Author: Dr. Saeed Qureshi, Ph.D.

In a recent article, titled “Stage Appropriate Dissolution Methods in Formulation Development,” published in the above-mentioned journal, the author presented a view as to how dissolution method requirements change as a project advances in time (link). Unfortunately, not only is this view logically flawed but scientifically invalid as well.

A dissolution method is used to estimate drug release characteristics of a product, mostly tablets, and capsules. Therefore, by definition, a method just like any other scale or measuring method (thermometer, weighing scale, density, etc.) must remain constant. A product, or stage, dependent scale/method will be considered scientifically invalid for this reason.

Further, during the product development stage, a dissolution method is used for evaluating the impact of different variables (formulation and/or manufacturing) so that a product with appropriate drug release characteristics is developed. Therefore, again, a constant method is required during the product development exercise. If the suggestion is to keep changing the methods (scales) at every stage, then one wonders how one would establish dissolution characteristics/rate of a product or any product. For a more detailed explanation and discussion on the topic, please follow the links:

(1)    Limitations of Some Commonly Described Practices in Drug Dissolution Testing and Suggestions to Address These. (link).

(2)    Blog (link)

In my view, the author had provided information that is not scientifically valid and would not help develop useful dissolution methods.

Note: This post has been shared with the author of the article, who provided the following response which is greatly appreciated. Also, I took the opportunity to introduce Dr. Hawley to the newly suggested crescent shape spindle which may help develop a “universal” dissolution tester. Saeed

I appreciate the thoughtful comments above, and especially the opportunity to respond to them.  However, I do disagree that the article we published was logically flawed and scientifically invalid.  The crux of the argument above is that the dissolution method should be an invariant test which is representative of the in-vivo system.  This method should remain in place throughout the product’s development from pre-clinical studies to commercial.  As such, it acts as an absolute arbiter of the performance of the formulations developed.  I have been extremely fortunate to work with many excellent scientists in industry in my career.  Unfortunately, I have not yet met any who have been able to easily identify a dissolution method to unfailingly predict the drug release characteristics of any drug product early in development.  If we could, I would agree with the critique above, this article would not need to have been written, and I would use this defined dissolution method without alteration through development.

In the course of developing a drug product however, we go through several phases.  In the early stage, when there is a large likelihood that the project will fail, we preserve our resource and may use something simple such as intrinsic dissolution or disintegration to assess the performance of our drug product.  Admittedly crude, yes; not really representative of the in-vivo situation, yes also.  However, these tests can identify critical flaws in the formulation approach which would impede the success of the clinical study, which is the real goal for the project.  Later on, we may have a totally different formulation approach as, for example, we move from a powder in capsule dosage form to a tablet.  If we had infinite resource to invest early on, we could develop the understanding to come up with a decent, representative method at this time.  However, I do not think that is wise deployment of either formulation or analytical resources.  Instead, much as many other analytical assays, as we progress the project, we learn and we revise our methods to enable us to measure the properties we are interested in.  As the project team comes closer to defining a formulation, we do lock in our dissolution method as soon as it is practical.  This paper was written to show what kinds of considerations should be taken into account when going through this process.

The purpose of this paper was really to discuss how to use different dissolution tests methods (rotating disk dissolution, USP Dissolution, multi-compartment dissolution) at different periods of the product development cycle to understand the mechanism by which the formulation works in order to design a better formulation (and we would argue – a better, final dissolution method).  The clinical model is the true unwavering test that we all need to perform against and that is the standard by which the performance of our formulations are really measured, not by the in-vitro assay.  When we reach the state where we have the ability to develop a representative dissolution method using little time, little resource and little API early in development, I will happily agree with the statements above and follow the protocol prescribed above.  Until then, however, I respectfully dissent.

Michael Hawley, Ph.D.

It is important to note that, by definition, a drug dissolution test has to be a bio relevant test. A non-bio relevant dissolution test is just like a non-bio-relevant thermometer or non-bio relevant pair of eyeglasses i.e. such things have no practical use or purpose. However, unfortunately, in the pharmaceutical area, in particular for oral (tablet/capsule) products, not only does such non-biorelevant testing exist (e.g. pharmacopeial) but it is the norm, strongly promoted and defended, which causes enormous confusion and financial losses.

The reason for this confusion is that non-biorelevant methods are presented as biorelevant and in fancy wrappings, or with catchy phrases, e.g. the one mentioned in the title (“biorelevant performance testing”) or by confusing with other names such as BCS, IVIVC, bio-waivers,  f2, QbD etc. In reality, the issue is not how dissolution testing is presented and described, but rather how the tests are conducted and evaluated.

For example: (1) the apparatuses currently used, even those recommended by regulatory authorities, have never been qualified and/or validated for dissolution testing purposes. In fact, it has been shown many times that the apparatuses provide irrelevant and unreliable results; (2) recommended experimental conditions are mostly selected arbitrarily lacking physiological or scientific rationale; (3) tests are conducted using product-specific (i.e., not product independent) procedures or experimental conditions thus results obtained are biased and cannot relate to the actual quality of a product; (4) there are no existing criteria or standards available which could be used to relate dissolution results for product quality. That is, no procedure is available to set physiologically relevant tolerances with scientific or statistical relevancy or credibility. For further details, see here.

