Atomic force microscopy studies on two-step nucleation and epitaxial growth

Continues advancement and rapid development of techniques operating at the nanoscale open new opportunities to revise and question commonly accepted nucleation and crystal growth theories. Atomic Force Microscopy (AFM) has been successfully involved in various aspects of active pharmaceutical ingredient (API) characterisation including crystal growth, stability of solid dispersions, surface morphology, phase changes and dissolution [1]. Recent studies conducted on proteins crystallisation at nanoscale show new evidence disproving generally accepted Classical Nuclea/on Theory (CNT)[2]. Currently, ‘dense liquid droplets’ seen in protein crystallisation and ‘pre-nucleation clusters’ [3] seen mostly in inorganic salt crystallisation, are two main concepts of non-classical nucleation theory, although no significant progress has been made towards better understanding of mechanisms controlling heterogeneous nucleation in small organic molecules systems, what is in particular interest, as an epitaxial ordering phenomenon is frequently used to enhance nucleation rates and control properties of materials. Our studies present a new light on heteronucleation and the epitaxial growth mechanisms based epitaxial growth of olanzapine dihydrate D on the surface of olanzapine form I (OZPN I) both in high humidity conditions and water solu*on. Results obtained from Peak Force Quan/ta/ve Nanomechanical Mapping Atomic Force Microscopy (PF- QNM-AFM) [4] indicate the presence of intermediate dense liquid-like phase in process of dihydrate D nucleation

Do metastable polymorphs always grow faster? Measuring and comparing growth kinetics of three polymorphs of tolfenamic acid

The phenomenon of molecular crystal polymorphism is of central importance for all those industries that rely on crystallisation for the manufacturing of their products. Computational methods for the evaluation of thermodynamic properties of polymorphs have become incredibly accurate and a priori prediction of crystal structures is becoming routine. The computational study and prediction of the kinetics of crystallisation impacting polymorphism, however, have received considerably less attention despite their crucial role in directing crystallisation outcomes. This is mainly due to the lack of available experimental data, as nucleation and growth kinetics of polymorphs are generally difficult to measure. On the one hand, the determination of overall nucleation and growth kinetics through batch experiments suffers from unwanted polymorphic transformations or the absence of experimental conditions under which several polymorphs can be nucleated. On the other hand, growth rates of polymorphs obtained from measurements of single crystals are often only recorded along a few specific crystal dimensions, thus lacking information about overall growth and rendering an incomplete picture of the problem. In this work, we measure the crystal growth kinetics of three polymorphs (I, II and IX) of tolfenamic acid (TFA) in isopropanol solutions, with the intention of providing a meaningful comparison of their growth rates. First, we analyse the relation between the measured growth rates and the crystal structures of the TFA polymorphs. We then explore ways to compare their relative growth rates and discuss their significance when trying to determine which polymorph grows faster. Using approximations for describing the volume of TFA crystals, we show that while crystals of the metastable TFA-II grow the fastest at all solution concentrations, crystals of the metastable TFA-IX become kinetically competitive as the driving force for crystallisation increases. Overall, both metastable forms TFA-II and TFA-IX grow faster than the stable TFA-I

A random forest model for predicting crystal packing of olanzapine solvates

A random forest model obtained from calculated physicochemical properties of solvents and observed crystallised structures of olanzapine has for the first time enabled the prediction of different types of 3-dimensional crystal packings of olanzapine solvates. A novel olanzapine solvate was obtained by targeted crystallization from the solvent identified by the random forest classification model. The model identified van der Waals volume, number of covalent bonds and polarisability of the solvent molecules as key contributors to the 3-D crystal packing type of the solvate

Pharmaceutical Digital Design: From Chemical Structure through Crystal Polymorph to Conceptual Crystallization Process

A workflow for the digital design of crystallization processes starting from the chemical structure of the active pharmaceutical ingredient (API) is a multistep, multidisciplinary process. A simple version would be to first predict the API crystal structure and, from it, the corresponding properties of solubility, morphology, and growth rates, assuming that the nucleation would be controlled by seeding, and then use these parameters to design the crystallization process. This is usually an oversimplification as most APIs are polymorphic, and the most stable crystal of the API alone may not have the required properties for development into a drug product. This perspective, from the experience of a Lilly Digital Design project, considers the fundamental theoretical basis of crystal structure prediction (CSP), free energy, solubility, morphology, and growth rate prediction, and the current state of nucleation simulation. This is illustrated by applying the modeling techniques to real examples, olanzapine and succinic acid. We demonstrate the promise of using ab initio computer modeling for solid form selection and process design in pharmaceutical development. We also identify open problems in the application of current computational modeling and achieving the accuracy required for immediate implementation that currently limit the applicability of the approach

A Prolific Solvate Former, Galunisertib, under the Pressure of Crystal Structure Prediction, Produces Ten Diverse Polymorphs

The solid form screening of galunisertib produced many solvates, prompting an extensive investigation into possible risks to the development of the favored monohydrate form. Inspired by crystal structure prediction, the search for neat polymorphs was expanded to an unusual range of experiments, including melt crystallization under pressure, to work around solvate formation and the thermal instability of the molecule. Ten polymorphs of galunisertib were found; however, the structure predicted to be the most stable has yet to be obtained. We present the crystal structures of all ten unsolvated polymorphs of galunisertib, showing how state-of-the-art characterization methods can be combined with emerging computational modeling techniques to produce a complete structure landscape and assess the risk of late-appearing, more stable polymorphs. The exceptional conformational polymorphism of this prolific solvate former invites further development of methods, computational and experimental, that are applicable to larger, flexible molecules with complex solid form landscapes

Facts and fictions about polymorphism

We present new facts and correct old fictions about polymorphism in molecular crystals.</p

Do metastable polymorphs always grow faster? Measuring and comparing growth kinetics of three polymorphs of tolfenamic acid

Acknowledgements: Pietro Sacchi would like to thank Eli Lilly and Company for funding, and Dr Thomas Vetter and Dr Alexandru Moldovan for helpful discussions.The crystal growth rates of three polymorphs of tolfenamic acid in isopropanol solutions are measured and compared to explore the relation between crystallisation kinetics and polymorph appearance.</jats:p