Influence of Solvent Selection on the Crystallizability and Polymorphic Selectivity Associated with the Formation of the "Disappeared" Form I Polymorph of Ritonavir.

The comparative crystallizability and polymorphic selectivity of ritonavir, a novel protease inhibitor for the treatment of acquired immune-deficiency syndrome, as a function of solvent selection are examined through an integrated and self-consistent experimental and computational molecular modeling study. Recrystallization at high supersaturation by rapid cooling at 283.15 K is found to produce the metastable "disappeared" polymorphic form I from acetone, ethyl acetate, acetonitrile, and toluene solutions in contrast to ethanol which produces the stable form II. Concomitant crystallization of the other known solid forms is not found under these conditions. Isothermal crystallization studies using turbidometric detection based upon classical nucleation theory reveal that, for an equal induction time, the required driving force needed to initiate solution nucleation decreases with solubility in the order of ethanol, acetone, acetonitrile, ethyl acetate, and toluene consistent with the expected desolvation behavior predicted from the calculated solute solvation free energies. Molecular dynamics simulations of the molecular and intermolecular chemistry reveal the presence of conformational interplay between intramolecular and intermolecular interactions within the solution phase. These encompass the solvent-dependent formation of intramolecular O-H...O hydrogen bonding between the hydroxyl and carbamate groups coupled with differing conformations of the hydroxyl's shielding phenyl groups. These conformational preferences and their relative interaction propensities, as a function of solvent selection, may play a rate-limiting role in the crystallization behavior by not only inhibiting to different degrees the nucleation process but also restricting the assembly of the optimal intermolecular hydrogen bonding network needed for the formation of the stable form II polymorph.

Universality of Hair as a Nucleant: Exploring the Effects of Surface Chemistry and Topography.

The ability to control crystal nucleation through the simple addition of a nucleating agent (nucleant) is desirable for a huge range of applications. However, effective nucleating agents are known for only a small number of systems, and many questions remain about the mechanisms by which they operate. Here, we explore the features that make an effective nucleant and demonstrate that the biological material hair-which naturally possesses a chemically and topographically complex surface structure-has excellent potential as an effective nucleating agent. Crystallization of poorly soluble compounds in the presence of hairs from a range of mammals shows that nucleation preferentially occurs at the cuticle step edges, while a novel microdroplet-based methodology was used to quantify the nucleating activities of different hairs. This showed that the activities of the hairs can be tuned over a wide range using chemical treatments. Analysis of the hair structure and composition using atomic force microscopy, scanning ion conductance microscopy, and X-ray photoelectron spectroscopy demonstrates that surface chemistry, surface topography, and surface charge all act in combination to create effective nucleation sites. This work therefore contributes to our understanding of heterogeneous nucleating agents and shows that surface topography as well as surface chemistry can be used in the design or selection of universal nucleating agents.

Serial small- and wide-angle X-ray scattering with laboratory sources.

Recent advances in X-ray instrumentation and sample injection systems have enabled serial crystallography of protein nanocrystals and the rapid structural analysis of dynamic processes. However, this progress has been restricted to large-scale X-ray free-electron laser (XFEL) and synchrotron facilities, which are often oversubscribed and have long waiting times. Here, we explore the potential of state-of-the-art laboratory X-ray systems to perform comparable analyses when coupled to micro- and millifluidic sample environments. Our results demonstrate that commercial small- and wide-angle X-ray scattering (SAXS/WAXS) instruments and X-ray diffractometers are ready to access samples and timescales (≳5 ms) relevant to many processes in materials science including the preparation of pharmaceuticals, nanoparticles and functional crystalline materials. Tests of different X-ray instruments highlighted the importance of the optical configuration and revealed that serial WAXS/XRD analysis of the investigated samples was only possible with the higher flux of a microfocus setup. We expect that these results will also stimulate similar developments for structural biology.

Positively Charged Additives Facilitate Incorporation in Inorganic Single Crystals.

