N-T-BUTYL-ANDROST-3,5-DIENE-17 beta -CARBOXAMIDE-3-CARBOXYLIC ACID POLYMORPH B

Abstract: Polymorph "B" is a novel polymorphic form of N-t-butyl-androst-3,5-diene-17 beta -carboxamide-3-carboxylic acid. Novel processes for preparing polymorph "B" are also disclosed.

Description: N-T-BUTYL-ANDROST-3.5-DIENE-17β-CARBOXAMIDE-3-CARBOXYLTC ACID POLYMORPH B The present invention relates to a novel polymorphic form of N-t-butyl-androst-3,5-diene-17β- carboxamide-3-carboxylic acid. Brief Description of the Drawings Figure I is an Infa-red spectrum of N-t-butyl- androst-3,5-diene-17β-carboxylic acid polymorph B. Figure II is an enhanced FT-IR spectrum of the 3399-3501 cm -1 region of polymorph B disclosing the characteristic N-H stretch of polymorph B. Detailed Description of the Invention N-t-butyl-androst-3,5-diene-17β-carboxamide-3- carboxylic acid is a compound which is disclosed and claimed as being useful in the treatment of benign prostatic hypertrophy in U.S. Patent No. 5,017,568, the entire disclosure of which is hereby incorporated by reference. Said compound can be prepared by methods such as described in U.S. Patent No. 5,017,568. The isolation and identification of the polymorphic forms of said compound is advantageous in identifying desirable physical characteristics of the different crystal forms of said compound. It has now been found that a polymorphic form (hereinafter polymorph B) of the compound N-t-butyl- androst-3,5-diene-17β-carboxamide-3-carboxylic acid can be obtained in a high state of polymorphic purity by crystallization or by precipitation of said compound from or by the trituration of said compound in a solvent consisting of or primarily consisting of acetonitrile, 2-butanone, methanol or tetrahydrofuran. Also, contemplated herein is the process of obtaining substantially pure polymorph B by crystallization or by precipitation of said compound from or by the trituration of said compound in a solvent consisting of a combination of solvents selected form acetonitrile, 2- butanone, methanol and tetrahydrofuran. Preferably, crude N-t-butyl-androst-3,5-diene-17β-carboxamide-3- carboxylic acid is dissolved in and substantially pure polymorph B is crystalized from a solution of boiling acetonitrile, said solution optionally containing a co- solvent, preferably methylene chloride, to aid dissolution. Preferably a 12-40% by weight slurry of N- t-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid in acetonitrile is stirred at above ambient temperature. Preferably a 14-20% by weight slurry of N- t-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid in boiling acetonitrile is stirred, preferably for about an hour. Preferably, crude N-t-butyl-androst-3,5- diene-17β-carboxamide-3-carboxylic acid is dissolved in and substantially pure polymorph B is precipitated from 2-butanone by concentration and with the addition of petroleum ether. Presently, N-t-butyl-androst-3,5-diene-17β- carboxamide-3-carboxylic acid is known to assume only two polymorphic forms, A and B. Table 1 displays the results of equilibrium solubility studies carried out on the two polymorphic forms of N-t-butyl-androst-3,5-diene-17β-carboxamide-3- carboxylic acid. The studies were carried out at ambient temperature and the concentration of N-t-butyl- androst-3,5-diene-17β-carboxamide-3-carboxylic acid in each solution was measured by ultra violet spectroscopy, Table 1 * 0.1 N Na 2 HP0 4 , pH 7.5 ** ND = Not detected, limit of detection was 0.001 mg/ml As indicated in Table 1 above, the polymorph B form is more soluble and has a faster rate of dissolution in water than the polymorph A form. Such enhanced solubility properties are advantageous in the preparation of pharmaceutical formulations of N-t-butyl- androst-3,5-diene-17β-carboxamide-3-carboxylic acid, such as creams or ointments, and indicates increased Ln vivo bioavailability of said compound. - A - By the term "crude" as used herein is meant that the isolated N-t-butyl-androst-3, 5-diene-17β- carboxamide-3-carboxylic acid starting material exist as an amorphous solid, in an undesired polymorphic form or as a plurality of polymorphic forms . By the term "N-t-butyl-androst-3, 5-diene-17β- carboxamide-3-carboxylic acid" as used herein is meant a compound of the structure N-t-butyl-androst-3, 5-diene-17β-carboxamide-3- carboxylic acid polymorph B (prepared by crystallization from acetonitrile) was analyzed by an X-ray powder diffraction (X-ray diffractometry (XRD) obtained from Micron Incorporated of Wilmington, Delaware) . The characteristic d-spacings, intensities, and 2-theta values for the diffraction pattern of Polymorph B are listed in Table 2 below. Table 2 X-ray diffraction pattern listing of N-t-butyl- androst-3,5-diene-17 β -carboxamide-3-carboxylic acid polymorph B. - 5 - The following examples illustrate the preparation of N-t-butyl-androst-3,5-diene-17β-carboxamide-3- carboxylic acid polymorph B. The examples are not intended to limit the scope of the invention as defined hereinabove or as claimed below. - 6 - Example 1 N-t-butyl-androst-3,5-dienβ-17β-carboxamJd -3-carboxylir. acid Polymorph B 33 g of crude N-t-butyl-androst-3,5-diene-17β- carboxamide-3-carboxylic acid was added to 150 ml of acetonitrile. The resulting slurry was heated to reflux and stirred for about two hours. The product was isolated by filtration and afforded 27.2 g of substantially pure N-t-butyl-androst-3,5-diene-17β- carboxamide-3-carboxylic acid as its B polymorph. The infa-red spectrum of the product is shown in figures one and two. Infra-red spectral absorbancies of N-t-butyl- androst-3,5-diene-17 β -carboxamide-3-carboxylic acid polymorph B (prepared by crystallization from acetonitrile) were obtained (spectrm obtained from Nujol (mineral oil) on sodium chloride plates) (Apparatus; Nicolet 6000 FT-IR using a mercury Cadmiun Telluride Detector, analysis time 7.6 minutes (800 scans), Enhancement Program Nicolet IRDCON) . Characteristic Polymorph B form bands occur at 3455, 3446 cm "1 (N-H stretch); and 1670 cm -1 (acid and amide C=0 stretch) . An FT-IR spectra of polymorph B is shown in figure 1 below. The resolution enhanced FT-IR spectra of the 3399-3501 cm _ l region disclosing said characteristic N-H stretch of polymorph B is shown in Figure 2 below. Example 2 N-t-butyl-androst-3,5-diene-17β-carboxamide-3-carobyxlic Acid Polymorph B Crude N-t-butyl-androst-3,5-diene-17β-carboxamide- 3-carboxylic acid (10 grams) was dissolved in methylene chloride (250 L) . The reaction solution was distilled at atmospheric pressure to about 85 mL and about 50 mL of acetonitrile was added. The mixture was again distilled until the head temperature reached 78°C, and the resulting suspension was then heated at reflux for about 1 hour. The slurry was chilled in an ice bath for about 1 hour. The product was isolated by filtration, washed thoroughly with cold acetonitrile, and dried under vacuum at 50-60°C to afford 9.7 grams of N-t- butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid as polymorph B. Example 3 N-t-butv]-androst-3,5-diene-17β-carboxamid -3-r.arboxylic. acid Polymorph B Substantially pure N-t-butyl-androst-3,5-diene-17β- carboxamide-3-carboxylic acid Polymorph B was obtained by precipitating approximately 10 g of crude N-t-butyl- androst-3,5-diene-17β-carboxamide-3-carboxylic acid, from 100 mL of 2-butanone by concentrating the solution under vacuum to about 20 mL and then treating the solution with 163 mL of petroleum ether. The product was collected by filtration, and was dried under vacuum at about 50°C to afford 6.4 g of substantially pure N-t- butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid Polymorph B.

