Improve The Solubility Of Antitumor Active Ingredients Regorafenib And Morin Through Cocrystal Technology

Solubility is very important to the absorption and clinical efficacy of drugs.At present,most of the active pharmaceutical ingredients discovered by combinatorial chemistry and high-throughput screening have poor solubility,which lead to low bioavailability,and unsatisfactory clinical efficacy or even make it impossible to be marketed.How to improve the solubility of drugs without affecting their biological activity is an urgent problem to be solved.Pharmaceutical cocrystals refer to crystals in which ative pharmaceutical ingredients and cocrystal formers are combined in the same crystal lattice through non-covalent bonds such as hydrogen bonds,halogen bonds,andπ-πstacking.Studies have shown that it is an effective method to improve the solubility of poorly soluble drugs through cocrystal technology.This dissertation attempts to improve the solubility of two anti-tumor active ingredients,regorafenib and morin,through cocrystal technology aiming to improve their clinical efficacy.Regorafenib(REG)is an oral multikinase inhibitor used to treat gastrointestinal stromal tumors,colorectal cancer and advanced hepatocellular carcinoma.Regorafenib is marketed as a monohydrate with poor solubility,which results in 160 mg/day oral dose to exert clinical efficacy.In this work,five cocrystals of regorafenib with malonic acid(REG-MA,1:1),glutaric acid(REG-GA,1:1),pimelic acid(REG-PA,2:1),suberic acid(REG-SA,2:1),and maleic acid(REG-MLA,1:1)have been obtained through design screening,and preparation.The cocrystals was fully characterized by X-ray diffraction analysis,thermal analysis,Fourier transform infrared and ~1H nuclear magnetic resonance spectroscopy and then were evaluated through powder dissolution,dynamic vapor adsorption,stability and compressibility experiments.As compared with REG·H2O,the water solubility of all cocrystals are significantly improved,especially the water solubility of REG-PA is increased by 70.3 times.The cocrystal hygroscopicity of REG-MA,REG-GA,REG-PA,REG-SA was also improved.All cocrystals show similar physicochemical stability and compressibility to the monohydrate.This work provides a research basis to reduce the oral dose of REG and develop improved innovative medicine.Morin(MOR)is a flavonoid compound and it can inhibit enzyme activity,showing anti-cancer,anti-pain,anti-bacterial,anti-inflammatory,and anti-stress activities.MOR usually exists in the form of a hemihydrate,which is a yellow or grayish-yellow powder and intends to become brown when stored in the air.It also has poor solubility,which greatly limits the clinical application of MOR.In this work,three cocrystals of MOR with isonicotinamide(MOR-IS,1:1),betaine(MOR-BE,1:1)and tetramethylpyrazine(MOR-TE,1:1)were obtained through design screening,and preparation.The cocrystals was fully characterized by X-ray diffraction analysis,thermal analysis,Fourier transform infrared and ~1H nuclear magnetic resonance spectroscopy and then were evaluated through powder dissolution,dynamic vapor adsorption,stability and compressibility experiments.i The solubility and hygroscopicity of MOR-IS and MOR-TE were significantly improved,with increase of 2.3 times and 2.2 times of apparent solubility,respectively.All cocrystals have good light stability,and MOR contents remain unchanged within 10 days.MOR-IS and MOR-BE show similar compressibility to MOR.This work provides the experimental and theoretical basis for the formulation development of MOR.