Incorporation of guest additives within inorganic single crystals offers a unique strategy for creating nanocomposites with tailored properties. While anionic additives have been widely used to control the properties of crystals, their effective incorporation remains a key challenge. Here, we show that cationic additives are an excellent alternative for the synthesis of nanocomposites, where they are shown to deliver exceptional levels of incorporation of up to 70 wt % of positively charged amino acids, polymer particles, gold nanoparticles, and silver nanoclusters within inorganic single crystals. This high additive loading endows the nanocomposites with new functional properties, including plasmon coupling, bright fluorescence, and surface-enhanced Raman scattering (SERS). Cationic additives are also shown to outperform their acidic counterparts, where they are highly active in a wider range of crystal systems, owing to their outstanding colloidal stability in the crystallization media and strong affinity for the crystal surfaces. This work demonstrates that although often overlooked, cationic additives can make valuable crystallization additives to create composite materials with tailored composition-structure-property relationships. This versatile and straightforward approach advances the field of single-crystal composites and provides exciting prospects for the design and fabrication of new hybrid materials with tunable functional properties.

A Digital Mechanistic Workflow for Predicting Solvent-Mediated Crystal Morphology: The α and ß Forms of l-Glutamic Acid.

The solvent-mediated crystal morphologies of the α and ß polymorphic forms of l-glutamic acid are presented. This work applies a digital mechanistically based workflow that encompasses calculation of the crystal lattice energy and its constituent intermolecular synthons, their interaction energies, and their key role in understanding and predicting crystal morphology as well as assessing the surface chemistry, topology, and solvent binding on crystal habit growth surfaces. Through a comparison between the contrasting morphologies of the conformational polymorphs of l-glutamic acid, this approach highlights how the interfacial chemistry of organic crystalline materials and their inherent anisotropic interactions with their solvation environments direct their crystal habit with potential impact on their further downstream processing behavior.

The structural pathway from its solvated molecular state to the solution crystallisation of the α- and ß-polymorphic forms of para amino benzoic acid.

Para amino benzoic acid (PABA) has two well-characterised α- and ß-polymorphic forms and, whilst both crystallise in the monoclinic space group P21/n, they have quite different crystal chemistry and crystallisability behaviour. Previous work has shown that the molecular conformation deformation energy in the crystalline state is higher for the ß-form than for the α-form and that the lattice energy for the former converges more slowly than for the latter overall. This suggests that not only is there a higher barrier to crystallisation for the ß-form but also that low solution supersaturations might be needed for it to preferentially nucleate. Additionally, solute cluster propensity and solute solvation energetic analysis highlight the importance of an aqueous solvation environment in inhibiting the α-form's strong OH⋯O carboxylic acid hydrogen bond (H-bond) dimer. Despite this, the detailed molecular-scale pathway from solvated molecules to 3D crystallographic structure still remains unclear, most notably regarding how the nucleation process is activated and how, as a result, this mediates the preferential formation of either of the two polymorphic forms. Molecular dynamics (MD) simulations coupled with FTIR studies and intermolecular synthon analysis address this issue through characterisation of the propensity of the incipient bulk synthons that are important in the crystallisation of the two polymorphic forms within the solution state. MD molecular trajectory analysis within crystallisation solutions reveals a greater propensity for OH⋯O synthons (both single H-bonds and homodimers) typical of the α-form and NH⋯O synthons found in both the α- and ß-forms when compared to aqueous solution but much lower propensities for the ß-form's "fingerprinting" OH⋯N and π-π stacking synthons. In contrast, data from the aqueous solution environment reveals a much greater propensity for the ß-form's π-π interaction synthons. IR dilution studies in acetonitrile in the carbonyl region reveal the presence of two CO vibrational stretching bands, whose relative intensities vary as a function of solution dilution. These were assigned to the solvated PABA monomer and a COOH dimer of PABA. Similar data in ethanol shows a main CO stretching band with a shoulder peak suggesting a similar monomer vs. dimer speciation may exist in this solvent. The IR data is consistent with the organic solvent MD data, albeit the corresponding analysis for the aqueous solution was precluded due to the latter's strong OH vibrational mode which restricted validation in aqueous solutions.

