FDA provides choices of experimental conditions for conducting drug dissolution/release tests for various drug products (Link). In total there are 789 entries in the database, including 228 where readers are referred to the USP monographs and 16 without suggestions and the sponsors are to develop their own. Therefore, there remains 545 (789-228-16) entries, which are used for the trend analysis. Continue reading →

Reporting and Analyzing Drug Dissolution Results: A Systematic Approach

… The preceding discussion is to emphasize the fact that drug dissolution testing is a relatively simple analytical technique. It should not require any more elaborate method development/ validation steps or reporting of results than any other simple analytical techniques such as the two mentioned above. Such an understanding of the underlying principle of dissolution testing will help in critically evaluating current complex practices of reporting and evaluating the dissolution results, and hence simplifying them…. American Pharmaceutical Review May/June, 2010. Link)

The lack of adequate stirring and mixing within Paddle and Basket apparatuses requires that the dissolution tests be conducted using product dependent experimental conditions. For example, the experimental conditions for carbamezepine described in the USP are as follows:

As the GI tract environment remains the same for both IR and ER products, testing using the above mentioned conditions would not be physiologically relevant. Furthermore, as the experimental conditions are different for each product, one cannot make a valid comparison between products. Thus, it would be impossible to establish whether the differences in the drug release characteristics of the product are because of the products or experimental conditions

On the other hand, if appropriate stirring and mixing environments are present within the dissolution vessels, such as by using crescent-shaped spindles, then such problems do not occur and all of the product can be analyzed using a single set of experimental conditions, such as:

The figure below shows dissolution profiles of carbamezepine products using the single set of experimental conditions as noted above (Source: Qureshi, Eur. J. Pharm. Sci., 2004).  Continue reading →

Recently a question has been asked that while conducting PVT (Performance Verification Test), only the basket apparatus met the criteria but not the paddle apparatus, is the apparatus acceptable for use if the basket is to be used for product testing?

In essence, the query relates to seeking an opinion that if such were the situation what would  the response be from a standard setting body? Obviously, a clear and a definite answer can only be provided by a representative of the standard setting body. If someone would like to contribute in this regard, please submit your response to the moderator of the site.On the other hand, however, some scientific discussion is provided here which may help in reaching an objective response.

To address this query, one has to ask a question as to whether meeting the PVT criteria does indeed reflect acceptable performance of dissolution apparatuses? Unfortunately, there is no or limited scientific evidence available to support the link of meeting the PVT criteria and the actual performance of a dissolution tester. Therefore, some standard setting organizations will accept evidence of apparatuses performance based on mechanical calibration alone without requiring the PVT.

It appears that the current practices of dissolution testing follow two separate and parallel paths. For example: a simple question would be “how to conduct a dissolution test?” Common response usually is to use any of the “approved” dissolution apparatuses such as USP Paddle/Basket with associated experimental conditions such as 1L capacity glass/plastic vessel, 900 mL or less medium (buffer or water), 50/75/100 rpm, if needed, some solubilising agent (e.g SLS) added to it along with all the instructions/suggestions to control the specifications and operation of the apparatuses/testing.

In reality, however, the question is usually not intended towards the available choices of apparatuses or associated experimental conditions but seeking a methodology to determine dissolution characteristics of a product. To answer this question, one has to have a standardized apparatus with fixed associated experimental conditions. This apparatus along with its associated experimental condition must be capable of providing dissolution results (verifiable independently from the dissolution tester) of a reference product. Therefore, for determining dissolution characteristics, one has to have a standardized tester (apparatus and associated fixed experimental conditions) and reference product with known dissolution characteristics. Once an analyst is able to determine the acceptable results of the reference product, using standardized tester, then this tester is to be used to determine the unknown dissolution characteristics of the test products. If the results are not as desired or expected then analyst must work with the product (formulation/manufacturing), and NOT with the experimental conditions, which would void the dissolution test and results.

