Anti-solvent precipitation and subsequent film formation of hydrophobic drugs for drug delivery
Department of Chemistry and Environmental Science
Doctor of Philosophy
Armenante, Piero M.
Dave, Rajesh N.
Gund, Tamara M.
It is estimated that about forty percent of the drug molecules being developed by the pharmaceutical industry are hydrophobic in nature, leading to poor water solubility and bioavailability in the gastrointestinal tract. Dissolution is a limiting factor in their in vivo performance, and increasing their dissolution rate is a major challenge. It has been proven that the dissolution rate is directly proportional to the specific surface area, which can be effectively increased by reducing the particle size. Therefore, considerable efforts have gone into developing reliable and efficient methods for the manufacture of fine particles. Particle size reduction technologies such as milling or high-pressure homogenization have been used over the years. However, controlling of size distribution, morphology, and surface properties can be challenging.
In recent years, bottom up processes have emerged as methods for the synthesis of drug particles for hydrophobic drugs. As many hydrophobic drugs are soluble in various water miscible organic solvents, an effective approach is the precipitation of fine particles from solution phase while mixing with an anti-solvent. The formation, stabilization and sedimentation of these particles depend upon the discreet steps of nucleation, condensation and coagulation into larger particles. Nucleation and condensation tend to be competing factors as both consume solute molecules, and the coagulation step involves the aggregation, often leading to bimodal particle size distribution. Therefore, suspension stabilization involves the optimization of the above mentioned competing factors.
The objective of this study is the anti-solvent synthesis of micron-size drug particles, their stabilization and subsequent self-assembly into polymer films suitable for drug delivery. The drug particles were produced with anti-solvent precipitation, while different stabilizers were used to stabilize the suspensions, and encapsulation into polymer films was carried out with hydroxypropyl methyl cellulose. The process was effective under low power ultrasonic agitation. The mean diameter of the small particles grew with time, while the overall particle size distribution showed a decrease in average particle size due to sedimentation. The results showed that a combination of polymers and surfactant reduced the average particle size more effectively than either only polymers or surfactant. The particles were distributed uniformly throughout the drugloaded polymer films and the release profiles from films showed marked improvements. Most importantly, the redispersion of the drug-loaded films in an aqueous matrix showed that the crystallinity remained unaltered, and there was no appreciable increase in the particle size distribution.
njit-etd2011-055 (131 pages ~ 7,050 KB pdf)
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Created July 26, 2011