Of diloxanide furoate

The pediatric dose of paromomycin is the same as that used in adults, whereas the pediatric dose of iodoquinol is 30 to 40 mg/kg (maximum 2 g) per day in three doses for 20 days, and the pediatric dose of diloxanide furoate is 20 mg/kg per day in three doses for 10 days. Paromomycin is the preferred agent in pregnant patients.3... 

The melting point of diloxanide furoate has been reported to be 114-116°C... 

The differential scanning calorimetry thermogram of diloxanide furoate is shown in Figure 2. The data were obtained using a DuPont TA-9900 thermal analyzer system interfaced with the DuPont data unit. The thermogram was recorded using a heating rate of 10°C/minute, over a temperature interval of 100-250°C. 

Figure 1. X-Ray powder diffraction pattern of diloxanide furoate.

Crystallographic Data from the X-Ray Powder Pattern of Diloxanide Furoate... 

Figure 2. Differential scanning calorimetry thermogram of diloxanide furoate.

The ultraviolet absorption spectrum of diloxanide furoate was recorded on a Shimadzu model 1601 PC LJV/VIS spectrophotometer, and is shown in Figure 3. In aqueous solution, the spectrum exhibited a single absorption maximum located at 260 nm. For this band, the A o/ .ic , value was 700, and the molar absorptivity equal to 22970. 

The fluorescence spectrum of diloxanide furoate in aqueous methanol (concentration of 8 pg/mL) was recorded using a Perkin Elmer NPF-44B fluorimeter system. As shown in Figure 4, the excitation maximum was noted at 240 nm, which agrees well with the absorption maxima observed in the UVA IS studies. The emission maximum was found at 335 nm. 

The infrared absorption spectrum of diloxanide furoate is shown in Figure 5, and was obtained as a KBr disc using a Perkin Elmer infrared spectrophotometer. The principal peaks were observed at energies of... 

Figure 3. Ultraviolet absorption spectrum of diloxanide furoate.

The proton NMR speetrum of diloxanide furoate was obtained using a Bruker system operating at 300, 400 or 500 MHz. Standard Brucker software was used to execute recording of DEPT, COSY, and HETCOR spectra. The sample was dissolved in CH30H-d4, and all resonance bands were referenced to the tetramethylsilane internal standard. 

The mass spectrum of diloxanide furoate was obtained using a Shimadzu PQ-5000 mass spectrometer, with the parent ion undergoing collision with helium carrier gas. The mass spectrum is shown in Figure 9, and features a base peak at m/z = 95, a molecular ion peak at m/e = 328, as well as numerous other fragments. Table 4 summarizes the proposed mass fragmentation pattern. 

The British Pharmacopoeia describes a non-aqueous titration method for the determination of diloxanide furoate [6]. To perform the test, one dissolves 0.3 g of diloxanide furoate in 50 mL of anhydrous pyridine, and titrates to a potentiometric end point using 0.1 N tetrabutylammonium... 

Roy and Prakash have developed a conductimetric method for the determination of diloxanide furoate [13]. The drug undergoes hydrolysis on heating with aqueous sodium hydroxide, and the excess sodium hydroxide is then determined conductimetrically. The method is reported to be useful for the analysis of the raw material, as well as for the analysis of tablets. 

Srinath and Bagavant reported a spectrophotometric method for the analysis of binary mixtures of diloxanide furoate and tinidazole or metronidazole [14]. The mixtures were analyzed at 258 and 310 nm, and it was found that Beer s law was obeyed over the range of 10 to 25 jrg/mL of tinidazole and diloxanide furoate. Analyte recoveries were in the range of 98.2 to 101.9%. 

Talwar et al. reported a simultaneous spectrophotometric determination of diloxanide furoate and metronidazole in dosage forms [15]. The drug substances were extracted from tablets with methanol, and the extract diluted with 0.01 M sodium hydroxide. The absorbance of the solution was measured at 247 and 320 nm against 0.01 M sodium hydroxide, and the concentration of each individual drug was calculated by the Vierordt method. Drug recoveries were in the range of 99 to 100%, and the method was satisfactorily applied to the analysis of commercial samples. 

