Identifying new solid forms of a labile pharmaceutical compound by additive assisted mechanochemistry.

Mechanochemical processing of labile active pharmaceutical ingredients (APIs) presents a fundamental trade-off: added solvent can accelerate solid form transformations yet may simultaneously promote chemical degradation. This study aims to explore this tension with an oxidation prone model pharmaceutical, cysteamine. Specifically, we examine the effects and interactions of antioxidant incorporation, reactant stoichiometry, ball to powder ratio (BPR), milling duration, and solvent assisted grinding on solid form screening success rates and yield. We find that the incorporation of ascorbic acid (ASC) as an antioxidant markedly improved resistance to oxidative degradation under a large set of milling conditions. Systematic variation of ASC molar ratios revealed an optimal composition at 1 : 1 : 2 (cysteamine : coformer : ASC) which reproducibly improved cysteamine recovery (90-110%, n = 3) and promoted the formation of a new crystalline phase, verified by PXRD. However, increasing the ASC ratio beyond 1 : 1 : 5 led to diminished product quality, indicating a threshold beyond which performance declines. These findings establish practical design insights for solid-form screening of chemically fragile pharmaceuticals.