Author: Dr. Saeed Qureshi, Ph.D.

There is no argument that the drug dissolution characteristic of a product (tablet/capsule) is one of the most critical and critical attributes. It is, and will remain, one of the critical parameters to evaluate for the development and evaluation of the products.

However, the issue is how one should measure the parameter (dissolution characteristics of a product) i.e. percent drug dissolved/released at times from a product? Obviously, one requires an apparatus/procedure to determine that. It is the most basic and scientific requirement for determining any characteristic/parameter. The apparatuses/methods used must first be qualified/validated, i.e., a priori shown to be fit for the purpose. However, none of the suggested/recommended apparatuses/methods have ever been shown as qualified and/or validated for dissolution testing. These are no different or better for dissolution testing than the use of a kitchen blender at a slower rpm.

Therefore, it is very important and critical to note that any results obtained using the suggested/recommended apparatuses/methods, particularly basket and paddle, have no scientific merit or use for any purpose, including QC, IVIVC QbD, etc. One should be extremely cautious in drawing any conclusions based on data obtained using these unqualified and non-validated apparatuses.

It is important to note that de-aeration may impact dissolution results, just like testing at different temperatures or RPMs can provide different results. Seeing different results does not mean much. These observations are pretty much irrelevant and useless for the purpose of dissolution testing. The requirement of de-aeration is irrelevant, just like that of conducting dissolution tests at a higher or lower temperature would be.

Dissolution tests should always be conducted under relevant experimental conditions considering the objective of the testing. For an appropriate dissolution testing, the media temperature should be maintained at 37 ºC, and the dissolved gasses levels should be equilibrated at this temperature. Otherwise, results obtained would be considered scientifically invalid and useless to evaluate the quality (e.g., QC) of products for human use.

No funny explanations or justifications, please!

It is well-established that current dissolution apparatuses (paddle/basket) are flawed and cannot provide relevant and reproducible results. The flaw is that poor hydrodynamics within a dissolution vessel i.e., product and medium, do not interact appropriately and reproducibly, resulting in cone formation, tablet/capsule positioning effects etc. Thus, tests provide highly variable and unpredictable results, shown in many reported experimental studies.

Rather than addressing the issue or the flaw, unfortunately, focus has been diverted in promoting that the reasons of such unpredictable behavior are due to lack of control of de-aeration of dissolution medium and presence of vibration in and around the apparatuses.  It is important to note that there is no logical or experimental basis or evidence available in support of such a view. However, there are persistent discussions and promotions of such views.

It may be important to further note that this promoted view of the de-aeration or vibration aspect originated from frequent failures of calibration of apparatuses using USP prednisone tablets. The effect of de-aeration and vibration on actual products for human use is almost non-existent. The use of chemical calibration has already been considered unreliable because of the unpredictability of results or failure of perfectly working dissolution apparatuses. Their use is gradually diminishing. However, “slogans and chanting” of de-aeration and vibration continues.

Therefore, analysts should critically evaluate the promoted views on the topic as these are not scientifically valid claims.

The dissolution tests are conducted to evaluate drug release characteristics of products in the human GI tract, which is neither de-aerated nor vibration-free. Therefore, conducting dissolution tests in a de-aerated medium and/or vibrating free environment should be considered a physiologically irrelevant practice.

For appropriate dissolution testing, the medium should be equilibrated with dissolved gases at 37 ºC and stirred gently but thoroughly.

However, it is important to note that none of the currently suggested apparatuses and procedures can provide relevant and accurate dissolution results for any product.

The reason being NONE of the suggested and recommended apparatuses/procedures are qualified and/or validated for dissolution testing. Most, if not all, reported testing and results do not reflect the dissolution characteristics of the products but rather the presumed ones obtained by selecting product-dependent experimental conditions. See link for further details (Drug dissolution testing: Limitations of current practices and requirements).

As all of the above-mentioned guidances are dependent mostly on drug dissolution results, obviously, these documents cannot provide an intended and useful interpretation about the quality of pharmaceutical products in particular tablets and capsules.

A new or modified apparatus and/or procedure is required for appropriate uses/applications of the above-mentioned documents. A modified dissolution tester with a crescent-shaped spindle and a single set of experimental conditions may be used to address the flaws of the current practice providing improved product development and evaluation. Link for further details: A Simple and Unique Approach for Developing and Evaluating Products.

The purpose of a dissolution test is to determine or establish drug dissolution or release characteristics of products, in particular tablets or capsules. To determine dissolution characteristics or any other characteristic in general, one would require a method and/or tester or apparatus. Prior to its use, it must be established that the method/tester can provide an expected outcome, i.e., in this case, the method/tester is capable of providing dissolution characteristics of a (tablet/capsule) product. In other words, the dissolution method/tester should be qualified and validated.

Unfortunately, suggested and commonly used dissolution testers have never been shown as qualified and validated dissolution testers. Therefore, reported results, and by extension conclusions drawn from these results, are of limited or no relevance or use. It is all an illusionary science and interpretation of data/results.

The crescent shape spindle has been proposed to address this present-day difficulty. The use of the spindle provides an ability to test products using a common, simple testing and product-independent approach.

I read a recent article published in the American Pharmaceutical Review titled “A Rational Approach to Development and Validation of Dissolution Methods” by G.P. Martin. In the article, author suggested approaches one may take in developing drug dissolution testing methods.

