Author: Dr. Saeed Qureshi, Ph.D.

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).

Before one uses a tester/method, in particular in a GMP environment, the validity of its use must be established, i.e., does the tester/method measure the expected characteristics of the product? In the case of a dissolution tester/method, one expects that it should measure the drug dissolution/release characteristics of a product and should be able to differentiate between products having different dissolution/release characteristics. In addition, a tester/method should not just measure and/or show such differences, but these measurements and differences have to be relevant and useful. Please click here for the complete article

It is very important to note that the objective of dissolution testing is to estimate/determine potential drug dissolution/release characteristics of a drug from a product using a simulated gastrointestinal (GI) tract environment. For dissolution testing purposes, the simulated GI tract environment is commonly represented by a medium such as water or an aqueous buffer (e.g., pH=6) in a container (vessel) maintained at 37 °C with gentle mixing/stirring. Suppose the volume of the medium is not sufficient to completely dissolve the expected amount of drug present in the product. In that case, a small amount of solubilizer (e.g. SLS) may be used. Dissolution results are often expressed as a percentage of the drug released at a single time (e.g., 30 or 45 minutes) or multiple times to establish a dissolution profile.

A dissolution test is like any other simple analytical test utilizing an instrument, such as a thermometer, viscometer, or pH meter that one uses to measure temperature, viscosity, and pH of a product, respectively. One does not require or develop a product-specific thermometer, viscometer, or pH meter. One just puts the thermometer or electrode into the liquid or pours the liquid into the viscometer to obtain the reading. This reading will reflect the property of the liquid.

A dissolution tester should be used exactly like that, i.e., monitoring/measuring dissolution/release characteristics of a product (tablet/capsule) by dropping a tablet/capsule into a dissolution vessel containing a standard volume of dissolution medium with a stirrer a pre-set rpm. The outcome of the test (% dissolved) will reflect the dissolution characteristics of the product.

No matter how one presents the argument, or dissolution results, describing them such as bio- or IVIVC relevant, discriminatory, or for QC use, the tests must be performed using pre-set and product independent experimental conditions. This is similar to the practice of not requiring discriminatory or bio-relevant and/or liquid-dependent thermometers, viscometers, or pH meters. Not only will it logically and scientifically be considered meaningless but it will never reflect the true product’s characteristics. Similarly, one should not ask for and/or try to develop product-dependent dissolution testers or methods (Please, click here to read in detail about dissolution testing).

Dissolution testing using the crescent shape spindle has been developed based on these thoughts which provide simple, scientifically valid, and product-independent testing and evaluation. For further information in this regard, please see the following links (1, 2).

December 11, 2012 | Author: Saeed Qureshi

A New Crescent-shaped Spindle for Drug Dissolution Testing—But Why a New Spindle? (Link).

Crescent-shape spindle: Facts sheet (Link)

Advantages of using the crescent shape spindles for drug dissolution testing (Link)

The following links are for the short video clips demonstrating comparative operations of the paddle and the crescent-shaped spindles.

Using a disintegrating tablet: Paddle and Crescent-shape spindle

Using a non-disintegrating tablet: Paddle and Crescent-shape spindle

Note: Dimensions may appear slightly distorted

On-site training/demonstration can be arranged. Post-graduate/doctoral fellows who are interested in using the crescent-shaped spindles for their ongoing research projects may request samples.

For further information and purchase inquiries, please contact by sending an email to (sales@pharmacomechanics.com) or call at: 1-613-797-9815.