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A drug dissolution test is one of the most critical and important tests used for developing and evaluating tablet/capsule products. However, unfortunately, as conducted at present, the test is also perhaps one of the most frustrating and the least value-adding tests one would use. The test is often promoted as a quality control test or tool as well, however, without defining or linking to a quality parameter/end-point. It is conducted using apparatuses that have never been validated for the intended purpose or objective, further increasing frustration. This article describes reasons for such practices and frustrations and suggests a simple approach to address the issues and concerns.
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USP is seeking comments on a draft of the revised “General Chapter <1092> The Dissolution Procedure: Development and Validation” (link). Also provided is a Stimuli article: “Revision of <1092> The Dissolution Procedure: Development and Validation” (link), which is to be published along with the proposed General Chapter providing the background information for the suggested revisions.

The following provides some comments for the consideration of the USP:

(1)    In general, the chapter appears poorly written, lacking focus and coherence of thoughts.

(2)    The claims made in the article for method development or validationare nvaguely described and For example:

  1. The suggested apparatuses, particularly paddle/basket, are flawed (lack reproducibility and relevancy) and have never been validated. Therefore, developing or validating a method using such apparatuses would not be possible.
  2. Validating a method requires a reference such as a product, parameter value (e.g. dissolution results), and/or experimental conditions established independently. As such a reference is not available at present. Thus the dissolution methods cannot be developed in particular for setting regulatory/pharmacopeial standards such as for USP.
  3. The suggested method development approach appears to be a vague narration of selecting experimental conditions to obtain certain pre-defined or pre-conceived dissolution characteristics of a product, not for determining the true characteristics of a product. It is important to note that the choice of the experimental conditions should be linked to the GI tract environment and not the product. As the physiological conditions (or experimental conditions) remain constant or independent of the drug/product, one should not be able to vary experimental conditions. The suggestions in the chapter concerning selecting product-dependent experimental conditions are scientifically invalid for this purpose.
  4. In general, if given a blinded product sample, which is a normal and common analytical practice, no matter how thoroughly or attentively one would follow the suggestions provided in the chapter it would not be possible to determine relevant and/or true dissolution characteristics of any product.

USP should consider addressing the above-mentioned deficiencies before finalizing the chapter.

The most commonly reported results from dissolution testing for establishing the performance of oral products (e.g. tablets/capsules), in particular for immediate-release (IR) products, is that products should meet a criterion of not less than 80% drug dissolution within less than 60 minutes, mostly 30 minutes.

Let us assume that a dissolution test (n=6) provides the following results (% drug dissolved) at 30 minutes (96, 88, 65, 110, 66, 65; Ave = 82; RSD = 23%). Obviously, this test/product, with a Q of 80%, would not meet the USP tolerance at the first stage. However, with a bit of luck and the second round of testing of 6 units it may meet/pass the USP Tolerance criteria. For details, please see the link, in particular the data set in row one.

Let us discuss the interpretation of these observed results. Read the rest of this entry �

The quality of a solid oral dosage form, such as a tablet or capsule product, may be defined as its ability to provide expected and consistent (reproducible) drug levels in plasma/blood. The product is introduced into the GI tract through the oral cavity (mouth) to release its drug, which gets dissolved in the aqueous milieu and gets transferred into the bloodstream to produce its therapeutic effects.

This drug transfer from the GI tract to the bloodstream is described by different terminologies, often interchangeably, such as permeability, absorption and bioavailability of the drug.  However, these terminologies have distinct meanings, and for clarity purposes, should not be interchangeably used. The purpose of this article is to describe and explain these terminologies to facilitate appropriate development and evaluation of the products in particular for the use of in vitro drug dissolution testing.  Please click here for the complete article

At the product development stage, the objective is to develop a product (tablet/capsule) having certain desired drug release/dissolution characteristics in humans. Therefore, one requires a dissolution method mimicking in vivo or the GI tract environment (particularly that of the intestinal). Commonly, this in vivo environment for dissolution testing purposes is represented by three variants: (i) temperature (37 ºC); (ii) an aqueous-based solvent/medium; (iii) a container or vessel with a stirrer to provide interaction between product and solvent.

Another requirement, which is perhaps the most critical one and is often overlooked, is that the method or testing environment must also be product independent, as does the GI tract environment.

It is further important to note that the method to be used must have already been developed and validated independently of the underdevelopment product. On the other hand, it is common for people to use or develop product-dependent dissolution methods. However, unfortunately, such a practice is neither scientifically valid nor correct. Furthermore, the use of a product-dependent method cannot provide true or actual dissolution characteristics of the product (link).

At present, none of the commonly suggested/recommended testers/methods, including pharmacopeial, provide common and/or product independent methods or experimental conditions. Thus such tests/methods cannot provide scientifically valid and/or true dissolution characteristics of a product during the product development stage.

This present-day limitation can easily be addressed by using the crescent-shaped spindle set at 25 rpm with 900 mL of water maintained at 37 ºC. A small amount of solubilizer may be added to water/medium if the drug is low aqueous solubility. For more details regarding the advantages of using a crescent-shaped spindle, please follow the link.

As a part of a discussion (link) on the LinkedIn Network group (Quality-by-Design), I posted the following response. For the interest of people who do not participate in the LinkedIn Network or the particular group, I am posting the response on the blog as well. I hope that you will find the post useful.

I think it is a critical and very important topic (FDA Seeks Metrics to Define Drug Quality, link) i.e., defining metric(s) for establishing the “quality” of pharmaceutical products. This has also been my view, and it has been stated on this forum a few times as well, that one cannot determine, monitor and/or improve the “quality” of a drug product until it is clearly defined (for example, see links, 1, 2). That is, what is a “quality product” and what parameter should be measured to reflect this “quality”.

