In its collaboration with Pfizer, XtalPi has developed a crystal free energy prediction technology that is based on a modified version of the pseudosupercritical (PSCP) path method. The method is fast, accurate, can be deployed on the cloud, and can handle highly flexible molecules that are common in the pharmaceutical industry. The crystal free energy prediction provides a thorough evaluation of the relative stabilities of different crystalline drug forms across a range of temperatures and has an accuracy to within 1 kJ/mol. The temperature corrected free energy ranking is particularly useful for enantiotropic systems, where the relative stabilities of polymorph forms change with temperature. From this prediction, the relative stabilities of experimental forms, such as hydrates, salts, cocrystals, free forms, etc., can be obtained. With these predictions, the most stable crystalline form can be selected for solid form development.
It is capable of calculating the relative free energy between different crystalline forms in the whole temperature range, which results in a relative stability ranking at different temperatures. It thus provides direct guidance for crystalline pattern screening.
The whole process of free energy calculation is fully automated. It achieves functionalities such as the automatic continuation of computation at breakpoints, adaptively adjustment of simulation at temperatures, real-time monitoring of important indicators, and is easily integrated with our crystal prediction and customized force field platforms.
A variety of strategies (such as efficient computational methods, parallelized thermodynamic cycle, specific cut-off settings for targeted simulations) and high parallel computation are employed to improve the computing capability, shortening its computing period from more than 10 days to 2-3 days.
A variety of methodologies of the free energy calculation can be used to achieve the optimum calculation accuracy, time, and cost. The methodologies include 1) PSCP considering the rigorous thermodynamic cycle and configuration sampling; 2) QHA involving the rapid molecular mechanics; 3) HA focusing on quantum mechanics.
It is applicable to various systems, such as different crystalline forms of single component crystals, different crystalline forms of salts and cocrystals, and also between crystals comprised of different molecules (e.g., hydrates to anhydrates, cocrystals to their component crystals).