The relevance of supersaturation and solubilization in the gastrointestinal tract for oral bioavailability: An in vitro vs. in vivo approach.

The influence of supersaturation and solubilization on oral absorption was assessed independently from the dissolution process for the non-formulated model drugs celecoxib and telmisartan. In vitro, physicochemical characterization and biphasic dissolution were used to characterize the supersaturation and solubilization effects of three water soluble polymers (copovidone, methylcellulose and Soluplus®) on the drugs. While celecoxib precipitated in a crystalline form resulting in pronounced stabilization of supersaturation, telmisartan precipitated as a highly energetic amorphous form and the potential of the polymers to enhance its solubility was subsequently, limited. In vivo, for the crystalline precipitating celecoxib, supersaturation and solubilization increased its oral bioavailability up to 10-fold. On the contrary, the amorphous precipitating telmisartan did not benefit from the limited stabilization in terms of oral exposure. Amongst all investigated in vitro tests the biphasic dissolution test was the most predictive in relation to supersaturation. However, for the potential micellar solubilization and the respective impact in the aqueous/organic interface, prediction accuracy of the biphasic dissolution test was limited in combination with Soluplus®. Despite the hetergeneous micellar distribution in vitro and permeation in vivo, the biphasic approach could clearly show the supersaturation potential on bioavailability (BA) for celecoxib on the one hand and the inferiority of supersaturation on BA for telmisartan.

Formulation of Ketoconazole Nanocrystal-Based Cryopellets.

Commercial development of nanosuspensions for oral drug delivery generally involves a drying step which aims to generate a stable product that rapidly releases the nanocrystals once rehydrated and can be easily processed into a final dosage form (e.g., filled into hard capsule). Cryopelletisation is a freeze drying technique allowing the production of lyophilised micrometric spheres with good flowability. In the current work, the possibility to formulate redispersible ketoconazole nanocrystal-based cryopellets able to withstand intensive handling was investigated. Cryopellets were generated by first freezing regular droplets of nanosuspension using liquid nitrogen followed by water removal by sublimation in a standard freeze dryer. Low-friable cryopellets (< 1%) were produced by embedding the nanocrystals in a stabilizing hydroxypropyl cellulose SSL grade matrix, thus proving that these structures can withstand intensive handling. A threshold quantity of hydroxypropyl cellulose SSL grade (5/20 hydroxypropyl cellulose SSL grade-to-drug mass ratio) was required in combination with D-α-tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS) to successfully recover the nanocrystals over storage. A further addition of micronised crospovidone has shown a positive effect on the dissolution performance of cryopellets. Altogether, this study demonstrated that the design of cryopellets combining the strengths of freeze-dried powders (porous internal structure, low residual humidity) and pellets (free-flowing units, mechanical resistance during handling) can potentially improve the nanocrystal's redispersibility compared with other drying techniques while facilitating the downstream processing.

Active freeze drying for production of nanocrystal-based powder: A pilot study.

Active Freeze Drying allows for producing lyophilised powders by progressive agitation of frozen blocks undergoing sublimation. One potential application of this process is the formulation design of unstable nanosuspensions for oral drug delivery, as here shown for nanocrystal-based ketoconazole powder. With this technique, a critical vapour flow needs to be achieved in order to obtain reasonable process yields (>78%). The size distribution of powder particles (median size between 21 and 44 µm) was affected by the nanocrystal concentration and the drug-to-stabilizer ratio. This was assumed to be related to the mechanical strength of the solid network from which the powder particles break off. The adjustments of the drug-to-stabilizer ratio and the freezing procedure proved to play a major role in improving powder redispersibility. However, differences in powder redispersibility did not translate into significant changes in in-vitro dissolution rates. Active Freeze Drying has confirmed to be a promising tool to efficiently produce redispersible nanocrystal powders.