BIOANALYTICX

BCS (Biopharmaceutic Classification System) is a classification approach in which drugs (APIs) are divided into four classes based on the extent (high or low) of their aqueous solubility and permeability through the GI tract wall, in particular intestinal. In this regard, these four classes are: (I) High Solubility and High Permeability drugs, (II) Low Solubility and High Permeability drugs, (III) High Solubility and Low Permeability drugs and, (IV) Low solubility and Low Permeability drugs.  It is important to note that BCS relates only to drugs (APIs) and their characteristics, not the products.

These two factors (solubility and permeability) play a critical role in keeping all other factors equal for evaluating absorption characteristics of drugs in humans. For example, if four drugs, one from each class in equal doses, are administered in solution forms, all would show differences in absorption through GI tract or appearances in the bloodstream depending on their solubility/permeability characteristics. Potentially, the drug in group I would show fast and high absorption (least hindrance to absorption), the drug in group IV would show slow and erratic absorption (highest hindrance), while drugs in groups II and III would show absorption in between. Therefore, BCS certainly provides a good basis for assessing the potential absorption behavior of a drug in humans.

The use of BCS may not, however, be extended for product evaluation. There are at least four reasons for this: (1) as described above BCS relates to drugs only and not the products; (2) for products evaluation, one assesses the effect(s) of formulation and manufacturing attributes while keeping the drug and its strength constant. Thus solubility and permeability do not usually differ during product testing (3) BCS refers to aqueous solubility. However, the product may be evaluated in buffer solutions with or without solubilizers. (4) Often, reference is made about BCS in predicting the bioequivalence of two products, based on their in vitro release (dissolution) characteristics, e.g., in the case of developing IVIVC. It is important to note that, one does not use BCS criteria for evaluating bioequivalence (which is in fact assessment of in vivo drug dissolution/release). Similarly, therefore, in vitro assessment of equivalence of two products having the same drug and strength should not require the use of BCS classification as well.

In vitro drug release or dissolution, tests are conducted to assess the dissolution of the drug in a medium in which the drug must be freely soluble. The choice of medium is made prior to conducting a dissolution test so that the medium provides sufficient solubility to achieve the so-called sink condition. All drugs must be freely (highly) soluble in the dissolution medium. Therefore, for the evaluation of in vitro drug release, there are not two classes but one, i.e., the high solubility of the drug in the medium.

It appears that the use and application of BCS criteria for in vitro drug release testing requires a careful reconsideration, and its use can be reduced without any negative impact on products evaluation, however, with potential gains in economic efficiencies.

Like any other product evaluation, pharmaceutical products are also evaluated using various analytical tests. Following the product development stage, these tests become quality control or assurance tests and are required to be conducted to establish the quality of the products for sale. Commonly, pharmacopeial, such as USP, standards are followed for this purpose.

For solid oral pharmaceutical products such as tablets and capsules, these tests include (1) Identification – to establish or confirm the expected identity of the drug within a product; (2) Assay or Potency – to establish the presence of the expected amount of drug in the product; (3) Uniformity of Content – to establish unit to unit (tablet/capsule) variation in the drug amount (4) Drug release/dissolution test – to establish that the drug would be released from the product in an expected and reproducible manner.

These tests are usually conducted separately. One common aspect of these tests is that these all usually require an extraction step followed by quantitation using chromatographic or spectrophotometric methods. Drug dissolution testing by itself is an extraction-based test in which a drug from the product is extracted in an aqueous-based solvent (e.g. water or buffer having pH 5-7) maintained at 37 ºC. The extraction using an aqueous-based solvent mimics the physiological environment of the human GI tract, where the drug is expected to be released for absorption. Drug dissolution testers, therefore, become a drug extracting apparatus or extractor. However, these apparatuses are not considered or have not been used as extractors because the apparatus’s stirring and mixing process is poor, thus providing poor extractions. Considering the poor stirring and mixing aspect of these apparatuses, in particular Paddle and Basket, these apparatuses do not generally provide an accurate reflection of the drug release characteristics of products, as has been reported frequently in the recent literature. To address this artifact of poor stirring and mixing within a dissolution tester, recently, a modified stirrer, known as crescent-shaped spindle, has been suggested for the dissolution apparatuses. It makes an apparatus an efficient extractor and thus provides improved drug dissolution characteristics.

With this modification, the apparatus may also be utilized as any other extractor and may be used for other above-mentioned tests. Thus, all the above-mentioned tests can be conducted using dissolution tester/extractor with the modified spindle or stirrer.

By reversing the logic, one could say that this modified dissolution tester may be used to conduct assays, content uniformity, and identification tests. However, rather than using a harsh stirring condition, as commonly used for such tests, one would use gentler conditions such as 25 rpm, thus the extraction step will become a dissolution test as well. Therefore, in a single step one would be able to evaluate all these attributes.

There are a number of advantages of using this approach. (1) Obviously, it will provide significant economic savings as one vs. four test would be needed. In addition, testing or product evaluation will be completed extremely fast, thus, saving time. (2) The testing will be more physiologically relevant as the test conditions (medium or stirring) mimic the GI tract environment. At present, tests are usually conducted without concern of the physiological aspect. These tests are usually conducted using organic solvents, high pH aqueous solvents, along with high impact processes such as crushing and extracting and at high rpms in blenders or using a mortal and pastel. (3) With the new spindle, the recommended experimental conditions are water (with or without a solubilizer) and 25 rpm, thus, nearer to physiological relevancy.

