Some Observations on 'Rethinking the
Use of Water as a Dissolution Medium'

Lewis J. Leeson, Ph.D.
LJL Associates, Montville, NJ

email for correspondence: lewisleeson@erols.com

In the November 1999 edition of Dissolution Technologies, a paper entitled, "Rethinking the use of Water as a Dissolution Medium" was presented by Noory, et. al.,(1). This publication proposes the replacement of water as a dissolution medium by media which the authors believe better simulate the physiological environment of the gastrointestinal tract. The authors state that water's lack of buffering capacity as well as its not being representative of gastrointestinal environment, have spurred them to undertake a study to evaluate simple alternative dissolution media for specific immediate release USP products which presently utilize water as the medium. This document questions the validity of making the changes proposed in the Noory publication.

In my opinion, a change in dissolution medium for these products implies that somehow we are getting incorrect release information by utilizing water as the medium. That is, batches of products which meet the present specifications may not perform properly in vivo. For example, some batches which meet the dissolution specifications in water may, when administered to patients, have a decreased bioavailability or behave as extended release rather than immediate release products. To the best of my knowledge this is not the case with those reported in Noory's paper. If such is true of any of these products, of course the medium should be changed to one that truly reflects its in vivo behavior since, in my opinion, the main purpose of a dissolution test is to portend when a product may not be performing properly in vivo. Therefore, not changing to the proposed new media is supported by the adage, "If it ain't broke, don't fix it".

In addition, is has long been felt by members of the USP and FDA, probably based upon empirical observations, that water is a better discriminating medium than the more physiological-like systems. The argument is that water appears to make it more difficult for some products to release the active ingredient and therefore good dissolution in water indicates that it will release even better in vivo. Is the purpose of the medium to make the product look good just to pass a test, or is it to anticipate potential absorption problems? For example, products formulated with excipients which are insoluble at pH values above 1-2, can release well when 0.1 N HCl is utilized for dissolution. However, in water this product would release much more slowly. Unfortunately, the physiological medium is not indicating what the release will be in achlorhydric subjects or simply when the stomach is not at a pH value of 1. This problem was encountered a number of years ago with at least one hydrochlorthiazide formulation.

It is most interesting to note that the results reported in the Noory publication (Table 1) indicate that the proposed new media release the active ingredient at the same rate as does water and the suggested specifications are the same for all of these products except Betamethazone tablets where Q is changed from 75% to 80%(a). So what has really been done is to demonstrate that the products appear to perform similarly in water and the newly proposed systems. Does this necessarily indicate that we have improved the predictability of the dissolution test, or that it now has more meaning?

I would like to state unequivocally that, in the realm of best dissolution media, I am not necessarily "pro-water" and would not even be concerned if everyone avoided it for future products. However, change based upon a physiological argument only, without demonstrating an advantage of improved in vivo performance prediction, does not seem to be the best approach. If we are going to utilize physiological media, we had better clearly develop the proper paradigm, which defines what we want from such a system and not merely select a medium because it causes rapid in vitro release of a product. It should be clearly remembered that a dissolution test, no matter what some researchers may say, is really expected to indicate in vivo release which in turn can markedly influence bioavailability. For example, in the case of immediate release amine compounds, we should want the dissolution medium to be one that simulates worse case situation in the stomach. That is, we should not rely on the stomach always being represented by simulated gastric fluid, but rather employ a medium pH value of 3-4 which often reflects the true gastic pH value. We should utilize this medium for all such drugs and not rely on simulated gastric fluid to make a product look better than it may actually perform under certain physiological conditions. We might even consider making this a universal dissolution medium for immediate release products providing solubility was not compromised. After all, an immediate release product first encounters medium in the stomach and it is there that we expect the active ingredient to begin releasing. I am not necessarily proposing this as the route to follow, but trying to suggest the type of thinking that should be considered if we are to rely on the "physiological" concept. I personally don't care what medium is used if it correlates well with the in vivo performance. I believe, and have always practiced the philosophy, that the more physiological systems should be investigated first. Only after evaluating these and other data (pH effect, BA, etc.) should one set of dissolution conditions be selected. However, if IVIVC has been properly demonstrated with any medium, I am not concerned whether that medium is physiological, buffered to any pH, pure water, only partially aqueous, or even my grandmother's chicken soup. That is the medium that should be utilized for the quality control of the given product.

In conclusion, I suggest that unless there are clinical considerations that take precedence over what has been said above, the dissolution medium for the USP products, studied by Noory, et. al., should not be changed. In addition, any attempt to utilize physiological conditions should be based upon a well defined plan and not be governed by whether a given medium makes the product release in vitro at a rapid rate, but may not be discriminatory.

Bibliography

(1) Noory, Carol, et. al., Rethinking the Use of Water as a Dissolution Medium, Dissolution Technologies, 6, No. 4, page 6, Nov. 1999.