Control of Heterogeneous Nucleation via Rationally Designed Biocompatible Polymer Surfaces with Nanoscale Features

Direct control of nucleation in a crystallization process is difficult to achieve but offers many potential benefits to the food, chemicals, and pharmaceutical industries. We demonstrate a rational approach for designing and fabricating biocompatible polymer films that can drastically enhance nucleation rates and enable polymorph selection of small-molecule compounds. The core design philosophy was to calculate angles between major crystal faces and determine suitable substrate geometry to use for enhancing heterogeneous nucleation. Aspirin and indomethacin were used as model compounds; poly­(vinyl alcohol) (PVA) with no additional chemical modification was made into films and imprinted with nanoscale features. Nucleation induction time experiments showed that using PVA films significantly reduced the nucleation induction time at a fixed supersaturation due to favorable chemical interactions and could be further reduced when the angles of the nano-indentations on the substrate matched the angles between different crystalline faces. X-ray diffraction (XRD) was used to reveal the interactions between the model compounds and PVA to suggest possible molecular packing in the indentations. Induction time and XRD results demonstrated validity of the rational design approach based on angle-directed nucleation. Finally, polymorph selection toward γ-indomethacin with PVA substrates showed that it is possible to control polymorph composition of the final crystalline product by kinetically controlling the nucleation process. For the aspirin system, the 85° angle led to the highest rate of nucleation; for the polymorphic indomethacin system, XRPD results showed that the gamma form preferentially formed on the PVA films with 65° and 80° angles leading to the largest reduction in nucleation induction time

Composite Hydrogels Laden with Crystalline Active Pharmaceutical Ingredients of Controlled Size and Loading

Efficient control of crystallization and crystal properties still represents a bottleneck in the manufacturing of crystalline materials ranging from pigments to semiconductor particles. In the case of pharmaceutical drug manufacture, current methods for controlling critical crystal properties such as size and morphology that dictates the product’s efficacy are inefficient and often lead to the generation of undesirable solid states such as metastable polymorphs or amorphous forms. In this work, we propose an approach for producing crystals of a poorly water-soluble pharmaceutical compound embedded in a polymer matrix. Taking advantage of the composite hydrogel structure, we control the crystallization of the active pharmaceutical ingredient (API), within the composite hydrogel, generating crystalline API of controlled crystal size and loading. The composite hydrogels initially consist of organic phase droplets, acting as crystallization reactors, embedded in an elastic hydrogel matrix. By controlled evaporation of this composite material, crystals of controlled size (330 nm to 420 μm) and loading (up to 85%w/w) are produced. Through the interplay of elasticity and confinement, composite hydrogels control the crystal size and morphology via a two-step mechanism. First, the elastic matrix counteracts evaporation-induced coalescence of the emulsion droplets, keeping droplets isolated. Second, a confinement-induced elastic energy barrier, limits the growth of crystals beyond the size designated by the droplets. The proposed approach can be applied to production of a wide range of crystalline materials

Application of Continuous Crystallization in an Integrated Continuous Pharmaceutical Pilot Plant

Real-time control using process analytical technology (PAT) tools is required for the implementation of continuous crystallization within integrated continuous manufacturing (ICM) of pharmaceuticals. However, appropriate selection of PAT tools is challenging, and the design and operation of automated control loops for continuous crystallization within a continuous pharmaceutical process brings forward important questions. This paper discusses the process design and operation of a continuous reactive crystallization of aliskiren hemifumarate as part of an ICM pilot plant. Several PAT tools were used within automated control loops to satisfy specifications on the critical materials attributes of the crystallization process. The operational performance of the process was maintained for periods of time over 100 h. The purity of the targeted product exceeded 99%, and the process yield reached 91.4%