Utility of hydroxypropylmethylcellulose acetate succinate (HPMCAS) for initiation and maintenance of drug supersaturation in the GI milieu.
OBJECTIVE
To identify materials and processes which effect supersaturation of the GI milieu for low solubility drugs in order to increase oral bioavailability.


METHODS
A variety of small and polymeric molecules were screened for their ability to inhibit drug precipitation in supersaturated solutions. The best polymeric materials were utilized to create spray-dried dispersions (SDDs) of drug and polymer, and these were tested for drug form and homogeneity. Dispersions were tested in vitro for their ability to achieve and maintain drug supersaturation, for a variety of drug structures.


RESULTS
Of the 41 materials tested, HPMCAS was the most effective at maintaining drug supersaturation. Drug/HPMCAS SDDs were consistently more effective at achieving and maintaining drug supersaturation in vitro than were SDDs prepared with other polymers. Drug/HPMCAS SDDs were effective in vitro for eight low solubility drugs of widely varying structure. Drug/HPMCAS SDDs were more effective at achieving and maintaining supersaturation than were rotoevaporated Drug/HPMCAS dispersions or physical mixtures of Drug and HPMCAS. The degree of achievable drug supersaturation increased with increasing polymer content in the SDD. The drug in Drug /HPMCAS SDDs was amorphous, and the dispersions were demonstrated to have a single glass transition and were thus homogeneous.


CONCLUSIONS
HPMCAS has been identified as a uniquely effective polymer for use in SDDs of low solubility drugs, with broad applicability across a variety of drug structures and properties.
Curatolo
William
W
Pfizer Global R&D, Groton, CT 06340, USA. william.j.curatolo@pfizer.com
Nightingale
James A
JA
Herbig
Scott M
SM
D011232:Chemical Precipitation; D002626:Chemistry, Pharmaceutical; D005079:Excipients / Q000737:chemistry*; D005766:Gastrointestinal Contents / Q000737:chemistry*; D006801:Humans; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D033362:Powder Diffraction; D012995:Solubility; D044366:Transition Temperature; D014961:X-Ray Diffraction
D005079:Excipients; D004364:Pharmaceutical Preparations; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose