Crystallization of active pharmaceutical ingredients in the presence of heterosurfaces

This research investigates the mechanism of the heterogeneous nucleation of active pharmaceutical ingredients (APIs) in the presence of different ‘heterosurfaces’, i.e. excipients and polymers films. In the first part of the work, shown in Chapter 3, 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 AAP, such as (a) the AAP solution/excipient contact time, (b) the AAP supersaturation, and (c) the 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. With the knowledge taken from the first part of the work, a different crystallization system was studied in Chapter 4. A poorly water-soluble API, fenofibrate (FF), with a much longer induction time was used to determine whether the processing parameters for heterogeneous API nucleation in the presence of different excipients could be optimised to decrease the induction time, increase the rate of API nucleation and control the API particle growth process such that the API’s dissolution rate could therefore be improved. The excipients were found to strongly enhance FF’s nucleation rate during its crystallization from supersaturated MeOH solutions relative to the rate observed in the absence of the excipients; this was accompanied by a pronounced reduction in the induction time for FF from > 22 hours in the absence of excipients to ca. 15 minutes in their presence at optimum conditions. Furthermore, the choice of excipient and process conditions can be used to reduce particle size and thus improve dissolution rates of these poorly water-soluble APIs. With the aim of understanding the effect of the surface topography and wettability of ‘heterosurfaces’ on the crystallization of APIs, static polymer coupons with different 7 | P a g e wettability properties and surface roughness were used as ‘heterosurfaces’ in Chapter 5. Polymers with high wettability facilitated a pronounced reduction in the induction time compared to that observed during homogeneous nucleation, with evidence that the nucleation initially started on the polymer surface. In addition, the reduction in the induction time was slightly higher when the polymer surface was covered with grooves instead of simply being presented as a relatively smooth flat surface. A homogeneously dispersed layer of small (<50 m) API particles on polymer surfaces can be obtained in less than 5 minutes using this approach. Such API-coated polymer surfaces could be potentially used as medical devices with ancillary medical substances. Finally, Chapter 6 provides an overview of the mechanism of heterogeneous crystallization by combining previous results with additional data to provide a clearer understanding of this type of crystallization process. As such, the crystallization of AAP and FF in the presence and in the absence of excipients was studied in detail by monitoring the processes at a 500 mL scale using FBRM and FTIR probes. An explanation for the heterogeneous crystallization of APIs on excipient surfaces is offered in terms of intermolecular functional group complementarity, molecular volume and solubility is given, which may be helpful to consider for the selection of APIs and excipients in the design of future heterocrystallization experiments.