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Solid-state analysis of a new quaternary solid-form of ritonavir: an oxalate salt oxalic acid co-crystal acetone solvate.

Comparison between solid- and solution-state intermolecular interactions identify solvent-dependant pathways directing crystallisation into different polymorphic forms.

The nucleation experiments of pimelic acid were investigated in the absence and presence of a template.

Crystal regeneration has been observed in macroscopic paracetamol crystals post breakage along their cleavage plane. High resolution imaging confirmed regeneration rates to be 3-fold faster than growth prior to breakage. Further analysis of the solute-solvent interactions is required to elucidate the process which currently lacks linearity with traditional growth theories.

Subfractionation of asphaltenes based on their interfacial activity has begun to highlight critical differences between those asphaltenes that are strongly interfacially active (IAA) and the remaining asphaltenes (RA). Following the methods of petroleomics, representative structures of the two asphaltene fractions were determined, reflecting differences in abundant heteroatom groups, carbon number, double-bond equivalents, and single-core/multicore motifs. Using atomistic-potential-based grid-search methods, the intermolecular interactions between asphaltene–asphaltene and asphaltene–solvent (water, heptane, and toluene) were rapidly screened to identify the most favorable and therefore most likely intermolecular interactions to occur. Asphaltene–water interactions were stronger for IAA (abundance-weighted average interaction energy of −9.29 kJ/mol) than for RA (−6.32 kJ/mol), with hydrogen bonding more significant in the IAA–H2O interaction. Dimer interactions of IAA–IAA were stronger than RA–RA, and from the top 100 most favored interactions, the contribution to the total interaction energy was almost exclusively van der Waals for RA–RA (only 3% electrostatic), while for IAA–IAA, electrostatic interactions (9%) and hydrogen bonding (2%) were significant contributors in the most favored interactions. As the relative contribution of the electrostatic interaction increased, the dimer orientation less resembled that of a π–π stack. With the conception of petroleomics and large structural databases, the grid-search method is a useful atomic/molecular screening approach that provides an ideal triaging tool to rapidly assess a wide range of different molecular structures and interactions. The method is complementary to the more computationally expensive precision molecular modeling tools that are not suited to such workflows.

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.

Para amino benzoic acid has two well-characterised polymorphic forms and, whilst both crystallise in the monoclinic space group, they have quite different crystal chemistry and crystallisability behaviour. The molecular conformation deformation energy in the crystalline state is higher for the β-form than for the α-form and the lattice energy for the former converges more slowly than for the latter. This suggests a higher barrier to crystallisation for the β-form and low solution supersaturations might be needed for it to preferentially nucleate. Solute cluster propensity and solute solvation energetic analysis highlights the importance of an aqueous solvation environment in inhibiting the α-form’s strong OH…O carboxylic acid hydrogen 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 to mediate the preferential formation of either of the two polymorphic forms. Molecular dynamics simulations coupled with FTIR studies and intermolecular synthon analysis addresses this issue through characterisation of the propensity of the incipient bulk synthons that are important in the crystallisation of these polymorphic forms within the solution state. Molecular trajectory analysis within organic solution simulations 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 β-forms when compared to aqueous solutions but much lower propensities for the β-form’s “fingerprinting” OH…N and π-π stacking synthons. In contrast, data from the aqueous solution environments reveals a much greater propensity for the β-form’s π-π interaction synthons. IR dilution studies in organic solvent 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. IR data is consistent with the organic solvent MD data, albeit IR aqueous solutions was precluded due to its strong OH vibrational mode which restricted validation in aqueous solutions.

A workflow for tailor-made additive screening and crystallization control using a combination of molecular modeling and experimental techniques is presented. The impact of seven structurally analog...

Polymorphic nucleation behavior of carbamazepine (CBZ) was investigated in terms of supersaturation in several solvents: nitromethane, acetonitrile, acetone, ethanol, 2-propanol and toluene. The solubility was measured and the effects of interaction between the solvent and CBZ on solubility and polymorphic nucleation were discussed. It was found that the polymorphic forms of CBZ largely depended on the solvent type and supersaturation ratio. The carbonyl group in acetone blocked the NH⋯O interaction between the dimer in form II by mimicking the same interaction with CBZ, then favored the nucleation of form III. The aromatic–aromatic interaction between CBZ and the solvent like toluene decreased the solute–solute interaction and favored the formation of form II. The nucleation domains of CBZ polymorphs (forms II and III) were separated as a function of supersaturation ratio range in each solvent, and the effects of solvents and supersaturation ratios on the induction time and transformation process were also explored. The interfacial energies of forms II and III in different solvents were calculated, and it was found that, at all investigated supersaturation ratios, the interfacial energy of form II in all solvents except acetone was always lower than that of form III, indicating that nucleation kinetics preferably favored the formation of form II. However, at lower supersaturation ratios, thermodynamics was critical and form III was obtained.

The interplay between the solution chemistry and crystallisability of eicosane in mixed toluene : acetone solutions is examined over the full compositional range from pure toluene to pure acetone, using a combination of polythermal crystallisation experiments and molecular modelling. Enthalpies of dissolution and mixing, as well as metastable zone widths increase with increasing acetone content, up to a mol fraction of 0.85 acetone, followed by a decrease in values to pure acetone solutions. Nucleation is found to occur via an instantaneous pathway for the pure solvent systems and also when toluene is in excess, in contrast to solutions where acetone is in excess, which are found to nucleate progressively. Rationalisation through molecular modelling highlights likely changes in the solution structure, whereby eicosane can be expected to be preferentially solvated by toluene, with this solvated cluster being surrounded by a ‘cage’ of acetone molecules. This proposed structure is consistent with a model whereby solute diffusion and hence clustering is hindered when acetone is in excess, decreasing the crystallisability of the solution and effecting a change in the mechanism of nucleation. However, above a critical acetone composition, the potential for complete toluene solvation is restricted and easier crystallisation is enabled.

