This article, based on material from a 2003 PhRMA workshop on acceptable analytical practices, provides guidance for developing dissolution testing for poorly soluble compounds. The first article from the workshop, about phased method validation, was published in November, Future articles will cover analytical method equivalency and justification of specifications.

Dissolution testing of poorly soluble compounds in immediate-release (IR) solid dosage forms poses many challenges. These challenges include developing and validating the test method, ensuring that the method is appropriately discriminatory, and addressing the potential for an in vivo-in vitro relationship (IVIVR) or correlation (IVIVC). The objectives of dissolution testing, in general, vary during the life cycle of a dosage form. The primary objective during Phases 0 and I is to develop a method to clearly establish the mechanism of in vitro drug release and solubilization. During Phases II and III, the objective shifts to identifying a test method that can provide an IVIVR, IVIVC, or other biorelevant information. At registration and beyond, the goal is to identify a quality control (QC) dissolution test method to verify process and product consistency.

It is preferable to identify a dissolution test method that can evaluate both product consistency and bioavailability. This goal, however, remains a significant challenge for pharmaceutical formulation and analytical scientists, and frequently is not achievable. The literature, including regulatory positions, provides little guidance about addressing these challenges for poorly soluble compounds.

To collate acceptable practices and provide more guidance, the Analytical Technical Group of the Pharmaceutical Research and Manufacturers of America (PhRMA) included dissolution testing of poorly soluble compounds in the PhRMA Acceptable Analytical Practices Workshop held in September 2003 (1-2). Representatives from PhRMA member companies met to discuss the topic, share current practices, and agree on acceptable practices that represent good science and meet current regulatory requirements. The group also identified areas in which strategies need to be developed. This article presents the output of these discussions by providing a general overview of dissolution testing and highlighting the relevant issues and test modifications needed to test the dissolution of poorly soluble compounds.

Why in-vitro dissolution testing?

Characterizing the drug-release mechanism by establishing an t in vitro dissolution test method (or an appropriate alternative method) to measure product performance is particularly important for poorly soluble compounds. Dissolution testing historically has been a key tool during the development stages of a compound as well as for commercial manufacturing. For a development compound, dissolution testing is used primarily to help develop and evaluate new formulations by evaluating the rate of drug release from dosage forms, evaluating the stability of these formulations, monitoring product consistency, assessing formulation changes, and establishing IVIVRs of IVIVCs. For a commercial product, dissolution testing is used primarily to confirm manufacturing and product consistency, to evaluate the quality of the product during its shelf life, and to assess postapproval changes and the need for bioequivalency studies (3).

A dissolution test measures the rate of release of the drug. The objective is to develop a discriminatory method that is sensitive to variables that affect the dissolution rate. Such variables may include characteristics of the active pharmaceutical ingredient (API) (e.g., particle size, crystal form, bulk density), drug product composition (e.g., drug loading, and the identity, type, and levels of excipients), the drug product manufacturing process (e.g., compression forces, equipment), and the effects of stability storage conditions (e.g., temperature, humidity). Although it also is desirable to develop a dissolution test that establishes an IVIVC or an IVIVR, that kind of correlation between observed changes in in vitro dissolution rate to meaningful in vivo product performance quality remains a key challenge, as will be explained below.

Classifying drugs according to dissolution and permeability properties

Mechanism of dissolution. The dissolution test determines the cumulative amount of drug that goes into solution as a function of time. As shown in Figure 1, dissolution of drug from a dosage form involves at least two consecutive steps: liberation of the solute or drug from the formulation matrix (disintegration), followed by dissolution of the drug (solubilization of the drug particles) in the liquid medium. The overall rate of dissolution depends on the slower of these two steps. The relative difference in rates should be carefully considered when designing the dissolution method.

[FIGURE 1 OMITTED]

The cohesive properties of the formulated drug playa key role in the first step of dissolution. For solid dosage forms, these properties include disintegration and erosion, whereas for semisolid or liquid formulations, the dispersion of lipids or partitioning of the drug from the lipid phase is the key factor. If the first step of dissolution is rate-limiting, then the rate of dissolution is considered to be disintegration controlled. Careful assessment of the intrinsic rate of dissolution and the effect of various aspects of the formulation (e.g., release profiles from precompressed granules, impact of compression force, porosity, and lubrication) can reveal the relative contribution of the disintegration step to the overall dissolution of the drug.

In the second step of dissolution--solubilization of the drug particles--the physicochemical properties of the drug such as its chemical form (e.g., salt, free acid, free base) and physical form (e.g., amorphous or polymorph, and primary particle size) play an important role. If this latter step is rate limiting, then the rate of dissolution is intrinsic dissolution controlled. This is the case for most poorly soluble compounds in IR formulations. For poorly soluble compounds in solubilized formulations, in vivo precipitation also may need to be considered when developing a dissolution test method, in particular for establishing an IVIVR or IVIVC.

The biopharmaceutics classification system (BCS) to define poorly soluble compounds. In addition to classifying drugs according to their disintegration and solubilization properties, drugs also may be classified by additional factors such as permeability. A classification system that uses permeability is the biopharmaceutical classification system (BCS), which is based on estimates of the contribution of solubility, permeability, and dissolution to oral drug absorption from IR dosage forms. First described in 1995, the BCS and its principles have been used in several guidances issued by the Food and Drug Administration (3-6).

BCS categories depend on a few key definitions, including low-solubility, high permeability, and rapidly dissolving:

* Based on the BCS, low-solubility compounds are compounds whose highest dose is not soluble in 250 mL or less of aqueous media from pH 1.2 to 7.5 at 37 [degrees]C. For a low-solubility compound, the highest dosage strength divided by the lowest solubility in the pH range 1.2-7.5 would be greater than 250. Solubility is primarily a property of the API and its salt form. Solubility usually is determined by measuring the concentration of a saturated solution after equilibration at 37 [degrees]C for 1 to 24 h. The equilibration time depends on the test duration time as well as the physical and chemical stability (e.g., conversion of salt to free base in vitro) of the drug.

* High permeability is defined as human absorption of 90% or more of the administered dose (6).

* A rapidly dissolving IR drug product is defined as one for which no less than 85% of the label claim is dissolved within 30 min, as tested using either USP Apparatus I at 100 rpm of USP Apparatus II at 50 rpm in pH 1.2 (0.1 N HCl or simulated gastric fluid USP, without enzyme), pH 4.5 buffer, and pH 6.8 buffer (or simulated intestinal fluid USP). (See discussion below in "Apparatus selection.")

Using these definitions, drugs fall into one of four BCS categories that describe the drug's permeability and absorption properties as well as its dissolution.

Class I: High solubility, high permeability compounds.

Class II: Low-solubility, high-permeability compounds. For these compounds, which are likely to demonstrate intrinsic dissolution-limited absorption (i.e., the rate of drug solubilization is much lower than the rate of drug absorption), it may be possible to establish an IVIVR of IVIVC.