Unfortunately, the author ignored the current views and literature highlighting flaws of current practices of drug dissolution testing. The scientific approaches described in the articles are weak and more appropriately inaccurate, but logical thinking would also not support the arguments presented. For example, it is stated that:

Please click here for the complete article

Scientific rationales/requirements dictate that:

(1)    A dissolution test should be conducted to reflect in vivo dissolution characteristics of a product (tablet/capsule). However, if and when results appear to match/associate with in vivo results (rare), the test will be considered successful. Otherwise, the failed tests will still be considered acceptable and used to assess future batches’ quality.

(2)    The failed or irrelevant dissolution methods should not be acceptable but are considered “fit for use” for the evaluation of the quality of the product for human use. Almost all tests at present, in particular pharmacopeial, are of this type.

(3)    The apparatuses/methods must be qualified and validated for their intended purpose. However, currently recommended apparatuses have never been validated or qualified for dissolution testing purposes. On the other hand, these apparatuses are the only ones that are expected to be used. If new or different apparatuses are to be used, then those are expected to provide comparable/similar results obtained using current apparatuses. That is, new apparatuses should also provide as irrelevant results as the current ones.

(4)    There should be a common product-independent method/approach available to determine the dissolution characteristics of a product. However, current practices require development and product-dependent methods, which obviously cannot provide dissolution characteristics of the product. There are hundreds, if not thousands, of dissolution methods available to use, in particular from pharmacopeias and standard-setting authorities. However, in reality, all these methods are not methods at all but sets of instructions to follow to obtain desired or expected dissolution results of products.

(5)    Both IR and ER type products are to be tested using the same set of experimental conditions, as the experimental conditions represent/simulate the human GI tract environment, which remains the same or constant. However, IR and ER products are expected to be tested using different in vitro experimental conditions even when comparisons are to be made with the in vivo results.

(6)    Some guidance or standards should be available to link in vitro dissolution results to the in vivo (bioavailability) outcomes. However, there are no such standards or criteria available. In vitro and in vivo results are often compared using the eye-balling technique (commonly referred to as rank-order match or comparison). Such qualitative (eye-balling) approach should be considered invalid, as the data obtained and presented from two sources are in different units and scales. The in vitro dissolution data is often presented in percentage units using a linear scale, while in vivo results are in concentration units (e.g., ng/mL) and exponential base.

(7)    The relationship between dissolution (in vitro or in vivo) and absorption/bioavailability should be used to predict plasma drug levels, the only objective for conducting drug dissolution testing. However, often requirements are imposed for developing a relationship as a mathematical model (equation) which provides no possibility of predicting/estimating plasma drug levels.

To address the above-mentioned deficiencies, a modified stirrer known as a crescent-shaped spindle has been proposed, along with a simple mathematical approach, to evaluate a product’s dissolution characteristics, including predicting plasma drug levels. The suggested approach provides a simple, efficient, and scientifically valid approach for dissolution testing as well as relating results to bioavailability characteristics of products in humans.

Evaluating dissolution characteristics of different products (e.g. IR and ER) using different methods is like measuring temperatures of a drink and meal/bread using two different scales to justify that they have different contents and/or are prepared differently. Bizarre!

It is hard to believe that we are to follow such unscientific, illogical and invalid reasoning and practices in this day and age.

If two different temperature scales (or thermometer scales) are used to monitor drinks and meal/bread temperatures, how will one establish which one is hotter/colder than the other?

Similarly, if dissolution/release characteristics of different products are to be measured using two different scales (in this case, methods, in particular, product-specific methods), then how will one know which one is of faster release and which one is slower release type?

In conclusion, using the current practices of dissolution testing, one never determines the dissolution/release characteristics of any product. Therefore, for appropriate testing, it is essential to have a single and product-independent tester and/or method.

It is often suggested that conducting IVIVC studies, i.e., developing a relationship between in vitro (dissolution) and in vivo (plasma drug level), are necessary for developing dissolution tests capable of reflecting or predicting plasma drug levels. Unfortunately, this is not a correct view, as explained below:

Please click here for the complete article

When an oral product, usually a tablet or capsule, is taken, it instantly goes into the stomach (gastric compartment). The gastric environment can be described as an acidic (mostly HCl-based) aqueous solution (pH 1 to 3) with a churning (moving and mixing) process. Assuming a disintegrating type product, the product will disintegrate into solid particles/aggregates. Once in this disintegrated form, the drug will behave exactly like granules in a dilute acidic solution with mild stirring in a beaker or flask. In the case of non-disintegrating type tablets, the drug will be released or leaked-out from the unit into the acidic solution.

If the drug is soluble, it will move into the intestine as a solution, otherwise as a slurry or suspension. The important thing to note here is that the drug will move into the intestinal component with some delay. Here the acid solution or suspension will be mixed with a strong buffer turning the acidic liquid to basic, more accurately less acidic in the pH range of 5 to 7. Considering the variability in contents and the rates of the entrance of the two solutions i.e. slurry from the stomach and the buffer from the pancreas, it is almost impossible to determine or establish the pH of the soup accurately. However, it is a well-established fact that pH in this area of intestine ranges between 5 and 7. Therefore, for all practical and standardization purposes, one can use pH of 6, an average of 5 and 7.

Please click here for the complete article