THE INFLUENCE OF FORMATION OF SURFACE SOLID DISPERSION ON THE DISSOLUTION AND BIOAVAILABILITY OF FENOFIBRIC ACID

• Main Author: Ninik Windriyati, Yulias
• Format: Dissertations
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/37134
• Institution: Institut Teknologi Bandung

Fenofibric acid is the active moiety of fenofibrate and is a peroxisome proliferatoractivated receptor ?(PPAR ?) ligand which is commonly used for antihyperlipidemia, cardiovascular diseases and diabetes complications. Fenofibrate is included in the list of drugs required for bioequivalence testing due to the variety of absorption as well as the marked effect of the excipients and their manufacturing processes on bioavailability. Fenofibric acid, on the other hand, is still excluded in the list since the effect of the excipients along with the manufacturing processes on both absorption and bioavailability remains unknown. Fenofibric acid is insoluble in gastric pH, but soluble in intestinal pH, and it is included in the Biopharmaceutical Classification System (BCS) class II, meaning that an approach is needed to increase its dissolution and bioavailability. This study aimed at investigating the influence of formation of surface solid dispersion on dissolution and bioavailability of fenofibric acid in order to obtain profile of fenofibric acid tablet that is bioequivalent to an innovator. Surface solid dispersions of fenofibric acid were made in numerous comparisons using the solvent evaporation method. The excipients chosen in this study covered microcrystalline cellulose, colloidal silicon dioxide, crospovidone, croscarmellose sodium, and sodium starch glycolate, which normally have large surface areas and are commonly used in the tablet manufacturing process. Each surface solid dispersion was tested for dissolution in phosphate buffer pH 6.8 and compared to the physical mixture and pure fenofibric acid. The optimum surface solid dispersion that succeeded to increase the dissolution of fenofibric acid was analyzed for characterization by XRD, DTA, FTIR, and SEM, then compared to its corresponding physical mixture and the pure fenofibric acid. Subsequently, it was compressed into tablets, tested for dissolution in various medium, and evaluated for bioavailability on healthy male subjects in fasting conditions in accordance with the protocol reviewed and approved by the Health Research Ethics Committee. In regard to dissolution, experiments with two different raw materials of fenofibric acid, obtained from Shijiazhuang and BOC Sciences, showed that the surface solid dispersion of fenofibric acid with croscarmellose sodium in the ratio of 1:1 increased dissolution more significantly than that with the physical mixture (DE60 81.23% vs 61.23% for raw material from Shijiazhuang and 82,43% vs 67,70% for that from BOC Sciences). The characterization using SEM indicated that these two raw materials had different crystal habits, but the recrystallization process of forming the surface solid dispersion turned the distinct crystal habits into the same and caused deposition on the particle surface area of croscarmellose sodium. Additionally, the SEM images revealed a decrease in terms of the size and deagglomeration of the fenofibric acid particles after the surface solid dispersion was formed. Based on the analysis with XRD, DTA and FTIR, both raw materials were of different polymorphs. In relation to crystallinity, the surface solid dispersion of fenofibric acid decreased crystallinity than that with pure fenofibric acid due to the presence of croscarmellose sodium. No chemical interaction occurred between fenofibric acid and croscarmellose sodium. However, polymorphic transformation took place in the formation of surface solid dispersion with the raw material from Shijiazhuang, but not with that from BOC Sciences. The later surface solid dispersion was selected for tablet preparation. The surface solid dispersion tablets of fenofibric acid fulfilled the pharmaceutical requirements in USP and the dissolution was equivalent to that of innovator tablets and even better than that of conventional tablets made with wet granulation. The bioavailability test resulted in no significant differences in the whole bioavailability parameters among surface solid dispersion tablets, conventional tablets and innovator tablets. There was a correlation of the dissolved fraction of fenofibric acid with the absorbed one, but there was no correlation with the amount of the absorbed fenofibric acid from its tablet. The surface solid dispersion and conventional tablets were bioequivalent to innovator. The formation of surface solid dispersion with croscarmellose sodium led to an increase in the dissolution of fenofibric acid (DE60 2 fold), but it exerted no effect upon the bioavailability in the fasting condition.