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Commonly dissolution tests are to be conducted to assess the potential in vivo drug release characteristics of the products in humans. It is to be noted that it is the only objective of conducting a drug dissolution test. However, there has been limited success in achieving this objective because the currently suggested (mandatory?) apparatuses lack in providing an appropriate in vivo environment, particularly in terms of stirring and mixing. Therefore, rather than addressing this deficiency, unfortunately, the testing is often presented with two made-up objectives, i.e., without a scientific basis, in particular for the tests described in the pharmacopeias (e.g., USP). (1) It is often described that pharmacopeial tests should only be considered as quality control (QC) tests. (2) Moreover, as these QC tests are often not linked to any “quality” attribute or performance of the products, these pharmacopeial tests are then suggested to be considered as tests for monitoring the lot-to-lot consistency of the products. Thus, as these so-called “QC” or “consistency check” tests have no link to the product attributes. Therefore, they can be developed using any of the experimental conditions to meet some arbitrary criteria.

One such arbitrary criterion is that about 80% of the drug should be released within 30 to 45 minutes using a Paddle or Basket apparatus for an IR product. This in essence, is the requirement for a pharmacopeial dissolution test.

To meet the criterion or requirement, the analysts/formulators have to search for an appropriate set of experimental conditions, mostly medium (nature, pH and volume) and rpm for paddle/basket. This search for the experimental conditions is then commonly referred to as the “method development” step or with other different names such as “developing a discriminatory method”. Furthermore, it is generally recognized that the use of paddle/basket apparatuses provides unusually high variability and unpredictability in results. Reporting of variability (%RSD or %CV) in results is generally ignored or not required! Thus, the pharmacopeial standards and requirements are of limited relevance to product characteristics.

An example may elaborate the above discussion based on the current USP requirements for doxycycline hyclate products which are:

Doxycycline Hyclate Tablets:
Test 1= Paddle (75 rpm) with water (900 mL); Test Duration=90 min with Q=NLT 85%
Test 2= Paddle (50 rpm) with water (900 mL); Test Duration=30 min with Q=NLT 85%
Doxycycline Hyclate Capsules:
Paddle (75 rpm) with water (900 mL); Test Duration=30 min with Q=NLT 80%)

NLT= “not less than.” It is important to note that there is also a unique requirement in the monographs that “the distance between the blade and the inside bottom of the flask being maintained at 4.5 ± 0.5 cm during the test”. Commonly, this distance is set at 2.5 ± 0.2 cm.

As there are two methods for the tablet products, the analyst is expected to try both methods. If the products meet the first method, then it should be considered as the choice. Otherwise, the labeling should indicate that “it (product) meets USP Dissolution Test 2” as per USP monograph. The test conditions for the capsule product are somewhat hybrid of the two tablet methods with a lower Q value.

There are no guidelines available in the literature to describe how one should select a particular set of experimental conditions. The only criterion, as stated above, is that one has to show that drug release should be around 80% within 30 to 45 minutes (In this case, the duration of the test is 90 minutes as well, why?). The time requirement increases from minutes to hours for extended-release products, commonly between 6 to 24 hours.

In short, the pharmacopeial methods and standards for drug dissolution testing are generally not linked to the products’ quality attributes or performance. These tests can be developed using any preferred experimental conditions to achieve the desired end point, such as NLT 80% drug release for IR products within 30 to 45 minutes.

It is important to note that if one would like to assess the actual (“true”) dissolution characteristics of a product or its quality, then one requires a validated method using a reference product, not based on the test product itself. As described currently in pharmacopeias, Method  For further discussion in this regard, please see the links (1, 2, 3).

The US FDA (CDER) released a document on the above-mentioned title (Link). This single-spaced 161-page long document provides an example of conducting and reporting studies for developing generic drug products as per the QbD (Quality by Design) approach.

It appears that this document may also be considered a “How-to manual on drug dissolution testing”, as a significant portion of the document describes the development and application of the dissolution testing.

It may be argued that if current practices of drug dissolution testing would not have faced so many problems/deficiencies and uncertainties, the procedures and documentations provided would certainly be simpler and shorter. Therefore, indirectly, the document may be considered as long-awaited recognition of the fact that current practices of drug dissolution testing are complicated and complex and may not be working as well as one should expect.(please click here for the complete post).

