Dissolution testing requirement

The Joint Panel proposed no in vivo requirements, but individual dissolution testing requirements were adopted in 12 compendial monographs. USP tests measured the time to attain a specified amount dissolved, whereas NF used the more workable test for the amount dissolved at a specified time. Controversy with respect to equipment selection and methodology raged at the time of the first official dissolution tests. As more laboratories entered the field, and experience (and mistakes ) accumulated, the period 1970-1980 was one of intensive refinement of official test methods and dissolution test equipment. 

INTRODUCTION AND IMPLEMENTATION OF COMPENDIAL DISSOLUTION TEST REQUIREMENTS... 

Product failed US Pharmacopoeia dissolution test requirements... 

Failed USP dissolution test requirements Microbial contamination of non-sterile products Lack of efficacy Impurities/degradation products Lack of assurance of sterility Lack of product stability Labeling Label error on declared strength Misbranded Promotional literature with unapproved therapeutic claims... 

Initial Situation An experimental granulation technique is to be evaluated a sample of tablets of the hrst trial run is sent to the analytical laboratory for the standard batch analysis prescribed for this kind of product, including content uniformity (homogeneity of the drug substance on a tablet-to-tablet basis, see USP Section (905)" ), tablet dissolution, friability (abrassion resistance), hardness, and weight. The last two tests require little time and were therefore done first. (Note Hardness data is either given in [kg-force] or [N], with 1 kg = 9.81 Newton). 

Determination of the time for a tablet to disintegrate when immersed in some test fluid has been a requirement in most compendia for many years. For many years, it was the only test available to evaluate the release of medicaments from a dosage unit. We now recognize the severe limitations of such tests in assessing this property—hence, the introduction of dissolution rate requirements. 

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. 

Dissolution indicates the rate-limiting step for compound absorption when drugs are administered orally. The solubility of a pharmaceutical compound represents its maximum concentration in an aqueous buffer. Additional compound will not dissolve above this concentration. The solubility value is often heavily dependent upon pH and temperature and is typically measured at physiologically important pH levels and body temperature. The standards for dissolution testing are determined by the United States Pharmacopoeia (USP). Testing typically requires sampling of a solution at 15, 30, 45, and 60 min for immediate-release products. /./Pl.C is ideally suited for use in conjunction with USP apparatus types I or II and can rapidly analyze multiple time points or replicate samples. 

It should be remembered that in 1970, when drug-release/dissolution tests first became official through the leadership of USP and NF, marketed tablets or capsules in general simply did not have a defined dissolution character. They were not formulated to achieve a particular dissolution performance, nor were they subjected to quality control by means of dissolution testing. Moreover, the U.S. Food and Drug Administration (FDA) was not prepared to enforce dissolution requirements or to even to judge their value. 

Compendial Requirements of Dissolution Testing—European Pharmacopoeia, Japanese Pharmacopoeia, United States... 

A dissolution test was first described in the JP in 1981 (18). General rules for capsules and tablets stated that the requirements of the disintegration test must be met unless otherwise specified. Several specific capsule and tablet monographs included new dissolution tests. 

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