Form 0 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 0 to clarithromycin Form II by slurrying.
Additionally, the present invention relates to a novel polymorph of clarithromycin, that is, clarithromycin Form IV, a process for its preparation, pharmaceutical compositions that include Form IV and methods of using Form IV as a therapeutic agent.
Clarithromycin Form IV can be characterized by its powder x-ray diffraction pattern, which exhibits characteristic peaks at 7.6°±0.2, 8.1°±0.2, 9.40°±0.2, 11.0°±0.2, 12.0°±0.2, 15.4°±0.2, 16.5°±0.2, 18.7°±0.2, and 19.3°±0.2.


REFERENCES:
patent: 4331803 (1982-05-01), Watanabe et al.
patent: 4349545 (1982-09-01), D'Ambrieres et al.
patent: 4640910 (1987-02-01), Faubl et al.
patent: 4670549 (1987-06-01), Morimoto et al.
patent: 4672056 (1987-06-01), Fernandes et al.
patent: 4672109 (1987-06-01), Watanabe et al.
patent: 4680386 (1987-07-01), Morimoto et al.
patent: 4957905 (1990-09-01), Hunt
patent: 4990602 (1991-02-01), Morimoto et al.
patent: 5274085 (1993-12-01), Amano et al.
patent: 5719272 (1998-02-01), Yang et al.
patent: 5756473 (1998-05-01), Liu et al.
patent: 5808017 (1998-09-01), Chang
patent: 5837829 (1998-11-01), Ku
patent: 5844105 (1998-12-01), Liu et al.
patent: 5852180 (1998-12-01), Patel
patent: 5858986 (1999-01-01), Liu et al.
patent: 5864023 (1999-01-01), Ku et al.
patent: 5872229 (1999-02-01), Liu et al.
patent: 5892008 (1999-04-01), Ku et al.
patent: 5932710 (1999-08-01), Liu et al.
patent: 5945405 (1999-08-01), Spanton et al.
patent: 6506886 (2003-01-01), Lee et al.
patent: 1 225 637 (1987-08-01), None
patent: 0 158 467 (1985-10-01), None
patent: 0 158 467 (1985-10-01), None
patent: 0 180 415 (1986-05-01), None
patent: 0 180 415 (1986-05-01), None
patent: 0 272 110 (1988-06-01), None
patent: 0 272 110 (1988-06-01), None
patent: 98/04574 (1998-02-01), None
patent: 98/31699 (1998-07-01), None
patent: 00/14099 (2000-03-01), None

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