Questions and Answers February 2023
Margareth R. Marques, Ph.D. and Mark Liddell, Ph.D.
The following questions have been submitted by readers of Dissolution Technologies. Margareth R. Marques, Ph.D., and Mark Liddell, Ph.D., United States Pharmacopeia (USP), authored responses to each of the questions. *Note: These are opinions and interpretations of the authors and are not necessarily the official viewpoints of the USP.
Email for correspondence: firstname.lastname@example.org
Q What is the recommended approach for the performance verification test (PVT) for the qualification of USP Apparatus 3. The USP general chapter <711> Dissolution currently does not state any guidance. The manufacturer of my equipment notes the use of USP Chlorpheniramine Maleate extendedrelease calibrator tablets; however, I am unable to source these tablets.
A The USP Chlorpheniramine Maleate Extended-Release Tablets Reference Standard catalog #1123102 was discontinued in 2013. The last lot sold, G1J218, expired on February 28, 2014. It was discontinued due to a revision to <711> that became official in USP 36-NF 31. Please refer to the currently official chapter in the USP-NF Online for test details. Currently, the principle of the approach used to qualify the instrument is through mechanical calibration and verification of the individual components of the system.
Q I am trying to trace some history on USP Apparatus 4 (Flow through Cell). In the past, probably between 2003 and 2006, USP Apparatus 4 was included in USP<724> Drug Release, whereas currently it is in USP<711> Dissolution. Could you please provide additional information about this change.
A USP Apparatus 4 was transferred from <724> Drug Release to <711> Dissolution in the Second Supplement of USP 29 with an official date of Aug 1, 2006 to align with other pharmacopeias.
Q We are developing a product as an immediate-release soft gelatin capsule. We would like to know when Tier 2 dissolution conditions are needed.
A Tier 2 dissolution testing is done only when there is evidence of cross-linking in the gelatin capsules. Evidence of cross-linking can include the formation of a pellicle or thin membrane, which prevents the contents from releasing or prevents the capsule from rupturing. Refer to USP general chapter <711> Dissolution and <1094> Capsules - Dissolution Testing and Related Quality Attributes for further guidance.
Q In the USP monograph for Alfuzosin Hydrochloride Extended-Release Tablets, Dissolution Test 2, at the 1-hour time point, the acceptance criteria is not in the range form, it is NMT 20%. How can the Acceptance Table 2 from the USP general chapter <711> Dissolution be applied in this case?
A In such a situation, NMT 20% can be expressed as 0-20%.
Q Why there is no dissolution test in the USP monograph for Sitagliptin Tablets?
A Dissolution test is not mandatory. In certain cases, with appropriate justification, the dissolution test can be replaced with a disintegration test. See USP general chapter <1711> Oral dosage Forms - Performance Tests for more information.
Q Is it necessary to correct the dissolution results for water content?
A Typically, the dissolution results are not corrected for the water content in the samples. When using USP reference standards to prepare standard solutions, some standards require correcting for water content to accurately determine the final solution concentration; however, the possible implications of the water content in the dissolution results should be evaluated during the product development and dissolution method validation on a case-by-case basis.
Q What is the tolerance in sampling time for USP apparatus 1 and 2?
A The tolerance for the sampling time is ± 2%. See USP general chapter <711> Dissolution, Procedure, Apparatus 1 and Apparatus 2, Immediate-Release Dosage Forms, Time.
Q What are the reasons for the the inclusion of a Blank solution to be made with one capsule dissolved in medium in the USP monograph for Cefdinir Capsules?
A The color of the capsule for the product marketed in the USA interferes with the quantitative procedure. As a result, the sample solutions are read using the capsule solution as blank to correct for the interference from the capsule components. This procedure should be evaluated using a case-by-case approach during the dissolution method validation and is required if the color or other capsule components interfere with the analytical procedure.
Q There is a USP monograph that states to do a background correction in the UV determination of the amount of drug substance released. The text in the monographs is "Analytical wavelength: 230 or 231 nm; use a suitable wavelength for background correction" What is the purpose of this correction and how is it done?
A The formulation that generated the dissolution test in the USP monograph has an interference from the placebo that can only be accounted for by performing a background correction at the specified wavelength. The absorbance measurement of the sample solution at 450 nm is subtracted from the absorbance obtained at 231 nm. As part of the dissolution method validation, the interference of placebo contents at the analytical wavelength of the active ingredient must be determined as well as the appropriate background correction wavelength. Determining the “suitable” wavelength for background correction will depend on the makeup of the placebo.
Q How should Simulated Intestinal Fluid (without enzyme) and Simulated Gastric Fluid (without the enzyme) be prepared?
A The instructions on how to prepare Simulated Intestinal Fluid and Simulated Gastric Fluid are in the Test Solutions section of USP-NF. Simply omit the addition of pancreatin to the intestinal fluid or pepsin in the case of gastric fluid.
Q When running a disintegration test, should we ensure that the immersion fluid start temperature is 37 ± 2° or is the intent to have a start and end temperature to ensure that this temperature is maintained throughout the testing?
A The temperature of the disintegration medium must be kept at 37 ± 2° during the entire test. The ability of the instrument to maintain temperature throughout the entire test should be part of the instrument qualification. Refer to the instructions recommended by the manufacturer of the disintegration instrument.
Q Why, in some USP monographs, is the quantitative procedure in the dissolution test different from the method used in the assay test?
A The quantitative procedure used in dissolution testing must be linear, precise, and accurate for entire dissolution profile. In most cases, the linearity range in dissolution is from around 5-15% up to 120-150% of the product label claim (considering the upper limit of the uniformity of dosage units test), this range is broader than that used for the assay test. It may be the case where the quantitative method used in the assay test does not provide the appropriate linearity, precision, and accuracy for this range, so another quantitative procedure must be used. In addition, because the assay sample and dissolution samples are prepared in different ways, issues such as the placebo interference, the effect of dissolution or extraction media, and other factors may be different in each case. Interference from various sources must be considered when selecting the appropriate quantitative procedure for each test.
Q In the USP monographs there is no mention of the type of sampling, automated or manual, used in the dissolution test. Which sampling procedure is the most appropriate?
A The sampling procedure is decided by the laboratory during the dissolution method validation process. There are no general rules other than the sampling method should meet the tolerance for the sampling time (± 2%) and sample volume accuracy (± 1%) as described in the general chapter <711> Dissolution. If automated sampling is going to be used, it must be validated for each product separately.
Q USP general chapter <701> Disintegration states that disks can only be used if specified or allowed in the monograph. We purchased new disintegration equipment that has disks with sensors that automatically detect the endpoint of the disintegration test. These disks must remain in the tubes for all tests during the entire test. How can we justify the use of the disks in all methods?
A To use this type of equipment, a validation of the new disintegration method using the disks should be performed. The goal of the method validation would be to demonstrate that the presence of the disks does not effect the disintegration evaluation for each of the products previously evaluated without disks.