X-ray powder diffractometric method for quantitation of crystalline drug in microparticulate systems. I. Microspheres.

Ethylcellulose microspheres containing tolnaftate (I) were prepared by the emulsion-solvent evaporation technique. An X-ray powder diffractometric method was developed to quantify the content of crystalline I in these microspheres. X-ray lines of I with d-spacings of 5.5 and 4.2 A were chosen for the quantitative analyses. Physical mixtures containing various weight fractions of I and blank (empty) microspheres were prepared and lithium fluoride (20% w/w) was added as the internal standard. The 5.5 and 4.3 A lines of I and the 2.3 A line of lithium fluoride were used for the quantitative analysis. A plot of the intensity ratio (intensity of the 5.5 A line of I/intensity of 2.3 A line of lithium fluoride) as a function of the weight percent of I in the mixture, resulted in a straight line. The crystalline content of I in the tolnaftate-loaded microspheres was determined using this standard curve. A second independent determination of the content of I was possible from the intensities of the 4.3 A line. The enthalpy of fusion of I, determined by differential scanning calorimetry (DSC), was also used as a measure of the crystalline content of I in the microspheres. The X-ray and DSC methods measure the content of crystalline I in the microspheres at room temperature ( approximately 25 degrees C) and at the melting point of I (111 degrees C), respectively. The total content of I in the microspheres was determined by HPLC. The DSC and X-ray results indicated that a substantial fraction of the incorporated I was dissolved in the ethylcellulose matrix.