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Provided are links to two recent articles, written by Dr. L.T. Grady who was Vice President and Director of USP Division of Standard Developments (1980-2000), from the website of Dr. T. Layloff, who later himself was Vice President and Director of USP Division of Standard Development. 

The titles of the articles are “Letter on the Adequacy of Dissolution Testing” and “Perspective on the History of Dissolution Testing”.

The contents of the articles are quite revealing, indicating that the high variability in dissolution results and their poor link to the product quality were well known within USP.

The objective of drug dissolution testing is to determine drug release characteristics of a product i.e. how fast or slow a drug would be released from the product reflecting its formulation and/or manufacturing attributes (properties).

In reality, however, current practices of dissolution testing seek product-dependent experimental conditions based on choices of apparatus, rpm/flow rate, and medium (its pH and strength) to attain a desired or expected dissolution rate. “True” dissolution characteristics of a product can never be known. Using the current dissolution practice or approach, multiple dissolution methods are often described for the same product under different names such as bio-relevant method, discriminating method, QC method, USP method, FDA method, etc. differing in experimental conditions, each providing different dissolution results.

That is why it is commonly referred that one should consult the authorities to establish the method and to determine if the results would be acceptable to the authorities.

For establishing “true” dissolution characteristics, like any other analytical method, a dissolution method must be product-independent. Developing a product independent test leading to determining “true” dissolution characteristics of a product is relatively simple, saving significant financial and human resources compared to the current practices. For further discussion on this aspect, please see the article and details of the upcoming course.

Summary:

Using a recently suggested approach, based on IVIVC principles, C-t profiles (or blood levels) are determined for different strengths and release types (IR and ER) of carbamazepine products from in vitro drug dissolution results. Drug dissolution tests were conducted using the crescent-shaped spindle (25 rpm) with 900 mL of water containing 0.5% of SLS as the dissolution medium. Predicted blood levels along with the derived pharmacokinetic parameters (Tmax, Cmax, and AUC) compare remarkably well with the corresponding human in vivo values reported in the literature. It appears that the approach described previously, and further detailed here, provides a powerful analytical technique for predicting blood levels and then evaluating product quality by establishing their equivalencies. (Link to complete article)

Often analysts face a dilemma as to how to approach the situations mentioned above, which appear to be quite common in the industry. Such situations arise because of the current practices of developing and using product-specific experimental conditions such as apparatuses, rpm, media, etc. The experimental conditions are set by obtaining desired or expected drug release characteristics of the test product, which are only associated with that test product. If the expectation of dissolution results are changed or change is made to the product (formulation/manufacturing), the test would require a different set of experimental conditions, reflecting new expectations. In short, the current practices do not provide true dissolution characteristics of products.

To avoid such a situation or developing a modified method, one should develop a product-independent method based on a physiologically relevant environment that does not change from product to product. The physiologically relevant method provides appropriate and unbiased dissolution characteristics of the products and frees the analyst from a constant struggle of looking into altering and selecting experimental conditions.

There are suggestions in the literature (1, 2, 3) for conducting physiologically relevant tests independent of products, which may answer the above-mentioned situations and significantly simplify dissolution testing in general.

The terminology of “developing IVIVC” is often used in the area of drug dissolution testing, which reflects developing a relationship between in vitro (dissolution) and in vivo (bioavailability) results.  However, the statement appears redundant, as this relationship always exists between in vitro and in vivo results. In fact, the existence of this relationship (IVIVC) forms the basis of dissolution testing practice. 