Sethi et al. reported the assay by two methods of diloxanide furoate and tinidazole in combined dosage forms, [16]. One of these was a dualwavelength spectrophotometric method, and the other a difference spectrophotometric method. In the first method, the absorbance of sample solution was measured at 259 and 311 nm. The concentration of tinidazole was calculated from absorbance at 311 nm, and the concentration of diloxanide furoate was calculated with the use of a given equation. In the second method, the absorbance of an aqueous solution of... 

Galal et al. determined diloxanide furoate and metronidazole in two-component tablets using first (Di) and second (D2) derivative spectrophotometrie methods [17]. The methods were based on the direct measurement of diloxanide furoate in 0.1 N hydrochloric acid solution at 262 nm (Dj method) and at 248 nm (D2 method), without any interference from the co-existing component. The methods were applied for the determination of diloxanide furoate in the laboratory-made mixtures and in tablets, and the authors reported a relative standard deviation less than 2%. 

Das and Haider described a simultaneous spectrophotometrie method for the analysis of binary dosage form mixtures of diloxanide furoate with metronidazole or with tinidazole [19], Powdered tablets or suspension, equivalent to 50 mg of the drug substances, were dissolved in 50 mL of dimethylformamide with shaking. After 15 minutes, the solution was diluted to 100 mL with water and filtered. A 1 mL portion of the filtrate was diluted to 50 mL with water, and the absorbance of the resulting solution measured at 320 and 262 nm for metronidazole and diloxanide furoate simultaneously. Alternatively, readings were taken at 318 and 262 nm for the simultaneous determination of tinidazole and diloxanide furoate. Recoveries were reported to be quantitative. 

Parimoo et al. have also reported the use of difference spectroscopy for the simultaneous quantitative determination of diloxanide furoate and... 

Two differential spectrophotometric methods were used by Chatterjee et al. for the simultaneous analysis of diloxanide furoate and metronidazole in pharmaceutical formulations [24]. The first method involved measurement of the absorbance of a methanolic solution of the two drugs at 259 and 311 nm. Since the absorbance of diloxanide furoate at 311 nm is zero, the concentration of metronidazole is directly measured, and a simple equation based on absorbance ratios is used to calculate the concentration of diloxanide furoate. The second method was a differential spectrophotometric determination based on pH-induced spectral changes, on changing from an acidic to an alkaline solution. A marked bathochromic shift was exhibited by metronidazole, while diloxanide furoate showed a slight hypsochromic shift. The wavelength of maximum absorption difference for diloxanide furoate was 267 nm, where metronidazole did not absorb. Similarly, diloxanide furoate did not interfere with metronidazole at when measured at 322 nm. 

Sadana and Gaonkar described a simultaneous derivative spectroscopic method for the determination of diloxanide furoate and tinidazole in pharmaceutical dosage forms [26]. Drugs were powdered and dissolved in methanol, and the solution set aside for 30 minutes with frequent shaking. After filtration, the filtrate and washings were diluted with methanol. A suspension equivalent to 150 mg of diloxanide furoate was extracted with chloroform. The filtered extract was evaporated to dryness, and the... 

Shah and Mehta described a calorimetric method for the estimation of diloxanide furoate in pharmaceutical formulations [27]. The method is based on its interaction with hydroxylamine in alkaline solution. This method was used for the determination of the drug either alone or when combined with other agents. 

Sastry and Aruna described the use of 3-methyl-2-benzothiazolinone hydrazone hydrochloride as a new technique for the spectrophotometric determination of diloxanide furoate and other anthelmentic and antiamoebic agents [29]. Aliquots of sample solutions containing 10-100 pg of drug substance were transferred into a series of 10 mL graduated test tubes, and the volume adjusted to 3 mL with the respective solvent blank. 3-Methyl-2-benzothiazolinone hydrazone hydrochloride and 1 mL of Cr(VI) were added, and the mixture diluted with methanol. The absorbance at 500 nm was measured against a reagent blank. 

Sastry et al. used iodine and isonicotinic acid hydrazide for the spectrophotometric determination of diloxanide furoate in tablets and in syrups [30]. Powdered tablets or syrup were dissolved in methanol and hydrolyzed under reflux with dilute hydrochloric acid. The mixture was cooled, and excess HCI removed under vacuum. The hydrolysate was dissolved in and diluted with water. Iodine solution and the isoniazid solution were added at two minute intervals to a potassium h) drogen phthalate/HCl buffer solution (pH 3), and diluted with water. The solution was set aside for 10 minutes, whereupon the absorbance was measured at 630 nm against a reagent blank. 

