Thermodynamic States Relevant for Drug Solubility

The intrinsic aqueous solubility S of a drug X is related to the Gibbs free energy AGs i of the transfer of the drug X from its lowest free energy crystalline form to a saturated solution of the neutral form of X in water by the simple equation  

There are other soUd states which sometimes confuse the measurement and definition of solubiUty. The dmg may crystaUize as a hydrate, i.e. under inclusion of water molecules. If the hydrate form is more stable than the pure form it may be difficult to measure the intrinsic solubility of the drug at all. Often drugs tend to precipitate in an amorphous form, often under the inclusion of impurities. As with metastable polymorphs, such amorphous precipitates may lead to erroneously high solubility measurements. CommerciaUy, drugs are often crystallized in salt form, e.g. as the hydrochloride salt, a cation with a chloride anion. In these co-crystallized salts, a much lower solubility than the intrinsic solubility will typi- 

It is not only the solid state of a drug that suffers from ambiguities, but also the aqueous state. The state relevant for the intrinsic solubility is the state of the saturated solution of the neutral species. Since most aqueous drug solubilities are small, direct interactions of the drug molecules are usually rare. Hence, this state is usually very similar to the state of the drug at infinite dilution in water. Most computational methods disregard saturation effects. Usually this is a good approximation, but one should keep in mind that this approximation may result in some moderate, but systematic errors at the upper end of the solubility scale. 

Although not directly related to aqueous solubility, the state of the drug dissolved in another solvent, most notably in 1-octanol, has been used often in the computa-hon of aqueous solubility. Hansch [9] introduced the simple linear relahonship of 

The last state in Fig. 11.1 that has not yet been discussed is the state of the neat liquid compound X. For liquid compounds this is the relevant initial state for solubility, but almost aU drug-Uke compounds are solid at room temperature. In this case the neat liquid is a virtual state of a supercooled liquid which can hardly be accessed experimentally. However, it is an interesting intermediate state because it allows us to split the calculation of solubility into two separate steps, which are conceptually and for some methods computationally easier to handle than the complete step from the crystaUine state of the drug to the liquid state of the drug dissolved in water. In the first step we only have to transfer the compound from its neat crystalline state to its neat liquid state. The free energy of this fusion transfer is usually called AG s (or if considered in the opposite direction). 

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