Structurally similar, functionally different: Impact of coformer positional isomerism on co-amorphous enzalutamide

Coamorphization is an attractive approach to modifying the physicochemical properties of drug molecules, especially the solubility, dissolution, and associated bioavailability. Although these formulations may be advantageous, they exhibit poor physical stability and undergo recrystallisation. To address this limitation, this study investigates the effect of positional isomerism on the coamorphous formation and associated physicochemical properties, to select an optimum solid form with improved stability. Enzalutamide (ENZ), a BCS class II drug, was used as a model compound. Four positional isomers including 2,3-, 2,4-, 2,5- and 2,6-dihydroxybenzoic acid (DHB) were used as coamorphous coformers. Coamorphous formulations were prepared by ball mill in a 2:1 molecular ratio (API:coformer). The solid-state properties of the prepared coamorphous forms were characterised using X-ray powder diffractometer (XRPD), modulated differential scanning calorimetry (mDSC), and Fourier transformed infrared spectrometry (FTIR). Additionally, intra isomer variability in the amorphization kinetics and dissolution enhancement of ENZ, along with physical stability, were evaluated. All coformers formed coamorphous systems, as confirmed by XRPD. mDSC data showed that the glass transition temperature (Tg) varied among the prepared coamorphous forms and was lower than that of pure ENZ. Although there was no significant difference in the dissolution behaviour, the physical stability data reveal a contrast trend. Among the prepared coamorphous forms, ENZ-24DHB^CAM exhibited superior stability, while ENZ-26DHB^CAM exhibited poor stability. This article summarises the similarities and differences between the physicochemical properties of coamorphous forms of Enz because of the change in coformer positional isomerism. Stability studies under different humidity conditions revealed significant differences: at 40% RH, all coamorphous forms remained stable for up to 8 weeks, with minor deviations for ENZ-23DHB^CAM and ENZ-25DHB^CAM. Under 75% RH, the stability varied markedly; ENZ-24DHB^CAM maintained stability for at least 8 weeks, while ENZ-26DHB^CAM became unstable within 1-2 weeks, and ENZ-AMP and ENZ-23DHB^CAM lost stability by week 6. These results demonstrate the careful selection of coformer positional isomer can quantitatively enhance the stability of coamorphous forms, highlighting the importance of positional isomerism associated chemical design space in optimizing solid-state properties.