Author: Dr. Saeed Qureshi, Ph.D.

For further details, please see the following links:

1. A Simple and Unique Approach for Developing and Evaluating Products (link)
2. Assay and Content Uniformity (CU) based on dissolution testing (Poster Presentation). (link)

Some more relevant links:

• The science of drug dissolution testing: Testers or apparatuses, experimental conditions, and interpretation of results – A systematic approach for learning. (link)
• Selecting a Dissolution Apparatus – Some Practical Considerations. (link)
• Drug Dissolution Testing Using Simple and Common Experimental Conditions (link)
• One Step (Product Evaluation) Approach (link)
• Can a dissolution test be used for assay and content uniformity testing? Of course! (link)

An In-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as “a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response.” For pharmaceutical products (tablets and capsules in particular) development purposes, in-vitro property and in vivo response mean in vitro drug dissolution/release characteristics and the plasma drug concentration profiles, respectively.

It is important to note that this relationship, or model, always exists between the two variables (dissolution vs plasma profile) for a given drug, which forms the basis for in vitro dissolution testing and its use to assess the quality of pharmaceutical products. Therefore, developing this relationship or modeling should have never been part of the practice of drug dissolution testing or its applications for products development or evaluation. However, this is precisely what has happened during the past two decades, i.e., repeated recommendations were made for correlating dissolution results with plasma drug levels. In fact, such developments have been suggested as regulatory requirements.

A quick review of the literature will clearly show that the exercises of developing IVIVC have never been successful. Obviously, the first question would then be why has the development of IVIVC not been successful when it always exists, as stated above? One of the main reasons for such a lack of success is the choice of experimental conditions, particularly dissolution testers. The recommended dissolution testers, particularly paddle and basket, have never been shown to provide in vivo (or bio-) relevant results. That is, these apparatuses have never been qualified and validated for their intended purpose. There are reports describing that these testers cannot provide bio-relevant dissolution results. Therefore, these recommended apparatuses should have never been suggested and used for IVIVC developments. On the other hand, sporadic claims of successes of IVIVC are usually based on adjusting dissolution experimental conditions to reflect in vivo results, which by definition are not IVIVC but matching of in vitro-in vivo results, with no predictability potential. Therefore, it is often difficult to accept, but the fact remains that the current practice of IVIVC development has been a futile exercise.

The second issue with the current practice of IVIVC is that it does not predict plasma drug concentrations/profiles, which has been the promoted objective of IVIVC. As noted above, it is an approach for describing a relationship between dissolution and plasma drug profiles, but not for predicting plasma drug profiles from dissolution results. However, the latter has been assumed, unfortunately incorrectly.

It is important to note that the only objective of conducting a dissolution test is to estimate/predict plasma drug levels/profiles from dissolution results. In particular, at the product development stage, a formulator would like to estimate in vivo behavior of a test product/formulation based on drug dissolution results. This can only be achieved by combining the dissolution results of the product with the pharmacokinetic characteristics of the drug (usually available from literature). The process of combining dissolution results and pharmacokinetic parameters is known as the convolution method/technique. Thus, there is no need for developing IVIVC if the objective is to estimate/predict plasma drug levels, which indeed it is.

In short, to predict/estimate plasma drugs levels from dissolution results, one does not require IVIVC or deconvolution approach, but the convolution. Therefore, the requirement or current practice may be considered as a futile exercise, which can easily be discontinued. In addition, even for the success of the convolution approach, one would require properly qualified dissolution apparatuses, certainly, paddle and basket apparatuses in this regard are to be avoided.

To address the above-described issues, the following two suggestions have been made:

• A modified apparatus; based on currently used vessel-based apparatuses, but with a modified stirrer, known as crescent shape spindle.
• A simple convolution-based approach using Excel spreadsheet software to determine plasma drug levels from drug dissolution results.

For further details in this regard, the following links would be helpful:

1. In Vitro-In Vivo Correlation (IVIVC) and Determining Drug Concentrations in Blood from Dissolution Testing – A Simple and Practical Approach. (link)
2. Determining blood concentration-time (C-t) profiles from in vitro dissolution results and product evaluation – carbamazepine. (link)
3. A New Crescent-shaped Spindle for Drug Dissolution Testing—But Why a New Spindle? (link)

Presently, only the use of the crescent shape spindle provides true dissolution characteristics of a product (link)

It is often suggested that it must first be validated to use an apparatus (or method) for dissolution testing. There is nothing wrong with this statement or requirement. One should follow this requirement.