In simple terms, a dissolution method transfer protocol (“protocol”) is a description of a mutual understanding of two parties, developer or current user of an analytical method (“originator”) and the receiver (“recipient”) of the method as to how a dissolution test is to be conducted.

There are numerous situations where such protocols are needed, such as transferring a method from R&D to the QC section, one plant to another plant, manufacturer to contract organization (CRO) or sub contractor, etc. The easiest and most practical approach for developing the protocol appears to be that both parties work together to develop step-by-step instructions that can be followed by current or future analysts to conduct the test as expected to produce consistent results.

The understanding between the two parties reflects how a test is to be conducted and what kind of output should be expected. The protocol can be: (1) simple/verbal understanding between parties such as preparation of a 0.05M phosphate buffer having pH 5.8 as per USP or; (2) detailed and documented (written) step by step set of instructions for conducting the analytical test, e.g., dissolution. In both cases, the common aspect is that the method should be able to provide an output that can be compared, for example, the final pH of the buffer solution or dissolution results. For the comparison of results between two parties, two sets of values are often used: the mean and standard deviation (STD) describing the characteristics of the test product.

Comparative testing is the most common form of method transfer approach in the pharmaceutical industry. It involves two or more laboratories executing a preapproved protocol resulting in data (means and STDs). The similarity or equivalency of these data is established based on statistical evaluation, often using a Student t-test.

The most critical thing to consider here is that similarity or equivalency of results from the two parties or laboratories can only be established based on statistical evaluation using means and STDs. If the laboratories or parties cannot provide appropriate values for these two parameters, then the method’s comparison cannot be established. There is no benefit of writing a protocol no matter how careful or elaborate practice of protocol writing may be.

In addition, a protocol requires a common product for testing with expected mean and STD values. This common product can be an in-house developed product or a reference product from an external source, such as a USP Reference Standard (RS).

In short, a method transfer protocol may be considered as a step-by-step cook-book type set of instructions (recipe) to follow for analyzing a (reference) product to obtain mean and STD values of parameter/characteristic, such as dissolution.

The question is, can such a protocol be written for a dissolution method transfer. The simple answer is, no. The dissolution tests as currently conducted would not meet the requirements for developing the protocol. Reason #1: A reference drug product with known dissolution characteristics, in particular, in humans, is not available. Reason #2: Commonly, dissolution results are reported as individual values (e.g., Q-based), mostly without STD values. Therefore, appropriate (statistical) comparisons of results would not be possible.

Often I have written about the deficiencies (flaws) of the Paddle and Basket apparatuses in obtaining relevant and useful dissolution results. The underlying cause of these deficiencies is a poor stirring and mixing environment within dissolution vessels. However, as a long-held tradition, these apparatuses are recommended and used for dissolution testing. As the apparatuses do not provide a relevant in vivo environment, obviously, in vitro results would not be relevant to in vivo characteristics of drugs and their products. However, to maintain the status quo, the dissolution results obtained are rationalized as legitimate and useful. Considering numerous queries in this regard about drug glimepiride, I came across a publication (link) which may help in explaining the current dilemma of an analyst in dealing with in vitro drug dissolution testing. (please click here for the complete post).

The most common dissolution/release tolerances for tablet and capsule products as per USP are 80% of the drug dissolved/released at the suggested time. The question is, where does the remaining 20% of the drug go, especially, when the product meets the requirement of Assay and CU of 100%. From a consumer/patient perspective, it is like buying a 1L milk carton but being assured of receiving only 800 mL! Please, note that in many cases, the USP tolerances can be as low as 70%.

If USP tolerances are considered correct, then a product user is expected to receive less and/or an inconsistent amount of drugs. It is to be noted that all bioavailability/bioequivalence (BA/BE) studies results are reported based on 100% deliverable drug. As Assay and CU show, on average, 100% content and BA/BE assumes delivery of 100% of the drug in humans, it indicates that demonstration or requirement of less than 100% in vitro dissolution/release is an inaccurate tolerance (standard).

