Developing Dissolution Tests for Modified Release Dosage Forms: General Considerations

John R. Crison*

PORT Systems, LLC

Introduction

In light of the FDA's recent guidances regarding oral modified release dosage forms, there is an increased awareness of the potential relevance of dissolution tests (1,2). What was at one time a test to differentiate a good batch of product from a bad one, is now developing into a tool for predicting bioavailability, and in some cases, replace clinical studies to determine bioequivalence. This is not to say that correlations between in vitro dissolution and in vivo bioavailability are new to the industry, however, the biopharmaceutical relevance of dissolution testing has certainly increased (3). The FDA provides guidelines for dissolution tests for oral modified release dosage forms, but also realizes the need for individualizing the method on a case by case basis leaving the justification of a given methodology up to the scientist. Therefore, the individual scientist is challenged to design an appropriate test based on the objectives to be accomplished, e.g., quality control, in vitro-in vivo correlations, showing bioequivalence, etc. Below are physical chemical parameters and physiological conditions to consider when designing a dissolution test for modified release delivery systems. The material focuses primarily on developing dissolution tests for in vitro-in vivo correlations and is by no means a complete guide to dissolution testing, but highlights important issues to consider and provides a starting point.

Physiological Conditions that can Effect Drug Release

Intestinal Transit Time, Gastric Emptying and Variable pH

The effect of gastric emptying on drug release from a modified release delivery system generally occurs when the dosage form is non-disintegrating and can result in variability in the Cmax and Tmax of the plasma profile. This is due to the variability of retention times in the stomach usually between the fed and fasted states but can occur within each condition as well. For example if the patient is in the fasted state, gastric emptying generally occurs within two hours. However, in the fed state, a non-disintegrating delivery system will remain in the stomach, either floating on top of the stomach contents or sinking to the bottom depending on the density (4). When this occurs, gastric emptying rather than the dosage form controls drug release. In addition, if the dosage form has a delayed release component, the drug may not be sufficiently protected for residence times at pH 1.2 > 2 hours.* Low pH may also alter the performance by causing chemical reactions of the materials used in the dosage for modifying the release of drug. Therefore, while the final dissolution test may only require a 1-2 hour presoak at gastric pH, the dosage form should be thoroughly evaluated at gastric pH if there is potential for long gastric residence times.

Recently, gastric emptying and duodenal transit of a magnetically marked capsule, 16.1 mm long and 5.7 mm in diameter, were measured using biomagnetic measuring equipment called Magnetic Marker Monitoring (5,6). In the fasted state, gastric emptying of the capsule ranged from 14 minutes, 5 seconds to 140 minutes. For these transit times, a dissolution test that includes 2 hours in simulated gastric fluid, pH 1.2 should be sufficient. However, duodenal transit times ranged from 7 seconds to 245 seconds with the proximal duodenum ranging from 3 to 17 seconds and the distal duodenum ranging from 4 to 235 seconds. If the goal of the dosage form is to release the drug in the duodenum, e.g., target transport through tight junctions, then the dissolution test should reflect the possibility of a short residence time. This is especially true if the mechanism for targeting the release is enteric coating, since 7 seconds may not be enough time for the enteric coating to dissolve and the drug to release. Further hampering of drug release can occur if the enteric coating erodes at pH 6.5, since the pH at the proximal duodenum is closer to 5.5 than 6.5. Therefore, an appropriate dissolution test for pH sensitive release mechanism such as enteric-coated dosage forms may require several pHs simultaneously taking into consideration the potential in vivo residence time at each pH.

Coated particles/beads currently used in both extended release and delayed release dosage forms offer advantages over larger, non-disintegrating delivery systems. These delivery systems can 1) disperse throughout the GI tract, 2) have multiple types of coatings to achieve a variety of release profiles, and 3) in most cases show dose proportionality. Gastric emptying of coated particles differs from the large non-disintegrating dosage forms in that they will empty from the stomach at a constant rate, provided the diameter and density are of the appropriate size. For example, teflon beads that have a diameter of 1.6 mm and a density of 1 gm/Cm3 empty from the stomach, in the fed state, at a rate of approximately 30%/hour (7). Depending on the design of the delivery system, dissolution tests for bead formulations may consist of 2-3 hours in simulated gastric fluid at pH 1.2, followed by 15-30 minutes in simulated intestinal fluid at pH 5.5, and then simulated intestinal fluid at pH 6.8 or pH 8.0.

