Knowing When To Stop—Trapping Metastable Polymorphs in Mechanochemical Reactions

The cocrystal formation of pyrazinamide (PZA) with malonic acid (MA) was studied in situ. The mechanochemical reaction proceeds via conversion of a crystalline intermediate (PZA:MA II) into the thermodynamically more stable form (PZA:MA I) upon further grinding. The information derived from in situ powder X-ray diffraction (PXRD) enabled the isolation of this new metastable polymorph. On the basis of the PXRD data, the crystal structure of the 1:1 cocrystal PZA:MA II was solved. The polymorphs were further characterized and compared by Raman spectroscopy, solid-state NMR spectroscopy, differential thermal analysis/thermogravimetric analysis, and scanning electron microscopy. Our study demonstrates how monitoring mechanochemical reactions by in situ PXRD can direct the discovery and isolation of even short-lived intermediates not yet accessed by conventional methods.