(68c) Production and Stabilization of Organic Crystalline Sub-Micron and Nanoparticles Using High Pressure Homogenization for Drug Delivery
- Conference: AIChE Annual Meeting
- Year: 2008
- Proceeding: 2008 Annual Meeting
- Group: Food, Pharmaceutical & Bioengineering Division
- Time: Monday, November 17, 2008 - 1:10pm-1:30pm
Many newly discovered drugs are found to be poorly soluble in water. It has been known for over a decade that forming finer particles (micron and smaller) can improve the bio-availability and the dissolution rate of drugs due to their increased surface area. However, there is little knowledge in the area of short- and long-term stabilization of the particles following production. This issue is critical because nanoparticles in suspension agglomerate intensely, making them hard to process and in some cases defeating the purpose of using nanoparticles in the first place. Thus, the goal of this work is to obtain well stabilized and deagglomerated nanoparticle systems. Such stable nanosuspensions can the be used to incorporate nanoscopic drugs into many products including strip films, tablets, and multilayer coatings loaded with drug nanoparticles for controlled release performance.
At the present time, methods for preventing nanoparticle agglomeration are essentially empirical. In this work, we investigate the well known particle creation technique High Pressure Homogenization (HPH) as a ?top down? approach to the creation of nanoparticles. The method has long been proven to create nanoparticles through the application of large amounts of shear and cavitation. We focus on the stabilization of the particles during creation rather than the creation technique itself. We have selected two hydrophobic drug materials as test cases; Fenofibrate (used to reduce the amount of cholesterol and triglycerides in blood) and Griseofulvin (antifungal type of antibiotic), both typically low dosage materials that are generally safe for laboratory use. Both drugs are Biopharmaceutics Classification System (BCS) Class II substances which are considered to have very poor water solubility, yet a high gastric permeability. The drugs are passed through a homogenizer to reduce the particle size by varying the pressure, solids loading, and concentration of surfactant. Several surfactants have been tested including Tween 80 and Poloxamer 407. However, better results were found using block co-polymers such as HPMC (hydroxypropyl-methylcellulose). Our experimental work suggests that using surfactants and polymers with a high affinity for the drug surface can effectively aid in stopping post production agglomeration of the particles both short-term and long-term. In addition to experimental results, several Molecular Dynamics (MD) studies have been conducted. The goal of these simulations is to test the molecular interactions between the surfactant and surface of the crystalline materials. The chemical functionality of a crystalline surface, the entropy of the lattice, and the energy of attachment derived from the MD simulations can indicate which stabilizers are optimal for the stabilization of the produced particles.