The Preformulation Investigation Of The New Drug SX004 For Acute Leukemia

Currently, drug developments of many compounds are limited due to their poor biopharmaceutical properties, which often lead to extended timelines and higher cost. To screen out new chemical entities, from a biopharmaceutical perspective, physicochemical parameters such as solubility, lipophilicity and stability are required to be investigated as soon as possible. SX004 in our study is a new chemical entity which is firstly developed at home and abroad. It can be used in the treatment of chronic myeloid leukemia. SX004 takes effect faster, and its efficacy is stronger than those of imatinib and nilotinib. Up to date, SX004 has not been reported in the publications. In this thesis, SX004 were systemically investigated by characterizations of solid state, solution state and excipients compatibility.In the second chapter, HPLC separating system and quantitative method were established. To screen the mobile phase, the acetonitrile-phosphate buffer system was firstly explored. The pH value of aqueous phase was adjusted in the condition of fixing the proportion of organic phase. The pH6.5 was selected as the optimum pH value of aqueous phase according to evaluations of tailing factor, impurity number and resolution, and the number of theoretical plates. After fixing the pH of aqueous phase, the proportion of organic phase was slightly adjusted according to retention time. The results showed that the optimum proportion of organic phase was 35%. In addition, the acetonitrile-methanol-phosphate system was also explored, but no satisfactory results were obtained. Therefore, the optimized mobile phase was as follows: acetonitrile-warter (35:65, pH6.5 adjusted with phosphoric acid) containing 0.5% triethylamine, and the methodology validation of established HPLC method was also performed. Ultimately, we provided an accurate, precise and stable analysis method for formulation screening, quality control and stability evaluation of SX004.The study on equilibrium solubility was performed in the third chapter. Firstly, the solubility of SX004 in the different polar solvents was determined according to the standard operation of solubility assay in Chinese Pharmacopoeia 2010. The results showed that the solubility of SX004 increased with greater polarity of solvent. In order to evaluate the solubility of SX004 in vivo, the solubility of SX004 in PBS with different pH value was investigated. The results suggested that the solubility of SX004 decreased with the pH value increasing.In the fourth chapter, the dissociation constant of SX004 was assayed through the nonlogarithmic titration method using different methanol-water solvents and 0.01mol·L^-1 HCl titration solution. The pK_b was calculated according to the Benet method. The results showed that the pK_b of SX004 was 7.743.The oil-water partition coefficient (logP) of SX004 was determined in the fifth chapter. A shaking flask-HPLC method was used to determine the concentration of SX004 in the aqueous phase after the partition equilibrium of SX004 in the n-octyl alcohol-water system. Then, the oil-water partition coefficient of SX004 was calculated. The results showed that the lgP almost unchanged when the pH value of aqueous phase was below 6.0 and above 7.0. SX004 mainly existed in the aqueous phase when the pH value of aqueous phase was below 6.0, and in the oil phase when the pH value was above 7.0. The logP of SX004 increased with the pH value of aqueous phase increasing in a range from 6.0 to 7.0.In the sixth chapter, the hygroscopicity of SX004 was determined at 25℃in different relative humidity (33.0%, 43.2%, 57.7%, 75.3%, 84.3%, 93.6%). The hygroscopicity equilibrium curve was plotted, and the CRH was calculated subsequently. The results showed that the CRH of SX004 was 63.33%, and it was very hygroscopic.In the seventh chapter, we screened the excipients having no influence on the stability of SX004, and designed the finally formulation. The ratio of SX004 to excipient was chosen according to the type of excipients. In the drug-excipient compatibility test, the content and related substance of SX004 were determined by HPLC after storage for 30 days at 40℃and 75% relative humidity. The results showed that the excipients, which were compatible with SX004, included microcrystalline cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, and french chalk.In the eighth chapter, the stability of SX004 was evaluated through influential factors test. The results suggested that SX004 was very sensitive to highly relative humidity. Therefore, SX004 was packed and monitored in a 3-month accelerated test at 40℃and 75% relative humidity. The results demonstrated that there were no significant differences on appearance characteristics, weight change, content and related substance of SX004 within three months.