Atovaquone Oral Suspension
» Atovaquone Oral Suspension contains not less than 90.0 percent and not more than 110.0 percent of the labeled amount of atovaquone (C22H19ClO3).
Packaging and storage— Preserve in tight, light-resistant containers.
USP Reference standards 11
USP Atovaquone RS Click to View Structure
USP Atovaquone Related Compound A RS Click to View Structure
cis-2[4-(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone.
Identification—
A: Ultraviolet Absorption 197U
Medium: a mixture of methanol and water (1:1).
Solution— Transfer 5.0 mL of the Assay preparation and 5.0 mL of the Standard preparation, prepared in the Assay, to separate 50-mL volumetric flasks, dilute with Medium to volume, and mix.
B: The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay.
Uniformity of dosage units 905
for oral suspension packaged in single-unit containers: meets the requirements.
Deliverable volume 698
for oral suspension packaged in multiple-unit containers: meets the requirements.
pH 791: between 3.5 and 7.0.
Sedimentation—
for oral suspension packaged in multiple-unit containers Transfer 50 mL of well-mixed Oral Suspension to a glass-stoppered graduated cylinder, and allow to stand for 16 hours. Measure the volume, if any, of clear liquid observed in the cylinder: not more than 1 mL of clear liquid is found.
Related compounds— Using the chromatograms of the Resolution solution, the Standard preparation, and the Assay preparation obtained in the Assay, calculate the percentage of atovaquone-related compounds, based on the labeled strength of atovaquone, by the formula:
Click to View Image
in which C is the concentration, in mg per mL, of USP Atovaquone RS in the Standard preparation; D is the density of Oral Suspension, in g per mL (1.04 g per mL at 20 to 25); S is the weight, in g, of Oral Suspension taken to prepare the Assay preparation; L is the labeled amount, in mg per mL, of atovaquone in the Oral Suspension; Fi is the response factor of an individual atovaquone related compound relative to the response of atovaquone, specifically, 1.08 for any peak observed at a relative retention time of about 0.65, 0.85 for any peak observed at a retention time corresponding to that of atovaquone related compound A, as determined from the chromatogram of the Resolution solution, and 1.0 for any other related compound peak; ri is the individual peak response of an atovaquone related compound, if any, in the chromatogram of the Assay preparation; and rS is the peak response of atovaquone in the chromatogram of the Standard preparation. Disregard any peak having a relative retention time of about 0.3, which is due to photodegradation during preparation of the Assay preparation. Not more than 0.5% of an atovaquone related compound with a relative retention time of about 0.65 is found; not more than 1.0% of atovaquone related compound A is found; not more than 0.3% of an atovaquone related compound with a relative retention time of about 0.88 is found; not more than 0.2% of any other atovaquone related compound is found; and the sum of all related compounds is not more than 2.0%.
Assay—
Mobile phase— Prepare a mixture of acetonitrile, water, methanol, and phosphoric acid (480:360:160:5). Make adjustments if necessary (see System Suitability under Chromatography 621).
Resolution solution— Prepare a solution in 0.1 M methanolic sodium hydroxide containing about 0.09 mg of USP Atovaquone RS and 0.01 mg of USP Atovaquone Related Compound A RS per mL. Store in a low-actinic glass container.
Standard preparation— Transfer about 30 mg of USP Atovaquone RS, accurately weighed, to a low-actinic 10-mL volumetric flask, and add 2 mL of water and 6 mL of 0.1 M methanolic sodium hydroxide. Sonicate for about 5 minutes or until the material has dissolved. Allow to cool, dilute with 0.1 M methanolic sodium hydroxide to volume, and mix. Transfer 3.0 mL of this solution to a low-actinic 100-mL volumetric flask, dilute with a mixture of methanol and water (1:1) to volume, and mix. [note—Minimize exposure of this solution to light. ]
Assay preparation— Transfer approximately 5.2 g of the well-mixed Oral Suspension, accurately weighed, to a low-actinic 250-mL volumetric flask. Add 50 mL of water, swirl for about 5 minutes, add 150 mL of 0.1 M methanolic sodium hydroxide, and sonicate for about 15 minutes. Allow to cool, dilute with 0.1 M methanolic sodium hydroxide to volume, and mix. Immediately filter a 20-mL portion, discarding the first 5 mL of the filtrate. Transfer 3.0 mL of the clear filtrate to a low-actinic 100-mL volumetric flask, dilute with a mixture of methanol and water (1:1) to volume, and mix. [note—Minimize exposure of this solution to light. ]
Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a 220-nm detector and a 4.6-mm × 12.5-cm column that contains packing L1. The flow rate is about 3 mL per minute. Chromatograph the Resolution solution, and record the peak areas as directed for Procedure: the relative retention times are about 0.86 for atovaquone related compound A and 1.0 for atovaquone. Chromatograph the Standard preparation, and record the peak areas as directed for Procedure: the tailing factor is not more than 1.5; and the relative standard deviation for replicate injections is not more than 2.0%.
Procedure— Separately inject equal volumes (about 20 µL) of the Standard preparation, the Resolution solution, and the Assay preparation into the chromatograph, record the chromatograms, and measure the areas for the major peaks. Calculate the quantity, in mg, of atovaquone (C22H19ClO3) in each mL of the Oral Suspension taken by the formula:
(25,000/3)(C/V)(rU / rS)
in which C is the concentration, in mg per mL, of USP Atovaquone RS in the Standard preparation; V is the volume, in mL, of Oral Suspension taken to prepare the Assay preparation; and rU and rS are the atovaquone peak areas obtained from the Assay preparation and the Standard preparation, respectively.
Auxiliary Information— Please check for your question in the FAQs before contacting USP.
Topic/Question Contact Expert Committee
Monograph Behnam Davani, Ph.D., M.B.A.
Senior Scientific Liaison
1-301-816-8394
(SM12010) Monographs - Small Molecules 1
Reference Standards RS Technical Services
1-301-816-8129
rstech@usp.org
USP35–NF30 Page 2266
Pharmacopeial Forum: Volume No. 34(2) Page 247