Questions and Answers February 2017
William Brown and Margareth Marques
The following questions have been submitted by readers of Dissolution Technologies. Margareth Marques, Ph. D. and Will Brown, United States Phamacopeia, 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 USP General Chapter <711> Dissolution, under Procedure, Apparatus 1 and Apparatus 2, says to “withdraw a specimen from a zone midway between the surface of the dissolution medium and the top of the rotating basket or blade.” Does this mean that the sampling zone is accurately equidistant from the top of the basket or blade and the surface of the medium? What is the tolerance for the sampling zone? Our equipment enables sampling through the paddle shaft, in the middle of the vessel, or through a cannula 1 cm from the vessel wall. Considering the hydrodynamics, would it be better to sample through the cannula, or if there is no impact, could we sample either in the middle or from the side of the vessel?
A The USP General Chapter states that the sampling should be done in a zone that is midway between the top of the basket or paddle and the level of dissolution medium and at least 1 cm from the vessel wall. There is no tolerance. Every time you sample in a different way or location from the one described in the USP chapter, you need to demonstrate that the results are equivalent to those obtained when the sampling is done according to the instructions in <711>. See the USP General Chapter <1092> The Dissolution Procedure: Development and Validation for more details.
Q USP General Chapter <711> Dissolution, under Procedure, Apparatus 1 and Apparatus 2, Time, says that “specimens are to be withdrawn only at the stated times, within a tolerance of ±2%.” Using this information, if we have a multipoint dissolution test and the last time point is, for instance, at 12 h, we assume that the sampling can be done within a time duration of ±14.4 min. Can we do manual sampling after the paddle or basket has stopped? In the case of autosamplers, the sampling is done by sampling probe after the specified time and the last timepoint after the agitation stops. Is this correct?
A Using your example of 12 h, according to the instructions in the USP chapter, the sampling must be done at 12 h ± 14.4 min. You have an interval from 12 h minus 14.4 min up to 12 h plus 14.4 min to withdraw the sample. The sampling must be done with the apparatus in motion because the sample has to represent the entire contents of the vessel or cell and it must be as homogeneous as possible. The agitation can only be stopped after the last sample has been withdrawn.
Q We are using the dissolution test in the USP monograph for Mebendazole Tablets, and our product and other brands are not meeting the acceptance criteria. Do you have some recommendations about the dissolution test for this product?
A Before using any USP monograph for finished products, check the label claims approved by FDA for the products marketed in the United States as they may be different from those approved in other regions. This information is available, free of charge, in the FDA Orange Book at http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm. Mebendazole has very low solubility in aqueous solvents, and it has three polymorphic forms that have very different physical-chemical characteristics. Consequently, the dissolution test conditions for mebendazole tablets will depend on the physical-chemical characteristics of the drug substance used and on the characteristics of the formulation. Keep in mind that the dissolution test must be discriminative for the critical quality attributes of the product, and these attributes are formulation and process dependent.
Q Are peak vessels a good choice for poorly soluble drugs or for instances when there is coning? Are peak vessels in compliance with USP, and can they be used during stability studies of the finished product?
A Peak vessels are not described in any of the major pharmacopeias. They should only be used with appropriate justification. The dissolution test conditions should be selected based on the discriminatory power of the test. The dissolution tests should be discriminative for the critical quality attributes of the product. Once the test conditions have been selected, they remain the same for any type of product evaluation such as batch release testing, dissolution profile comparison, stability studies, and so forth. The dissolution conditions may be reevaluated if there are any major modifications in the formulation, manufacturing processes, or in the characteristics of any of the formulation components.
Q What are the special conditions in which peak vessels can be used, and what is the acceptable justification for doing so? What is the difference between compendial and noncompendial equipment?
A Compendial equipment are the ones described in a pharmacopeia. Dimensions, materials of construction, and operational and qualification procedures are standardized and well known for compendial equipment. They should be the first choice when developing a new dissolution or disintegration test. Noncompendial equipment are the ones not described in any pharmacopeia, and they should be used with appropriate justification and when the most discriminatory power of the dissolution or disintegration test can only be obtained using equipment or conditions not described in pharmacopeias. Therefore, peak vessels should only be used after demonstrating that the equipment and conditions described in a pharmacopeia do not provide the appropriate discriminatory power for the test.
