A recently developed method (Hammond et al., 2006) for estimating solution binding at crystal habit surfaces and hence
interfacial tension is extended to calculations of solution-effected attachment energies and hence to the prediction of solvent-mediated
crystal morphology. The method is validated through examination of the morphology of aspirin crystallized from aqueous ethanolic solutions.
The influence of supersaturation on the resultant crystal morphology is also discussed with reference to the differing intermolecular packing
on this material's different crystal habit surfaces. The importance of preventing kinetic roughening via maintaining a facetted external
growth morphology in terms of minimizing product purity is also highlighted.
A molecular modeling approach is used to study the stability of different polymorphic forms of l-glutamic acid through building and optimizing molecular clusters of different sizes and shapes with the latter corresponding to the predicted crystal growth morphologies. The results reveal that the initially nucleating (according to Oswald rule) metastable (alpha) form is the more energetically stable form at small cluster sizes of ca. 200 molecular units, whereas the stable (beta) form is more stable when the cluster size is larger.
Although there are significant number of in-silico models, it has been proven very difficult to predict aqueous solubility accurately. Therefore, we have taken a different approach where the solubility is not predicted directly but is de-convoluted into two constituent features.
The synthonic modeling approach provides a molecule-centered understanding of the surface properties of crystals. It has been applied extensively to understand crystallization processes. This study aimed to investigate the functional relevance of synthonic modeling to the formulation of inhalation powders by assessing cohesivity of three active pharmaceutical ingredients (APIs, fluticasone propionate (FP), budesonide (Bud), and salbutamol base (SB)) and the commonly used excipient, α-lactose monohydrate (LMH). It is found that FP (-11.5 kcal/mol) has a higher cohesive strength than Bud (-9.9 kcal/mol) or SB (-7.8 kcal/mol). The prediction correlated directly to cohesive strength measurements using laser diffraction, where the airflow pressure required for complete dispersion (CPP) was 3.5, 2.0, and 1.0 bar for FP, Bud, and SB, respectively. The highest cohesive strength was predicted for LMH (-15.9 kcal/mol), which did not correlate with the CPP value of 2.0 bar (i.e., ranking lower than FP). High FP-LMH adhesive forces (-11.7 kcal/mol) were predicted. However, aerosolization studies revealed that the FP-LMH blends consisted of agglomerated FP particles with a large median diameter (∼4-5 μm) that were not disrupted by LMH. Modeling of the crystal and surface chemistry of LMH identified high electrostatic and H-bond components of its cohesive energy due to the presence of water and hydroxyl groups in lactose, unlike the APIs. A direct comparison of the predicted and measured cohesive balance of LMH with APIs will require a more in-depth understanding of highly hydrogen-bonded systems with respect to the synthonic engineering modeling tool, as well as the influence of agglomerate structure on surface-surface contact geometry. Overall, this research has demonstrated the possible application and relevance of synthonic engineering tools for rapid pre-screening in drug formulation and design.
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