In conclusion, if dissolution results have been obtained using traditional approaches/methods, then their interpretation and usefulness will be of questionable merit at best.

It is generally accepted that for a drug to be absorbed from the human gastrointestinal (GI) tract, it should be in a solution form established based on the drug’s solubility/dissolution characteristics. This in vivo dissolution is determined using in vitro drug dissolution tests.

It is also generally accepted that the higher the solubility of the drug, the higher the dissolution and absorption, and their corresponding rates, will be.  In addition, it is also a well-established fact that absorption preferentially occurs from the non-polar or undissociated form of a drug. On the other hand, the undissociated, or non-polar moiety, of a drug often shows lesser aqueous solubility compared to its polar version.

For example, propranolol is a basic drug with a pKa value of 9.42 and its aqueous solubility is 61.7 mg/L or 1 part in ~16,000 (link). Therefore, propranolol should be considered to be a low solubility drug. However, its products are usually manufactured using the drug in its hydrochloride salt form,i.e., propranolol·HCl, which is freely or highly soluble in water. It would exist in its ionic/protonated form in water, which would be less absorbable than the native propranolol. On the other hand, propranolol is known to be highly absorbable/permeable (bioavailability higher than 90%), which suggests that in reality, the body sees propranolol as non-polar/undissociated moiety. Therefore, for in vivo dissolution/absorption purposes, the solubility of native propranolol should be considered, not of its salt form. This means that in reality, propranolol (and other similar drugs) is a BCS class II drug and not the class I drug, as commonly considered.

In conclusion, for drug dissolution and absorption evaluation purposes, one should consider solubility characteristics of a drug in its native form and not that of its salt form. For further discussion on the topic, the following links would be useful (1, 2, 3, and 4).

Drug dissolution tests are routinely conducted to evaluate drug release characteristics of pharmaceutical products such as tablets and capsules. These tests should be conducted to reflect in vivo drug release, which in turn is reflected by the observed plasma drug conc.-time (C-t) profiles in humans.

In this regard, a simple convolution-based method using spreadsheet software has been suggested to convert dissolution results into C-t profiles (link1, link2). This article provides another example describing the estimation of plasma drug levels from OROS-based nifedipine products using the suggested convolution approach.

Please click here for the complete article

There are about 500+ dissolution methods listed in the FDA database and about 600+ methods (monographs) in the USP. In addition to these, there are many more, perhaps in the hundreds, dissolution methods described in the literature. Moreover, as part of new product development exercises, it is a common and expected practice to develop additional new or revised methods.

It may be interesting to note that the objective of drug dissolution testing has never been to develop methods but to determine/estimate drug dissolution/release characteristics of products. By developing drug and/or product-specific dissolution tests, one, in fact, would never know or determine the actual dissolution characteristics of any product. The current practices of method development simply defeat the purpose of products evaluation.

For products evaluation, one requires a test/method which is independently developed and established. Therefore, current practices of method developments are scientifically invalid and useless and a waste of time and resources.

Using the crescent shape spindle with a common set of experimental conditions is suggested to address the current difficulties. The suggested approach practically eliminates the need for method developments, particularly product dependent, and provides a scientifically sound and valid drug dissolution testing and product evaluation approach (e.g., see link, link2).

The following links may be useful for further information regarding the difficulties of the current practices:

• Drug Dissolution Testing – A serious concern! (link)
• Costly mistake formulators/analysts often make, i.e., developing a product dependent dissolution test (link)
• Selecting a Dissolution Apparatus – Some Practical Considerations (link).
• (Developing) a discriminatory vs. bio-relevant test (link)
• Method Validation: A Unique Problem Concerning the Drug Dissolution Testing (link)
• Where does 20% of the drug go? (link)
• Dissolution method development – a practice that causes confusion and hinders in product evaluation. (link)
• Drug Dissolution Testing Mosaic. (link)
• Product dependent dissolution testing – a scientifically invalid practice. (link)
• How to conduct a dissolution test? A simple question but confusing answers. (link)
• An incorrect reason for developing and conducting a dissolution test. (link)
• Method development practices: Are these achieving their intended purpose? (link)
• Dissolution method development – what it is not! (link)
• Generics and discriminatory dissolution tests (link)
• Validation (Method/Apparatus) Practices (link).
• Selecting an apparatus and its associated experimental conditions for testing (link).
• The science of drug dissolution testing: Testers or apparatuses, experimental conditions, and interpretation of results – A systematic approach for learning (link)

Developing an IVIVC and its applications are often described in the literature as follows (e.g., see link):

“In vitro – in vivo correlation (IVIVC) allows prediction of the in vivo performance of a drug based on the in vitro drug release profiles. To develop an IVIVC, the physicochemical and biopharmaceutical properties of the drug and the physiological environment in the body must be considered. Key factors include drug solubility, pKa, drug permeability, octanol-water partition coefficient, and pH of the environment.”

