目的:无定形固体分散体(ASDs),其中药物分子分散在聚合物中,能提高难溶性药物的物理稳定性和口服生物利用度。通常使用高聚合物浓度来避免药物结晶的风险。然而,我们最近证明了重叠浓度,C*,在药物熔体中的聚合物是在快速骤冷后保持药物处于无定形状态所需的最小聚合物浓度。对于与聚乙烯吡咯烷酮(PVP)混合的几种药物,这一结论得到了证实。在这里,我们评估了用各种聚合物和药物以及在各种聚合物浓度(C)和分子量(MWs)下配制的ASD的固态稳定性。我们进一步检验了以下假设:药物结晶程度随C/C*的增加而降低,当C>C*时消失。其中C*取决于聚合物MW和药物-聚合物相互作用的强度。
方法:我们用由酮康唑与聚丙烯酸混合组成的ASD来检验我们的假设,聚甲基丙烯酸和聚(甲基丙烯酸-共-丙烯酸乙酯);和非洛地平与PVP和聚(乙烯基吡咯烷酮-共-乙酸乙烯酯)混合。熔融药物中聚合物的C*值是用流变学方法测定的。通过测量熔融焓来评估结晶行为,ΔHf和X射线衍射。
结果:我们确认ΔHf/ΔHf,C=0=f(C/C*),并且当C>C*时基本上不发生结晶。
结论:我们的发现将帮助研究人员设计或选择合适的聚合物来抑制难溶性药物的结晶。该研究还表明,通过流变学确定的C*可用于比较类似分子量聚合物的药物-聚合物相互作用。
OBJECTIVE: Amorphous solid dispersions (ASDs), wherein a drug is molecularly dispersed in a polymer, can improve physical stability and oral bioavailability of poorly soluble drugs. Risk of drug crystallization is usually averted using high polymer concentrations. However, we demonstrated recently that the overlap concentration, C*, of polymer in drug melt is the minimum polymer concentration required to maintain drug in the amorphous state following rapid quench. This conclusion was confirmed for several drugs mixed with poly(vinylpyrrolidone) (PVP). Here we assess the solid-state stability of ASDs formulated with a variety of polymers and drugs and at various polymer concentrations (C) and molecular weights (MWs). We further test the hypothesis that degree of drug crystallization decreases with increasing C/C* and vanishes when C>C*, where C* depends on polymer MW and strength of drug-polymer interaction.
METHODS: We test our hypothesis with ASDs consisting of ketoconazole admixed with polyacrylic acid, polymethacrylic acid and poly (methacrylic acid-co-ethyl acrylate); and felodipine admixed with PVP and poly (vinylpyrrolidone-co-vinyl acetate). Values of C* for polymers in molten drug are rheologically determined. Crystallization behavior is assessed by measuring enthalpy of fusion, ΔHf and by X-ray diffraction.
RESULTS: We confirm that ΔHf/ΔHf, C = 0 = f(C/C∗), and essentially no crystallization occurs when C>C*.
CONCLUSIONS: Our findings will aid researchers in designing or selecting appropriate polymers to inhibit crystallization of poorly soluble drugs. This research also suggests that C* as determined by rheology can be used to compare drug-polymer interactions for similar molecular weight polymers.