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In cases where drug solubility is low and where it may limit exposure efforts are focussed on understanding the factors that limit solubility and identification of strategies to improve it. Typically different enabling formulations are used. Formulation solubilising vehicles including cosolvents, surfactants, complexation agents and oils/lipids are considered. In early stages of development, simple strategies are required to ensure that solubility does not limit the generation of data from an ascending dose study, thus a cosolvent approach can be a simple workaround at this stage yet would not be suitable for the commercial formulation. Typical cosolvents used include polyethylene glycol (PEG400), propylene glycol and ethanol.

For ionic drug compounds, commonly used approaches include pH adjustment and salt formulation. A salt screen can be performed to identify the most suitable counter ion. There are several examples of salt forms having large differences in solubility. For example, terfenadine salts formed with phosphoric acid, hydrochloric acid, methanesulphonic acid and lactic acid showed up to 10‐fold differences, ranging from 0.5 to 5 mg/mL [17]. There are some concerns about the common‐ion effect where the presence of ionic components, for example NaCl within the gastrointestinal media may affect the solubilisation rate (dissolution) where sodium or chloride was the counterion for the salt present.

Amorphous drug forms can be a useful strategy for drug compounds with a high melting temperature; the amorphous form disrupts the crystal packing and thus shows rapid dissolution, although there can be risks of precipitation. It is important that the amorphous form is stabilised during manufacture and storage. Often a solid dispersion, where the amorphous form of a drug is intimately mixed with a polymer provides a matrix to stabilise the amorphous form and prevent recrystallisation. There are many commercial examples including Kaletra which contains both lopinavir and ritonavir stabilised in PVPVA [18].

The use of lipid or oil‐based formulations is a strategy used for lipophilic drug compounds; these formulation can also improve permeability and lymphatic transport. In these formulations, the drug is blended with lipidic excipients including long‐chain triglyceride (such as sesame or other vegetable oils), long‐chain monoglycerides and diglycerides (such as Peceol®) or medium‐chain triglyceride (eg, Miglyol® 812), medium‐chain monoglycerides & diglycerides (eg, Capmul® MCM), phospholipids (eg, Phosal® 53 MCT). The most commonly cited example is Neoral, a lipidic formulation of cyclosporin A.

Surfactant formulations are another strategy to improve solubility of drugs. In oral liquid formulations, surfactants can be added to the formulation to improve solubility, typically by the formation of micelles within the liquid that can contain the drug to solubilise it. Examples of surfactants used include the following: Polysorbate 80 (Tween 80), Polyoxyl‐35 castor oil (Cremophor® EL/Kolliphor® EL), caprylocaproyl polyoxyl‐8 glycerides (Labrasol) and sodium lauryl sulphate (SLS) [19].

Cyclodextrin formulations can be also used to improve drug solubility. These are also known as inclusion complex formulations. Cyclodextrins have an exterior that is water soluble yet they contain an internal hydrophobic cavity; drugs can sit within this cavity forming an inclusion complex. There are several marketed cyclodextrin‐containing formulations [20].