Linearity dissolution test

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.

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. 

In a recent study, Mirza et al. have pointed out that despite the obvious advantages, fiber-based dissolution studies are not yet implemented in industry. They have validated a fiber-optic based dissolution test for linearity, precision, accuracy, specificity and robusmess, with excellent results. 

Range. The results of the linearity, accuracy, and precision will help determine the range for the dissolution test (e.g., 25 to 125% of nominal for a single-point dissolution and 20% of the stated range for a dissolution profile for a modified release formulation). 

This guideline refers to terms and definitions of parameters included in validation experiments, whereas Q2B describes the way in which validation can be performed. Attributes covered in Q2A include specificity (for identification tests) accuracy, precision, specificity, detection limit, quantitation limit, linearity, and range (for impurity tests) and accuracy, precision, specificity, linearity, and range for assay measurements (e.g., content, potency, and dissolution testing). 

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... 

A drawback of Gran plots is the fact that all deviations from the theoretical slope value cause an error and that side reactions are not considered. The method was modified by Ingman and Still [63], who considered side reactions to a certain degree, but the equilibrium constants and the concentrations of the components involved must be known. The Gran method is, however, advantageous for determinations in the vicinity of the determination limit The extrapolation of the linear dependence yields the sum + c, where c, is the residual concentration of the test component produced by impurities, dissolution of the ISE membrane, etc. 

As mentioned previously, the physical state of a solute is susceptible to modifications by interaction with cosolvents. In principle, a cosolvent can enhance solute solubility by changing the solvency of the medium, by direct solute interaction, by adsorption, or by partitioning (Chiou et al. 1986). In a batch experiment testing the effect of humic acid on kerosene dissolution in an aqueous solution, Dror et al. (2000a) found a linear correlation between the amount of humic acid and the amount of kerosene that dissolved (Fig. 6.5). 

Fig. 13. Relationship between the normalized apparent dissolution rate of HT materials, r(glaxs)l1(lnn and their free energy of hydration, ACh>lir. calculated for the pH values measured after one day and 10 days of corrosion. For comparison, the literature-extracted results (Plodinec and Wicks 1994) obtained for 115 glasses of different origins corroded under the conditions of the MCC-I test are reproduced. For simplicity, data obtained after three days of corrosion are not shown their linear fit lies between the ones of the one-day and the 10-day corrosion experiments.

Accuracy. Sample solutions of known concentration (e.g., spiked placebo) are used for the accuracy determination. Experimental work may be organized so that the same stock solutions are used to prepare both linearity and accuracy solutions. The accuracy solution must be exposed to normal test conditions (e.g., mixing in a heated dissolution vessel). Determine any bias that is caused by the sampling and analysis of the solutions. If a dissolution profile of the drug product is required, accuracy determinations at different concentrations of the required profile will need to be performed (e.g., at 40, 75, and 110% of theoretical release). The results are reported as percent theory. 

FtG. 3.11. Tests of the rate law in Eq. 3.64 for albite,9 anorthite [C. Amrhein and D. L. Suarez, The use of a surface complexation model to describe the kinetics of ligand promoted anorthite dissolution, Geochim. Cosmochim. Acta 52 2785 (1988)], goethite,36 and S-A1203.36 A linear plot is consistent with the rate law. 

Figures 10a and b show the plots of logarithmic intensity (after Cook s correction) versus elapsed time for the phase separation and phase dissolution, respectively. The plots in the former are hardly linear, and deviations are severe, particularly at late stages of phase separation. This observation is not surprising in view of the fact that the peak invariance is only seen at a very short interval of 80 to 94 s in Figure 8a. Thus, the R(q) can not be determined with good accuracy as it is affected by the non-linear contribution. The data points in the phase dissolution show linear relationships as predicted by the linearized theory. However, it is important to test the linearized theory quantitatively in terms of Equation 4.

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