Development of a Melting Point Depression Method to Measure the Solubility of a Small-Molecule Drug in Poly-Lactic-co-Glycolic Acid (PLGA).

IF 3.5 3区医学 Q2 CHEMISTRY, MULTIDISCIPLINARY

Pharmaceutical Research Pub Date : 2025-03-01 Epub Date: 2025-03-06 DOI:10.1007/s11095-025-03840-4

Coleman Johnson, Feng Zhang

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引用次数: 0

Abstract

Purpose: The solubility of a crystalline drug in a polymer is commonly determined by measuring melting point depression with differential scanning calorimetry (DSC). The accuracy of this measurement depends on rapid dissolution of the drug into the molten polymer during the DSC heating scan. A preferred method of accelerating this dissolution process is to preblend the drug and polymer by cryo-milling. However, cryo-milling may be unsuitable for water-sensitive drugs or polymers such as poly(lactic-co-glycolic acid) (PLGA). The purpose of this study was to develop a PLGA-specific melting point depression method that did not require a cryo-milling operation.

Methods: A three-step DSC method was used to measure the solubility of a small-molecule drug, voriconazole, in amorphous PLGA (Resomer ® RG 502H). First, drug/PLGA powder mixtures of multiple drug loadings were melted and rapidly cooled to form glassy solid solutions. Second, these solid solutions were heated above their T_g until the drug crystallized. Third, these crystallized samples were slowly heated to measure melting point depression (i.e., solubility temperatures).

Results: The crystallization procedure generated the desired drug polymorph and likely generated small, well-mixed crystalline drug particles, as the drug dissolved rapidly into the molten polymer during melting point depression scans. Drug/PLGA solubility temperatures were determined with confidence between 40 - 100% drug loading. The solubility curve was extrapolated to lower drug loadings using the Flory-Huggins model.

Conclusion: This technique can assist product development of high-drug-loaded PLGA products, particularly those manufactured by melt extrusion.

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熔点降低法测定小分子药物在聚乳酸-羟基乙酸（PLGA）中的溶解度

目的：晶体药物在聚合物中的溶解度通常是用差示扫描量热法（DSC）测量熔点下降来确定的。该测量的准确性取决于DSC加热扫描期间药物在熔融聚合物中的快速溶解。加速这一溶解过程的一种优选方法是通过冷磨预混合药物和聚合物。然而，低温铣削可能不适用于对水敏感的药物或聚合物，如聚乳酸-羟基乙酸（PLGA）。本研究的目的是开发一种不需要低温铣削操作的plga特异性熔点降低方法。方法：采用三步DSC法测定小分子药物伏立康唑在非晶PLGA （Resomer®RG 502H）中的溶解度。首先，将多种药物负载的药物/PLGA粉末混合物熔化并快速冷却，形成玻璃状固溶体。其次，将这些固溶体加热到高于Tg的温度，直到药物结晶。第三，将这些结晶样品缓慢加热以测量熔点下降（即溶解度温度）。结果：结晶过程产生了所需的药物多晶型，并且可能产生了小的、混合良好的结晶药物颗粒，因为药物在熔点下降扫描期间迅速溶解到熔融聚合物中。药物/PLGA溶解度温度测定的置信度为载药量的40 - 100%。利用Flory-Huggins模型外推溶解度曲线以降低药物负荷。结论：该技术可辅助高载药PLGA产品的开发，特别是熔融挤压法制备的产品。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pharmaceutical Research 医学-化学综合

CiteScore

6.60

自引率

5.40%

发文量

276

审稿时长

3.4 months

期刊介绍： Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to: -(pre)formulation engineering and processing- computational biopharmaceutics- drug delivery and targeting- molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)- pharmacokinetics, pharmacodynamics and pharmacogenetics. Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.