Effect of Particle Size and Polymer Loading on Dissolution Behavior of Amorphous Griseofulvin Powder

Abstract

The effect of particle size on the dissolution behavior of the particles of amorphous solid dispersions (ASDs) of griseofulvin (GF), with 0%-50% Kollidon ® VA 64 as a crystallization inhibitor is investigated. Both the final dissolved GF concentration and the dissolution rate of GF ASDs were found to be inversely proportional to the particle size. The solution concentrations for the smallest (45-75 mm) size group with different polymer loadings were significantly higher than those for the largest (250-355 mm) group regardless of the initial GF amount. Specifically, the dissolution rate of GF ASDs with 50% polymer loading for the finest group was 2.7 times higher than for the largest group under supersaturating conditions. The rates of dissolution and recrystallization were assessed through surface concentration (C s) and Avrami recrystallization rate kinetics, where the solid-state recrystallization was confirmed using Raman spectroscopy. Outcomes indicated that particle size reduction enhanced ASD drug loading by reducing the amount of polymer necessary as finest size ASDs initially dissolve faster, negating their higher recrystallization rate. Kollidon® VA 64 at 30% loading was sufficient to inhibit the GF recrystallization. Overall, the combination of particle size reduction and recrystallization inhibition is effective for improved dissolution behavior of GF ASDs.

Impact of Matrix Surface Area on Griseofulvin Release from Extrudates Prepared via Nanoextrusion

“…Unlike for the ASDs, the matrix size/surface area impact does not seem to be remarkable for the nanocomposites because the observed lower extent of GF dissolution was mostly controlled by the lower thermodynamic solubility of the nanocrystalline drug itself (Figure 7c-f). Our findings agree well with the findings from a recent study by Zhang et al [56], wherein 25% proprietary drug-loaded HPMCAS-(hydroxypropyl methylcellulose acetate While full release of the drug is important for achieving a desired pharmacokinetic profile and ensuring complete utilization of the drug dose, immediate release (80% drug released in 30 min) is not a requirement for solid dosages containing poorly soluble drugs and it may not even be achievable (e.g., [57,99]), and/or desirable except for therapeutic indications where a rapid onset of action is required, for example, pain management [100]. In this study, although GF is an antifungal drug, immediate release from the 10% GF loaded, milled extrudates was regarded to be "desirable" within the context that a higher GF loading could cause a significant dissolution slow-down [57] (see also Section 3.5).…”

“…More importantly, the impact of matrix size in various sieved size fractions on drug release has not been extensively examined and related to the specific surface area of the respective size fractions. Two recent studies [ 56 , 57 ] regarding matrix size effect on drug release from ASDs prepared by HME and melt-quenching will be discussed in Section 3.4 of this paper. When nanocomposites were produced by nanoextrusion, the impact of matrix size has not been investigated [ 40 , 47 ] or has not been examined extensively and systematically and analyzed for multiple size fractions and drug loadings [ 41 ].…”

Influence of Particle Size and Drug Load on Amorphous Solid Dispersions Containing pH-Dependent Soluble Polymers and the Weak Base Ketoconazole

“…Zhang et al (2018) compared very fine ASD particles obtained by spray-drying with coarse ASD particles obtained by hot-melt extrusion and they found that the production technique profoundly impacted the dissolution properties (29). Zheng et al (2019) showed that the dissolution rate were inversely proportional to the particle size (30). However, also the recrystallization kinetics were dependent on the particle size since the extent of supersaturation and the supersaturation generation rate are determinative for the nucleation rate (31,32).…”

Processing of Polyvinyl Acetate Phthalate in Hot-Melt Extrusion—Preparation of Amorphous Solid Dispersions

“…However, the placebo extrudates dissolved relatively faster than the IND ASDs at a respective pH. This is quite plausible due to the fact that the presence of a drug with a considerably high logP value (4.3) within the polymeric carrier increases the lipophilicity of the drug-containing ASD compared to the pure polymer [27,28]. Consequently, the increased lipophilicity led to a slower dissolution rate for the drug-containing ASD.…”

“…Zhang et al (2018) showed that the particle size profoundly impacted the performance of an ASD, where a moderate particle size was superior to very fine powder due to the avoidance of a premature release of the weakly basic drug. Zheng et al (2019) observed that finer ASD particles tended towards faster recrystallization as compared to more coarse particles [27,28].…”