There is a number of deficiencies in the description mentioned above. For example:

• “in vivo performance of the drug,” IVIVC studies are commonly conducted for products (such as tablets and capsules) and not for drugs.
• An IVIVC does not allow the prediction of in vivo performances from in vitro results. Therefore, in vitro studies (testing) are conducted based on the assumption that the IVIVC already exists.
• Furthermore, considering the existence of IVIVC, in vitro (dissolution) results are used to reflect or predict expected plasma drug concentration-time profiles.
• The mathematical approach used to predict plasma concentration-time profiles is not the IVIVC but the convolution technique. This (convolution) is the only technique that can be used or applied for the prediction of plasma drug profiles of products.
• The parameters mentioned above such as, drug solubility, pKa, drug permeability, and octanol-water partition coefficient, are all drug characteristics and not those of the products for which dissolution tests are conducted. Therefore, these parameters often remain constant or are kept constant to evaluate the impact of formulation and/or manufacturing attributes on the release/dissolution characteristics of a product.
• Regarding the “pH of the environment”, this is linked to GI tract physiology and is independent of the drugs and products. Thus for drug dissolution testing, the environment must also remain constant and independent of products and/or drugs.

Therefore, the IVIVCs as currently conducted or promoted are not of any practical use and can easily be ignored or avoided.

Drug dissolution tests are conducted to determine the dissolution/release characteristics of a product. Therefore, one requires a pre-established set of experimental conditions (apparatus, rpm, medium volume or pH, etc.) independent of the product to determine the actual or true characteristics (i.e. dissolution).

However, current practices, in particular using paddle and basket apparatuses, require that the analyst MUST first know, or anticipate, dissolution characteristics of the test product and then ADJUST experimental conditions to achieve the desired or anticipated results. As dissolution method development practices, selections or adjustments of such experimental conditions are then described or promoted incorrectly. Almost every product came with its own set of experimental conditions and expected dissolution results (commonly referred to as Tolerances). At present, one cannot know or determine the actual or true dissolution characteristics of the products. It is, therefore, very important and critical to note that current practices of dissolution testing are practically a complete waste of time and resources.

The suggestion of dissolution testing using the crescent-shaped spindle, along with a single set of experimental conditions (which are product independent as well) addresses the current issues and provides a simple, practical, and scientifically valid approach for dissolution testing. For further detail, please see these links (1, 2, 3).

It is important to note that drug dissolution tests are conducted for products (tablets/capsules) and not for drugs (APIs). Therefore, it is not accurate to use or develop drug-specific experimental conditions as commonly reported.

On the other hand, drug dissolution characteristics are mostly dependent on the formulation and manufacturing attributes of a product, i.e., a dissolution test is conducted to evaluate the impact of formulation and manufacturing. Therefore, for determining the dissolution characteristics of a product, the test must be independent of the formulation and manufacturing characteristics of the product under consideration. This means that one is required to use a pre-established dissolution test independent of the product under consideration. Developing a dissolution test for a product, which is being developed, and then using it to show its own dissolution characteristics, as currently done, is obviously a scientifically invalid practice.

Furthermore, it is to be noted that dissolution medium and other experimental conditions are linked to the physiology of the human GI tract, which remains constant, and also drug and product independent. Therefore, if one uses drug/product-dependent experimental conditions, then this will make a dissolution test bio irrelevant and product evaluation pretty much useless, even for QC purposes. The following link may be of further help in this regard (link).

Recently I participated in a discussion on a LinkedIn forum (Quality by Design or QbD) explaining the relevance and the critical importance of drug dissolution testing for QbD, manufacturing of the products (tablet/capsules), and their evaluations.

Continuing on the topic, I believe a better organized explanation may be useful in clarifying issues related to the assessment of the quality of pharmaceutical products. This article provides the explanation. It is important to note that the following discussion is restricted to tablet and capsule products only. Please click here for the complete article

It is commonly accepted, and as described in one of the FDA guidance documents (link), that “For highly water-soluble (BCS classes 1 and 3) immediate-release products using currently available excipients and manufacturing technology, an IVIVC may not be possible.” i.e., a relationship may not exist between in vitro dissolution and in vivo dissolution. So then, the obvious question is why one should use the dissolution test to evaluate such products, even for quality control purposes? The purpose of a QC test is to indicate the potential deviation of in vivo drug release characteristics. However, if the assumption/view is that the relationship between in vitro and in vivo behavior does not exist, what is the use of such a QC test, particularly for IR products with highly soluble drugs.  

The reality is that the relationship between in vitro and in vivo dissolution always exists, which forms the basis for drug dissolution testing. However, the way drug dissolution tests are conducted at present, using commonly recommended apparatuses, particularly paddle and basket, does not measure the dissolution properties accurately and reproducibly, which is reflected/considered as a lack of in vitro-in vivo relationship. In addition, dissolution studies were never intended to develop or establish IVIVC but to use the relationship to predict plasma drug levels.

In this regard, if one uses a modified apparatus, such as with the crescent shape spindle, which provides appropriate product/medium interaction, then the dissolution tests can generate in vivo relevant results, as expected. For further details on conducting appropriate dissolution studies and in predicting blood levels, please see the links (1, 2).