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 carbamezepine described in the USP are as follows:

As the GI tract environment remains the same for both IR and ER products, testing using the above mentioned conditions 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 and all of the product can be analyzed using a single set of experimental conditions, such as:

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

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 if such were the situation what would  the response be from a standard setting body? Obviously, a clear and a 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 acceptable performance of dissolution apparatuses? Unfortunately, there is no or limited scientific evidence available to support the link of 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?” 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, if needed, some solubilising agent (e.g SLS) 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. This apparatus along with its associated experimental condition must be capable of providing 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 reference product with known dissolution characteristics. Once an analyst is able to determine the acceptable results of the reference product, using standardized tester, then this tester is to be used to determine the unknown dissolution characteristics of the test products. If the results are not as desired or expected then 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 a dissolution tester nor a reference product is available to the analyst, but technique is expected to provide dissolution characteristics of a test product. The analyst has to be confused and frustrated, as well as 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).

As described earlier (link), the main purpose of dissolution testing is to establish the drug dissolution/release characteristics of a product. However, current practices do not provide such an answer, but suggest choices in selecting experimental conditions to achieve or set desired dissolution results/characteristics of products. Thus, the current practices appear to defeat the purpose of dissolution testing.

The only way the objective/purpose of dissolution testing can be achieved is to have some sort of common experimental conditions. Significant work has been done and published for developing such common experimental conditions. The main difference in the current practices and the suggested approach is that of the use of a different type of spindle (stirrer), known as crescent-shaped or brush spindle. For further details about the spindle and the suggested experimental conditions, please see under subheading/title –“Know Ur Product”.

The new spindle provides a simple, efficient and product independent approach in determining drug dissolution/release characteristics of a product. Even without official recognition, the spindle may be employed to facilitate developing dissolution test conditions using traditional apparatuses such as Paddle and Basket. This may be achieved by conducting a dissolution test using a single set of experimental conditions with crescent-shaped spindle to establish the drug dissolution characteristics of the product. The observed dissolution characteristics then may be used as reference to obtain experimental conditions using Paddle or Basket apparatus for complying with the regulatory requirements.

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 choice of apparatuses, rpms or flow-rates, media (nature and volumes) etc. Thus, current practices defeat the purpose of dissolution testing which are, in fact, 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 this practice of 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 in finding the actual drug dissolution or release characteristics of a product or will help in knowing one’s product. If one keeps on changing the experimental conditions, one will never know the true (dissolution) characteristics of the products.

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 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.)  Continue reading →

It is a very well established fact that the USP apparatus PVT (Performance Verification Test) using prednisone tablets faces significant criticism regarding 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 are needed to reflect true (high) variability of the test. 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. Continue reading →