The crystallization of fenofibrate (FF) from methanol (MeOH) was carried out in the presence of the following dispersed excipients: α/β-lactose (α/β-Lac), d-mannitol (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 MeOH 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 ∼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.

It is known that chemical and physical compatibility between a heterosurface and the crystallizing molecule promotes heterogeneous nucleation. In this work, acetaminophen (AAP), α/β-lactose (α/β-Lac), and methanol (MeOH) were selected as the model active pharmaceutical ingredient, excipient, and solvent, respectively. The excipientsuspended in a supersaturated solution of AAP in MeOHwas used as a heterogeneous surface ("seed"), and parameters influencing the heterogeneous nucleation of the AAP, such as (a) AAP solution/excipient contact time, (b) AAP supersaturation, and (c) AAP to excipient loading, were varied to demonstrate how the nucleation rate and the degree of crystallization can be manipulated to control the particle size and the balance between nucleation and growth. In this regard, the crystallizations were performed at a supersaturation which was shown not to promote nucleation of AAP up to 2 h in the absence of α/β-Lac. Thereafter, during the heterogeneous crystallizations of AAP in the presence of α/β-Lac, AAP particles nucleated on the α/β-Lac surface and then grew uniformly, producing small AAP particles (<15 μm) in a robust manner such that the particle size distribution was maintained constant over a range of contact times, supersaturations, and AAP loadings (%).