(526a) Quiescent and Agitated Redispersion of Griseofulvin Nanoparticles From Nanocomposite Microparticles in Water: Impact of a Wet-Milled Swellable Dispersant

Reduction of drug particle size down to nanometer or sub-micron scale has been an effective way of increasing the dissolution rate of poorly water-soluble drugs¹. Production of nanoparticles leads to an increase in the surface area and thereby increases the dissolution rate as per the Noyes–Whitney equation². Wet stirred media milling has been commonly used as a top down approach to produce drug nanoparticle suspensions, also referred to as nanosuspensions^3-6. Nanoparticles are prone to aggregation in suspensions. To ensure chemical and physical stability of the suspensions during a potential long-term storage and meet patient needs/demands, drug nanosuspensions are typically dried into nanocomposite microparticles (NCMPs), in the form of powders, which are then incorporated into various solid dosage forms such as tablets, capsules, sachets, etc. using standard pharmaceutical unit operations. Unfortunately, during the drying processes, drug nanoparticles may form hard aggregates or drug–polymer agglomerates within the structure of NCMPs^6,7. Another problem is that even if the drug nanoparticles do not form hard aggregates, they may not be recovered from the NCMPs completely and quickly upon redispersion in fluids during in vivo or in vitro dissolution⁶. In either case, the latent large surface area of the nanoparticles will not be exposed. As a result, the dissolution rate and bioavailability of the drug can be significantly reduced even though the drug has been wet-milled to nanoparticle scale. Therefore, an understanding of nanoparticle recovery during the redispersion of NCMPs in water or other biorelevant media may be of fundamental importance in explaining and/or predicting the dissolution and bioavailability of poorly water-soluble drugs⁶.

   A great majority of prior work in pharmaceutical literature on drug NCMPs did not focus on the redispersion phenomenon at all. In fact, some researchers inferred the redispersion behavior inversely from the standard dissolution testing on drug NCMPs^8,9. However, such studies completely disregarded the fundamental mechanisms associated with the redispersion. In redispersion tests, NCMPs are suspended in an aqueous medium (usually water) and subjected to relatively low shear/agitation while nanoparticles are released from the NCMPs. Drug solubility in the aqueous medium is usually very low; hence, little to no drug is dissolved. The aqueous redispersion can be performed either in a cylindrical vessel with a stirring element or sonication probe followed by particle size analysis of several time samples taken during the redispersion^6,10 or in the sample cell of a particle size measuring equipment with size measurements taken over a period of time¹¹. Comparison of the particle size distribution of the wet media milled suspension and that of the aqueous redispersion as a function of time reveals the extent–dynamics of the drug nanoparticle recovery from the NCMPs. It is clear that the majority of the redispersion testing in pharmaceutical literature relies on particle sizing.

   In this study, the redispersion behavior of nanocomposite microparticles (NCMPs) incorporating griseofulvin (GF, model drug) nanoparticles and wet-milled swellable dispersant particles^12,13 along with other dispersants was investigated using two agitation methods, i.e., no external agitation (near-quiescent condition) and paddle-stirring, with several independent characterization methods. In the first method, NCMPs were added to initially-quiescent water inside a test tube, and the redispersion dynamics were studied by measuring the turbidity and analyzing the images of the particle population as recorded by a camera. Similarly, NCMPs were added to initially-quiescent water inside the cuvette of a dynamic light scattering equipment, and the particle size of the redispersion was measured. To get a better understanding of the redispersion under near-quiescent conditions, the response of a single NCMP exposed to a drop of water was observed under an optical microscope. In the second method, NCMPs were added to water agitated by a paddle stirrer, and both the particle size distribution and the GF assay of the centrifuged redispersion were determined. NCMPs used in this redispersion study were prepared with several dispersants that modulate the redispersion behavior. Superdisintegrants can be used as inexpensive, model, swellable dispersant particles with or without wet-milling along with drugs. Suspensions of GF along with various dispersants produced by wet-milling were coated onto Pharmatose^®to prepare core-shell type NCMPs in a fluidized bed process. Hydroxypropyl cellulose (HPC, neutral polymer) alone and with sodium dodecyl sulfate (SDS, anionic surfactant) was used as base-line stabilizer/dispersant during milling. Croscarmellose sodium (CCS, anionic superdisintegrant) and Mannitol (sugar alcohol) were used as additional dispersants to prepare surfactant-free NCMPs. Unmilled (sieved CCS) and wet-milled CCS, co-milled with GF for different times, were used to investigate the impact of CCS particle size on the redispersion response.

   The images taken during the redispersion of NCMPs in a test tube and optical microscopy images of a single redispersing NCMP illustrated several stages of the redispersion phenomenon: particle wetting and sinking, swelling, erosion, and dispersion of the nanoparticles. Furthermore, the turbidity after the near-quiescent redispersion in the test tube correlated well with the extent of GF nanoparticles recovered during the redispersion test with a paddle stirrer. Both agitation methods yielded a similar rank-ordering of the redispersibility of the different NCMP formulations. A comprehensive analysis and interpretation of the redispersion test results also enabled us to develop a fundamental understanding of the roles of various dispersants used in the NCMP formulations. In the absence of CCS or SDS, NCMPs containing no dispersants, HPC alone, or HPC/Mannitol were not redispersible because of the poor wettability of these NCMPs and slow dissolution of the HPC embedding the relatively hydrophobic GF nanoparticles. Incorporation of SDS enhanced the wettability and HPC dissolution, which in turn allowed weakening/breakage of the NCMP shell and resulting clusters from this breakage fast. Due to the extensive swelling capacity of CCS, incorporation of wet-milled CCS into the NCMPs caused effective breakage of the NCMP structure and bursting of nanoparticle clusters, leading to fast release of the GF nanoparticles. It was also found that a mixture of colloidal and unmilled CCS particles with a broad multimodal size distribution promoted the GF nanoparticle recovery better than either the unimodal, colloidal CCS particles or the unimodal, unmilled, micron-sized CCS particles.

   With the ultimate goal of improving the bioavailability of poorly water-soluble drugs, the results demonstrate that a precursor suspension of wet co-milled drug–superdisintegrant particles and unmilled superdisintegrant particles in the presence of soluble polymers may be used to produce fast redispersible, surfactant-free drug NCMPs. The GF nanoparticle recovery during the redispersion tests also correlated significantly with the GF dissolution using water and paddle-stirring in both experiments, thus confirming the predictive capability of the redispersion tests. The near-quiescent and agitated redispersion tests presented here are expected to be widely used by formulators/engineers in designing robust NCMP formulations.

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