Stability of Pharmaceutical Cocrystal During Milling: A Case Study of 1:1 Caffeine–Glutaric Acid

Despite the rising interest in pharmaceutical cocrystals in the past decade, there is a lack of research on the solid processing of cocrystals downstream to crystallization. Mechanical stress induced by unit operations such as milling could affect the integrity of the material. The purpose of this study is to investigate the effect of milling on pharmaceutical cocrystals and to compare the performance of ball mill and jet mill, using caffeine–glutaric acid (1:1) cocrystal as the model compound. Our results show that ball milling induced polymorphic transformation from the stable Form II to the metastable Form I, whereas Form II remained intact after jet milling. Jet milling was found to be effective in reducing particle size, but ball milling was unable to reduce the particle size beyond a certain limit even with increasing milling intensity. The heating effect during ball milling was proposed as a possible explanation for the difference in the performance of the two types of mill. The local increase in temperature beyond the polymorphic transformation temperature may lead to the conversion from stable to metastable form. At longer ball milling duration, the local temperature could exceed the melting point of Form I, leading to surface melting and subsequent recrystallization of Form I from the melt and agglomeration of the crystals. The findings in this study have broader implications on the selection of mill and interpretation of milling results for not only pharmaceutical cocrystals but pharmaceutical compounds in general.