Holm Tobias Palle, Knopp Matthias Manne, Löbmann Korbinian, Berthelsen Ragna
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Bioneer:FARMA, Department of Pharmacy, Copenhagen, Denmark.
Eur J Pharm Sci. 2021 Aug 1;163:105858. doi: 10.1016/j.ejps.2021.105858. Epub 2021 Apr 19.
Amorphisation within the final dosage form, i.e. in situ amorphisation, seeks to circumvent the potential stability issues associated with poorly soluble drugs in amorphous solid dispersions (ASDs). Microwave irradiation has previously been shown to enable in situ preparation of ASDs, when a high amount of microwave absorbing water was introduced into the final dosage form by conditioning at high relative humidity. In this study, an alternative to this conditioning step was investigated by introducing crystal water in form of sodium dihydrogen phosphate (NaHPO) di-, and monohydrate, in compacts prepared with 30 % w/w celecoxib (CCX) in polyvinylpyrrolidone K12 (PVP). As controls, compacts prepared with NaHPO anhydrate and without NaHPO were included in the study. The quantification of amorphous CCX after microwave irradiation showed an increase in CCX amorphicity for compacts containing NaHPO di-, and monohydrate with increasing irradiation time. Complete amorphisation of CCX in compacts containing NaHPO di-, and monohydrate was observed after 6 min, while no appreciable amorphisation was observed for the control compacts containing NaHPO anhydrate and without NaHPO. Modulated differential scanning calorimetric analysis revealed that a homogenous ASD was formed after 12 min and 6 min for compacts containing NaHPO di-, and monohydrate, respectively. Thermal gravimetric analysis indicated that NaHPO monohydrate showed higher dehydration rates compared to the dihydrate, which in turn resulted in higher compact temperatures, and overall increased the rate of amorphisation and reduced the microwave irradiation time necessary to achieve a homogenous ASD. The present results confirmed the suitability of NaHPO di- and monohydrate as alternative sources of water, the primary microwave absorbing material, for in situ microwave amorphisation. The use of crystalline hydrates as water reservoirs for in situ amorphisation circumvents the time-consuming and highly impractical conditioning step previously reported in order to achieve complete amorphisation. Additionally, it allows for easier and more accurate adjustment of the compacts water content, which directly affects the temperature reached during microwave irradiation, and thus, the rate of amorphisation.
在最终剂型中实现非晶化，即原位非晶化，旨在规避与非晶态固体分散体（ASD）中难溶性药物相关的潜在稳定性问题。先前研究表明，当通过在高相对湿度下进行处理，将大量吸收微波的水引入最终剂型时，微波辐射能够实现ASD的原位制备。在本研究中，通过在以聚乙烯吡咯烷酮K12（PVP）为载体、含30% w/w塞来昔布（CCX）制备的压片中引入磷酸二氢钠（NaH₂PO₄）二水合物和一水合物形式的结晶水，对这一处理步骤的替代方法进行了研究。作为对照，研究中纳入了用无水NaH₂PO₄制备的压片以及不含NaH₂PO₄的压片。微波辐射后非晶态CCX的定量分析表明，含NaH₂PO₄二水合物和一水合物的压片中，CCX的非晶化程度随辐射时间增加而提高。含NaH₂PO₄二水合物和一水合物的压片中，CCX在6分钟后实现了完全非晶化，而含无水NaH₂PO₄的对照压片和不含NaH₂PO₄的对照压片未观察到明显的非晶化现象。调制式差示扫描量热分析表明，含NaH₂PO₄二水合物和一水合物的压片分别在12分钟和6分钟后形成了均匀的ASD。热重分析表明，与二水合物相比，一水合NaH₂PO₄的脱水速率更高，这进而导致压片温度更高，总体上提高了非晶化速率，并缩短了实现均匀ASD所需的微波辐射时间。本研究结果证实了NaH₂PO₄二水合物和一水合物作为水的替代来源（主要的微波吸收材料）用于原位微波非晶化的适用性。使用结晶水合物作为原位非晶化的水源，规避了先前报道的为实现完全非晶化而进行的耗时且极不实用的处理步骤。此外，它允许更轻松、更准确地调节压片的含水量，而含水量直接影响微波辐射过程中达到的温度，进而影响非晶化速率。
