Spray Dried Nano-Crystalline Powders and In Vitro Dissolution Performance

Quality by Design principles has been applied to understand formulation and optimization of nano-crystalline spray-dried powders of poorly soluble drugs. The objectives of this research were to: 1) investigate the effect of wet media milling on nano-crystalline suspensions; 2) investigate the effect of spray-drying process and formulation parameters on nano-crystalline suspensions; 3) understand role of bulking agents during spray or freeze-drying of nano-crystalline suspensions; and 4) investigate the effect of different sized spray-dried nano-crystals on in vitro dissolution performance. Poorly soluble drugs were utilized to investigate the aggregation of nano-crystals during the spray drying process. It was determined that temperature and excipient utilized in the formulations plays an important role in nano-crystal aggregation. Low inlet temperature (preferably less than drug melting temperature) for spray drying processing and the addition of stabilizers/excipients with favorable or strong interaction (such as ionic or hydrogen bonding etc.) with the drug will provide better stability of the nano-crystals and thus no or minimal nano-crystal aggregation. The percent yield of spray-dried powders is dependent on the glass transition temperature of the formulations and/or bulking agents utilized. Small molecular weight bulking agents (or matrix formers) prevented nano-crystal aggregation due to favorable interactions with the stabilizers. Stabilizers with favorable or strong interaction with the drug are preferred for the stability of nano-crystalline suspensions but this may cause physical and chemical instability (such as solid-state transformation, drug degradation etc.) during high intensity wet milling processing. USP apparatus II was modified to hold dialysis sacs and this method was utilized to test and distinguish nano-crystalline formulations based on their size. The developed in vitro release testing method (or dissolution method) was able to distinguish nano-crystalline formulations based on size. This method can be utilized for routine quality control assays performed in the pharmaceutical industry and potentially for the development of IVIVC for these formulations. In conclusion, QbD (or specifically DoE) studies performed in this research are examples of how this approach can be utilized to understand formation and stabilization of nano-crystalline suspensions during milling and/or drying to achieve non-aggregating stable nano-crystalline powders for desired in vitro and/or in vivo performance