See under “Useful Lists”.

A common query with regard to a dissolution test is how one should conduct the test for a drug. Further, in response to such queries, different suggestions are made for choosing the apparatus, rpm, medium etc. However, unfortunately, such queries and the responses lack scientific merit and logical thinking. The reason is that a dissolution test is conducted for a product and not for a drug (active ingredient). That is why pharmacopeial monographs, in particular USP, do not have dissolution tests under drugs (active ingredients) but products.

Therefore, one can only suggest a testing procedure for products and not for drugs. Further, a testing procedure is not, or should not, be linked to a product, because testing is done to evaluate product. Therefore, the procedure must be product independent. The question then becomes how one should set up the experimental conditions. The answer is that the dissolution testing conditions should be reflective of the GI tract environment, in particular intestinal. As the GI tract environment does not change from product to product, the testing procedure therefore should be fixed as well.

 A common testing environment may be based on water maintained at 37 °C, with some solubiliser to dissolve low aqueous solubility drugs, and a simple stirring mechanism which should provide efficient/thorough product-medium interaction.  Hope this suggestion will help in answering the common and frequent queries.

In a recent publication, USP describes prednisone based performance verification test (PVT) as,

“Lot P1 demonstrates sensitivity to test performance parameters (vessels and degassing)”.

It appears that that the use of PVT has been reduced to establishing the appropriateness of vessels and degassing of the medium rather than a performance evaluation test for the apparatuses or procedure as it is supposed to. Even claims for sensitivities of the two suggested parameters may be of questionable merit. Because; Continue reading →

In a recent publication, USP describes the dissolution procedure as,

“The procedure can function both as a quality control tool and, under specified circumstances, as a predictor of the dosage form’s performance in vivo.”

One may interpret this as an indication of very weak support for the continuation of the procedure, at least in its current format.

Stating that the procedure could be a predictor of in vivo performance of the product under certain specified circumstances, is a clear deviation from the commonly accepted understanding. The only reason a dissolution test was introduced was to replace a disintegration test which was considered a poor predictor of in vivo performance of the products. Therefore, now as per the publication, the current dissolution procedure appears to have the same limitation as that of the disintegration test, which obviously has limited use.

Further, if the procedure is to work in some cases, one would require some form of guidance in determining how these specified circumstances are to be determined or established.

On the other hand, describing the procedure as a quality control tool may also become redundant without in vivo relevance. In general, it is accepted that if a dissolution test, as a quality control tool, shows unexpected drug release, it would reflect potential unexpected in vivo drug release of the drug, leading to concerns about the quality of the product. However, if the in vitro and in vivo link is severed or weak, then what would be the rationale of using a dissolution procedure as a quality control tool?

The publication appears to have added serious confusion regarding the usefulness of the PVT procedure and the current practices of dissolution testing.

In a recent publication from USP it is concluded that,

“Apparatus 1 results are stable over time. Those in Apparatus 2 show a decrease over time in the geometric mean but show no trend in variability”.

If all things being equal for testing except differences in apparatuses used, then is it not obvious that instability in results would reflect the instability of Apparatus 2? The conclusion from the USP supports the observation/results reported in the literature regarding poor performance of Apparatus 2. This poor performance in testing is a reflection of poor hydrodynamic environment within dissolution vessels as described extensively in literature. Thus, the use of Apparatus 2 would require caution.

 USP calendar shows an entry of a planed webinar to address the problems in the dissolution testing area. USP is requesting submission of questions so that issues and concerns may be addressed in this regard. The following are some suggested questions/concerns which USP may consider addressing during the webinar or later.

1. USP usually recommends the use of Paddle and Basket apparatuses for drug dissolution testing as a first choice. Are there any documented reasons (evidence) for these choices showing their superiority compared to other apparatuses? How have these apparatuses been validated as appropriate dissolution apparatuses to evaluate pharmaceutical products for human use?
2. Commonly, as a general practice, USP suggests experimental conditions for individual products (monographs) to establish their drug dissolution characteristics. This aspect is also described in more detail in the chapter <1092>. The practice Continue reading →

It is important to note that the emphasis is on the “practice” and not the drug dissolution testing itself. A drug dissolution test is an important and extremely useful test and is required for the development and evaluation of pharmaceutical products, in particular tablet and capsule. However, how the test is conducted, which is referred here as the “practice”, is very different from dissolution testing itself. One should keep this difference in mind.  Continue reading →

Hello Vivian:

As suggested, I am posting your response to the above mentioned post, along with an Editorial note from myself. Regards. Saeed

Editorial Note:

To address this response, I would like to make it clear that in my post I was referring to a potentially diminished role in the future. Also, I assume that your comments are reflective of your personal views and not those of the USP or the new Expert Advisory Committee.

