(298j) Fast, Immediate Drug Release from High Drug-Loaded Spray-Dried Nanocomposites: Criticality of Polymer Molecular Weight

Owing to their large surface area and supersaturation capability, drug nanoparticles prepared via wet stirred media milling in the form of nanosuspensions have been widely used to address inadequate bioavailability of poorly water-soluble drugs [1,2]. Particle size growth and aggregation occur in drug suspensions during wet media milling, storage, and downstream processing, and the extent of such phenomena must be reduced as they reduce drug surface area available for dissolution [1]. To prevent gross physical instability, drug nanosuspensions are usually dried into nanocomposites that are then incorporated into standard solid dosage forms such as tablets and capsules [2]. This approach also helps to achieve patient compliance because solid oral dosage forms incorporating drug nanoparticles are preferred over parenteral/injectable–oral drug nanosuspensions.

In this study, we examine the impact of various polymers/MW on the stabilization of wet-milled ITZ suspensions and ITZ dissolution from spray-dried suspensions (nanocomposites). To this end, aqueous ITZ suspensions containing HPC with SSL, SL, and L grades having MW of 40, 100, and 140 kg/mol, respectively, HPMC (E3 grade with 10 kg/mol MW), PVP (K30 grade with 50 kg/mol MW), SDS, and HPC SL–SDS were wet-milled in a high-energy stirred mill. The milled suspensions were spray-dried to prepare ITZ-laden nanocomposites. Laser diffraction, viscometry, and scanning electron microscopy were used to characterize the milled suspensions, while optical microscopy, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and UV-spectroscopy were used to characterize the nanocomposite powders. Using the modified Washburn method, drug wettability enhancement by the polymers was investigated. Redispersion of the nanocomposites was examined by off-line analysis via laser diffraction and optical microscopic imaging. Dissolution of the nanocomposites was performed in a USP II paddle apparatus. By calculating the difference and similarity factors and fitting the dissolution data via the Korsmeyer‒Peppas model, initial ITZ release kinetics was examined.

This study has demonstrated that wet-milled stable 10% ITZ nanosuspensions showing near-Newtonian flow behavior can be prepared with 4.5% HPC SL/L (100 and 140 kg/mol MW, respectively). At 4.5% 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. Spray drying of the ITZ suspensions yielded nanocomposites with 60–78% mean ITZ loading, which is higher than that in the ITZ nanocomposites produced in prior studies, and acceptable content uniformity. Severe aggregation occurred during the milling/drying when 4.5% polymers with MW £ 50 kg/mol were used. Their nanocomposites did not redisperse into ITZ nanoparticles/aggregates due to negligible/slow matrix erosion in the redispersion test; thus, they did not exhibit immediate release during the dissolution test. While the use of higher MW HPC (100 and 140 kg/mol) was more favorable from both nanosuspension stabilization and ITZ release perspectives, there exists an optimal MW; the fastest ITZ release among the nanocomposites with 4.5% polymer was achieved by HPC SL (100 kg/mol).

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.