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A common and frequent response to a number of different queries regarding choices in apparatuses, media, or other experimental conditions, is that the changes and choices must be validated. The responses are as varied as the number of respondents and their views. This leaves people usually even more confused than before asking the question. The reason for this confusion is that one cannot validate an apparatus or method using current practices of dissolution testing. Therefore, in good faith, most respondents suggest what it may be, not what it is or should be because no one knows what it is and what is expected.

The question may only be answered if one has a procedure or lead to a procedure, as to how an apparatus was validated to start with. For example, how was it established that paddle/basket is indeed validated apparatuses? How was this shown that paddle/basket apparatuses are suitable for their purpose (QC, discriminatory, IVIVC etc.)? If we have that procedure, we may follow the procedure to establish the validity of other secondary steps (changes, alteration, improvements, etc.). However, as we, to our knowledge, do not have that initial procedure that was used to establish the validity of paddle/basket, we cannot perform a secondary validation.

Thus, it should be kept in mind that current validation practices in this respect are more like rituals/traditions than based on facts from experimental science.

It is hoped that this will help and simplify your future dissolution work and validation steps.

There are four apparatuses generally recognized by pharmacopeias (e.g. USP) and other regulatory bodies that may be used for drug dissolution testing for product evaluation. However, choosing one of these apparatuses, or any other, is difficult as there are no appropriate scientific or rationale criteria available for such selections. 

All four apparatuses usually provide different results for the same product, and choice is left to the analyst to select one that meets the product’s expected behavior. This approach has two flaws: (1) indeed, these apparatuses are not measuring the same property (dissolution). Otherwise, the results would have been the same. A product cannot have four or more values for the same parameter; (2) a product, or its property, cannot be evaluated using itself as a reference to select a technique (apparatus).

Drug dissolution testing is commonly performed using vessel-based apparatuses with Paddle/Basket spindles. The objective of testing is to establish the dissolution or release characteristics of a test product.

Current practices, however, seek and provide experimental conditions such as choice of the spindle, rpm, dissolution medium (nature and strength) to define such characteristics based on analysts’ expectations. Another way of saying the same thing is that an analyst sets the experimental conditions to obtain desired quality of results, or products, e.g., less variable, discriminatory or not, slow or fast, bio-relevant or not. The analyst would never know the actual release characteristics of a product, thus its quality.

The reason for such inadequacy with the use of Paddle/Basket is that they do not provide an efficient mixing and stirring environment within dissolution vessels, the most critical and necessary process for the dissolution itself. Therefore, their future use certainly warrants caution.

Dissolution tests are employed to establish drug release characteristics of solid oral products, such as tablets and capsules. The rationale for conducting these tests is that for a product to be therapeutically effective, the drug must be released from the product and should generally be dissolved in the gastrointestinal (GI) tract fluid. The drug in solution form facilitates the absorption of the drug from the GI tract into the systemic (blood) circulation to reach its desired target (site of action) to exert its effect.  Therefore, a dissolution test may be considered a critical step for developing and assessing the quality of products linked to their safety and efficacy attributes. Thus, drug dissolution studies are conducted at every stage of a product’s life, including obtaining approval for marketing in a country from local regulatory authorities.

In reality, dissolution testing may be considered as an extraction technique such as a Soxhlet extractor for extracting compounds from their matrixes or perhaps a simple shake-flask technique for solubility determination. It is not to say that dissolution apparatuses may be replaced or substituted by apparatuses for the two types of techniques mentioned, but highlighting the fact that they all work on the same principle but with different objectives. The extraction techniques mentioned concerns with extraction/dissolution to the maximum of the test compounds using rather harsh experimental conditions such as boiling liquids, vigorous shaking and/or stirring at very high speeds. On the other hand, the dissolution technique is based on the extraction process with rather restrictive solvents, temperature, and stirring/shaking. The extraction solvents used in dissolution testing are limited to water or aqueous-based solutions with pH 5 to 7 and maintained at 37 °C. The stirring and mixing must be thorough but gentle to avoid any harsh abrasive impact on the product. The chosen solvent and experimental conditions are representative of the fluid present in the gastrointestinal (GI) tract to simulate the extraction process within the GI tract.

It is important to note that dissolution extractor/tester, which is commonly based on a vessel and stir the combination, does not reflect the GI physiology but the environment and process of the extraction within the human GI tract. Following the extraction, as for the other techniques mentioned above, samples are withdrawn, filtered and quantified using common methods such as chromatographic/spectroscopic. The results are commonly obtained in the units of amount/volume (e.g. mg or ug/mL). However, these results are further converted to other units, for example, for solubility expression, they are reported as amount/100 mL. However, results from the Soxhlet apparatus or dissolution technique are reported in percentage of the extracted amount based on the total amount of the matrix (Soxhlet) or the total expected amount of the drug present in the product.

The preceding discussion about the similarity of dissolution testing to other extraction techniques highlights the fact that drug dissolution testing is a relatively simple analytical technique. It should not require any more elaborate method development/validation steps or results reporting than other simple analytical techniques such as the two described above. Such an understanding of the underlying principle of dissolution testing will help critically evaluate current complex practices of reporting and evaluating the dissolution results and further simplify them.

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.