Topalović Igor A, Marković Olivera S, Pešić Miloš P, Kathawala Mufaddal H, Kuentz Martin, Avdeef Alex, Serajuddin Abu T M, Verbić Tatjana Ž
University of Belgrade-Faculty of Chemistry, Studentski trg 12-16, 11000 Belgrade, Serbia.
University of Belgrade-Institute of Chemistry, Technology and Metallurgy, Department of Chemistry, Njegoševa 12, 11000 Belgrade, Serbia.
Pharmaceutics. 2024 Dec 2;16(12):1545. doi: 10.3390/pharmaceutics16121545.
BACKGROUND/OBJECTIVES: Clofazimine (CFZ) is a Biopharmaceutics Classification System (BCS) II drug introduced in the US market in 1986 for the treatment of leprosy. However, CFZ was later withdrawn from the market due to its extremely low aqueous solubility and low absorption. In the literature, the intrinsic solubility of CFZ has been estimated to be <0.01 μg/mL, and solubilities of its different salt forms in simulated gastric and intestinal fluids are <10 µg/mL. These are extremely low solubilities for the dissolution of a drug administered orally at 100-200 mg doses.
In the present investigation, seven weak organic acids (adipic, citric, glutaric, maleic, malic, succinic, and tartaric) were tested by determining the aqueous solubility of CFZ as the function of acid concentration to investigate whether any of the acids would lead to the supersolubilization of CFZ.
There were only minimal increases in solubilities when concentrations of acids in water were increased up to 2.4 M. The solubilities, however, increased to 0.32, 1.23, and 10.68 mg/mL, respectively, in 5 M solutions of tartaric, malic, and glutaric acids after equilibration for 24 h at 25 °C. Crystalline solids were formed after the equilibration of CFZ with all acids. Apparently, salts or cocrystals were formed with all acids, except for glutaric acid, as their melting endotherms in DSC scans were in the range of 207.6 to 248.5 °C, which were close to that of CFZ itself (224.8 °C). In contrast, the adduct formed with glutaric acid melted at the low temperature of 77 °C, and no other peak was observed at a higher temperature, indicating that the material converted to an amorphous state.
The increase in CFZ solubility to >10 mg/mL in the presence of 5 M glutaric acid could be called supersolubilization when compared to the intrinsic solubility of the basic drug. Such an increase in CFZ solubility and the conversion of the glutarate adduct to an amorphous state are being exploited to develop rapidly dissolving dosage forms.
背景/目的：氯法齐明（CFZ）是一种生物药剂学分类系统（BCS）II类药物，于1986年在美国市场推出用于治疗麻风病。然而，由于其极低的水溶性和低吸收性，CFZ后来被撤出市场。在文献中，CFZ的固有溶解度估计<0.01μg/mL，其不同盐形式在模拟胃液和肠液中的溶解度<10μg/mL。对于口服剂量为100 - 200mg的药物溶解来说，这些溶解度极低。
在本研究中，通过测定CFZ的水溶性作为酸浓度的函数，测试了七种弱有机酸（己二酸、柠檬酸、戊二酸、马来酸、苹果酸、琥珀酸和酒石酸），以研究是否有任何一种酸会导致CFZ的增溶。
当水中酸的浓度增加到2.4M时，溶解度仅有极小的增加。然而，在25℃平衡24小时后，CFZ在5M酒石酸、苹果酸和戊二酸溶液中的溶解度分别增加到0.32、1.23和10.68mg/mL。CFZ与所有酸平衡后形成了结晶固体。显然，除戊二酸外，与所有酸都形成了盐或共晶体，因为它们在DSC扫描中的熔融吸热峰在207.6至248.5℃范围内，与CFZ本身的（224.8℃）接近。相比之下，与戊二酸形成的加合物在77℃的低温下熔化，在较高温度下未观察到其他峰，表明该物质转变为无定形状态。
与碱性药物的固有溶解度相比，在5M戊二酸存在下CFZ溶解度增加到>10mg/mL可称为增溶。CFZ溶解度的这种增加以及戊二酸加合物转变为无定形状态正被用于开发快速溶解的剂型。
