Author: Dr. Saeed Qureshi, Ph.D.

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:

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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:

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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.

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Suppose someone is given an assignment to obtain/extract propranolol (PL) from a mixture of microcrystalline cellulose (MC) and a propranolol·HCl (PL·HCl). In a sense, it will be a fractional extraction procedure where one would exploit differences in these two compounds’ chemical or physical nature. The first difference one observes will be their aqueous solubilities; MC is not soluble in water, but PL·HCl is. So, one can separate PL·HCl from MC by simply adding some water and filtering it. The PL·HCl will remain in solution form, but MC will be separated out as a precipitate.  However, PL will still be in its hydrochloride form. To extract the PL, one may require a liquid-liquid extraction step. In this regard, one first needs to adjust the pH of the aqueous solution so that the HCl part can be neutralized and PL·HCl should be available as PL, which could then be extracted with an organic solvent (e.g., hexane or dichloromethane).  Adding some alkaline solution to the PL solution will increase the pH of the solution to a much higher level, e.g., pH 12. Most of the PL will now be in undissociated form and can be extracted into the organic phase. One or two extraction repeats will transfer PL into the organic phase, which may be removed by evaporation, leaving behind pure PL in its native or basic form.

On the other hand, if one is unable to increase the pH of the solution to 12 to avoid potential complications, then a lower pH may be used. Then, the same extraction step can be used. However, one would require an increased number of extraction repeats to complete PL extraction from the aqueous solution. The end result will be the same i.e. complete extraction of PL form in its native or basic form in the organic solvent.

It is important to note that one can also perform the above-described extraction in one step (i.e. without separating MC by filtration first). In this case, adding some milder buffer having a pH around 7 to the mixture, to avoid any complications of higher pH with MC.

Now let us assume that this extraction process of PL is to occur in the intestinal tube rather than in a glass test tube, as explained above. The content of the intestinal tube is at a pH between 5 and 7 and contains multiple endogenous and exogenous compounds, including PL and MC. The organic phase for the test tube experiment is replaced with the lipid layers of the intestinal tube walls. When the undissociated PL comes into contact with the intestinal tube’s lipid part, it will get absorbed or extracted. This process will occur almost an infinite number of times (considering the vast surface area of the intestines). Once PL, or any other drug, gets absorbed, it will be transferred to the bloodstream.

This process of liquid-liquid drug extraction is commonly referred to as absorption of drugs in humans by passive diffusion. However, the process in both cases (in vitro vs in vivo) is almost the same, if not exactly the same. It is worth remembering that most drugs absorbed through the GI tract occur through a passive diffusion process.

This means that when someone takes a solid oral product (tablet and capsule), the drug must first come out of the product and then dissolve as a non-polar (undissociated) drug in the intestinal fluid. The drug does not have to be completely dissolved but to the extent that the continuous process of extraction/absorption occurs efficiently and sufficiently within the intestine.

In conclusion, drug absorption occurs as a liquid-liquid extraction process for which dissolution of the drug within the GI tract is one of the most critical steps. However, it is generally not necessary or required that the drug has to be completely dissolved at a given time for successful and efficient drug absorption. Efficient and successful drug absorption can occur by continuously replenishing the extracted/absorbed portion of the drug, as often low solubility drugs (mostly non-polar) show quite a high and efficient drug absorption.

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).