Excipient quantitation and drug distribution during formulation optimization.

Abstract

An oral granules formulation experienced high drug content and increased variability when the process was scaled up from lab scale to clinical manufacturing scale. It was suspected that mannitol, due to its smaller particle size and lower density, was preferentially lost during the top spray granulation process, thereby causing active enrichment in the remaining granules. In order to troubleshoot the problem, rapidly evaluate solutions, and further optimize the formulation, a simple and rapid analytical technique was required. Since mannitol does not have a UV chromophore, conventional HPLC/UV analysis could not be used. Three alternative analytical techniques were evaluated in terms of ease of use, reproducibility, linear dynamic range and rapidity. The HPLC/RID (refractive index detector) and HPLC/ELSD (evaporative light scattering detector) provided rapid, reproducible alternate techniques to HPLC/UV, whereas LC/MS showed poor reproducibility. Analysis of the sieve samples of the granulations by HPLC/RID and HPLC/ELSD confirmed that poor active drug distribution was due to mannitol losses in the filter bag, as well as increased low size granules low in active drug content. The resultant formulation process was modified and a reduction in the initial air flow at start-up reduced losses of mannitol in the granulator filters.