Crystal size, shape, and conformational changes drive both the disappearance and reappearance of ritonavir polymorphs in the mill.

Organic compounds can crystallize in different forms known as polymorphs. Discovery and control of polymorphism is crucial to the pharmaceutical industry since different polymorphs can have significantly different physical properties which impacts their utilization in drug delivery. Certain polymorphs have been reported to 'disappear' from the physical world, irreversibly converting to new ones. These unwanted polymorph conversions, initially prevented by slow nucleation kinetics, are eventually observed driven by significant gains in thermodynamic stabilities. The most infamous of these cases is that of the HIV drug ritonavir (RVR): Once its reluctant form was unwillingly nucleated for the first time, its desired form could no longer be produced with the same manufacturing process. Here we show that RVR's extraordinary disappearing polymorph as well as its reluctant form can be consistently produced by ball-milling under different environmental conditions. We demonstrate that the significant difference in stability between its polymorphs can be changed and reversed in the mill-a process we show is driven by crystal size as well as crystal shape and conformational effects. We also show that those effects can be controlled through careful design of milling conditions since they dictate the kinetics of crystal breakage, dissolution, and growth processes that eventually lead to steady-state crystal sizes and shapes in the mill. This work highlights the huge potential of mechanochemistry in polymorph discovery of forms initially difficult to nucleate, recovery of disappearing polymorphs, and polymorph control of complex flexible drug compounds such as RVR.

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.

Complex Growth of Benzamide Form I: Effect of Additives, Solution Flow, and Surface Rugosity.

Understanding crystal growth kinetics is of great importance for the development and manufacturing of crystalline molecular materials. In this work, the impact of additives on the growth kinetics of benzamide form I (BZM-I) crystals has been studied. Using our newly developed crystal growth setup for the measurement of facet-specific crystal growth rates under flow, BZM-I growth rates were measured in the presence of various additives previously reported to induce morphological changes. The additives did not have a significant impact on the growth rates of BZM-I at low concentrations. By comparison to other systems, these additives could not be described as "effective" since BZM-I showed a high tolerance of the additives' presence during growth, which may be a consequence of the type of growth mechanisms at play. Growth of pure BZM-I was found to be extremely defected, and perhaps those defects allow the accommodation of impurities. An alternative explanation is that at low additive concentrations, solid solutions are formed, which was indeed confirmed for a few of the additives. Additionally, the growth of BZM-I was found to be significantly affected by solution dynamics. Changes in some facet growth rates were observed with changes in the orientation of the BZM-I single crystals relative to the solution flow. Of the two sets of facets involved in the growth of the width and length of the crystal, the {10l̅} facets were found to be greatly affected by the solution flow while the {011} facets were not affected at all. Computational fluid dynamics simulations showed that solute concentration has higher gradients at the edges of the leading edge {10l̅} facets, which can explain the appearance of satellite crystals. {10l̅} facets were found to show significant structural rugosity at the molecular level, which may play a role in their mechanism of growth. The work highlights the complexities of measuring crystal growth data of even simple systems such as BZM-I, specifically addressing the effect of additives and fluid dynamics.