The current situation is that neither a standardized a dissolution tester nor a reference product is available to the analyst, but technique is expected to provide dissolution characteristics of a test product. The analyst has to be confused and frustrated, as well as the pharmaceutical industry, which loses significant amounts of money for conducting dissolution testing of limited value.

To address this confusion a new approach in dissolution testing using a new spindle has been suggested. For further discussion in this regard please see the title “Know Ur Product” and other links (1, 2, 3, 4).

As described earlier (link), the main purpose of dissolution testing is to establish the drug dissolution/release characteristics of a product. However, current practices do not provide such an answer, but suggest choices in selecting experimental conditions to achieve or set desired dissolution results/characteristics of products. Thus, the current practices appear to defeat the purpose of dissolution testing.

The only way the objective/purpose of dissolution testing can be achieved is to have some sort of common experimental conditions. Significant work has been done and published for developing such common experimental conditions. The main difference in the current practices and the suggested approach is that of the use of a different type of spindle (stirrer), known as crescent-shaped or brush spindle. For further details about the spindle and the suggested experimental conditions, please see under subheading/title –“Know Ur Product”.

The new spindle provides a simple, efficient and product independent approach in determining drug dissolution/release characteristics of a product. Even without official recognition, the spindle may be employed to facilitate developing dissolution test conditions using traditional apparatuses such as Paddle and Basket. This may be achieved by conducting a dissolution test using a single set of experimental conditions with crescent-shaped spindle to establish the drug dissolution characteristics of the product. The observed dissolution characteristics then may be used as reference to obtain experimental conditions using Paddle or Basket apparatus for complying with the regulatory requirements.

Although, not generally recognized, current practices of dissolution testing seek to adjust experimental conditions to obtain desired or expected drug release/dissolution characteristics. The variations or adjustments in experimental conditions, which are commonly referred to as method development steps, often relate to choice of apparatuses, rpms or flow-rates, media (nature and volumes) etc. Thus, current practices defeat the purpose of dissolution testing which are, in fact, supposed to be conducted to evaluate or establish drug release characteristics of a product, in particular, at the method development stage.  In addition, most standards and requirements are based on this practice of selecting and setting experimental conditions rather than evaluating products. 

For appropriate dissolution testing, the tests are to be conducted using product independent and fixed experimental conditions. This will facilitate in finding the actual drug dissolution or release characteristics of a product or will help in knowing one’s product. If one keeps on changing the experimental conditions, one will never know the true (dissolution) characteristics of the products.

The most widely used and referred dissolution tolerances are based on the USP Acceptance Table. The results are evaluated in stages. This means repeats are allowed with relaxed tolerances and higher degree of variances for each subsequent test.

(The Q-values are provided in individual product monographs, representing expected percent drug release (dissolution) at times, such as 30, 45, 60 minutes etc.)  Continue reading →

It is a very well established fact that the USP apparatus PVT (Performance Verification Test) using prednisone tablets faces significant criticism regarding lack of its relevance to the performance of the apparatuses. This criticism originates from the unexpected/unpredicted failures of the PVTs, by providing (dissolution) results outside the expected ranges, also called suitability ranges. Although not generally recognized, the main reason for such failures is that expected ranges are set tighter than are needed to reflect true (high) variability of the test. Therefore, in reality, when a PVT fails, it does not reflect a substandard apparatus or the testing, but is a reflection of the actual/true variability of the testing. Often suggestions are given for addressing this situation by adjusting apparatus/testing parameters, however, a common view in the scientific community is that repeating the test, single or multiple times, often provides the desired outcome. Therefore, the current practice of PVT has become an exercise of obtaining dissolution results within an expected range rather than evaluating the performance of the apparatus/test. Continue reading →

