| Objective Due to the poor solubility of pipemidic acid（PPA）,it has gradually withdrawn from clinical medicinal use,thus becoming an"old drug".In order to improve the physicochemical properties of pipemidic acid,pharmaceutical cocrystals of pipemidic acid were designed and synthesized and the relationships between structure and properties were analyzed.On this basis,the synthesis conditions and laws of the pipemidic acid pharmaceutical cocrystals were explored,which may provide preliminary experimental experience and preliminary theoretical basis for obtaining the target solid form of pipemidic acid.Methods The pharmaceutical cocrystals of pipemidic acid（PPA）with oxalic acid（OXA）,fumaric acid（FUM）,m-hydroxybenzoic acid（MHA）,cateholcarboxylic acid（CCA）,o-phthalic acid（OPA）,iso-phthalic acid（IPA）,p-phthalic acid（PTA）and sulfosalicylic acid（SSA）were prepared by solvent evaporation method.The single-crystal X-ray diffraction,PXRD,IR,1H-NMR,TGA and Hirshfeld surface were used to characterise and analyse the structure of pipemidic acid pharmaceutical cocrystals.The solubilities were tested by basket method,shake flask methods were applied to test the oil-water partition coefficient,and Franz diffusion cells were used to determine the permeabilities.The hygroscopicities were investigated under gradient humidity condition.The plasma concentration of PPA pharmaceutical cocrystals was determined by HPLC;Kirby-Bauer agar diffusion methods were detected the in vitro antibacterial activity of PPA pharmaceutical cocrystals.Results 4 categories 8 kinds of pipemidic acid pharmaceutical cocrystals were prepared through solvent evaporation method:the pharmaceutical cocrystals of pipemidic acid with dicarboxylic acids,pipemidic acid-oxalic acid(2(C14H18N5O3)·C2O4·5（H2O）,PPA-OXA)and pipemidic acid-fumaric acid（C14H18N5O3·0.5（C4H2O4）,PPA-FUM）;pipemidic acid with hydroxybenzoic acid,pipemidic acid-m-hydroxybenzoic acid（C14H18N5O3·C7H5O3·C7H6O3·2（H2O）,PPA-MHA）andpipemidic acid-cateholcarboxylic acid（C14H18N5O3·C7H5O4·2（H2O）,PPA-CCA）;pharmaceutical cocrystals of pipemidic acid with phthalic acid,pipemidic acid-o-phthalic acid（C14H18N5O3·C8H5O4·CH4O,PPA-OPA）,pipemidicacid-i-phthalic acid（2（C14H18N5O3）·C8H4O4·C8H6O4·CH4O·H2O,PPA-IPA）andpipemidic acid-p-phthalic acid（C14H18N5O3·0.5（C4H2O2）,PPA-PTA）;pipemidic acid-sulfosalicylic acid（C14H18N5O3·C7H5O6S·3（H2O）,PPA-SSA）.Single-crystal X-ray diffraction and Hirshfeld surface analysis indicated that the N atom on the piperazine ring of PPA molecule can form CAHBs with coformers.The maximum solubility of the PPA pharmaceutical cocrystals in water increased by 17.0,5.5,4.2,11.2,20.2,17.2,13.5 and15.3 times,respectively.The lipid solubilities of PPA pharmaceutical cocrystals are better than PPA.In comparison,the permeability of the PPA pharmaceutical cocrystals increased by 6.2,1.9,6.6,4.1,8.1,6.7,2.4 and 1.3 times respectively;the bioavailability experiments showed that compared with PPA,bioavailabilities were increased by 1.08,1.09,1.10,1.06,1.05,1.11,1.26 and 1.28 times,respectively;hygroscopicity experiments showed that compared with PPA,the hygroscopic stabilities of PPA pharmaceutical cocrystals under three different relative humidity were improved;in vitro antibacterial experiments showed that the inhibitory zones of PPA pharmaceutical cocrystals against E.coli and S.typhi were greater than PPA.Conclusions In this paper,4 types of 8 kinds of unreported pharmaceutical cocrystals of pipemidic acid were prepared.The structural analysis showed that coformers which can donate hydrogen protons will be beneficial to the formation of CAHBs with pipemidic acid and promote the stacking of cocrystal to obtain crystal structures which is stable.The solubility,lipid solubility,permeability and hygroscopic stability of the pipemidic acid pharmaceutical cocrystals can be improved by introducing coformers to form CAHBs with pipemidic acid.The increased transdermal flux of pipemidic acid leads to an increase in the bioavailability of the pipemidic acid pharmaceutical cocrystal;and the active site of pipemidic acid,that is,the N atom of the piperazine group,forms charge-assisted hydrogen bond with the coformers.The electron cloud density of N atom was changed,so that the antibacterial activity of pipemidic acid pharmaceutical cocrystal was changed.The use of pharmaceutical cocrystal technology can effectively improve the physicochemical properties and biological activity of pipemidic acid by introducing appropriate coformers without changing the structure of pipemidic acid.Therefore,this work indicated that CAHBs recognition plays a key role in the preparation of pipemidic acid pharmaceutical cocrystal and the improvement of physicochemical properties,which may provide preliminary experimental experience and preliminary theoretical exploration for"revival"of PPA. |
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