Author: Dr. Saeed Qureshi, Ph.D.

The purpose of a dissolution tester is to test a tablet/capsule product for its potential dissolution characteristics in the human GI tract. In general, it is now well recognized that the currently used dissolution testers, in particular paddle and basket, do not provide such dissolution characteristics. In fact, they cannot provide dissolution characteristics because of the flaws of poor product/medium interaction within the apparatuses. Therefore, these apparatuses cannot be qualified and/or validated as dissolution testers and thus cannot be used to develop and evaluate the products.

The practices of the past many years have been to keep using these apparatuses for product development and evaluation (isn’t this bizarre?) with a change/twist in the objective of dissolution testing by calling it a quality control test. However, how does one link the dissolution test to the quality of the product when it requires its link to the dissolution characteristics in vivo, i.e., human GI tract? Oops, there is no link here, as stated in the paragraph above.

The objective of the testing should be twisted again. This time it would be called testers/testing for batch-to-batch consistency check. As the link or relevance of the test to its original and actual objective has been severed, but the same testing is still required to be done. Therefore, certain practices (“rituals”) have to be suggested to come up with some standards, any standard, that everyone has to follow. Presently, this standard is called Q-Value (to make it sound professional!), which is 80/30, i.e., 80% of the drug should dissolve within 30 minutes. Where did this number, 80/30, come from? One is not expected to ask or know! One just has to accept it. However, one can negotiate this number, based on one’s negotiating skills, to get another number for one’s product say, 70/45 or 75/20 or any other.

Now there is a problem: it is often difficult to meet this standard (80/30 or a different one) because the tester itself is highly variable in nature. One cannot obtain repeatable and reproducible results within the expected norms.

So, what should one do now? Let us introduce a Performance Verification Test (PVT) to test the tester. What is a PVT?  It is a dissolution test, using in-house developed tablets, which everyone is expected to conduct to get one’s own product approved. How does this PVT help in improving the tester? No one knows. It is assumed that the PVT establishes: the validity of a vibration-free environment in and around the tester, the de-aeration content of the medium, the perfectness of the vessel dimensions, and its alignment. Oops, what happened to the evaluation of the performance of the tester? Does it improve the repeatability and reproducibility of the testers? Of course not, because the issue of repeatability and reproducibility relates to spindle/vessel combination remains the same, so remains the problem.

So, what should be done now? Let us get rid of this PVT. It causes too much hassle and frustration. Let us have something else and call it the Enhanced Mechanical Qualification (EMQ or simply MQ). What is the MQ? It is a set of (same old) physical specifications but with somewhat tighter tolerances. Now everyone is required to get certified that the tolerances are within the expectations. How does MQ establish or improve the performance of the tester? It does not. It is assumed that if one has certificates and good record keeping, the performance of the testers will be considered (assumed) improved or OK. But the lack of performance, or flaws, was not because of the broader tolerances. It is because the combination of spindle/vessel. As the spindle/vessel combination remains the same, so does the problem. However, one will not see the problems anymore, as there is no performance test associated with MQ. Therefore, the idea is if one does not see the problem, it is safe to assume that the problem does not exist. So, how could the MQ help? It does not.

 What should be done now? Develop a performance qualifier for the PVT and/or MQ.  What is a performance qualifier? It is a piece of equipment that perhaps costs many thousands of dollars, which will help show that the apparatus is within required specifications. The question is, why would the specifications change when the manufacturers provide all the certifications. Remember, you are not supposed to ask questions! Will this performance qualifier help? Of course not, because it was never a specification issue, tight or broad, so how it can be addressed or solved. It does not.

Specifications were correct all along. These are the same apparatuses/testers with practically the same specifications and tolerances, but maybe with some tweaking for personal gratification, otherwise nothing has changed.

We started with the use of these apparatuses as dissolution testers but generated a whole new industry of the performance verification/validation and qualification, which is based on made-up requirements of MQ and PVT for monitoring irrelevant and useless parameters.

Let us hope that this practice stops here. If you ask my opinion, then I will say that brakes have already been applied to use paddle and basket apparatuses. It is just taking time to formalize and generalize it. People have already started evaluating other alternatives because current apparatuses are not qualified and validated for the intended purpose and thus, the results obtained from them cannot be trusted.

These apparatuses:

1. Lack of scientific merit and support. Experimental studies have shown that they will provide highly variable and unpredictable results because of poor product/medium interaction.

2. Cannot be qualified/validated using commonly used industry-wide practices of qualifications for analytical instruments. In particular, they do not meet the requirements of design qualification (not fit for intended use) and operation qualification (cannot be qualified using a reference product).

