Dissolution testing

An in situ probe is a slender probe of either transflectance or transmission design that is permanently inserted into each dissolution bath in an apparatus. This has the advantage of allowing measurements at the same physical location in the vessel where the sipper tube had been positioned, according to USP guidelines. A disadvantage is the disturbance of the laminar flow in the stirred vessel - thus there has been an effort to make this probe with as small a diameter as possible (1/8 or less). 

In a third configuration, a probe is dipped into the vessel only when it is time to make a measurement in the vessel. Once the data have been collected, the probe is withdrawn. This minimizes the flow disturbance in the vessel, while still allowing sampling at the same location as the sipper tube. A disadvantage of this method is that a film may form on the optical surfaces of the probe as they dry while the probe is suspended in air over the dissolution bath. 

There are three instrument designs in use with fiber-optic probes. One system makes simultaneous measurements on up to eight dissolution bath probes using a CCD-based spectrophotometer with xenon flash lamp source. The signals from all eight probes are simultaneously imaged onto a single CCD detector and concentrations determined in real 

---

Dissolution of Human Urinary Calculi in Vitro. Five human urinary calculi containing various proportions of Ca3(P04)2, Ca(C204), CaC03, and MgNH4(P04) were subjected to similar dissolution tests at pH 7 (Table 11). The same dissolution patterns as those of the model phosphate and oxalate calculi are found. That is, for phosphate calculi no. 1-4, X is more effective than [18]aneN6 or EDTA and for oxalate calculus no. 5, EDTA is best. 

Figure 4.50. Cumulative dissolution results. Two experimental tablet formulations were tested against each other in a dissolution test in which tablets are immersed in a stirred aqueous medium (number of tablets, constructional details and operation of apparatus, and amount of medium are givens). Eighty or more percent of the drug in either formulation is set free within 10 minutes. The slow terminal release displayed by formulation B could point towards an unwanted drug/excipient interaction. The vertical bars indicate ymean - with Sy 3%. A simple linear/exponential model was used to approximate the data for the strength 2 formulation. Strengths I and 3 are not depicted but look very similar.

Reppas, C., Shah, V. P. Dissolution testing as a prognostic tool for oral drug absorption immediate release dosage forms. Pharm. Res. 1998, 15, 11-22. 

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). 

S. Riegelman, Dissolution Testing in Drug Development and Quality Control, The Academy of Pharmaceutical Sciences Task Force Committee, American Pharmaceutical Association, 1979, p. 31. 

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]. 

KS Murthy, RG Reisch, Jr., MB Fawzi. Dissolution stability of hard-shell capsule products. Part II the effect of dissolution test conditions on in vitro drug release. Pharm Technol 13(6) 53-58, 1989. 

M Aikman, L Augsburger, I Berry et al. Collaborative development of two-tiered dissolution testing for gelatin capsules and gelatin-coated tablets using enzyme-containing media. Pharmacop Forum 24(5) 7045-7050, 1998. 

RJ Withey, CA Mainville. A critical analysis of a capsule dissolution test. J Pharm Sci 58 1120-1126, 1969. 

FW Goodhart, RH McCoy, FC Ninger. New in vitro disintegration and dissolution test method for tablets and capsules. J Pharm Sci 62 304-310, 1973. 

The test apparatus chosen for disintegration testing and dissolution testing should be one of those described in the Ph Eur unless another pharmacopoeial or a noncompendia method can be justified. The test conditions and the proposed release rates should be justified in terms of batch reproducibility. 

The product specification should include a measure of uniformity of content and a dissolution test following the release of the active ingredient until steady state is achieved (or justifying shorter periods of testing). Where possible, the dissolution specification (often expressed as quantity of active ingredient released per unit area of surface per unit time) should be related to the results obtained from batches found to be acceptable in clinical studies. In these tests six units should be tested for dissolution characteristics and the mean value stated with a measure of variability. 

The information requirements for products such as prolonged-release oral dosage forms will depend on whether or not it has been possible, during the development of the product, to establish an in vivo-in vitro correlation between clinical data and dissolution studies. In vivo-in vitro correlations should be attempted using product at different stages of development, but bioavailability and pharmacokinetics data from pivotal clinical studies using at least pilot-scale production materials and possibly routine production material are particularly important. Where it is not possible to establish an in vivo-in vitro correlation, additional data will be required to compare the bioavailability of product developed at laboratory scale, pilot scale, and production scale. In the absence of an in vivo-in vitro correlation, the dissolution test will be a quality control tool rather than a surrogate marker for in vivo performance of the product. 

Dissolution test data will be required in all cases (and for all strengths of product) for development and routine control and should be based on the most suitable discriminatory conditions. The method should discriminate between acceptable and unacceptable batches based on in vivo performance. Wherever possible Ph Eur test methods should be used (or alternatives justified). Test media and other conditions (e.g., flow through rate or rate of rotation) should be stated and justified. Aqueous media should be used where possible and sink conditions should be maintained. A small amount of surfactant may be added where necessary to control surface tension or for active ingredients of very low solubility. Buffer solutions should be used to span the physiologically relevant range—the current advice is over pH 1 6.8 or perhaps up to pH 8 if necessary. Ionic strength of media should be reported. The test procedure should employ six dosage forms (individually) with the mean data and a measure of variability reported. 

The sponsor of an NDA will normally have extensive pharmacokinetic and pharmacodynamic information available at the time the NDA is submitted. It may be appropriate to use data such as the slope of the dose-response curve in support of a contention that, for example, dissolution testing may be, in some instances at least, be sufficient for the demonstration of development bioequivalency. Certainly, we may conclude that the requirements for development bioequivalence should never be more rigorous than those applied in consideration of generic bioequivalency. 

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

At steady state, the concentration does not change with time. It is recognized that the concentration profile is angularly symmetrical the concentration, therefore, does not change with 0. We also assume that the disk is infinitely wide so that the concentration is a function of z only. This assumption can be justified since the diameter of the solute loaded is usually much smaller than that of the disk. Also, no production of drug occurs during dissolution testing. Consequently, Eq. (134) can be reduced to... 

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. 

Shah, G. L. Amidon, J. B. Dressman. Dissolution testing as a prognostic... 

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. 

Extensions of BCS beyond the oral IR area has also been suggested, for example to apply BCS in the extended-release area. However, this will provide a major challenge since the release from different formulations will interact in different ways with in vitro test conditions and the physiological milieu in the gastrointestinal tract. For example, the plasma concentration-time profile differed for two felodipine ER tablets for which very similar in vitro profiles had been obtained, despite the fact that both tablets were of the hydrophilic matrix type based on cellulose derivates [70], This misleading result in vitro was due to interactions between the gel strength of the matrix and components in the dissolution test medium of no in vivo relevance. The situation for ER formulations would be further complicated by the need to predict potential food effects on the drug release in vivo. 

---