The formulation of naturally-occurring polyphenolic nutraceutical agents using hot-melt extrusion

The process of pharmaceutical formulation is constantly evolving as many new active compounds are being discovered in order to overcome the challenges associated with producing viable dosage forms to reach the target tissues by these compounds. Perhaps, the most important property for a drug to be effectively formulated into a dosage form are adequate miscibility and solubility which may be in an organic solvent vehicle but is mainly in water. Water solubility along with solubility in the body fluids is critical from the point of view of achieving the desired levels of the drug in the body for effective therapy against a disease condition. Since antiquity, active pharmaceutical compounds have been extracted from various natural sources such as plants and animals. In plants, compounds have been extracted from seeds, leaves, roots and fruits of the plant. The compounds resveratrol and quercetin belong to a class of compounds called polyphenols that have shown activity against a few disease conditions. These compounds have very low aqueous solubility and bioavailability and for achieving efficient therapeutic activity, may have to be formulated into more soluble and bioavailable dosage forms. Hot-melt extrusion is a novel technique that has been explored for pharmaceutical manufacturing in recent years. Applied on a large scale in the plastics industry, hot- melt extrusion has been employed in improving the solubility of poorly soluble compounds by producing an amorphous solid solution of the drug in a medium such as an edible or erodible biocompatible polymer. It involves few processing steps and has a few advantages over other formulation methods used for pharmaceutical processing of poorly soluble active compounds. It was hypothesized that hot-melt extrusion would assist in improving the solubility and bioavailability upon oral delivery of the polyphenols in a viable dosage form. The polymer employed for the study was a novel polymeric solubilizer, Soluplus®. The study involved hot-melt extrusion of resveratrol and quercetin separately with Soluplus®, described in Chapter 1, and analysis of the mixtures thus produced by using analytical techniques such as high performance liquid chromatography, differential scanning calorimetry and Fourier transform infra-red spectroscopy. Additionally, studies to determine the improvement in solubility and miscibility were conducted on the hot-melt extruded and physical mixtures of resveratrol and quercetin with Soluplus ® and the properties of the mixtures upon formulation as films for topical delivery and formulation as tablets were studied. The dissolution characteristics of the hot-melt extruded mixture of resveratrol and Soluplus® were studied and compared to the dissolution characteristics of the corresponding physical mixture of resveratrol and Soluplus®. Lastly, the effect of forced degradation on the mixtures was studied and analyzed by high performance liquid chromatography. The methodology employed for this study has been described in Chapter 3. From the results and interpretations described in Chapter 4, it is observed that the hot-melt extruded mixtures of resveratrol and quercetin with Soluplus® might form stable, amorphous solid mixtures of the polyphenol in the polymer which was determined using differential scanning calorimetry. The high performance liquid chromatography analysis and the Fourier transform infra-red spectroscopy technique perhaps indicate that the content remains uniform even though different proportions of the active polyphenol were used with the polymer and that there is an intimate chemical interaction that may result in changes within the active polyphenol causing a change in the functional group characteristics of the polyphenols upon extrusion with Soluplus® as was observed through the Fourier transform infra-red spectroscopy technique. The formulation of the mixtures of resveratrol and quercetin with Soluplus® as films for topical delivery failed due to unstable films being produced and re-crystallization of the active polyphenol upon drying of the films. Tablet formulations of the hot-melt extruded and physical mixtures of both resveratrol and quercetin were produced and properties of the tablets were assessed. The tablets produced by the hot-melt extruded mixtures of quercetin were harder, less friable and had suitable disintegration times as compared to the tablets produced from the hot-melt extruded mixtures of resveratrol. From the dissolution studies performed, it is perhaps observed that a smaller particle size of the hot-melt extruded mixture of resveratrol and Soluplus® has a faster release rate as compared to the larger particle size fractions of the hot-melt extruded mixture of resveratrol and Soluplus®. Lastly, the forced degradation studies might indicate that the hot-melt extruded mixtures of resveratrol and quercetin with Soluplus® undergo degradation at elevated temperature conditions and perhaps, there is loss of the active polyphenols from the mixtures as a result