Tripathi Devika, Sharma Dinesh Kumar, Sahoo Jagannath
PSIT-Pranveer Singh Institute of Technology (Pharmacy), Kanpur, Uttar Pradesh, India.
Department of Pharmacy, VMSB, Uttarakhand Technical University, Dehradun, India.
Curr Radiopharm. 2025;18(2):100-119. doi: 10.2174/0118744710311951241018054453.
In the pharmaceutical sciences, the solubility profile of therapeutic molecules is crucial for identifying and formulating drugs and evaluating their quality across the drug discovery pipeline based on factors like oral bioavailability, metabolic transformation, biodistribution kinetics, and potential toxicological implications. The investigation aims to enhance the solubility parameters of ketoprofen (BCS-II class), which exhibits low solubility and high permeability.
In this method, hydrotrope blends of aromatic sodium benzoate and electrolyte sodium acetate were employed to enhance the solubility parameter of ketoprofen. Several batches of solid dispersion of ketoprofen were made using a solvent evaporation method, and the response surface method 3² factorial design was used to find the best one. The optimised formulation, KSD9, underwent in-vitro drug dissolution, DSC, pXRD, and SEM studies.
The optimized batch demonstrated substantial improvement in ketoprofen solubility, attributed to mixed hydrotropy. The results indicated that both solubility and %CDR improved when hydrotropes were employed, suggesting a direct proportionality between the rise in solubility and % CDR. Formulations KSD1-KSD9 exhibited solubility enhancements ranging from 2.23 to 5.77-fold, along with an elevation in % CDR from 72.28% to 94.76%. This implies that the % CDR was modulated by the hydrotropes, specifically influenced by the concentration levels of the independent variables. An increase in hydrotrope levels corresponded to an increase in % CDR. The positive coefficients in the quadratic equation for % CDR underscored the significant role of these independent variables in augmenting the in-vitro release of Ketoprofen. Similarly, during a comparative dissolution investigation, the optimized KSD9 formulation exhibited remarkable solubility and drug content compared to conventional Ketoprofen dispersible tablets.
The synergistic effect of combining two hydrotropic agents significantly increased the solubility of ketoprofen by up to 58 times. The results indicated that the independent variables exerted a positive influence on solubility and % CDR. Furthermore, the responses were contingent on the specific hydrotropes selected, which functioned as the independent variables. Analyzing the r² and ANOVA results suggested that the dependent variables aligned well with the chosen model. Visual representations, such as the 3D response surface plot and contour plot, demonstrated the impact of each hydrotrope individually and when combined. Overall, employing hydrotropes led to improved solubility and % CDR, highlighting a direct proportionality between the rise in solubility and % CDR. Mixed hydrotropic lessens the toxicity associated with individual hydrotrope concentrations while also offering a sustainable and eco-friendly alternative. This study paves the way for future research aiming to improve the solubility of low- solubility drugs, broadening their clinical applications.
在药物科学领域，治疗性分子的溶解度特征对于药物的识别、制剂开发以及基于口服生物利用度、代谢转化、生物分布动力学和潜在毒理学影响等因素在整个药物研发流程中评估其质量至关重要。本研究旨在提高酮洛芬（BCS-II类）的溶解度参数，该药物具有低溶解度和高渗透性。
在本方法中，采用芳香族苯甲酸钠和电解质醋酸钠组成的助溶剂混合物来提高酮洛芬的溶解度参数。使用溶剂蒸发法制备了几批酮洛芬固体分散体，并采用响应面法3²析因设计来找出最佳配方。对优化后的制剂KSD9进行了体外药物溶出、差示扫描量热法（DSC）、粉末X射线衍射（pXRD）和扫描电子显微镜（SEM）研究。
优化后的批次显示酮洛芬溶解度有显著提高，这归因于混合助溶作用。结果表明，使用助溶剂时溶解度和累积溶出率（%CDR）均有所提高，表明溶解度升高与%CDR之间存在正比关系。制剂KSD1-KSD9的溶解度提高了2.23至5.77倍，%CDR从72.28%提高到94.76%。这意味着%CDR受助溶剂调节，具体受自变量浓度水平影响。助溶剂水平的增加对应着%CDR的增加。%CDR二次方程中的正系数强调了这些自变量在提高酮洛芬体外释放方面的重要作用。同样，在对比溶出研究中，与传统酮洛芬分散片相比，优化后的KSD9制剂表现出显著的溶解度和药物含量。
两种助溶剂联合使用的协同效应使酮洛芬的溶解度显著提高，最高可达58倍。结果表明自变量对溶解度和%CDR有积极影响。此外，响应取决于所选的特定助溶剂（作为自变量）。对r²和方差分析结果的分析表明，因变量与所选模型拟合良好。三维响应面图和等高线图等可视化表示展示了每种助溶剂单独及联合使用时的影响。总体而言，使用助溶剂导致溶解度和%CDR提高，突出了溶解度升高与%CDR之间的正比关系。混合助溶降低了与单个助溶剂浓度相关的毒性，同时还提供了一种可持续且环保的替代方案。本研究为未来旨在提高低溶解度药物溶解度、拓宽其临床应用的研究铺平了道路。