In this work a novel quercetin and dimethyl sulfoxide (DMSO) solvate (QDMSO) crystal structure was grown from a mixture of DMSO and water as solvent. Quercetin is a naturally occurring bioflavonoid widely used in the nutraceutical industry due to its many health benefits. Understanding quercetin solvates formation is essential for the design of novel particulate products with tailored quality attributes, including solubility, thermal resistance and bioavailability. Here, the physiochemical properties and phase transitions of QDMSO were characterized by a wide range of experimental techniques, and the crystal structure, molecular packing and intermolecular interactions (synthons) within the crystal lattice were modelled. Modelling and experimental results were compared to those of other known quercetin crystal structures, an anhydrous, a monohydrate and a dihydrate form, to elucidate the role of the solvent molecules on the molecular packing and intermolecular interactions and, ultimately, on the physiochemical properties of each crystal form. It was found that in QDMSO, hydrogen bonds and dipole-dipole interactions had a greater contribution to the total lattice energy, and quercetin-solvent hydrogen bonds were stronger in energy compared to those of the other quercetin structures. These findings were used to explain the superior thermal stability of the QDMSO structure as well as its moisture-dependent behavior. This work demonstrates a coupled modelling and experimental methodology that relates intermolecular interactions and molecular packing in different solvated forms to physiochemical properties and can help in a better prediction and design of particulate products via rational choice of the solid form.

The solvent‐dependent polymorphism of the active pharmaceutical ingredient (API) carbamazepine is interpreted from calculations of the solid‐state and API‐solvent intermolecular interactions. These simulations suggested that apolar solute‐solute interactions could be disrupted by apolar solvents. In contrast, the polar solute‐solute interactions were found to be easily disrupted by polar and protic solvents. This is consistent with experimental observations that the crystallization of the metastable form II is more dominant in apolar solvents. The Mercury program remains the gold standard in terms of usability; however, further expansion into more complex simulation techniques could make this package of even greater use in pharmaceutical manufacturing workflows.

We present a grid-based molecular modeling approach and software application for screening the solute–solvent and solute–solute interactions of organic molecules. This tool can provide a deeper understanding of solubilization of organic molecules, intended to guide scientists to intuitive conclusions about whether a solute/solvent pair may provide desired physical properties, such as crystallizability, solubility, and crystal polymorphism. This study focused on solutions of p-aminobenzoic acid in acetonitrile, ethanol, and water. Acetonitrile molecules are found to form the weakest interactions with the solute molecule, although they also form weak interactions with themselves. In contrast, water forms strong interactions with the solute molecule, with a strong preference to interact with the carboxylic acid group, although they also form strong self-interactions. Ethanol forms strong interactions with all of the solute molecules, along with reasonably strong interactions with itself. The looser solvation of the carboxylic acid group by acetonitrile is thought to drive the crystallization of the α polymorph, by lowering the crystallization kinetic energy barrier. In ethanol, the strong interactions of the solvent are thought to contribute to significant undercooling of ethanolic solutions observed in previous studies. Water’s strong interactions with the carboxylic acid of the solute may drive the self-assembly of the α-form by interactions of the phenyl groups and also contribute to the nucleation of the β-form from this solvent. This workflow can provide valuable guidance on the solvation properties of organic molecules and clusters, producing low-energy solvation shells of molecules and clusters to be utilized as starting points for more sophisticated simulations, such as molecular dynamics.

Hydrated structures of a specific compound can often have different physiochemical properties compared to the anhydrous form. Therefore, being able to predict and understand these properties, especially the stability, is critical. In this study quercetin, a flavonoid molecule, is modelled in three different states of hydration to gain an understanding of the effect of water molecules on the structure, packing and conformation energetics of the three forms. Conformational analysis and modelling of intermolecular interactions (synthonic modelling) have been performed. It was found that in the anhydrous form hydrogen bonding is the strongest type of interaction while in the two hydrate structures, the incorporation of water within the lattice leads to the formation of hydrogen bonds between the quercetin and water molecules. Within hydrates quercetin molecules adopt a more planar conformation which allows them to pack more closely by strong π-π stacking interactions, thus resulting in a higher relative stability. The modelling results highlight the importance of water in the stabilization of the lattice and explain the preferential nucleation of the dihydrate form. It is further demonstrated how synthonic modelling can be a predictive tool for the product’s properties, leading to more efficient product design and faster development.

Polyproline II (pPII) is a left-handed 31-helix conformation, which has been observed to be the most abundant secondary structure in unfolded peptides and proteins compared to α-helix and β-sheet. Although pPII has been reported as the most stable conformation for several unfolded short chain peptides in aqueous solution, it is rarely observed in their solid state. Here, we show for the first time a glycine homopeptide (gly-gly-gly) adopting the pPII conformation in its crystalline dihydrate structure. The single crystal X-ray structure with molecular dynamic simulation suggests that a network of water and the charged carboxylate group is critical in stabilizing the pPII conformation in solid state, offering an insight into the structures of unfolded regions of proteins and the role of water in peptide crystallization.