Solubility behavior of polymorphs I and II of mefenamic acid in solvent mixtures

The dissolution profile and solubility of two polymorphic forms of mefenamic acid were studied in solvent mixtures of ethanol-water and ethyl acetate-ethanol. The solubility parameter (delta) was used to study the effect of polarity on the solubility behavior of the two polymorphs. Differential scanning calorimetry and infrared spectroscopy were performed on the original powders and on the solid phases after contact with the solvent systems for the characterization and identification of the polymorphs. The dissolution rates of both polymorphs is greater in the less polar mixtures (ethyl acetate-ethanol) of lower solubility parameter values. Form II showed larger dissolution rates and saturation concentrations than Form I in all the solvent systems studied. The solid phase of Form II converts totally to Form I after equilibration with the solvents. The rate of conversion was faster in the least polar mixtures. The solubility of both polymorphs reaches a single maximum at 80% ethyl acetate in ethanol, delta = 20.09 MPa1/2. The modified extended Hildebrand method was used to predict the solubility profile of each polymorph. A single equation was obtained for both polymorphs which includes the solubility parameter of the mixtures and the logarithm of the solubility mole fraction of each polymorph in water. The Hildebrand solubility parameter of mefenamic acid is independent of the crystalline form and was determined from two methods giving quite similar values, delta 2 = 20-21 MPa1/2.     

HPLC法测定甲芬那酸胶囊中甲芬那酸的含量

目的建立HPLC法测定甲芬那酸胶囊中甲芬那酸含量的分析方法。方法采用Gemin C18(250mm×4.6mm,5μm)色谱柱;流动相:0.05mol·L-1磷酸二氢铵溶液(用氨试液调节pH值至5.0)-乙腈-四氢呋喃(40:46:14);流速1.0mL·min-1;检测波长254nm。结果甲芬那酸质量浓度在13.18～210.88μg·L-1范围内呈良好的线性关系,r=1.0000,平均回收率为98.9%,RSD为0.5%。结论方法简便、准确、灵敏度高。     

Thermodynamic and structural study of tolfenamic acid polymorphs

The article deals with the study of two polymorphic modifications in the space groups P2₁/c (white form) and P2₁/n (yellow form) of the tolfenamic acid. It also describes how the white form vapor pressure temperature dependence was determined by using the transpiration method and how thermodynamic parameters of the sublimation process were calculated. We have estimated the difference between the crystal lattice energies of the two polymorphic forms by solution calorimetry and found that the crystal lattice energy of the yellow form is 6.7 ± 1.2 kJ mol⁻¹ higher than that of the white form, whereas Gibbs free energies of the forms obtained from the vapor pressure temperature dependence are practically the same. The modifications under consideration are monotropically related. From the practical point of view, the white form is more preferable due to its lower crystal lattice energy and better performing procedure. We have also studied the solubility, solvation and transfer processes of the tolfenamic acid white form in buffers (with various values of pH and ionic strengths), n-hexane and n-octanol. The thermodynamic parameters of the investigated processes have been discussed and compared with those determined for others fenamates. In the study we estimated specific and non-specific contributions of the solvation enthalpic term of the fenamate molecules with the solvents as well. The driving forces of the transfer processes from the buffers with pH 7.4 and different ionic strengths to n-octanol were analyzed. It was found that the relationship between the enthalpic and entropic terms depends essentially on the ionic strength. For the considered fenamates the transfer processes of the neutral molecules and the ionic forms are enthalpy-determined, whereas for the niflumic acid this process is entropy-determined.     