The question, however, is how one should validate a dissolution apparatus? This is where the problem is! In principle, validation means establishing that an apparatus is capable of measuring required characteristics. Here capability means the ability to measure relevant dissolution characteristics or results.

In the case of current practices of dissolution testing, however, there is an interesting twist in the validation requirement. Here, promoted validation means obtaining dissolution results similar to those obtained using one of the compendial apparatuses, particularly paddle or basket apparatus. It is important to note that the requirement is not that of relevant and/or reproducible results, but the similarity of results obtained using compendial apparatuses (read similar practices with vibration and de-aerations aspects). This would have been acceptable if compendial apparatuses were validated themselves against some relevant reference product or value. Unfortunately, the compendial apparatuses have never been validated. In fact, these apparatuses have been shown repeatedly to provide irrelevant and irreproducible results. As per current practices or requirements, any new or different apparatus also become non-validated, by default, if it provides similar results as those of the compendial apparatuses. Therefore, current recommendations require developing and using non-validated apparatuses and methods.

Not only are the current requirements and practices scientifically invalid, they also create serious hindrances in developing new and improved apparatuses and methods. For example:

(1) Current recommendations will allow using only those apparatuses that will be as bad as the current ones known to be flawed (particularly paddle and basket).

(2) In reality, the requirement/practice will not allow using any comparable method as it will be argued that if one obtains similar results using current apparatuses, then why introduce new variations. In fact, it is a clever way of maintaining the status quo or the use of flawed apparatuses and methods.

(3) It is very important to note that any new or improved apparatuses will have to provide different results, which will be the only reason for their development or use. However, considering the current mindset, these improved variations will be considered non-validated as the results obtained will be different than the ones obtained using currently recommended approaches. Therefore, improved apparatuses (or methods) would be rejected against current practices.

The implication of the above-mentioned practices may be explained as follows: Suppose someone would like to develop a physiologically or bio-relevant apparatus. Such an apparatus would be based on simulating the physiological environment. As the physiological environment is product independent and consistent across products (e.g. IR and ER), the new and improved method will be based on a single set of product independent experimental conditions. However, current requirements promote and stress product-dependent experimental conditions. Therefore, if one will compare results based on current requirements with those obtained with an improved method, those will not be equivalent or comparable. Therefore, the results obtained will be considered non-validated and will be rejected (even those obtained using an improved method simulating the physiological environment). Therefore, if current promoted validation practices continue, there is a limited chance of developing an improved and physiologically relevant dissolution method, apparatuses or obtaining dissolution results.

The only option available to develop physiologically or bio-relevant and reproducible apparatuses and/or methods is to validate these against their intended purpose and not against results obtained using arbitrarily selected apparatuses, methods and experimental conditions.

In conclusion, one should be watchful of current validation recommendations and requirements. These requirements are logically and scientifically invalid. The validation should be performed against the intended objective and not by comparing results obtained from non-validated or irrelevant apparatuses and/or using arbitrary experimental conditions.

Before using any tester, it is commonly understood and often, in fact, is a requirement to establish that the tester is capable of measuring the expected parameter or characteristics. For example, before its use, the apparatus or tester must be shown to provide appropriate dissolution characteristics (i.e., percent drug dissolution at times) of a pharmaceutical product. There are different ways of saying the same thing, for example:

The tester can measure the dissolution characteristics with the required precision; the tester is fit for its intended purpose, or the tester is qualified and validated for its intended purpose.

A usual practice for establishing a tester’s “fit-for-purpose” or performance would be determining a reference product’s dissolution characteristics with its associated precision. If the tester provides the dissolution value with the required precision, then the tester will be considered qualified and validated.

One of the critical requirements for the reference product would be that it must be directly linked to the products the tester will be used for. This reference product must be a drug product (tablet/capsule) for human use with a known dissolution value because this is what the tester will be used for, i.e., evaluating products for human use. If one does not have such a (reference) product, one cannot establish the tester’s performance. Thus, it cannot be used to determine a product’s dissolution characteristics, hence its quality.

As no reference product is available with known dissolution characteristics, one cannot check/establish the performance of any of the dissolution testers. Therefore, the testers should not be considered as qualified and validated dissolution testers. Hence, results obtained using these testers/apparatuses should not be considered valid for the assessment of any product, new or old.

