[Show abstract][Hide abstract] ABSTRACT: Biopharmaceutical evaluation of crystalline celecoxib salts in novel solid formulations, which were designed to simultaneously facilitate dissolution and inhibit precipitation in vitro, showed fast and complete absorption in beagle dogs at doses up to 7.5 mg/kg orally. In contrast, 5 mg/kg celecoxib in the form of Celebrex(R) showed approximately 40% absolute bioavailability in a cross-over experiment. An in vitro-in vivo correlation was observed in dog, and a threshold level of in vitro dissolution needed to maximize in vivo performance was highlighted. Oral bioavailability was limited in the absence of excipient combinations that delayed precipitation of celecoxib free acid as the salt neutralized in the GI fluid. Formulations of crystal forms having high energy (a 'spring'), thus transiently increasing solubility in aqueous solution relative to the free acid, combined with excipients functioning as precipitation inhibitors ('parachutes') were shown to provide both enhanced dissolution and high oral bioavailability.
No preview · Article · Oct 2007 · Journal of Pharmaceutical Sciences
[Show abstract][Hide abstract] ABSTRACT: Acetaminophen is both polymorphic and prone to the formation of a trihydrate. The recently discovered trihydrate is a lath-like crystalline form that is highly metastable with respect to conversion to the thermodynamically stable form I polymorph. While the trihydrate is physically stable in ice-cold aqueous suspension (with up to 50% propylene glycol or glycerol), conversion of trihydrate takes place at temperatures above 5 °C via a solution-mediated transformation pathway to produce form I. On drying, the optically transparent trihydrate laths transform to an opaque, micronized form I. The metastable trihydrate is characterized as a maximally solvated form that appears to defy Ostwald's rule of stages and thus behaves fundamentally differently from the highly metastable polymorph form III.
[Show abstract][Hide abstract] ABSTRACT: Three crystal forms of acetaminophen were prepared and characterized using a newly developed high-throughput crystallization platform, CrystalMax. The platform consists of design software, robotic sample dispensing and handling, and high-throughput microanalytics and is capable of running thousands of crystallizations in parallel using several different methods to drive supersaturation and subsequent crystallization. Additionally, structural models of the elusive third form of acetaminophen will be discussed on the basis of powder X-ray diffraction data. One structure suggested has a bilayer motif, held together by O-H...O(H) hydrogen bonds, and helps explain the difficulty associated with preparing this form from solution.
No preview · Article · Oct 2002 · Journal of the American Chemical Society