Pharmaceutical Hydrates Analysis—Overview of Methods and Recent Advances

Abstract

This review discusses a set of instrumental and computational methods that are used to characterize hydrated forms of APIs (active pharmaceutical ingredients). The focus has been put on highlighting advantages as well as on presenting some limitations of the selected analytical approaches. This has been performed in order to facilitate the choice of an appropriate method depending on the type of the structural feature that is to be analyzed, that is, degree of hydration, crystal structure and dynamics, and (de)hydration kinetics. The presented techniques include X-ray diffraction (single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD)), spectroscopic (solid state nuclear magnetic resonance spectroscopy (ssNMR), Fourier-transformed infrared spectroscopy (FT-IR), Raman spectroscopy), thermal (differential scanning calorimetry (DSC), thermogravimetric analysis (TGA)), gravimetric (dynamic vapour sorption (DVS)), and computational (molecular mechanics (MM), Quantum Mechanics (QM), molecular dynamics (MD)) methods. Further, the successful applications of the presented methods in the studies of hydrated APIs as well as studies on the excipients’ influence on these processes have been described in many examples.

A Cu(ii)-MOF based on a propargyl carbamate-functionalized isophthalate ligand

“…In the ideal absence of contaminants, TGA experiments can be safely used to estimate the amount of water content, but, as [Cu(1,3-YBDC)]· x H 2 O contains water molecules loosely bound to the framework ( vide infra ), very much as the prototypical channel hydrates found in zeolites and in molecular organic species of pharmaceutical interest, their amount can vary depending on the history of the sample and on the relative humidity conditions. 38 Accordingly, the stoichiometry of this crystal phase is somewhat undefined, and may vary depending upon the external conditions.…”

Isostructural cocrystals of metaxalone with improved dissolution characteristics

“…Hydrates are generally less soluble than their anhydrous counterparts due to higher lattice energy. 27 In addition, all the cocrystals melted lower than the native drug that qualify the thumb rule of inverse correlation between solubility and melting point. (2.62Å, 166.6 ).…”

Hydrate vs Anhydrate under a Pressure-(De)stabilizing Effect of the Presence of Water in Solid Forms of Sulfamethoxazole

“…This leads to the second focus area of crystal research, the importance of learning and understanding the polymorphic and pseudopolymorphic landscape of the API, alongside a determination of the preferred conditions for the crystallization of each form, including the assessment of the transformations in the solid state . Any phase transitions should be detected, especially if, due to the medical benefits (higher solubility or bioavailability), the metastable forms are selected for the final drug product over the more stable polymorphs. ,, Moreover, the anhydrate–hydrate transition also needs to be carefully investigated, as anhydrous forms of the APIs can spontaneously transform into hydrates when water from moisture in the air is adsorbed. , All of this information is essential for the design of a reliable and reproducible manufacturing process, that will ensure the crystal form tailored best for the specific application is obtained and preserved during the shelf life of the drug product . Finally, newly discovered crystal forms or their crystallization protocols can be patent-eligible matter, as long as eligibility criteria, i.e.…”

“…19,23,24 Moreover, the anhydrate−hydrate transition also needs to be carefully investigated, as anhydrous forms of the APIs can spontaneously transform into hydrates when water from moisture in the air is adsorbed. 25,26 All of this information is essential for the design of a reliable and reproducible manufacturing process, that will ensure the crystal form tailored best for the specific application is obtained and preserved during the shelf life of the drug product. 19 Finally, newly discovered crystal forms or their crystallization protocols can be patenteligible matter, as long as eligibility criteria, i.e.…”