BIOANALYTICX

The other day someone indicated that even products of drugs from BCS class II (low solubility and high permeability) had not shown successful IVIVC. These drugs, at least in theory, provide the best-case scenario for successful IVIVCs. The question was then asked what may be the reason for such a general lack of success.

For any successful IVIVC, one needs to conduct dissolution tests by mimicking the in vivo environment as closely as possible. This is usually done by conducting a dissolution test using water or aqueous buffers having pH in the range of 5 to 7 maintained at 37C. These conditions represent the GI tract (intestinal) environment.

 On the other hand, the tests are conducted mostly using paddle and basket apparatuses to simulate mixing and stirring environment. Unfortunately, the stirring and mixing environment of these apparatuses lack simulation of the in vivo environment. In fact, these apparatuses almost provide no stirring and mixing. Therefore, because of this mismatch, one should not expect successful IVIVC. For successful IVIVC, one requires an efficient (gentle but thorough) stirring environment. One such possibility to address this issue may be the use of a crescent-shaped spindle. For further discussion on the use of a crescent-shaped spindle, one may search this site or literature in general.

 In short, one should not expect success in developing IVIVC using paddle and basket apparatuses.

It is often described that one of the purposes, or perhaps the only purpose, of drug dissolution testing is to monitor batch-to-batch consistency in manufacturing processes. I believe that this view is described to maintain the use of dissolution testing based on paddle and basket apparatuses. This view appears to have been out of frustration due to a lack of success with dissolution testing regarding its relevance to a product’s in vivo performance.

 The question remains, can the testing be used for the consistency check? The answer appears to be a NO. The testing cannot be used for consistency checks in particular using paddle and basket apparatuses. The reason being that for monitoring the consistency of a product or process, the consistency (reproducibility) of the test itself must be established and known first. Unfortunately, consistency (reproducibility) of the testing based on paddle and basket apparatuses has never been established or available. There are literature reports available that provide a measure of expected variability in dissolution testing. The reported variability values in terms of RSD can be as high as 37% using these apparatuses, with the apparatuses working as expected and meeting the USP specifications. Such high variability in testing instruments is not usually acceptable, as the test would not be capable of providing stringent quality control standards for pharmaceutical products where generally desired variability (RSD) of 10% or less is expected or desired.

 Thus, dissolution testing based on paddle and basket apparatuses may not be used for batch-to-batch consistency checks.

PVT (Performance Verification Test) is frequently described as necessary to assess the performance of dissolution apparatuses (paddle and basket). Interestingly, the test quite often fails, i.e., test results often fall outside the expected range, without any known reason or cause.

Commonly described reasons/causes are: worn-out ball bearings, loose motor belts, misalignment of spindles or vessels, inaccurate gap between the bottom of spindle and base of vessel, lack of straightness of spindle rods, wobbling, vibration in the instrument and/or around its surrounding, high/low humidity affecting tablets, inappropriate de-aeration of the medium, inaccuracy in measured rpm, variations in vessel dimensions, mismatch of vessels from different suppliers, not using vessels from the instrument supplier, use of plastic vs. glass vessels, using scratched or not clean vessels, not withdrawing a sample from an appropriate position, not appropriately dropping the tablet or pouring the medium in the vessels, lack of an analyst’s training, in addition, any combination/permutation of these reasons.

 Most interesting is the fact that there has been no experimental evidence available in support of these claims i.e., there is no experimental data available to indicate that these aberrations provided results outside the expected range. To rationalize its continued use, supporters of the PVT maintain the claim that failures indicate potential deficiencies or aberrations, but how?

Drug dissolution testing is an important and critical technique for developing and evaluating the quality of a drug product based on its release characteristics in vivo, i.e., in the human GI tract, in particular the small intestine.

Often dissolution studies are conducted using paddle and basket apparatuses. However, testing using these apparatuses has shown significant frustrations in obtaining relevant results with acceptable variability (reproducibility).

 Significant literature is available describing the flaws of these two apparatuses. One such flaw is that, although generally assumed, these apparatuses have never been validated for their intended purpose, i.e., obtaining relevant and reproducible results.

 Even though these flaws are generally recognized, these apparatuses are in use as a “tradition” because these are the ones most commonly suggested and employed in the past. Another reason for their continued use is an apparent and unfortunate twist in the objective of the dissolution testing. That is, rather than evaluating the dissolution characteristics of a product; it is often suggested to establish the experimental conditions that show the desired dissolution characteristics. Thus, there is a large waste of human and financial recourses in developing drug and product-dependent procedures.

 The practice of obtaining or showing the desired and product-dependent dissolution results has no purpose other than rationalizing the continued use of paddle and basket apparatuses.

 To conduct appropriate dissolution studies, one needs to focus on the true objective of the testing i.e., to observe drug dissolution/release characteristics of a product in vivo. With this objective, things will start to fall in place. This will allow the analyst to use more efficient apparatuses and simple experimental conditions to obtain useful results.