Preparation And Evaluation Of Physicochemical Properties Of Sinomenine Co-amorphous And Crystalline Complexes

Sinomenine（SIN）is an alkaloid isolated from the traditional Chinese medicine Caulis sinomenii.C.It possesses diverse biological activities,including anti-inflammatory,immunosuppressive,antitumor,analgesic,and others.Currently,its hydrochloride（SIN-HCl）has been prepared as drugs for the treatment of rheumatoid arthritis（RA）in China for years.Unfortunately,SIN-HCl exhibits short half-life,rapid metabolism,and low oral bioavailability.Frequent drug administration should be carried out to achieve desired therapeutic effects.It was reported that SIN-HCl also promotes the release of histamine,which leads to various side effects,such as allergic and gastrointestinal reactions.In addition,as a water-soluble drug with a short half-life,its rapid release and clearance in vivo would lead to a huge fluctuation of drug-plasma concentrations,thereby affecting its efficacy and increasing the likelihood of side effects.Recently,several sustained-release strategies such as microcapsules and microspheres were adapted to lengthen the half-life of SIN-HCl and stabilize its drug-plasma concentrations in vivo.However,the complex preparation processes may limit their further development.Moreover,the commercial oral extended-release formulation of SIN-HCl has already been marketed,while its sustained-release effect is not obvious,which should still be used twice daily.Hence,it is necessary to develop novel formulations with longer sustained-release behaviors.So far,the development of SIN sustained-release formations has mainly been based on SIN-HCl,and no other solid forms have been studied.In recent years,the potential of drug solid-state chemistry in improving the physicochemical properties of drugs and enhancing their bioavailability and efficacy has been extensively studied.We reasoned this strategy may be potentially useful to address the loopholes of SIN mentioned above.Firstly,phenolic compounds including salicylic acid（SAA）,2,3-dihydroxybenzoic acid（23DHB）,and 2,4-dihydroxybenzoic acid（24DHB）were employed as co-formers for constructing three homogeneous SIN co-amorphous systems.All of them were analyzed by powder X-ray diffraction（PXRD）,temperature-modulated differential scanning calorimetry（m DSC）,and Fourier transform infrared spectroscopy（FTIR）.Salt formation occurred between the alkaline SIN and phenolic acids.Co-amorphous systems of SIN-SAA,SIN-23DHB,and SIN-24DHB possess their glass transition temperatures at 109.5,124.9,and 135.3°C,respectively.In physical stability tests,the three co-amorphous systems exhibit better physical stability than amorphous SIN.Compared to SIN-HCl,all of them displayed significant sustained-release behaviors.Hence,these co-amorphous systems may hold promise to substitute SIN-HCl in the sustained-release formulation development of SIN.In addition,three unreported crystalline complexes were obtained after the dissolution experiments of co-amorphous systems.Furthermore,we designed three series of drug-drug co-amorphous systems aiming at the clinical needs in RA treatment and the alleviation of the possible side effects of SIN.First,in order to obtain new solid forms of SIN with sustained release behaviors and provide potential synergistic treatment strategies for RA at the same time.Three non-steroidal anti-inflammatory drugs commonly used for RA therapy including indometacin（IND）,naproxen（NAP）,and sulindac（SUL）were employed as co-formers for building SIN co-amorphous systems.Second,three SIN co-amorphous systems with different ratios（1:2,1:1,and 2:1）of antihistamine drug tranilast（TRA）were also constructed for providing a potential dual strategy for relieving the side effects of SIN as well as achieving its sustained release.Third,as microbial infections one of the underlying pathogenic reasons of RA,and also caused by immune system disorders during RA therapy.We prepared two co-amorphous systems of SIN and two potent antibiotics including sulfasalazine（SULF）and platensimycin（PTM）to provide a potential synergistic therapeutic strategy for infection-associated RA,and to achieve sustained release of SIN at the same time.The drug-drug co-amorphous systems prepared above were comprehensively characterized by PXRD,m DSC,FTIR,X-ray photoelectron spectroscopy（XPS）,and scanning electron microscopy（SEM）.Their intermolecular interactions in solid-states were further explored.Under 25°C and 75%relative humidity condition,the co-amorphous systems showed excellent physical stability,and no recrystallization was observed during 4–6 months of tests.In dissolution experiments,different degree of gelation behaviors among these co-amorphous systems were observed,which resulted in a few of them,i.e.,co-amorphous forms of SIN-IND,SIN-TRA（1:2 and 1:1）,SIN-PTM,and SIN-SULF,showed poor SIN solubility in comparison to crystalline SIN.Compared to SIN-HCl,all of them exhibited obvious sustained release behaviors.For co-amorphous SIN-PTM and SIN-SULF,their cumulative release of SIN within 6 h was even lower than 20%.The poor release behaviors of co-amorphous SIN-PTM and SIN-SULF were further improved by adding a small amount of drug excipients including polyvinylpyrrolidone K30（PVP-K30）,poloxamer（Polo）,sodium dodecyl sulfate（SDS）.The cumulative release of the co-amorphous SIN-PTM subsequently increased from 16.1%to 48.3–72.4%.To explore the underlying molecular mechanism that why co-amorphous systems possess better physical stability than amorphous SIN,enthalpy relaxation experiments were conducted on co-amorphous SIN-SULF and SIN-PTM for investigating their molecular mobility.Co-amorphous systems exhibited lower molecular mobility compared to that of amorphous SIN.In addition,the intermolecular interactions of the components in co-amorphous systems of SIN-TRA,SIN-PTM,and SIN-SULF in DMSO-d₆ were explored by liquid NMR techniques,which explained the changes of their dissolution behavior.Finally,three crystalline complexes were formed during the dissolution of SIN-phenolic co-amorphous systems.According to simultaneous thermal analysis and FTIR,all of them were confirmed as monohydrate salts.However,no single crystals of these three monohydrates and SIN were obtained.While three single crystals of SIN-ETOH-H₂O,SIN-23DHB,and SIN-24DHB-MEOH-H₂O were accidentally harvested,and their crystalline structures were next resolved.The three monohydrates exhibited better compressibility than SIN,since they were easier to be compressed into tablets.In dissolution tests,all of them showed different degrees of solubility improvement of SIN.In in vitro release and intrinsic dissolution rate tests,all crystalline complexes exhibited much lower release rate than that of SIN-HCl.The release rate order of all SIN solid forms is SIN-HCl>>SIN-SAA-H₂O>SIN>SIN-23DHB-H₂O>SIN-24DHB-H₂O.Thus,the three monohydrates may be potentially used for the development of sustained-release SIN formulations.In conclusion,new co-amorphous and crystalline complex forms of SIN were obtained,which may provide excellent opportunities for the development of sustained-release formulations of SIN.These new solids forms may also hold advantages of reduction of side effects during SIN usage,and potential drug synergistic therapies in the treatment of RA.Generally,co-amorphous technology is used for improving the solubilities and release rates of poorly soluble drugs.However,the co-amorphous samples obtained in this work showed different degree of sustained release behaviors,which may provide a new approach for producing sustained-release formulations in the future.