Poor biopharmaceutical performance
of Biopharmaceutical Classification
System (BCS) class II drug molecules is a major hurdle in the design
and development of pharmaceutical formulations. Anisotropic surface
chemistry of different facets in crystalline material affects physicochemical
properties, such as wettability, of drugs. In the present investigation,
a molecule-centered approach is presented toward crystal habit modification
of celecoxib (CEL) and its effect on oral bioavailability. Two crystal
habits of CEL, acicular crystal habit (CEL-A) and a plate-shaped crystal
habit (CEL-P), were obtained by recrystallization from toluene at
25 and 60 °C, respectively. Compared to CEL-A, CEL-P exhibited
significantly faster dissolution kinetics in aqueous media and significantly
higher C
max and shorter T
max in an oral bioavailability study. The significant
enhancement in dissolution and biopharmaceutical performance of CEL-P
was attributed to its more abundant hydrophilic surfaces compared
to CEL-A. This conclusion was supported by wettability and surface
free energy determination from contact angle measurements and surface
chemistry determination by X-ray photoelectron spectroscopy (XPS),
crystal structure modeling, and crystal face indexation.
A new class of potent PI3Kα inhibitors is identified based on aryl substituted morpholino-triazine scaffold. The identified compounds showed not only a high level of enzymatic and cellular potency in nanomolar range but also high oral bioavailability. The three lead molecules (based on their in vitro potency) when evaluated further for in vitro metabolic stability as well as pharmacokinetic profile led to the identification of 26, as a candidate for further development. The IC50 and EC50 value of 26 is 60 and 500 nM, respectively, for PI3Kα enzyme inhibitory activity and ovarian cancer (A2780) cell line. The identified lead also showed a high level of microsomal stability and minimal inhibition activity for CYP3A4, CYP2C19, and CYP2D6 at 10 μM concentrations. The lead compound 26, demonstrated excellent oral bioavailability with an AUC of 5.2 μM at a dose of 3 mpk in mice and found to be well tolerated in mice when dosed at 30 mpk BID for 5 days.
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