For immediate-release dosage forms, the duration of the dissolution procedure is typically 30–60 min; in most cases, a single time point specification is adequate for pharmacopeial purposes. For method development, however, a sufficient number of time points should be selected to adequately characterize the ascending and plateau phases of the dissolution curve. Industrial and regulatory concepts of product comparability and performance may require additional time points, which may also be required for product registration or approval. According to the Biopharmaceutics Classification System referred to in several FDA Guidances, highly soluble, highly permeable drugs formulated into very rapidly dissolving products need not be subjected to a profile comparison if they can be shown to release 85% or more of the drug substance within 15 min. For these types of products, a one-point test or disintegration will suffice. However, most products do not fall into this category. Dissolution profiles of immediate-release products typically show a gradual increase reaching 85%–100% at about 30–45 min. Thus, sufficient dissolution time points are chosen to characterize the performance for most immediate-release products. For some products, including suspensions, useful information may be obtained from earlier points, e.g., 5–10 min. For slower-dissolving products, time points later than 60 min may be useful. Dissolution test times for compendial tests are usually established on the basis of an evaluation of the dissolution profile data.

The f2 similarity factor may not be useful when more than 85% is dissolved at 15 min. If the f2 similarity factor is to be used, multiple time points for the dissolution test are required, with at least two time points with mean percent dissolved (typically for n = 12) below 85% dissolved and only one point above 85% for both products (16). Therefore, the addition of early time points may be useful.

For testing an extended-release dosage form, at least three time points are chosen, to guard against dose dumping, to define the in vitro release profile, and to show that essentially complete release (>80%) of the drug is achieved. Additional sampling times may be useful. Certain IVIVC criteria, such as level B correlation (according to In Vitro and In Vivo Evaluation of Dosage Forms 1088), require the experimental determination of the time to dissolve 100% of the label claim. Selection of the final time points is reflective of the data from the drug release profile that are generated during development. For products containing more than a single active ingredient, determine the drug release for each active ingredient.

Delayed-release dosage forms usually require specifications for at least two time points; therefore, it is important during development to evaluate the entire dissolution profile. In the case of enteric-coated dosage forms, the functionality of the coating is usually proven by challenge in an acid medium, followed by a demonstration of dissolution in a higher-pH medium. Chapter 711 gives a standard buffer medium for that stage of testing but other media may be used if justified. The timing of the acid stage is typically 2 h, and release in the buffer is similar to the timing for immediate-release forms. For delayed-release dosage forms that are not enteric coated, setting of specifications is different. Unlike delayed release, the onset of release is not determined by the experimental design, which is the pH change; multivariate specifications, therefore, may be needed to define time ranges and corresponding percentage ranges.

So-called infinity points can be useful during development studies. To obtain an infinity point, the paddle or basket speed is increased at the end of the run (after the last time point) for a sustained period (typically, 15–60 min), after which time an additional sample is taken. Although there is no requirement for 100% dissolution in the profile, the infinity point can be compared to content uniformity data and may provide useful information about formulation characteristics during initial development or about method bias.

Visual observations and recordings of product dissolution and disintegration behavior are useful because dissolution and disintegration patterns can be indicative of variables in the formulation or manufacturing process. For visual observation, proper lighting (with appropriate consideration of photo-degradation) of the vessel contents and clear visibility in the bath are essential. Documenting observations by drawing sketches and taking photographs or videos can be instructive and helpful for those who are not able to observe the real-time dissolution test. Observations are especially useful during method development and formulation optimization. It is important to record observations of all six vessels to determine if the observation is seen in all six vessels, or just a few. If the test is performed to assist with formulation development, provide any unique observations to the formulator. Examples of typical observations include, but are not limited to, the following:

Observations also help to document that the proper procedure has been followed, or more importantly, that a deviation has occurred. Examples include the confirmation that a dosage form is actually in the vessel during the test or that more than one dosage form are inadvertently in the same vessel, or that a filter from the autosampler has dropped into the vessel.

Importance is placed on evaluation of the cleaning process between tests. Changes of dissolution medium and/or product necessitate the need for cleaning. Residues on the vessels can affect the results (e.g., adsorbed residues may dissolve and alter subsequent media properties or interfere with the sample analysis), and effective cleaning will return them to a suitable state. Automated systems are discussed in section 4.4 Cleaning.

For the analytical finish, repeatability is evaluated by obtaining replicate measurements of standard and/or spiked placebo/standard addition solutions. It can be determined by calculating the RSD of the multiple injections or spectrophotometric readings for each standard solution, or by using the accuracy or linearity data. ICH guidance, Validation of Analytical Procedures: Methodology, recommends that repeatability should be assessed using a minimum of nine determinations covering the specified range for the procedure (i.e., three concentrations and three replicates of each concentration) or using a minimum of six determinations at 100% of the test concentration. A typical acceptance criterion is an RSD of <2%. The demonstration of the repeatability for the dissolution step is conducted by performing the dissolution step on separate units of a well-characterized dosage form or equivalent composite.

