When an oral product, usually a tablet or capsule, is taken, it almost instantaneously goes into the stomach (gastric compartment). The gastric environment can be described as an acidic (mostly HCl based) aqueous solution (pH 1 to 3) with a churning (moving and mixing) process. Assuming a disintegrating type product, the product will disintegrate into solid particles/aggregates. Once in this disintegrated form, the drug will behave exactly like granules in dilute acidic solution with mild stirring in a beaker or flask. In case of non-disintegrating type tablets, the drug will be released or leaked-out from the unit into the acidic solution.

If the drug is soluble then it will move into the intestine as a solution, otherwise as a slurry or suspension. The important thing to note here is that with some delay, the drug will move into the intestinal component. Here the acid solution or suspension will be mixed with a strong buffer turning the acidic liquid to basic, more accurately less acidic in the pH range of 5 to 7. Considering the variability in contents and the rates of entrance of the two solutions i.e. slurry from the stomach and the buffer from pancreas, it is almost impossible to accurately determine or establish the pH of the soup. However, it is a well-established fact that pH in this area of intestine ranges between 5 and 7. Therefore, for all practical and standardization purposes one can use pH of 6, an average of 5 and 7.

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Suppose someone is given an assignment to obtain/extract propranolol (PL) from a mixture of microcrystalline cellulose (MC) and a propranolol·HCl (PL·HCl). In a sense, it will be a fractional extraction procedure where one would exploit differences in the chemical or physical nature of these two compounds. The very first difference one observes will be in their aqueous solubilities; MC is not soluble in water, but PL·HCl is. So, one can separate PL·HCl from MC by simply adding some water and filtering it. The PL·HCl will remain in solution form but MC will be separated out as precipitate.  However, PL will still be in its hydrochloride form. To extract the PL, one may require a liquid-liquid extraction step. In this regard, one first needs to adjust the pH of the aqueous solution so that the HCl part can be neutralized and PL·HCl should be available as PL which could then be extracted with an organic solvent (e.g. hexane or dichloromethane).  Adding some alkaline solution to PL solution will increase the pH of the solution to a much higher level, e.g. pH 12. Most of the PL will now be in undissociated form and can be extracted into the organic phase. One or two extraction repeats will transfer PL into the organic phase which may be removed by evaporation, leaving behind pure PL in its native or basic form.

On the other hand, if one is unable to increase the pH of the solution to 12, to avoid potential complications, then a lower pH may be used. The same extraction step can be used, however, one would require an increased number of extraction repeats for complete extraction of PL from the aqueous solution. The end result will be the same i.e. complete extraction of PL form in its native or basic form in the organic solvent.

It is important to note that one can also perform the above described extraction in one step (i.e. without separating MC by filtration first). In this case, adding some milder buffer having a pH around 7 to the mixture, to avoid any complications of higher pH with MC. Continue reading →

In a recent article, titled “Stage Appropriate Dissolution Methods in Formulation Development”, published in the above mentioned journal, the author presented a view as to how dissolution method requirements change as a project advances in time (link). Unfortunately, not only is this view logically flawed but scientifically invalid as well.

A dissolution method is used for the estimation of drug release characteristics of a product, mostly tablets and capsules. Therefore, by definition, a method just like any other scale or measuring method (thermometer, weighing scale, density, etc.) must remain constant. A product, or stage, dependent scale/method will be considered scientifically invalid for this reason.

Further, during the product development stage, a dissolution method is used for evaluating the impact of different variables (formulation and/or manufacturing) so that a product with appropriate drug release characteristics is developed. Therefore, again, a constant method is required during the product development exercise. If the suggestion is to keep changing the methods (scales) at every stage, then one wonders how would one establish dissolution characteristics/rate of a product or any product. For a more detailed explanation and discussion on the topic please follow the links:

(1)    Limitations of Some Commonly Described Practices in Drug Dissolution Testing and Suggestions to Address These. (http://www.drug-dissolution-testing.com/?p=810).

(2)    Blog (www.drug-dissolution-testing.com)

In my view, the author had provided information which is not scientifically valid, and would not be helpful in developing useful dissolution methods.

Note: This post has been shared with the author of the article, who provided the following response which is greatly appreciated. Also, I took the opportunity in introducing Dr. Hawley to the newly suggested crescent shape spindle which may help in developing a “universal” dissolution tester. Saeed

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It is important to note that by definition a drug dissolution test has to be a biorelevant test. A non-biorelevant dissolution test is just like a non-biorelevant thermometer or non-biorelevant pair of eye glasses i.e. such things have no practical use or purpose. However, unfortunately, in the pharmaceutical area, in particular for oral (tablet/capsule) products, not only does such non-biorelevant testing exist (e.g. pharmacopeial) but it is the norm, strongly promoted and defended which causes enormous confusion and financial losses.

The reason for this confusion is that non-biorelevant methods are presented as biorelevant and useful in fancy wrappings, or with catchy phrases, e.g. the one mentioned in the title (“biorelevant performance testing”) or by confusing with other names such as BCS, IVIVC, bio-waivers,  f2, QbD etc. In reality, the issue is not how is dissolution testing presented and described, but rather how the tests are conducted and results are evaluated.

For example: (1) the apparatuses currently used, even those recommended by regulatory authorities, have never been qualified and/or validated for dissolution testing purposes. In fact, it has been shown many times that the apparatuses provide irrelevant and unreliable results; (2) recommended experimental conditions are mostly selected arbitrarily lacking physiological or scientific rationale; (3) tests are conducted using product specific (i.e. not product independent) procedures or experimental conditions thus results obtained are biased and cannot relate to the actual quality of a product; (4) there are no existing criteria or standards available which could be used to relate dissolution results for product quality. That is, no procedure is available to set physiologically relevant tolerances with scientific or statistical relevancy or credibility. For further details see here.

In conclusion, if dissolution results have been obtained using traditional approaches/methods then their interpretation and usefulness will be of questionable merit at best.