Stabilizing High Energetic States of Pharmaceutical Drugs

Modification of the physical state of low soluble drugs, as amorphization, is a promissory strategy to increase their solubility, since this intrinsically disordered state promotes solubilisation. In the present work, a composite has been prepared and characterized aiming to improve the aqueous solubility of a drug by amorphization, and able to be used for controlled drug delivery. Simvastatin (SIM) is the target drug, belonging to statins family, used to reduce the levels of cholesterol in blood and with high efficiency in bone regeneration. To achieve SIM’s amorphization, it was incorporated in unmodified and surface treated by methylation SBA-15 mesoporous matrices. Nuclear magnetic resonance and infrared spectroscopy together with thermogravimetric analysis evidenced efficient inclusion in matrices and the absence of strong guest-host interactions. Native SIM’s phase transformations were studied by differential scanning calorimetry, allowing the identification of melting close to 140 ºC. After cooling from the melt, crystallization is avoided and SIM solidifies in a glassy state. The glass transition, detected in subsequent heating, is clearly seen with a midpoint temperature (Tg.mid) of 33 ºC. In the composites the glass transition is also detected showing that the drug is in the amorphous state, however emerging at higher temperature compared with the native drug. Dielectric Relaxation Spectroscopy results of incorporated SIM indicate that molecular motions are hindered by the presence of the silica matrix, in agreement with the calorimetric Tg’s increase. Cytotoxicity assays were performed using confluent and non-differentiated Caco-2 cells. The results demonstrate that at higher concentrations simvastatin is less cytotoxic when incorporated in the silica pores. Release assays were done to simulate drug delivery in the organism using conditions similar to intestinal fluid such as pH 6.8. Monitoring by UV-Vis spectroscopy revealed that simvastatin is easily released from both silicas. Preliminary results suggest a faster release from the unmodified silica. Both assays allow concluding that the studied composites are promissory to be used as drug delivery systems. The work here reported was accepted to be presented as a poster communication in Chempor 2018