The role of solid state properties on the dissolution performance of flufenamic acid

Highlights

• Flufenamic acid solid dosage forms presented bioinequivalence problems.

• Two batches were submitted to different technological processes and characterized.

• Recrystallization from EtOH or EtOH/W produced a transition from Form I to III.

• Polymorphism didn’t affect drug solubility and dissolution rate.

• The compacted powders showed a different intrinsic dissolution rate and wettability.

Abstract

Flufenamic acid is a nonsteroidal anti-inflammatory drug characterized by a low solubility and a variable oral bioavailability. Flufenamic acid is present in the commercial products in two polymorphic enantiotropic forms (Form I and III). Bioinequivalence was observed for commercial solid dosage forms due to the different dissolution rate of batches. Aim of this work is the full characterization of the solid state properties of flufenamic acid in order to evidence reasons of its variable dissolution properties. Two different batches of pure drug obtained by different suppliers were fully characterized. In order to evaluate the effect of the technological processes used for tablet production, the powders were submitted to grinding, kneading, and compression. Thermal analysis and X-ray diffraction studies proved that the drug was provided by both suppliers as Form I, Form III is obtained by recrystallization from ethanol or ethanol/water of both batches and no changes were observed after the different mechanical treatments. No difference was observed between the two forms in terms of equilibrium solubility values. Dissolution rate studies evidenced a difference between the two batches due to their different particle size, which disappeared after sieving. Interestingly, a significant difference in terms of intrinsic dissolution rate and surface wettability of the two compacted powders was observed, even after sieving, probably related to a different behavior of the two powder samples under compaction. These results should be taken into account, during a tablet formulation, in order to obtain a reproducible dissolution performance of the drug, regardless of its original supplier.

Introduction

Flufenamic acid (FFA) is a nonsteroidal anti-inflammatory drug (NSAID), belonging to the class of N-phenyl-anthranilic acid derivatives, widely used as analgesic, anti-inflammatory and antipyretic agent applied in the treatment of rheumatoid arthritis, osteoarthritis and other painful inflammatory conditions [1]. Its pharmacologic effect is mainly attributable to the reduction of prostaglandin biosynthesis from arachidonic acid by cyclo-oxygenases inhibition [2,3]. Moreover, it has recently been found that FFA also shows new interesting and promising activities such as ionic channels modulation [4], which could be useful not only as a pharmacological tool but, hopefully, for the treatment of epilepsy and other serious diseases.

As most of NSAIDs, FFA is classified as a class II drug according to the biopharmaceutical classification system (BCS), being characterized by low solubility and high permeability [5]. Dissolution rate represents the main limiting factor to the oral absorption of BCS Class II drugs, giving rise to problems of low and variable oral bioavailability and bioinequivalence. In fact, problems of large inter-subject variability in FFA bioavailability after oral administration of commercial capsules have been reported [[6], [7], [8]], which could be related to the different dissolution rates of FFA highlighted from different commercial tablets and also inter-lots [9].

Solubility and dissolution rate of orally-administered drugs, particularly if poorly soluble, can be influenced by a lot of factors, including not only the properties of the dosage form and the conditions used for its production, but also the intrinsic solid state properties of the drug, such as particle size, surface wettability, crystalline or amorphous state, different crystalline habitus, solvated or anhydrous form, presence of different polymorphic forms. In particular, the impact of polymorphism on bioavailability and stability of scarcely water soluble drugs has been widely proved, as illustrated in a recent review [10].

FFA with its nine forms, is one of the most polymorphs’ rich APIs presently known [[11], [12], [13]]. However, only Form I (melting point 407 K) and Form III (melting point 399 K) exist at room temperature and can be found from commercial products [[14], [15], [16]]. The FFA molecules present in these two forms differ for the value of the angle between the two phenyl rings giving raise to conformational polymorphs [17]. It has been reported that Forms I and III are enantiotropically related, being Form III (looking as a yellow powder), the thermodynamic stable form below the transition temperature (42 °C), and Form I (looking as a white powder) the stable one above 42 °C [18]. Form I is moreover kinetically stable at room temperature. Infrared and Raman spectroscopy have been used to identify the FFA polymorphic Forms I and III [15,17,19].

Possible interconversion between metastable and stable drug polymorphic Forms could happen during technological processes used to obtain the final dosage form, like grinding, compression, heating or wet granulation [20,21], with the possibility of rendering technological processes non-reproducible and tablets batches non-bioequivalent. On the other hand, investigations about the possibility of stabilizing metastable but more soluble drug polymorphic Forms have been performed [22].

Based on these premises, and considering the increasing interest towards this drug, due to the possibility of extending its therapeutic use, we considered it worthy of interest to perform an in depth study aimed at the full characterization of the solid state properties of FFA, in order to obtain more insight about the possible reasons of its variable solubility and dissolution rate, which are the main cause of its currently limited oral use, giving rise to problems of low and variable oral bioavailability and bio-inequivalence among pharmaceutically equivalent dosage forms.

With this purpose, we examined and compared the properties of two different batches of FFA powder (obtained from two different suppliers), in terms of thermal behavior, phase composition and behavior, morphology, particle size, poured and tapped density, flowability, compressibility, wettability, solubility, dissolution rate and intrinsic dissolution rate. The effect of powder recrystallization from different solvents (pure ethanol or water-ethanol mixtures) was also investigated.