The Application Research Of Drug-drug Co-crystallization System In Improving The Dissolution And Efficacy Of Three Drugs

The dissolution of drug includes dissolution rate and solubility.For solid drugs,poor dissolution performance will lead to its inability to be fully absorbed in the body,directly affecting the bioavailability of drugs,and thus affecting the efficacy of drugs.At present,more than 40% of the drugs in clinical use have poor dissolution problems.The Co-crystallization system,based on the effective combination of drugs and ligands,has the potential to improve the dissolution performance of drugs.In co-crystallization system,drugs and corresponding ligands aggregate to form supramolecular complexes under the influence of non-covalent forces,which can change their original lattice arrangement pattern and thus affect their physical and chemical properties,so as to improve the dissolution performance of drugs.By making multiple drugs into co-crystallization system,it is also possible to make multiple drugs needed by the patient into a single dosage,resulting in a fixed dose combination(FDC).FDC can not only achieve enhanced efficacy through synergy or cooperation but reduce the number of times for patients to take medicine,improve the patients compliance,and reduce the adverse drug reactions caused by missed or misuse of medication.With three representative drugs with poor dissolution as the main problem,Celecoxib(CEL),Paliperidone(PAL),antischizophrenia and Brexpiprazole(BRE)in hand,the research plan was to improve the poor dissolution performance of the series of drugs by preparing drug-drug co-crystallization system while improve the efficacy of drugs through multi-drug coordination.The studies aimed to provide safer and more effective FDC treatment.The detail were as below:(1)Based on the drug efficacy characteristic of CEL,central analgesic Tapentadol hydrochloride(TAP),antidepressant milnacipran hydrochloride(MIN)and duloxetine hydrochloride(DUL)were selected as the co-crystalllization ligand.The dimer of TAP,MIN,DUL and CEL in the lowest energy state was obtained by virtual docking.The density functional theory was used to calculate the binding energy of the dimer.The results suggested that they tended to formed eutectics(EU).The CEL-TAP-EU CEL-TAP-EU,CEL-MIN-EU,CEL-DUL-EU were then obtained through liquid-assisted grinding,which verified the theoretical calculation result.According to the DSC results,the eutectic proportion were determined for 6:4,5:5 and 5:5 respectively.Differential thermal scanning analysis,single crystal diffraction,powder diffraction,total reflection fourier transform infrared spectroscopy,Raman spectroscopy,solid-state nuclear magnetic resonance,scanning electron microscopy results verified the formation of eutectic mixture.The results of in vitro powder dissolution test and in vitro intrinsic test suggested that the dissolution performance of CEL eutectics had significantly improved.CEL-TAP-EU and CEL-MIN-EU showed enhanced in vivo analgesic efficacy and antidepressant efficacy in mice acetic acid writhing experiment and mice forced swimming experiment,respectively.Pharmacokinetic experiments showed that the pharmacokinetic performance of CEL-TAP-EU and CEL-MIN-EU was significantly improved.The fluidity of CEL-TAP-EU powder was significantly enhanced.(2)Based on the structure and drug efficacy properties of PAL,Risperdone(RIS),the active precursor of PAL were selected as the co-crystallization ligand of PAL.PAL and RIS were were likely to form solid solution with the characteristic of PAL lattice arrangement pattern as density functional calculation suggested.The solid solution PAL-RIS-1 and PAL-RIS-2 were successfully prepared by solvent cooling precipitation method.The content of PAL in the two solid solutions was 77.1% and 46.6%,respectively.The single crystal diffraction test suggested that the lattice patterns of PAL-RIS-1 and PAL-RIS-2were consistent with those of PAL,which confirmed the prediction of theoretical calculation.PAL-RIS-3 and PAL-RIS-4 were prepared by liquid-assisted grinding.A series of solid state characterization confirmed the consistency of PAL-RIS-3 and PAL-RIS-4 with PAL-RIS-1 and PAL-RIS-2.In vitro dissolution experiments of PAL-RIS-3 and PAL-RIS-4 showed that the dissolution performance of PAL in the solid solution was significantly improved.(3)Based on the drug efficacy characteristic of BRE,Querectin(QUE)was chosen as the co-crystallization ligand of BRE for its liver protection efficacy.The virtual docing results of BRE-QUE dimer and functional density theoretical calculation resuslts suggested that BRE and QUE had relatively strong binding energy.BRE-QUE tended to form cocrystal.Then,BRE-QUE cocrystal was obtained by solvent volatilization method,which was in consistent with the results of theoretical calculation results.The ratio of BRE:QUE in cocrystal was 1:1.A series of solid state characterization confirmed the formation of cocrystal.In vitro dissolution experiments showed that BRE solubility was significantly enhanced in BRE-QUE cocrystal.In conclusion,the poor dissolution of CEL,PAL and BRE can be solved by preparing series of drug-drug co-crystallization system while realize drug-drug synergies and synergies at the same time.CEL series of eutectic mixtures showed excellent pharmacodynamic and pharmacokinetic properties in further animal experiments,which had a high potential for clinical application as a new FDC.Meanwhile,the design method based on virtual molecular docking and crystal structure analysis combined with functional density theory calculation established in the study provided guidance for more innovative drug-drug co-crystallization design in the future.