So, then the question is, why are these IVIVC development studies frequently conducted and described in the literature? The reason may be explained as follows:
 
The apparatuses commonly used for dissolution testing, particularly paddle and basket, do not provide relevant dissolution results as they do not appropriately simulate an in vivo environment. So, instead of using apparatuses that would appropriately simulate an in vivo environment, studies are conducted to find or “develop” experimental conditions to obtain in vitro results that match the in vivo results. Thus this practice of developing product-specific experimental conditions (apparatus, medium, rpm, etc.) has become known as “developing IVIVC”. However, this practice of IVIVC does not serve any useful purpose for predicting in vivo results, relating in vitro results to in vivo outcomes or assessing drug release characteristics of the product. Having said that, the question then becomes, what is the intended purpose of IVIVC development?  The purpose is not to develop IVIVC, as stated above, this relationship always exists, but to determine/predict the drug concentrations in blood utilizing the IVIVC concept. Thus, the practices of IVIVC and dissolution testing are for establishing (calculating/predicting) drug concentration-time (C-t) profiles in humans. For a more detailed discussion on this subject, along with a description of a simple method for determining C-t profiles,  please see the article (The Open Drug Delivery Journal, 2010, 4, 38-47. (Link).

European Medicines Agency (July 14, 2010): A concept paper on the revision of the note for guidance on the quality of modified-release oral dosage forms and transdermal dosage forms: Section I (quality).

… The main topics to be discussed during the revision of the guideline in the context of modified-release oral dosage forms are: … (Link)

USP provides Reference Standards (Abbreviated by RS symbol) for drug substances. In practical terms, their purpose is to provide a goal post or reference against which purity (quality) of drug substances, and then drug products, be established. An RS comes with its purity certificate, established independently by different analytical tests. These RS compounds are used extensively for qualification, development, and validation of analytical methods such as chromatographic or spectrophotometric. In addition, for cost/expense savings, often these standards are used as primary standards for developing in-house secondary standards.

As stated above, these standards are used for various purposes utilizing numerous analytical techniques, such as HPLC, TLC, GC, GC/MS, and other much more involved analytical techniques. However, they are not described as performance evaluation standards or faults/deficiencies detectors of the apparatuses. These standards are to be used to indicate deviation/variations in diameters of the glass capillary or HPLC columns, flow rate of mobile phase (gas or solvent) through columns, temperatures of oven or enclosures of columns, or the training/expertise of the analysts. It is usually understood that if the apparatuses are operating under their expected physical and operational specifications in the hands of experienced and trained analysts, then their output using RS would be exactly as described in the certificate of analyses. If not, then necessary corrective measures are to be taken, which may or may not be relevant to the technique itself. For example, purity or composition of the mobile phase and the instability of electric current may cause out-of-spec results or apparatus performance. This does not mean that the RS will become a performance evaluation procedure for solvent purity or stability of electric current or related circuit boards.

With this background, if one sees the current practices of Performance Verification Test or Tablets (PVT), which are also marketed by the USP as Dissolution RS Tablets, these tablets do not appear to meet the requirement of a reference standard. The reasons are: (1) Dissolution RS Tablets release values are not independently determined. The values are set using the apparatuses, which are then assessed by the use of these tablets. (2) The RS tablets have different values for different apparatus (e.g., Basket and Paddle). PVT must have the same values for all commonly referred apparatuses, Basket, Paddle, Reciprocating, Flow-through, and any other apparatus or technique suggested in the future. This is similar to the current practices for other RS standards, which are expected to provide the same results (purity) whether tested by UV, TLC, HPLC, GC, etc. (3) These PV Tablets do not have desired outcome characteristics. As the dissolution testers are used to establish potential drug release quality/characteristics of products in humans, the RS tablets should have known release characteristics in humans independently determined, e.g. based on pharmacokinetic studies. (4) Similarly, the RS Tablets should also be from an approved product for human use and within its shelf-life duration.

It is hoped that the suggestion will help develop improved RS Tablets and alleviate the difficulties one faces in using current Performance Evaluation Tablets.

In the absence of appropriate RS tablets, one may evaluate and establish operational parameters of the apparatus based on relative dissolution testing. In this case, one may analyze two products of know release characteristics in humans of the same API product, such as IR and ER. Both products should provide differential drug release characteristics within their recommended (prescription) dosage intervals. Based on such testing, the operational parameters of the apparatuses are set (fixed), which would be used for testing the test product. The product(s) used to establish or determine the operating parameters for the apparatuses would become the RS Tablets.

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.