The Regulation Of Biomacromolecule On The Polymorph Of Theophylline And Tolbutamide

It is important to control crystal form in solution for the investigation andproduction of polymorph drug. In this article, adding biomacromolecule additives insolution was used to control the polymorph of theophylline (TP) and tolbutamine(TB), experimental and molecule simulation methods were employed to explore theregulation effect of DNA additives in solution systematically.Firstly, the molecular arrangement, hydrogen-bond interactions and Hirshfeldsurface of TP polymorph (I, II, IV and M) were analyzed. TP crystal forms werepacking polymorph and the stability order of anhydrous forms (IV> II> I) wasconfirmed. From the perspective of structural similarity, DNA-A20and DNA-T20wereselected as additives, and two supersaturation ratios were investigated. The resultsdemonstrated that, whether DNA-A20or DNA-T20, specific additive amount couldinduce the produce of form II of TP (medicinal crystal form), and the morphology ofTP changed with the adding amount of DNA.The mechanism of DNA inducing metastable form II of TP was discussedemploying molecular simulation. The possible reason of the experimental resultscould be interpreted as follow: special amount of DNA competing with the stableself-association of TP molecules made the formation of the less stable binding mode,as the pattern in form II. In addition, the morphology of form II and M of TP werepredicted, and the binding energy of DNA to the crystallographic important faces wascalculated. The results suggested that in both A and T cases of DNA monomer, thebinding energy of DNA monomer to crystal surface of form II was relatively weakexcept (201), which promoted the growth of form II. Moreover, the preferentialbinding energy of additive to the possible stable cluster surface (form M) restraintedthe growth of form M further. Thus, the common function of the two factors led to theformation of form II.Finally, in order to further explore the role of DNA, another polymorph drugtolbutamine was investigated. Both DNA-A20and DNA-T20could induce theformation of metastable form IV of TB, which was not easy to get in solution. Theeffects of different cooling rates on the crystallization process of TB were alsoconsidered, and form IV of TB was got at the cooling rate of0.5and1.0oC min-1. This finding suggested that in the crystallization of TB, the effect of DNA additiveand faster cooling rate was the same, which further confirmed the ability of DNAadditive to maintain metastable crystal nucleus. However, in the absence of DNA,faster cooling rate did not work in the crystallization of TP, which indicated that themetastable crystal nucleus of TB was more stable than that of TP.