Mechanical approach for creating different molecular adducts and regulating salt polymorphs: a case study of the anti-inflammatory medication ensifentrine†

An intriguing technique for crystal engineering is mechanochemistry, which frequently yields various solid forms (salts, cocrystals, polymorphs, etc.) that are challenging to acquire using traditional solution-based approaches. However, generating new and potentially beneficial solid forms remains an ongoing task in this field. Moving forward in this demanding arena, several molecular adducts (salts and salt polymorphs) of the model drug ensifentrine (ENSE) with different GRAS (generally recognized as safe) co-former were synthesised for the first time using a mechanochemical technique, followed by a slow evaporation crystallisation procedure. All the newly obtained solid forms were characterized by employing single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Crystal structure analysis verified salt generation, revealing proton transfer from the carboxylic acid group of salt formers to the mesitylimino nitrogen atom of ENSE. Additionally, the phase transition behaviour of the produced salt polymorphs was examined through variable temperature PXRD (VT-PXRD) analysis. Furthermore, a detailed investigation of the physicochemical features of these recently produced entities was carried out, and their solubility in pH 1.2 and pH 7 environments was examined. Results demonstrate that, as compared to the parent drug, the binary adduct's solubility rate significantly increased at pH 7. Moreover, a thorough examination of the residue recovered after solubility confirmed that the majority of the molecular adducts were stable at pH 7 and did not show any phase change or dissociation, whereas at pH 1.2, the majority of the adducts were stable, except for those generated with malonic acid, which moved to a new stable form—a comprehensive study revealed that it was converted into ENSE·Cl salt. To the best of our knowledge, this is the first study to investigate various forms of ENSE, demonstrating that mechanical energy can be employed as a powerful control parameter to produce novel solid forms with superior physicochemical features. We hope that the current discovery will offer a valuable outlook prior to ENSE drug formulation.