Dissolution testing calibration

During the dissolution test, the hydrodynamic aspects of the fluid flow in the vessel have a major influence on the dissolution rate (1). Therefore, the working condition of the equipment is of critical importance. In this chapter, the qualification and calibration of the equipment referred to in the two USP General Chapters related to dissolution, < 711 > Dissolution and < 724 > Drug Release (2), will be discussed. Sources of error when performing dissolution... 

When performing dissolution testing, there are many ways that the test may generate erroneous results. The testing equipment and its environment, handling of the sample, formulation, in situ reactions, automation and analytical techniques can all be the cause of errors and variability. The physical dissolution of the dosage form should be unencumbered at all times. Certain aspects of the equipment calibration process may show these errors as well as close visual observation of the test. The essentials of the test are accuracy of results and robustness of the method. Aberrant and unexpected results do occur, however, and the analyst should be well trained to examine all aspects of the dissolution test and observe the equipment in operation. 

Once the appropriate dissolution conditions have been established, the method should be validated for linearity, accuracy, precision, specificity, and robustness/ruggedness. This section will discuss these parameters only in relation to issues unique to dissolution testing. All dissolution testing must be performed on a calibrated dissolution apparatus meeting the mechanical and system suitability standards specified in the appropriate compendia. 

Calibration of dissolution equipment. It is very important to ensure that the calibration of the dissolution equipment is kept up to date. The expiry date of the calibration status should be checked each time that dissolution testing is performed. 

The apparatus suitability test described in USP General Chapter <711> Dissolution is equivalent to a performance qualification.5 The determination of suitability of a test assembly to perform dissolution testing must include conformance to the dimensions and tolerances of the apparatus. In addition, the critical test parameters that have to be monitored periodically include volume and temperature of the dissolution medium, rotation speed (Apparatuses 1 and 2), dip rate (Apparatus 3), and flow rate of medium (Apparatus 4). This test requires that the USP Calibrator Tablets (now known as Performance Verification Standard Tablets) be tested the dissolution results must be within the ranges stated in the certificate of the calibrator tablets. The performance verification standard tablets include USP Chlorpheniramine Maleate Extended-Release Tablets RS, USP Prednisone Tablets RS, and USP Salicylic Acid Tablets RS. 

All apparatus must be calibrated and the variables standardized and known. Experimental design in dissolution testing to examine residual variation between experimental runs and individual dissolution vessels is feasible. The objective is to minimize errors in experimental set-up, achieved by using mean dissolution times and partial balancing. Lower coefficients of variation occur at higher hydrodynamic intensities. 

Qureshi, S.A. McGilveray, I.J. Typical variability in drug dissolution testing study with USP and FDA calibrator tablets and a marketed drug (glibenclamide) product. Eur. J. Pharm. Sci. 1999, 7, 249-258. 

Vitamins Bi, B2, B6 Tablet dissolution tests Fluorimetry Not relevant 135 Chemometrics involving an artificial neural networks calibration/zone stopping at the detector [156]... 

Dissolution testing is a key technique in pharmaceutical development laboratories. Methods are described in various pharmacopoeias, along with the calibration of the testing apparatus. Specifications of the precision of the testing... 

Care must be taken for cleaning and storing dissolution testing units and vessels. Each vessel is calibrated at a certain position of the dissolution unit. All vessels must be cleaned and appropriately stored. 

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... 

PhRMA Subcommittee on Dissolution Calibration, Brune S, Bucko J, Emr S, Gray V, Hippeli K, Kentrup A, Whiteman D, Loranger M, Oates M. Dissolution calibrator recommendations for reduced chemical testing and enhanced mechanical calibration. Pharm Forum 2000 26(4) 1149-1166. 

Thakker KD, Naik NC, Gray VA, Sun S. Fine-tuning of dissolution apparatus for the apparatus suitability test using the USP dissolution calibrators. Pharm Forum 1980 6(4) 177—185. 

In this example, of transfer of a drug product dissolution method, the samples are independent (as test is destructive in nature) and additional variability due to different baths/standard sets are assumed to be negligible (dissolution baths were independently calibrated as per USP criteria). Based on the receiving site s familiarity with the methodology to be transferred, only one analyst/dissolution bath per site was used. The analyses were performed at USP level 2, i.e. 12 individual samples were tested. The standard deviation on 12 replicate analyses from an earlier study was 3.02 (Borman et al., 2009). The authors indicated that as this estimate is based on a limited number of replicates, it was good practice to use a pre-defined multiplier, which allows for uncertainty (Hahn and Meeker, 1991), in this case 1.255 (multiplier for... 

Apparatus suitability test Dissolution calibrator, disintegrating, and nondisintegrating types Not specified Not specified... 

The FDA expects the phase I and phase II investigation efforts to proceed beyond the batch in question and to other batches that were also manufactured under the same circumstances leading to failure of the OOS batch. If the investigation has revealed an operator-related or process-related error (e.g., ingredient test failure, equipment malfunction, calibration expiration, irregularity in process execution) and other batches were made using one or more common elements, they should also be investigated for compliance with all acceptance criteria. In the case above, dissolution results should be scrutinized. 

The USP 24 specified apparatus suitability tests based on the operating conditions, involving the USP Dissolution Calibrator, Disintegrating Type or the USP Dissolution Calibrator, non-disintegrating type. The apparatus is deemed suitable if the obtained results are within the accepted range stated for that type of calibrator. 

Fig. 4 Schematic of USP drug dissolution apparatuses 1 (basket) and 2 (paddle). (From Qureshi, S.A. Calibration the USP dissolution apparatus suitability test. Drug Inf. J. 1996, 30, 1060, Fig. 2.)...

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