18 research outputs found
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
Simulated superficial and deep tissue doses using niobium filtration for cephalometric radiography
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%