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Modifiers are commonly used in natural, biological, and synthetic crystallization to tailor the growth of diverse materials. Here, we identify tautomers as a new class of modifiers where the dynamic interconversion between solute and its corresponding tautomer(s) produces native crystal growth inhibitors. The macroscopic and microscopic effects imposed by inhibitor-crystal interactions reveal dual mechanisms of inhibition where tautomer occlusion within crystals that leads to natural bending, tunes elastic modulus, and selectively alters the rate of crystal dissolution. Our study focuses on ammonium urate crystallization and shows that the keto-enol form of urate, which exists as a minor tautomer, is a potent inhibitor that nearly suppresses crystal growth at select solution alkalinity and supersaturation. The generalizability of this phenomenon is demonstrated for two additional tautomers with relevance to biological systems and pharmaceuticals. These findings offer potential routes in crystal engineering to strategically control the mechanical or physicochemical properties of tautomeric materials.

Developing crystallisation processes in the pharmaceutical industry is material and resource intensive due to the large design space, i.e. many different process parameters and combinations thereof. Furthermore, small scale experimental results don't necessarily translate when volume is scaled up due to changes in liquid flow, mixing and heat transfer surface area. However, indications that knowledge-driven resource reduction on a small scale is possible and results may be worth investigating at larger scales. Therefore, this study presents and evaluates a knowledge-driven workflow which achieves its goal of reducing the necessary resources previously required to develop a crystallisation process suitable for commercial manufacture in a pharmaceutical setting. By following this workflow, thermodynamic and isothermal kinetic data for the cooling crystallization of (3S,5R)-3-(aminomethyl)-5-methyl-octanoic acid (PD-299685) within an 8-week timeframe were obtained. Moreover, the workflow was expanded to include isothermal kinetic parameters from a 50-fold scaled-up cooling crystallisation, as well as antisolvent and seeded crystallisation of PD-299685. The systematic and standardised data collection facilitated by this workflow enabled the design and optimisation of the PD-299685 crystallisation process. The proposed scalable industrial crystallisation route for PD-299685 combines cooling and antisolvent techniques, offering a wide metastable zone width to facilitate speck-free filtration and effective seeding. This approach allows for control over product quality, resulting in particles with a desired aspect ratio of 0.766 and a d(v,90) value of 234 μm through wet milling. These parameters align with the proposed API material target specifications for solid oral dosage form quality, specifically oral bioavailability and content uniformity, and efficient drug product manufacture all whilst demonstrating a significant reduction in material usage. [ABSTRACT FROM AUTHOR]

We present a workflow that uses digital tools to optimise the experimental approach and maximise the efficiency in achieving the required process parameters for a desired set of crystallisation responses, kinetics and objectives. Model-driven small-scale experiments can contribute to reducing time and material waste in the development of pharmaceutical crystallisation processes. The workflow presented here guides the development of a small-scale batch cooling crystallisation process via solubility measurements, particle shape and size determination, form identification and preliminary kinetic parameter estimation to make crystals that satisfy quality target parameters (for shape, size and solubility) for a given active pharmaceutical ingredient (API). The case study herein follows the development of a crystallisation process for lamivudine, an API used in the preventative treatment of human immunodeficiency virus (HIV). This work identifies ethanol as a suitable solvent, meeting the acceptable solubility parameters for industrially relevant processes and yielded the biorelevant form, form I. The target kinetic parameters that were measured included induction time, growth rate and nucleation rate for lamivudine in ethanol under a range of conditions as guided by experimental planning models. Data was collected as part of the development of a DataFactory platform in which experimental optimisation can be autonomously implemented and all measurements stored in a crystallisation parameter database. This database will have further value in informing model development and continuous crystallisation process design and optimisation. The model objective-driven development workflow identified the following conditions, 19.9 °C, 600 RPM and supersaturation of 1.70, as achieving the desired objective successfully in 80 polythermal and 28 isothermal experiments. Integration of the workflow alongside the optimisation algorithm within the automated DataFactory system will enable fully autonomous, rapid data collection for small-scale API crystallisation. Such autonomous systems could play vital roles in pharmaceutical development and manufacturing driving towards more efficient and sustainable practices via digital transformation. [ABSTRACT FROM AUTHOR]

The molecular coordination compound trans-[Cu[Cl.sub.2][(3-Clpy).sub.2]] (3-Clpy = 3-chloropyridine), which is prepared as a microcrystalline powder, is reacted directly with gaseous HCl in the absence of water to yield the crystalline salt [(3-ClpyH).sub.2][Cu[Cl.sub.4]]. The reversible uptake of HCl molecules from the gas phase by a nonporous crystalline solid has proceeded in the absence of any solvent and with retention of crystallinity, despite many changes that are required by this process.

An extensive search was carried out for a dimer-based crystal structure of polymorphs of the 3-azabicyclo[3.3.1]nonane-2,4,-dione. It was found that the imide group of 3-azabicyclo[3.3.1]nonane-2,4,-dione could form two hydrogen bond motifs.

A comprehensive characterization of the structure and dynamics of maleic anhydride is discussed using experimental methods like single-crystal neutron diffraction, infrared, Raman and inelastic neutron scattering (INS) spectroscopies and computational methods like AM1 and two levels of density functional theory. Force fields derived by empirical means and ab initio data predict the INS spectrum.