The crystallization of seven active pharmaceutical ingredients (APIs) (acetaminophen (AAP), carbamazepine (CBMZ), caffeine (CAF), phenylbutazone (PBZ), risperidone (RIS), clozapine base (CPB), and fenofibrate (FF)) was studied in the absence and presence of microcrystalline cellulose (MCC) which acted as a heterosurface. Two of the active pharmaceutical ingredients (APIs), namely, AAP and CBMZ, possess hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) functionalities, whereas the other five possess HBA functionality only. Density functional theory (DFT) and molecular dynamics calculations complemented the experimental study. The smallest nucleation rate enhancement was observed for CBMZ at 1.4 times, and the largest was observed for FF at 16 times. For all the APIs studied, the interfacial energy was similar for crystallizations performed in the presence and absence of the heterosurface. By contrast, the pre-exponential factor was larger by a factor of ca. 2 and more for crystallizations carried out in the presence of the heterosurface. Arising from this study, a model of heterogeneous crystallization was developed wherein two influencing factors were identified. The first involves the issue of hydrogen bond complementarity between heterosurface and API. Hence, a HBD rich heterosurface will provide a hydrogen-bond mediated option for API cluster formation that would otherwise not be specifically available in solution to APIs possessing HBAs only. The second factor identified is that the lifetime of the hydrogen bond made by an individual API molecule or small API cluster with the heterosurface is up to 1000 times longer than (i) the lifetime of API−API interactions in a solution phase, or (ii) the time required for an API molecule to add to a growing crystal. This lifetime effect arises from the greater stability of an adsorbed species, and this extended lifetime increases the probability that other molecules or small clusters of the API in solution will add to the already adsorbed or attached species, thus encouraging the heterogeneous route to crystallization.

This study is based on the heterogeneous nucleation of active pharmaceutical ingredients (APIs) 2 in the presence of various excipients widely used in the pharmaceutical industry. Carbamazepine (CBMZ) was successfully crystallized in the presence of the following heterosurfaces: α/β-4 Lactose, β-D-Mannitol, microcrystalline cellulose and carboxymethyl cellulose. The successful 5 crystallization of CBMZ FIII in the presence of all the excipients was confirmed by powder X-6 ray diffraction and scanning electron microscopy, while CBMZ crystals apposition was 7 confirmed using in-situ SEM-Raman. A pronounced improvement in the dissolution of CBMZ 8 FIII was observed when crystallized in the presence of excipients when compared with CBMZ 9 FIII recrystallized using same conditions in the absence of the excipients. The isolated solids 10 could be simply tabletted by direction compression upon mixing with the desired amount of 11 disintegrant and lubricant. Hence employing this process could potentially streamline the 12 downstream process in pharmaceutical industries and also increase the throughput with reduced 13 cost. 14

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.

No abstract

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 (%).