Miconazole nitrate

Miconazole. Miconazole nitrate [22832-87-7] (Fig. 2), the 1-phenethyl-imidazole derivative first described in 1969, interferes at low doses with the cytochrome P-450 dependent ergosterol biosynthesis in yeasts and fungi. The result is accumulation of C-14 methylated sterols on the one hand and reduction of the ergosterol levels in the membranes on the other hand (12). Analogous to clotrimazole, this leads to a disturbance in the membranes it results in inhibition of ceU repHcation, mycelium development (in C. albicans) and finally, ceU death. High concentrations of miconazole, which may be achieved with topical use, disturb the orientation of phosphoHpids in the membranes, which produces leaks (13). 

Miconazole base is a white or almost white powder. Miconazole nitrate is a white or almost white powder [1-3]. 

Miconazole is an imidazole antifungal agent used as miconazole base or miconazole nitrate for the treatment of superficial candidiasis and of skin infections dermato-phytosis and pityriasis versicolor. The drug has also been given intravenously by infusion for the treatment of disseminated fungal infections. Miconazole can be given by mouth in a dose of 120-240 mg, as oral gel four times daily after food, for... 

Miconazole nitrate was prepared by Godefori and co-workers [5-7]. Imidazole 1 was coupled with brominated 2,4-dichloroacetophenone 2 and the resulting ke-tonic product 3 was reduced with sodium borohydride to its corresponding alcohol 4. The latter compound 4 was then coupled with 2,4-dichlorotoluene by sodium borohydride in hexamethylphosphoramide (an aprotic solvent), which was then extracted with nitric acid to give miconazole nitrate. 

Phenyl methyl ketone 1 was brominated to give l-phenyl-2-bromoethanone 2. Compound 2 was treated with methylsulfonic acid to yield the corresponding methylsulfonate 3. Etherification of 3 gave the a-benzyloxy derivative 4 and compound 4 was then chlorinated to give the 2,4-dichlorinated derivatives in both aromatic ring systems 5. Compound 5 reacted with imidazole in dimethylformamide to give miconazole 6 [7], which is converted to miconazole nitrate. 

The X-ray powder diffraction pattern of miconazole was performed using a Simmons XRD-5000 diffractometer. Figure 1 shows the X-ray powder diffraction pattern of miconazole nitrate, which was obtained on a pure sample of the drug substance. Table 1 shows the values for the scattering angles (26 (°)), the interplanar <7-spacing (A), and the relative intensities (%) observed for the major diffraction peaks of miconazole. 

Table 1. The X-ray powder diffraction pattern of miconazole nitrate...

The ultraviolet absorption spectrum of miconazole nitrate in methanol (0.0104%) shown in Fig. 3 was recorded using a Shimadzu Ultraviolet-visible spectrophotometer 1601 PC. The compound exhibited three maxima at 264, 272, and 280 nm. Clarke reported the following Methanol 264 and 272 nm = 17a), 282 nm [2]. 

Fig. 2. Differential scanning calorimetry thermogram of miconazole nitrate.

The infrared absorption spectrum of miconazole nitrate was obtained in a KBr pellet using a Perkin-Elmer infrared spectrophotometer. The IR spectrum is shown in Fig. 4, where the principal peaks were observed at 3140, 3070, 2995, 2920, 1566, 1525, 1445, 1385, 1310, 1070, and 710 cm-1. Assignments for the major infrared absorption band are provided in Table 2. Clarke reported principal peaks at 1085, 1319, 827, 1302, 1038, and 812 cm-1 (miconazole nitrate, KBr disc) [2]. 

Fig. 4. Infrared absorption spectrum of miconazole nitrate (KBr pellet).

Table 2. Vibrational assignments for miconazole nitrate infrared absorption bands...

The proton NMR spectrum of miconazole nitrate was obtained using a Bruker Instrument operating at 300, 400, or 500 MHz. Standard Bruker Software was used to execute the recording of DEPT, COSY, and HETCOR spectra. The sample was dissolved in DMSO-d6 and all resonance bands were referenced to the tetramethyl-silane (TMS) internal standard. The 1H NMR spectra of miconazole nitrate are shown in Figs. 5-7 and the COSY 1H NMR spectrum is shown in Fig. 8. The H NMR assignments for miconazole nitrate are provided in Table 3. 

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