Dissolution testing profiles

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). 

At steady state, the concentration does not change with time. It is recognized that the concentration profile is angularly symmetrical the concentration, therefore, does not change with 0. We also assume that the disk is infinitely wide so that the concentration is a function of z only. This assumption can be justified since the diameter of the solute loaded is usually much smaller than that of the disk. Also, no production of drug occurs during dissolution testing. Consequently, Eq. (134) can be reduced to... 

Extensions of BCS beyond the oral IR area has also been suggested, for example to apply BCS in the extended-release area. However, this will provide a major challenge since the release from different formulations will interact in different ways with in vitro test conditions and the physiological milieu in the gastrointestinal tract. For example, the plasma concentration-time profile differed for two felodipine ER tablets for which very similar in vitro profiles had been obtained, despite the fact that both tablets were of the hydrophilic matrix type based on cellulose derivates [70], This misleading result in vitro was due to interactions between the gel strength of the matrix and components in the dissolution test medium of no in vivo relevance. The situation for ER formulations would be further complicated by the need to predict potential food effects on the drug release in vivo. 

The second situation when IVIVC is not likely for class II drugs is where the absorption is limited by the saturation solubility in the gastrointestinal tract rather than the dissolution rate, as discussed in more detail above. In this situation, the drug concentration in the gastrointestinal tract will be close to the saturation solubility, and changes of the dissolution rate will not affect the plasma concentrationtime profile and in vivo bioavailability. Standard in vitro dissolution tests are carried out under sink conditions , i.e., at concentrations well below the saturation solubility. Thus, only effects related to dissolution rate can be predicted in vitro. If more physiologically relevant dissolution media are used, which do not necessarily provide sink conditions , the possibility for IVIVC could be improved, as has been indicated by the results of recent studies using simulated intestinal medium [76],... 

A biowaiver is applicable for beaded capsules when the lower strength differs only in number of beads of active drug and the dissolution profile is similar in the recommended dissolution test media and conditions. 

Nicolaides E, Symillides M, Dressman JB, Reppas C. Biorelevant dissolution testing to predict the plasma profile of highly lipophilic drugs after oral administration. Pharm Res 2001 18(3) 380-388. 

For formulations not meeting the criterion for very fast release of drug substance, similarity of profiles may be evaluated by model-independent or model-dependent methods as stated in the Guidance for Industry—Dissolution Testing of IR Solid Oral Dosage Forms (1,2). 

In general, if an IVIVC method has been established, the requirement for additional dissolution test conditions is waived in favor of multi-point dissolution testing according to the in vitro method with which the IVIVC has been established. For level 3 changes, multi-point dissolution testing according to application-release test conditions is required in addition to in vivo BE. If IVIVC is available, this requirement is reduced to comparison of dissolution profiles of... 

In order to obtain an in vitro-in vivo relationship two sets of data are needed. The first set is the in vivo data, usually entire blood/plasma concentration profiles or a pharmacokinetic metric derived from plasma concentration profile (e.g., cmax, tmax, AUC, % absorbed). The second data set is the in vitro data (e.g., drug release using an appropriate dissolution test). A mathematical model describing the relationship between these data sets is then developed. Fairly obvious, the in vivo data are fixed. However, the in vitro drug-release profile is often adjusted by changing the dissolution testing conditions to determine which match the computed in vivo-release profiles the best, i.e., results in the highest correlation coefficient. 

Sinkers can significantly influence the dissolution profile of a drug. Therefore, the use of sinkers should be part of the dissolution method validation. If equivalent sinkers are identified during the sinker evaluation and validation, the equivalent sinkers should be listed in the written dissolution test procedure. When a dissolution method utilizes a dissolution sinker and is transferred to another laboratory, the receiving laboratory should duplicate the validated sinker design(s) as closely as possible. 

Key operating parameters that may change (or be optimized) throughout a product s development and approval cycle are dissolution sampling time points and dissolution limits or specifications by which the dissolution results should be evaluated. The results generated from the dissolution test need to be evaluated and interpreted based on the intended purpose of the test. If the test is used for batch-to-batch control, the results should be evaluated in regard to the established limits or specification value. If the test is being utilized as a characterization test (i.e., biopharmaceutical evaluations, formulation development studies, etc.) the results are usually evaluated by profile comparisons. 

With the exception of the formulation obtained by direct compression in a rotary machine, the dissolution profiles were well fitted by the Weibull function. A high density in the centre of the tablets may explain the sigmoid dissolution profiles. A percentage of the drug remains imprisoned in the matrix after the dissolution test. It is possible to suppose that, in the densified central zone of the tablet, the diameters of the pores are smaller than the diameters of the drug particles covered by the inert polymers. 

---