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It can be complicated to define the minimum solubility required for any compound as this depends on the permeability and dose. A review of published high throughput solubility screening tests reported by the pharmaceutical industry reported that the target solubility ranged from 100 to 1000 μM in media containing a mix of DMSO and buffers at pH 6.5–7.4 [3] or greater than 65 μg/mL [1].

For a compound with average permeability, a lower aqueous solubility would be acceptable whereas a higher solubility is required for a poorly permeable compound.

The equation for the maximum absorbable dose links drug solubility with permeability and the intestinal physiology.

where S = aqueous solubility (mg/mL, at pH 6.5); K_a = intestinal absorption rate constant (min⁻¹) (permeability in rat intestinal perfusion experiment, quantitatively similar to human K_a); SIWV = small intestine water volume (~250 mL); SITT = small intestine transit time (~270 min).

The aqueous solubility is the simplest of these inputs to adjust thus there are some estimates for the minimum solubility to achieve the maximum absorbable dose for given values of the permeability. An example is shown in Table 4.1.

Table 4.1 shows that as the dose increases the solubility must also increase; this highlights the importance of potent molecules to achieve sufficient exposure. Formulation design can aid in transient increases in the solubility to minimise precipitation of compounds to ensure that sufficient amount of the drug is absorbed.

There are clinical examples of very poorly soluble drugs that are marketed, for example candesartan cilexetil, an antihypertensive drug in use since 1997, has a water solubility of approximately 0.1 μg/mL.

Table 4.1 Impact of dose and permeability on the target solubility for a candidate drug.

Dose (mg)	Permeability (Ka) High = 0.03	Minimum acceptable aqueous solubility (mg/L)
1	Low = 0.003	High = 0.03	0.0493	0.494
10	Low = 0.003	High = 0.03	0.494	4.94
100	Low = 0.003	High = 0.03	4.94	49.4
1000	Low = 0.003	High = 0.03	49.4	494