Sanghavi et al. reported a colorimetric method for the estimation of diloxanide furoate [31]. 

Clarke described three thin layer chromatography (TLC) systems for the separation of diloxanide furoate [7]. 

Clarke has described a gas chromatography system for the determination of diloxanide furoate [7]. The column is a 2 m x 4 mm internal diameter glass column containing 2.5% SE 30 on 80-100 mesh Chromosorb G (acid washed and dimethyldichlorosilane-treated). It is essential that the column... 

Sane et al. reported the determination of diloxanide furoate in pharmaceuticals by gas chromatography [36]. A sample of powdered tablets equivalent to 250 mg of drug was dissolved in chloroform and diluted to a concentration of 5 mg/mL. A mixture of 2 mL of the sample solution and 1 mL of bromhexine hydrochloride solution (the internal standard) was diluted to 5 mL with chloroform, was used for the analysis. The injection volume was 400 nL, which was analyzed at 265°C on a stainless steel column (3 m x 2 mm) containing 3% OV-13 on Chromosorb W-HP (80-100 mesh). Nitrogen was used as the carrier gas at a flow rate of 50 mL/min, and analyte detection was effected using a dual flame ionization detector. 

The separation and estimation of diloxanide furoate and metronidazole in solid dosage forms was reported by Bhoir et al., using packed column supercritical fluid chromatography [38], A JASCO Cig colunm (10 pm particle size, 25 cm x 4 mm) was used at 40°C, with an injection volume of 20 pL. The mobile phase consisted of 26% methanol in CO2 (flow rate of 2 mL/min), and operated at a pressure of 17.6 MPa. When detected on the basis of its ultraviolet absorbance at 230 nm, the retention time for the drug was 1.6 minutes. The linear region of the calibration graph was reported to be 20-70 pg/mL. 

El-gizawy reported the analysis of diloxanide furoate in its dosage forms by a HPLC method [40]. Furazol tablets containing 200 mg of metronidazole and 250 mg of diloxanide furoate were treated with 50 mL of methanol, sonicated for 10 minutes, and diluted to 100 mL with methanol. A portion of the resulting solution was centrifuged, and a 20 pL portion of the clear supernatant solution diluted to 10 mL with the mobile phase. This process yielded a final analyte concentration equivalent to 5 pg/mL. 20 pL aliquots of the solution were annualized by HPLC using a stainless steel column (10 cm x 4.6 mm) packed with Cyclobond I. The mobile phase consisted of 13 7 0.05 M phosphate buffer (pH 7) methanol (flow rate of 1 mL/min), and detection was performed at 254 nm. 

Rao et al. reported a high performance liquid chromatographic method to determine diloxanide furoate and metronidazole in single and in combined dosage forms [41]. A 30 mg equivalent of diloxanide furoate and 25 mg of metronidazole (either as the bulk drug substances or in powdered tablets) was dissolved in methanol, amidopyrine added as the internal standard, and the mixture analyzed by HPLC at room temperature. The analytical column (30 cm x 3.9 mm) consisted of p-Bondapak Cig, with 9 9 1 1 methanol water 0.05 M KH2PO4 0.05 M NaH2P04 as the mobile phase. The flow rate was 1 mL/min), and detection was performed at 254 nm. 

Diloxanide furoate is a dichloroacetamide derivative. It is an effective luminal amebicide but is not active against tissue trophozoites. In the gut, diloxanide furoate is split into diloxanide and furoic acid about 90% of the diloxanide is rapidly absorbed and then conjugated to form the glucuronide, which is promptly excreted in the urine. The unabsorbed diloxanide is the active antiamebic substance. The mechanism of action of diloxanide furoate is unknown. 

The structure of diloxanide furoate has been further modified by incorporating its nitrogen in a cyclic structure resulting in the active compound quinfamide (16) [19]. Elslager and coworkers [40] have replaced the phenyl ring of chlorbetamide by various heterocycles the most promising compound in this series was N-(2-hy-droxyethyl)-N-(4-pyridylmethyl)dichloroacetamide (17). These compounds are not in clinical use. 

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