Question and Answer Section

William Brown and Margareth Marques
Will Brown and Margareth Marques share responsibilities as liaisons to the USP Expert Committee on Biopharmaceutics. United States Pharmacopeia, Rockville, MD
Email for correspondence: web@usp.org

Q ­ Can I have dissolution results higher than 100.0% of the label claim?

A ­Yes, you can have results higher than 100.0% for several reasons. First, in most cases the acceptance criteria for the Assay of the drug is a range that has an upper limit higher than 100.0%. For instance, the range for the Assay test in the USP-NF monograph for Dextroamphetamine Sulfate Tablets is "not less than 93.0 percent and not more than 107.0 percent of the labeled amount of dextroamphetamine sulfate." Second, the acceptance criteria for dosage uniformity (see USP-NF general chapter <905> Uniformity of Dosage Units) is the range from 85.0% to 115.0% of the label claim for tablets. Dissolution results higher than 100.0% should be less frequent because they depend on the probability of testing a tablet with a dose higher than 100% of the label claim.
If you frequently have dissolution results higher than 100.0%, this may be an indication of interference in your dissolution system. You need to verify that substances are not leaching from the filter and interfering with the measurements. Other sources of interference could be carryover in automatic sampling systems and inappropriate cleaning procedures.

Q ­ Should I make a correction to the dissolution results based on the results obtained with the Assay?
A ­No. The dissolution results always refer to the label claim and not to the Assay values.

Q­ Can I carry out only the dissolution test and not the assay and estimate the assay results from the dissolution results?
A ­ The dissolution test and the Assay measure different attributes. In the Assay the amount of active ingredient in the dosage form is measured. In general, the sample is a composite of several units of the dosage form being tested, and an extraction procedure generally is be used to extract the active ingredient from the dosage form as completely as possible and in a much shorter time than given for the dissolution test. The dissolution test is a performance test that measures the rate of active ingredient released from each unit of the dosage form. Although the dissolution test procedure often can be used to completely extract the contents of a dosage form, that is not its primary function.

Q­ I am analyzing a tablet that has a label claim of 250 mg. The tolerance in the dissolution test for this particular tablet is not less than 80% (Q) of the labeled amount dissolved in 30 minutes. What amount, 200 or 212.5 mg, represents the acceptance criterion given by the dissolution test for this product?
A - The tolerances in the monograph define the value of Q. In this case it will be 80% of the label claim of 250 mg or 200 mg. However, the acceptance criterion is defined by the acceptance table (see USP-NF general chapter <711> Dissolution and <724> Drug Release), unless a different acceptance table is presented in the specific monograph. The acceptance table under <711>states that for the S1 stage the acceptance criterion is "each unit is not less than Q + 5%." For your product it means 200 mg (Q) + 5% of 250 mg, equal to 212.5 mg.

Q ­ When opened, our bottle of Salicylic Acid Tablets had a large amount of powder inside. Can I expect the dissolution to be affected?
A ­ Salicylic acid has a high vapor pressure and will sublime completely at about 70 °C. Typically some powder will be found inside the bottles due to recrystallization. Brush off any powder from the tablets before use. Studies have found that the dissolution performance of the salicylic acid tablets is not affected. .

Q ­ Why would the specification for an oral extended-release product list multiple tests under <724> Drug Release? Which test should I use?
A ­ Extended release formulations use various physical mechanisms to control the rate of drug delivery in vivo; these formulations may or may not have different in vitro drug release profiles. In most cases, when a new monograph for an oral extended-release product is introduced in the USP-NF, this monograph is written based on documentation from the innovator and, therefore, there will be only one Drug Release test. In order to market generic versions of extended release oral dosage forms in the US, bioequivalence to the reference listed drug must be demonstrated to the Food and Drug Administration. This is in addition to the submission of the chemistry, manufacturing, and controls information. An in vitro drug release test must be included for quality control purposes. When the FDA receives multiple product applications, the agency indicates their therapeutic equivalence status in the Approved Drug Products with Therapeutic Equivalence Evaluations ("Orange Book"). As a result of differences in drug release properties, bioequivalent products may not perform identically in vitro but can be approved by FDA with different drug release tests. The USP monograph reflects this by including multiple tests under <724> Drug Release. FDA must have previously approved the use of each of these tests The product label must indicate which of these tests was used to demonstrate compliance with the monograph.