基于理化性质的枸橼酸托法替布处方前研究

Pre-prescription Study Based on Physical and Chemical Properties of Tofacitinib Citrate

关键词:  枸橼酸托法替布  平衡溶解度  脂水分配系数  影响因素试验  接触角  差示扫描量热法  扫描电镜法  X-射线衍射法  红外光谱法

Key words:  tofacitinib citrate  equilibrium solubility  lipid-water partition coefficient  influencing factor test  contact angle  differential scanning calorimetry  scanning electron microscope  X-ray diffraction  infrared spectroscopy

摘要:

目的 考察枸橼酸托法替布理化性质，为其制剂处方、工艺设计、包装和储藏等提供理论依据。方法 采用HPLC测定药物在不同pH缓冲液及水中的平衡溶解度、脂水分配系数(P)及润湿性；对药物进行影响因素试验；测定药物的粒度、粒度分布、红外光谱(FTIR)、X-射线衍射图谱(XRD)、差示扫描量热图谱(DSC)和扫描电镜图谱(SEM)。结果 枸橼酸托法替布在pH 1.0~8.0的缓冲液及水中的平衡溶解度为0.183 4~22.594 1 mg·mL^-1，属高溶解性药物，其中在pH 1.0缓冲液中的平衡溶解度最大；在上述各介质中，lgP为-1.34~1.28，属低渗透性药物，其中在pH 3.6缓冲液中的lgP最大；在上述各介质中，接触角均<90°，均易于被润湿；枸橼酸托法替布在高温、高湿及强光照射下均较为稳定；平均粒径为(29.85±0.17)µm；XRD、DSC及SEM结果均表明枸橼酸托法替布为结晶性药物，熔点为210 ℃；FTIR结果表明，枸橼酸托法替布在3 375.44，3 134.51，1 732.54，1 711.78，1 625.24，1 551.03，1 529.52，1 473.76，1 448.28，1 409.48，1 348.17，1 213.59，1 170.22，1 115.37，1 077.68，1 023.87，916.97，846.38，775.66，741.84，703.42，603.15，444.07 cm^-1有较强的红外特征峰。结论 枸橼酸托法替布为BCSⅢ类药物，宜设计成胃内滞留型给药系统，有利于药物在上消化道溶解与吸收，以提高生物利用度；本研究使用的枸橼酸托法替布为稳定的结晶性药物，可满足一般制剂生产、包装、贮藏等要求。

Abstract:

OBJECTIVE To investigate the physical and chemical properties of tofacitinib citrate, to provide theoretical basis for its formulation, process design, packaging and storage, etc. METHODS HPLC was used to determine the equilibrium solubility, lipid-water partition coefficient(P) and wettability of the drug in different pH buffers and water. The influencing factor trials of the drug were tested. The particle size, particle size distribution, infrared spectroscopy(FTIR), X-ray diffraction(XRD), differential scanning calorimetry(DSC) and scanning electron microscope(SEM) of the drug were determined. RESULTS The equilibrium solubility of tofacitinib citrate was 0.183 4-22.594 1 mg·mL^-1 in pH 1.0-8.0 buffer and water, which was a highly soluble drug. Among them, the equilibrium solubility in pH 1.0 buffers was the largest. The lgP was -1.34-1.28 in the above medium, belongs to a low permeability drug. Among them, the lgP in pH 3.6 buffer was the largest. The contact angles in the above medium were all <90°, and they were all easily wetted by these media. Tofacitinib citrate was stable under high temperature, high humidity and strong light irradiation. The average particle size of tofacitinib citrate was (29.85±0.17)µm. XRD, DSC and SEM results all showed that tofacitinib citrate was a crystalline drug, the melting point was 210 ℃. FTIR results showed that tofacitinib citrate had strong infrared characteristic peaks at 3 375.44, 3 134.51, 1 732.54, 1 711.78, 1 625.24, 1 551.03, 1 529.52, 1 473.76, 1 448.28, 1 409.48, 1 348.17, 1 213.59, 1 170.22, 1 115.37, 1 077.68, 1 023.87, 916.97, 846.38, 775.66, 741.84, 703.42, 603.15, 444.07 cm^-1, etc. CONCLUSION Tofacitinib citrate is a BCS class III drug. It is suitable to be designed into a gastric retention type drug delivery system, which is beneficial to the dissolution and absorption of the drug in the upper digestive tract to improve the bioavailability. The tofacitinib citrate used in this experiment is a stable crystalline drug that can meet the requirements of general preparation production, packaging, and storage.