Kinetic study of the transformation of mefenamic acid polymorphs in various solvents and under high humidity conditions

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Abstract

The transformation kinetics of mefenamic acid form II to form I in three kinds of solvents and under high humidity conditions were extensively investigated. Form II crystals were suspended in water, 50% ethanol and ethanol at 28, 33 and 37 °C, or stored at 50, 60 and 70 °C at 97% RH. Form II transformed to form I under all storage conditions and the rate of transformation depended on the kind of solvent. The transformation followed the three-dimensional nuclei growth mechanism, depending on temperature. The nuclei formation and growth processes were significantly accelerated in ethanol compared with water. The addition of seed crystals of the stable form I shortened the both nuclei formation and growth processes and therefore the transformation was accelerated.

Introduction

Polymorphs are solid crystalline phases of a drug compound, resulting from at least two different molecular arrangements of the compound in the solid state. The various physical properties of drugs showing polymorphism, for example, crystal habit, intermolecular interaction, particle density, thermodynamic activity, solubility, dissolution rate and chemical and physical stability, have been reported (Matsuda and Tatsumi, 1990, Otsuka and Matsuda, 1995, Singh et al., 1998, Ashizawa, 2001, Kushida and Ahizawa, 2002). The differences of physical properties may affect the reproducibility of the manufacturing process of dosage forms and their performance. In addition, the solubility can affect the drug absorption and therefore its bioavailability (Aguiar and Zelmer, 1969, Kokubo et al., 1987). The pharmaceutical applications of polymorphs have also been reviewed (FDA guidelines; Haleblian, 1975, Byrn et al., 1995).

Since polymorphs have different lattice energies, the more energetic ones seek to revert to the most stable or the latest energetic form. Hence, polymorphs can transform to other crystal forms during manufacturing processes, including grinding, kneading and tabletting (Summer et al., 1976, Summer et al., 1977, Otsuka et al., 1997, Otsuka et al., 1999a, Otsuka et al., 1999b, Otsuka et al., 2000, Zhang et al., 2002, Airaksinen et al., 2003). It is also widely known that the storage conditions, such as temperature, humidity or pharmaceutical excipients, affect the stability of metastable crystal forms (Matsuda and Kawaguchi, 1986, Matsuda and Tatsumi, 1990, Otsuka et al., 1993, Zhang et al., 2002, Tang et al., 2002). It is therefore important to characterize the polymorph and clarify the physicochemical properties of bulk drugs during the manufacturing processes and storage period.

Mefenamic acid is a non-steroidal anti-inflammatory drug and widely used as an antipyretic analgesic and antirheumatic drug. It has been reported that mefenamic acid has two polymorphs, forms I and II, and that they showed different solubility and stability. Form II exhibited higher solubility than form I in several solvents (Aguiar and Zelmer, 1969, Romero et al., 1999). The dissolution profile of form II showed supersaturation accompanying the decrease down to the solubility of form I due to the transformation to form I. Conversely, form I transformed to form II at high temperature (142.5–150 °C) and this transformation followed the zero-order reaction mechanism (Polany-Winger equation) (Umeda et al., 1985).

The purpose of this study was to more precisely investigate the stability of forms I and II at high humidity and in water and ethanolic suspensions, assuming the effect of the addition of kneading solvents in the granulation process. The kinetic transformation of form II to form I using several solid-state reaction models was also discussed.

Section snippets

Materials and methods

A bulk powder of mefenamic acid of JP grade was obtained from Yamamoto Chemical Co., Japan. Form I crystals were prepared by saturating 50 mL of acetone with an excess amount of the drug. The undissolved drug was filtered off and the saturated acetone solution was cooled slowly in an ice bath. This solution was left overnight, and the recrystallized crystals were filtered, washed with water and dried at room temperature. Form II crystals were prepared from an N,N-dimethylformamide solution of

Physicochemical characterization of forms I and II

Fig. 1 shows the XRD patterns and DSC profiles of forms I and II. The characteristic XRD peaks of form I were observed at 6.3°, 21.3° and 26.3° (2θ), while those of form II were observed at 11.8°, 17.9°, 23.8° and 25.6° (2θ). These results coincided with those reported previously (Aguiar and Zelmer, 1969). Therefore, the quantitative analysis was performed by using these peak intensities of form II. DCS profiles of form I showed two endothermic peaks at 170 and 231 °C due to the transformation

Conclusions

When incorporating metastable polymorph crystals in the dosage forms, it is essential to investigate the stability of this crystalline form to ensure pharmaceutical quality and bioavailability. Form II crystals have higher solubility than that of form I and it is therefore preferable to use form II for pharmaceutical preparations. However, from the results of the present study, form II transformed to the stable form I, following the three-dimensional nuclei reaction mechanism under all storage

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