Active ingredients within dosage forms

A 1986 paper by Ciurczak and Maldacker [45] using NIR for tablet formulation blends examined the use of spectral subtraction, spectral reconstruction, and discriminant analysis for the analysis of dosage forms. Blends were prepared where actives—aspirin (ASA), butalbital (BUT), and caffeine (CAP)—were omitted from the formulation or varied over a range from 90 to 110% of label strength. For spectral subtraction, spectra of true placebos were subtracted, yielding spectra very close to those of the omitted drug. 

Identification of constituents by spectral reconstruction was performed with commercially available software, based on work by Honigs [46], later expanded upon by Honigs et al. [47]. Using a series of mixtures of known concentrahons, the spectrum of the drug was reconstructed, providing identification of achves in the blend. 

A third set of experiments classified samples by discriminant analysis. In one series of blends, the CAP, BUT, and ASA concentrations vari independently between 90 and 110% of the labeled claim. In another series, one of the three drugs was excluded from the mixture, while the others were varied between 90 and 110%. The Mahalanobis distance statistic was used for classification of formulations. This technique was used for samples of complete formulations (all three drugs at 100% of label strength), borderline formulations, and samples lacking one active component. 

In 1986, Whitfield [48] used discriminant analysis to ascertain that a veterinary drug dosed in chicken feed was present before conducting a quantitative analysis. 

A considerable amount of (unpublished) work has been performed by Ciurczak on counterfeit tablets. Using the same algorithms that have been applied to discriminate between placebos and active products, counterfeit products may be easily identified. The spectral variability stems from different raw materials and manufacturing processes, even though the active may be present at the correct level. Moffat et al. [49], Rodionova et al. [50], and Polli et al. [51] published examples of use of NIR to detect counterfeit drugs. 

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The Committee for Proprietary Medicinal Products [8] applied the BCS, with certain requirements, to dispense with bioequivalency tests if the active pharmaceutical ingredient is class I and the in vitro dissolution of the finished dosage form is fast [9], An active substance is considered highly soluble if the amount contained in the HDS of an IR product is dissolved in 250 ml of each of three buffers within the range of pH 1-8 at 37°C (e.g., pH 1.0, 4.6, and 6.8). There should be linear and complete absorption, which indicates HP to reduce the possibility of an IR dosage form influencing the bioavailability [8], The similarity of the dissolution profiles of the test and reference products is demonstrated in each of three buffers within the range of pH 1-8 at 37°C (e.g., pH 1.0,4.6, and 6.8). If there is rapid dissolution of the product, where at least 85% of the active substance is dissolved within 15 min, no further comparison of the test and reference is required. Further requirements include that excipients be well established and have no interaction with the pharmacokinetics of the active substance and that the method of manufacture of finished product... 

Example In a product consisting of active ingredient A, lactose, microcrystalline cellulose, and magnesium stearate, the lactose and microcrystalline cellulose should not vary by more than an absolute total of 5% (e.g., lactose increases by 2.5% and microcrystalline cellulose decrease.s by 2.5%) relative to the target dosage form weight if it is to stay within the level 1 range. 

Active and inactive ingredients are not in exactly the same proportion between different strengths as stated above, but the ratios of inactive ingredients to total weight of the dosage form are within the limits defined by the SUPAC-IR and SUPAC-MR guidances (up to Level II). 

Identity is a general requirement for dosage forms. When determining specificity for identity, the assay and related substances or the content uniformity methods can be used. Assay and content uniformity methods are quantitated by external reference standard. This identity test confirms that the correct active ingredient (s) is present and is present in correct ratio if multiple variants are available. The method could also be used for post-packaging analysis. The general requirements are that the sample and standard chromatograms should correspond in retention time and normalized peak area within 10%. 

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