CHEN SHU-PING
CHAN HARDY (US)
CHANG YU-SHENG
CHEN SHU-PING
GUNNET J.W. ET AL.: "Hormones, Sex Hormones", KIRK-OTHMER ENCYCLOPEDIA OF CHEMICAL TECHNOLOGY, vol. 27, no. 4, 4 December 2000 (2000-12-04), pages 15 - 16
SAUER G. ET AL.: "Synthesis of D-Norgestrel", ANGREW. CHEM. INT. ED., vol. 14, no. 6, 1975, pages 417
VAN GEERESTEIN V.J. ET AL.: "Structure of Modifications (I) and (II) of 13-Ethyl-17beta-hydroxy-18,19- dinor-17 alpha-pregna-4,15-dien-20-yn-3-one(Gestodene)", ACTA CRYST., vol. C43, 1987, pages 2402 - 2405
CLAIMS
-the claims : 1. A crystalline polymorph of levonorgestrel exhibiting an X-ray powder diffraction pattern comprising a peak in degrees 2θ ±.0.2° 2θ at 13.8.
2. A crystalline polymorph of levonorgestrel according to claim 1 further comprising peaks in degrees 2θ ±.0.2° 2θ at 14.1 and 14.4.
3. The crystalline polymorph of levonorgestrel according to claim 1 further comprising peaks in degrees 2θ ±.0.2° 2θ at 15.7 and 15.9.
4. The crystalline polymorph of levonorgestrel according to claim 1 exhibiting an X-ray powder diffraction pattern substantially as shown in Figure 4.
5. The crystalline polymorph of levonorgestrel according to claim 1 exhibiting a diffuse reflectance spectrum substantially as shown in Figure 1.
6. A method of preparing a crystalline polymorph of levonorgestrel comprising the steps of: (a) dissolving levonorgestrel in ethyl acetate at an elevated temperature to form a solution; (b) adding n-heptane to the solution at the elevated temperature; (c) cooling the mixed solution to produce the crystalline polymorph of levonorgestrel.
7. A method of preparing a crystalline polymorph of levonorgestrel comprising the steps of: (a) dissolving levonorgestrel in methanol at an elevated temperature to form a solution; and (b) cooling the solution to produce the crystalline polymorph of levonorgestrel.
The method according to claim 7 further comprising the step of adding water to the solution at the elevated temperature after step (a) and before step (b) . |
LEVONORGESTREL CRYSTALLIZATION
BACKGROUND OF THE INVENTION
1. Field of the Invention [0001] The present application claims priority to Provisional Patent Application 60/967,949, filed September 7, 2007, and incorporates herein the entire disclosure of the provisional patent application.
SUMMARY OF THE INVENTION [0002] The present invention provides for a method of crystallizing levonorgestrel, and a novel crystalline polymorph of levonorgestrel.
BRIEF DESCRIPTION OF THE DRAWINGS [0003] Figure 1 is the diffuse reflectance spectrum of the crystalline polymorph of levonorgestrel of the present invention.
[0004] Figure 2 provides the peak positions within the diffuse reflectance spectrum of Figure 1, as well as an expansion of a certain region of that spectrum. [0005] Figure 3 provides an expansion of various regions of the diffuse reflectance spectrum of Figure 1. [0006] Figure 4 shows the X-ray powder diffraction pattern of the crystalline polymorph of levonorgestrel of the present invention in intensity versus degrees in two theta.
[0007] Figure 5 shows the X-ray powder diffraction pattern of the crystalline polymorph of levonorgestrel of the present invention in intensity versus d-spacing. [0008] Figure 6 a and b list the peak positions and their intensities.
DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED
EMBODIMENTS
[0009] The method of crystallizing the polymorph of the present invention is by the following procedures: (A) Ethyl acetate / n-Heptane
[0010] To a suitable reactor is charged ethyl acetate (EA) (about 25mL) and levonorgestrel (about 1 g) . The slurry is stirred and heated to reflux (75~78°C) to form clear solution. n-Heptane (about 75mL) is slowly charged and the solution is kept at 70~75 °C. The solution is cooled to 0-5 0 C in not less than (NLT) 90 minutes, and held for NLT 2 hours. The slurry is filtered and dried at 20~30 0 C to obtain about 0.5 g of Levonorgestrel.
(B) Methanol / Water [0011] Methanol (about 25mL) is charged with
Levonorgestrel (about 1 g) . The slurry is stirred and heated to reflux (64~65°C) to form clear solution. Water (about 75mL) is slowly charged and the solution is kept at 65~70°C. The solution is cooled to 40-45 0 C in NLT 50 minutes, and hold for 1 hour. The slurry is filtered and dried at 20-30 0 C to obtain levonogestrel (about 0.6 g) .
(C) Methanol
[0012] Methanol (about 25mL) is charged with Levonorgestrel (about 1 g) . The slurry is stirred and heated to reflux (64~65°C) to form clear solution. The solution is cooled to 0-5 °C in NLT 50 minutes, and hold
for 1 hour. The slurry is filtered and dried at 20~30°C to obtain levonorgestrel (about 0.4 g) .
[0013] Representative infrared spectrum and X-ray powder diffraction pattern for the crystalline levonorgestrel product are provided in the figures herein.
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