K. Six

Characterization of solid dispersions of itraconazole and hydroxypropylmethylcellulose prepared by melt extrusion. Part I

Solid dispersions containing different ratios of itraconazole and hydroxypropylmethylcellulose (HPMC) were prepared by solvent casting. Based on dose, differential scanning calorimetry and dissolution results, a drug/polymer ratio of 40/60 w/w was selected in order to prepare dispersions by melt extrusion. The melt extrusion process was characterized using a design of experiments (DOE) approach. All parameter settings resulted in the formation of an amorphous solid dispersion whereby HPMC 2910 5 mPas prevents re-crystallization of the drug during cooling. Dissolution measurements demonstrated that a significantly increased dissolution rate was obtained with the amorphous solid dispersion compared to the physical mixture. The outcome of DOE further indicated that melt extrusion is very robust with regard to the itraconazole/HPMC melt extrudate characteristics. Stability studies demonstrated that the itraconazole/HPMC 40/60 w/w milled melt extrudate formulation is chemically and physically stable for periods in excess of 6 months as indicated by the absence of degradation products or re-crystallization of the drug.

Investigation of thermal properties of glassy itraconazole: identification of a monotropic mesophase

Abstract The purpose of the present work is the elucidation of two endothermic transitions at 74 and 90°C, respectively, observed during differential scanning calorimetry of glassy itraconazole. Modulated temperature DSC (MTDSC), hot-stage microscopy (HSM), HPLC and high temperature X-ray diffraction (HT-X ray) were used to examine the thermal properties of glassy itraconazole. It was found that the preparation mode of the glass does not seem to influence the appearance of both endothermic transitions since they were present during heating of glassy itraconazole which was prepared by cooling the melt or by rapid solvent evaporation of an itraconazole solution. These observations suggest that the appearance of the two endothermic transitions require the liquid state prior to glass formation. The transitions are not due to impurities in the starting material, nor are they caused by thermal decomposition. This was further confirmed by HPLC-analysis. HSM showed structure formation following cooling of the melt, at approximately 87°C; cooling the product further showed a second change in optical contrast. HT-X ray confirmed and identified the formation of a nematic mesophase. The appearance of the two endothermic signals during scanning of glassy itraconazole points to the formation of a mesophase. Due to the nature of itraconazole, it appears as a chiral nematic phase of which the mobility is frozen into a glass upon cooling below 59°C thereby impeding further crystallization.

Characterization of glassy itraconazole: a comparative study of its molecular mobility below Tg with that of structural analogues using MTDSC

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.

Identification of Phase Separation in Solid Dispersions of Itraconazole and Eudragit® E100 Using Microthermal Analysis

AbstractPurpose. To evaluate the phase separation in itraconazole/Eudragit® E100 solid dispersions prepared by hot-stage extrusion. Methods. Extrudates were prepared using a corotating twin-screw extruder at 180°C. Micro-TA was used to evaluate the phase separation, where the AFM mode is used to visualize the different phases and local thermal analysis (LTA) to characterize the different phases Results. Itraconazole formed a homogeneous mixture with Eudragit® E100 with drug concentrations up to approximately 20%. Above this concentration, phase separation was observed. MTDSC revealed two Tgs and the mesophase of free glassy itraconazole. Performing micro-TA on the surface of these dispersions indicated an increase in sample roughness in the z-axis piezo signal, which could be an indication of free glassy itraconazole. However, thermal conductivity did not reveal differences between separate phases. Performing LTA, where only a small area (20 × 20 μm) is heated, showed two separate and mixed phases of itraconazole and Eudragit® E100. Tip penetration in itraconazole and Eudragit® E100 occurred at 332K and 383K respectively. The difference in tip penetration was explained in terms of the difference in fragility. Conclusion. Micro-TA makes it possible to characterize separate phases of itraconazole and Eudragit® E100, thereby confirming the MTDSC results on phase separation.

Thermal Properties of Hot-Stage Extrudates of Itraconazole and Eudragit E100. Phase separation and polymorphism

Solid dispersions of itraconazole and eudragit E100 were prepared by hot-stage extrusion. Analysis of the physical structure revealed the existence of different phases, depending on the manufacturing condition. Extrudates prepared at 453 K existed as a molecular dispersion of itraconazole in eudragit E100 when the drug concentration did not exceed ca. 13% mass/mass. At higher concentrations, a second phase consisting of pure glassy itraconazole emerged. In other dispersions prepared at 413 K, the second phase consisted of pure crystalline itraconazole. The difference can be attributed to the relation of the process-temperature to the melting point. Heating of both dispersions induced cold crystallization. Extrudates prepared at 453 K showed comparable behavior before and after milling, with the exception that unmilled dispersions with a drug load of ≥60% mass/mass recrystallized upon heating into a polymorphic modification of itraconazole (Tm=431 K). Upon further heating the polymorph recrystallized to the stable crystalline form (Tm=441 K).

Evaluation of different calorimetric methods to determine the glass transition temperature and molecular mobility below Tg for amorphous drugs

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).