RESUMEN
The purpose of the present study was to compare different calorimetric methods used to determine the glass transition temperature (T(g)) and to evaluate the relaxation behaviour and hence the stability of amorphous drugs below their T(g). Data showed that the values of the activation energy for the transition of a glass to its super-cooled liquid state qualitatively correlate with the values of the mean molecular relaxation time constant of ketoconazole, itraconazole and miconazole, three structurally related drugs. Estimation of the molecular mobility by activation energy calculation indicated that loperamide was more stable than its two building blocks T263 and R731. It was further shown that the most commonly used approach to determine T(g) (T(g (1/2 c(p))) leads to erroneous values when enthalpy recovery is significant. In this case, an alternative method based on enthalpic considerations leads to results in accordance to basic thermodynamics. Estimation of molecular mobility based on activation energy calculations is therefore considered to be a valuable alternative for the method based on measurement of the extent of relaxation. When enthalpy relaxation is important, the use of T(g 1/2c(p)) leads to an overestimation of the T(g).
Asunto(s)
Azoles/química , Fluorouracilo/análogos & derivados , Fluorouracilo/química , Loperamida/química , Poliésteres/química , Rastreo Diferencial de Calorimetría , Fenómenos Químicos , Química Física , Estabilidad de Medicamentos , Itraconazol/química , Cetoconazol/química , Miconazol/química , TemperaturaRESUMEN
The 64-kDa autoantigen D1 or 1D, first identified as a potential autoantigen in Graves' disease, is similar to the tropomodulin (Tmod) family of actin filament pointed end-capping proteins. A novel gene with significant similarity to the 64-kDa human autoantigen D1 has been cloned from both humans and mice, and the genomic sequences of both genes have been identified. These genes form a subfamily closely related to the Tmods and are here named the Leiomodins (Lmods). Both Lmod genes display a conserved intron-exon structure, as do three Tmod genes, but the intron-exon structure of the Lmods and the Tmods is divergent. mRNA expression analysis indicates that the gene formerly known as the 64-kDa autoantigen D1 is most highly expressed in a variety of human tissues that contain smooth muscle, earning it the name smooth muscle Leiomodin (SM-Lmod; HGMW-approved symbol LMOD1). Transcripts encoding the novel Lmod gene are present exclusively in fetal and adult heart and adult skeletal muscle, and it is here named cardiac Leiomodin (C-Lmod; HGMW-approved symbol LMOD2). Human C-Lmod is located near the hypertrophic cardiomyopathy locus CMH6 on human chromosome 7q3, potentially implicating it in this disease. Our data demonstrate that the Lmods are evolutionarily related and display tissue-specific patterns of expression distinct from, but overlapping with, the expression of Tmod isoforms.
Asunto(s)
Proteínas Portadoras/genética , Proteínas de Microfilamentos , Secuencia de Aminoácidos , Animales , Autoantígenos/biosíntesis , Autoantígenos/química , Autoantígenos/genética , Proteínas Portadoras/biosíntesis , Mapeo Cromosómico , Cromosomas Humanos Par 7 , Evolución Molecular , Etiquetas de Secuencia Expresada , Duplicación de Gen , Expresión Génica , Genoma Humano , Enfermedad de Graves/inmunología , Humanos , Ratones , Datos de Secuencia Molecular , Músculo Liso/metabolismo , Miocardio/metabolismo , Homología de Secuencia de Aminoácido , Distribución Tisular , TropomodulinaRESUMEN
The objective of the present study was to estimate the molecular mobility of glassy itraconazole below the glass transition, in comparison with structural analogues (i.e. miconazole and ketoconazole).Glassy itraconazole and miconazole were prepared by cooling from the melt. The glassy state of the drug was investigated with modulated temperature DSC using the following conditions: amplitude +/-0.212 K, period 40 s, underlying heating rate 2 K/min. The glass transition was determined from the reversing heat flow and occurred at 332.4 (+/-0.5) K and 274.8 (+/-0.4) K for itraconazole and miconazole, respectively. The jump in heat capacity at the glass transition was 303.42 (+/-3.43) J/mol K for itraconazole and 179.35 (+/-0.89) J/mol K for miconazole. The influence of the experimental conditions on the position of the glass transition of itraconazole was investigated by varying the amplitude from +/-0.133 to +/-0.292 K and the period from 25 to 55 s, while the underlying heating rate was kept constant at 2 K/min. Glass transition temperature, T(g), was not significantly influenced by the frequency of the modulation nor by the cooling rate. However, the relaxation enthalpy at the glass transition increased with decreasing cooling rate indicating relaxation during the glass formation process. To estimate the molecular mobility of the glassy materials, annealing experiments were performed from T(g)--10 to T(g)--40 K for periods ranging from 15 min to 16 h. Fitting the extent of relaxation of glassy itraconazole to the Williams--Watts decay function and comparing the obtained values with those of amorphous miconazole and ketoconazole indicated that the molecular mobility is influenced by the complexity of the molecular structure. The more complex the structure, the more stable the amorphous state.