Quantitative Analysis of Drug Supersaturation Region by Temperature-Variable Nuclear Magnetic Resonance Measurements, Part 2: Effects of Solubilizer
Quantitative Analysis of Drug Supersaturation Region by Temperature-Variable Nuclear Magnetic Resonance Measurements, Part 2: Effects of Solubilizer
复制标题
通过变温核磁共振测量对药物过饱和区域进行定量分析，第 2 部分：增溶剂的影响
DOI：
10.1021/acs.molpharmaceut.3c00050
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发表时间：
2023
影响因子：
4.9
通讯作者：
Moribe Kunikazu
中科院分区：
文献类型：
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作者：
Ueda Keisuke;Higashi Kenjirou;Moribe Kunikazu
本研究利用变温核磁共振（NMR）光谱研究增溶剂对酮洛芬（KTP）过饱和区域的影响。定量核磁共振分析表明，增溶剂十六烷基三甲基溴化铵（CTAB）增加了结晶和无定形溶解度的KTP，转移KTP过饱和区域的KTP浓度范围更高。KTP的无定形溶解度被发现是独立的对映体组成的KTP，即使在存在的CTAB。然而，KTP的S-对映体（s-KTP）在CTAB溶液中的过饱和区域小于KTP的外消旋形式（rac-KTP），这可能是因为s-KTP的更高的结晶溶解度。当KTP通过液-液相分离从KTP过饱和溶液中形成富KTP相时，观察到CTAB分布到富KTP相中，降低了KTP的化学势和KTP在水相中的最大热力学活性。此外，将CTAB掺入到富KTP相中减少了CTAB胶束在水相中的增溶作用，在更高的KTP剂量浓度下在更大程度上缩小了KTP过饱和区域。此外，在CTAB的存在下，KTP的过饱和溶解区域的温度上限降低，这是合理的KTP晶体的熔点下降后，与CTAB混合。这项研究的结果强调了考虑增溶剂对药物过饱和区域的分子水平影响的重要性，以充分利用过饱和制剂的潜在益处。
This study utilized temperature-variable nuclear magnetic resonance (NMR) spectroscopy to investigate the effects of a solubilizing agent on the ketoprofen (KTP) supersaturation region. Quantitative NMR analysis showed that the solubilizing agent cetyltrimethylammonium bromide (CTAB) increased both the crystalline and amorphous solubilities of KTP, shifting the KTP supersaturation region to a higher KTP concentration range. The amorphous solubility of KTP was found to be independent of the enantiomeric composition of KTP, even in the presence of CTAB. However, the supersaturation region of theS-enantiomer of KTP (s-KTP) in CTAB solutions was smaller than that of the racemic form of KTP (rac-KTP), likely because of the higher crystalline solubility of s-KTP. When KTP formed a KTP-rich phase via liquid–liquid phase separation from KTP-supersaturated solutions, CTAB was observed to be distributed into the KTP-rich phase, decreasing the chemical potential of KTP and the maximum thermodynamic activity of KTP in the aqueous phase. Additionally, the incorporation of CTAB into the KTP-rich phase diminished the solubilization effect of CTAB micelles in the aqueous phase, narrowing the KTP supersaturation region to a greater extent at higher KTP dose concentrations. Furthermore, the upper-temperature limit of the supersaturated dissolvable region of KTP was lowered in the presence of CTAB, which was rationalized by the melting point depression of the KTP crystal upon mixing with CTAB. The findings of this study highlight the importance of considering the molecular-level impact of solubilizing agents on the drug supersaturation region to fully exploit the potential benefits of supersaturated formulations.