Response:

Dear Saeed, I feel I have to respond your recent posting on your website about Changes at USP. Please be sure you have seen the article in the August issue of Dissolution Technologies that gives the make up of the new USP committee. This information in is the USP update with Tom Foster achieving the Beal award. In that article the new members of the new committee are listed. There are five members of the BPC committee that are now on this new committee. They are Mario Gonzalez, Johannes Kramer, Tom Foster, Alan Parr and I. These people were very much involved with the PVT and I can assure you that the work will continue in the new committee and at the USP labs. The USP has published many articles in Pharmacopeial Forum (PF) about the PVT and evaluations of variables using the Prednisone Standard Tablets. Also if you look in Dissolution Technologies (DT), www.dissolutiontech.com back issue there are a plethora of articles on the dissolution variables and the USP Prednisone Tablets. Also in DT we have reprinted many of the PF articles about the PVT and the new criteria. So the “absence of clear information” is not accurate. If you go to the USP website there are many places for information on the subject including the USP Tool Kit on mechanical calibration. As a point of interest, the PF will be available on line for free in 2011.

I was hoping that I could respond on your website but the comments are closed. Please consider posting my reply to you in this public forum.

Best regards, Vivian

9 Yorkridge Trail
Hockessin, DE 19707 USA
Tel. 302-235-0621
Fax 443-946-1264

vagray@rcn.com
www.vagrayconsulting.net
www.dissolutiontech.com (now searchable, check it out)

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.

Current practices of drug dissolution testing require that the experimental conditions, such as medium and its volume and apparatus and its associated stirrer rotation speed, be established for each test product to achieve certain ‘expected’ dissolution characteristics or results. In reality, however, the purpose of dissolution testing should be to determine potentially unknown dissolution results reflective of a test product based on its formulation and/or manufacturing attributes. For appropriate testing, in particular for comparative purposes, the experimental conditions must be the same or consistent from product to product i.e. product independent. This article describes a newly developed spindle, known as crescent-shaped, which can easily be installed in the vessel-based dissolution apparatuses (basket and paddle) to provide a product-independent dissolution testing approach for improved drug dissolution assessments. The new spindle provides an improved stirring and mixing environment, leading to better characterization of pharmaceutical products. The use of the crescent-shaped spindles offers additional significant advantages over the current practices, such as: (1) allows analyses using a single method, compared to hundreds as currently required, for both immediate and extended-released products having the same or different active ingredients; (2) provides improved dissolution characteristics of products by avoiding false slow release properties for fast release type products; (3) simplifies testing by avoiding the necessity of developing separate QC and bio-relevant dissolution methods; (4) provides a rugged testing environment free from common sensitivities, in particular to de-aeration and vibration effects. (Link to the article).

The upcoming 1-day course will cover this topic in further detail.

It may be said that analysts performing drug dissolution tests are in a pretty difficult situation. They are expected to conduct appropriate dissolution tests to determine the quality of a product based on its in vitro drug release characteristics. However, procedures described in the literature (e.g. USP <1092>) or commonly taught in courses provide suggestions for choosing/selecting experimental conditions to achieve (match) a desired or pre-set dissolution outcome. These desired dissolution characteristics are commonly obtained by selecting apparatuses (mostly between basket and paddle) and/or by adjusting rpm, pH or molarity of medium/buffer and/or solubiliser (nature or amount). Therefore, it is important to note that the analyst, following the currently suggested procedures, will never know the true or actual nature of drug dissolution characteristics of the product, thus its quality. Continue reading →

The USP in general, and its Biopharmaceutics Expert Advisory Committee (EAC) in particular, has been at the centre of developing standards and procedures for drug dissolution testing for the past three decades. However, this EAC has been dissolved for the coming cycle (2010-2015) of the USP expert committees. The activities/responsibilities of the now-dissolved EAC have been transferred to a committee for General Chapter on Dosage Forms, with very few members from the earlier EAC. There has been lack of clear information from the USP on this particular change, especially at a time, when the dissolution community is seeking answers for the difficult and frustrating problems related to the drug dissolution testing. Often, these relate to the use of drug dissolution testing for product evaluations and the use and relevance of PVT.

 In the absence of clear information and an apparent significantly diminished role in the future, one can only speculate on the possible scenarios. One of those could be that the USP may be reducing its laboratory based activities (research?) in the dissolution area as there has been limited or no success, but rather frustrations, during the past number of years. The USP may be reversing to a more traditional role for setting objective standards based on the contributions from external sources. If this assumption is correct, then the change at the USP may be considered good. This will provide the industry and others to make needed contributions and for the USP an approach for critically evaluating the problems and accepting the solutions.

