Heterogeneous Crystallization of Fenofibrate onto Pharmaceutical Excipients

The crystallization of fenofibrate (FF) from methanol (MeOH) was carried out in the presence of the following dispersed excipients: a//beta -lactose (a/beta -Lac), Dmannitol (D-Man), microcrystalline cellulose, carboxymethyl cellulose (CMC), silica (SiO2), and polycaprolactone (PCL). More control was achieved over the nucleation and crystal growth of the FF particles in the presence of excipients relative to its conventional crystallization using FF seed. Each of the excipients was found to strongly reduce the FF induction time during its crystallization from supersaturated Me0H solutions relative to the rate observed in the absence of the excipients; there was a pronounced reduction in the induction time for FF from >22 h in the absence of excipients to similar to 15 min in their presence at optimum conditions. These results are rationalised in terms of the lifetime of FF molecules attached to the excipient surface by hydrogen bonding. Additionally, the FF particle size can be optimized by adjusting the FF loading (% w/w) and the crystallization temperature. The dissolution rate of the small FF particles generated via crystallization in the presence of excipients was comparable to the dissolution rate of the ground commercial FF (Lipantil Supra) and was faster compared to that of the FF crystallized in the presence of seed. Thus, the process parameters of heterogeneous crystallization in the presence of pharmaceutical excipients can reduce induction times and control API particle size.