Often a reason provided, in the literature, that it is a test to differentiate drug release characteristics of a product reflecting potential impact of formulation and/or manufacturing differences. This type of tests usually does not have a link or association with in vivo drug release characteristics of the products. Such tests are often referred to as “discriminatory tests”. The underlying reason for such a “discriminatory test” is that if the test relates dissolution differences to formulation/manufacturing differences, then the test will flag potential deviation from the expected behavior of the product in vivo (humans). The main assumption here is that the differences in formulation and/or manufacturing attributes would result in vivo differences in drug release characteristics which may produce a substandard product.  This unfortunately is an incorrect assumption, because the differences in formulation and/or manufacturing, on their own, do not necessarily result in differences in vivo drug release, at least not in most cases. If this assumption would have been correct then generic products, and the industry, would not have existed. The reason being, the generic products, which are based on vastly different formulation and manufacturing attributes, but are required to provide the same drug release characteristics in vivo (humans).  In addition, the generic products are also required to provide similar dissolution characteristics, thus forms the basis of pharmacopeial (USP) testing.

Therefore, developing or conducting an in vitro dissolution test just to evaluate/assess differences in formulation/manufacturing, without its link to in vivo, is of limited value or use, and in fact may be an incorrect practice.

IVIVC (In vitro-in vivo correlation) is a desired feature in the practice of drug dissolution testing. An appropriate IVIVC provides credibility to an in vitro dissolution test by avoiding false negative indications concerning quality and manufacturing of a product. It further enhances economic benefits to the manufactures by providing efficient development and modification of products, thus obtaining regulatory approvals.

Developing an IVIVC may be considered a two-part process: (1) analyzing the in vitro dissolution data and relating it to in vivo results. This has been the subject of the last few posts (1, 2, 3); (2) conducting an actual dissolution test for generating appropriate data. This post is regarding the later aspect.

For an appropriate dissolution test, in general and in particular for developing IVIVC, one requires to conduct the test selecting experimental conditions to simulate an in vivo environment as closely as possible. Commonly the following experimental conditions should be considered in this regard.

1. A dissolution medium should be an aqueous solution having a pH in the range of 5-7 and be maintained at 37C. The expected amount of the drug present in the product must be able to freely dissolve in the volume of the medium used, often 900 mL. If the drug is not freely soluble in water as such, then small amounts of solublizing agent such as SLS may be used.
2.  The dissolution medium should not be de-aerated. Preference should be given that the medium be equilibrated at 37C with dissolved air/gasses, particularly for IVIVC studies.
3.  An apparatus should be selected to have an appropriate mechanism to provide thorough but gentle mixing and stirring for an efficient product/medium interaction. Use of sinkers may be avoided as these often alter the dissolution characteristics of the test products. Paddle and basket apparatuses are known for their inefficient stirring and mixing, thus their use should be critically evaluated before use for IVIVC studies.
4. Frequent samples (8-10) should be withdrawn to obtain a smooth dissolution profile leading to complete dissolution within the dosing interval of the test product in humans.
5. If the dissolution results are not as expected, then the product/formulation should be modified to obtain the desired/expected release characteristics of the product. However, altering experimental conditions such as medium, apparatus, rpm etc. should be avoided as these are generally linked to GI physiology which remains the same for test to test or product to product. Obtaining dissolution results by altering testing (experimental) conditions may void the test for IVIVC purposes.

As explained in an earlier post, commonly used convolution/deconvolution techniques for IVIVC purposes, link three functions together. The three functions are input (absorption/dissolution results), output (plasma drug concentrations) and weighting function (usually plasma drug concentrations following an intravenous dose).

Deconvolution will be the option one would use when plasma drug concentrations of the test products are available and one would like to determine the in vivo dissolution results. These in vivo dissolution results are compared with the in vitro dissolution results.

Convolution will be the option one would use when in vitro dissolution results are available and one would like to determine plasma drug concentrations of the test product. During the product developmental stage, where a formulator likes to have an idea of potential in vivo output, a convolution technique would be the only choice. For comparison of release (dissolution) characteristics of products for generic developments or product modifications etc., again one may use the convolution technique. In this case, based on obtained dissolution results from two or more products, one would be able to obtain respective plasma drug concentration profiles, which can be compared using standard and accepted parameters of Cmax and area under the plasma drug concentration curves (AUC).