3. Require meeting undefined and unqualified requirements such as de-aeration of the medium and control of vibration in and around the equipment.

4. Require drug and/or product-dependent experimental conditions. Therefore, it will not be possible to know whether dissolution characteristics reflect the products or the experimental conditions used.

5. Do not differentiate between IR and ER products. The analyst must first know what type of release/dissolution to expect from the product and then use the design of the experimental conditions to provide the presumed released/dissolution characteristics.

6. Are routinely used for evaluating drug products for human use (e.g., pharmacopeial testing). However, they have never been validated to demonstrate that they can provide bio- or physiologically relevant results.

7. Are often used for quality control and to check lot-to-lot consistency purposes. However, a link of these apparatuses, and associated experimental conditions, to the quality of a product, and consistency thereof, is unknown or undefined. The only criterion used for this purpose is that the dissolution results must meet some arbitrary standards/tolerances. If the criterion is not met, it is assumed that the products may be of substandard attributes.

8. Are expected to provide discriminatory tests which should be capable of showing formulation/manufacturing differences among products and/or batches. On the other hand, it is a well-known fact that these apparatuses frequently provide discriminatory results lacking any physiological significance or consequence.

9. Do not simulate in vivo or physiological environment (stirring and mixing) thus, one cannot develop bio-relevant tests.

10.   Require tolerances be set lower than potency and content uniformity values. Thus, results will reflect the inaccurate and inappropriate quality of perfectly acceptable products.

Considering the above-mentioned deficiencies, results obtained using these apparatuses can easily be questioned/challenged for their validity and relevance.

It is a fact and often a regulatory requirement that one has to demonstrate that an apparatus is capable of providing the intended and expected outcome. A simple and common example of this requirement is the calibration of a laboratory weighing scale or balance. Initially, when a balance is purchased, and then occasionally after that, it must be calibrated against reference weights to show that the balance can provide accurate weights of the references. If the balance does not perform as expected, then it has to be adjusted accordingly. please click here for the complete article

It is often asked which approach one should choose and why, i.e., is there a reason for the preference for one over the other?

Such a question has two components; (1) scientific or logical (2) required standards. Generally, the required standards component is based on the first one, i.e., science and logic. Unfortunately, in the case of the current practices of dissolution testing, scientific principles are entirely absent from the standardization. That is why there is so much difficulty, along with the associated frustrations.

I provide suggestions based on underlying scientific principles, which often do not fit well with the current practices because, as I stated above, the current practices lack scientific reasoning and logic. People say that both MQ and PVT are good and valid, which is correct, and an analyst can choose either. However, the next question is, which one is better and why. That is where the difficulty is. If one likes to know which one is better, then one has to know the reason behind conducting these tests, which will help decide and rationalize the preferred one.

So, the question is, why these MQ and PVT are done? The answer is to establish that the apparatuses fit their intended purpose, i.e., apparatuses can be used to evaluate the dissolution characteristics of a product for human use. The next question is, or at least should be, that if one meets the requirements of MQ/PVT, will the apparatuses be considered fit for evaluating the product for human use. The answer is no because both MQ/PVT lack the critical link between apparatuses and the evaluation of dissolution characteristics of a drug product (please use the link to read the article for further discussion). Therefore, in general, MQ and PVT are not useful practices and requirements and are unnecessary burdens on the pharmaceutical industry.

If the testing (MQ/PVT) lacks any real benefit, but has to be performed to meet the requirement, I would prefer the MQ. The MQ takes the responsibility away from the analysts and transfers it to the vendors of the dissolution testers. They can provide certification that the testers meet the specifications, which they usually provide when one purchases an apparatus and may provide later as well. In addition, the beauty of MQ is that no one can question that an apparatus does not work/perform as expected because there is no way to prove that it does not work, as the performance of the apparatuses is not associated with the MQ requirements. So, my dear analysts, go with the MQ and say goodbye to the PVT and its so-called “best practices”.

This article provides a discussion based on data presented in the literature that a direct comparison of dissolution results (profile) with blood levels (C-t profiles) can lead to misleading interpretation. For a more appropriate comparison, dissolution results should first be converted to C-t (plasma drug conc.-time) profiles. Examples are provided for converting dissolution profiles, using convolution techniques, to C-t profiles, which improve dissolution results evaluation. The article also presents an argument that for proper reflection of bio-relevancy of dissolution results, the tests require higher agitation (or product/medium interaction) relative to what is provided by the paddle apparatus at 50 and 75 rpm. please click here for the complete article

Predicting drug concentration-time (C-t) profiles in humans is highly desirable and needed for appropriate development of products and establishing their quality during production. Based on the convolution approach, a simple method to predict or estimate the C-t profiles has been suggested [link].

