Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-07-30
2004-02-24
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S412000, C514S415000, C514S419000, C514S951000, C424S400000, C424S489000, C548S491000, C378S070000
Reexamination Certificate
active
06696479
ABSTRACT:
The present invention is directed to novel crystalline forms of Fluvastatin sodium, processes for their preparation and pharmaceutical compositions comprising these crystalline forms.
Fluvastatin sodium is known by its chemical name (±)-7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl)-3,5-dihydroxy-6-heptenoic acid monosodium salt. Fluvastatin sodium is a racemic mixture of the 3R,5S- and 3S,5R-dihydroxy enantiomers and has the following formula:
Fluvastatin sodium is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) and is used to lower the blood cholesterol level.
Fluvastatin as well its sodium salt are disclosed in U.S. Pat. No. 4,739,073. In this patent Fluvastatin sodium is obtained by lyophilization. WO-A-97/49681 and its US equivalent U.S. Pat. No. 6,124,340 describe that lyophilization of Fluvastatin sodium yields a mixture of a crystalline form, designated as Form A, and amorphous material, and disclose a new crystalline form, designated as Form B. The estimated amount of form A obtained by lyophilization as described in these patents is about 50%. The crystalline Form B is obtained either by transformation of material containing Form A in a slurry of a mixture of an organic solvent and water, or by crystallization from an organic solvent and water mixture. It is also described that form B is less hygroscopic than Form A or the amorphous form of Fluvastatin sodium which improves handling and storage of the compound. However, there is still a need for new crystalline forms which are less hygroscopic than Form A and which can be obtained from aqueous solutions.
We have now surprisingly found that Fluvastatin sodium can be prepared as novel crystalline hydrates which have improved stability and are obtained from aqueous solutions without the risk of residual organic solvent. These novel crystalline hydrates, herein designated as Form C, D, E and F, are less susceptible towards air humidity, and show high stability and are easier to handle at normal environmental humidity levels. The novel crystalline forms of Fluvastatin sodium are novel hydrates with water contents ranging from 3 to 32%. In addition we found a new process for the preparation of highly crystalline Fluvastatin sodium Form A. Thus the present invention provides the following novel crystalline forms of Fluvastatin sodium:
A crystalline polymorph of (±)-7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl)-3,5-dihydroxy-6-heptenoic acid monosodium salt which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å):
23.8 (vs), 11.8 (w), 7.8 (vs), 7.6 (vw), 7.4 (vw), 6.4 (vw), 6.1 (vw), 5.90 (w), 5.00 (vw), 4.88 (w), 4.73 (m), 4.56 (w), 4.40 (vw), 4.12 (vw), 4.03 (vw), 3.96 (vw), 3.50 (vw), 3.36 (vw), 2.93 (vw), herein designated as Form C. Here and in the following the abbreviations in brackets mean: (vs)=very strong intensity; (s)=strong intensity; (m)=medium intensity; (w)=weak intensity; and (vw)=very weak intensity. A characterisitic X-ray powder diffraction pattern for Form C is depicted in FIG.
2
.
A crystalline polymorph of (±)-7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl)-3,5-dihydroxy-6-heptenoic acid monosodium salt which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å):
24.6 (vs), 12.5 (w), 8.3 (vs), 7.4 (vw), 6.2 (m), 4.97 (w), 4.85 (vw), 4.52 (vw), 4.40 (vw), 4.14 (vw), 3.96 (vw), 3.41 (vw), 3.10 (vw), herein designated as Form D. A characteristic X-ray powder diffraction pattern for Form D is depicted in FIG.
3
.
A crystalline polymorph of (±)-7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl)-3,5-dihydroxy-6-heptenoic acid monosodium salt which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å):
27.6 (m), 13.9 (vw), 9.2 (m), 8.5 (vw), 8.1 (vw), 7.4 (vw), 6.9 (s), 6.1 (vw), 4.98 (m), 4.77 (m), 4.63 (m), 4.15 (w), 4.03 (w), 3.97 (vw), 3.52 (vw), 3.33 (vw), 3.08 (vw), 2.99 (vw), herein designated as Form E. A characteristic X-ray powder diffraction pattern for Form E is depicted in FIG.