Sub menu “List of Publications” has been changed to “Useful Lists” as there will be more than one list under this sub-heading which will include the publications list (appears quite popular and frequently downloaded). A new list has been added to include titles of the posts with hyperlinks for your convenience of access and reading. 

Your interest in our website is highly appreciated and we look forward to your feedback and suggestions for improvement. Please submit your comments and suggestions to the moderator.

Like any other analytical test, a dissolution test must also be repeatable and reproducible, with a reasonable/acceptable variability as reflected by RSD (or CV) values, say within 5 to 10%. This acceptable variability should be based on a reference product (e.g. PVT) and obtained from a multi-lab evaluation.

It has been shown from experimental studies, and computer simulation models, that such a desired variability is not possible to obtain using the current apparatuses, in particular paddle/basket. Recent discussions of unexplained high failure rate of PVT are also a reflection of high variability in testing. Therefore, in general, it is not possible to rely on such a highly variable method to establish consistency of the product quality.

As a common practice, analysts prefer to use compendial methods, if available, to evaluate pharmaceutical products. There are clear advantages of using such methods, as the results obtained are easier to be accepted by third parties including regulatory agencies.

On the other hand, in some cases, where compendial methods lack desired characteristics or found to have flaws, then such a practice seriously hampers the appropriate testing and thus proper evaluations of the products. This leads to significant frustrations on analysts’ part as well as demands for a large resource (human and financial) burden on the pharmaceutical industry. Continue reading →

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 current practice or approach, often multiple dissolution methods are 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 which would save 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 seminar.

This course is designed to provide: (1) clear understandings of the principles, uses and practices of dissolution testing; (2) suggestions for improving and simplifying the testing by addressing the limitations of current practices; (3) demonstration and availability info for the crescent-shaped spindle. For information on future courses, please email: (contact)

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 how to approach the above mentioned situations, 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 associated with that test product only. If the expectation of dissolution results are changed or change is made to the product (formulation/manufacturing), the test would require different set 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 which does not change from product to product. The physiologically relevant method not only provides appropriate and unbiased dissolution characteristics of the products, but also 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 provide answers to 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, in reality, the statement and view appear redundant, as this relationship always exists between in vitro and in vivo results. In fact, 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, in particular paddle and basket, do not provide relevant dissolution results as they do not appropriately simulate an in vivo environment. So, instead of using apparatuses which would appropriately simulate an in vivo environment, studies are conducted to find or to “develop” experimental conditions to obtain in vitro results which would match the in vivo results. Thus this practice of developing product specific experimental conditions (apparatus, medium, rpm etc) has become known as “developing IVIVC”. This practice of IVIVC does not serve any useful purpose for predicting in vivo results, relating in vitro results to in vivo outcome or assessing drug release characteristics of the product.

Having said that, question then becomes, what is the intended purpose of IVIVC development?  The purpose is not to develop IVIVC, as stated above this relationship always exist, but determining/predicting the drug concentrations in blood utilizing the IVIVC concept. Thus, the practices of IVIVC and dissolution testing are in fact for establishing (calculating/predicting) drug concentration-time (C-t) profiles in humans. For a more detailed discussion on this subject alongwith description of a simple method for determining C-t profiles,  please see the article (The Open Drug Delivery Journal, 2010, 4, 38-47. (Link).
 
It is very important that one keeps this understanding in mind, otherwise conducting a dissolution test and the results obtained from the testing would be of limited or no value.

European Medicines Agency (July 14, 2010): Concept paper on the revision of the note for guidance on 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 own purity certificate, established independently by different analytical tests. These RS compounds are used extensively for qualification, development and then 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. Continue reading →

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 very important to note that BCS relates only to drugs (APIs) and their characteristics and not to the products.

These two factors (solubility and permeability) indeed play a critical role, keeping all other factors equal, for the evaluation of 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 blood stream depending on their solubility/permeability characteristics. Potentially, the drug in the group I would show fast and high absorption (least hindrance to absorption), drug in group IV would show slow and erratic absorption (highest hindrance) while drugs in group II and III would show absorption in between. Therefore, BCS certainly provides a good basis for assessing potential absorption behavior of a drug in humans. Continue reading →

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. Continue reading →

A number of guidances are available from different regulatory agencies, in particular 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, success or applications of these guidances are dependent on the outcome from these apparatuses.

In recent years, it has generally been recognised 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 which are free from the deficiencies of Paddle and Basket, that is apparatuses with improved and efficient stirring and mixing environments.