Batch dissolution method

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. 

In a batch dissolution method the analyzed concentration c of a well-stirred solution is representative of the entire volume V of the dissolution medium, so that... 

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]. 

Therefore, the development and validation of a scientifically sound dissolution method requires the selection of key method parameters that provide accurate, reproducible data that are appropriate for the intended application of the methodology. It is important to note that while more extensive dissolution methodologies may be required for bioequivalency evaluations or biowaivers (i.e., multiple media, more complex dissolution media additives, and multiple sampling time points), it is also essential for the simplified, routine quality control dissolution method to discriminate batch-to-batch differences that might affect the product s in vivo performance. 

Chelators such as EDTA, nitrilotriacetic acid (NTA), 1,2-aminocyclohexane 7V,7V,7V ,N7-tetraacetic (DCyTA), and ethylene glycol-bis(2-aminoethyl)-(V,(V, 7V ,7V -tetraacetic acid (EGTA) have been studied extensively and are well summarized (Peters, 1999). Chelator concentration and reaction pH influence metal complexation and the success of removal from soils. Sun et al. (2001) observed that batch extraction methods result in 1 1 molar extraction ratios of EDTA/metal (Pb, Cd, Zn, Cu) and reveal which metal is more or less soluble in EDTA solutions. Column leaching studies, however, relate the elution patterns and recalcitrance of the metals to desorption and dissolution by EDTA. There is concern over the detrimental effects on soil quality from using chelators because of their biotoxicity, persistence in soil environment, and their removal of beneficial micro-and macronutrients, which leave the washed soil infertile for revegetation when it is backfilled. 

An in vitro dissolution method for batch QC is always defined for a new solid dosage form product. However, this method may not be sufficient for all the different aims of dissolution testing that might arise. The choice of dissolution method and test conditions should therefore be adapted to best serve their purpose. For example, simplicity and robustness are crucial properties of a QC method whereas physiological relevance may overrule these factors when a method is used for in vivo predictions. 

Polymers are widely used in various pharmaceutical formulations, such as traditional oral formulations (tablets and capsule) and complex parenteral formulations (such as microspheres, nanoparticles, implants, and in situ forming gels). Dissolution testing is used in formulation development, quality control for batch release of product, and in vitro-in vivo correlations. FDA has a database listing dissolution methods for around 1000 formulations such as tablets, capsules, granules, and injectable suspensions. These methods provide information about the standardized USP apparatus used, testing speed, type and volume of release medium, and the recommended sampling points. For detailed informadon abont the seven standardized dissolution apparatuses, method development, and validation of compendial methods, the reader is referred to USP Chapters 711,... 

Our formulation development activities we developed both a biorelevant dissolution method, and a drug product release method. At this point in development, all of our formulation development activities are complete, making the biorelevant method less important. The formulation(s) is fixed, and we are now concerned with demonstrating that we can consistently manufacture batches of drug product. We will also want to show that the release characteristics of the dosage unit do not change on stability. Oiu" drug product release method will fulfill this role and will be the primary dissolution method, until the method conditions need to be revisited when in vivo data become available from om first clinical studies. At that time, the method should be revisited to evaluate how biorelevant our in vitro data are. 

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. 

In general, aqueous ophthalmic solutions are manufactured by methods that call for the dissolution of the active ingredient and all or a portion of the excipients into all or a portion of the water and the sterilization of this solution by heat or by sterilizing filtration through sterile depth or membrane filter media into a sterile receptacle. If incomplete at this point, this sterile solution is then mixed with the additional required sterile components, such as previously sterilized solutions of viscosity-imparting agents, preservatives, and so on, and the batch is brought to final volume with additional sterile water. 

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. 

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],... 

Alternative methods and algorithms may be used, such as the model-independent approach to compare similarity limits derived from multi-variate statistical differences (MSD) combined with a 90% confidence interval approach for test and reference batches (21). Model-dependent approaches such as the Weibull function use the comparison of parameters obtained after curve fitting of dissolution profiles. See Chapters 8 and 9 for further discussion of these methods. 

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