Formulation and performance of Irbesartan nanocrystalline suspension and granulated or bead-layered dried powders - Part I.

Nanocrystalline suspensions offer a promising approach to improve the dissolution rate of BCS Class II/IV drugs and hence oral bioavailability. Irbesartan (crystalline Form B), a poorly soluble drug substance was chosen as a model compound for the study. The objectives of the study were to formulate Irbesartan nanocrystalline suspension via media milling, study the effects of process and formulation variables on particle size reduction, and evaluate bead layering or spray granulation as drying processes. A Design of Experiment approach was utilized to understand the impact of formulation variables on particle size reduction via media milling. Drug concentration and type of stabilizer were found to be significant in particle size reduction. Optimized Irbesartan nanocrystalline suspension (i.e. at 10% w/w with 1% w/w poloxamer 407) showed superior in vitro dissolution profile compared to unmilled suspension. Optimized Irbesartan nanocrystalline suspension was converted into dried powders either by bead layering (with microcrystalline cellulose) or by spray granulation (either with mannitol or microcrystalline cellulose). DSC and PXRD studies revealed that Irbesartan remained crystalline post drying. Microcrystalline cellulose beads layered with Irbesartan nanocrystals showed about 65% drug dissolution within the first 10 min of dissolution study. Mannitol granules containing Irbesartan nanocrystals were fast dissolving (i.e. >90% drug dissolution within 10 min) compared to microcrystalline cellulose granules (i.e. approx. 46% drug dissolution within 10 min). Irbesartan nanocrystalline suspension had the fastest dissolution rates (i.e. >90% drug dissolution in two minutes) followed by mannitol-based granules containing dried Irbesartan nanocrystals (i.e. >90% drug dissolution in ten minutes).