Drug dissolution testing is an approach to evaluate drug release characteristics of a product (tablets/capsules) in vitro. The technique is very well established and extensively used at every stage of product manufacturing (development, production, QC as well as for regulatory surveillance). The technique sound in concept, but its practice has not been successful and provides numerous frustrations and challenges. For example see, http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=9845813&ordinalpos=11&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

There has been a prevalent belief and acceptance that the cause of the problems is related to mechanical or operational deviations of the testing. Therefore, most of the past, and to some extent, recent emphasis has been on controlling/tightening the mechanical specifications and tolerances. Please see recent guidance from FDA (http://www.fda.gov/CDER/GUIDANCE/7232dft.pdf). However, problems of high variability and lack of bio-relevancy of results still persist as were some 30+ years ago. It may be argued that situation may have gotten worse.

If one observes critically, drug dissolution testing can be considered as a bridged science of two specialities; analytical chemistry and pharmacology (pharmacokinetics/bioavailability). It is my view that, at present drug dissolution discussion is dominated from the analytical chemistry perspective, (see www.dissolution.com) with limited input and contribution from pharmacokinetic side. Therefore, not only analytical problems are NOT resolved, but the testing is done using non-physiological environments such as simulating GI tract environment without any stirring and mixing, using simulating gastric juice with de-aerated (de-gassed) media. Therefore, success was not possible, and may not be possible in future if same practices are to follow.

By participating on this forum, I would like to initiate scientific discussion from pharmacology (pharmacokinetics) aspect so that dissolution testing should be better focused and more appropriately conducted. Perhaps a quick read of one of my publications for an overview may be a good start (http://www.dissolutiontech.com/DTresour/200411Articles/DT200411_A02.pdf).

Let us hear from the participants.

Saeed

Disclaimer: Views expressed here are for scientific discussion purposes only and may not be reflective of opinions and policies of my employer.

It is my view that scientists in the area of pharmacology/pharmacokinetics see the dissolution testing with a suspicion. They generally consider this in vitro technique as a poor match or simulation of in vivo behavior (physiology). Unfortunately, this is how dissolution has been presented and causes its own lack of credibility. This leads to limited and improper use of a very simple but powerful technique. However, if dissolution tests are conducted with proper consideration it can make the drug product development and manufacturing significantly easier and less expensive.

In this regard, rather than considering GI tract physiology itself, if one considers physiological environment (GI tract soup in a flexible container constantly turning and tossing) then one will easily see the problems of current practices. Furthermore, these problems can easily be addressed which will provide significantly improved dissolution results.

I would like to hear comments and suggestions in this regard and will be happy to provide further discussion on the topic.

Saeed

Disclaimer: Views expressed here are for scientific discussion purposes only and may not be reflective of opinions and policies of my employer.

In a recent article from USP, the following conclusion has been reported Dissolution experiments and statistical analyses demonstrated that the dissolution assembly and its associated variables contribute importantly to variability in dissolution results. (http://www.ncbi.nlm.nih.gov/pubmed/18172581?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum)


Not only this study confirms the inherent problems of high variability in dissolution test, as have been discussed extensively on this board, but, clearly raises serious questions about testing and test results obtained using the current technique in assessing the quality of the pharmaceutical products. One should be cautious in demonstrating quality of products based on the use of currently used apparatuses (App 1 and 2).

Saeed

Disclaimer: Views expressed here are for scientific discussion purposes only and may not be reflective of opinions and policies of my employer.

A question was asked Can we use 0.001 M HCl as a dissolution medium?

As dissolution tests are conducted which generally lack bio-relevancy (e.g. use of Paddle apparatus) therefore, one may use any experimental condition to obtain desired results as long as one can rationalize the result. This is weakness of current practice, as it does not seek product characteristics but some pre-set results.

Saeed

Disclaimer: Views expressed here are for scientific discussion purposes only and may not be reflective of opinion and policies of my employer.

A question was asked:

At present I am dealing with the assimilation of the methodology of manufacture and evaluation IVIVC. Earlier IVIVCforERdosageforms was suggested to assist with the minor changes in the formulation, process, equipment, the size of a batch and the manufacturing plot. For more than 10 years the discussions about the application of IVIVC as a substitute instead of studying the bioequivalence have been held. Is it possible at present and, if yes, in what cases would it be possible? Are there any guidelines concerning it? How much does the manufacture of IVIVC helps to save the resources and the time comparing to the studying of the bioequivalence? Does it really helps to save the resources and the time?


Response: The concept of IVIVC is valid and in reality IVIVC should be achievable. However, use of current apparatuses, in particular Paddle, which have artifact of poor stirring and mixing thus would not be able to provide bio-relevant results, at least in most cases. If bio-relevant results cannot be obtained then IVIVC cannot be obtained either using these apparatuses.

Your question, Does it really helps to save the resources and the time? In my opinion not at all, in fact, one may spend lot more time and resources without gaining any useful information.

Saeed

Disclaimer: Views expressed here are for scientific discussion purposes only and may not be reflective of opinion and policies of my employer.

It appears that there is general awareness about the problems associated with the current practices of drug dissolution testing. There is now general acceptance of deficiencies of current approaches of calibration (or performance evaluation test) of dissolution apparatuses.
In this regard, one of my recent articles may be of interest. Hope you may find it useful. (http://www.americanpharmaceuticalreview.com/ViewArticle.aspx?SID=fgrdsq45qcfkgkjaee2uyti4&ContentID=3479)
Saeed
Disclaimer: Views expressed here are for scientific discussion purposes only and may not be reflective of the opinions and policies of my employer.