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Reporting and Analyzing Drug Dissolution Results: A Systematic Approach

… The preceding discussion is to emphasize the fact that drug dissolution testing is a relatively simple analytical technique. It should not require any more elaborate method development/ validation steps or reporting of results than any other simple analytical techniques such as the two mentioned above. Such an understanding of the underlying principle of dissolution testing will help in critically evaluating current complex practices of reporting and evaluating the dissolution results, and hence simplifying them…. American Pharmaceutical Review May/June, 2010. (Link)

The lack of adequate stirring and mixing within Paddle and Basket apparatuses requires that the dissolution tests be conducted using product-dependent experimental conditions. For example, the experimental conditions for carbamazepine described in the USP are as follows:

As the GI tract environment remains the same for both IR and ER products, testing using the conditions mentioned above would not be physiologically relevant. Furthermore, as the experimental conditions are different for each product, one cannot make a valid comparison between products. Thus, it would be impossible to establish whether the differences in the drug release characteristics of the product are because of the products or experimental conditions

On the other hand, if appropriate stirring and mixing environments are present within the dissolution vessels, such as by using crescent-shaped spindles, then such problems do not occur. Therefore, all of the products can be analyzed using a single set of experimental conditions, such as:

The figure below shows dissolution profiles of carbamazepine products using the single set of experimental conditions as noted above (Source: Qureshi, Eur. J. Pharm. Sci., 2004). 

Recently a question has been asked that while conducting PVT (Performance Verification Test), only the basket apparatus met the criteria but not the paddle apparatus, is the apparatus acceptable for use if the basket is to be used for product testing?

In essence, the query relates to seeking an opinion that what would the response be from a standard-setting body? A clear and definite answer can only be provided by a representative of the standard-setting body. If someone would like to contribute in this regard, please submit your response to the moderator of the site. On the other hand, however, some scientific discussion is provided here, which may help in reaching an objective response. To address this query, one has to ask a question as to whether meeting the PVT criteria does indeed reflect the acceptable performance of dissolution apparatuses? Unfortunately, there is no or limited scientific evidence available to support the link between meeting the PVT criteria and the actual performance of a dissolution tester. Therefore, some standard-setting organizations will accept evidence of apparatuses’ performance based on mechanical calibration alone without requiring the PVT.

It appears that the current practices of dissolution testing follow two separate and parallel paths. For example, a simple question would be, “how to conduct a dissolution test?” A common response usually is to use any of the “approved” dissolution apparatuses such as USP Paddle/Basket with associated experimental conditions such as 1L capacity glass/plastic vessel, 900 mL or less medium (buffer or water), 50/75/100 rpm. Then, if needed, some solubilizing agent (e.g., SLS) may be added to it along with all the instructions/suggestions to control the specifications and operation of the apparatuses/testing.

In reality, however, the question is usually not intended towards the available choices of apparatuses or associated experimental conditions but seeking a methodology to determine dissolution characteristics of a product. To answer this question, one has to have a standardized apparatus with fixed associated experimental conditions. Furthermore, this apparatus and its associated experimental condition must provide dissolution results (verifiable independently from the dissolution tester) of a reference product. Therefore, for determining dissolution characteristics, one has to have a standardized tester (apparatus and associated fixed experimental conditions) and a reference product with known dissolution characteristics. Once an analyst can determine the acceptable results of the reference product using a standardized tester, then this tester is to be used to determine the unknown dissolution characteristics of the test products. Suppose the results are not as desired or expected. In that case, analyst must work with the product (formulation/manufacturing) and NOT with the experimental conditions, which would void the dissolution test and results.

The current situation is that neither a standardized dissolution tester nor a reference product is available to the analyst, but the technique is expected to provide dissolution characteristics of a test product. The analyst has to be confused and frustrated and the pharmaceutical industry, which loses significant amounts of money for conducting dissolution testing of limited value.

To address this confusion, a new approach in dissolution testing using a new spindle has been suggested. For further discussion in this regard please see the title “Know Ur Product” and other links (1, 2, 3, 4).

