School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA.
Zeeh Pharmaceutical Experiment Station, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA.
J Pharm Sci. 2021 Nov;110(11):3670-3677. doi: 10.1016/j.xphs.2021.07.018. Epub 2021 Aug 8.
Lumefantrine (LMF), a high-mobility and easy-to-crystallize WHO drug for treating malaria, can form an amorphous salt with poly(acrylic acid) (PAA) that is remarkably stable against crystallization at high humidity and temperature and has fast dissolution rate. The amorphous salt up to 75% drug loading was synthesized under a mild slurry condition easily implemented in basic facilities for global health. Salt formation was confirmed by IR spectroscopy and the much elevated glass transition temperature. At 50% drug loading, the amorphous salt resists crystallization for at least 18 months under the highly stressful condition of 40 °C and 75% RH. In contrast, the dispersion containing neutral LMF in PVP fully crystallized in 4 d and the dispersion in HPMCAS, a weak polyelectrolyte of lower charge density than PAA, crystallized by 50% in 7 d. The amorphous salt at 50% drug loading showed much faster dissolution than crystalline LMF: In SGF, the area under the curve (AUC) was 30 times larger within the gastric emptying time (4 h); in FaSSIF, the enhancement was even larger - by 200 times. Nanodroplets were detected during the dissolution in SGF, possibly accounting for the apparent enhancement of dissolution rate. The LMF-PAA example as a challenging case, along with the previously reported clofazimine-PAA, demonstrates the general utility of amorphous drug-polymer salts to achieve high stability under tropical conditions and enhanced dissolution and bioavailability.
磷酸咯萘啶（LMF）是世界卫生组织推荐的一种高效抗疟药，可与聚丙烯酸（PAA）形成无定形盐，该无定形盐在高湿度和高温下具有显著的抗结晶稳定性，且溶解速度快。在温和的浆液条件下，可将高达 75%药物负载量的无定形盐轻易地合成，这种条件易于在全球医疗保健基础设施中实施。通过红外光谱和明显提高的玻璃化转变温度确认了盐的形成。在 50%药物负载的情况下，无定形盐在 40°C 和 75%相对湿度的高应激条件下至少可抵抗结晶 18 个月。相比之下，在 PVP 中含有中性 LMF 的分散体在 4 天内完全结晶，而在电荷密度低于 PAA 的弱聚电解质 HPMCAS 中的分散体在 7 天内结晶 50%。50%药物负载的无定形盐的溶解速度明显快于结晶 LMF：在 SGF 中，在胃排空时间（4 小时）内曲线下面积（AUC）大 30 倍；在 FaSSIF 中，增强甚至更大——200 倍。在 SGF 中溶解过程中检测到纳米液滴，这可能是溶解速率明显提高的原因。磷酸咯萘啶-PAA 这个具有挑战性的例子，以及之前报道的氯法齐明-PAA，证明了无定形药物-聚合物盐在热带条件下实现高稳定性、增强溶解和生物利用度的普遍适用性。