A dissolution tester, thus, with crescent-shaped spindle provides not only more appropriate drug dissolution evaluation but also simultaneously provides answers for other quality tests. Hence, the term One Step (Product Evaluation) Approach is coined, reflecting improved testing along with savings of time and money. For further description about using a dissolution tester, please see the publication for other quality parameters. The Open Drug Delivery Journal, 2008, 2, 33-37. (Link)

The FDA provides 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.

Breakdown of apparatuses use

*Other RPMs include (30, 40, 150, 175 and 200 =10 entries)

**Other RPMs include (40, 120, 150 and 180 = 6 entries)

^#27 were others including 2 for flow-through.

Breakdown of media use

There are 270 unique entries in the medium category, which may be considered 270 different types of media employed. These differences are based on different combinations/permutations of the nature of the medium (HCl, water, phosphate, acetate, citrate etc.), molarities/normalities, and pHs. If one adds to these the choices of apparatuses and their RPMs, then the unique entries become 317.

The majority of the suggested experimental conditions appear to be based on Paddle Apparatus (413/545), using media in the pH range of 5 to 7.5, which would include water as well (317/545).

The obvious question is that if most of the tests can be conducted using the paddle apparatus and a medium having a pH between 5 and 7.5, such as water itself or phosphate buffer (~pH 6), why so many unique experimental conditions? This may indicate the deficiency/limitation of current practices of dissolution testing, which should be addressed.

Notes:

1. In many cases, the breakdown is subjective as it is difficult to categorize the choice e.g., the entry (Water, pH 3.0, adjusted with 0.1 N or 2 N HCl) was excluded as it neither represents water nor HCl. On the other hand, the 2 entries: (1) pH 6.8 buffer and (2) 0-2 hours: 0.003% polysorbate 80, pH 1.2 2-8 hours: phosphate buffer, pH 7.2; are considered to be phosphate buffer.
2. In some cases, multiple media are suggested, e.g. (50 mM potassium dihydrogen phosphate buffer pH 6.5 Comparative dissolution data should also be provided in 900 ml pH 0.1 HCl, pH 4.5 buffer, and water using Apparatus II). Thus, there is a discrepancy between the total number of entries and the sum for the individual medium.

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 carbamazepine described in the USP are as follows:

As the GI tract environment remains the same for both IR and ER products, testing using the conditions mentioned above 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. Therefore, all of the products can be analyzed using a single set of experimental conditions, such as:

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

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 what would the response be from a standard-setting body? A clear and 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 the acceptable performance of dissolution apparatuses? Unfortunately, there is no or limited scientific evidence available to support the link between 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?” A 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. Then, if needed, some solubilizing agent (e.g., SLS) may be 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. Furthermore, this apparatus and its associated experimental condition must provide 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 a reference product with known dissolution characteristics. Once an analyst can determine the acceptable results of the reference product using a standardized tester, then this tester is to be used to determine the unknown dissolution characteristics of the test products. Suppose the results are not as desired or expected. In that case, 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 dissolution tester nor a reference product is available to the analyst, but the technique is expected to provide dissolution characteristics of a test product. The analyst has to be confused and frustrated and 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).

A number of guidance documents are available from different regulatory agencies, particularly the US FDA, to facilitate and expedite drug products development and evaluations. These guidances are related to dissolution method developments, apparatus calibration, and product evaluations. In many cases, these guidances and related practices are commonly referred to by their acronyms, such as BCS, IVIVC, SUPAC, bio-waivers, similarity factor (F2), QbD, PVT, mechanical calibration. Examples of such commonly referred guidance documents are listed under the publications section.

It is important to note that these guidances solely or significantly depend on the use of dissolution (Paddle and Basket) apparatuses. Therefore, the success or applications of these guidances are dependent on the outcome of these apparatuses.

In recent years, it has generally been recognized that Paddle and Basket apparatuses do not provide relevant and reproducible dissolution results. This is because of the poor hydrodynamics (or lack of efficient stirring and mixing) within dissolution vessels. Therefore, intended benefits from the use of the guidance documents may also become suspect.

Appropriate use and interpretation of the guidance documents require relevant and reproducible results. This may be achieved by conducting dissolution tests using apparatuses that are free from Paddle and Basket’s deficiencies, that is, apparatuses with improved and efficient stirring and mixing environments.

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 the choice of apparatuses, RPMs or flow rates, media (nature and volumes), etc. Thus, current practices defeat the purpose of dissolution testing, which is 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 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 finding the actual drug dissolution or release characteristics of a product or help in knowing one’s product. If one keeps on changing the experimental conditions, one will never know the products’ true (dissolution) characteristics.

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 a 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.) 

Considering the above criteria with a Q-value of 80, one can obtain the following set for acceptable results.

Therefore, one may observe an RSD (CV) of 20% or more, and the results/product would be of acceptable quality for regulatory purposes. The expected high variability (RSD/CV) in results is built in the tolerances.

In this particular case, the test would meet the criteria at the stage 1, thus testing for the next stages would not be required. However, this may be a random phenomenon and one may get results as shown for Stage 2 or 3, at the first stage as well. These tolerances are for last dissolution sampling time, where dissolution is the highest with the least variable results. However, if dissolution results are to be reported for earlier times (such as for extended-release products), the expected variability would be higher.

Therefore, the above discussion clearly indicates that the dissolution results, particularly using Paddle/Basket apparatuses, are expected to be highly variable, often more than 20% RSD. Therefore, as often desired or suggested, setting tolerances tighter would not be scientifically valid or achievable. In that case, one would face a higher number of failures without any apparent reason, as is the case with the testing of the USP PVT prednisone tablets where tolerances are usually set tighter than one would observe in real life, thus failures.