Role of Solvates in Drug Discovery
July 4, 2023
This blog aims to highlight the impact of solvates in the process of developing a novel drug compound.
What Are Solvates?
Crystal solvates are multicomponent crystalline solids that contain molecules of solvent incorporated into their crystal lattice structure . In pharmaceutical solids, the active pharmaceutical ingredient (API) or excipient can be seen as the host molecule, and any molecule of the solvents used during the isolation of the active material is a potential guest . In the specific case of water as the guest, the compound is called hydrate.
How Common Are Hydrates?
Hydrates are the solvate form that is most frequently found in crystalline organic molecules in the pharmaceutical industry. A water molecule can in fact be very easily incorporated into a crystal lattice because of its small size and its capability to form multidirectional hydrogen bonds . More specifically, water molecules contain atoms that are both hydrogen bond donor and acceptor, allowing the formation of intermolecular hydrogen bonds with the host molecules .
Why Is the Study of Solvates Important?
The presence of solvent molecules within the crystal lattice can affect the level of intermolecular interactions, causing changes in the internal energy and enthalpy, and can impact the degree of crystalline disorder, causing changes in the entropy . Hence, there could be the case in which the solvent induces disorder within the structure, leading to the formation of metastable systems. In contrast, the solvent molecules might instead form strong interactions and hydrogen bonding with the APIs or with other solvent molecules, stabilizing a metastable form .
For these reasons, solvent molecules incorporated during crystallization can cause changes in several properties of the pharmaceutical molecules when compared to their anhydrous forms, such as stability, dissolution rates, bioavailability, morphology, vapor pressure, and tabletability .
What Is Their Role in Drug Discovery?
Solid form control and engineering is an essential step in small molecule drug development, and in most cases, solvates represent a challenge for this step . The hydrate form of an API, for example, is less soluble in an aqueous environment than its anhydrous form, leading to a reduction of its bioavailability . On the other hand, the use of solvates of APIs is discouraged in pharmaceuticals because even traces of an organic solvent can be harmful . Additionally, the dehydration of hydrates can lead to the loss of water molecules from the crystal and the consequent formation of activated sites. These sites can then either reabsorb other solvent molecules or associate themselves with other moieties available in proximity, changing the crystal packing .
There are only a few cases in which solvates instead represent an advantage. During the development of a new drug, the discovery of the formation of solvates can limit the selection of solvents used during the crystallization process of the desired crystal form . This could be seen as a limitation, but it could also ensure that the isolated product is pure when a suitable solvent is used. Solvates can also be used as intermediates for producing the polymorph that is required, as sometimes it is possible to form a specific polymorph from only the desolvation of a particular solvate . Finally, solvates can help in controlling the particle size distribution when the nonsolvated forms are difficult to crystallize .
Despite the fact that the use of solvates might present a few benefits in some cases, the use of the most physically stable crystal form is instead still preferred. The limitations for the use of solvates in the pharmaceutical industry are given both by the toxicity of the solvents used and by their possibility to accelerate the drugs decomposition . Their use nowadays is hence strictly regulated by authorities.
What Can Be Done To Better Understand Solvate Formation?
Solvate formation can be predicted via computational methods, even if solvates are still a challenging group of solid forms for crystal structure prediction.
An interesting study was done by Sarah E. Wright and co-workers, who did an in-depth conformational analysis using the Cambridge Structural Database (CSD) in combination with molecular modelling .
Among the 20,958 structures of organic solvates reported in the CSD, the group started by selecting the 17,603 structures that included the ten most frequent solvents: water, methanol, DCM, chloroform, acetonitrile, benzene, acetone, DMF, DMSO, and ethanol . It is worth mentioning that the CSD was searched for solvates containing only one solvent component.
The group proceeded by then identifying the molecular structure of the neat forms (forms with no molecules of solvent), finding that only 9% of solvate crystal structures have a neat form counterpart . The reason behind this low percentage was attributed to the increasing complexity of molecules that are therefore more likely to include cavities and channels within their packing arrangement .
Finally, from the comparison between the conformation of the solvates with that of the neat forms, it was seen that on average 46% of the pairs experienced a conformational change, with an incidence of 64% for the pairs including ethanol (highest value) and 35% for the pairs including DMSO (lowest value) .
This study proved the fact that conformational changes between the solvate and the neat forms of a crystal structure are a relatively common phenomenon, showing how likely it is for solvates to induce a change in the crystal packing.
In conclusion, despite the availability of computational tools to help perform solvate formation studies, the presence of hydrates and solvates during drug discovery is still a challenging factor that can impact on product development.
Find out more about the CSD.
Download the article with the conformational analysis discussed above here.
 Anne Marie Healy, Zelalem Ayenew Worku, Dinesh Kumar, Atif M. Madi, Advanced Drug Delivery Reviews, (2017), 117, 25-46. https://www.sciencedirect.com/science/article/pii/S0169409X17300327
 Amy L. Gillon, Neil Feeder, Roger J. Davey, Richard Storey, Crystal Growth & Design, (2003), 3, 5, 663-673. https://pubs.acs.org/doi/full/10.1021/cg034088e
 Dongyue Xin, Nina C. Gonnella, Xiaorong He, Keith Horspool, Crystal Growth & Design, (2019), 19, 3, 1903–1911. https://pubs.acs.org/doi/full/10.1021/acs.cgd.8b01883
 Amit Bhatia, Shruti Chopra, Kalpana Nagpal, Pran Kishore Deb, Muktika Tekade, Rakesh K. Tekade; Chapter 2 – Polymorphism and its Implications in Pharmaceutical Product Development, Advances in Pharmaceutical Product Development and Research, Dosage Form Design Parameters, Academic Press, 2018, Pages 31-65. https://www.sciencedirect.com/science/article/pii/B9780128144213000026
 Puigjaner Cristina, Anna Portell, Arturo Blasco, Mercè Font-Bardia, Oriol Vallcorba, Crystals, (2021), 11, 342. https://www.mdpi.com/2073-4352/11/4/342
 Sarah E. Wright, Jason C. Cole, and Aurora J. Cruz-Cabeza, Crystal Growth & Design, (2021), 21, 6924-6936. https://pubs.acs.org/doi/10.1021/acs.cgd.1c00833
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