Food Effects

The extent of a food effect on the performance of a dosage form is very difficult to establish, and in many cases just as difficult to mimic with a dissolution test. As discussed above, food can affect gastric emptying, but may also alter the release of the drug from the dosage form, the solubilization of the drug, and the transport of the drug across the intestinal wall. For lipophilic, water-insoluble drugs, fatty meals can do one, or both, of two things. First, a fatty meal can increase gastric residence time thereby increasing the time available for solubilization. Second, fatty meals may enhance the solubilization of the drugs by the lipids contained in the meal, or by increasing the amount of bile salts released into the intestine, or both. Dissolution media for water insoluble drugs generally contains a surfactant to aid in the dissolution. Previous dissolution tests consisted of hydroalcoholic mixtures, however this combination was abandoned for the more physiologically relevant surfactants (11,12). Formulas of dissolution media with mixed micelles designed to mimic the fed state are available in the literature, but can be very costly due to the bile salts and lecithin (8-10). These formulas generally consist of mixtures of sodium taurocholate and egg lecithin. One study in particular showed that a 4:1 ratio of bile salt to lecithin could be used as a dissolution medium for water insoluble drugs. The same author compared the effect of bile salt concentration and lecithin/bile salts mixtures on the dissolution of several poorly soluble drug salts and developed a correlation between the log of the octanol:water partition coefficient and the solubility of several poorly soluble steroids in 15 mM sodium taurocholate. Also important from this work was the finding that no significant increase in solubility was observed at "fasted" concentrations of the bile salt. Routine use of such media for determining batch to batch variability during manufacturing may be costly; however the benefit may outweigh the cost when establishing IVIVC's for scale-up and post approval changes (SUPAC).

The use of oil/water emulsions as dissolution media to mimic a fatty meal have also been considered, however these systems can be difficult to work with (13). Agitation and elevated temperatures, i.e. 37°C, can affect the stability of the emulsion thus limiting the length of time available for dissolution. In addition, extraction of the drug from the oil phase may require several steps thereby lengthening the analytical time and cost of operation. However, when food effects are observed in vivo, dissolution media with a higher lipid content may be necessary if an IVIVC is the desired endpoint. As with the micellar systems, current efforts have focused on studying the solubilization and dissolution of water insoluble drugs into emulsions formulated with different synthetic surfactants.

Studies have shown that foods may also alter the permeability of the intestine. While this may have little relevance in designing the dissolution media, it can impact the IVIVC. For example, lipids may increase the fluidity of the intestinal wall thereby increasing the permeability or high concentrations of glucose may increase the leakiness of the tight junctions.

Metabolism

Intestinal metabolism of drugs has received much attention over the last few years and enzymes have been routinely added to both simulated gastric and simulated intestinal fluid. A thorough understanding of the stability of the drug and dosage form in the presence of gastrointestinal enzymes is important when determining the need for enzymes in the media. As with the use of lecithin and bile salts, lumenal enzymes can be costly but necessary if the goal is an IVIVC.

Dissolution Testing Equipment

While modified release delivery systems appear, for the most part, similar in size and shape to conventional immediate release dosage forms, the mechanisms for controlling the release of the drugs are becoming very sophisticated. FDA guidances recommend USP dissolution apparatus 1, 2, 3 or 4 for modified release dosage forms, and in most cases this equipment works very well. However, sometimes current dissolution equipment may require modifications or completely new designs to accommodate these new release mechanisms. For example, non-disintegrating dosage forms requiring a delivery orifice for drug release may dictate a special design or modification of the dissolution apparatus so that the orifice is not blocked. In contrast, disintegrating or eroding delivery systems pose the challenge of transferring the dosage form to different media without losing any of the pieces. In general, methods of agitation, changing the media, and holding the dosage form in the media without obstructing the release mechanism are relevant to drug release and require careful planning. Simulating the in vivo release of the delivery system on a computer often helps in designing an appropriate dissolution test. It is important, however, to take into consideration certain physical-chemical and physiological parameters such as variability in gastric emptying and GI transit time and change in the environment. Knowing the solubility and permeability characteristics of the compound, in combination with release rate from the delivery system, helps to predict whether drug release is occurring under sink vs. non-sink conditions.

A challenging component of a dissolution test for a modified release delivery system is changing the media to obtain a pH gradient or simulate fed and fasted conditions. The ability to easily change the media is the focus of commercially available dissolution equipment targeted for modified-release delivery systems and several equipment designs are available. The USP Apparatus 3, reciprocating cylinder, dips a transparent cylinder containing the dosage form at a rate determined by the operator (14, 15). The tubes have a mesh base to allow the media to drain into a sampling reservoir as the tube moves up and down thus creating convective forces for dissolution. The cylinders can also be transferred to different media at specified times, automatically. A second design is the rotating bottle apparatus, which also allows for changing of media to simulate a pH gradient or fed and fasted conditions. The USP Apparatus 4 is a flow-through cell containing the dosage form that is fed with dissolution media from a reservoir. Directing the fluid through a porous glass plate or a bed of beads produces a dispersed flow of media. Turbulent or laminar flow can be achieved by changing the bottom barrier. As with Apparatus 3, the media can be changed to provide a pH gradient, surfactants, etc.

 

Summary

Subjecting the dosage form to the same conditions as in the GI tract to establish an IVIVC is often easier said than done. As the complexities of the GI tract unfold, drug classification based on permeability, as well as solubility, is gaining recognition and may be extremely useful in the early stages of dissolution methodology development. Changing the dissolution media allows for testing the dosage form under conditions similar to the GI tract, and commercially available dissolution equipment, such as USP Apparatus 3 and Apparatus 4, are well suited for the operations. However, in some cases it may be necessary to make further modifications to the dissolution equipment so that the dissolution test does not interfere with the release mechanism of the dosage form. A good understanding of the release mechanism of the dosage form as well as the physical chemical properties of the drug will enable development of accurate dissolution tests and aid in establishing IVIVC's.


* Non-disintegrating capsules have been shown to stay in the stomach > 12 hours under fed conditions (see reference 4).


References