Break

Owing to their large surface area and supersaturation capability, drug nanoparticles prepared via wet stirred media milling have been widely used to address inadequate bioavailability of poorly water-soluble drugs [1,2]. Unfortunately, stabilization of drug nanoparticles in aqueous medium poses challenges as nanoparticles tend to aggregate, leading to loss of surface area available for dissolution. Thus, drug nanosuspensions necessitate the use of various dispersants/stabilizers. According to some published work [3,4] and prevailing notion among pharmaceutical formulators, low MW polymers are usually more effective than and preferred over high MW polymers in the production and stabilization of drug nanosuspensions. This study subjects this commonly-held notion to serious scrutiny. In this study, we explore the impact of various polymers and their molecular weight (MW) on the aggregation state and rheology of wet-milled suspensions of itraconazole (ITZ), a poorly water-soluble drug. ITZ suspensions with SSL, SL, and L grades of hydroxypropyl cellulose (HPC) having MW of 40, 100, and 140 kg/mol, respectively, hydroxypropyl methyl cellulose (HPMC E3 with 10 kg/mol), polyvinylpyrrolidone (PVP K30 with 50 kg/mol), sodium dodecyl sulfate (SDS, surfactant), and HPC SL–SDS were wet-milled in a stirred media mill. Laser diffraction, viscometry, scanning electron microscopy, and electrophoretic light scattering (ELS) were used to characterize the milled suspensions.

Laser diffraction results show that 2.5% HPC SL–0.2% SDS led to the finest ITZ nanosuspension, whereas without SDS, only 4.5% HPC with SL/L grades ensured minimal aggregation. Rheological characterization reveals that aggregated suspensions exhibited pronounced pseudoplasticity, whereas stable suspensions exhibited near Newtonian behavior. Wet-milled stable 10% ITZ nanosuspensions exhibiting near-Newtonian flow behavior were prepared with 4.5% HPC SL/L (100 and 140 kg/mol MW, respectively). At this concentration, HPC SSL (40 kg/mol), HPMC E3 (10 kg/mol), and PVP K30 (50 kg/mol) could not suppress ITZ nanoparticle aggregation, leading to significant pseudoplastic behavior. Contrary to previous studies that highlight the favorability of low MW polymers [3,4] (specifically <50 kg/mol for ITZ–HPC [3]), our study demonstrated that higher MW HPC (100 and 140 kg/mol) is more favorable for ITZ nanosuspension stabilization, which in line with the thermodynamic considerations of polymer adsorption. Unfortunately, studies like [3,4] that used low-energy mills do not truly reflect the impact of different polymers or MW on steric stabilization and reduction of drug aggregate formation. The use of higher MW polymer and/or higher polymer concentration causes more pronounced viscous dampening [5], which slows down the breakage in low-energy mills more profoundly than in high-energy mills like wet stirred media mills used in this study. Hence, such studies drew somewhat confounded conclusions about the impact of polymer MW due to pronounced impact of viscous dampening. Not only did high-energy, wet stirred media milling enabled faster production of ITZ nanoparticles than low energy mills used in ref. [3] for ITZ–HPC, but also it allowed us to elucidate the role of polymer MW in stabilization of drug nanoparticles, which in line with the thermodynamic consideration of polymer adsorption. Although higher MW HPC led to better stabilization of the ITZ nanosuspensions here, the use of HPC with MW >140 kg/mol could cause more pronounced viscous dampening and ensuing slower breakage. Hence, overall our results point out the criticality of choosing optimal polymer MW in the stabilization of wet-milled drug nanoparticles and invalidity of the commonly-held notion that low-MW polymers are more effective than high-MW polymers for the stabilization of drug nanosuspensions.

References:

1. Li, M. Azad, R. Davé, E. Bilgili, Nanomilling of drugs for bioavailability enhancement: a holistic formulation–process perspective, Pharmaceutics, 8 (2016) 27.
2. Bhakay, M. Rahman, R. N. Dave, E. Bilgili, Bioavailability enhancement of poorly water-soluble drugs via nanocomposites: Formulation processing aspects and challenges, Pharmaceutics, 10 (2018) 86.
3. -Y. Choi, C. H. Park, J. Lee, Effect of polymer molecular weight on nanocomminution of poorly soluble drug, Drug Delivery, 15 (2008) 347–353.
4. Sepassi, D. Goodwin, A. Drake, S. Holland, G. Leonard, L. Martini, M. Lawrence, Effect of polymer molecular weight on the production of drug nanoparticles, J. Pharm. Sci., 96 (2007) 2655–2666.
5. E. Bilgili, A. Afolabi, A combined microhydrodynamics–polymer adsorption analysis for elucidation of the roles of stabilizers in wet stirred media milling, Int. J. Pharm., 439 (2012) 193–206.