This article provides an application of the approach for the evaluation of metoprolol tartrate tablet products. Furthermore, it also demonstrates that the approach can be used to predict the C-t profiles for a sub-population as well. please click here for the complete post

A commonly asked question is how one should select a dissolution apparatus. It may be of interest to know that such a question is often asked when a dissolution analyst gets frustrated with the unexpected or unanticipated dissolution behavior of a test product. However, such a question is seldom asked at the beginning of the project as it is always understood or assumed that one will most likely use a paddle apparatus. Furthermore, the analyst will try some variations of rpm (50, 75, or 100) or medium (different buffers and pHs). If this does not work, the basket apparatus may be tried with similar variations in RPMs and buffers. In the end, the analyst usually settles on a test that will provide the anticipated/expected characteristics of the test product. Please click here for the complete post

It appears that there is confusion in the description of these terminologies. In reality, these are one and the same thing. Let me explain:

A bio-relevant dissolution test is a test, which should be able to differentiate (discriminate) between the in vivo behavior of two or more products. The in vivo behavior means bioequivalency or bio-in-equivalency of the tested products. Therefore, by its very nature, a bio-relevant test becomes a discriminatory test as well.

So, why are these two terminologies often referred to as different or separate? It is due to the fact that in the dissolution testing area, a discriminatory test is also described as, wrongly, an in vitro dissolution test, which may show formulation/manufacturing differences without their in vivo relevance or consequence. Such tests are often described as QC or consistency-check tests (e.g., in pharmacopeias). It is important to note that these tests do not relate to the in vivo characteristics of products. However, they are still expected to reflect quality of the products for humans uses. How? It is not clear and is the most confusing part of current dissolution practices! In my opinion, these tests (QC or in vitro discriminatory) and their requirements are not very useful and conducted as a “tradition”.

It is like developing a (“discriminatory”) thermometer which will show differences of a couple of degrees of temperature from person to person (or within a person) and then developing another (real/actual) thermometer which will reflect whether a person has a fever or not based on a difference in the temperature reading. In dissolution terminology, the first type of thermometer would be called a “discriminatory” test or tester and the second type as “bio-relevant.” Can anyone tell me why we should have the first type of thermometer or test?

The purpose of this explanation is, if possible, to avoid using the word/terminology of a “discriminatory” test, as it takes an analyst away from the objective of drug dissolution testing. The only test required is the one that should be bio-relevant.

For developing such a test, one first has to define what a bio-relevant test is. I have explained this in one of my earlier posts (see Link). Briefly, a bio-relevant test is a test that not only provides physiologically relevant results, but these results must be obtained using physiologically relevant experimental conditions. Trying experimental conditions without their physiological significance or relevance would not be a useful exercise.

One main consideration in this regard is that as human physiology remains the same, the experimental conditions should also remain the same. Therefore, working with different experimental conditions, particularly specific to your product, will violate the fundamental requirements of (bio-relevant) dissolution testing.

The physiological environment dictates the following single set of experimental conditions. (1) Temperature 37 °C (2) Medium: aqueous buffer having pH between 5 and 7 (use of water can be a good choice or start), with or without solubiliser (3) Mixer: To provide gentle but thorough stirring and mixing. That is it!

One does not have the option of trying different experimental conditions. It is very important to note that, if one deviates from this testing requirement, then that test may not be considered as a bio-relevant test, even if it provides matching bio results, as they are not obtained using bio-relevant experimental conditions.

Presently, paddle/basket apparatuses are used as mixers/stirrers, which have been shown to provide no or limited stirring and mixing. Therefore, one should NOT expect to obtain bio-relevant results using these apparatuses. If one obtains bio-relevant results using apparatuses, these should be considered as a match by chance.

Therefore, the first thing in trying to obtain bio-relevant results is to try a different stirring/mixing approach. There is no simple or practical option available, at least in my view, other than to try a different apparatus which shows gentle but thorough mixing and stirring environment.

Another important thing to consider is that one cannot develop a method using a product that is still under development (see link). One has to have a reference product with known drug dissolution characteristics which unfortunately is not available at present.

In the absence of such a reference product, one may consider developing a method based on an approach of relative dissolution testing (as explained here).

In short, therefore, one needs to develop a bio-relevant dissolution test which by default will be discriminatory. The choice of experimental conditions should be based on the physiological environment. The experimental conditions should be established using well-established products for human use and must not be based on a product that is under development.

