Biorelevant media

The choice of medium is expected to play a very important role in the dissolution of BCS Class II drug substances. The media used need to closely represent the in vivo conditions in the upper GI tract to achieve a meaningful IVIVC. As discussed in this 

The relationship between the hydrodynamics in the GI tract and that in the current available dissolution tests is another factor that must be considered. It has been reported that, provided an appropriate composition is chosen for the dissolution test, the United States Pharmacopeia (USP) paddle apparatus can be used to reflect variations in hydrodynamic conditions in the upper GI tract [67-69]. However, more data are warranted, as this might insert uncertainty into the interpretation of dissolution tests, even when the composition of the GI milieu is well simulated. 

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E. S. Kostewicz, U. Brauns, R. Becker, J. B. Dressman. Forecasting the oral absorption behavior of poorly soluble weak bases using solubility and dissolution studies in biorelevant media. Pharm. Res. 2002, 19, 345-349. 

The first step is to assess the solubility and dissolution characteristics of the pure drug in biorelevant media which cover the usual pH range in the GI tract. Some useful compositions are shown in Table 4. 

Table 4 Some Useful Media For Preparation and Use as Biorelevant Media...

For even less soluble, weak acid drugs, the situation is not so simple, because the solubility even in biorelevant media is very low. A typical example is troglitazone, an antidiabetic... 

In summary, use of biorelevant media to determine solubility in the upper gut combined with assessment of formulations with respect to robustness and ability to protect the drug from precipitation are key to an efficient development process for compounds that are poorly soluble and weakly basic. 

Table 8 Biorelevant Media for Studying Food Effects on Release from MR Dosage Forms...

The fed and fasted state may also have significant effects on the absorption or solubility of a compound. Compositions of media that simulate the fed and fasted states can be found in the literature (19) (see also Chapter 5). These media reflect changes in the pH, bile concentrations, and osmolarity after meal intake and therefore have a different composition than that of typical compendial media. They are primarily used to establish in vitro-in vivo correlations during formulation development and to assess potential food effects and are not intended for quality control purposes. For quality control purposes, the substitution of natural surfactants (bile components) with appropriate synthetic surfactants is permitted and encouraged because of the expense of the natural substances and the labor-intensive preparation of the biorelevant media. 

Biorelevant media, such as FaSSIF and FeSSIF, that model composition of the gastric and intestinal contents before and after meal intake... 

In Eq. (1) the parameter D is temperature dependent. Consequently, both the temperature of the dissolution fluid and its viscosity (which is also temperature dependent) should be carefully controlled. In addition, the presence of electrolytes and changes in pH may influence the diffusing species by altering their ionization. Such factors imply that dissolution fluids should be as simple as possible. However, this is in contrast with the need for complex, biorelevant media to be used if any attempt is to be made to use a product s in vitro dissolution to make useful estimates of its likely in vivo activity. 

Lipophilic drugs, being either weak acids, weak bases or non-ionized compounds, are dissolved in the lipid fraction of the food when the macroscopic structure of the food is broken down into microscopic particles during the formation of chyme. Consequently, lipophilic molecules are predissolved in triglyceride droplets when they enter the small intestine. For these compounds, it is especially relevant to include lipolysis products in the biorelevant media simulating the intestinal fluids. Sunesen et al. (2005) could only obtain fVTVC in the fed state for a non-ionized compound (danazol), when including lipolysis products in the media. 

Although it is the ultimate goal to predict in vivo formulation behavior based on in vitro dissolution testing using biorelevant media, the number of studies in which in vitro-in vivo correlations (IVIVC) have been described, is limited. Finding a correlation between in vitro dissolution testing and in vivo performance will be challenging due to the multiple factors which affect the blood concentration-time prohle. 

This study indicates that dissolution-limited absorption is a prerequisite for rVrVC using dissolution, but one should also realize that modihcation of the biorelevant media, in terms of composition, but also dissolution conditions, might result in development of a model that does provide for an IVIVC. 

Table 4. Composition of biorelevant media. Fa and Fe denotes fasted and fed state media, respectively. (Sunesen et al., 2005).

Apparently, it is possible to modify the biorelevant media and also the involved hydrodynamics, flow rate so as to achieve IVIVC in this particular situation. However, more studies with different BCS class II compounds are needed. 

Kostewicz ES, Brauns U, Becker R, and DressmanJB. Forecasting the Oral Absorption Behavior of Poorly Soluble Weak Bases using Solubility and Dissolution Studies in Biorelevant Media. Pharm Res 2002 19 345-349. 

Swelling is one of the functional properties used to characterize biopolymers required for modified or controlled drug delivery systems. The biopolymers employed for modified drug delivery applications are hydrogels that form three-dimensional polymeric networks when they come into contact with water, they absorb many times their weight of water but they do not dissolve. Swelling of the ceUulosics in different biorelevant media must be established. 

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