Continuous production of drug nanoparticle suspensions via wet stirred media milling: a fresh look at the Rehbinder effect

Abstract

Nanoparticles of BCS Class II drugs are produced in wet stirred media mills operating in batch or recirculation mode with the goal of resolving the poor water-solubility issue. Scant information is available regarding the continuous production of drug nanoparticles via wet media milling. Griseofulvin and Naproxen were milled in both recirculation mode and multi-pass continuous mode to study the breakage dynamics and to determine the effects of suspension flow rate. The evolution of the median particle size was measured and described by an empirical breakage model. We found that these two operation modes could produce drug nanosuspensions with similar particle size distributions (PSDs). A reduced suspension flow rate slowed the breakage rate and led to a wider PSD and more differentiation between the two operation modes. The latter part of this study focused on the roles of stabilizers (hydroxypropyl cellulose and sodium lauryl sulfate) and elucidation of the so-called Rehbinder effect (reduction in particle strength due to adsorbed stabilizers such as polymers and surfactants). Milling the drugs in the absence of the stabilizers produced primary nanoparticles and their aggregates, while milling with the stabilizers produced smaller primary nanoparticles with minimal aggregation. Using laser diffraction, BET nitrogen adsorption, scanning electron microscopy imaging, and a microhydrodynamic analysis of milling, this study, for the first time, provides sufficient evidence for the existence of the Rehbinder effect during the milling of drugs. Not only do the polymers and surfactants allow proper stabilization of the nanoparticles in the suspensions, but they also do facilitate drug particle breakage.

An Intensified Vibratory Milling Process for Enhancing the Breakage Kinetics during the Preparation of Drug Nanosuspensions

“…Comparative analysis of these thermograms to that of the as-received GF with T m =220°C and ΔH m =91.2 J/g suggests that the reduced ΔH m and T m upon milling could be mostly attributed to the dilution and encapsulation of the drug particles by the amorphous polymer (HPC). This finding accords very well with previous work (27) on the wet stirred media milling of GF, which showed identical DSC thermograms for the milled GF without stabilizers and the as-received GF. Overall, both the PXRD and DSC results here suggest that although vibratory media milling might have caused some defect formation in GF crystals, the crystalline nature of GF was largely preserved.…”

“…Overall, both the PXRD and DSC results here suggest that although vibratory media milling might have caused some defect formation in GF crystals, the crystalline nature of GF was largely preserved. This finding is not surprising because comprehensive characterization of the milled GF particles via DSC, XRD, and Raman spectroscopy demonstrated that even apparently more aggressive wet stirred media milling process did not cause notable change to the crystallinity (27,44). Moreover, similar observations were made for the crystallinity of other wet media milled, poorly water-soluble drugs such as fenofibrate (49)(50)(51) and indomethacin (44).…”

“…4). As compared to the diffractograms of both the as-received GF and the physical mixture, the peak positions remained the same with slightly lower peak intensity for Run 13, which could be attributed to defect formation and accumulation during milling (27). DSC thermograms (Fig.…”

“…Another disadvantage of wet media milling is the risk of contamination due to media wear (22) and phase transition of drug induced by high mechanical stresses (23). Despite these disadvantages, wet stirred media milling has been preferred over other top-down methods in the pharmaceutical industry as it is continuous, scalable, solvent-free, and environmentally benign (24)(25)(26)(27). Moreover, nanosuspensions prepared via wet media milling have the distinct advantages of high drug loading, low excipient side effects, and can be generally formulated for most drug candidates (28).…”

Using USP I and USP IV for Discriminating Dissolution Rates of Nano- and Microparticle-Loaded Pharmaceutical Strip-Films

“…The suspension produced from WSMM exhibited a median particle size of 0.144 μm while the suspensions made using as-received GF exhibited a median particle size of 5.031 μm. Extensive characterization of the dried GF nanosuspensions and GF-loaded films via DSC, PXRD, and Raman spectroscopy suggested that the crystalline nature of GF was largely preserved after wet milling (42) and incorporation into films including subsequent drying (36). Figure 4 shows SEM images for the cross-section of strip-films.…”