Preparation of sufentanil citrate and sufentanil base

1. A process for preparing crystals of sufentanil citrate, the process comprising:

a) forming a solution of sufentanil citrate by contacting sufentanil citrate with a polar non-aqueous solvent chosen from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, or combination thereof at a temperature from about 70° C. to about 90° C.;

b) cooling the solution of sufentanil citrate to a temperature from 50° C. to about 70° C. to form a plurality of crystals of sufentanil citrate; and

c) filtering the plurality of crystals of sufentanil citrate at a temperature from 50° C. to about 60° C. thereby isolating crystals of sufentanil citrate, wherein said crystals of sufentanil citrate contain less than 5000 ppm of the polar non-aqueous solvent.

2. The process of claim 1 , wherein the polar non-aqueous solvent is 2-propanol.

3. The process of claim 1 , wherein sufentanil citrate at step a) is formed by contacting sufentanil base with citric acid in the presence of the polar non-aqueous solvent.

4. The process of claim 3 , wherein the contacting is conducted at a temperature from about 20° C. to about 90° C.

5. The process of claim 1 , wherein step b) further comprises seeding with crystals of sufentanil citrate.

6. The process of claim 1 , wherein the plurality of crystals of sufentanil citrate formed at step b) is maintained at 50° C. to about 60° C. for up to about 24 hours prior to step c).

7. The process of claim 1 , wherein said crystals of sufentanil citrate contain less than about 4000 ppm of the polar non-aqueous solvent.

8. The process of claim 7 , wherein said crystals of sufentanil citrate contain less than about 3000 ppm of the polar non-aqueous solvent.

9. The process of claim 8 , wherein said crystals of sufentanil citrate contain less than about 2000 ppm of the polar non-aqueous solvent.

10. The process of claim 9 , wherein said crystals of sufentanil citrate contain less than about 1000 ppm of the polar non-aqueous solvent.