Scientists are mapping water into molecular crystals, aiding drug development

Molecular crystals—the building blocks that make up many drugs and other products—sometimes take on water molecules that can alter the crystals in unforeseen ways. It should be noted that predicting which crystals are likely to contain water and at what level is difficult and requires many calculations. This problem is of considerable industrial interest, especially in pharmaceuticals, but the enormous challenges associated with it require new and effective approaches.

Driven by these challenges, researchers from New York University, in collaboration with scientists from the biopharmaceutical company AbbVie, have developed a new computational tool that can quickly and efficiently map the position of water molecules in crystal structures. The findings that appear in the journal Proceedings of the National Academy of Sciences (PNAS), can be used during the drug development and discovery process to predict which crystals are likely to include water and to predict the different possible structures of a drug formulation.

Molecular crystals can take up water either during the crystallization process or by absorbing it from the environment. These water-holding crystals, known as crystalline hydrates, account for a significant proportion of proprietary drugs, and approximately one-third of commercially available drugs have active ingredients in hydrated form.

Adding water to the crystals can change their properties—for example, improving or impairing their ability to dissolve, which is critical for orally ingested drugs that must be absorbed to work. The crystalline hydrate drug may also be considered a different formulation than the dry form of the drug, raising the possibility of patent disputes. This issue arose in the late 1990s and early 2000s in litigation over paroxetine hydrochloride (the antidepressant Paxil, crystalline hydrate), when a generic manufacturer tried to patent a dry version but was accused of patent infringement due to the dry a form that absorbs water in humid conditions and turns into a hydrate.

“Industries that rely on crystalline hydrates, from pharmaceuticals to agrochemicals to electronics, face the challenge of predicting when hydrates will form and determining how the presence of water affects the properties of those crystals,” said Mark Tuckerman, professor of chemistry and Mathematics and Chair of the Department of Chemistry at New York University and senior author of the study.

To address this challenge, the researchers developed a computational protocol that can quickly determine whether a compound is likely to form a crystalline hydrate. They created a system to predict both stoichiometric and non-stoichiometric hydrates, the latter of which was extremely difficult to implement. Stoichiometric hydrates—which have a certain ratio of water molecules to other molecules—are not difficult to predict, but standard protocols require significant computational resources that can be time-consuming and expensive. In contrast, there are no existing tools to easily and accurately predict non-stoichiometric hydrates, which do not have a defined ratio of water molecules to other molecules in the crystal.

The researchers developed a protocol they call MACH, or Mapping Approach for Crystal Hydrates. MACH establishes a set of rules to systematically determine where water is likely to be introduced into a crystal based on the unique structure and chemical environment within each crystal.

The MACH algorithm first instructs the computer to build a crystal structure in dry form. He then tested whether water would fit into the dry framework by overlaying a liquid water sample on top of the crystal structure. Some water molecules will try to occupy the same space as the host crystal molecules, which violates the basic laws of physics; these water molecules are immediately eliminated by the MACH algorithm.

MACH then considers additional rules for how water will interact with the host crystal, further reducing the number and location of water molecules that can be incorporated into the crystal. These steps are then repeated many times with different configurations of water molecules.

“Because we know how water likes to interact with the molecules in the host crystal, we can teach the computer to look for appropriate patterns, such as hydrogen bonds,” Tuckerman said. “Computationally, it’s cheap and fast—we can do these steps thousands of times in a few hours.”

Finally, the researchers are left with a map of the remaining water molecules, illustrating which crystals are likely to form hydrates—both stoichiometric and non-stoichiometric—and where the water molecules are involved.

The researchers demonstrated MACH’s ability to provide precise mapping of water molecules in three drugs: a plant-derived compound called brucine, the antidepressant paroxetine hydrochloride, and the diabetes drug sitagliptin tartrate. The crystal structures of each drug have structural voids of different sizes and chemical environments—for example, some are quite small while others repel water—making them ideal MACH probes to determine regions where water can exist. Additionally, the different crystal structures of these drugs (with and without water) have now been confirmed in laboratory experiments, giving the researchers a benchmark against which to compare the water maps created using MACH.

“These computer-generated hydrate structures provide unique insights that can aid drug and materials design in identifying molecules that may be prone to hydrate formation,” added Tuckerman. “Given its simplicity and speed, MACH offers a promising tool for efficient hydrate prediction and can be integrated into drug development and formulation workflows to build a more complete landscape of possible crystal structures.”

“The development of MACH illustrates the synergies in university-industry collaboration for ready-to-deployment conceptualization of new approaches to solve relevant industrial challenges,” said Ahmad Sheikh, Head of Solid State Chemistry at AbbVie and author of the study.

Additional study authors include Richard C. Hong of AbbVie and New York University and Alessandra Mattei of AbbVie. AbbVie sponsored and partially funded the study.

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