A Study On Drug-drug Salt Consisting Of Metformin And Aspirin

Drug-drug salts could combine two or more active pharmaceutical ingredients?APIs?into a form through the salt formation,and the physicochemical properties,such as dissolution rate,hygroscopicity,and stability of the involved APIs could be modulated to some extent.Thus,the design and synthesis of drug-drug salts have attracted significant research interest.Diabetes mellitus?DM?is the most widespread metabolic disease and has become a heavy burden of public health systems.It has been reported that over 420 million of people have been suffering from DM and type 2 diabetes mellitus?T2DM?accounts for around 90%of all the patients.Furthermore,the T2DM patients have an increased risk of developing cardiovascular disease which is the major cause of mortality and morbidity.Metformin?MET?,a biguanide antihyperglycemic agent,is commonly available as a hydrochloride salt?MET-HCl?which is the first choice for treating T2DM.Aspirin?ASP?,which is an analgesic and anti-inflammatory drug,has been used for over a century.It is also currently used as a cardioprotective and antithrombotic agent for its anti-platelet effects.In order to prevent the associated cardiovascular disease for the T2DM patients,ASP is usually recommended to be co-administrated with MET-HCl in clinical.Based on the pKa difference between the imino group?pKa=13.8?of MET and carboxylic acid group?pKa=3.5?of ASP is greater than 3 which is prone to forming a salt,the drug-drug salt?metformin acetylsalicylate?composed of MET and ASP was investigated in this study.Three forms of metformin acetylsalicylate were obtained and characterized by single crystal X-ray diffraction,powder X-ray diffraction,thermogravimetric analysis,differential scanning calorimeter and infrared spectrometer,et al.Form I powders were precipitated from acetone containing MET and ASP with 1:1stoichiometric ratio.The single crystals of form I were obtained by cooling the acetone solution.The results revealed that form I was anhydrous,crystal system:monoclinic;space group:P2₁/c;a???=9.982?4?;b???=10.918?3?;c???=15.273?2?;??°?=90.00;??°?=107.315;??°?=90.00;V??³?=1589.18.H1 were obtained by exposing form I powders under the conditions of over 75%relative humidity?RH?and simultaneously obtained its single crystals at the edge of the powder sample.The results revealed that H1 was hemihydrate,Mr:318.34;crystal system:triclinic;space group:P-1;a???=9.0858;b???=11.9718;c???=16.5784;??°?=69.90;??°?=75.11;??°?=67.88;V??³?=1551.83;the dehydration temperature of H1 was 92.66°C.H2 were obtained by exposing the powders which were precipitated from the solution of warter:acetone?5:95/v:v?containing MET and ASP with 1:1 stoichiometric ratio to the conditions of over 75%RH,the results revealed H2 is a monohydrate,the dehydration temperature was 74.09°C,and the single crystal of H2 was not obtained.The transition relationship of form I,H1 and H2 was studied by scanning electron microscopy and polarized light microscopy,et al.The results revealed that form I could transform into H1 under the conditions of over 75%RH,and both H1 and H2transformed into form I after dehydration.According to the experimental results,it was supposed that the transition of form I into H1 refers to the hydrolic faces of 011/0-1-1induced recrystallization process.The hygroscopicity of three forms of metformin acetylsalicylate were further determinated The results showed that the order of hygroscopicity between the three forms was:form I<H1<H2.Intrinsic dissolution rate?IDR?analysis was conducted in a simulated gastric environment?pH 1.2 buffer?at 37°C to compare the dissolution properties of the salt versus the individual components,namely,MET-HCl and ASP.The IDRs of metformin acetylsalicylate,MET-HCl and ASP were 0.011mmol cm^-2 min^-1,0.029mmol cm^-2 min^-1,0.003mmol cm^-2 min^-1,respectively.It revealed the release of ASP from metformin acetylsalicylate was 3 times that of ASP,in contrast,the release of MET from metformin acetylsalicylate was less than half that of MET-HCl.Therefore,the gastrointestinal side effects associated with the solubility properties of ASP and MET could be recduced to some extent by the salt formation.The hydrolysis rate of metformin acetylsalicylate in pH 1.2 buffer was lower than that of aspirin,indicating that metformin acetylsalicylate was relatively stable in gastric environment.Further,the chemical stability of three forms of metformin acetylsalicylate under different conditions?40°C,60°C,45%RH,60%RH,75%RH and 5500 lx?were investigated.It was found that the stability of three forms was different,and the form I is the most stable form in three forms of the salt.