Spontaneous Crystallinity Loss of Drugs in the Disordered Regions of Poly(Ethylene Oxide) in the Presence of Water

The physical stability of active pharmaceutical ingredients (APIs) formulated in the crystalline state may be compromised in the presence of excipients. In the present study, it is shown that at high relative humidity, several model crystalline drugs compacted into a matrix of poly(ethylene oxide) (PEO) may dissolve into the disordered regions of the polymer. The purpose of this project is to identify both the physicochemical properties of the API and the polymer which may lead to such a transformation and the mechanism of transformation. Crystalline drugs and PEO were physically mixed, compressed into tablets, and stored in a dessicator at 94% RH. The physical state of the drug and the polymer were determined using Raman spectroscopy and X-ray powder diffraction. The solubility of each drug in PEG 400 was measured by ultraviolet spectroscopy, the thermal properties of each compound were measured using differential scanning calorimetry, and the amount of water sorbed into these systems from the vapor phase was determined by gravimetric analysis. A spontaneous loss of crystallinity was observed for many of the model drugs when stored at high relative humidity and in the presence of PEO. In the absence of PEO, no changes in the crystalline material were observed. However, the structure of PEO was dramatically altered when exposed to high relative humidity. Specifically, it was found that PEO undergoes a very slow deliquescence increasing the disordered fraction of the polymer which facilitates the “dissolution” of the crystalline drug into these disordered regions. The degree of transformation, estimated from Raman spectroscopy, was found to qualitatively correlate with the aqueous solubility of the compounds. It can be concluded that for the systems studied here, the phase stability of the polymer was compromised at high relative humidity and the polymer underwent deliquescence. The equilibrium phase of several of the crystalline drugs studied here was then altered as evidenced by a loss in crystallinity.