# Phase diagrams of pharmaceutical solvates from mechanochemistry

## TL;DR

The paper introduces a new method to quickly determine the stability of pharmaceutical solvates, which could improve drug development processes.

## Contribution

The novel CSA-LAG method enables rapid and accurate mapping of solvate phase boundaries using small amounts of material.

## Key findings

- CSA-LAG reaches equilibrium within minutes and identifies critical solvent activities for solvate stability.
- The method successfully reproduces slurry boundaries and quantifies thresholds for different solvation types.
- CSA-LAG reduces the time and material needed for solvate screening compared to traditional methods.

## Abstract

Crystalline solvates, including hydrates, hold untapped potential in pharmaceutical development, yet their exploitation remains minimal due to the difficult and laborious task of unequivocally establishing their physical stabilities. We introduce Controlled Solvent-Activity Liquid-Assisted Grinding (CSA-LAG), a mechanochemical protocol that offers solvate phase boundary elucidation by varying the activity of a chosen solvent in defined binary/ternary mixtures and analysing the equilibrated resulting solid form. Using small API amounts, CSA-LAG reaches equilibrium within minutes and yields critical solvent activities that delimit neat, hydrated, solvated and competing-solvate domains. The method uses mixtures of known thermodynamic activities, requires far less material and time than traditional slurries and affords high reproducibility. Applied to four pharmaceutical compounds, CSA-LAG reproduces slurry boundaries and quantifies activity thresholds for single, stepwise and competitive solvations. Defining these boundaries enables rational form selection and process design either by avoiding or targeting solvates, whilst turning a month-scale empirical screening into a rapid, thermodynamically guided workflow.

Crystalline solvates have potential uses in pharmaceutical applications, but establishing physical stability is challenging. Here, the authors report the development of a screening method, controlled solvent activity liquid assisted grinding, for accurate mapping of solvate stability regions.