(730c) Investigating the Impact of Undercooling During Eutectic Solidification On the Dissolution Rate of Pharmaceuticals

The solubility of drugs is still one of the largest challenges in formulation development since the compound must be present at its biological target to be effective. For oral solid products, absorption is a two step process where 1) dissolution of the drug must occur to form a solution and 2) the dissolved drug must be transported across the gastrointestinal membrane into the blood stream. Most poorly soluble compound's oral bioavailability is limited by the dissolution step. Therefore, if more drug molecules can be in solution at the gastrointestinal membrane, then there should be a higher absorption of the drug into the blood stream.

Eutectic mixtures are a useful formulation technique to change the dissolution rate of pharmaceuticals. A pharmaceutical eutectic mixture is defined as an intimate mixture of crystals of one component intermixed with crystals of another, where the mixture has a lower melting point than any of the pure substances and all substances are mutually miscible in the molten phase. At the eutectic composition there is a direct phase transformation of all components from the solid phase into the liquid phase. The main advantages of eutectic mixtures for manipulating drug dissolution is that the drug crystals will be solidified in their thermodynamically stable form so conversion upon storage is not an issue and the solidification process produces an intimate mixture of fine crystals. As intimacy of the mixture increases, due to decreased particle size of the two components, so should the amount of solid-solid interface which is hypothesized to correlate with the rate of phase transformation from the solid to liquid phase. Also, as the particle size decreases the dissolution rate of the compounds should increase. The particle size of the solidified crystals is inversely proportional to the degree of undercooling, from the equilibrium temperature of the eutectic mixture, during solidification.

The model eutectic system of acetaminophen and anhydrous caffeine was used to investigate the effect of changing the degree of undercooling during solidification on dissolution rate and heat flow through the mixture. Mixtures at the eutectic composition were solidified at five different temperatures and used to make dissolution samples. The rate of melting was assessed with differential scanning calorimetry.

The results of the dissolution studies showed that the dissolution rates of acetaminophen and anhydrous caffeine in the eutectic mixtures could be manipulated to be faster or slower than a powder sample. This change in dissolution rate was shown to correlate with the rate of melting for the various samples. An additional study to correlate rate of phase transformation with sample structure showed that as the number of solid-solid interfaces increased so did the rate of phase transformation. This work will outline some general conclusions on how the results can be implemented in formulation design of small molecule pharmaceuticals.