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There is no doubt that drug dissolution testing is an important and useful subject. However, currently used techniques and practices are generally not science-based and do not provide answers to questions people often ask. For example:

When apparatuses (dissolution tester) are sold by vendors, particularly Paddle and Basket, they do not provide evidence that the testers are capable of providing dissolution characteristics of a product (e.g. see link). The capability of a tester as a dissolution tester can only be provided if a vendor provides dissolution characteristics of a reference product or a test product given by the purchaser. Presently, the vendors only provide apparatuses that meet the expected physical specifications of a reproducible stirrer or mixer. They are not capable of providing the dissolution characteristics of a product in particular for human use.

A formulator or drug developer would not be able to develop a product using the testers, in particular the Paddle and Basket, because testers do not have defined and set experimental conditions capable of reflecting a product’s behavior in vivo (humans). The formulator requires an acceptable set of experimental conditions to evaluate and develop products that are not available.

A manufacturer cannot use these apparatuses to establish the reproducibility or consistency in lot-to-lot production, as the consistency of the testing itself is unknown, or at best, extremely high.

The evaluator, in particular for regulatory purposes, requires evidence that indeed the dissolution test employed can differentiate between an acceptable product and an un-acceptable product. These acceptability criteria require that dissolution tests should predict, or link, dissolution behavior to the in vivo results, i.e., should have a successful IVIVC. However, on the other hand, it is very well known that the current approaches of testing, in particular using the Paddle and Basket apparatuses, almost never predict the in vivo characteristics of a product. Therefore, an evaluator will always have difficulty in making a decision based on the data provided, using these dissolution apparatuses.

The obvious question is, why are we continuing with these practices and making claims of “success” and “usefulness” of the current practices? The answer is that old traditions take a long time to die.

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Drug dissolution studies are often reported in the literature as:

(1) Influence of formulation parameters on dissolution rate … (2) Formulation and evaluation of extended-release matrix tablets using factorial design (3) Development of novel … controlled-release tablets … and the effect of co-excipients on in vitro drug release rates. (4) Change in the drug release behavior of tablets …

These are few examples of partial titles selected at random from a quick review of the literature. The results and conclusions drawn from these studies are all based on in vitro drug dissolution testing only using the paddle or basket apparatuses. There is no harm in conducting in vitro dissolution testing and drawing conclusions from such studies based on the obtained results. However, it is important to note that the conclusions drawn can, and in fact most likely will, be erroneous and misleading. The reason is that these conclusions always appear to imply that they are reflective of potential in vivo behaviour. In general, such an assumption may be accurate, but in the case of drug dissolution testing, it is not valid, as the commonly used apparatuses are not validated apparatuses.

It is a common assumption and understanding that whenever an apparatus or procedure is to be used, its usefulness for the intended purpose must have been established, i.e., the apparatus must have been validated for its purpose, otherwise, data obtained would be of no use. For example, if a lab uses a weighing balance to determine or compare an item’s weight, it must use an appropriately validated balance. Similarly, if a dissolution apparatus is to be used to determine the dissolution rate of a product, the analyst and/or the vendor must first have to demonstrate that the apparatus (paddle/basket) is validated, i.e., capable of measuring dissolution rate appropriately and accurately. In this regard, it is to be noted that dissolution apparatuses have never been validated, in particular for evaluating products for human use.

Using apparatuses without validation, and obtaining results using test-product dependent methods, produce only numbers that are of limited use or relevance. It is often argued that a dissolution test is only an in vitro test for such testing as monitoring lot-to-lot consistency and product stability evaluations. Thus in vivo relevance or validation can be ignored. Obviously, it is a weak and scientifically invalid argument.  

Analysts/formulators must seek a validated dissolution apparatus to conduct dissolution tests and to evaluate products. Otherwise, their reported results and conclusions can easily be challenged to their great disappointment

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Commonly dissolution tests are to be conducted to assess the potential in vivo drug release characteristics of the products in humans. It is to be noted that it is the only objective of conducting a drug dissolution test. However, there has been limited success in achieving this objective because the currently suggested (mandatory?) apparatuses lack in providing an appropriate in vivo environment, particularly in terms of stirring and mixing. Therefore, rather than addressing this deficiency, unfortunately, the testing is often presented with two made-up objectives, i.e., without a scientific basis, in particular for the tests described in the pharmacopeias (e.g., USP). (1) It is often described that pharmacopeial tests should only be considered as quality control (QC) tests. (2) Moreover, as these QC tests are often not linked to any “quality” attribute or performance of the products, these pharmacopeial tests are then suggested to be considered as tests for monitoring the lot-to-lot consistency of the products. Thus, as these so-called “QC” or “consistency check” tests have no link to the product attributes. Therefore, they can be developed using any of the experimental conditions to meet some arbitrary criteria.

One such arbitrary criterion is that about 80% of the drug should be released within 30 to 45 minutes using a Paddle or Basket apparatus for an IR product. This in essence, is the requirement for a pharmacopeial dissolution test.

To meet the criterion or requirement, the analysts/formulators have to search for an appropriate set of experimental conditions, mostly medium (nature, pH and volume) and rpm for paddle/basket. This search for the experimental conditions is then commonly referred to as the “method development” step or with other different names such as “developing a discriminatory method”. Furthermore, it is generally recognized that the use of paddle/basket apparatuses provides unusually high variability and unpredictability in results. Reporting of variability (%RSD or %CV) in results is generally ignored or not required! Thus, the pharmacopeial standards and requirements are of limited relevance to product characteristics.