The USP promotes its prednisone tablets as performance verification tablets (PVT) for two apparatuses, paddle/basket. As described above, in the true sense of the requirements, these tablets cannot be considered PVT because they neither represent a product for human use nor have known dissolution characteristics. The dissolution values reported for the USP PVT are arbitrary because the same product cannot have two or more sets of values for the same parameter. It is like saying one can have multiple solubility values of a compound depending on how it is measured (e.g., using a beaker with a laboratory stirrer, an Erlenmeyer flask with a magnetic stirrer, or using a top-loading shaker, etc.). Obviously, it will not be accurate because the solubility of a compound is the property of the compound and should be independent of the method used to measure it.

On the other hand, there are no PVT/tablets available for other commonly suggested apparatuses (USP 3 and USP 4). Therefore, no mechanism is available to establish the validity of claims for these to be considered as (qualified and validated) dissolution testers.

With an apparent twist in defining and practice of PVT, USP promotes the use of these tablets for monitoring the appropriateness of de-aeration of dissolution media, establishing a vibration-free environment of a dissolution tester and its surroundings and/or overall establishing “fitness” of the testers/analysts. Unfortunately, these are not legitimate claims and may be considered as scientifically invalid or useless, as explained below with an analogy.

In seeking the source of the lack of stability of results from a laboratory balance, one might consider that the instability issue may be due to instability of the laboratory environment, such as room temperature and/or airflow within a laboratory. To monitor the stability (or lack) of laboratory environment, the laboratory balance itself be used as a monitor by weighing a Styrofoam-based piece (say a tablet). Note, by its very nature, Styrofoam material, due to its lightness, will add to the variability.  The question would be; why is the performance of a balance to be monitored using a Styrofoam tablet and not using the reference weight itself? What is the link between the Styrofoam tablet, room temperature and airflow? If the issue is the instability of room temperature and/or airflow, then these should be measured using their own respective meters or instruments; how does the balance become the monitor of these variables?

This is precisely the situation with PVT for paddle and basket, in that they are being suggested for monitoring stability or “fitness” of the dissolution media and/or vibration-free laboratory environment. This is simply not a logical or scientific practice. The reality is that, at present, these are made-up reasons for calibration or performance verifications that have no relation to assessing or validating a dissolution apparatus/tester. The fact is that these testers are neither stable nor relevant for drug dissolution testing, and unfortunately, attention has been diverted to promoting useless practices rather than fixing the problem.

In short, as of now, used dissolution testers are not qualified and validated dissolution testers. Their qualification and validation can only be performed using a reference product with known dissolution characteristics, which is not currently available.

In the interim, one may qualify and validate the testers using a relative dissolution testing approach. Relative dissolution testing refers to evaluating two products (approved for human use), one IR and the other ER, having the same drug using the same experimental conditions. Using the tester and experimental conditions to provide the dissolution characteristics reflective of the drug’s bio behavior (bioavailability/bioequivalence) in humans. Such a tester would be considered an appropriate tester. They should be used to evaluate the test products using the same experimental conditions.  For further detail and explanation, the following links may be of help:

(1)    Apparatus Calibration or Performance Verification: Misleading Conclusions and False Comfort (link)

(2)    MQ (Mechanical Qualification) vs PVT (Performance Verification Testing) which one to choose and why? (link)

(3)    Two-Tier System for Setting Tolerances – (PVT vs Products) (link)

(4)    PVT (Performance Verification Test) – Difficulties and a suggestion to address those (link)

(5)    The issue of validation/qualification of dissolution apparatuses (link)

To establish the quality of a product or bio-relevancy of dissolution results, obviously, one first has to determine the dissolution characteristics of the product. To determine relevant dissolution results, one is required to have an agreeable or validated dissolution method (tester and experimental conditions).  The difficulty is that, at present, one does not have an agreeable or validated dissolution method or tester. Thus one cannot determine dissolution characteristics of a, or any, product as a result of its quality and/or bio-relevancy.

At present, people are trying to develop a dissolution method for the test product. However, it is impossible to develop a method using a product that is under development or evaluation. Therefore, a (dissolution) method can only be developed using a product of known or agreeable dissolution characteristics (i.e., a reference product).

It is important to note that the current practices of method development for dissolution testing are not at all method development practices as one does not have a reference product with known dissolution characteristics. On the other hand, one cannot determine the dissolution characteristics of any product, as one does not have a validated dissolution method or tester. Therefore, it is not possible to evaluate the quality of the product and/or the relevancy of dissolution results to in vivo results.

