Role of hydrogen bonding lifetime and complementarity in heterogeneous nucleation

This work investigates the mechanism for the heterogeneous nucleation of active pharmaceutical ingredients (APIs) in the presence of different excipient heterosurfaces. By elucidating this mechanism for a range of API molecules, the appropriate crystallisation conditions and heterosurfaces can be selected in silico for individual APIs to then generate API crystals of the desired size and morphology via controlled heterogeneous crystallisation processes, thus facilitating control over the API dissolution process. The crystallisation of seven 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 the excipients α/β-lactose (α/β-lac), β-D-mannitol (β-D-man), dextran (DEX), chitosan (CHT), carboxymethyl cellulose (CMC) and microcrystalline cellulose (MCC), each of which acted as a heterosurface. Two of the APIs, namely AAP and CBMZ, possess hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) functionalities whereas the other five only possess HBA functionality. The crystallisation experiments for all seven APIs were carried out within or at the limit of their respective metastable zones at supersaturation ratios in the range of 1.08 to 1.50. A novel methanol solvate of CPB was also discovered during these crystallisation experiments. API crystallisations in the presence of a heterosurface were accompanied by a more pronounced acceleration of the crystallisation for those APIs possessing only HBA functionality relative to the acceleration observed for the APIs possessing HBA and HBD functionalities. The smallest heterosurface acceleration of crystallisation 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 crystallisations carried out in the presence and absence of the heterosurface; by contrast, the pre-exponential factor was generally larger for crystallisations carried out in the presence of the heterosurface than in its absence. Density Functional Theory (DFT) and Molecular Density calculations complemented the above experimental study. Thereafter, a model of heterogeneous crystallisation was developed wherein two factors were identified. The first of these was the complementarity of hydrogen bonding between the heterosurface and the APIs. Hence the crystallisation of APIs without HBD functionality was accelerated more strongly than for those with HBA and HBD functionality because the heterosurface provided the HBD functionality lacking in these APIs which allowed them to attach or adsorb to the heterosurface and thus act as nucleation points for the API’s crystallisation. The second factor identified was that the hydrogen bonding lifetime of the individual API molecules or small API clusters attached to a heterosurface is much longer (up to 1000 times) than (i) the lifetime of API-API interactions in the 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 molecules or small clusters of the API in solution will add to the adsorbed or attached species thus favouring the heterogeneous route to crystallisation. In addition to enhanced control over nucleation and particle growth, the resultant APIexcipient composites from this heterogeneous nucleation process were shown to demonstrate improved dissolution profiles and could be directly tableted, with lower downstream processing requirements than homogeneously crystallised API. Specifically, a pronounced improvement in the dissolution of CBMZ FIII and desolvated CPB was observed when crystallised in the presence of excipients when compared with the physical mix of APIexcipient. The isolated solids were mixed with disintegrant and lubricant, and were tabletted by direction compression to confirm the tabletability. Hence heterogeneous nucleation can potentially help in reducing the downstream processing.