4
.
A crystalline polymorph of (±)-7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl)-3,5-dihydroxy-6-heptenoic acid monosodium salt which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å):
29.6 (w), 14.8 (vw), 9.9 (w), 8.6 (vw), 8.3 (vw), 7.4 (s), 6.6 (vw), 6.2 (vw), 5.93 (w), 5.03 (m), 4.94 (m), 4.35 (vw), 4.23 (w), 3.98 (vw), 3.54 (vw), 2.98 (vw), herein designated as Form F. A characteristic X-ray powder diffraction pattern for Form F is depicted in FIG.
5
.
Furthermore, the present invention is directed to processes for the preparation of Form C, D, E, F and highly crystalline Form A.
Forms C, D, E and F can be prepared according to a process, wherein Fluvastatin sodium is exposed to an atmosphere having a defined relative humidity.
Form C of Fluvastatin sodium can generally be prepared from either the crystalline Forms A, D, E, F or amorphous Fluvastatin sodium, or mixtures thereof, for example by equilibration under relative humidity conditions from about 15 to 25% (for example for 6 to 24 hours). As a rule the estimated water content can range from 3-6%.
Form D of Fluvastatin sodium can generally be prepared from either the crystalline Forms A, C, E, F or amorphous Fluvastatin sodium, or mixtures thereof, for example by equilibration under relative humidity conditions from about 30 to 50% (for example for 6 to 24 hours). As a rule the estimated water content can range from 6-12%.
Form E of Fluvastatin sodium can generally be prepared from either the crystalline Form A, C, D, F or amorphous Fluvastatin sodium, or mixtures thereof, for example by equilibration under relative humidity conditions from about 55 to 75% (for example for several days). As a rule the estimated water content can range from 15-22%.
Form F of Fluvastatin sodium can generally be prepared from either the crystalline Form A, C, D, E or amorphous Fluvastatin sodium, or mixtures thereof, for example by equilibration under relative humidity conditions from about 80 to 90% (for example for several days). As a rule the estimated water content can range from 24-32%.
Highly crystalline Fluvastatin sodium Form A can generally be prepared by equilibration of an aqueous suspension or solution of Fluvastatin sodium for several hours at temperatures from about 0 to 10° C. and subsequent drying by lyophilization. The process can be accelerated by additional seeding with crystals of Form A during the equilibration period. A characteristic X-ray powder diffraction pattern for highly crystalline Form A is depicted in FIG.
1
. The crystallinity of this material is estimated by the powder diffraction spectrum to be more than 90%. The estimated water content is below 2%.
A preferred process for the preparation of highly crystalline Fluvastatin sodium Form A comprises treating an aqueous solution of (±)-7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl)-3,5-dihydroxy-6-heptenoic acid monosodium salt in order to effect at least minimal precipitation of the compound, followed by freeze drying.
It is preferred that the aqueous solution is cooled and subsequently the suspension is freeze dried. As to this embodiment it is preferred that the aqueous solution is prepared at a temperature of 20 to 80° C., especially 30 to 80° C., and is cooled to a temperature of 0 to 15° C. in order to effect precipitation of the compound.
Advantagously seeding crystals of Form A can be added.
Small changes in the relative air humidity can cause small deviations in the d-values of characteritic peaks in the X-ray powder diffraction patterns. For example, crystalline Fluvastatin sodium Form D prepared under a relative humidity of 35% exhibits characteristic X-ray powder diffraction peaks in d-values (Å) at 24.6 (vs), 12.5 (w), 8.3 (vs) and 6.2 (m), whereas a sample prepared under a relative humid
Burkhard Andreas
Marcolli Claudia
Szelagiewicz Martin
Van Der Schaaf Paul Adriaan
Wolleb Annemarie
Ciba Specialty Chemicals Corporation
Krass Frederick
Mansfield Kevin T.
Ostrup Clinton
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