Abstract
An understanding of the structure–properties relationship of crystals is one of the principles of crystal engineering. It is well established that the physicochemical properties of solids, such as their temperature and pressure stability, can be modified by the diversification of the chemical composition: i.e., by the synthesis of multicomponent crystals. This method is widely used in the pharmaceutical industry in the search for novel crystal forms providing higher bioavailability and better processability during the manufacturing process. It is also crucial to thoroughly study, analyze, and compare multicomponent crystals with neat crystals to assess to what extent their properties were altered. In this work we investigate the effect of the presence of water molecules on the pressure stability of crystals, on an example of an antibiotic sulfamethoxazole in its neat form (polymorph I, SMX I) and as a hemihydrate (SMX·0.5H2O). The crystals were investigated under high pressure in a series of hydrostatic media up to ca. 4 GPa. SMX I was established to be the preferred and stable solid form of sulfamethoxazole under the studied conditions, while the compression of crystals of SMX·0.5H2O above 3.7 GPa led to a reversible isostructural solid-to-solid phase transition to phase II (named SMX hemihydrate-II). The difference between SMX hemihydrates I and II and a comparison of the pressure stability of the investigated forms of SMX are discussed in terms of intermolecular interactions, Full Interaction Maps (FIMs), structural voids, and changes in crystal density. It has been shown that lower density and less ordered molecular arrangement in crystals of SMX hemihydrate, a direct effect of the presence of water molecules, contribute to its lower pressure stability in comparison to crystals of SMX I.
Highlights
The exposure of crystals of SMX·0.5H2O to a pressure of approximately 3.7 GPa resulted in a solid-to-solid phase transition, reflected in the discontinuity of the pressure dependence of the lattice parameters (Figure 1)
For the three crystal forms, Full Interaction Maps (FIMs) calculated for crystal structures at the lowest and highest pressure show that regions expected to be occupied by H-donor and H-acceptor groups in most cases correlate with the actual position of functional groups of SMX molecules involved in hydrogen bonds (Figures S34−S38)
The change associated with the phase transition is clearly noticeable in the alteration in the relative positioning of two symmetry-independent SMX molecules in crystals of SMX hemihydrate
Summary
Active pharmaceutical ingredients (APIs) in their crystalline state are preferably used in dosage forms of orally administrated drugs, as they offer high purity, stability, and reproducibility of the manufacturing process.[1,2] it is unsurprising that the pharmaceutical industry is highly invested in researching crystal forms of drug substances, focusing on (i) tailoring the physicochemical properties of solid APIs by modifying the crystal structure,[3] (ii) understanding the relationships between different crystal forms to prevent undesirable events during the manufacturing process, transportation, and storage of the final drug product,[4,5] and (iii) issues concerning intellectual property.[6,7] The first focus area utilizes the structure−properties relationship of the crystals, as the molecular packing and intermolecular interaction pattern present in the crystal structure determine the physicochemical properties of the crystalline state.[3]. For the three crystal forms, FIMs calculated for crystal structures at the lowest and highest pressure show that regions expected to be occupied by H-donor and H-acceptor groups in most cases correlate with the actual position of functional groups of SMX (or water) molecules involved in hydrogen bonds (Figures S34−S38). Vacancy in FIMs is partially overcome in the crystal structure of the hemihydrate, where the region near the primary amine group is occupied by a water molecule H-bonded to SMX (Figure 3b) This can explain the drive of SMX molecules to form a hydrate despite the need to increase Z′ and lower the crystal symmetry. The sample of high-pressure studies of hydrate/anhydrate pairs available at the moment is small, and more systematic studies would be required to establish a general correlation between hydrate vs anhydrate behavior under pressure
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