Studies have shown that the convolution technique provides better accuracy of outcome (plasma drug concentrations) than the deconvolution technique.  Moreover, computation-wise, convolution technique could be simplified and calculation may be performed using simple spreadsheet software rather complex mathematical software. Therefore, it is suggested that one may consider convolution as a first choice for developing IVIVC.

A plasma drug concentration-time profile is usually the net effect of two simultaneous processes: (1) absorption of the drug from the GI tract. As absorption is proportional to drug dissolution thus absorption and dissolution are used interchangeably; (2) elimination of the drug from the blood. These two actions, and their net effect, are represented by three profiles and are shown in the figure. In mathematical terminology, these three curves (profiles) are known as functions, dissolution or absorption as input, blood concentrations as output and the elimination as the weighting factor or function. To further simplify, in the analogy of linear regression used for calibration curves, output function may be considered as “Y or dependent variable”, “X or input function” and “M or slope/proportionality constant”. In case of linear regression analysis X, Y and M parameters have values (numbers), however, in the case of drug concentration profiles, these are functions. So solving these function based equations is a bit more complicated.

The procedure is similar to that of linear regression which is commonly used in establishing calibration curves and then using the calibration curve to determine the unknown concentrations or response (e.g. absorption or peak height/area values). So, if “Y” is known then “X” may be determined and vice versa. Similarly, if input function is known, one can determine output function and vice versa. Determining output function (plasma blood concentrations), if input function (dissolution results) is available, the procedure will be called convolution technique and inverse of it, that is obtaining input function (absorption/dissolution results) if output function is provided, the procedure will be called deconvolution.

There are computer software available which provide the capability of solving for a function when the others are available. However, the convolution approach could be simpler where use of commonly available spreadsheet software may also be used.  For further detail see, Qureshi, SA. In Vitro-In Vivo Correlation (IVIVC) and Determining Drug Concentrations in Blood from Dissolution Testing – A Simple and Practical Approach. The Open Drug Delivery Journal, 2010, 4, 38-47. (Link)

Theoretical Consideration:  The most commonly used definition of IVIVC (In Vitro/In Vivo Correlation) is the one described in one of the FDA guidance documents (link). It defines IVIVC as a predictive mathematical model describing the relationship between an in vitro property of a dosage form (usually the rate or extent of drug dissolution or release) and a relevant in vivo response, e.g., plasma drug concentration or amount of drug absorbed.

In this regard, the most sought after relationship is of “Level A”, which is further defined as a predictive mathematical model for the relationship between the entire in vitro dissolution/release time course and the entire in vivo response time course, e.g., the time course of plasma drug concentration or amount of drug absorbed.

Practical Consideration: On the practical side, the purpose of IVIVC is to use drug dissolution results from two or more products to predict similarity or dissimilarity of expected plasma drug concentration (profiles). Before one considers relating in vitro results to in vivo, one has to establish as to how one will establish similarity or dissimilarity of in vivo response i.e. plasma drug concentration profiles. The methodology of establishing similarity or dissimilarity of plasma drug concentrations profile is known as bioequivalence testing. There are very well established guidances and standards available for establishing bioequivalence between drug profiles and products.

Ideally, therefore, one should focus on predicting or calculating plasma drug concentration profiles from drug dissolution results for an appropriate IVIVC. A common mathematical technique employed for this purpose is known as convolution, which basically convolutes (combines) dissolution results (profile) with plasma concentrations following intravenous (IV) drug administration to provide expected plasma concentrations for solid oral dosage forms. In mathematical terminology, dissolution results become an input function and plasma concentrations (e.g. from IV) become a weighting factor or function resulting in an output function representing plasma concentrations for the solid oral product.

Further details about this methodology and its use will be described in future posts.

