Formulation of poorly water-soluble drugs for oral administration: Physicochemical and physiological issues and the lipid formulation classification system

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Abstract

Poorly water-soluble drug candidates often emerge from contemporary drug discovery programs, and present formulators with considerable technical challenges. The absorption of such compounds when presented in the crystalline state to the gastrointestinal tract is typically dissolution rate-limited, and the drugs are typically BCS class II or class IV compounds. Class IV compounds, which have low membrane permeability as well as poor aqueous solubility, are often poor candidates for development, unless the dose is expected to be low. The rate and extent of absorption of class II compounds is highly dependent on the performance of the formulated product. These drugs can be successfully formulated for oral administration, but care needs to be taken with formulation design to ensure consistent bioavailability. Essentially the options available involve either reduction of particle size (of crystalline drug) or formulation of the drug in solution, as an amorphous system or lipid formulation. The performance of amorphous or lipid formulations is dependent on their interaction with the contents of the gastrointestinal tract, therefore, a formulation exercise should involve the use of techniques which can predict the influence of gut physiology. A major consideration is the fate of metastable supersaturated solutions of drug, which are formed typically after dispersion of the formulation and its exposure to gastrointestinal digestion. A better understanding of the factors which affect drug crystallization is required, and the introduction of standardised predictive in vitro tests would be valuable. Although many bioavailability studies have been performed with poorly water-soluble drugs, thus far this research field has lacked a systematic approach. The use of a lipid formulation classification system combined with appropriate in vitro tests will help to establish a database for in vitroin vivo correlation studies.

Section snippets

Introduction: opportunities and challenges

There is general consensus in the pharmaceutical industry that poorly water-soluble drug candidates are becoming more prevalent (Lipinski et al., 1997, Lipinski, 2000). If a drug candidate has reasonable membrane permeability then often the rate-limiting process of absorption is the drug dissolution step. This is characteristic of compounds which can be categorised as biopharmaceutical classification system (BCS) class II (Yu et al., 2002). Formulation plays a major role in determining the rate

Dispersion, digestion and metastability

Many amorphous solid solutions or lipid systems contain a considerable proportion of water-soluble excipients, such as water-soluble polymers (e.g. PVP, PEG), low molecular weight cosolvents (ethanol, propylene glycol, PEG 400, transcutol, etc.) or hydrophilic surfactants (polysorbate 80, ethoxylated triglycerides, etc.). The polymers and cosolvents are particularly prone to causing drug precipitation on dilution because the relationship between drug solubility and cosolvent concentration

Digestion and solubilization in the small intestine

The solubilization capacity of the digestive system is considerable and its presence has an effect on the dissolution and absorption of lipophilic drugs from all formulations (Embleton and Pouton, 1997). The solubilising power is greater after a fatty meal, hence, food often has a positive effect on bioavailability of dissolution rate-limited BCS class II drugs. Bile salt concentrations in the gut are 3–5 mM on a fasted stomach and approximately 15 mM after food. Formulae for simulation of

Amorphous formulations

Amorphous formulations, such as ‘solid dispersions’ may allow drugs to disperse as supersaturated solutions, at least temporarily, but eventually the drug will relax into its most thermodynamically favourable crystalline state. At present the kinetics of crystallization cannot be predicted for an individual drug, which presents the formulator with some technical problems. In some cases crystallization takes place in minutes but in others the supersaturated system may be stable for many hours.

‘Lipid’ formulations

‘Lipid’ systems have the advantage that they can present the drug as a stable liquid solution, but the term ‘lipid formulation’ has come to mean one of a large group of formulations which share some common features (Table 1). Lipid systems may include triglycerides, mono and diglycerides, lipophilic surfactants, hydrophilic surfactants and cosolvents; excipients with a wide variety of physicochemical properties. A classification system was introduced in 2000 to help identify the critical

In vitro testing of lipid formulations

In vitro tests can be used to help predict the effect of dilution and digestion, and it would be appropriate for standard tests to be defined for regulatory use. There are a number of useful tests available to the formulator. These include bile salt solubility tests, formulation dispersion/ drug precipitation tests, and in vitro digestion tests. Bile salt mixed micelle solubility is easy to determine and can give a good indication of whether the solubilising capacity of the gut will be of

Conclusions

The most significant issue to consider when formulating poorly water-soluble drugs is the threat of drug precipitation in the lumen of the gastrointestinal tract. The fate of the formulated product can be predicted using a range of in vitro tests to investigate the effects of dispersion, digestion, and gastric emptying on the fate of the drug. It would be useful to establish standard test protocols, particularly in the case of the lipolytic digestion test for lipid formulations, so that

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This paper was presented in an earlier form at the Gattefosse Academie des Alpilles, June 2005, St. Remy, France.

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