Pietrzak Tomasz, Szendzielorz Ziemowit, Borychowska Joanna, Ratajczak Tomasz, Kubisiak Marcin
Research and Development Department, Pharmaceutical Works Polpharma S.A., Pelplińska 19, 83-200 Starogard Gdański, Poland.
Pharmaceutics. 2025 Jun 3;17(6):735. doi: 10.3390/pharmaceutics17060735.
Long-acting injections (LAIs) are innovative drug delivery systems that improve patient compliance by maintaining therapeutic drug levels over extended periods. Micro- and nanosuspensions are commonly used in LAIs to enhance bioavailability, but their thermodynamic instability poses challenges, including particle aggregation and growth. This study aimed to evaluate the impact of two helping processes-vehicle thermal treatment and high-shear homogenization-on the stability and manufacturing efficiency of aripiprazole monohydrate (AM) suspensions. AM suspensions containing sodium carboxymethyl cellulose (CMCNa), mannitol and disodium phosphate in water for injections (WFIs) were prepared using a combination of thermal treatment of the vehicle solution, high-shear homogenization and bead milling. Four manufacturing variants were tested to assess the influence of these processes on particle size distribution (PSD), viscosity and stability during a 3-month accelerated stability study. Molecular weight changes in CMCNa from thermal treatment were analyzed using size exclusion chromatography with multiangle scattering (SEC-MALS), and PSD was measured using laser diffraction. Thermal treatment of the vehicle solution had minimal impact on CMCNa molecular weight, preserving its functionality. High-shear homogenization during bead milling significantly reduced particle aggregation, resulting in improved PSD and reduced viscosity. Synergistic effects of the two helping processes used in one manufacturing process were observed, which led to superior stability and minimal changes in PSD and viscosity during storage. Batches without the helping processes exhibited increased particle size and viscosity over time, indicating reduced suspension stability. Incorporating vehicle thermal treatment and high-shear homogenization during bead milling enhances the stability and manufacturing efficiency of AM suspensions. These findings underscore the importance of optimizing laboratory-scale processes to ensure the quality and safety of pharmaceutical suspensions.
长效注射剂（LAIs）是一种创新的药物递送系统，通过在较长时间内维持治疗药物水平来提高患者的依从性。微悬浮液和纳米悬浮液常用于长效注射剂中以提高生物利用度，但其热力学不稳定性带来了挑战，包括颗粒聚集和生长。本研究旨在评估两种辅助工艺——载体热处理和高剪切均质化——对阿立哌唑一水合物（AM）悬浮液稳定性和生产效率的影响。使用载体溶液热处理、高剪切均质化和珠磨相结合的方法，制备了含有羧甲基纤维素钠（CMCNa）、甘露醇和磷酸氢二钠的注射用水（WFIs）中的AM悬浮液。在为期3个月的加速稳定性研究中，测试了四种生产变体，以评估这些工艺对粒度分布（PSD）、粘度和稳定性的影响。使用多角度散射尺寸排阻色谱法（SEC-MALS）分析热处理导致的CMCNa分子量变化，并使用激光衍射法测量PSD。载体溶液的热处理对CMCNa分子量影响最小，保留了其功能。珠磨过程中的高剪切均质化显著减少了颗粒聚集，从而改善了PSD并降低了粘度。观察到在一个生产过程中使用的两种辅助工艺的协同效应，这导致了在储存期间具有优异的稳定性以及PSD和粘度的最小变化。没有这些辅助工艺的批次随着时间的推移粒径和粘度增加，表明悬浮液稳定性降低。在珠磨过程中加入载体热处理和高剪切均质化可提高AM悬浮液的稳定性和生产效率。这些发现强调了优化实验室规模工艺以确保药物悬浮液质量和安全性的重要性。