Bio-waiver is a term used for establishing and accepting quality of a pharmaceutical product (tablet and capsule) based on in vitro drug dissolution testing without corresponding bioavailability/bioequivalence data.

The scientific rationale behind this practice is that, in general, the bioavailability of a drug product depends on its release and solution formation (dissolution) characteristics. This, in vivo (physiological) dissolution is monitored or simulated in vitro by a dissolution test. Therefore, an assumption made here is that the in vitro dissolution test will appropriately and accurately reflect in vivo dissolution in humans and thus the bioavailability/bioequivalence characteristics of the products. This linkage is commonly referred to an in vitro-in vivo (co)relationship or IVIVC. Therefore, a pre-requisite for bio-waiver practices is a well established IVIVC.

It is, however, generally well recognized and documented in the literature that current practices of dissolution testing do not relate well to in vivo outcomes or often lack IVIVC. Therefore, presently, a bio-waiver should be considered as a scientifically weak case.

There are, however, guidances available for considering bio-waivers in certain, very specific, cases.  For example, bio-waivers are considered for products having drugs with high aqueous solubilities and absorbabilities from the GI tract in humans. In addition, the products should show fast dissolution. The underlying thought is that if drugs are highly soluble and absorbable, and the products show fast and complete in vitro dissolution (usually in less than 30 minutes), then the products are not expected to pose any potential problems in vivo, and thus they may be considered for bio-waivers. Therefore, it may be assumed that current practices of bio-waivers are based on faith rather their scientific merits.

In short, for an appropriate and scientifically valid bio-waiver inference, one has to establish IVIVC, with evidence that the techniques and methodologies (dissolution apparatus, medium and associated experimental conditions) employed are indeed capable of providing physiologically relevant results.

In continuation of the earlier post (link), this post describes some of the steps which are commonly described in the literature as method development, but should not be considered as method development steps. These steps are usually variations in experimental conditions to achieve certain desired characteristics of a dissolution test such as discriminatory, improved reproducibility and/or bio-relevancy. The variations can be are numerous, such as choice of apparatus (paddle or basket), spindle rpm (50, 75, or 100), media (water or buffer), pH (between 1 and 6), choice of de-aeration or its technique, use and choice of a sinker, etc.

Considering these steps or practices as method development is incorrect because of two reasons:

1. These practices are commonly used during product development stage. At this stage an analyst is working with the variations in the product (formulation and manufacturing attributes) which requires a fixed dissolution method, not variations in the method itself, to evaluate the impact of product variations.
2. The products are developed for human use. The drug is expected to be released from the product in the GI tract environment, which remains constant, from product to product. The in vitro dissolution testing conditions simulate this GI tract environment, therefore, these conditions should also remain constant.

It is, therefore, critical that a dissolution test method should be decided and fixed, reflecting GI tract environment, prior to working on the development of a product.

The role of an (or any) analytical method validation (chromatographic/spectrophotometric) is to demonstrate that the method is capable of measuring an analyte accurately (accuracy, which includes specificity) and reliably (precision, which includes repeatability and reproducibility). In addition, if the analyte is expected to be in a wider range e.g. zero to 100 %, which is usually the case in dissolution testing, then one has to establish that concentrations and responses have a linear relationship (linearity), by measuring responses at different concentrations.

All of the above mentioned practices (tests) boil down to determining responses (UV absorptions or peak height/area for chromatography) against concentrations and are to be done in replicate (5/6 times) to be able to determine a standard deviation (variance) to establish confidence in the results. In short, if one has different solutions of 100, 50 and 25% concentrations (strength) of drug and measure their responses, which come out in the ratios as the concentrations (by doing it repeatedly 5/6 times), then the method has been validated.

