(126b) Morphology, Growth And Stability Of Poorly Water Soluble Drug Crystals By The Addition Of Surfactants In Different Solvent Media Using Both An Experimental And Simulations Approach
- Conference: AIChE Annual Meeting
- Year: 2007
- Proceeding: 2007 Annual Meeting
- Group: Food, Pharmaceutical & Bioengineering Division
- Time: Monday, November 5, 2007 - 3:55pm-4:20pm
Most new drugs are found to be poorly soluble in water, and it has been known for over 100 years that forming finer particles (micron and smaller) can improve their bio-availability or the dissolution rate due to their increased surface area. However, a limiting aspect is the lack of fundamental understanding of most particle formation techniques, thus results are often unpredictable. At the present time, methods for preventing nanoparticle agglomeration are essentially empirical. In this work we investigate morphology changes, growth and stability properties of two model drugs in the presence of several surfactants and solvents. We have selected two 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. These are two examples of poorly water soluble drugs that, when brought to the nanoscale present a significant increase in solubility in water, however, they need to be mixed up with surfactants to maintain their size in solution . We focus on two solvent systems, which represent both an environment where the drugs are highly soluble (dimethylformamide, DMSO) and sparingly soluble (aqueous). Then, the use of several different surfactants including Tyloxapol, Tween 80, Poly-vinyl alcohol and the Poloxamer series are shown to have an impact on growth and morphology using both experimental and computational techniques. Our experimental results indicate that depending on the type of solvent considered and degree of polarity of the surfactant, the adsorption of surfactant molecules on the surface of the crystal is in some cases surface specific and it is correlated with the type of solvent in which the drug is recrystallized. The results obtained are then compared with molecular dynamics simulations containing the same drug in similar solvent and surfactant environments. It is shown that the morphology and size of the Griseofulvin drug is significantly affected by the solvent used in the crystallization. In addition the use of the varied surfactants of different concentrations has shown to alter and control the growth rate and mechanics of the crystals in both the aqueous, and DMF solvent systems. The results from the recrystallization experiments are in agreement with the data recorded from the molecular dynamics simulations of the same system. The simulations approach we follow is in line with previous work. Based on the chemical functionality of a crystalline surface, on the entropy of the lattice, and on the energy of attachment of solvents/polymers/surfactants to these crystal surfaces, it is possible to predict what surfactants/polymers act as stabilizers and which ones act as surface modifiers (i.e. the most appropriate polymers, surfactants and solvents (polar/non polar) that interact favorably with a particular face of the crystal, allowing that face to grow, or on the contrary, if they interact unfavorably, preventing or delaying growth on that face (quenchers)).