The current practice of drug dissolution testing often implies the development of dissolution methods rather than determining dissolution characteristics of the test product. There are hundreds, if not thousands, of dissolution methods available in the literature, not only drug/product specific but also application-specific (QC, bio-relevant, IVIVC, etc.). The important point is that there is a serious (flawed) mindset as people develop dissolution methods by assuming or expecting, a priori, dissolution characteristics of the product rather than using a dissolution method to determine the product’s dissolution characteristics. Therefore, it is very important to note that using the current dissolution testing practices or thinking one never determines dissolution characteristics.

Another way of saying the same is that the development of a dissolution method and the use/application of a dissolution method for the assessment of the quality of a product or its bio-relevancy are mutually exclusive exercises. They cannot be done together. Suppose one is using a dissolution method to develop a product or evaluate its characteristics (most common use of dissolution testing). In that case, one cannot develop a dissolution method at the same time. The validated dissolution method must be available a priori and independent of the product under consideration. People who are involved in such exercises (product development and evaluation) should pay attention to the current scientifically invalid practices.

For further discussion on the topic and potential solutions to such difficulties, the following link may help.

(1)    Why are current practices of dissolution testing so confusing, frustrating, and complex? Because they are not based on scientific principles but rituals! (link)

(2)    Assessing drug dissolution characteristics using product-dependent methods is simply unscientific and invalid practice. (link)

(3)    Dissolution method development: Perhaps the most wasteful of all the current practices! (link)

(4)    Worth repeating it: Drug and/or product-dependent dissolution tests are scientifically invalid. They do not provide dissolution characteristics of products even for QC purposes. (link)

(5)    A simple approach to assess the validity of a dissolution tester/method (link)

(6)    Drug dissolution testing: Limitations of current practices and requirements (link)

(7)    Presently, only the use of the crescent shape spindle provides true dissolution characteristics of a product (link)

(8)    The science of drug dissolution testing: Testers or apparatuses, experimental conditions and interpretation of results – A systematic approach for learning (link)

(9)    Selecting a Dissolution Apparatus – Some Practical Considerations (link)

(10)  A Simple and Unique Approach for Developing and Evaluating Products (link)

A common query regarding drug dissolution testing is; how should I (scientist or analyst) get desired dissolution characteristics? The desired characteristics mean (1) slower or faster dissolution results than observed; (2) discriminatory profiles; (3) bio-relevant or IVIVC results (4) QC- or batch-to-batch testing criteria, etc. Often, such a question is not directly but indirectly as to how I (scientist or analyst) should develop a dissolution method for my product, implying how to achieve a desired/expected dissolution characteristic of the product. It would be interesting to note that dissolution tests are conducted to evaluate impact of formulation/manufacturing on the drug release characteristics. Often the questioner does not provide (or cannot, because of confidential/proprietary reasons) the formulation/manufacturing attributes of the product. Then, how would someone be able to provide an appropriate response to such a question?

On the other hand, even without knowing the formulation/manufacturing attributes, people provide endless suggestions/recommendations of trying different experimental conditions (apparatuses, dissolution media, stirring speeds etc.) to achieve what a scientist or analyst is trying to achieve, i.e. desired dissolution results. How can such advice be considered valid or relevant? Unfortunately, the current mindset is to provide advice after advice as to how to conduct dissolution tests – more appropriately how to play with experimental conditions to achieve certain desired dissolution results.

The purpose of dissolution testing and the queries is obvious that the scientists/analysts would like to know dissolution characteristics of a product and not the available choices of experimental conditions.  Therefore, providing advice about selecting or playing with experimental conditions for dissolution testing, in particular product dependent, is clearly inaccurate and false help. One should be aware of such practices, which may cause serious loss of time and resources.

To determine the value of a parameter/property, including dissolution, one requires a well-established and validated tester and method. Unfortunately, none of the apparatuses described, including the associated methods (experimental conditions), are qualified and/or validated for the intended purposes i.e. to determine dissolution characteristics. Therefore, advice for conducting dissolution testing based on currently recommended apparatuses and/or experimental conditions becomes even more strange and a self-deceiving exercise. One should be extremely cautious in following such “help” or “advice.”

To conduct a dissolution test i.e. to evaluate dissolution characteristics of a product, one requires a common, and product-independent set of experimental conditions. The crescent shape spindle and associated experimental conditions have been suggested to address the difficulties and flaws of the current practices, thus providing an option for appropriate evaluation of dissolution characteristics of products.

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.