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Formulation strategies for oral bioavailability enhancement

With tablets and capsules convenient for patients to take and cost-effective to manufacture, it’s little wonder that oral delivery is the preferred route of administration for most pharmaceutical development projects. Yet current discovery strategies are increasingly resulting in larger, more lipophilic drug candidates. It’s thought that up to 70% of new drug candidates under development are poorly water-soluble.

For these BCS Class II type drugs, dissolution, rather than membrane permeability, is the rate limiting factor for absorption. This is a problem, as poor bioavailability is often a contributing factor to project failure. One way to overcome these bioavailability challenges is through the use of formulation strategies that enhance water solubility – and there are a wide range of technologies to choose from.

Solid dispersion strategies to overcome crystallization challenges

Formulation strategies for oral bioavailability enhancementStable crystalline drug forms present a challenge in terms of solubility, as they require a large amount of energy to dissolve. One way to reduce the tendency for APIs to crystallize is through the use of amorphous solid dispersions – essentially solid solutions – where drug molecules are typically dispersed within a polymer matrix. Because the API is already highly dispersed prior to dissolution, solubility is significantly easier.

Amorphous solid dispersions can be produced by a number of techniques, however spray drying and hot-melt extrusion are the most commonly employed. While both methods are highly scalable and can be used for the manufacture of tablets and capsules, the choice of method is often dependent on the properties of the API, with hot-melt coating more suited to lower melting point APIs.

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Particle size reduction strategies to enhance solubility

As drug molecule solubility increases with surface area, reducing particle size can be a very effective way of enhancing dissolution rates. Well-established micronization strategies such as jet milling and ball milling are often used to improve solubility through the use of particle sizes in the region of 2 to 5 μm.

Further reduction in particle size to the nanometer scale can be achieved using wet milling techniques. Wet bead milling, for instance, can be easily scaled from sub-gram quantities to manufacturing scale.The resulting nanosuspensions can be processed as a free-flowing dry powder using techniques such as spray drying or spray granulation.

Lipid formulation strategies are increasingly being adopted

As drug molecules have become more lipophilic in nature, lipid-based formulations such as microemulsions and self-emulsifying drug delivery strategies (SEDDS) are increasingly being adopted. These types of formulations, based on mixtures of oil, surfactant, co-surfactant and solvent, can quickly produce fine oil-in-water emulsions upon mild agitation in order to solubilize the API in the aqueous environment of the gastrointestinal tract.

Here, successful formulations are based on a sound understanding of the properties of the API, and should be achieved through careful selection of non-toxic and non-irritant surfactants and solvents, and consideration of the resulting formulation’s rheological properties.

Want to learn more about how formulation strategies can be used to enhance drug bioavailability? Watch our short webinar here.

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Topics: Drug Development