My interest/expertise lies in the area of solid oral dosage forms (e.g., tablet/capsule products), where the “quality” of a product may be defined as achieving expected and consistent levels of the drug in blood/plasma or body. Therefore, assessing plasma drug concentration-time profiles (aka bioavailability/bioequivalence) becomes a “quality” metric for solid oral dosage forms.

However, because of ethical, time, and financial reasons/constraints, this parameter cannot be used on a routine basis for manufacturing purposes. Therefore, an in vitro surrogate of concentration-time profiles is required. Drug dissolution testing is that surrogate, with very valid scientific reasons, and has been in use precisely for this purpose for many years.

The most unfortunate and ironic part is that the test itself is scientifically valid. However, the way testing has been done, or required to be done by standard-setting organizations, is scientifically and logically invalid and useless. There are at least two reasons which make the current practices invalid: (1) persistent requirement of using dissolution apparatuses/testers which have never been validated for dissolution testing purposes. In fact, suggested/recommended testers, in particular paddle/basket, are flawed and are incapable of providing dissolution results of any product (link); (2) most, if not all, dissolution methods are product dependent, thus cannot provide unbiased or “true” dissolution characteristics of the products (link).

Using a slightly modified dissolution tester and a suggested simpler method development approach can resolve such issues and help define and monitor the needed “quality” metric for the solid oral dosage forms (link).

An in vitro drug dissolution test is conducted to assess in vivo dissolution characteristics of products, usually tablets and capsules. The reason or logic behind conducting this test is that if a drug is to exert its therapeutic effect after administration, it should be absorbed from the GI tract (mostly the small intestine). Further, for a drug to be absorbed, it should be available in dissolved (solution) form in the GI tract. Thus, measurement of the dissolution of a drug in the GI tract becomes one of the most critical steps for establishing and/or monitoring the efficacy and quality of the drug or its product.

Usually, it is not possible that the in vivo dissolution of a drug be monitored directly. Therefore, it is monitored indirectly by measuring the bioavailability of the drug, which is estimated from the drug concentrations in the blood or plasma, commonly known as plasma drug concentration-time profiles. On the other hand, as the in vitro dissolution test is used to evaluate in vivo dissolution monitored by bioavailability, the in vitro test dissolution test and bioavailability assessment thus become interlinked.

It is very important to note that the only purpose or use of drug dissolution testing is to assess the bioavailability of a drug from its product, which then reflects the quality of the product. It is also equally important to note that the link between dissolution testing and the quality of the product is through bioavailability assessment only. Otherwise, dissolution testing has no link to the quality of the product or its assessment. Often, it is promoted that dissolution testing is used and/or valuable for monitoring manufacturing efficiency/quality or its consistency. However, unfortunately, this is simply a false description or promotion of dissolution testing. A dissolution test cannot monitor anything but dissolution characteristics of a product, which is then used for bioavailability assessment.

It is now also well accepted that the current practices of dissolution testing have not been successful in predicting bioavailability assessment. Recently USP clearly described this situation by including the following statement in one of its general chapters, i.e. “Compliance with any of the [dissolution] tests does not assure bioequivalence or bioavailability” (link).

Obviously, it is clear that dissolution testing cannot be used for bioavailability assessment. What then is the purpose of such (pharmacopeial) dissolution tests? The answer is not much.

On the other hand, if one would address well known deficiencies of the currently suggested dissolution testers/apparatuses, in particular paddle/basket, then not only can dissolution testing be made bio-relevant, but also be vastly simplified and improved.

A modified apparatus/procedure has been suggested using the crescent-shaped spindle, with a single set of experimental conditions, to address the above-mentioned deficiencies. For further details in this regard, please follow the link.

Drug absorption from the GI tract is generally dependent on dissolution characteristics of a product, which depends on the aqueous solubility of the drug. In general, it is assumed that the higher the solubility, the higher the expected drug absorption will be, and vice versa.

Before considering the link between absorption and solubility, it should be prudent to define and establish the solubility characteristics of a drug for absorption purposes. In this regard, it is a well-known fact that drugs are mostly absorbed from the intestinal part of the GI tract (link). The liquid phase in the intestine is aqueous-based, having a pH in the range of 5 to 7. For all practical purposes, one may consider a pH of 6 (average of 5 to 7) for the intestinal fluid. Thus, to represent intestinal fluid, for dissolution testing, one may use water itself, which usually has pH around six or a (phosphate) buffer having a pH of 6. Therefore, in the following discussion, the solubility of drugs in water will only be considered.(continue here)

In simple terms current practices of dissolution method development may be described as:

“A practice of selecting experimental conditions (e.g. apparatus, rpm, medium) to achieve or observe expected or perceived dissolution characteristics of a product.”

The selected methods (i.e. experimental conditions) are then “labeled” differently at one’s own choosing, such as the QC-method, bio-relevant, discriminatory, etc. There are no differences in such methods and/or in their development approaches.

It is important to note that one never determines or establishes dissolution characteristics of any product, one just selects experimental conditions to achieve certain desired results. Therefore, one can never determine/establish quality for QC or bio-relevance (IVIVC, bio-waiver, product development etc.) for product development purposes. It has all been a serious and unfortunate marketing illusion.

Moreover, all the suggested or recommended apparatuses, e.g., compendial, have never been qualified and/or validated for dissolution testing purposes, for both bio-relevancy and/or manufacturing links. Therefore, dissolution results commonly obtained using these apparatuses, particularly basket/paddle, are no different or better than those obtained using desk-top blenders, shakers, mixers, etc. The point is that at present, all the dissolution results, and their interpretations, reported have no meaning, use and/or relevance.

Considering the limitations of current practices, a new and very simple approach has been suggested which addresses the issues described above. Further information in this regard can be obtained by visiting the site/blog (link).