Effects of additives on the molecular-level behavior of disordered pharamceuticals

Abstract

Amorphous solid dispersions (ASDs) can improve the oral bioavailability of poorly water-soluble drugs. However, the physical instability of the amorphous form, denoted by the propensity to recrystallize, is a major barrier to the use of ASDs. The overarching goal of this thesis was to understand the mechanisms by which two major classes of additives – antiplasticizers (various polymers) and plasticizers (mainly glycerol) – affect the physical stability of amorphous formulations, in the dry solid form, as well as in aqueous solution. In the first project, we investigated the impact of the strength of drug–polymer interactions, on the dissolution performance of ASDs. With ketoconazole and three polymers as model compounds, we observed that the interactions that stabilize amorphous drugs in the solid state, can also be relevant and important in sustaining the level of supersaturation in aqueous solution. The second project explored the use of analytical ultracentrifugation as a novel technique for characterizing drug–polymer interactions in aqueous buffers. It was possible to quantify the “free” versus “bound” fractions of drug in aqueous solution, and to semi-quantitatively assess the impact of interactions on the dissolution performance of ASDs. The third and fourth projects evaluated the effects of glycerol on the molecular mobility and physical stability of amorphous itraconazole (ITZ), in the “solid” state. It is well-known that small molecule plasticizers, such as water or glycerol, increase the molecular mobility and accelerate the crystallization of amorphous drugs. In the case of amorphized ITZ, however, glycerol at low concentrations did not cause physical instability. Rather, the smectic state (one of the intermediate liquid-crystalline phases of ITZ) was selectively stabilized. The mechanism by which glycerol stabilized the smectic state was investigated with high resolution techniques (synchrotron diffractometry, differential and adiabatic scanning calorimetry, and spectroscopy). The results revealed that additives with fast dynamics, can drive weak first-order (or second-order) intermediate liquid-crystalline phase transitions, to strong first-order transitions, by a possible coupling of the additive concentration to the order parameter. We also demonstrated that the stabilized smectic state can perform the dual role of maintaining good physical stability while achieving adequate dissolution performance.