Dissolution testing, strength

Figure 4.50. Cumulative dissolution results. Two experimental tablet formulations were tested against each other in a dissolution test in which tablets are immersed in a stirred aqueous medium (number of tablets, constructional details and operation of apparatus, and amount of medium are givens). Eighty or more percent of the drug in either formulation is set free within 10 minutes. The slow terminal release displayed by formulation B could point towards an unwanted drug/excipient interaction. The vertical bars indicate ymean - with Sy 3%. A simple linear/exponential model was used to approximate the data for the strength 2 formulation. Strengths I and 3 are not depicted but look very similar.

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. 

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. 

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. 

Failed USP dissolution test requirements Microbial contamination of non-sterile products Lack of efficacy Impurities/degradation products Lack of assurance of sterility Lack of product stability Labeling Label error on declared strength Misbranded Promotional literature with unapproved therapeutic claims... 

A brief description of the IR products used for dissolution testing, including information on batch or lot number, expiry date, dimensions, strength, and weight... 

Comparative dissolution testing on the higher strength of the test and reference products is submitted and found to be appropriate. 

During development of Compound B, several low-dose tablet formulations were investigated in clinical studies, including 0.05, 0.1, 0.25, and 0.4 mg tablet strengths. With these low-dose tablets, dissolution testing in 500 mL yielded low sample... 

For a low-dose dmg product, the ability to maximize the detected analyte response during dissolution testing becomes a critical factor. For an immediate release, oral dmg product ranging in capsule strength from 10-100 ig, the analyte concentration... 

Although conventional dissolution tests try to reflect either one or a combination of the following factors pH, ionic strength of GI fluid, and the agitation intensity (motility) of the GI tract, methods that show the effect of a mechanical destructive force on drug release are relatively limited. Therefore, in vitro studies using the conventional methods are sometimes unable to predict drug behavior in vivo, particularly in the fed state. To estimate this influence, a multicompartmental, dynamic, computer-controlled system that simulates... 

A drug release test, dissolution, was a satisfactory standard every time there was a problem of any practical consequence. Of equal significance was the recognition of the strength of dissolution testing as a tool for quality control. Thus, equivalence in dissolution... 

Additional strength For the registration of an additional strength of a generic product, comparative in vitro dissolution tests may be accepted in principle, if certain conditions have been met. 

For delayed-release tablets, when the multisource product is in the same dosage form, but in a different strength, and is proportionally similar in its active and inactive ingredients and has the same delayed-release mechanism, a lower strength can be granted a biowaiver if it exhibits similar dissolution profile, f, > 50, in the recommended test condition for delayed-release product, i.e. dissolution test in acid medium (pH 1.2) for 2 hours followed by dissolution in pH 6.8. 

Medicine Highest oral strength according to WHO Essential Medicines List" Solubility Permeability BCS class Dissolution test (for biowaiver)" Potential risks Indication(s) according to WHO Essential Medicines List" Comments and special dosage form indications"... 

---