Tablet testing dissolution test

In the intervening years, the increase in specifications for oral dosage forms dissolution has been less dramatic. The 14th edition of the Japanese Pharmacopoeia (2002) has included additional dissolution tests for tablets and capsules. Out of a total of 61 tablet monographs, dissolution tests are included in 32. From four capsule monographs, one dissolution test is given (19). 

The various applications of the analysis of tablets for dissolution testing, content uniformity, stability-indicating assays, and routine quality control assays have all been targets of automation using a robot system. 

Some individual monographs already describe and require noncompendial equipment, such as Felodipine extended-release tablets, for dissolution testing.19 For example, one monograph describes a noncompendial probe inserted into Apparatus 2 as a wafer-like basket to the side of the paddle. Monographs with dissolution tests that require special equipment for low-dose products would most likely use a noncompendial apparatus in this manner. Use of noncompendial equipment should not be an obstacle as long as appropriate justification is provided and necessary qualification of the equipment is performed. 

Figure 3 Effect of the pH of the dissolution medium on the release of mesalazine tablets tested in pH 6.5 (open symbols) and 7.0 (closed symbols) mixed phosphate buffers. The mesalazine core tablets were coated with Eudragit LlOO-55 and Eudragit SlOO combinations of 1 4 (squares), 1 5 (triangles), and 0 1 (circles) ratios (w/w) and tested in 0.1 N HCl for 120 min prior to the buffer stage. The dissolution test was performed using United States Pharmacopoeia method B for extended-release tablets. The vertical bars indicate standard errors of the means (n = 6). (Adapted from Ref. 35.)...

In-vitro bioavailahility tests usually form part of the criteria for evaluating the individual batches of a product. These are based on monitoring the rate of release of the drug substance from the pharmaceutical form, usually by observing the dissolution rates of tablets or capsules. 

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). 

Note on GMPs The assays are conducted on individual dosage units (here tablets) and not on composite samples. The CU test serves to limit the variability from one dosage unit to the next (the Dissolution Rate test is the other test that is commonly used). Under this premise, outlier tests would be scientific nonsense, because precisely these outliers contain information on the width of the distribution that one is looking for. The U.S. vs. Barr Laboratories Decision makes it illegal to apply outlier tests in connection with CU and DR tests. This does not mean that the distribution and seemingly or truly atypical results should not be carefully investigated in order to improve the production process. 

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.

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). 

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. 

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. 

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. 

Product bioavailability is mentioned, especially where it is low. Where there are differences between the formulations tested for bioavailability during the development process and the formulation to be marketed, there is considerable discussion of the data provided on the bioequivalence of the different products and/or formulations. This is particularly so where, for example, early clinical studies were undertaken with capsules but the marketed dosage form is to be a tablet. Bioequivalence data and pharmacokinetic data (e.g., in crossover studies) and comparative dissolution studies are usually reported. This is particularly significant where the different strengths of the final products are not achieved by using different quantities of the same granulate formulation. Process optimization may also be addressed in such cases. 

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. 

Garlic supplements - powder tablets or capsules, steam-distilled oil, vegetable oil macerate extract, or extract aged in dilute alcohol - are widely available and are taken by millions. Since the active principle, allicin, is not present in garlic bulb, the supplements rely on the presence of precursor alliin and enzyme alliinase. In tests on 24 commercial brands of enteric-coated tablets, all except one gave low dissolution allicin release 83% of the brands released less than 15% of their potential allicin.78,79 Relevant factors were impaired enzyme activity caused by excipients and slow tablet disintegration. Caveat emptor ... 

Studies involving instrumented compaction equipment can be extremely useful in the development of dosage forms, especially when the amount of drug substance is limited in quantity. Marshall has described a program in which dynamic studies of powder compaction can be used at all stages of the development process to acquire formulation information [63]. The initial experiments include a determination of the intrinsic compactability of the compound. In subsequent work, simple tablets are prepared, and tested for dissolution, potency, and content uniformity. Through studies of the compaction mechanism, it becomes possible to deduce means to improve the formulation under study. 

In the disc method, the powder is compressed by a punch in a die to produce a compacted disc, or tablet. The disc, with one face exposed, is then rotated at a constant speed without wobble in the dissolution medium. For this purpose the disc may be placed in a holder, such as the Wood et al. [Ill] apparatus, or may be left in the die [112]. The dissolution rate, dmldt, is determined as in a batch method, while the wetted surface area is simply the area of the disc exposed to the dissolution medium. The powder x-ray diffraction patterns of the solid after compaction and of the residual solid after dissolution should be compared with that of the original powder to test for possible phase changes during compaction or dissolution. Such phase changes would include polymorphism, solvate formation, or crystallization of an amorphous solid [113],... 

Most manufacturers of dissolution testing devices offer semi-automated systems that can perform sampling, filtration, and UV reading or data collection. These systems automate only a single test at a time. Fully automated systems typically automate entire processes including media preparation, media dispensing, tablet or capsule drop, sample removal, filtration, sample collection or analysis (via direct connection to spectrophotometers or HPLCs), and wash cycles. A fully automated system allows automatic performance of a series of tests to fully utilize unused night and weekend instrument availability. 

In pharmaceuticals, NIR is used for, of course, moisture, polymorphic (drug) forms, percent crystallinity, isomer purity, tablet/capsule assay, coating levels, evaluation of dissolution times, and numerous process tests. It is a rapid means for the Food and Drug Administration to check for counterfeit drugs, and for the Drug Enforcement Agency to ascertain what type of materials are impounded in drug raids. ... 

Disintegration official in Brit Pharmacon and USP PMA Tablet Committee proposes 1% solubility threshold USP and NF Joint Panel on Physiological Availability chooses dissolution as a test chooses an apparatus Initial 12 monograph standards official Variables assessment more laboratories, three Collaborative Studies by PMA and Acad. Pharm. Sci First calibrator tablets pressed First Case default proposed to USP... 

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. 

Over the years, dissolution testing has expanded beyond ordinary tablets and capsules—first to extended-release and delayed-release (enteric-coated) articles, then to transder-mals, multivitamin and minerals products, and to Class Monographs for non-prescription drug combinations. (Note at the time, sustained-release products were being tested, unofficially, in the NF Rotating Bottle apparatus). 

Figure 6 Different cell types for dissolution testing using the flow-through system. Type (a) tablet cell (12 mm), (b) tablet cell (22.6 mm), (c) cell for powders and granulates, (d) cell for implants, (e) cell for suppositories and soft gelatin capsules, (f) cell for ointments and creams.

---