Journal Name COMMUNICATION This journal is © The Royal Society of Chemistry 20xx J. Name ., 2013, 00 , 1-3 | 1 Please do not adjust margins Please do not adjust margins Received 00th January 20xx, Accepted 00th January 20xx DOI: 10.1039/x0xx00000x www.rsc.org/ Solid Form and Solubility Christopher A. Hunter* a and Rafel Prohens b Factors that determine the solubility of polymorphs and cocrystals are analysed using experimental data to show that the change in the solubility of a compound produced by the formation of a multicomponent crystal can be estimated in a straightforward manner, if the solubilities of the pure compound and the coformer are known. Bioavailability 1 is one of the most important issues in the development of a new drug, and water solubility 2 is one of the most important parameters that has an impact on the oral bioavailability. Since the fraction of new drug candidates with poor water solubility is very high (≈ 70%), 3 different strategies are being pursued to develop more soluble drugs. 4 One option is solid form modification. Amorphous materials and metastable polymorphs have relatively high solubilities, but these materials have associated risks, because they can transform into the most stable and less soluble polymorph during formulation or in storage. 5 The use of multicomponent crystals is a promising approach to improving the solubility of an active pharmaceutical ingredient (API) as a stable solid form. 6 However, the number of potential coformers available to modify solubility is very high, so there is a need for methods to predict which compounds are likely to form cocrystals and what the impact on solubility is likely to be. 7 In this paper, we use experimental data to investigate the relationship between solubility and the free energy differences between different solid forms. The free energy differences between different solid phases (polymorphs or cocrystals) can be related to solubility products in a specific solvent through the thermodynamic cycles depicted in Figure 1. Fig. 1. Relationship between solubility products in a specific solvent, KS, and the free energy difference between two different solid forms, ∆G°, at a given temperature: (a) two polymorphs of compound A and (b) the m:n cocrystal of A and B. Thus in a polymorphic system the free energy difference between two polymorphs can be directly related to the difference in their solubilities (Figure 1a, Equation 1). ∆ ° = − ! + n ! ! Eq. 1 Similarly in a two component cocrystal the free energy difference between the cocrystal and the pure solid phases of the components can be related to the difference between the solubility of the cocrystal and the solubilities of the pure components (Figure 1b, Equation 2). Δ ° = − ! !!!  ! A − ! !!!  ! B + ! !!!  ! (A !  ! ) Eq. 2 where m and n define the cocrystal stoichiometry, ∆G° is the free energy change per total number of moles of the two components in the cocrystal (i.e. m+n), K S (A m B n ) is the solubility product of the cocrystal in a specific solvent, and K S (A) and K S (B) are the solubility products of the pure components, A and B, in the same solvent.