A number of guidance documents are available from different regulatory agencies, particularly the US FDA, to facilitate and expedite drug products development and evaluations. These guidances are related to dissolution method developments, apparatus calibration, and product evaluations. In many cases, these guidances and related practices are commonly referred to by their acronyms, such as BCS, IVIVC, SUPAC, bio-waivers, similarity factor (F2), QbD, PVT, mechanical calibration. Examples of such commonly referred guidance documents are listed under the publications section.

It is important to note that these guidances solely or significantly depend on the use of dissolution (Paddle and Basket) apparatuses. Therefore, the success or applications of these guidances are dependent on the outcome of these apparatuses.

In recent years, it has generally been recognized that Paddle and Basket apparatuses do not provide relevant and reproducible dissolution results. This is because of the poor hydrodynamics (or lack of efficient stirring and mixing) within dissolution vessels. Therefore, intended benefits from the use of the guidance documents may also become suspect.

Appropriate use and interpretation of the guidance documents require relevant and reproducible results. This may be achieved by conducting dissolution tests using apparatuses that are free from Paddle and Basket’s deficiencies, that is, apparatuses with improved and efficient stirring and mixing environments.

Although not generally recognized, current practices of dissolution testing seek to adjust experimental conditions to obtain desired or expected drug release/dissolution characteristics. The variations or adjustments in experimental conditions, which are commonly referred to as method development steps, often relate to the choice of apparatuses, RPMs or flow rates, media (nature and volumes), etc. Thus, current practices defeat the purpose of dissolution testing, which is supposed to be conducted to evaluate or establish drug release characteristics of a product, in particular, at the method development stage.  In addition, most standards and requirements are based on selecting and setting experimental conditions rather than evaluating products. 

For appropriate dissolution testing, the tests are to be conducted using product-independent and fixed experimental conditions. This will facilitate finding the actual drug dissolution or release characteristics of a product or help in knowing one’s product. If one keeps on changing the experimental conditions, one will never know the products’ true (dissolution) characteristics.

The most widely used and referred dissolution tolerances are based on the USP Acceptance Table. The results are evaluated in stages. This means repeats are allowed with relaxed tolerances and a higher degree of variances for each subsequent test.

(The Q-values are provided in individual product monographs, representing expected percent drug release (dissolution) at times, such as 30, 45, 60 minutes etc.) 

Considering the above criteria with a Q-value of 80, one can obtain the following set for acceptable results.

Therefore, one may observe an RSD (CV) of 20% or more, and the results/product would be of acceptable quality for regulatory purposes. The expected high variability (RSD/CV) in results is built in the tolerances.

In this particular case, the test would meet the criteria at the stage 1, thus testing for the next stages would not be required. However, this may be a random phenomenon and one may get results as shown for Stage 2 or 3, at the first stage as well. These tolerances are for last dissolution sampling time, where dissolution is the highest with the least variable results. However, if dissolution results are to be reported for earlier times (such as for extended-release products), the expected variability would be higher.

Therefore, the above discussion clearly indicates that the dissolution results, particularly using Paddle/Basket apparatuses, are expected to be highly variable, often more than 20% RSD. Therefore, as often desired or suggested, setting tolerances tighter would not be scientifically valid or achievable. In that case, one would face a higher number of failures without any apparent reason, as is the case with the testing of the USP PVT prednisone tablets where tolerances are usually set tighter than one would observe in real life, thus failures.

It is a very well-established fact that the USP apparatus PVT (Performance Verification Test) using prednisone tablets faces significant criticism regarding the lack of its relevance to the performance of the apparatuses. This criticism originates from the unexpected/unpredicted failures of the PVTs, by providing (dissolution) results outside the expected ranges, also called suitability ranges. Although not generally recognized, the main reason for such failures is that expected ranges are set tighter than needed to reflect the test’s true (high) variability. Therefore, in reality, when a PVT fails, it does not reflect a substandard apparatus or the testing but is a reflection of the actual/true variability of the testing. Often suggestions are given for addressing this situation by adjusting apparatus/testing parameters. However, a common view in the scientific community is that repeating the test, single or multiple times, often provides the desired outcome. Therefore, the current practice of PVT has become an exercise of obtaining dissolution results within an expected range rather than evaluating the performance of the apparatus/test.

