Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract1

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Abstract

The rate-limiting step to absorption of drugs from the gastrointestinal (GI) tract is often dissolution from the dosage form. Consideration of the Noyes-Whitney dissolution model shows that drug diffusivity, solubility in the gastrointestinal contents, the surface area of the solid wetted by the lumenal fluids and the GI hydrodynamics all play a role in determining the in vivo dissolution rate. Solubility in the GI contents is determined by aqueous solubility, crystalline form, drug lipophilicity, solubilization by native surfactants and co-ingested foodstuffs, and pKa in relation to the GI pH profile. Compounds with aqueous solubilities lower than 100 μg/ml often present dissolution limitations to absorption. The dose:solubility ratio of the drug provides an estimate of the volume of fluids required to dissolve an individual dose, and when this volume exceeds 1 l, dissolution is often problematic. The surface area of a drug available for dissolution depends on the particle size of the solid and its ability to be wetted by lumenal fluids. Other physiological factors that can play a role in dissolution include the viscosity of the lumenal contents, through its effect on the diffusivity, and mixing and flow patterns within the gut. In order to better predict in vivo dissolution of drugs, dissolution tests which more adequately simulate the physiological conditions are needed.

Introduction

The lack of ability of a drug to go into solution is sometimes a more important limitation to its overall rate of absorption than its ability to permeate the intestinal mucosa. For many drugs that cross the intestinal mucosa easily, the onset of drug levels will be dictated by the time required for the dosage form to release its contents, and for the drug to dissolve. We may define a drug as `poorly soluble' when its dissolution rate is so slow that dissolution takes longer than the transit time past its absorptive sites, resulting in incomplete bioavailability.

The aqueous solubility of a drug is a prime determinant of its dissolution rate and, in the case of `poorly soluble' drugs (as defined above), the aqueous solubility is usually less than 100 μg/ml. A further parameter that is useful for identifying `poorly soluble' drugs is the dose:solubility ratio of the drug. The dose:solubility ratio can be defined as the volume of gastrointestinal fluids necessary to dissolve the administered dose. When this volume exceeds the volume of fluids available, one may anticipate incomplete bioavailability from solid oral dosage forms. Griseofulvin provides a classic illustration of the utility of the dose:solubility ratio. With an aqueous solubility of 15 μg/ml at 37°C and a dose of 500 mg, griseofulvin has a dose:solubility ratio of about 33 l [1]. Thus the combination of its poor solubility and high dose constitutes a severe limitation to its oral bioavailability.

From the following modification of the Noyes-Whitney equation (Eq. (1)), the important factors to the kinetics of drug dissolution can be identified.DR=dXdt=A∗DhCsXdVwhere DR is the dissolution rate, A is the surface area available for dissolution, D is the diffusion coefficient of the drug, h is the thickness of the boundary layer adjacent to the dissolving drug surface, CS is the saturation solubility of the drug, Xd is the amount of dissolved drug and V is the volume of dissolution media.

There are many physicochemical and physiological factors which can have a great influence on the factors in Eq. (1) and therefore on the dissolution rate.

Section snippets

Factors influencing the saturation solubility (CS)

The saturation solubility is a key factor in the Noyes-Whitney equation, as, together with the concentration of drug already dissolved and the thickness of the boundary layer, it determines the concentration gradient across the boundary layer, which is the driving force for dissolution.

Various physicochemical and physiological factors influence the saturation solubility of a drug in the gastrointestinal tract. These include its crystalline form, its lipophilicity and the ability of the drug to

Particle size

An important factor determining the dissolution rate is the particle size of the drug. The dissolution rate is directly proportional to the surface area of the drug, which in turn increases with decreasing particle size. Micronization to particle sizes of about 3–5 μm is often a successful strategy for enhancing the dissolution rate, for example in the case of griseofulvin. The effective surface area also depends on the ability of the fluid to wet the particle surface. When the dissolution

Factors influencing the volume available for dissolution

One of the ways in which food intake influences the dissolution rate is through the increase in volume of the GI contents. Fluids ingested with the meal can increase the available gastric volume by as much as 1.5 l. Not only do the ingested food and fluids directly influence the volume in the upper GI tract, they also stimulate secretion of gastric acid, bile and pancreatic juice. Furthermore, ingestion of hypertonic substances can stimulate net water efflux across the intestinal wall into the

Factors influencing the diffusivity

The Stokes-Einstein equation describes the relationship between diffusivity and viscosity, showing that the diffusivity, D, is inverse to the viscosity, η,D=k∗T6πηrwhere D is the diffusivity, T is the temperature, η is the viscosity of the medium, r is the radius of the drug molecule and k is the Boltzmann constant.

The dissolution rate of benzoic acid in methylcellulose solutions was shown to be inversely proportional to the viscosity of the dissolution medium. Dissolution studies carried out

Factors influencing the boundary layer thickness and time available for dissolution

The two types of contractile patterns that are most important to the transit of dosage forms and the absorption of drugs are the propagated and the segmental contractions. Propagated contractions, as the name suggests, tend to propel the lumenal contents towards more distal locations and act over distances of up to 20–25 cm. Segmental contractions, by contrast, travel only over very short distances (1–4 cm) but encourage mixing of the lumenal contents.

In the fasted state, the proximal GI tract

Conclusion

The foregoing discussion shows that the physical chemical properties of a compound have a strong influence on its dissolution in the gastrointestinal tract, and hence on whether or not dissolution will be the rate limiting step to its absorption. Furthermore, the extant physiological conditions in the GI lumen can have a profound effect on the dissolution of certain drugs. The poor match between physiological conditions and those used in in vitro dissolution test systems is the primary reason

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    PII of original article: S0169-409X(96)00487-5. The article was originally published in Advanced Drug Delivery Reviews 25 (1997) 3–14.

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