Dissolution rate, batch method

The wide variety of methods for determining the dissolution rates of solids may be categorized either as batch methods (Fig. 13A) or as continuous-flow methods (Fig. 13B). The common batch-type dissolution methods are derived from the beaker-stirrer method of Levy and Hayes [89] and include a number of thoroughly standardized procedures, especially those defined by the U.S. Pharmacopoeia [90]. 

The dissolution rate of a solid may be defined as dm/dt, where m is the mass of solid dissolved at time t. In a batch dissolution method, the analyzed concentration, cb, in the solution (if well stirred) is representative of the entire volume, V, of the dissolution medium, so that... 

While batch dissolution methods are simple to set up and to operate, are widely used, and may be carefully and reproducibly standardized, they suffer from the following disadvantages (1) the hydrodynamics are usually poorly characterized, with the notable exception of the rotating disc method, (2) a small change in dissolution rate will often create an undetectable and therefore an immeasurable perturbation in the dissolution time curve, and (3) the solute concentration cb may not be uniform throughout the solution volume V. 

The intrinsic dissolution rates of pharmaceutical solids may be calculated from the dissolution rate and wetted surface area using Eq. (36) or (37). For powdered solids, two common methods are available the powder intrinsic dissolution rate method, and the disc intrinsic dissolution rate method. In the former method, the initial dissolution rate of one gram of powder is determined by a batch-type procedure as illustrated in Fig. 13A. The initial wetted surface area of one gram of powder is assumed to equal the specific surface area determined by an established dry procedure, such as monolayer gas adsorption by the Brunauer, Emmett, and Teller (BET) procedure [110]. 

In the disc method, the powder is compressed by a punch in a die to produce a compacted disc, or tablet. The disc, with one face exposed, is then rotated at a constant speed without wobble in the dissolution medium. For this purpose the disc may be placed in a holder, such as the Wood et al. [Ill] apparatus, or may be left in the die [112]. The dissolution rate, dmldt, is determined as in a batch method, while the wetted surface area is simply the area of the disc exposed to the dissolution medium. The powder x-ray diffraction patterns of the solid after compaction and of the residual solid after dissolution should be compared with that of the original powder to test for possible phase changes during compaction or dissolution. Such phase changes would include polymorphism, solvate formation, or crystallization of an amorphous solid [113],... 

With all batch techniques, there is the common problem of not removing the desorbed species. This can cause an inhibition of further adsorbate release (Sparks, 1985, 1987a), promote hysteretic reactions, and create secondary precipitation during dissolution of soil minerals (Chou and Wollast, 1984). However, one can use either exchange resins or sodium tetraphenylboron, which is quite specific for precipitating released potassium, as sinks for desorbed species and still employ a batch technique (Sparks, 1986). Also, since in most batch methods the reverse reactions are not controlled, problems are created in calculating rate coefficients. This is particularly true for heterogeneous systems such as soils. 

In the disc method for conducting intrinsic dissolution studies, the powder is compressed in a die to produce a compact. One face of the disc is exposed to the dissolution medium and rotated at a constant speed without wobble. The dissolution rate is determined as for a batch method, while the wetted surface area is simply the area of the disc exposed to the dissolution medium. 

The choice between both methods is to be made in the product design phase. Ideally these in vitro methods are meant to mimic the behaviour in the intestinal environment in vivo. In practice the determination of the dissolution rate is meaningful as a tool in the design phase and as a means to monitor possible changes in (particle size of) raw materials and the production process. If changes are under control (no changes happen) then this test may not be required as part of the batch release specification. 

The dissolution efficiency (DE) of the batches was calculated by the method mentioned by Khan (Khan, 1975). It is defined as the area under the dissolution curve between time points ti and t2 expressed as a percentage of the curve at maximum dissolution, ylOO, over the same time period or the area under the dissolution curve up to a certain time, t, (measured using trapezoidal rule) expressed as a percentage of the area of the rectangle described by 100% dissolution in the same time. DEeo values were calculated from dissolution data and used to evaluate the dissolution rate (Anderson et al., 1998). 

Chemical development Proof of structure and configuration are required as part of the information on chemical development. The methods used at batch release should be validated to guarantee the identity and purity of the substance. It should be established whether a drug produced as a racemate is a true racemate or a conglomerate by investigating physical parameters such as melting point, solubility and crystal properties. The physicochemical properties of the drug substance should be characterized, e.g. crystallinity, polymorphism and rate of dissolution. 

The test apparatus chosen for disintegration testing and dissolution testing should be one of those described in the Ph Eur unless another pharmacopoeial or a noncompendia method can be justified. The test conditions and the proposed release rates should be justified in terms of batch reproducibility. 

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. 

In the presence of an IVIVC, the FDA stated that If an in vitro in vivo correlation is established, the dissolution test—after proper validation—can be used as a qualifying control method with the in vivo relevance, while in case of the absence of an IVIVC, the dissolution test can be used only as quality control method. In this case, the limits are set after calculating the plasma concentration time profile using convolution techniques or other appropriate modeling techniques, and determining whether the batches with the fastest and slowest release rates allowed by the dissolution specifications result in a maximal difference of 20% in the predicted Cmax and AUC. Of course an established IVIVC may allow the setting of wider dissolution specifications than the usual 10%. This would be dependent on the predictions of the IVIVC (i.e., 20% differences in the predicted Cmax and AUC) (Fig. II). 

Many solid dosage forms are designed for controlled dissolution or liberation of the drug substance, controlled in the sense that its release is slow compared with the rate of systemic absorption. Dissolution testing using pharmacopoeia and other methods is an essential element of the pharmaceutical development process. There are still arguments about its relevance to the in vivo situation and there are still those who maintain that it cannot be anything other than a quality control tool to ensure batch to batch consistency. 

Harvey et al. (2006) measured the rate of scorodite (FeAs04 2H20) dissolution using a batch reactor. One of the experiments produced the concentration of arsenic versus time data given in Table 4.1. These data can be analyzed to find the initial rate using either the polynomial fit method or the chord method. 

Product quality is usually determined and certified off-line in a quality control laboratory to ensure that specified properties of a production batch fall within the established range. Specifications related to molecular weight, charge density, composition, particle size, viscosity, rate of dissolution, solution viscosity, and residual monomer are common. Production batches that do not meet the specifications either require further processing, rework, or disposal and reduce production efficiency. As online analytical methods are employed, first pass yields (the proportion of production that meets specifications the first time) usually increase. 

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