In addressing the potential cause of this high variability and unpredictability, a common focus has been the quality of the PVT (prednisone) tablets. However, if this had been true, the issue could have been resolved by using different tablets of the same or different active ingredients. In addition, there are many studies described in the literature using many other well-established products approved for human use, which demonstrate similar high variability in dissolution results. As an example, the figure below shows the dissolution characteristics of furosemide tablet products analyzed in different laboratories. The results show similar, if not worse, variability than of prednisone (PVT) tablets. Then, why is the high variability aspect often described with respect to prednisone (PVT) and not for other products? The reason is that prednisone (PVT) tablets are analyzed in multiple labs, thus higher visibility of the problem (variability). On the other hand, other products are usually tested internally, within the lab, or in few labs. Thus the problem is less visible. However, variability and unpredictability of results in both cases, PVT or products testing, is exactly the same.

The obvious logical conclusion from such observations would be that if the problem is not because of the tablets, the technique could potentially be the reason. However, studies are now reported in the literature, based on laboratory experiments and computer simulation exercises, which clearly demonstrate that the currently used apparatuses (Paddle/Basket) should indeed provide highly variable and unpredictable results. This variability and unpredictability results come from the poor flow dynamics within dissolution vessels, resulting in highly variable and unpredictable product-medium interactions. Therefore, it is a problem of the apparatuses/technique and not that of the products or PVT tablets, in particular.

Obviously, as the technique/apparatuses are the prime suspects of the high variability and unpredictability problem, then all results obtained using these apparatuses will become suspect, potentially undermining the quality of the products and adding cost to the product development and evaluation.

Often a reason is provided, in the literature, that it is a test to differentiate drug release characteristics of a product reflecting the potential impact of formulation and/or manufacturing differences. This type of test usually does not link or associate with the products’ in vivo drug release characteristics. Such tests are often referred to as “discriminatory tests.” The underlying reason for such a “discriminatory test” is that if the test relates dissolution differences to formulation/manufacturing differences, then the test will flag potential deviation from the expected behavior of the product in vivo (humans). The main assumption here is that the differences in formulation and/or manufacturing attributes would result in vivo drug release characteristics, producing a substandard product.  This, unfortunately, is an incorrect assumption because the differences in formulation and/or manufacturing, on their own, do not necessarily result in differences in vivo drug release, at least not in most cases. If this assumption had been correct, then generic products and the industry would not have existed. The reason being, the generic products, which are based on vastly different formulation and manufacturing attributes, but are required to provide the same drug release characteristics in vivo (humans).  In addition, the generic products are also required to provide similar dissolution characteristics, thus forms the basis of pharmacopeial (USP) testing.

Therefore, developing or conducting an in vitro dissolution test just to evaluate/assess differences in formulation/manufacturing, without its link to in vivo, is of limited value or use and may be an incorrect practice.

The purpose of any analytical method development, including dissolution testing, is to have a method that would describe the unknown property of the material it tests. The foremost requirement for method development practices is that one must have reference material, or a product, of the known value of the parameter or dissolution result. A method will be considered developed when this method provides the value of the reference product’s parameter (dissolution results) accurately with acceptable confidence (variance).

Unfortunately, in the case of drug dissolution testing, no such reference product is available with known or accepted dissolution value/result. Thus, in the true sense of the meaning of method development, it is impossible to develop a dissolution method that could be used to determine the unknown dissolution results of a test product.

On the other hand, current practices use the terminology of method development to choose apparatuses and associated experimental conditions that would reflect the expected or desired behavior of the test product. Another way of saying this is, the test product becomes its own “reference.”  That is why products often come with their methodologies. Obviously, it is not the correct and valid understanding and method development approach, thus requiring reconsideration. An obvious outcome of such practices is that the developed method would not allow the comparison of drug dissolution (release) characteristics between products. In addition, one would never know the true dissolution rate (characteristics) of any product.

Therefore, in reality, current practices of method development in drug dissolution testing are neither accurate nor serving their intended purpose.