Mitrović Jelena R, Bjelošević Žiberna Maja, Vukadinović Aleksandar, Knutson Daniel E, Sharmin Dishary, Kremenović Aleksandar, Ahlin Grabnar Pegi, Planinšek Odon, Lunter Dominique, Cook James M, Savić Miroslav M, Savić Snežana D
Department of Pharmaceutical Technology and Cosmetology, University of Belgrade-Faculty of Pharmacy, Vojvode Stepe 450, Belgrade 11221, Serbia.
Department of Pharmaceutical Technology, University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000, Ljubljana, Slovenia.
Eur J Pharm Sci. 2023 Oct 1;189:106557. doi: 10.1016/j.ejps.2023.106557. Epub 2023 Aug 6.
Recently, nanocrystal dispersions have been considered as a promising formulation strategy to improve the bioavailability of the deuterated pyrazoloquinolinone ligand DK-I-56-1 (7‑methoxy-2-(4‑methoxy-d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one). In the current study, the freeze-drying process (formulation and process parameters) was investigated to improve the storage stability of the previously developed formulation. Different combinations of lyoprotectant (sucrose or trehalose) and bulking agent (mannitol) were varied while formulations were freeze-dried under two conditions (primary drying at -10 or -45 °C). The obtained lyophilizates were characterized in terms of particle size, solid state properties and morphology, while the interactions within the samples were analyzed by Fourier transform infrared spectroscopy. In the preliminary study, three formulations were selected based on the high redispersibility index values (around 95%). The temperature of primary drying had no significant effect on particle size, but stability during storage was impaired for samples dried at -10 °C. Samples dried at lower temperature were more homogeneous and remained stable for three months. It was found that the optimal ratio of sucrose or trehalose to mannitol was 3:2 at a total concentration of 10% to achieve the best stability (particle size < 1.0 μm, polydispersity index < 0.250). The amorphous state of lyoprotectants probably provided a high degree of interaction with nanocrystals, while the crystalline mannitol provided an elegant cake structure. Sucrose was superior to trehalose in maintaining particle size during freeze-drying, while trehalose was more effective in keeping particle size within limits during storage. In conclusion, results demonstrated that the appropriate combination of sucrose/trehalose and mannitol together with the appropriate selection of lyophilization process parameters could yield nanocrystals with satisfactory stability.
最近，纳米晶体分散体被认为是一种很有前景的制剂策略，可提高氘代吡唑并喹啉酮配体DK-I-56-1（7-甲氧基-2-(4-甲氧基-d3-苯基)-2,5-二氢-3H-吡唑并[4,3-c]喹啉-3-酮）的生物利用度。在当前研究中，对冷冻干燥过程（制剂和工艺参数）进行了研究，以提高先前开发制剂的储存稳定性。在两种条件下（-10或-45°C进行一次干燥）对制剂进行冷冻干燥时，改变了冻干保护剂（蔗糖或海藻糖）和填充剂（甘露醇）的不同组合。对获得的冻干产品进行粒度、固态性质和形态表征，同时通过傅里叶变换红外光谱分析样品内部的相互作用。在初步研究中，根据高再分散指数值（约95%）选择了三种制剂。一次干燥温度对粒度没有显著影响，但在-10°C干燥的样品在储存期间的稳定性受到损害。在较低温度下干燥的样品更均匀，并且在三个月内保持稳定。发现蔗糖或海藻糖与甘露醇的最佳比例为3:2，总浓度为10%，以实现最佳稳定性（粒度<1.0μm，多分散指数<0.250）。冻干保护剂的无定形态可能与纳米晶体提供了高度的相互作用，而结晶甘露醇提供了良好的块状结构。在冷冻干燥过程中，蔗糖在保持粒度方面优于海藻糖，而海藻糖在储存期间将粒度保持在限度内更有效。总之，结果表明，蔗糖/海藻糖和甘露醇的适当组合以及冻干工艺参数的适当选择可以产生具有令人满意稳定性的纳米晶体。
