Dissolution testing requirement during

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. 

V. REQUIREMENTS OF HPLC METHODS FOR DISSOLUTION TESTING DURING DRUG DEVELOPMENT PROCESS... 

Qualitative assessment of dissolution testing during the initial stage of method development can save a great deal of time, because if certain gross requirements of the test are not met, the sample analysis portion of the test can be eliminated. Examples of some of the possible observations of dosage-form performance and their related issues are ... 

USP Dissolution Apparatus 1 (basket) and 2 (paddle) are commonly used for immediate-release formulations. USP Apparatus 3 (reciprocating cylinders) is the system of choice for testing extended-release products or a dosage form that requires release profiling at multiple pH levels and time points. Low-dose products may require the use of flow-through analysis or other low-volume test techniques (noncompendial 100- or 200-mL dissolution vessels). Once the apparatus is selected and has been shown to be suitable during method development, no further evaluation of another apparatus is required during validation. 

There are various situations during the life cycle of a dissolution test that will require revalidation of the method. These are similar to those described for the potency assay in Chapter 2. 

Typical tests involved during development and their usual applicability are shown in Table 1. The use of these tests varies widely according to the requirements of the particular region of the world where the product will be marketed. The results of these tests and their effect, if any, on product effectiveness should demonstrate which tests are critical and need to be incorporated into the final product specifications. Tests that invariably become a part of the final product specifications are identity, assay, content uniformity, disintegration or dissolution, degradation products and tests such as visual inspection. 

In vitro and in vivo biocompatibUity tests are required by government agencies for drug delivery system and biomedical device approval [16]. In vitro dissolution testing is used to assess in vivo performance and is important during formulation development as weU as for product quality assurance. Standardized dissolution methods are under development for novel polymeric formulations such as microspheres, nanoparticles, and in situ forming gels [17]. 

The USP/EP/JP flow-through apparatus (Figure 3) should be considered if the drug substance exhibits low solubility or if pH changes to the dissolution medium are required during the dissolution test, as in the case of controlled or delayed release products. 

Since transport across the biological membrane of weak bases will be more pronounced in the small intestine (uptake of the unionized form), sufficient precipitation inhibition (polymer) is required upon transfer of the supersaturated solution to the intestine. Therefore, one cannot rely on dissolution studies at constant acidic pH to predict the performance of formulations of weak bases in vivo (Miller et al. 2007). For instance. Six et al. (2005) observed a discrepancy between the results of in vitro dissolution tests in acidic medium and in vivo absorption for four solid dispersions of ITR faster release and increased supersaturation in acidic medium correlated with lower bioavailability. Presumably, this effect can be explained by differences in crystallization rate upon transfer to the small intestine (increased driving force for precipitation in case of higher supersaturation). Thus, it is crucial to simulate the GI pH shift during supersaturation dissolution testing of weak bases to evaluate whether supersaturation is maintained in the small intestine. 

So-called infinity points can be useful during development studies. To obtain an infinity point, the paddle or basket speed is increased significantly (e.g., 150 rpm) at the end of the run and the test is allowed to run for an extended period of time (e.g., 60 min), and then an additional sample is taken. Although there is no requirement for 100% dissolution in the profile, the infinity point can provide data that may provide useful information about the formulation characteristics during the initial development. 

---