Preparation of sufentanil citrate and sufentanil base

1. A process for preparing sufentanil citrate from sufentanil base, the process comprising:

(a) forming a reaction mixture comprising sufentanil base, citric acid, and isopropyl alcohol;

(b) heating the reaction mixture to a temperature of 70° C. to 90° C. to form a solution comprising sufentanil citrate;

(c) cooling the solution comprising sufentanil citrate to 50° C. to 70° C., seeding with crystals of sufentanil citrate, and maintaining the temperature at 50° C. to 60° C. thereby forming a slurry, the slurry comprising solid sufentanil citrate; and

(d) maintaining the temperature of the slurry at 50° C. to 60° C. and filtering the slurry at 50° C. to 60° C. to recover the solid sufentanil citrate, which contains less than about 2000 ppm of isopropyl alcohol.

2. The process of claim 1 , further comprising:

(e) contacting the mixture remaining after recovery of solid sufentanil citrate with a proton acceptor to form a sufentanil base mixture;

(f) cooling the sufentanil base mixture to form solid sufentanil base; and

(g) recovering solid sufentanil base.

3. The process of claim 2 , further comprising contacting solid sufentanil base from step (g) with a non-polar solvent to form a mixture, heating the mixture to dissolve the sufentanil base, and cooling the mixture to form crystalline sufentanil base.

4. The process of claim 3 , wherein the proton acceptor comprises a hydroxide and the non-polar solvent is an alkane.