Dosage forms dissolution testing

This is the place to start, since most often, analytical chemists are trying to help solve someone else s problem. We need to define the solute and its matrix as well as the nature of the analytical problem. For example, in the world of pharmaceuticals, there are raw material identification and purity determinations, in-process testing, dosage-form determinations, content uniformity, dissolution testing, stability studies, bioavailability, pharmacokinetics, and drug metabolism, to name a few. Each of these analytical problems has its own specific requirements. The matrix can be a raw material, granulation, tablet, capsule, solution, lotion, cream, syrup, dissolution medium, blood serum, urine, or various body tissues and fluids. Similar definitions can be described for virtually any industrial area and problem set. These definitions will help select sample preparation, separation, and detection techniques. 

Reppas, C., Shah, V. P. Dissolution testing as a prognostic tool for oral drug absorption immediate release dosage forms. Pharm. Res. 1998, 15, 11-22. 

The information requirements for products such as prolonged-release oral dosage forms will depend on whether or not it has been possible, during the development of the product, to establish an in vivo-in vitro correlation between clinical data and dissolution studies. In vivo-in vitro correlations should be attempted using product at different stages of development, but bioavailability and pharmacokinetics data from pivotal clinical studies using at least pilot-scale production materials and possibly routine production material are particularly important. Where it is not possible to establish an in vivo-in vitro correlation, additional data will be required to compare the bioavailability of product developed at laboratory scale, pilot scale, and production scale. In the absence of an in vivo-in vitro correlation, the dissolution test will be a quality control tool rather than a surrogate marker for in vivo performance of the product. 

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 dissolution specification for prolonged-release dosage forms should cover a minimum of three points one to ensure that dose-dumping does not occur (early, typically 20-30% release), one to confirm compliance with the dissolution curve profile (around 50% release), and one to ensure that the majority of the dose has been released (often more than 80% released). The robustness of the test procedure should be considered (e.g., to temperature, pH, and rotational speed). 

Product bioavailability is mentioned, especially where it is low. Where there are differences between the formulations tested for bioavailability during the development process and the formulation to be marketed, there is considerable discussion of the data provided on the bioequivalence of the different products and/or formulations. This is particularly so where, for example, early clinical studies were undertaken with capsules but the marketed dosage form is to be a tablet. Bioequivalence data and pharmacokinetic data (e.g., in crossover studies) and comparative dissolution studies are usually reported. This is particularly significant where the different strengths of the final products are not achieved by using different quantities of the same granulate formulation. Process optimization may also be addressed in such cases. 

CDER Guidance for Industry. SUPAC-IR Immediate-Release Solid Oral Dosage Forms Scale-Up and Post-Approval Changes Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation US Food and Drug Administration, 1995. 

Studies involving instrumented compaction equipment can be extremely useful in the development of dosage forms, especially when the amount of drug substance is limited in quantity. Marshall has described a program in which dynamic studies of powder compaction can be used at all stages of the development process to acquire formulation information [63]. The initial experiments include a determination of the intrinsic compactability of the compound. In subsequent work, simple tablets are prepared, and tested for dissolution, potency, and content uniformity. Through studies of the compaction mechanism, it becomes possible to deduce means to improve the formulation under study. 

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]. 

Dissolution testing of pharmaceutical dosage forms, one of the most frequent tasks to be performed in a pharmaceutical laboratory, is another laborious and time-consuming process that generates a... 

The USP 27, NF22 (11) now recognizes seven dissolution apparatus specifically, and describes them and, in some cases allowable modifications, in detail. The choice of the dissolution apparatus should be considered during the development of the dissolution methods, since it can affect the results and the duration of the test. The type of dosage form under investigation is the primary consideration in apparatus selection. 

The European Pharmacopoeia (Ph. Eur.) has also adopted some of the apparatus designs (12) described in the USP, with some minor modifications in the specifications. Small but persistent differences between the two have their origin in the fact that the American metal processing industry, unlike the European, uses the imperial rather than the metric system. In the European Pharmacopeia, official dissolution testing apparatus for special dosage forms (medicated chewing gum, transdermal patches) have also been incorporated (Table 2 provides an overview of apparatus in Ph. Eur.). 

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