利用 UV/VIS 漫反射和固态 NMR 光谱测定含柠檬酸盐、磷酸盐和组氨酸缓冲液的冻干海藻糖的固态酸度。

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL
Journal of pharmaceutical sciences Pub Date : 2024-12-01 Epub Date: 2024-09-21 DOI:10.1016/j.xphs.2024.09.019
Ashley Lay-Fortenbery, Xiaoda Yuan, Lukáš Veselý, Dominik Heger, Evgenyi Shalaev, Yongchao Su, Eric Munson
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引用次数: 0

摘要

冻干蛋白质质子化状态的变化会影响结构的完整性、化学稳定性以及重组时的聚集倾向。在选择缓冲液时,冷冻/干燥过程可能会因缓冲液的电离偏移而导致蛋白质质子状态的剧烈变化。为了确定是否发生了质子转变,可在制剂中加入可电离的探针。光学探针(染料)在冻干产品中显示出显著的电离变化,但目前还不清楚 pH 指示剂在整个基质中是否均匀,也不清楚 pH 指示剂的变化是否实际反映了药物的电离变化。在固态核磁共振(SSNMR)光谱中,羧酸中羰基碳的化学位移对酸的电离状态非常敏感。因此,通过在制剂中使用少量同位素标记的羧酸种类,SSNMR 可用来测量冻干基质中的电离变化。本文使用 SSNMR 和紫外可见光漫反射光谱法 (UVDRS) 比较了六种含曲卤糖的冻干缓冲体系的表观 pH 值。使用两种不同电离探针(分别为丁酸和溴甲酚紫)的 SSNMR 和 UVDRS 结果表明,与柠檬酸钠缓冲液中的冻干前溶液相比,表观酸度变化不大,但在磷酸二氢钾、磷酸钠和组氨酸缓冲液中观察到的变化较大。虽然两种方法的趋势相似,但两种方法的等效 pH 值(pHeq)却存在差异。本文讨论了造成差异的潜在原因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Determination of solid-state acidity of lyophilized trehalose containing citrate, phosphate, and histidine buffers using UV/VIS diffuse reflectance and solid-state NMR spectroscopy.

Changes in the protonation state of lyophilized proteins can impact structural integrity, chemical stability, and propensity to aggregate upon reconstitution. When a buffer is chosen, the freezing/drying process may result in dramatic changes in the protonation state of the protein due to ionization shift of the buffer. In order to determine whether protonation shifts are occurring, ionizable probes can be added to the formulation. Optical probes (dyes) have shown dramatic ionization changes in lyophilized products, but it is unclear whether the pH indicator is uniform throughout the matrix and whether the change in the pH indicator actually mirrors drug ionization changes. In solid-state NMR (SSNMR) spectroscopy, the chemical shift of the carbonyl carbon in carboxylic acids is very sensitive to the ionization state of the acid. Therefore, SSNMR can be used to measure ionization changes in a lyophilized matrix by employing a small quantity of an isotopically-labeled carboxylic acid species in the formulation. This paper compares the apparent pH of six trehalose-containing lyophilized buffer systems using SSNMR and UV-Vis diffuse reflectance spectroscopy (UVDRS). Both SSNMR and UVDRS results using two different ionization probes (butyric acid and bromocresol purple, respectively) showed little change in apparent acidity compared to the pre-lyophilized solution in a sodium citrate buffer, but a greater change was observed in potassium phosphate, sodium phosphate, and histidine buffers. While the trends between the two methods were similar, there were differences in the numerical values of equivalent pH (pHeq) observed between the two methods. The potential causes contributing to the differences are discussed.

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来源期刊
CiteScore
7.30
自引率
13.20%
发文量
367
审稿时长
33 days
期刊介绍: The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.
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