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

Kato, Fumie; Otsuka, Makoto; Matsuda, Yoshihisa

doi:10.1016/j.ijpharm.2006.04.020

Cited by 49 publications

(60 citation statements)

References 23 publications

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“…Establishing the polymorphic behaviour of a drug molecule early in development minimizes the number of unsuitable candidates developed and reduces the risk of encountering issues later which may have a major financial and time impact. 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 [1]. The differences of physical properties may affect the reproducibility of the manufacturing process of dosage forms and their performance.…”

Section: Introductionmentioning

confidence: 99%

Crystallization of mefenamic acid and polymorphs

Cesur¹,

Gokbel

2008

Cryst. Res. Technol.

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The crystallization of Mefenamic Acid, (MA), which has a prevalent usage in drug formulation, was investigated. MA is a high-dose, anti-inflammatory, analgesic agent used for pain in menstrual disorders. Some negative properties of MA are a high hydrophobicity and propensity to stick to surfaces, which cause great problems during granulation and tabletting. To facilitate tabletability, enhance dissolution rates, and develop a stable and reproducible dosage form, investigation of the physicochemical properties of mefenamic acid is necessary. Pharmaceutical drugs are commonly crystalline materials and are therefore subject to polymorphism. Polymorphism, the ability of a substance to exist in more than one crystalline form, is a significant phenomenon in the field of chemical engineering sciences, including pharmaceutical development. Establishing the polymorphic behaviour of a drug molecule early in development minimizes the number of unsuitable candidates developed and reduces the risk of encountering issues later which may have a major financial and time impact. Mefenamic acid crystals were recrystallized from five different solvents of N, Ndimethylformamide (DMF), acetone, N, N-dimethylacetamide (DMA), Dimethylsulfoxide (DMS) and Ethyl Acetate (EA). In order to characterize the Mefenamic Acid crystal structure and the polymorphic forms of the crystals obtained by recrystallization, the scanning electron microscopy (SEM), Raman diffractometry and Xray pattern were used. From the industrial crystallization point of view, the crystal size distribution (CSD), the crystal shape, the polymorphic form and the crystallization steps are important factors that affect the quality and bioavailability of a drug. For the determination of crystal size distribution of MA, The Focused Beam Reflectance Measurement (FBRM) technique was practiced and CSD profiles were obtained.

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Section: Introductionmentioning

confidence: 99%

Crystallization of mefenamic acid and polymorphs

Cesur¹,

Gokbel

2008

Cryst. Res. Technol.

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“…The presence of carboxylic and amine group in its chemical structure demonstrates polar protic characteristics, 3 Solid line, this work; and dashed line, Kato and co-workers. 3 RI stands for relative intensities.…”

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Solubility and Dissolution Thermodynamic Data of Mefenamic Acid Crystals in Different Classes of Organic Solvents

et al. 2013

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Different classes of solvents provide different polarity values, which influence the solubility of pharmaceutical solids. In this article, the solubility of mefenamic acid in different classes of organic solvents, including polar protic, dipolar aprotic, and apolar aprotics at a range of temperatures from (298 to 323) K are reported. It has been found that mefenamic acid shows high solubility in dipolar aprotic solvents (N,N-dimethylacetamide, N,N-dimethylformamide, ethyl acetate, and propanone), moderate solubility in polar protic solvents (ethanol and propan-2-ol), and poor solubility in apolar aprotic solvents (hexane, heptane, and cyclohexane) and water.

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“…7,8) Moreover, storage conditions (such as temperature and humidity), grinding conditions, or pharmaceutical excipients affect the stability of the metastable crystal forms. [9][10][11] Therefore, characterization of polymorphs and elucidation of the physicochemical properties of bulk drugs during both the manufacturing process and the storage period are extremely important. 12) Azelnidipine ((3-[1-(diphenylmethyl)-3-azetidinyl]-5-(1-methyl ethyl-2-amino-1,4-dihydro-6-methyl-4-(3-nitro phenyl)-3,5-pyridinedicarboxylate), Fig.…”

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Solid State Characterizations and Analysis of Stability in Azelnidipine Polymorphs

Liu

Wang

Yang

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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Azelnidipine, a new dihydropyridine calcium ion antagonist, was protected by patent in Japan. In present study, identifications of the crystal phases, including two polymorphic and a pseudopolymorphic crystal forms of azelnidipine, were attempted using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), IR-, Raman-, THz-, and ss-NMR-spectroscopy. PXRD identified three different crystal forms, while, spectroscopy analysis provided the information of crystal structure involving intermolecular interactions. The transition thermodynamics of the azelnidipine polymorphs were extensively investigated by solubility method. The solubility of the two polymorphs of α and β in 50% ethanol at 25, 31, 37, 42, and 49°C was investigated; the values obtained were used to calculate the thermodynamic parameters of the transition reaction. The temperature of polymorphic phase transition in 50% ethanol was 50.78°C, and the values of ΔG α,β θ , ΔH α,β θ , and ΔS α,β θ at 25°C were 1.18 kJ·mol 1 , 14.81 kJ·mol 1 , and 45.73 J·mol 1 ·K 1 , respectively. Form β was proved to be thermodynamic stable form at room temperature and enantiotropically related with form α. The kinetics of the solid-state decomposition, studied using DSC analysis, showed that the activation energies of decomposition of the polymorphs α and β at high temperatures were 148.67 and 151.93 kJ·mol 1 .Key words azelnidipine; polymorph; solid state NMR; THz spectrum; solubility; thermodynamics Polymorphs are different solid crystalline phases of the same drug or compound, which result from at least two different molecular arrangements of the compound in the solid state. In solvatomorphism, the formation of various crystals is the result of solvent molecules being incorporated in the crystal structure. A recent study estimated that 80-90% of organic compounds are capable of existing in polymorphic forms.

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

Cited by 49 publications

References 23 publications

Crystallization of mefenamic acid and polymorphs

Crystallization of mefenamic acid and polymorphs

Solubility and Dissolution Thermodynamic Data of Mefenamic Acid Crystals in Different Classes of Organic Solvents

Solid State Characterizations and Analysis of Stability in Azelnidipine Polymorphs

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