Dose uniformity

The dose uniformity of tablets can be determined by two different general approaches the weight variation between a specified number of tablets or the extent of drug content uniformity. The USP permits the latter approach in all cases. Moreover, drug content uniformity must be measured for coated tablets because... 

Half-unit doses are discouraged for tablets. Where it is possible to justify a half-unit dosage, then additional information will be required for dose uniformity within the halves and on the breakability of the dosage form in patient use conditions. 

The delivery system needs to be discussed. This will include consideration of surface charges of the particles and of the device, the development of charges during filling of the product and during in-use streaming, and any relevant changes in effective particle size. Where the prototype device differs from the production device, additional data may be required. Dose uniformity and fine particle assessments at the relevant air flow rates should be reported. 

M. J. (1994). An inter-company cross-validation exercise on capillary electrophoresis testing of dose uniformity of paracetamol contents In formulations. Chromatographia 39, 180—184. 

Altria, K. D., Clayton, N. G., Hart, M., Harden, R. C., Hevizi, J., Makwana, J. V, and Portsmouth, M. J. (1994). Inter-company cross-validation exercise on capillary electrophoresis testing of dose uniformity of paracetamol content in formulation. Chromatographia 39, 180—184. 

Currently the U.S., European, and British pharmacopeias specify different requirements for delivered dose uniformity. Table 5 describes these requirements as well as proposed FDA expectations [33]. The Japanese pharmacopeia does not speeify a delivered dose uniformity requirement. Current compendia should be eonsulted as referenees. 

Of the four pharmacopeias, the U.S. pharmacopeia (USP) has the strietest requirements for delivered dose uniformity. Although the British pharmaeopeia (BP) allows the same performance range, the USP defines the range around the label claim and the BP defines the range around the average value. The FDA expeetation for delivered dose uniformity is currently tighter than that stated in all the pharmaeopeias. 

Various dry powder attributes are assessed at release and on stability. These include physieal eharaeteristies sueh as appearance, content uniformity, delivered dose uniformity, and partiele size distribution. Chemieal attributes that may be assessed include drug eontent, purity, and identity, as well as the water content. Dry powders may also undergo mieroseopie evaluation for foreign particulate matter, unusual agglomeration, and partiele size. Mierobial limits should also be examined, including the total aerobie, yeast, and mold eounts. The presence of specific pathogens should be ruled out. The dry powders may be dissolved to test for pH. 

In addition, eertain eompendial requirements for content and delivered dose uniformity should be measured. The USP and EP propose that the total aerobic count not exceed 100 CFU/g (colony-forming imits) that the total yeast and mold counts not exceed 10 CFU/g and that no specific pathogens be detectable. Specifications for the other attributes should be based on the intended use and the historical performance of the product. As with other dosage forms, specifications must be met throughout the intended shelf life of the product. 

Adhesive mixtures require large carrier crystals to improve the handhng properties of the powders. Dispersion of the small drng particles over the larger carrier material should assure dose uniformity. However, the small dmg particles shonld be removed from the carrier material dnring inhalation, to render an aerosol clond of respirable particles. If the particles remain on the carrier, month or throat deposition of the drng will occur, which might decrease therapeutic efficacy or cause serious side-effects. 

Sadrieh, N., Brower, J., Yu, b., Doub, W., Straughn, A., Machado, S., Pelsor, F., Saint Martin, E., Moore, T., Reepmeyer, J., Toler, D., Nguyenpho, A., et al. (2005). Stability, dose uniformity, and palatability of three counterterrorism drugs-human subject and electronic tongue studies. Pharm. Res. 22(10), 1747-1756. 

The dose uniformity across the width of the beam, measured by placing the film chips at about 1 in. (25 mm) intervals or using a long strip of film across the entire width of the beam. 

Flowability is important to the successful scale-up of a tableting process. The rate at which the precompacted blend flows into the hoppers of the tablet press and subsequently into the die cavity could be crucial to dose uniformity. Three measurements are most commonly used to measure flow ... 

The over-all dimensions of the active portion of the plaques are 42.2 inches high by 56.2 inches wide and the center line distance between the two plaques is 16 inches. The original center line distance between the two plaques of 11 inches was changed to 16 inches to improve the over-all dose uniformity in the carriers. 

Miller, N. C., Schultz, R. K., Schachtner, W. J. Through-life dose uniformity in pressurized metered dose inhalers. Pharm Res 7(9, suppl.) S-88 (1990). 

Qualified technical personnel should oversee PQ studies however, the execution can be left to specially trained hourly personnel. For larger projects it may be necessary to use a team approach to ensure that the requisite technical skills are available. Evaluation of dose uniformity may require the skills of a quality control analyst, formulation expert, and statistician. In these circumstances, report preparation may have to be split among the team members. 

Non-uniformity of the batch was not discovered during the limited dose uniformity testing performed during the release process. 

Ojile JE, Macfarlane CB, Selkirk AB. 1982. Drug distribution during massing and its effect on dose uniformity in granules. Int. J. Pharm. 10 99-107. 

Reaction rate parameters required for the distributed pharmacokinetic model generally come from independent experimental data. One source is the analysis of rates of metabolism of cells grown in culture. However, the parameters from this source are potentially subject to considerable artifact, since cofactors and cellular interactions may be absent in vitro that are present in vivo. Published enzyme activities are a second source, but these are even more subject to artifact. A third source is previous compartmental analysis of a tissue dosed uniformly by intravenous infusion. If a compartment in such a study can be closely identified with the organ or tissue later considered in distributed pharmacokinetic analysis, then its compartmental clearance constant can often be used to derive the required metabolic rate constant. 

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