The reason for this discrepancy (observance of lower in vitro dissolution/release) is the poor stirring and mixing environment within the dissolution vessels using paddle and basket stirrers.  The poor stirring environment creates unstirred pockets within the vessels where the drug hides. These pockets depend on the nature of the product, in particular excipients, and can hide as much as 40% of the drug as in the case of the dissolution results of the USP Performance Verification Tablets (see Figure). If this flaw of unstirred pockets is addressed, then one can observe the release/dissolution of 100% of the drug. This means that not only will dissolution results match with the Assay and CU results, but SEPARATE monitoring of Assay and CU becomes redundant. This leads to simplification, efficiency, and accuracy in overall product evaluation and development (see also related links 1, 2, 3).

Estimating drug conc.-time (C-t) profiles from drug dissolution results requires the use of a few PK parameters of the drug (link). The values for the parameters can be obtained from the literature, however, these values may vary from study to study or source to source. This makes the comparison of results (profiles) between studies difficult. To minimize such differences and for improved comparison, a list of values of these parameters would be useful.

To fulfill this need a new list under the “Useful Lists” section has been added (link). The values described in the list are those which are considered appropriate at this time. However, the list and values are subject to change if and when more appropriate values are suggested. Please consider contributing to the list by submitting suggestions for new additions and/or revisions to moderator@drug-dissolution-testing.com

Commonly pharmaceutical products are evaluated and developed based on four “quality” parameters/measurements: (1) Identity, to show that a product contains the expected drug; (2) assay, to show that a product contains expected amount of drug (dose); (3) Content Uniformity (CU), to establish that the dose or drug content in each unit varies within an expected range; (4) Dissolution/release, to show that the drug will be released from the product in an expected manner. All these tests are simple chemical tests based on solvent extractions, i.e., the drug is extracted from the product and measured using any of the quantitative techniques such as spectrophotometric or chromatographic.  For the complete article, click here.

Drug dissolution test as a quality control test: In simple terms, at present, a dissolution test as a QC test means conducting a dissolution test as described in a pharmacopeia, in particular USP. If the test meets the pharmacopeial (Tolerances) requirements, the product may be considered a “Quality” product. It is, however, not clear what “quality” the test refers to or to what product property the test is linked to? Therefore, to overcome this lack of objectivity/relevancy, pharmacopeial tests are described as “consistency” tests. Again, it is not clear the “consistency” of which property or parameter the test is referring to?

Dissolution testing during product development: One of the main uses of dissolution testing is to facilitate product development. This use is based on the principle that the tests should be able to provide potential in vivo drug release behavior information. However, this is a commonly recognized fact that currently used dissolution tests generally do not provide in vivo relevant product characteristics. Thus, current practices of dissolution testing at the product development stage appear to lack relevancy and objectivity.    

Practices of methods development: Developing a method requires a well-established and accepted reference (product or parameter). In this case, a reference product should be available with known drug dissolution results established independently. As there is no reference product with known dissolution results available at present, it is not possible to develop a dissolution method. As commonly suggested in the literature, developing a method based on test products (with unknown dissolution characteristics) is neither scientifically valid nor possible.

Dissolution apparatus selection: Selecting adissolution apparatus should also be part of a method development exercise. An apparatus must be able to provide a relevant testing environment. Current practices appear to suggest that relevant apparatuses, and associated experimental conditions, are those which are described in the pharmacopeias only. On the other hand, it has never been shown that suggested apparatuses and the associated experimental conditions are suitable for their intended purpose. That is, the suggested apparatuses have never been validated for the intended purpose.

Selecting experimental conditions: Choices of experimental conditions such as rpm and buffers described in the literature appear to be arbitrary and random. Moreover, experimental conditions are selected to achieve some desired dissolution characteristics of the test products. Thus, a formulator/analyst would never know the “true” dissolution characteristics of the product. Experimental conditions must be linked to the physiological environment and be product-independent. Drug and/or product-dependent experimental conditions, as commonly described, are neither scientifically valid nor relevant.

Establishing IVIVC: Developing IVIVC commonly refers to RELATING in vitro dissolution results to in vivo dissolution results using a mathematical approach of de-convolution.However, in general, dissolution tests are conducted based on the principle that in vitro release should relate well with in vivo results. Therefore, it is unclear why every manufacturer/analyst has to go through this exercise of establishing this in vitro-in vivo link for each product. In addition, as stated above, the current apparatuses/practices of dissolution testing have never been validated for providing relevant in vivo dissolution characteristics, so why should one be expected to achieve appropriate IVIVC?