As a starting point, the following may be considered: water as a medium (900 mL), with or without a solubilizer, maintained at 37 °C with a gentle but thorough stirring and mixing, perhaps using the crescent-shape spindle or another similar approach.

Links to two other articles which you may find helpful as well (article1, article2)

As described in one of my earlier posts, one can easily perform an analytical method validation by spiking the dissolution medium using a solution of a drug (API, link). The suggested approach is scientifically correct and valid. However, I do see where dissolution scientists, in general, will face difficulties. Let me explain:

Suppose an analyst follows the suggestion made and obtains a %RSD of “X” for the method (say less than 5) and the analyst is happy with it. Then, the analyst proceeds to the next step, test the tablets, and gets a %RSD of “Y”.  Under normal circumstances, this will reflect the %RSD of the product, including %RSD of the method. Usually, there are no concerns as this value of “Y” often comes out acceptable, between 5 and 10.

However, dissolution testing, particularly using paddle/basket, faces a unique problem, that it introduces one additional variability component, which is very well documented in the literature. This is because of the positioning effect of the tablet/capsule i.e., where it settles at the bottom of the vessel (link1, link2, link3). Unfortunately, people do not realize how such a minor variation can cause a big problem, but it does. As one cannot control this positioning effect, one cannot control variability due to this effect. It is totally random. The contribution from this random effect is reported to produce very high RSD, up to 37% (link). So, when it is asked what should be the expected variability for drug dissolution testing of a product, a safe bet/estimate is 37%. A product may have excellent repeatability/reproducibility of its drug dissolution characteristics (with extremely low %RSD). However, dissolution results may or may not reflect this low variability.

It is just like any other biased but random phenomenon, where one may or may not succeed. However, one always sees advertisements of some examples of big winnings/successes. In dissolution terminology, one may observe some low %RSD values at random, but overall variability using paddle/basket apparatuses will always be high. There are many publications available describing this high variability aspect, which may be useful. In addition, some posts may also be useful in this regard e.g., see link.

It is often noted that drug dissolution results fail to reflect the in vivo behavior of a product, i.e., lack of relationship to bioequivalence of two test products. Therefore, it is usually inquired as to how one should explain the lack of relevance and/or how to address this issue.

There could be a number of potential causes for such a problem (lack of bio-relevance). In addition, the problem could only be related to the specific product. In such cases, it is difficult for others to provide suggestions without knowing the details about the formulation of the product, which are often not available because of the proprietary nature of the information. Therefore, it is almost impossible that one can obtain a direct and/or a correct suggestion to address the problem. The formulator should be aware that he/she might obtain completely unrelated suggestions that may waste a lot of time. Keeping these thoughts in mind, a few very general suggestions are provided here, which may be helpful in such situations.

There are usually two potential outcomes in such situations (lack of bio-relevance) (1) in vitro dissolution tests show different (the so called “discriminatory”) results, but the in vivo results are similar (2) in vitro dissolution test show similar results, but the in vivo results are not similar i.e. bio-in-equivalent.

In the first scenario, the most likely cause is that the test may have been conducted using much softer conditions (in particular, related to stirring/mixing) under the “requirements” of obtaining “discriminatory” results. For example, if the formulations of the two products are such that one hides the drug (API) better than the other at the bottom of the vessel then one will observe different in vitro dissolution results, but most likely similar in vivo results. Drugs with low aqueous solubility and/or of low content would show such a problem. This is the most commonly observed issue with the use of paddle/basket apparatuses as these provide poor, and/or lack of, stirring and mixing required. Commonly such tests are referred to as “overly discriminatory”. However, in reality these tests are incorrect tests, mostly because of the incorrect choice of a dissolution apparatus.

In the second scenario, the most likely cause would be of chemical nature, such as an interaction between a drug and an excipient. It is possible that during dissolution testing, a complex has been formed or dissociated, with much higher solubility, which may not be the case in vivo. The likely suspect, in this case, maybe the pH of the medium. One should make sure that the pH of the medium has not been inadvertently increased as this will certainly cause this problem (use of larger amounts of SLS may be a prime suspect here). Some focus on the chemistry aspect of the product (drug excipient interaction) would be very helpful.

The next consideration should be given to the use of the paddle/basket apparatuses themselves. If possible, avoid using these apparatuses as these can be the main cause of the problem. Even if you are going to try the suggestions provided above, the use of a paddle/basket may hinder in establishing the cause of the problem. Consider using an apparatus that will provide efficient and reproducible mixing and stirring.