9.
4.3 What Level of Solubility Is Required?
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); Ka = intestinal absorption rate constant (min−1) (permeability in rat intestinal perfusion experiment, quantitatively similar to human Ka); 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 |
4.4 Solubility‐Limited Absorption
Drug solubility within intestinal fluids can limit the overall absorption, as described in the maximum absorbable dose equation. This can become evident in early clinical testing where a single ascending dose study is planned. This study is used to determine the pharmacokinetic profile of a drug following a series of ascending oral doses as well as to explore the pharmacodynamic effects of an increasing dose. It is used within the safety assessment of a drug. If the solubility limits the exposure then work is required to ensure that the formulation used within the ascending dose study achieves the appropriate exposure to ensure linear pharmacokinetics. This is shown in Figure 4.1.
Figure 4.1 Image showing plasma pharmacokinetics from a study in which an oral ranging from 80 to 1000 mg was administered. It can be seen that the solubility limitation is reached at 400 mg whereby further increases in dose do not show increased Cmax or AUC.
4.5 Methods to Assess Solubility
It is important to report the method used to assess solubility when reporting the solubility value. A range of methods are available, yet the most common method used for biopharmaceutics is the shake‐flask method that is recommended by the regulatory agencies (FDA and EMA). In the shake‐flask method excess drug is added to the solvent to form a saturated solution which is noted by the observation of undissolved material within the flask. The total content of the flask is then transferred to a shaker and agitated for a predetermined time to reach equilibrium solubility at a fixed temperature (usually 37 °C).
However, during the drug development process often high throughput or in silico methods are used during lead optimisation and candidate selection. In silico methods to predict solubility use structural parameters including the use of 2D and 3D chemical structures, log P and melting point models [4]. Within high throughput methods, solubility is measured based on a small amount of drug that was dissolved in DMSO; then precipitated prior to dissolution in buffers at pH 6.5 or 7.4. However, these high throughput methods have been demonstrated to overestimate solubility, most likely due to residual DMSO present within the solvent.
A second common method is the intrinsic dissolution rate (IDR) which is defined as the dissolution rate of the drug substance from a constant surface area and stirring speed in a solvent with defined pH and ionic strength. The IDR is calculated as the mass rate transferred from the solid surface to the solvent phase. The major differences between IDR and the shake‐flask are that the shake‐flask method provides an equilibrium solubility measurement whereas the IDR is a rate measurement. The notation of dissolution can cause confusion in this context. However, the intrinsic dissolution rate relates to the drug substance and how rapidly the drug substance achieves saturated solubility. Dissolution in the context of biopharmaceutics relates to the rate of solvation of the drug substance from the formulated drug product, dissolution is discussed in detail in Chapter 6.
It is important that solubility is assessed by the most suitable method at the appropriate stage during development, particularly as it is known that the crystalline form will affect the solubility recorded.
4.6 Brief Overview of Forces Involved in Solubility
The solubility of a solute depends upon its relative affinity to the solvent as well as other solute molecules; the nature of the affinity will dictate the type of bond or interaction involved.
4.6.1 van der Waals Interactions
Solute molecules that have a permanent dipole, as a result of the molecular structure, will result in a degree of polarity. Some molecules can be strongly polar whilst others are weakly polar. Van der Waals forces are a result of dipole interactions where