甲芬那酸分散片在健康人体的生物等效性评价

目的:研究甲芬那酸分散片和普通片在健康人体的药动学特征和生物等效性.方法:采用标准两周期交叉设计自身对照试验方法,18名健康志愿者单剂量口服500 mg甲芬那酸分散片或普通片,用反相高效液相色谱法(RP-HPLC)测定血清中甲芬那酸的浓度,计算其药动学参数并评价两种制剂的生物等效性.结果:甲芬那酸分散片和普通片的主要药动学参数Tmax(实测值)分别为(1.1±0.6)h和(2.1±0.8)h,Cmax(实测值)分别为(5.8±2.2)mg·L-1和(5.9±3.0)mg·L-1,AUC(0-14 h)分别为(18.1±3.4)mg·L-1·h和(17.3±5.0)mg·L-1·h,AUC(0-inf)分别为(18.7±3.3)mg·L-1·h和(18.0±4.9)mg·L-1·h,T1/2Ke分别为(2.0±0.8)h和(2.3±1.2)h.除Tmax外,甲芬那酸分散片和普通片各主要药动学参数间差异无显著性(P＞0.05);甲芬那酸分散片对普通片的相对生物利用度为(111.3±31.9)%.结论:健康人单剂量口服500mg甲芬那酸分散片与普通片具有生物等效性.     

Characterization of nicergoline polymorphs crystallized in several organic solvents

Nicergoline (NIC), a poorly water-soluble semisynthetic ergot derivative, was crystallized from several organic solvents, obtaining two different polymorphic forms, the triclinic form I and the orthorhombic form II. NIC samples were then characterized by several techniques such as (13)C cross-polarization magic angle spinning solid-state spectroscopy, room-temperature and high-temperature X-ray powder diffraction, differential scanning calorimetry, and by analysis of weight loss, solvent content, powder density, morphology, and particle size. Solubility and intrinsic dissolution rates determined for the two polymorphic forms in water and hydrochloride solutions (HCl 0.1 N) were always higher for form II than for form I, which is actually the form used for the industrial preparation of NIC medicinal products. Preformulation studies might encourage industry for the evaluation of polymorph II, as it is more suitable for pharmaceutical applications. Results in drug delivery, as well as those obtained by the above-mentioned techniques, and the application of Burger-Ramberger's rules make it possible to conclude that there is a thermodynamic relation of monotropy between the two polymorphs. This last assumption may help formulators in predicting the relative stability of the two forms.     

Phase transformation in conformational polymorphs of nimesulide

Nimesulide is a nonsteroidal anti-inflammatory drug (NSAID) and a COX-2 inhibitor. The native crystal structure of nimesulide (or Form I) has been characterized in the literature by X-ray powder diffraction (XRPD) lines, whereas full three-dimensional coordinates are known for a second polymorph (Form II). A detailed structural characterization and phase stability of nimesulide polymorphs were carried out. Rod-like crystals of Form I (space group Pca2(1); number of symmetry-independent molecules, Z' = 2) were crystallized from EtOH concomitantly with Form II (C2/c, Z' = 1). These conformational polymorphs have different torsion angles at the phenoxy and sulfonamide groups. The crystal structures are stabilized by N-H · · · O hydrogen bonds and C-H · · · O, C-H · · · π interactions. Phase transition from the metastable Form (II) to the stable modification (I) was studied using differential scanning calorimetry, hot-stage microscopy, solid-state grinding, solvent-drop grinding, and slurry crystallization. The phase transition was monitored by infrared, Raman, and ss-nuclear magnetic resonance spectroscopy; and XRPD and single-crystal X-ray diffraction. The stable polymorph I was obtained in excess during solution crystallization, grinding, and slurry methods. Intrinsic dissolution and equilibrium solubility experiments showed that the metastable Form II dissolves much faster than the stable Form I.     

Use of in situ FT-Raman spectroscopy to study the kinetics of the transformation of carbamazepine polymorphs

The solid-state transformation of carbamazepine from form III to form I was examined by Fourier Transform Raman spectroscopy. Using a novel environmental chamber, the isothermal conversion was monitored in situ at 130 degrees C, 138 degrees C, 140 degrees C and 150 degrees C. The rate of transformation was monitored by taking the relative intensities of peaks arising from two CH bending modes; this approach minimised errors due to thermal artefacts and variations in power intensities or scattering efficiencies from the samples in which crystal habit changed from a characteristic prism morphology (form III) to whiskers (form I). The solid-state transformation at the different temperatures was fitted to various solid-state kinetic models of which four gave good fits, thus indicating the complexity of the process which is known to occur via a solid-gas-solid mechanism. Arrhenius plots from the kinetic models yielded activation energies from 344 kJ mol(-1) to 368 kJ mol(-1) for the transformation. The study demonstrates the value of a rapid in situ analysis of drug polymorphic type which can be of value for at-line in-process control.     

