Crystalline Efavirenz
AssigneeBristol-Myers Squibb Pharma Company
InventorsLilian A. Radesca, Michael B. Maurin, Shelley R. Rabel, James R. Moore
Life of this patent
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Abstract
The potent reverse transcriptase inhibitor Efavirenz is produced in crystalline form. Crystalline Efavirenz exists in several physical forms which are-designated Forms 1, 2, 3 and 4, and are characterized by x-ray powder diffraction and differential scanning calorimetry. Pharmaceutical compositions and methods are useful for the treatment of the human immunodeficiency virus (HIV).
Claims45
Form 2 of crystalline Efavirenz which is characterized by an x-ray powder diffraction pattern substantially in accordance with that shown in FIG. 2.
A process for preparing Form 4 of crystalline Efavirenz which is characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 8, the process comprising:
- 1) adding a suitable second solvent to a solution of Efavirenz in a first solvent to produce a final solution;
- 2) distilling the final solution to a solvent composition from which Efavirenz crystallizes as Form 4 crystals;
- and
- 3) isolating the crystals.
Form 5 of crystalline Efavirenz which is characterized by an x-ray powder diffraction pattern comprising four or more 2θ values selected from the group consisting of:
- 10.2±0.2, 11.4±0.2, 11.6±0.2, 12.6±0.2, 19.1±0.2, 20.6±0.2, 21.3±0.2, 22.8±0.2, 24.8±0.2, 27.4±0.2, 28.2±0.2, and 31.6±0.2.
Form 2 of crystalline Efavirenz which is characterized by an differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 6.
Form 5 of crystalline Efavirenz which is characterized by a differential scanning calorimetry thermogram having a peak at about 108° C. to about 110° C.
Form 2 of crystalline Efavirenz which is characterized by an x-ray powder diffraction pattern comprising four or more 2θ values selected from the group consisting of:
- 6.8±0.2, 9.2±0.2, 12.3±0.2, 16.2±0.2, 21.4±0.2, 22.7±0.2, 24.1±0.2, and 28.0±0.2.
A process for preparing Form 1 of crystalline Efavirenz, which is characterized by an x-ray powder diffraction pattern substantially in accordance with that shown in FIG. 1, the process comprising:
- 1) crystallizing Form 4 of crystalline Efavirenz from a solution of THF/heptane wherein the solution of THF/heptane is at about a 5% concentration of THF and is reduced to about a 1% concentration of THF;
- and
- 2) heating Form 4 of crystalline Efavirenz to a temperature of about 80° C. to about 100° C.
A process for preparing Form 1 of crystalline Efavirenz, which is characterized by an x-ray powder diffraction pattern comprising four or more 2θ values selected from the group consisting of:
- 6.0±0.2, 6.3±0.2, 10.3±0.2, 10.8±0.2, 14.1±0.2, 16.8±0.2, 20.0±0.2, 20.5±0.2, 21.1±0.2, and 24.8±0;
- the process comprising:
- 1) crystallizing Form 4 of crystalline Efavirenz from a solution of THF/heptane wherein the solution of THF/heptane is at about a 5% concentration of THF and is reduced to about a 1% concentration of THF;
- and
- 2) heating Form 4 of crystalline Efavirenz to a temperature of about 80° C. to about 100° C.
A process for preparing Form 1 of crystalline Efavirenz, which is characterized by a differential scanning calorimetry thermogram having a peak at about 138° C. to about 140° C., the process comprising:
- 1) crystallizing Form 4 of crystalline Efavirenz from a solution of THF/heptane wherein the solution of THF/heptane is at about a 5% concentration of THF and is reduced to about a 1% concentration of THF;
- and
- 2) heating Form 4 of crystalline Efavirenz to a temperature of about 80° C. to about 100° C.
A process for preparing Form 1 of crystalline Efavirenz, which is characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 5, the process comprising:
- 1) crystallizing Form 4 of crystalline Efavirenz from a solution of THF/heptane wherein the solution of THF/heptane is at about a 5% concentration of THF and is reduced to about a 1% concentration of THF;
- and
- 2) heating Form 4 of crystalline Efavirenz to a temperature of about 80° C. to about 100° C.
Dependencies are inferred from the claim text.