Q How is the sample prepared, and how it is it added to the dissolution equipment for dissolution testing of a dry syrup for oral suspension?
A Dry syrup is not an official name for any dosage form. The correct name is powder or granules for oral solution. See the official names of pharmaceutical dosage forms in the USP General Chapter <1151> Pharmaceutical Dosage Forms. If a product, powder or granule, when reconstituted as directed in the instructions to the patient, results in a solution, no dissolution test is required. If a product, when reconstituted according to the instructions to the patient, results in a suspension, then a dissolution test is needed. The amount of product to be transferred to the dissolution equipment must correspond to the highest dose of the product that can be given. The sample is reconstituted according to the labeled instructions. These conditions must be standardized and thoroughly described in the final dissolution procedure. The introduction of the sample into the vessel can have a big impact on the dissolution behavior of the product, and it must be evaluated in a case-by-case approach. A good example of possible ways of introducing the sample into the dissolution equipment can be found in the USP monograph for Megestrol Oral Suspension.
Q How can the interference of excipients in the dissolution results be minimized when the quantitative procedure is by UV-vis spectrophotometry?
A An excipient can have two major effects on the results of a spectrophotometric analysis of a dissolution sample. First, there is the light scattering caused by undissolved matter, and secondly, there is the contribution to the observed absorption at the analytical wavelength by dissolved excipients. Sample filtration eliminates most of the scattering by particulates. If scattering losses are a problem, two approaches have been used: use of derivative spectral information and estimation of the contribution to scattering at the analytical wavelength by measurement at an alternative wavelength for which the analyte of interest has minimal absorbance. The derivative spectrum is useful because it is less affected by scattering losses than the untransformed spectrum. Scattering losses have an effect that is continuous over a wavelength range, so the effect on absorption at one wavelength can be calculated from the effect on absorbance at another wavelength in that range. If absorption by the dissolved excipient is a problem, its contribution can be estimated by determining the ratio of its absorbance at the analytical wavelength and at an alternative wavelength for which the excipient has a measurable absorbance but the analyte of interest does not. In this case, the absorbance spectrum for the excipient is determined, and the ratio of absorbance of the neat excipient solution at two wavelengths is determined so that the absorbance of the same material in the sample solution can be subtracted from the combined absorbance at the wavelength of interest. This is a variation on the use of the Beer-Lambert relationship that forms the basis for the spectrophotometric analysis at the analytical wavelength.
Q We have a dissolution method for a particular product with an acceptance criteria of Q = 80% in 30 min. The precision of the method was validated by two independent determinations at 30 min using the finished product. If there are any changes in the acceptance criteria, for instance changing to 15 or 20 min, is the validation still valid for the new time point?
A You should have evaluated a range of sample concentrations. If the new sampling time point represents the same concentration and position on the dissolution profile, then the original precision should apply. However, uniformity of dissolution results tends to vary based on position on the profile, and if the shorter specification time point means that the samples are representative of a position on the profile with greater expected variability, the validation should be repeated.
Q The USP General Chapter <1092> The Dissolution Procedure: Development and Validation states that the evaluation of repeatability can be performed by spiking the placebo. Doing so, we are going to evaluate the repeatability of the method itself, excluding the variability caused by the manufacturing process. Is it correct to evaluate this parameter with only a spiked sample and not with the finished product?
A Repeatability is a validation attribute of the analytical finish. The results of a dissolution experiment will incorporate this repeatability in its precision, and this is the reason it is studied.
Q If the validation of repeatability can be done with a spiked placebo, how should the levels of spiked placebo be chosen?
A Both the USP General Chapter <1092> and the ICH guidance Q2(R1) (www.ich.org) recommend that repeatability should be assessed using a minimum of nine determinations covering the specified range for the procedure (i.e., three concentrations and three replicates of each concentration) or using a minimum of six determinations at 100% of the test concentration.