Chemical Nature of the Extracting Medium  

 Of all the parameters involved in generating the extract, the extracting medium is the most critical because it is the extracting medium that accomplishes the extraction, and all other parameters merely facilitate the extraction. Establishing and justifying the extracting medium (or media) is both straightforward strategically and complex tactically. 

Strategically, if the purpose of a particular extraction study is, for example, to simulate a worst-case leachables profile, then the ideal situation is for the extracting solvent to have a similar or greater propensity to extract substances as the formulation, thus obtaining a similar qualitative and quantitative extractables profile. This is clearly stated in regulatory guidances and best practice recommendations (1, 4–6). 

Therefore, the most logical tactic for this simulation study is to use the formulation itself as the extracting medium and in the absence of complicating factors, such an approach is recommended. However, in certain cases the use of the formulation as an extracting medium complicates extract characterization to such an extent that it is impractical. The various guidances and recommendations suggest that if the use of the drug product as the extracting solvent is not feasible, then the drug product vehicle, or placebo, could be used as an effective extracting medium. 

This recommendation is derived from the fact that the drug substance itself does not typically create the “leaching power” of a drug product but rather that it is the formulation's ingredients (drug product vehicle) that establish the drug product's ability to leach substances from a contacted material.   

When circumstances require that an extraction study must be accomplished with a simulating solvent(s), it is necessary to establish and justify the composition of these solvents. In order to accomplish this objective, one must consider all the physicochemical characteristics of a formulation and/or simulating solvent that influence its “extracting power”. In certain circumstances, the formulation is sufficiently simple that the critical characteristics can be readily delineated and simulated. 

For example, the extracting power of polar aqueous drug products consisting of soluble ingredients (such as an injectable with a drug substance, buffers, and diluent) is, for organic extractables, driven primarily by drug product pH. In such a circumstance, simulating the drug product pH with an analytically viable buffer system for the extraction study may be appropriate and justifiable. For inorganic extractables, utilization of a simulating solvent having similar metal-chelating properties as the drug product vehicle may also be appropriate and justifiable. 

It may also be the case that largely non-polar drug products can be readily simulated with analytically expedient organic solvents. For example, chlorofluorocarbon and hydrofluoroalkane propellants used in metered dose inhalers (MDIs) can be simulated with dichloromethane as an extracting solvent and isopropanol can be used to simulate ethanol, a common co-solvent in MDI formulations.   

Many drug products are compositionally intermediate between the polar and nonpolar examples just discussed. Examples of such products include “aqueous” drug products that contain stabilizers, solubilizing agents, chelating agents and buffers, lipid-containing products, and biotechnology products containing proteins, peptides, and blood-derived products. Such products have a characteristic polarity which establishes their “extracting power”. Thus, an appropriate simulating solvent will have a polarity that matches that of the drug product. Binary mixtures of miscible solvents (such as alcohol/water) have been utilized as simulating solvents for these types of drugs product.   

It may be that a single simulating solvent cannot be established and justified for a specific drug product, or that the focus of the extractables assessment is a material or system that will be characterized for use with multiple, compositionally diverse drug products. In such circumstances, the drug product's ability to leach chemical entities from a packaging system can be established based on the use of multiple extracting solvents, each of which addresses one (or more) of the extracting “mechanisms” that are relevant to the drug product (or drug products) under investigation. 

The use of multiple solvents is consistent with industry-driven best-practice recommendations for drug products that have a relatively high risk of dosage form interaction with the packaging system and a relatively high safety risk relative to the route of administration (e.g., inhalation aerosols and solutions, injectables and injectable suspensions) (1). Therefore, the use of multiple solvents (or extracting media) with different polarities, or extracting powers, is recommended for high risk dosage form packaging system components and materials requiring extraction studies in order to simulate a drug product leachables profiles (see Table 1).

Table 1. Possible Extracting Media Relative to Particular Packaging Components 
Packaging Component
Possible Extracting Media(a)
MDI valve elastomer seal (MDI formulation contains 1,1,1,2-tetrafluoroethane and ethanol)
Dry powder inhaler mouthpiece
Water (pH 7)
Small-volume parenteral vial rubber stopper (aqueous formulation buffered at pH 6.5)
Water (pH 5.2)
Water (pH 9.5)
Isopropanol:water (50:50)(d)
Large-volume parenteral plastic bag (aqueous formulation buffered at pH 7.2)
Water (pH 5.2)
Water (pH 9.5)
Isopropanol:water (50:50)
a  The possibilities listed in Table 1 are provided for example only and should not be interpreted as standard practice recommendations.

b  These extraction media reflect the varying polarities of the organic solvents used in MDI formulations.

c  These extraction media reflect both the hydrophilic and lipophilic character of human saliva and allow materials characterization.

d  These extraction media reflect the chemical nature of the formulation. Using media whose pH range encompasses, and slightly exceeds, the pH limits of the product addresses the potential effect of pH on the extractables profile. The use of an aqueous mixture containing an organic solvent takes into account the possible presence of formulation additives such as solubilizing agents that can influence the leaching power of the formulation. The specific organic solvent used and its proportion in the extracting medium depends on the specific chemical nature of the formulation and on practical issues associated with testing the extract.

  If the goal of an extractables assessment is materials characterization, then simulating a drug product vehicle is both unnecessary and undesirable since these goals require qualitatively and quantitatively efficient extractions. Such extractions generally are only achieved with relatively powerful organic solvent systems capable of softening, swelling, or dissolving the material's polymer matrix and releasing quantitative levels of additives and other chemical entities.