Abstract
Flufenamic acid (FFA) is a non-steroidal anti-inflammatory drug characterised by a low solubility and problems of variable dissolution rate and bio-inequivalence. Different FFA batches, obtained by different suppliers, showed different powder characteristics (particle size, shape and surface properties) that may affect its dissolution behaviour from solid dosage forms. Aim of this work was the improvement of FFA solubility and dissolution rate by the use of cyclodextrins (CDs) and the obtainment of an effective tablet formulation by direct compression. Several CDs have been tested, both in solution and in solid state and several binary systems drug-CDs have been obtained with different techniques, with the scope to select the most effective system. Grinding technique with randomly methylated-β-cyclodextrin (RAMEB) was the only one that allowed the complete drug amorphization, together with the highest improvement in drug dissolution rate, and was then selected for tablets formulation. Conventional and immediate release tablets were obtained and fully characterised for technological properties. In both cases an improved and well reproducible drug dissolution performance was obtained, independently from the FFA supplier and thus no more affected by the differences observed between the original FFA crystalline samples.
Highlights
Oral route is the main way of administration of drugs, especially by the use of tablets.The bioavailability of an orally administered drug mainly depends on its solubility in the gastrointestinal tract fluids and its permeability through the biological membranes [1]: its dissolution in gastrointestinal fluids is a prerequisite for enabling a drug to permeate through the biological membranes and reach the systemic circulation and exploit its therapeutic action
This work aimed to develop new tablet formulations with improved dissolution properties of Flufenamic acid (FFA) that would allow to overcome the problems of bio-inequivalence, and variable bioavailability shown by commercial dosage forms, related to its poor solubility and dissolution rate
The FFA-RAMEB co-ground product was formulated as immediate-release tablets (IRTs) or conventional tablets suitable for enteric coating (CTs)
Summary
Oral route is the main way of administration of drugs, especially by the use of tablets.The bioavailability of an orally administered drug mainly depends on its solubility in the gastrointestinal tract fluids and its permeability through the biological membranes [1]: its dissolution in gastrointestinal fluids is a prerequisite for enabling a drug to permeate through the biological membranes and reach the systemic circulation and exploit its therapeutic action. Poor solubility continues to represent a major obstacle in the successful development of new medicines. For this reason, the development of new drug-delivery strategies enabling effective formulations of such drugs, able to improve and make more reproducible their bioavailability and overcome problems of bio-inequivalence among pharmaceutically equivalent dosage forms, or even among different production batches, is of great interest [3]. Solubility and dissolution rate of a drug depend upon its particle size, solid-state (crystalline or amorphous, crystal habitus, anhydrous or solvated form, polymorphic form), and physicochemical properties (partition coefficient, lipophilicity, wettability, etc.), and upon the properties of the dosage form used to administer the drug. In the case of tablets, it is important to carefully evaluate the properties of the excipients used (wettability, particle size, solid state . . . ) and the conditions and technological processes used for their
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