Molecular, Solid-State and Surface Structures of the Conformational Polymorphic Forms of Ritonavir in Relation to their Physicochemical Properties.

PURPOSE: Application of multi-scale modelling workflows to characterise polymorphism in ritonavir with regard to its stability, bioavailability and processing. METHODS: Molecular conformation, polarizability and stability are examined using quantum mechanics (QM). Intermolecular synthons, hydrogen bonding, crystal morphology and surface chemistry are modelled using empirical force fields. RESULTS: The form I conformation is more stable and polarized with more efficient intermolecular packing, lower void space and higher density, however its shielded hydroxyl is only a hydrogen bond donor. In contrast, the hydroxyl in the more open but less stable and polarized form II conformation is both a donor and acceptor resulting in stronger hydrogen bonding and a more stable crystal structure but one that is less dense. Both forms have strong 1D networks of hydrogen bonds and the differences in packing energies are partially offset in form II by its conformational deformation energy difference with respect to form I. The lattice energies converge at shorter distances for form I, consistent with its preferential crystallization at high supersaturation. Both forms exhibit a needle/lath-like crystal habit with slower growing hydrophobic side and faster growing hydrophilic capping habit faces with aspect ratios increasing from polar-protic, polar-aprotic and non-polar solvents, respectively. Surface energies are higher for form II than form I and increase with solvent polarity. The higher deformation, lattice and surface energies of form II are consistent with its lower solubility and hence bioavailability. CONCLUSION: Inter-relationship between molecular, solid-state and surface structures of the polymorphic forms of ritonavir are quantified in relation to their physical-chemical properties.

Habit Modification of the Active Pharmaceutical Ingredient Lovastatin Through a Predictive Solvent Selection Approach.

An analysis of the important intermolecular interactions of the active pharmaceutical ingredient lovastatin which contribute to the surface chemistry and attachment energy morphology is presented. The analysis is supported by a recent redetermination of the single-crystal structure (orthorhombic space group P212121) and targets the understanding and potential control of the morphology of lovastatin, which tends to crystallize in a needle-like morphology, where the aspect ratio varies depending on the nature of the solvent. The lattice energy was calculated to be -38.79 kcal mol-1 with a small contribution of -2.73 kcal mol-1 from electrostatic interactions. The lattice structure is significantly stabilized by the hexahydronaphthalene ring of the molecule, which contributes 43.39% of the lattice energy. Synthon analysis shows that the dominant intermolecular interaction within the lattice structure of lovastatin is found to be along the a crystallographic axis, associated with a dispersive stacking interaction due to the close packing of 2 hexahydronaphthalene rings resulting in a total interaction energy of -6.46 kcal mol-1. The attachment energy morphology correlates well with the observed crystal morphology which exhibits a needle-like habit dominated by {0 1 1}, {0 2 0}, {0 0 2}, and {1 0 1} crystal forms. The needle capping faces are found to contain the short stacks of hexahydronaphthalene rings where the strong intermolecular synthon is found to contribute positively to the attachment energy and hence growth at this surface. This dominant intermolecular synthon is concluded to be the major cause of enhanced growth along the crystallographic a axis leading to the formation of a needle-like morphology. A habit modification strategy is discussed which uses recrystallization from apolar solvents to reduce the effective growth rate at the needle-capping surfaces. This is supported through experimental data which shows that crystals obtained from crystallization in hexane and methyl-cyclohexane have significantly reduced aspect ratios in comparison to those grown from the more polar methanol and ethyl acetate solutions. Crystals obtained from nitromethane solutions were also found to have a very large reduction in aspect ratio to a prismatic morphology reflecting this solvent's propensity to interact with hydrophobic surfaces, critically with no polymorph change.