An example may elaborate the above discussion based on the current USP requirements for doxycycline hyclate products which are:

Doxycycline Hyclate Tablets:
Test 1= Paddle (75 rpm) with water (900 mL); Test Duration=90 min with Q=NLT 85%
Test 2= Paddle (50 rpm) with water (900 mL); Test Duration=30 min with Q=NLT 85%
Doxycycline Hyclate Capsules:
Paddle (75 rpm) with water (900 mL); Test Duration=30 min with Q=NLT 80%)

NLT= “not less than.” It is important to note that there is also a unique requirement in the monographs that “the distance between the blade and the inside bottom of the flask being maintained at 4.5 ± 0.5 cm during the test”. Commonly, this distance is set at 2.5 ± 0.2 cm.

As there are two methods for the tablet products, the analyst is expected to try both methods. If the products meet the first method, then it should be considered as the choice. Otherwise, the labeling should indicate that “it (product) meets USP Dissolution Test 2” as per USP monograph. The test conditions for the capsule product are somewhat hybrid of the two tablet methods with a lower Q value.

There are no guidelines available in the literature to describe how one should select a particular set of experimental conditions. The only criterion, as stated above, is that one has to show that drug release should be around 80% within 30 to 45 minutes (In this case, the duration of the test is 90 minutes as well, why?). The time requirement increases from minutes to hours for extended-release products, commonly between 6 to 24 hours.

In short, the pharmacopeial methods and standards for drug dissolution testing are generally not linked to the products’ quality attributes or performance. These tests can be developed using any preferred experimental conditions to achieve the desired end point, such as NLT 80% drug release for IR products within 30 to 45 minutes.

It is important to note that if one would like to assess the actual (“true”) dissolution characteristics of a product or its quality, then one requires a validated method using a reference product, not based on the test product itself. As described currently in pharmacopeias, Method  For further discussion in this regard, please see the links (1, 2, 3).

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The US FDA (CDER) released a document on the above-mentioned title (Link). This single-spaced 161-page long document provides an example of conducting and reporting studies for developing generic drug products as per the QbD (Quality by Design) approach.

It appears that this document may also be considered a “How-to manual on drug dissolution testing”, as a significant portion of the document describes the development and application of the dissolution testing.

It may be argued that if current practices of drug dissolution testing would not have faced so many problems/deficiencies and uncertainties, the procedures and documentations provided would certainly be simpler and shorter. Therefore, indirectly, the document may be considered as long-awaited recognition of the fact that current practices of drug dissolution testing are complicated and complex and may not be working as well as one should expect.(please click here for the complete post).

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In simple terms, a dissolution method transfer protocol (“protocol”) is a description of a mutual understanding of two parties, developer or current user of an analytical method (“originator”) and the receiver (“recipient”) of the method as to how a dissolution test is to be conducted.

There are numerous situations where such protocols are needed, such as transferring a method from R&D to the QC section, one plant to another plant, manufacturer to contract organization (CRO) or sub contractor, etc. The easiest and most practical approach for developing the protocol appears to be that both parties work together to develop step-by-step instructions that can be followed by current or future analysts to conduct the test as expected to produce consistent results.

The understanding between the two parties reflects how a test is to be conducted and what kind of output should be expected. The protocol can be: (1) simple/verbal understanding between parties such as preparation of a 0.05M phosphate buffer having pH 5.8 as per USP or; (2) detailed and documented (written) step by step set of instructions for conducting the analytical test, e.g., dissolution. In both cases, the common aspect is that the method should be able to provide an output that can be compared, for example, the final pH of the buffer solution or dissolution results. For the comparison of results between two parties, two sets of values are often used: the mean and standard deviation (STD) describing the characteristics of the test product.

Comparative testing is the most common form of method transfer approach in the pharmaceutical industry. It involves two or more laboratories executing a preapproved protocol resulting in data (means and STDs). The similarity or equivalency of these data is established based on statistical evaluation, often using a Student t-test.

The most critical thing to consider here is that similarity or equivalency of results from the two parties or laboratories can only be established based on statistical evaluation using means and STDs. If the laboratories or parties cannot provide appropriate values for these two parameters, then the method’s comparison cannot be established. There is no benefit of writing a protocol no matter how careful or elaborate practice of protocol writing may be.

In addition, a protocol requires a common product for testing with expected mean and STD values. This common product can be an in-house developed product or a reference product from an external source, such as a USP Reference Standard (RS).

In short, a method transfer protocol may be considered as a step-by-step cook-book type set of instructions (recipe) to follow for analyzing a (reference) product to obtain mean and STD values of parameter/characteristic, such as dissolution.

The question is, can such a protocol be written for a dissolution method transfer. The simple answer is, no. The dissolution tests as currently conducted would not meet the requirements for developing the protocol. Reason #1: A reference drug product with known dissolution characteristics, in particular, in humans, is not available. Reason #2: Commonly, dissolution results are reported as individual values (e.g., Q-based), mostly without STD values. Therefore, appropriate (statistical) comparisons of results would not be possible.

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Often I have written about the deficiencies (flaws) of the Paddle and Basket apparatuses in obtaining relevant and useful dissolution results. The underlying cause of these deficiencies is a poor stirring and mixing environment within dissolution vessels. However, as a long-held tradition, these apparatuses are recommended and used for dissolution testing. As the apparatuses do not provide a relevant in vivo environment, obviously, in vitro results would not be relevant to in vivo characteristics of drugs and their products. However, to maintain the status quo, the dissolution results obtained are rationalized as legitimate and useful. Considering numerous queries in this regard about drug glimepiride, I came across a publication (link) which may help in explaining the current dilemma of an analyst in dealing with in vitro drug dissolution testing. (please click here for the complete post).