Indulkar Anura S, Alex Samantha, Zhang Geoff G Z
Small Molecule CMC Development, Research and Development, AbbVie Inc., North Chicago, IL 60064, United States.
Small Molecule CMC Development, Research and Development, AbbVie Inc., North Chicago, IL 60064, United States.
J Pharm Sci. 2025 Jan;114(1):497-506. doi: 10.1016/j.xphs.2024.10.028. Epub 2024 Oct 23.
Amorphous solid dispersions (ASDs) are widely employed as a strategy to improve oral bioavailability of poorly water soluble compounds. Typically, optimal dissolution performance from a polyvinylpyrrolidone vinyl acetate (PVPVA) based ASD is observed at relatively low drug loading limit. Above a certain drug load, termed limit of congruency (LoC), the release from ASDs significantly decreases. So far, the majority of the dissolution behavior has been tested in conditions where the drug primarily exists in unionized form. In this work, the impact of pH of the dissolution environment on the release performance of ASDs of an ionizable drug was studied. Atazanavir (ATZ), a weakly basic drug with a pK of 4.5 was used as a model compound and PVPVA was used as a non-ionizable matrix polymer. Dissolution rate was measured using Wood's apparatus which normalizes the surface area of the dissolving tablet. The pH of the dissolution media was varied between 1 and 6.8, to cover a range where ATZ exists as >99 % ionized or unionized species. At pH 6.8, near complete release was observed only when the drug load was ≤ 6 %. Unlike typically observed drastic decline in release behavior for PVPVA based ASDs above LoC, ATZ ASDs underwent gradual decline in dissolution behavior when the DL was increased to 8 %. This was attributed to potential formation of an ATZ-PVPVA associated phase with dissolution rate slower than neat PVPVA. However, the 10 % DL ASD showed negligible ATZ release. On another extreme (pH 1) where ATZ is ∼100 % ionized, the dissolution rate of ATZ was faster than that of PVPVA. ASD dissolution rate was found to be slower than that of the neat drug but faster than PVPVA and interestingly, did not change with DL. This can be attributed to formation of an ionized ATZ-PVPVA phase which controls the dissolution rate of the ASD. At pH 3, where the drug is ∼97 % ionized, near complete release was observed for drug loads ≤ 8 %. To observe significant increase in drug loading with near complete release, >98 % ionization of ATZ was required. At pH 2 where ATZ is ∼99.7 % ionized, near complete release was observed for drug loads up to 30 %. Furthermore, the deterioration in dissolution performance with an increase in drug load continued to be gradual at pH 2. The enhancement in dissolution performance did not correlate with solubility enhancement of ATZ due to ionization. We theorize that the enhancement in the dissolution performance due to ionization is the result of formation of an ionized ATZ-PVPVA phase which increases the hydrophilicity and the miscibility of the ASD. This can help resist water induced phase separation during ASD dissolution and therefore, result in continuous, and congruent dissolution of the drug and polymer.
无定形固体分散体（ASDs）被广泛用作提高难溶性化合物口服生物利用度的一种策略。通常，基于聚醋酸乙烯酯聚乙烯吡咯烷酮（PVPVA）的ASD在相对较低的药物载量限制下表现出最佳的溶出性能。超过某个药物载量，即协同极限（LoC），ASDs的释放会显著降低。到目前为止，大多数溶出行为是在药物主要以非离子化形式存在的条件下进行测试的。在这项工作中，研究了溶出环境的pH值对可电离药物ASDs释放性能的影响。阿扎那韦（ATZ）是一种pK为4.5的弱碱性药物，用作模型化合物，PVPVA用作非离子化的基质聚合物。使用伍德装置测量溶出速率，该装置可使溶解片剂的表面积标准化。溶出介质的pH值在1至6.8之间变化，以覆盖ATZ以>99%离子化或非离子化形式存在的范围。在pH 6.8时，仅当药物载量≤6%时才观察到接近完全释放。与通常观察到的基于PVPVA的ASDs在LoC以上释放行为的急剧下降不同，当药物载量增加到8%时，ATZ ASDs的溶出行为逐渐下降。这归因于可能形成了一种ATZ-PVPVA缔合相，其溶解速率比纯PVPVA慢。然而，10%药物载量的ASD显示出可忽略不计的ATZ释放。在另一个极端情况（pH 1）下，ATZ约100%离子化，ATZ的溶出速率比PVPVA快。发现ASD的溶出速率比纯药物慢，但比PVPVA快，有趣的是，它不随药物载量变化。这可归因于形成了离子化的ATZ-PVPVA相，该相控制了ASD的溶出速率。在pH 3时，药物约97%离子化，对于药物载量≤8%的情况观察到接近完全释放。为了观察到药物载量显著增加且接近完全释放，需要ATZ>98%离子化。在pH 2时，ATZ约99.7%离子化，对于高达30%的药物载量观察到接近完全释放。此外，在pH 2时，随着药物载量增加，溶出性能的恶化仍然是逐渐的。溶出性能的增强与由于离子化导致的ATZ溶解度增强无关。我们推测，由于离子化导致的溶出性能增强是形成了离子化的ATZ-PVPVA相的结果，该相增加了ASD的亲水性和混溶性。这有助于在ASD溶解过程中抵抗水诱导的相分离，因此，导致药物和聚合物持续、协同地溶解。
