Crystalline forms of macrolide antibiotic

Details Crystalline forms of macrolide antibiotic Crystalline forms of macrolide antibiotic

2000-05-02

2003-06-24

Siew, Jeffrey (Department: 1637)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S007400, C536S124000, C514S029000

Reexamination Certificate

active

06583274

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel crystalline forms of a macrolide antibiotic, compositions comprising them, and methods of their preparation and use.
BACKGROUND OF THE INVENTION
The macrolide referred to herein as CP-472,295 has the structure shown in Formula 1:
CP-472,295 possesses antibiotic properties, and is useful in the treatment of, for example, bacterial and protozoal infections. As with all drugs, the safe and effective use of CP-472,295 depends on the ability of those skilled in the art to accurately administer it in precise amounts.
The accurate delivery of precise amounts of a drug is facilitated by the preparation of dosage forms. It is well known, however, that the ease with which dosage forms are prepared depends on factors such as, but not limited to, the solubility, homogeneity, hygroscopicity, and flow characteristics of the drug. Often, these properties are improved if crystalline, rather than amorphous, forms of the drug can be produced. There thus exists a need for well characterized, crystalline forms of CP-472,295. A particular need exists for non-hygroscopic forms of CP-472,295.
SUMMARY OF THE INVENTION
This invention is directed to crystalline forms of CP-472,295, to pharmaceutical compositions comprising these crystalline forms, and to methods of their preparation and use.
A first embodiment of the invention thus encompasses crystalline forms of a compound of Formula 1.
A preferred crystalline form of the compound of Formula 1 is anhydrous.
A preferred crystalline form of the compound of Formula I has an X-ray powder diffraction pattern which exhibits characteristic peaks expressed in 2&thgr; at about 6.0, 8.6, 9.7, 15.4, 15.9, 17.5, 18.2, 18.7, and 21.
A preferred crystalline form of the compound of Formula 1 has a differential scanning calorimetry spectrum comprising an event with an onset at about 193° C.
A preferred crystalline form of the compound of Formula 1 is non-hygroscopic for about 72 hours when stored at about 87% relative humidity and 25° C.
A preferred crystalline form of the compound of Formula 1 is a monohydrate.
A preferred crystalline form of the compound of Formula 1 has an X-ray powder diffraction pattern that exhibits characteristic peaks expressed in 2&thgr; at about 6.2, 7.6, 9.2, 9.5, 12.3, 12.9, 14.2, 4.6, 17.8, and 19.5.
A preferred crystalline form of the compound of Formula 1 has single crystal parameters which are substantially the same as those provided in Table 1:
TABLE 1
Crystal Parameters
Unit Cell Dimensions
a = 10.557(1) Å
b = 19.396(1) Å
c = 23.223(1) Å
&agr; = 90.00°
&bgr; = 90.0°
Y = 90.0°
V = 4755.26(6) Å
3
Space Group
P2
1
2
1
2
1
Molecules per Unit Cell
4
Density (g/cm)
1.151
A particularly preferred crystalline form of the compound of Formula 1 comprises atoms at atomic positions relative to the origin of the unit cell as set forth below in Table 2, bond lengths as set forth below in Table 3, or bond angles as set forth in Table 4.
A preferred crystalline form of the compound of Formula 1 has a differential scanning calorimetry spectrum comprising an event with an onset at about 75° C.
A preferred crystalline form of the compound of Formula 1 is non-hygroscopic for about 7 days when stored at about 87% relative humidity and 25° C.
A preferred crystalline form of the compound of Formula 1 is a sesquahydrate.
A preferred crystalline form of the compound of Formula 1 has an X-ray powder diffraction pattern that exhibits characteristic peaks expressed in 2&thgr; at about 5.2, 7.4, 11.2, 11.7, 12.3, 12.9, 14.9, 15.4, 16.7, and 17.9.
A preferred crystalline form of the compound of Formula 1 has a differential scanning calorimetry spectrum comprising an event with an onset at about 101° C.
A second embodiment of the invention encompasses pharmaceutical compositions comprising a crystalline form of a compound of Formula 1 and a pharmaceutically acceptable carrier. The crystalline form of the compound of Formula 1 can be anhydrous, a monohydrate, or a sesquahydrate. The pharmaceutical compositions of the invention are suitable for oral, rectal, parental (intravenous, intramuscular), transdermal, buccal, nasal, sublingual, or subcutaneous administration.
A third embodiment of the invention encompasses processes of preparing crystalline forms of a compound of Formula 1.
A preferred process is a process of preparing a crystalline anhydrous form of a compound of Formula 1 which comprises: dissolving an amount of a compound of Formula 1 in an anhydrous, low polarity solvent; cooling the solution to a temperature at which the full amount of the compound of Formula 1 is no longer soluble in the solution; and isolating by filtration any crystals that are formed. The invention encompasses products of this process.
A preferred process is a process of preparing a crystalline monohydrate form of a compound of Formula 1 which comprises: dissolving an amount of a compound of Formula 1 in a non-aqueous solvent containing between about 0.05 and about 15 percent by volume water; cooling the solution to a temperature at which the full amount of the compound of Formula 1 is no longer soluble in the solution; and isolating by filtration any crystals that are formed. The invention encompasses products of this process.
A preferred process is a process of preparing a crystalline sesquahydrate form of a compound of Formula 1 which comprises: dissolving an amount of a compound of Formula 1 in ethyl acetate containing between about 1 and about 10 percent by volume water; cooling the solution to a temperature at which the full amount of the compound of Formula 1 is no longer soluble in the solution; and isolating by filtration any crystals that are formed. The invention encompasses products of this process.
A fourth embodiment of the invention encompasses a method of treating a bacterial or protozoal infection in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a crystalline form of a compound of Formula 1. The crystalline form of the compound of Formula 1 can be anhydrous, a monohydrate, or a sesquahydrate.


REFERENCES:
patent: 5441939 (1995-08-01), Yang
patent: 5844105 (1998-12-01), Liu et al.
patent: 6268489 (2001-07-01), Allen et al.
patent: 9856802 (1998-12-01), None
patent: WO 98/56802 (1998-12-01), None
Wilkening et al.('Novel Transannular Rearrangements of Azalide Iminoethers, Tetrahedron vol. 53, No. 50, pp. 16923-16944, 1997).

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