For the purpose of drug dissolution testing, one has to demonstrate that if the drug is in solution then the analytical method is capable of measuring it accurately and reliably. Therefore, for validation of such methods, one needs to add the drug (“spiking”) in solution form to a dissolution testing apparatus  i.e. vessel containing required volume of medium maintained at 37 ºC and spindle rotating. Samples are withdrawn and processed exactly as if these were from a product (filtration, dilution/concentration, extraction etc) and responses are measured accordingly. If responses and concentrations are as one would expect (as explained above), then that dissolution method has been validated.

One should, then, be able to use this method (validated) for measuring dissolution of a drug from a product. Method validation steps are independent of drugs and products.

On the other hand, a method development exercise is drug and product dependent. In (analytical) method development, an analyst needs to select appropriate parameters such as wavelength, chromatographic column, dilution, extraction steps, filters etc. Once such parameters are established, one then moves to the method validation exercise as a second step.

Assay and content uniformity (CU) are two tests generally required for establishing quality of a pharmaceutical product. In one case (assay), the testing is done by pooling the content of multiple units (tablets/capsules) together while in the second case, CU, evaluation of the units is done individually. The evaluation procedure usually remains the same, or almost the same, that is grinding the product, dissolving/extracting the drug using an appropriate solvent and then assaying it using an analytical technique e.g. chromatographic/spectroscopic.

The drug dissolution testing is based on the extraction (procedure) step, perhaps simpler as it does not require grinding of the product. Another advantage of using dissolution tests for extraction purposes is that the choice of a solvent is simple (water, with or without a solubilizer) which is physiologically relevant as well. Thus, one can evaluate CU and assay while conducting a dissolution test.

The question is why has not this simple approach been adopted or commonly used currently. The reason is that currently used dissolution methods, based on Paddle and Basket apparatuses, do not provide accurate and reproducible results. A more appropriate and reproducible apparatus can certainly provide such simplicity and efficiency. For further detail on this topic please see, The Open Drug Delivery Journal, 2008, 2, 33-37, (link) and AAPS Poster presentation (link).

Recently, a comment is made by a poster that “This whole new PVT Prednisone Lot thing is a Joke!” expressing his/her frustration with the use of the tablets or the practice of PVT. Such comments reflecting the erratic and unpredictable behavior of PVT, previously called apparatus calibration, are not new and have been reported extensively in the literature.

However, a more serious question and concern should be that if the performance of an apparatus cannot be verified appropriately, as recommended and required by the USP, then how reliable would the testing of the pharmaceutical products be using such an apparatus?

This seems to confirm literature reports that there are problems in using the apparatuses, because of poor hydrodynamics within dissolution vessels. Therefore, caution should be observed in assessing the quality of products using such apparatuses.

It is a common query as to what should be suggested dissolution test conditions for a drug, XYZ, in particular, if the drug XYZ happens to be of low solubility in water. Unfortunately, it is not a correct question, as dissolution tests are mostly conducted for products and not for drugs. Furthermore, even a product does not dictate test conditions, because an analyst likes to determine/establish the property (dissolution) of the product itself, which would require an unbiased method. Therefore, a dissolution method should not be product/drug specific or dependent.

Often it is suggested that if a product (tablet or capsule) floats or moves randomly during dissolution testing, it may produce variable results, therefore, one should use a sinker to avoid mobility to reduce the variability in dissolution results. However, it should be noted that use of sinkers may invalidate dissolution testing/results and their relevance, because:

1. Dissolution tests are conducted to determine potential drug release characteristics in vivo, where mobility of the products is natural and expected. Therefore, use of a sinker makes drug dissolution testing physiologically not relevant.
2. When a sinker is used, it forces the product to settle at the bottom of the vessel, where interaction between product and dissolution medium is minimal, resulting in inefficient dissolution. In addition, the caging effect of sinkers may further reduce the dissolution rate. In fact, the use of a sinker may exaggerate effect of poor hydrodynamics within a vessel. Thus, its use will provide inaccurate results even for in vitro dissolution characteristics of the test product. 
3. It would not be possible to accurately compare the dissolution characteristics of two products in which one would float, and the other not. In such cases, how would one subtract the effect of the sinker from the product which requires one and other which does not, so that a proper comparison of dissolution characteristics of the two products can be made?

