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Simultaneous drug particle formation, suspension stabilization with cellulose and subsequent film formation


The enhancement of aqueous solubility and the dissolution rate is major challenge in the development of hydrophobic drug molecules. It has been shown that both dissolution rate and the bioavailability of such compounds can be improved by reducing the particle size and morphology. In recent years, direct particle formation processes such as controlled crystallization or precipitation have emerged as methods for the synthesis of poorly water soluble drugs. Precipitation by the anti-solvent method is a direct and functionally simple procedure for the preparation of submicron particles for drug delivery. The important issue is that finely dispersed drug particles in an aqueous media tend to agglomerate easily to form large particles. This lowers their stability in suspensions, therefore novel approaches for their stabilization is of great importance.

Novel approaches for particle formation and stabilization has been developed by an IGERT research team consisting of Drs. Somenath Mitra, Piero M. Armenante, Rajesh Dave and associated students (NSF ERC: EEC-0540855; IGERT: DGE-0504497). This work focused on the development of a method for particle formation and stabilization, particle encapsulation with polymers during anti-solvent precipitation. This has been applied to pharmaceuticals for the formulation of drug delivery systems and has been scaled up to continuous processes.

In this approach the drug is first dissolved in a solvent, and then mixed with a miscible anti-solvent. In order to control the nucleation and particle growth, the precipitated drug suspension is stabilized using stabilizers, which are added to the drug solution, anti-solvent, or both. In this work the antifungal agent, Griseofulvin (GF), was used as a model drug. Its solubility is only 12 ?g/ml in water, which leads to poor absorption in the gastrointestinal tract. The side effects and intake of this drug can be minimized by improving the effectiveness in terms of increasing the drug dissolution rate. The main findings of this work were the use of different biopolymers and surfactants to produce micron and submicron size drug particles in aqueous media. The particles thus formed are then encapsulated in polymers to form edible films.

A wide range of celluloses, surfactants were studied and their stability over long periods of time was quantified. The study of encapsulation into films included the methods for uniformly distributing the particles in the films and characterizing their morphology. Drug encapsulated edible films containing as much as 50 wt% of drug was casted by solvent evaporation method. In figure 1 a, shows typical particles generated by the anti-solvent method and figure 1 b shows the distribution of these particles in polymer films. The final outcome of this project was the proof of concept that micron and submicron particles can be synthesized and embedded in polymer films for drug delivery.

Address Goals

This activity addresses the primary goal of discovery by uncovering the nanoscale mechanisms of drug particle formation and stabilization. This activity enhances research infrastructure by promoting the development of methods for making stable nanosuspensions, which can then be used in many other applications, and by promoting methods for characterizing such nanosuspensions. Such methods are of significant value in many other areas of nanotechnology research.