Choice of a dissolution medium is an important and critical variant for drug dissolution testing. The reported choices range from a simple solvent (water) to complex solutions, often drug and/or product dependent. However, making a choice is not so simple or straightforward, but confusing and often scientifically or logically not convincing or valid. This article provides a discussion in this regard leading to suggestions for selecting an appropriate dissolution medium.
Dissolution tests are employed to establish drug (Active Pharmaceutical Ingredient, API) release characteristics of solid oral products, such as tablets and capsules. The rationale for conducting these tests is that for a product to be therapeutically effective, the drug must be released from the product and should generally be dissolved in the fluid of the gastrointestinal (GI) tract. The API in solution form facilitates the absorption of the drug from the GI tract into the systemic (blood) circulation to reach its desired target (site of action) to exert its effect. Therefore, a dissolution test may be considered as a critical step for the development and assessment of the quality of products linking to their safety and efficacy attributes. For sustained released are dosages forms that release drug over a longer period of time and generally take phosphate buffer pH 7.4 for its dissolution study.
To choose an appropriate dissolution medium and its volume solubility study is required. Equilibrium solubility using shake-flask method is more common, although other approaches are also acceptable (e.g., dynamic solubility, potentiometric titration, or turbidity measurements etc.).
Since the objective of drug dissolution testing is to assess the expected drug dissolution in the GI tract, the medium should be representative of the liquid-phase present in the tract, which is aqueous. Therefore, to be physiologically or bio-relevant, the dissolution medium has to be water or water-based. However, one may not use media such as potassium or sodium hydroxide solutions which, although water-based, their use is restricted by their high pH values not found in the GI tract.
Thus, since drug absorption depends on dissolution, and most absorption occurs in the intestine, physiological aspects dictate that a medium should be aqueous having pH in the range of 5-7. Based on the preceding discussion, a logical first choice for a dissolution medium would be water itself. Incidentally, the pH of purified water falls in the range of 5-7, thus it would fulfil the physiological relevancy of the pH aspect well.
Since the GI tract physiology remains the same as assumed for IR products where the medium is linked to the GI tract environment, the choice of medium will therefore remain the same. The difference here would be that the ER products are different from IR products in formulation and/or manufacturing attributes to retard or slow the dissolution/release of the API.
Therefore, to evaluate the impact of change in formulation and/or manufacturing attributes or differences in IR vs ER, all other experimental conditions, including dissolution medium, must remain constant. To observe differences/discrimination in release rates between IR and ER products or within the ER category, one has to alter the formulation/manufacturing not the medium. The changing of dissolution medium would imply that somehow human physiology will change with an ER product, which is not a correct assumption. Thus, the choice of a dissolution medium in case of ER products of highly soluble drugs remains the same as for IR products, i.e., water.
As describe before, if the drug has low aqueous solubility one would require a solublising agent in the medium. Since physiological environment is the same and comparison has to be made against the IR product, the appropriate medium choice would exactly be the same as for low solubility drugs in IR type products.
The commonly suggested dissolution testing approach for such products is based on two media; one to test if the product resists the stomach acidic environment by testing in dilute HCl (pH ~1) and the second in a dissolution medium of higher pH (6.8) representing intestinal phase.
Things to be considered for choosing a buffer or acid:
- Compatibility with drug substance
- Concentration of buffer or acid that influence solubilizing effect
- Potential ion effect between drug substance and buffer
Low-dose drugs will sometimes require lower dissolution volumes so that the drug can be quantified. There are several options to do lower dissolution volumes with vessel conversion kits. 100, 200, and 250mL kits can allow operational volumes as low as 40mL. These smaller vessels can be used with minipaddles, minibaskets, standard sized baskets, as well as some more niche options.
The advantages of these small volume kits are that they don't require purchasing a new dissolution apparatus and they can be still be used with automation such as autosamplers, Online UV, NanoDis, etc.