Assuming that the major contributor to the variance is from the dissolution step, intermediate precision may be evaluated to determine the effects of random events on the precision of the dissolution procedure. This evaluation is typically done later in the development of the drug product and is required for full method validation. For many analytical procedures intermediate precision is typically assessed by determination of contributions to variance and, possibly, by a comparison of means. The use of an experimental matrix design is encouraged for evaluation of intermediate precision because interaction effects may be observed more clearly relative to a single variable experiment. In dissolution testing, a ruggedness approach that compares means alone is often taken to investigate the factors that contribute to intermediate precision. The ruggedness can be evaluated across the range of product strengths. Typical variations to be studied include different days, analysts, and equipment. If possible, ruggedness can be evaluated using a drug product lot if well characterized, for example, by having tight content uniformity and uniform performance, but if this type of lot is not available, a premeasured placebo with active ingredients may be used to investigate the intermediate precision. The use of such a spiked placebo would additionally support the assessment of the contribution of the analytical finish to the observed variability of results.

The dissolution procedure on the same lot of well-characterized dosage form may be run by at least two different analysts from the same laboratory, with each analyst preparing the standard solutions and the medium and following the defined extraction/quantification procedure. Typically, the analysts use different dissolution baths, spectrophotometers or HPLC equipment (including columns), and autosamplers, and they perform the test on different days. Full profiles are assessed where relevant to the product. This procedure may not be necessary at each strength; instead, bracketing with high and low strengths may be acceptable.

Acceptance criteria for intermediate precision or for ruggedness are predetermined. A typical acceptance criterion for ruggedness is that the difference in the mean value for dissolution results between any two conditions, using the same strength, does not exceed an absolute 10% at time points with <85% dissolved and does not exceed 5% for time points >85%. Acceptance criteria may be product specific, and other statistical tests and limits may be used.

Once the Q value is established, the dissolution test is a staged test of three levels. In the first level of testing called S1, six dosage forms are tested. Each dosage form must be Q + 5% (absolute percentage points) dissolved at a specified time. For example, the time and tolerances in a monograph would be:

If the Q value for a 200-mg label claim (LC) immediate-release tablet is specified as 80% and the time point is 30 min, then NLT 85% LC (170 mg) of the drug substance in each tablet must be dissolved at 30 min.

If this criterion is not met, then 6 additional tablets are tested at level 2 (S2). To pass the S2 acceptance criteria, the average of all 12 tablets must be equal to or greater than Q (80% LC; 160 mg in the above example), and no tablet has less than Q – 15% (65% LC; 130 mg in the above example).

If these criteria are not met, then level 3 or S3 testing must be performed by testing 12 additional tablets. To pass S3, the average of all 24 tablets must be equal to or greater than Q (80% LC; 160 mg in the above example). Two additional criteria must be met as well: 1) no more than 2 tablets are less than Q – 15% (65% LC; 130 mg in the above example), and 2) no tablet is less than Q – 25% dissolved (55% LC; 110 mg in the above example.)

An aliquot of the acid medium from each vessel is analyzed at the end of the acid stage. For the acid stage, the acceptance criteria have three levels. Level 1 (A1) testing is passed if no individual value exceeds 10% dissolved. If the A1 criteria are not met, then the dissolution test is performed on 6 additional dosage forms for level 2 (A2) testing. Level A2 criteria are passed if the average of all 12 dosage forms in the acid stage is NMT 10% dissolved and if no individual dosage form is more than 25% dissolved. Level 3 testing is performed if the A2 criteria are not met. The A3 criteria are passed if the average of all 24 dosage forms in the acid stage is NMT 10% dissolved and if no individual tablet is more than 25% dissolved. For the special case in which the solubility of the drug in an acidic medium because of conversion to the free acid is too low to support an acceptance criterion of not more than 10% the drug product should be exposed to the acid stage for the defined duration and then exposed to the buffered medium. Alternate acceptance criteria for the acid stage based on drug solubility may be justified.

For delayed-release dosage forms, the total percentage dissolved is determined by adding the measured amounts in the acid and buffer phases for each individual dosage form. These calculated values are then compared to staged acceptance criteria (B1, B2, and B3) that are based on a Q value. The B1, B2, and B3 criteria are identical to those for the immediate release S1, S2, and S3 criteria.

In the following hypothetical example, which is used to describe the criteria for an extended-release dosage form, the time points are 1, 4, and 8 h. The acceptance range for each time point is as follows:

Acceptance ranges are often expressed in tabular form in the USP–NF (see Table 3):

Six tablets are analyzed at Level 1 (L1); acceptance criteria are met if no individual value lies outside each of the stated ranges, and no individual value is less than the percentage specified for the final time point. If the L1 criteria are not met, then 6 additional tablets are analyzed at level 2 (L2). The L2 criteria are met if these three conditions are met:

For the above example, the L2 acceptance criteria for the 12 tablets (see Table 4) are as follows:

If the L2 criteria are not met, then 12 additional tablets are tested at level 3 (L3). The L3 criteria are met if these five conditions are met:

The L3 acceptance criteria for the 24 tablets in the above example are summarized in Table 5: