Formulation possibilities of a weak base with a narrow solubility range

Márta Venczel, Ida Szvoboda, Benjámin Podányi, Delphine Valente, Jerome Menegotto, Klára Pintye-Hódi, Gabriella Ujhelyi

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The target of this article is to summarize the chemical and pharmaceutical (formulation) approaches that were found to be suitable for increasing the bioavailability of a model weak base (SAR1) with a very narrow good solubility range at physiologically relevant pH.(1) As part of the preformulation and formulation development to support toxicological and first in man studies of a free base (SAR1), several formulation approaches, including particle size reduction, emulsions, permeability enhancers, amorphous dispersions, salt formation, and co-crystal formation, were screened by in vitro dissolution methods and in vivo pharmacokinetic (PK) studies to evaluate and rank formulation performance. From the PK studies, it was observed that a suspension formulation containing a SAR1 fumaric acid (1:1) co-crystal provided the best oral exposure. Sensitivity of the co-crystal to physical disintegration into base and fumaric acid was solved by including Cremophor ELP as a solubility enhancer, surfactant, and co-crystal protector. This formulation was well-tolerated in rat. A flow-through dissolution method was more discriminating than the paddle type dissolution equipment for evaluation of co-crystal containing solid formulations.

Original languageEnglish
Pages (from-to)1101-1110
Number of pages10
JournalCrystal Growth and Design
Volume12
Issue number3
DOIs
Publication statusPublished - Mar 7 2012

ASJC Scopus subject areas

  • Chemistry(all)
  • Materials Science(all)
  • Condensed Matter Physics

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  • Cite this

    Venczel, M., Szvoboda, I., Podányi, B., Valente, D., Menegotto, J., Pintye-Hódi, K., & Ujhelyi, G. (2012). Formulation possibilities of a weak base with a narrow solubility range. Crystal Growth and Design, 12(3), 1101-1110. https://doi.org/10.1021/cg200462g