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Aqueous solubility-enhancing excipient technologies: a review of recent developments

Posted: 2 January 2018 | | No comments yet

At least some degree of solubility in water is necessary for active ingredients in pharmaceutical products to be effective in vivo. However, as efforts to discover and synthesise new active ingredients are pursued by industrial and academic medicinal chemists, achieving sufficient aqueous solubility can often be a significant limitation to clinical and commercial success…

Aqueous solubility-enhancing excipient technologies: a review of recent developments

Given the frequency and significance of this problem over the recent past, multiple solutions are being researched and applied in academia and industry.1 This review article provides a high-level description of the poor solubility problem and suggests a few techniques to deal with it.

The pharmaceutical discovery process can vary significantly depending on the characteristics of the intended target and therapeutic indication, availability of compounds with suitable properties to hit the target, and robustness of in vitro assays, among other differences. Irrespective of these differences, at some point in the discovery process the newly synthesised compounds will be dosed to animals to determine their pharmacological and toxicological activity in vivo. This is the point at which their aqueous solubility often becomes important. Occasionally, this realisation will occur during in vitro studies, but poor aqueous solubility is usually masked by the nature of these assays.2

Aqueous solubility is an obvious requirement if the chosen route of administration is intravenous or subcutaneous injection; aqueous vehicles are highly preferred (eg, as opposed to using solvents and surfactants) to minimise off-target effects due to the dosing vehicle. Additionally, it should be recognised that a solubilised formulation may precipitate in vivo and particles may be harmful because they can occlude capillary vessels. When the intended dose to the target animal cannot be solubilised in a typical aqueous vehicle, such as 5% dextrose or physiological saline, effort must be made to either apply a solubilising formulation to the existing compounds or direct the synthetic programme towards compounds with higher aqueous solubility.

It may be less obvious that compounds administered orally also need adequate aqueous solubility. For an oral medication, the solubility requirement stems from the fact that absorption typically occurs in the small intestine and only solubilised compounds can be absorbed. A simplified depiction of the oral absorption process is shown in Figure 1. The diagram also highlights the need for permeability through intestinal tissue. Since intestinal mucosa is principally hydrophobic, this characteristic usually means that hydrophobic compounds have better permeability than hydrophilic ones. Furthermore, successful oral absorption requires a balance of permeability and solubility. In recognition of these requirements, Pfizer researchers pioneered the ‘Rule of five’ concept in the late 1990s to direct medicinal chemists’ synthetic efforts.3 In a further elaboration of their approach, the concept of ‘Minimal acceptable solubility’ was developed, in which the importance of biological potency is incorporated,4,5 as illustrated in Figure 2.

Aqueous solubility-enhancing excipient technologies: a review of recent developments

Figure 1: Simplified schematic of oral absorption process for solid dosage forms

While it should be noted that these predicted solubilities may not be accurate, what is important is the concept and trade-offs when considering solubility, permeability and potency for a series of discovery compounds to be administered orally…

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