Physicochemical information necessary to characterize the drug substance in a modified-release dosage form should generally be no less than for the drug substance in an immediate-release dosage form. Additional physicochemical information may be needed on polymorphism, particle size distribution, solubility, dissolution rate, stability, and other release-controlling variables of the active drug entity under conditions that may react to the extremes of the physiologic environment experienced by the dosage form. For purposes of this chapter, active drug entity is taken to be the official drug substance.

It is recommended to characterize thoroughly the input absorption profile of the active drug entity from a rapidly available preparation (an intravenous solution or oral solution or a well-characterized FDA-approved immediate-release drug product), which serves in turn as a reference to evaluate the input profile of the modified-release dosage form. This information together with the biological disposition characteristics for the active drug entity can characterize and predict changes in the bioavailability of the drug when input is modified as in the case of the modified-release dosage form. For example, if the active drug entity exhibits saturable first-pass hepatic metabolism, a reduction in systemic availability could result after oral administration if the input rate is decreased.

In designing an oral modified-release dosage form, it may be useful to determine the absorption of the active drug entity in various segments of the gastrointestinal tract (particularly in the colon in the case of dosage forms that may release drug in this region). The effects of food also may be important, and should be investigated.

The information required to characterize the processes of disposition of the active drug entity from a modified-release dosage form should include those generally determined for the same drug in an immediate-release dosage form. This may include the following:

Prior to developing a modified-release dosage form, information described below should be gathered.

Concentration-response relationships should be available over a dose range sufficiently wide to encompass important therapeutic and adverse responses. In addition, the equilibration time1 characteristics between plasma concentration and effect should be evaluated. These concentration-response relationships should be sufficiently characterized so that a reasonable prediction of the safety margin can be made if dose-dumping from the modified-release dosage form should occur. If there is a well-defined relationship between the plasma concentration of the active drug entity or active metabolites and the clinical response (therapeutic and adverse), the clinical performance of a new modified-release dosage form could be characterized by plasma concentration-time data. If such data are not available, clinical trials of the modified-release dosage form should be carried out with concurrent pharmacokinetic-pharmacodynamic measurements.

The variables employed to characterize the physicochemical properties of the active drug entity as it exists or is discernible in the dosage form should be the same as those employed to characterize the drug substance. Solubility and dissolution profiles over a relevant pH range, usually from pH 1 to pH 7.4, should be obtained, with particular attention given to the effect of the formulation (as compared to the active drug entity). Characterization of formulations that are insoluble in aqueous systems may require the addition of sodium lauryl sulfate or other surfactant.

The types of pharmacokinetic studies that should be conducted are a function of how much is known about the active drug entity, its clinical pharmacokinetic and biopharmaceutic properties, and whether pharmacokinetic studies are intended to be the sole basis for product approval. As a minimum, (1) a single-dose crossover study for each strength of a modified-release dosage form and (2) a multiple-dose, steady-state study using the highest strength of a modified-release dosage form are required to characterize the product. Some appropriate single-dose crossover and multiple-dose steady-state studies are described below.

In some modified-release capsule dosage forms, the strengths differ from each other only in the amount of identical beaded material contained in each capsule. In this case, a single-dose and a multiple-dose steady-state study at the highest dosage strength are sufficient. Other strengths may be characterized on the basis of comparative in vitro dissolution data.

The following pharmacokinetic studies would be needed for most modified-release dosage forms. Such studies may, in this instance, constitute the basis for characterization of the dosage form. If approval is to be sought without conducting clinical trials, it is recommended that there be preconsultation with the regulatory authorities to ensure that an adequate database exists for such approval.

The types of studies generally conducted can be categorized as follows.

Initial attempts at developing in vitro–in vivo correlations of modified-release products utilized the same concepts as those employed with immediate-release dosage forms. Thus, numerous attempts have been made to correlate one or more pharmacokinetic parameters, determined from in vivo studies of a product, with the amount released in a given time in an in vitro dissolution test. These were essentially single-point correlations. Such relationships might indicate that increasing or decreasing the in vitro dissolution rate of the modified-release dosage form would result in a corresponding directional change in the product's performance. However, they revealed little about the overall plasma level curve, which is a major factor for drug performance in the patient.

The recognition and utilization of deconvolution techniques as well as statistical moment calculations represented a major advance over the single-point approach in that these two methodologies utilize all of the dissolution and plasma level data available to develop the correlations. Therefore, there are at least three correlation techniques (i.e., deconvolution, statistical moment, and single point), available to the pharmaceutical scientist. There are marked differences in the quality of the correlation obtained with each procedure. Thus, these methods have been categorized and are discussed in terms of the advantages of each along with the resulting potential utility as a predictive tool for the pharmaceutical scientist.

Reasonable upper and lower dissolution values are selected for each time point established from the biobatch. Historically, dissolution specifications have been selected by using the average dissolution of the development batches, with a range of ± 2.5 to 3 standard deviations. It is now expected that the average dissolution values are approximately the same as those of the biobatch. The dissolution curves defined by the upper and lower extremes are convoluted to project the anticipated plasma level curves that would result from administration of these formulations to the same panel to which the biobatch was administered. If the resulting plasma level data fall within the 95% confidence intervals obtained in the definitive BA-BE study, these ranges can be considered to be acceptable. An alternative acceptance approach that has been suggested is that when the therapeutic window for a drug has been defined, one may establish an upper and lower limit if the convolution results fall within the therapeutic window, even if they fall outside the confidence interval. If they fall outside the intervals, a more limited range must be established. This should be continued until the predicted values meet the desired ranges.

An acceptable set of plasma-level data is established both for a batch of material demonstrating a more rapid release and for one demonstrating a slower release than that of the biobatch. These may be selected by using the extremes of the 95% confidence intervals or ±1 standard deviation of the mean plasma level. These curves are then deconvoluted, and the resulting input rate curve is used to establish the upper and lower dissolution specifications at each time point.

In the case of Level B and C correlations, batches of product must be made at the proposed upper and lower limits of the dissolution range, and it must be demonstrated that these batches are acceptable by performing a BA-BE study.

Since the mechanisms for release of drug from modified-release dosage forms are more complex and variable than those associated with immediate-release dosage forms, it would be anticipated that an in vitro-in vivo correlation would be easier to develop with the later formulations. Unfortunately, most of the correlation efforts to date with immediate-release dosage forms have been based on the correlation Level C approach, although there also have been efforts employing statistical moment theory (Level B). Although it is conceivable that the same Level A correlation approach may be utilized with immediate-release dosage forms, until data have been gathered to support this concept, Level B and Level C are the best approaches that can be recommended with these dosage forms.