In vitro dissolution testing

G. Levy, J. R. Leonards, and J. A. Procknal, Development of in vitro dissolution tests which correlate quantitatively with dissolution rate-limited drug absorption in man, J. Pharm. Sci., 54, 1719-1722 (1966). K. A. Javaid and D. E. Cadwallader, Dissolution of aspirin from tablets containing various buffering agents, J. Pharm. Sci., 61, 1370-1373 (1972). 

It is interesting that the in vitro dissolution test (USP) was more sensitive to the piroxicam formulation variables than the biodata. The fast, moderate, and slow products were found bioequivalent to each other and to the lot of innovator product studied [100]. It is possible that either the formulation variables studied did not affect in vivo dissolution and/or the differences were not discernible because of the long biological half-life of piroxicam [146]. 

The bioavailability of the drug is demonstrated to be governed by dissolution if an in vitro dissolution test is to be used. 

A Shah, C Peot, J Ochs. Design and evaluation of a rotating filter-stationary basket in vitro dissolution test apparatus I Fixed fluid volume system. J Pharm Sci 64 671, 1973. 

The BCS has been developed primarily for regulatory applications, although its use has been extended beyond this area (as discussed in more detail below). The aim of the BCS in a regulatory context is to provide a basis for replacing certain bioequivalence studies by equally or more accurate in vitro dissolution tests. This could reduce costs and time in the development process as well as reducing unnecessary drug exposure in healthy volunteers, which is normally the study population in bioequivalence studies. 

In vitro dissolution testing is an important tool in the development of solid drug products, as well as in batch quality controls. The aim of the test is to see that the drug is appropriately dissolved in the gastrointestinal tract and made available for absorption. It is therefore highly desirable that the in vitro tests provide data that correlate to the in vivo situation. However, attainment of IVIVC has often failed-and the concept of IVIVC has been challenged. 

The BCS could be used as a framework for predictions when IVIVC could be expected for solid IR products, as summarized in Table 21.5. It is important to realize that the in vitro dissolution test only models the release and dissolution of the active drug substance from the formulation, and it is only when these processes are rate-limiting in the absorption process that IVIVC can be expected. In... 

The second situation when IVIVC is not likely for class II drugs is where the absorption is limited by the saturation solubility in the gastrointestinal tract rather than the dissolution rate, as discussed in more detail above. In this situation, the drug concentration in the gastrointestinal tract will be close to the saturation solubility, and changes of the dissolution rate will not affect the plasma concentrationtime profile and in vivo bioavailability. Standard in vitro dissolution tests are carried out under sink conditions , i.e., at concentrations well below the saturation solubility. Thus, only effects related to dissolution rate can be predicted in vitro. If more physiologically relevant dissolution media are used, which do not necessarily provide sink conditions , the possibility for IVIVC could be improved, as has been indicated by the results of recent studies using simulated intestinal medium [76],... 

The absorption of class III drugs is limited by their permeability over the intestinal wall. Thus, as this process is not at all modeled by the classical in vitro dissolution test, no IVIVC should be expected. When drug dissolution becomes slower than gastric emptying, a reduction in the extent of bioavailability will be found in slower dissolution rates as the time when the drug is available for permeation over the gut wall in the small intestine will then be reduced. Thus, the same type of relationship can be expected between bioavailability and in vitro dissolution, as shown in Fig. 21.12 for a class I drug. 

CDER Guidance for Industry. SUPAC-IR Immediate-Release Solid Oral Dosage Forms Scale-Up and Post-Approval Changes Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation US Food and Drug Administration, 1995. 

Several in vitro tests are currently employed to assure drug product quality. These include purity, potency, assay, content uniformity, and dissolution specifications. For a pharmaceutical product to be consistently effective, it must meet all of its quality test criteria. When used as a QC test, the in vitro dissolution test provides information for marketing authorization. The dissolution test forms the basis for setting specifications (test, methodology, acceptance criteria) to allow batch release into the market place. Dissolution tests also provides a useful check on a number of physical characteristics, including particle size distribution, crystal form, etc., which may be influenced by the manufacturing procedure. In vitro dissolution tests and QC specifications should be based on the in vitro performance of the test batches used in in vivo studies or on suitable compendial specifications. For conventional-release products, a single-point dissolution... 

Ishii K, Saito Y, Takayama K, Nagai T. In vitro dissolution test corresponding to in vivo dissolution of sofalcone formulations. STP Pharm Sci 1997 7 270-276. 

Additional criteria for waiver of evidence of in vivo BA/BE are given in 21 CFR 320.22 (d)(3). For certain solid oral dosage forms (other than a delayed or extended-release dosage forms), a waiver for the submission of in vivo evidence of BA/BE is possible if the drug product has been shown to meet the requirements of an in vitro dissolution test, which in turn has been shown to correlate with in vivo data. A biowaiver may also be addressed to a reformulated solid oral dosage form identical to another drug product except for color, flavor, or preservatives for which the same manufacturer has obtained approval, if BA data are available for the approved... 

Kramer J. In Role of in Vitro Dissolution Test. Tokyo Bioavailability, Bioequivalence and Pharmacokinetic Studies, 1996. 

TABLE 2 Different Roles of In Vitro Dissolution Testing During Drug Development... 

Recently, Yoshikawa et al. [70] reported a new in vitro dissolution test, called the rotating beads method, for drugs formulated in pressure-controlled colon delivery capsules. This dissolution method was applied to acetominophen sustained-release tablets and two other drugs having low solubility in the colon, tegafur and 5-ASA. There was good correlation between the in vitro dissolution rates and the in vivo absorption rates. 

FDA, September 1997, Guidance for Industry SUPAC-MR modified release solid oral dosage forms scale-up and post-approval changes chemistry, manufacturing and controls, in vitro dissolution testing, and in vitro bioequivalence documentation. 

SUPAC-MR Modified release solid oral dosage forms. Scale-up and postapproval changes chemistry, manufacturing, and controls in vitro dissolution testing and in vivo bioequivalence documentation (September 1997). 

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