Crotamiton Cream

Acaricide.

Crotamiton Cream contains Crotamiton in a suitable basis.

The cream complies with the requirements stated under Topical Semi-solid Preparations and with the following requirements.

93.0 to 107.0% of the stated amount.

A. Mix a quantity of the cream containing 0.5 g of Crotamiton with 50 mL of water and then slowly add 50 mL of 1m sodium hydroxide while stirring vigorously. Filter the mixture, adjust the filtrate to pH 7 with 5m hydrochloric acid and extract with 50 mL of ether. Wash the ether layer with 10 mL of a saturated solution of sodium chloride, dry the organic layer over anhydrous sodium sulfate, filter and evaporate to an oily residue. The light absorption, Appendix II B, in the range 220 to 350 nm of a 0.003% w/v solution of the residue in cyclohexane exhibits a maximum only at 242 nm. The A(1%, 1 cm) at the maximum is about 315.

B. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions in absolute ethanol.

(1) 0.25% w/v of the residue obtained in test A.

(2) 0.25% w/v of crotamiton BPCRS.

(3) A mixture of equal volumes of solutions (1) and (2).

(a) Use as the coating silica gel GF₂₅₄.

(b) Use the mobile phase as described below.

(c) Apply 5 µL of each solution.

(d) Develop the plate to 15 cm.

(e) After removal of the plate, dry in air and examine under ultraviolet light (254 nm).

Shake 98 volumes of chloroform with 2 volumes of 18m ammonia, dry over anhydrous sodium sulfate, filter and mix 97 volumes of the filtrate with 3 volumes of propan-2-ol.

The principal spot in the chromatogram obtained with solution (1) corresponds to that in the chromatogram obtained with solution (2), but if not, the principal spot in the chromatogram obtained with solution (3) appears as a single compact spot.

C. In the Assay, the principal peak in the chromatogram obtained with solution (2) has the same retention time as the principal peak in the chromatogram obtained with solution (3).

Carry out the method for liquid chromatography, Appendix III D, using solutions (1), (4), (5), (6) and (7) as described under the Assay. For solution (1) allow the chromatography to proceed for 2.5 times the retention time of the principal peak.

Use the chromatographic conditions described under Assay.

The test is not valid unless, in the chromatogram obtained with solution (6), the resolution factor between the peaks corresponding to the E-isomer and to crotamiton impurity A is at least 4.5.

In the chromatogram obtained with solution (1):

the area of any peak corresponding to crotamiton impurity A is not greater than the area of the corresponding peak in the chromatogram obtained with solution (4) (3%);

the sum of the areas of any secondary peaks apart from any peaks corresponding to the Z-isomer and to crotamiton impurity A is not greater than the sum of the areas of the peaks corresponding to the E- and Z-isomers in the chromatogram obtained with solution (5) (1%).

Disregard any peak with an area less than 0.02 times the area of the principal peak in the chromatogram obtained with solution (5) (0.02%) and any peak with the same retention time as the principal peak in the chromatogram obtained with solution (7).

Not more than 15% of the total content of E- and Z-isomers determined in the Assay.

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Add 2 mL of water and 100 mL of cyclohexane to a quantity of the preparation being examined containing 0.1 g of Crotamiton, shake for 10 minutes and separate the lower, aqueous layer. Repeat the extraction using two 10 mL quantities of cyclohexane, filter the combined extracts and add sufficient cyclohexane to produce 200 mL.

(2) Dilute 1 volume of solution (1) to 20 volumes with cyclohexane.

(3) 0.0025% w/v of crotamiton BPCRS in cyclohexane.

(4) 0.0015% w/v of crotamiton impurity A EPCRS in cyclohexane.

(5) Dilute 1 volume of solution (1) to 100 volumes with cyclohexane.

(6) Dilute 1 volume of a 0.015% w/v solution of crotamiton impurity A EPCRS to 10 volumes with solution (1).

(7) 0.001% w/v of methyl hydroxybenzoate in cyclohexane.

(a) Use a stainless steel column (25 cm × 4 mm) packed with silica gel for chromatography (5 µm) (Lichrosorb Si60 is suitable).

(b) Use isocratic elution and the mobile phase described below.

(c) Use a flow rate of 1 mL per minute.

(d) Use an ambient column temperature.

(e) Use a detection wavelength of 242 nm.

(f) Inject 20 µL of each solution.

8 volumes of tetrahydrofuran and 92 volumes of cyclohexane.

For solutions (4) and (6), when the chromatograms are recorded under the prescribed conditions, the retention times relative to the principal peak (E-crotamiton) are: Z-isomer, about 0.5; N-ethyl-N-(2-methylphenyl)but-3-enamide (crotamiton impurity A), about 0.8. Adjust the sensitivity of the system so that the height of the principal peak in the chromatogram obtained with solution (4) is at least 70% of the full scale of the recorder.

The test is not valid unless, in the chromatogram obtained with solution (6), the resolution factor between the peaks corresponding to the E-isomer and to crotamiton impurity A is at least 4.5.

Using chromatograms (2) and (3), calculate the contents of the E- and Z-isomers in the preparation being examined using the declared contents of E- and Z-crotamiton in crotamiton BPCRS and hence calculate the content of C₁₃H₁₇NO in the preparation being examined.