The Effect Of Solvent And DNA On Controlling Polymorphs Of Tolbutamide

The control of pharmaceutical polymorphs has always been an important issue inthe field of drug research and manufacturing. In this paper, the effect of solvent andaddition of DNA on the selective crystallization of tolbutamide was studied by acombination of experimental and computational methods.The rapid-cooling crystallization of TB was carried out from ethanol andethanol–water solutions at different initial supersaturations (3.5and2.7). PXRD andFTIR were used to characterize the polymorphs. It was found that the metastableForm IV with advanced solubility and bioavailability was obtained fromethanol–water solutions at the higher supersaturation, while stable Form III directlycrystallized from ethanol at both supersaturations and from ethanol–water solution atthe lower supersaturation. The mechanism of selective crystallization of themetastable polymorph of tolbutamide in ethanol–water solution was disclosed bymolecular dynamics simulation. It was indicated that stronger interactions betweenTB and solvents weaken the TB–TB intermolecular NH…O hydrogen bonds and thuspromote TB molecules to form dimers by π-π stacking.The effect of addition of DNA-A20and DNA-T20on selective crystallization ofTB from ethanol-water solution with supersaturations of3.5was also studied. It wasfound that DNA-A20and DNA-T20could induce the formation of TB Form II andForm IV, respectively. The results showed that the addition of DNA-T20prevent thetransformation of metastable Form IV to the stable Form III. The morphologies of TBI~IV polymorphs were calculated by BFDH and AE methods. And the binding energycalculation for the major faces of TB and DNA disclosed the experimental results ofTB polymorphs formation with the induction of DNA-A20and DNA-T20.