Developing Dissolution Methods for Pharmacopeial Purposes – Deficiencies

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.

The analysts/formulators have to search for an appropriate set of experimental conditions, mostly medium (nature, pH and volume) and rpm for paddle/basket, to meet the criterion or requirement. 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 meets the first method then it should be considered as the choice, otherwise, as per USP monograph, the labeling should indicate that “it (product) meets USP Dissolution Test 2”. 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 apparently, as stated above, is that one has to show that drug release should be around 80% within 30 to 45 minutes (In this case, duration of test is 90 minutes as well, why?). For extended release products, the time requirement increases from minutes to hours, 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 of the preferred experimental conditions to achieve a 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. Method as described currently in pharmacopeias cannot be used to assess the dissolution characteristics of a product or its quality. For further discussion in this regard, please see the links (1, 2, 3).

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