Therefore, one should be careful when using a sinker as the tests/results may provide inaccurate reflection product characteristics.

Generics are drug products which are considered identical in dose, strength, route of administration, safety, efficacy, and intended use as an innovator’s product. However, generics are different from innovators’ products with regard to formulation and manufacturing attributes. Because of these differences in formulation and manufacturing, it is expected from the generics that they demonstrate that the drug release from their product is similar to those of the corresponding innovators’ product.

This similarity or equivalence in drug release between generic and innovator products is established by conducting bioavailability/bio-equivalence studies. Such bioequivalence studies, in fact, establish that drug release (dissolution) in vivo from both products is the same. A very important point in understanding this principle is that generics strive to achieve similarity of drug release from innovators’ products in vivo having vastly different formulation and manufacturing attributes. Otherwise, generics and innovators’ products would have different bio-availabilities and would not be bioequivalent, Therefore, a difference in formulations or manufacturing attributes, or finding these differences by in vitro dissolution tests, are of no real consequences. Thus, the practice of finding such differences or developing dissolution tests under the terminology of “discriminatory test”, is an erroneous and misguided exercise.

The purpose of any analytical procedure, including dissolution testing, is to determine an unknown property of a test substance/matrix. However, in the case of current practices of drug dissolution testing, this is not the situation. Here, one seeks experimental conditions to obtain desired or expected release characteristics of the products. These are then described, incorrectly, as procedures for method development, obtaining discriminatory tests and/or bio-relevant tests, etc. Furthermore, it is important to note that for all these practices, a test product itself is used as its own reference. Therefore, one can never know the actual or real dissolution characteristics of any product.
 
For appropriate dissolution testing, the dissolution method (apparatus with associated experimental conditions) must remain constant, i.e., these should not change from product to product. For example, a method must remain the same if one would like to test or compare characteristics of an IR vs ER product. For further discussion, the linked article may be useful.

Quality control (QC) aspect of dissolution testing is linked to the release characteristics of drug from its product, commonly tablet or capsule. This release characteristic, which is measured in vitro, is supposed to reflect/simulate drug release in vivo. Therefore, the QC test is a reflection of drug release in vivo in humans, thus establishes the quality of product. That is why, such tests are conducted using experimental conditions which simulate human physiological conditions of GI tract as closely as possible. However, recent studies (see publication section) reflect that experimental conditions used (e.g. apparatuses) do not simulate appropriate GI tract environment such as they lack the needed mixing and stirring in the dissolution vessels. Therefore, current practices of dissolution testing may not reflect quality of the products and the test may not be considered as a QC test.

On the other hand, considering this lack of QC aspect, commonly dissolution test is presented as a test for consistency check for batch to batch evaluations, but still appears to be implied as a QC test. This obviously creates significant confusion in properly describing and/or differentiating the test as a QC or consistency-check test. As stated above in its current form dissolution test does not appear to be a QC test, therefore, it should be considered as a consistency-check without its link to in vivo release and to the quality of the product.

As a consistency-check test, it may be performed using any of the experimental conditions which may or may not be physiologically relevant. For example, organic solvents vs aqueous based, higher or lower temperatures vs 37 ºC, any other type of stirring device (magnetic bar, shakers, propeller with high speed motors etc) vs commonly used paddle and basket apparatuses. Further, one may report the results for any sampling time which appear to be most stable and reproducible. Obviously, this has never been the intent that the dissolution test be conducted in this manner, in particular as a QC test.

Therefore, to conduct a dissolution test as a QC test, as was originally intended, the test has to be conducted by creating or simulating more appropriate physiological environment, i.e. improved stirring and mixing. This improved stirring and mixing aspect indeed appears to address the limitations of current practices and its artefacts. For further discussion on this topic please see the recent literature under the publication section.