School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.
Department of Pharmacy, University of Copenhagen, 2100 Copenhagen, Denmark.
Int J Pharm. 2021 Nov 20;609:121157. doi: 10.1016/j.ijpharm.2021.121157. Epub 2021 Oct 6.
Microwave-induced in situ amorphization is an emerging technology to tackle the persistent stability issue of amorphous solid dispersions (ASDs) during manufacture and storage. The aim of this study was to introduce new effective polymeric carriers with diverse properties to microwave-induced in situ amorphization and to better understand their functions in relation to the final dissolution performance of microwaved tablets. Tablets composed of indomethacin (IND) and different polymers were compacted, stored at 75% relative humidity for at least 1 week and microwaved at 1000 W to induce amorphization. A series of polymers, polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios displaying varyingproperties in functional groupratio, hygroscopicity, molecular weight (M), and glass transition temperature (T) of the polymer were used as model carriers. The results suggested that more than 90% of IND was amorphized after 20 mins microwaving in all 20% (w/w) drug loaded tablets except for IND:PVAc tablets presenting approx. 36% residual crystallinity. Among them, tablets composed of PVP/VA I-335 and PVP K30 achieved complete in situ amorphization upon microwaving. Further analysis indicated that the influencing factors, polymer M and T of moisture-plasticized polymer, played a major role in microwave-induced in situ amorphization. In in vitro dissolution study, ASDs containing PVP/VA I-535 with moderate hydrophilicity and 0.96 ± 1.92% IND residual crystallinity showed the most rapid and complete drug release among all formulations, presenting the most promising dissolution performance. Further study on the chemical stability of such formulation showed a statistically insignificant decrease of drug content after pre-conditioning and microwaving (P = 0.288 > 0.05).
微波诱导原位非晶化是一项新兴技术，可解决非晶固体分散体（ASD）在制造和储存过程中持续存在的稳定性问题。本研究旨在引入具有不同性质的新型有效聚合物载体进行微波诱导原位非晶化，并更好地了解它们在与微波片剂最终溶解性能的关系中的作用。将吲哚美辛（IND）和不同聚合物压制成片剂，在相对湿度为 75%的条件下储存至少 1 周，然后在 1000 W 下微波诱导非晶化。使用一系列具有不同单体重量比的聚维酮/醋酸乙烯酯共聚物（PVP/VA）作为模型载体，这些聚合物在功能基团比、吸湿性、分子量（M）和聚合物玻璃化转变温度（T）方面具有不同的性质。结果表明，除了 IND:PVAc 片剂呈现约 36%的残余结晶度外，在所有 20%（w/w）载药量的片剂中，经过 20 分钟微波处理后，超过 90%的 IND 被非晶化。其中，PVP/VA I-335 和 PVP K30 片剂在微波处理后完全实现了原位非晶化。进一步分析表明，影响因素是聚合物的 M 和水分增塑聚合物的 T，在微波诱导原位非晶化中起主要作用。在体外溶解研究中，含有具有适度亲水性和 0.96±1.92%IND 残余结晶度的 PVP/VA I-535 的 ASD 在所有配方中表现出最快和最完全的药物释放，呈现出最有前途的溶解性能。对该制剂的化学稳定性的进一步研究表明，在预处理和微波处理后药物含量没有统计学上的显著下降（P=0.288>0.05）。
