Pharmaceutical co-crystal compositions

Example 1

1:1 carbamazepine:saccharin co-crystals (Form I) were prepared. A 12-block experiment was designed with 12 solvents. 1152 crystallization experiments were carried out using the CMAX platform. The co-crystal was obtained from a mixture of isopropyl acetate and heptane. Detailed characterization of the co-crystal is listed in Table V. (See FIGS. 1 and 2)

Example 8

Co-crystals of itraconazole and succinic acid were prepared. Approximately 51.1 mg of cis-itraconazole free base, 0.75 mL of THF, and a magnetic stir bar were charged into a screw cap vial, heated to reflux to dissolve, and then the vial was closed with the screw cap and placed on top of a hot plate maintained at a temperature between 60 and 75 degrees C. A solution of 77.7 mg of succinic acid in 1.58 mL of THF was prepared. 0.20 mL of the succinic acid solution was added to the cis-itraconazole solution and the solution remained clear. 0.75 mL of iso-propylacetate was added and the solution was seeded with <1 mg of the L-tartaric acid co-crystal salt from Example 10 below. The heat was turned off and the sample crystallized as it cooled to room temperature. The cooled sample was suction filtered. It was rinsed with 0.2-0.3 mL of THF. The filter cake was broken-up and allowed to air-dry for 1 hour prior to analysis. (See FIGS. 12 and 13)

Example 9

Co-crystals of itraconazole and fumaric acid were prepared. Approximately 500 mg of cis-itraconazole free base was placed in a 50 mL screw top bottle along with 33.33 mL of tetrahydrofuran (THF). 3.0887 mL of fumaric acid stock solution (prepared in Example 1) was then added to the beaker (resulting in a 1.05:1 ratio of salt former to free base). The cap was screwed on to seal the bottle and the bottle was placed in a 70 degrees C. oven (Model # 1400E, VWR Scientific) and heated for approximately 1 hour. Thereafter, the bottle was removed from the oven, the cap from the bottle was removed, and the sample was allowed to evaporate under flowing air under ambient conditions. When all but about 5 mL of the solvent had evaporated, the remaining solvent was removed by decantation and the solid was isolated by filtering over a Whatman filter using suction. This solid was returned back into the 50 mL bottle with the remaining solid and the bottle was placed into the vacuum oven at approximately 25 mm Hg and the solid was allowed to dry for 4 days prior to analysis. (See FIGS. 14 and 15)

Example 10

Co-crystals of itraconazole and tartaric acid were prepared. Approximately 100.4 mg of cis-itraconazole free base, 0.90 mL of THF, and a magnetic stir bar were charged into a screw cap vial, heated to reflux to dissolve, and then the vial was closed with the screw cap and placed in an oil bath maintained at 70 degrees C. A solution of 138.5 mg of L(+) tartaric acid in 1.15 mL of THF was prepared. 0.21 mL of the L(+)tartaric acid solution was added to the cis-itraconazole solution and the solution remained clear. 0.90 mL of iso-propylacetate was added and the solution was seeded with <1 mg of the salt from a preparation of DL-tartaric acid co-crystal. The sample was allowed to crystallize over about 5 minutes in the 70 degrees C. oil bath before it was removed and allowed to cool to room temperature. The cooled sample was suction filtered. It was rinsed with 0.2-0.3 mL of THF. The filter cake was broken-up and allowed to air-dry for 4 hours prior to analysis. (See FIGS. 16 and 17)

Example 42

A co-crystal with reduced form diversity as compared to the API has been prepared. Co-crystals of carbamazepine and saccharin have been prepared via method shown in example 1.