The potential and promise of mefenamic acid

Clinical use of mefenamic acid has generally declined in an era where other NSAID use has flourished. While having modes of action and general toxicities similar to other NSAIDs, mefenamic acid, as a member of the fenamates, nevertheless possesses some unique in vitro effects that have the potential to distinguish this agent from others. Use of this drug remains relevant for pain syndromes and some gynecological disorders, albeit with considerable competition from other NSAIDs. New basic science has considerably improved the understanding of the biochemistry of mefenamic acid. As well as maintaining its use in traditional settings, there is a tremendous potential for expanding the application of mefenamic acid to niche roles.     

高湿和高温对齐墩果酸滴丸稳定性的影响

目的考察齐墩果酸滴丸的稳定性。方法采用高温、高湿、光照、加速试验及室温留样考察。结果本品极易吸湿，但在密封、阴凉、干燥的条件下储存，稳定性良好。结论该滴丸的有效期可暂定为1年。     

The solution properties of mefenamic acid and a closely related analogue are indistinguishable in polar solvents but significantly different in nonpolar environments

This study investigates the cosolute effects of mefenamic acid (XA) and flufenamic acid (FA). These compounds serve as model of a drug discovery lead compound and a structural analogue. The activity coefficients of XA and FA in different solvents were obtained from solubility measurements at 25°C. The effect of varying concentrations of FA on the solubility of XA in four different solvents, including toluene, cyclohexane, ethanol, and an ethanol–water mixture (80:20, v/v), was investigated. The magnitude of change in the activity coefficient of XA in the presence of FA in different solvents was used to elucidate the thermodynamic effect of FA on the solubility of XA. Nuclear magnetic resonance and Fourier‐transform infrared spectroscopy were used to obtain molecular level information about the interactions of the compounds in solution. The presence of FA increases XA solubility in toluene and in cyclohexane as much as seven‐fold. Conversely, in ethanol and the ethanol–water mixture, similar levels of FA have essentially no effect on the solubility of XA. The solution properties investigated show that despite the close structural similarity between XA and FA, the two compounds are strongly distinguishable in nonpolar solvents. Conversely, the solution properties of the same two solutes are indistinguishable in polar solvents. A solubilization model based on solute‐cosolute interactions is presented.     

Flow-injection spectrofluorimetric determination of flufenamic and mefenamic acid in pharmaceuticals

Two sensitive and rapid flow-injection (FI) spectrofluorimetric methods are proposed for the determination of flufenamic acid (FF) and mefenamic acid (MF), based on the formation of complexes of these compounds with Al(III) in an ethanolic medium. The calibration graphs resulting from the measurements of the fluorescence at λ_exc = 351 nm and λ_em = 440 nm, and λ_exc = 355 nm and λ_em = 454 nm for the complexes with FF and MF, respectively, are linear over the range 0.030–1.20 μg ml⁻¹ for FF and 0.30–16.1 μg ml⁻¹ for MF. The methods have been applied to the determination of these drugs in pharmaceutical preparations.     

Polymorphic transformation of indomethacin under high pressures

To study the effect of pressure on polymorphic transformation, intact powder, and ethanol slurry of alpha, gamma, and amorphous forms of indomethacin (IMC) were compressed under high pressures. A quantifying method for the percentages of these three constituents in sample powder was established. Using this method, analysis of compressed samples revealed that alpha form, which is difficult to prepare in stable form under atmospheric pressure, was easily obtained in stable form from the ethanol slurry of the amorphous IMC, which does not include any specific crystalline forms. In the ethanol slurry of gamma form, transformation to alpha form was observed: a reciprocal phenomenon under atmospheric pressure. These results can be rationally explained as follows: alpha form is more easily crystallized than gamma form in the ethanol solution, the more closely-packed crystal structure of alpha form is thermodynamically predominant over gamma form under high pressure, and pressure-induced amorphization occurs. This study indicates that crystallization experiments from the slurry of amorphous samples under various pressures can be useful in screening polymorphic or other solid states.