Claims: What is claimed is: 1. A compound of the structure substantially in polymorph B form. 2. A compound according to Claim 1 having the infa-red spectrum as shown in Figure 1 and the x-ray diffraction pattern listing shown in Table 2. 3. A compound according to claim 1 having the infa-red spectrum as shown in Figure 2 and the x-ray diffraction pattern listing shown in Table 2. 4. A process for preparing a compound of the structure substantially in the polymorph B form, which process comprises triturating or crystallizing or precipitating crude N-t-butyl-androst-3, 5-diene-17 β -carboxamide-3- carboxylic acid from a solution consisting of or primarily consisting of acetonitrile, 2-butanone, methanol or tetrahydrofuran with subsequent isolation of said polymorph. 5. A process according to claim 4 which comprises triturating crude N-t-butyl-androst-3, 5-diene-17β- carboxamide-3-carboxylic acid in a solution of boiling acetonitrile with subsequent isolation of said polymorph. 6. A process according to claim 4 which comprises precipitating crude N-t-butyl-androst-3, 5-diene-17β- carboxamide-3-carboxylic acid from 2-butanone by concentration and with the addition of petroleum ether with subsequent isolation of 'said polymorph. 7. A process for preparation of a compound of the structure substantially in the polymorph B form, which comprises triturating or crystallizing or precipitating crude N-t- butyl-androst-3, 5-diene-17β-carboxamide-3-carboxylic acid from a solvent consisting of a combination of solvents selected from acetonitrile, 2-butanone, methanol and tetrahydrofuran with subsequent isolation of said polymorph.

Inventors: BAINE NEIL HOWARD, ERHARD KARL, GOODYEAR MICHAEL DAVID, OWINGS FRANKLIN F, WEBB ROBERT LEE, ZUBER GARY EDWARD, BAINE, NEIL, HOWARD, ERHARD, KARL, GOODYEAR, MICHAEL, DAVID, OWINGS, FRANKLIN, F., WEBB, ROBERT, LEE, ZUBER, GARY, EDWARD
Applicants: SMITHKLINE BEECHAM CORP, SMITHKLINE BEECHAM CORPORATION
Application year: 1993
Main classification: C07J41
IPC codes: C07J41, C07J75