Three polymorphs of tolbutamide (I^L, II, and III) were studied using single-crystal X-ray diffraction, from 100 K to room temperature (forms II and III) and to 350 K (form I), and differential scanning calorimetry. The reversible transformation, I^L ⇔ I^H, was found to be of the single-crystal to single-crystal type and the structure of the high-temperature form (I^H) was solved and refined. The structure of I^H differs from that of I^L only in the conformation of the molecule, with molecular arrangements being practically unchanged (isostructural conformational transformation). The transition takes place at 313 K with no sign of hysteresis. The volume change, ΔV/V, across the reversible transformation I^L ⇔ I^H was calculated and compared to those for the other conformational transformations. Two types of conformational polymorphic transformations (irreversible reconstructive and reversible isostructural) in tolbutamide and chlorpropamide were compared.

A mechanochemical procedure of ball milling was applied to a solvent-free synthesis of natural alkaloid lappaconitine derivatives. A mixture of purely solid lappaconitine and 3-Cl-perbenzoic acid reacted to give lappaconitine N(20)-oxide with a good isolated yield (57percnt after workup). The ball milling of solid lappaconitine and N-bromosuccinimide affords N(20)-deethyllappaconitine with an acceptable (42percnt) yield. The mechanochemical approach was also applied for acylation of the anti-inflammatory drug piroxicam to improve its therapeutical properties. Consequently piroxicam 4-nitrobenzoate was obtained under the solvent-free reaction conditions with a moderate yield as a result of mechanical activation of the reaction between piroxicam and 4-nitrobenzoyl chloride in the presence of the aluminum oxide impregnated with thriethylamine. The reaction mixtures were analyzed after ball milling by HPLC in the proposed conditions.