264040 Preparation of Co-Ground Drug-Superdisintegrant Nanosuspensions As a Precursor to the Production of Fast Dissolving Surfactant-Free Nanocomposite Microparticles
About 40% of the newly discovered drug compounds in the pharmaceutical industry exhibit poor water solubility, which usually leads to poor drug bioavailability. The dissolution rate and bioavailability can be improved by producing nano-sized drug crystals as nanoparticle suspensions (nanosuspensions). In the manufacture of various solid dosage forms, nanosuspensions are dried to prepare nanocomposite microparticles, which are then incorporated into the dosage forms via standard pharmaceutical unit operations. During drying of the nanosuspensions, formation of drug nanoparticle aggregates, solid bridges and agglomerates, and fused (hard) aggregates leads to incomplete recovery of the nanoparticles and ensuing slower dissolution. As a class of dispersants, surfactants play a critical role in fast recovery and dissolution of drug particles from the nanocomposite microparticles (Bhakay et al., 2012). However, surfactants can cause several issues such as physical instability of the nanosuspensions via Ostwald ripening and toxicity especially in inhalation applications, etc. Therefore, surfactants should be eliminated or used sparingly to minimize all potential negative impact. Hence, production of surfactant-free nanosuspensions as a precursor material for nanocomposite microparticle production is of utmost interest to formulators.
Nano-sized superdisintegrants (SDIs) can be used in nanocomposite microparticles as a novel class of dispersants for fast recovery and dissolution of drug nanoparticles (Bilgili et al., 2012). SDIs are water-insoluble, swellable, cross-linked polymers that are traditionally used for fast disintegration of tablets. Unfortunately, the smallest size of SDIs available is in the several microns range. To the best knowledge of the authors, there is no information available in the literature about the nano-sized SDIs. In this study, two commonly used SDIs, sodium starch glycolate (SSG) and crospovidone (CP), were milled in a wet stirred media mill. Aqueous colloidal suspensions of these SDIs were produced in the presence or absence of stabilizers. To incorporate SDIs in the nanosuspensions of drug, SDIs were also co-ground with the drug. Fenofibrate (FNB) was used as a model poorly water-soluble drug. FNB was milled in the presence of an anionic surfactant (sodium dodecyl sulfate, SDS), and was also co-ground with SSG or CP in the absence of SDS. In both cases, a soluble biopolymer (hydroxypropyl cellulose, HPC) was used as a steric stabilizer. We have successfully demonstrated the feasibility of preparing stable SDI and FNB-SDI suspensions using HPC as the stabilizer. The particle size distribution of the FNB-SSG suspension was similar to that of the FNB-SDS suspension. This finding suggests that colloidal SDIs may replace the surfactants or minimize their use in nanocomposite microparticles. The potential implications of the findings are discussed in terms of the redispersion and dissolution of the drug nanoparticles.
1. Bhakay, A., Dave, R., Bilgili, E. 2012. Recovery of BCS Class II Drugs during Aqueous Redispersion of Core-Shell Type Nanocomposite Particles Produced via Fluidized Bed Coating. Powder Technol., doi: 10.1016/j.powtec.2011.12.066, in press.
2. Bilgili, E. A., Bhakay, A., Azad, M., Dave, R. 2012. System and Method for Superdisintegrant-Based Composite Particles for Dispersion and Dissolution of Active Pharmaceutical Agents. Provisional Patent, Application No. 61625082, Filed on April 16, 2012.
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