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, in particular Paddle and Basket, they do not provide evidence that the testers are, indeed, 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 are only providing apparatuses, which 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 which are not available.

A manufacturer cannot use these apparatuses to establish the reproducibility or consistency in lot-to-lot production, as 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 behaviour of tablets …

These are few examples of partial titles selected at random from a quick review of 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 being, that these conclusions always appear to imply that they are reflective of potential in vivo behaviour of the products. 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. Continue reading →

To cite a post from this blog, you may use the following format which is in the Harvard Referencing Style:

“Saeed A. Qureshi. (2010). Determining blood concentration-time (C-t) profiles from in vitro dissolution results and product evaluation–carbamazepine. Available: http://www.drug-dissolution-testing.com/blog/blood%20levels%20carbamazepine.pdf. Last accessed 25h Jan 2010.”

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 of the currently suggested (mandatory?) apparatuses lack in providing an appropriate in vivo environment, in particular 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 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 for an IR product about 80% of the drug should be released within 30 to 45 minutes using a Paddle or Basket apparatus. This in essence is the requirement for a pharmacopeial dissolution test. Continue reading →