Dissolution rate measurement procedure

One approach to the study of solubility is to evaluate the time dependence of the solubilization process, such as is conducted in the dissolution testing of dosage forms [70], In this work, the amount of drug substance that becomes dissolved per unit time under standard conditions is followed. Within the accepted model for pharmaceutical dissolution, the rate-limiting step is the transport of solute away from the interfacial layer at the dissolving solid into the bulk solution. To measure the intrinsic dissolution rate of a drug, the compound is normally compressed into a special die to a condition of zero porosity. The system is immersed into the solvent reservoir, and the concentration monitored as a function of time. Use of this procedure yields a dissolution rate parameter that is intrinsic to the compound under study and that is considered an important parameter in the preformulation process. A critical evaluation of the intrinsic dissolution methodology and interpretation is available [71]. 

The study of the dissolution behavior involves measurements of film thickness as a function of time. Although the simplest procedure requires manual measurements of the initial thickness and the thickness after development for a given period of time to generate average dissolution rates, automated in situ thickness measurement methods are much more preferred as kinetics information is much more valuable than simple average dissolution rate data. Two methodologies are available laser interferometry and quartz crystal microbalance (QCM). 

The initial supersaturation is recorded and the desupersaturation decay is monitored by continuous or frequent intermittent solution analysis, e.g. by measuring some relevant physical property such as density, refractive index, conductivity, etc. The same procedure may be used, with appropriate nomenclature changes, to determine overall dissolution rates by measuring the increase in solution concentration. 

Other Measurements. Other tests include free moisture content, rate of dissolution and undissolved residue in acids and alkaH, resin and plasticizer absorption, suspension viscosity, and specific surface area. Test procedures for these properties are developed to satisfy appHcation-related specifications. 

Dissolution test data will be required in all cases (and for all strengths of product) for development and routine control and should be based on the most suitable discriminatory conditions. The method should discriminate between acceptable and unacceptable batches based on in vivo performance. Wherever possible Ph Eur test methods should be used (or alternatives justified). Test media and other conditions (e.g., flow through rate or rate of rotation) should be stated and justified. Aqueous media should be used where possible and sink conditions should be maintained. A small amount of surfactant may be added where necessary to control surface tension or for active ingredients of very low solubility. Buffer solutions should be used to span the physiologically relevant range—the current advice is over pH 1 6.8 or perhaps up to pH 8 if necessary. Ionic strength of media should be reported. The test procedure should employ six dosage forms (individually) with the mean data and a measure of variability reported. 

Using the pKa and the estimated So, the DTT procedure simulates the entire titration curve before the assay commences. Figure 6.7 shows such a titration curve of propoxyphene. The simulated curve serves as a template for the instrument to collect individual pH measurements in the course of the titration. The pH domain containing precipitation is apparent from the simulation (filled points in Fig. 6.7). Titration of the sample suspension is done in the direction of dissolution (high to low pH in Fig. 6.7), eventually well past the point of complete dissolution (pH <7.3 in Fig. 6.7). The rate of dissolution of the solid, described by the classical Noyes-Whitney expression [37], depends on a number of factors, which the instrument takes into account. For example, the instrument slows down the rate of pH data taking as the point of complete dissolution approaches, where the time needed to dissolve additional solid substantially increases (between pH 9 and 7.3 in Fig. 6.7). Only after the precipitate completely dissolves, does the instalment collect the remainder of the data rapidly (unfilled circles in Fig. 6.7). Typically, 3-10 h is required for the entire equilibrium solubility data taking. The more insoluble the... 

Figure 15 Procedure used to obtain a database of nuclear fuel (U02) corrosion rates (currents) (B) from a Tafel relationship for the anodic dissolution currents for U02 and a series of EC0Rr values measured in radiolytically decomposed solutions (A).

In addition to the procedures and precautions required for aqueous systems, others inherent to non-aqueous systems must be observed. These are often ignored by the research worker unfamiliar with the nature of organic solvent systems. They can be divided into five categories (1) solvent purity, (2) solubility of solutes and nature of dissolved species, (3) rate of dissolution of solutes, (4) solvent vapour pressure and (5) measurements in dilute solution. While these same items arise in work with aqueous solutions, they do not occur with such frequency and cause such practical difficulties as with non-aqueous solvents. 

The mass transfer coefficients in the crossflow cell were estimated from independent measurements of dissolution of a plate of benzoic acid into water at two different crossflow rates 50 L h and 120 L h , at 30 °C. Mass transfer coefficients for docosane and TOABr were estimated based on the experimentally measured benzoic add mass transfer coefficients values and the Chilton-Colbum mass transfer coeffident correlation. Details of the procedure applied are described elsewhere [32]. 

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