Use of polymer additives to inhibit phenytoin nucleation and crystal growth from supersaturated aqueous solution

Thean Y Yeoh, Purdue University


Cosolvents and pH are increasingly being used to solubilize highly water insoluble drugs for intravenous delivery. Upon dilution with physiological buffers, the aqueous solubilities of the drugs are exceeded and precipitation may result. Using phenytoin as a model drug, this study aims to (1) propose a simple polymer co-incubation method to inhibit crystallization; (2) elucidate the crystal growth inhibition mechanism; and (3) model the crystal growth inhibition process mathematically. A number of water soluble polymers such as PVP, HPC, HEC, MC and HPMC were found to be effective crystal growth inhibitors. By constructing crystal growth rate profiles as a function of co-incubating polymer concentration, a general inverse S-shape profile was observed. From each profile, the minimum polymer concentration that produces the minimum crystal growth rate was identified. This polymer concentration is a measure of crystal growth inhibition efficiency. Adsorption of polymers on crystal surface is believed to be a necessary condition for crystal growth inhibition. Using 10K PVP as a model polymer, Langmuir adsorption isotherm was observed. When crystals were co-incubated in the presence of 10K PVP and HEC-250GR, another model polymer, polymer incorporation into the growing crystals was detected. The incorporation amount, as well as the crystal morphology resulted, is highly polymer concentration dependent. The changes in the crystal morphology also correlated strongly with the crystal growth rate. These results identify three rate processes, namely the solute deposition rate, the polymer adsorption rate and the polymer depletion rate, as determinants of the overall rate of crystal growth or the extent of crystal growth inhibition. Based on the knowledge gained, a mathematical description of the crystal growth inhibition was developed. The final equation resulting from the derivation relates the crystal growth inhibition efficiency to the solution supersaturation, polymer type and polymer size. This equation can also be used to predict the minimum required amount of polymer necessary for achieving crystal growth inhibition. Using the polymer co-incubation technique, a way to produce smooth and spherical phenytoin crystals was found. Three factors, namely solution supersaturation, initial phenytoin supersaturation and polymer concentration, were identified as the controlling variables that when optimally selected allows the production of smooth and spherical crystals.




Kildsig, Purdue University.

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