Chromatography as an Enabling Technology in Pharmaceutical Process Development: Expedited Multikilogram Preparation of a Candidate HIV Protease Inhibitor

Abstract

Chromatography plays a vital role in supporting preclinical pharmaceutical development, whether in providing assays for purity determinations, preparative separation of small amounts of intermediates for route selection studies, or purification of bulk drug substances on multikilogram scale. All three approaches are illustrated in the recent development of a candidate HIV protease inhibitor in these laboratories. Chiral supercritical fluid chromatography (SFC) on the hundreds-of-milligrams scale afforded an enantiopure intermediate to facilitate early synthetic studies, HPLC on the tens-of-grams scale provided purified material for use in salt form investigations, and HPLC using a 30 cm column was used to purify 5.6 kg of a key intermediate to provide material for early preclinical evaluations.