Formation Of Furosemide In Pharmaceutical Cocrystal And Synthesis Of Isoniazid Derivatives

Recently,crystal engineering is widely used in medicine.Most of the active ingredients?API?belong to BCS II and IV drugs,which owning poor solubility in clinical.In order to improve the physical properties,the pharmaceutical cocrystal is introduced as alternative API solid form.Cocrystals can improve the physicochemical properties of drugs without compromising their therapeutic benefit.Sulfonyl group can offer two hydrogen-bond receptors,attracting extensive attention from scientists.Based on acid???amine supramolecular synthons widely used in crystal engineering,different kinds of pharmaceutical cocrystal/salts were designed and synthesized by mechanochemistry and traditional solution methods with furosemide as API.Isonicotinic acid hydrazide derivatives were synthesized with camphorsulfonic acid.The main content as following:1.Two salts?FS?₁?HTEM?₁??FS?₁?Amd?₁ and a cocrystal?FS?₁?INZ?₁ were formed by grinding and solvents method,using Furosemide?FS?as API,and their structure were characterized by PXRD and SC-XRD.The thermal stability,solvent stability and hygroscopic stability studies revealed excellent results by pulping experiment,dynamic vapor adsorption experiment,differential scanning calorimetry and thermogravimetry.Solubility experiments showed that the solubility of?FS?₁?HTEM?₁ and?FS?₁?INZ?₁ were higher than that of the pure material FS.At pH=6.8,cocrystal/salts and pure drug both own the highest solubility.Besause of favourable property,the?FS?₁?Amd?₁ salt shows a faster dissolution rate than pure FS and other cocrystal/salt over the entire time span?60 min?in pH 6.8.2.A isonicotinic acid hydrazide derivative was synthesized by condensation reaction of camphorsulfonic acid with isonicotinic acid hydrazide,and the reaction process was non-catalytic.The single crystal structure was obtained in the mixed solvent?ethyl alcohol and water?,and the structure was characterized by PXRD,SC-XRD,UV,FT-IR and ¹H-NMR.Thermal stability was studied by differential scanning calorimetry and thermogravimetry.In this work,a novel compound prepared by dehydration condensation reaction of a carbonyl group and an amino group under a catalyst-free condition by using two drug molecules as a precursor is expected to reduce the side effects of isoniazid and develop the application value of isoniazid hydrazide compound.And the problem of weak ketone carbonyl reactivity is solved by a green chemical method.