Hydrate Screening Approaches
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Solid form screening is a key component in pharmaceutical development of new drug substances. The focus is often on anhydrous forms whilst hydrates are considered a nuisance.  However, in recent years the number of hydrates taken into development has significantly increased.  Perhaps a reason is Active Pharmaceutical Ingredients (APIs) becoming increasingly more complex with more hydrogen bond donors and acceptors that participate in inter- and intramolecular hydrogen bond formation.  Hydrates, even more so than polymorphs, have significant different solubility and dissolution rate profiles than their anhydrous counterparts.  A well executed solid form investigation should, therefore, always include the search for hydrates.  Often hydrate formations are only discovered in late stage development during long term stability studies or in formulation processes.  Equally important as understanding the hydrate formation is knowledge of the process of hydration and dehydration that may occur during pharmaceutical processing and storage.

A first step to investigate the potential of a solid API to convert from an anhydrous crystalline form into a hydrated form is by exposure to moisture by storing the API at ambient temperature in desiccators with defined relative humidity levels for a period of time.  At regular intervals the samples are weighted and at completion the samples are characterized by techniques such as DSC, TGA and XRPD.  Changes in the crystalline form will become apparent and a distinction can be made between water sorption and true hydrate formation.  A major drawback of this approach is the time required.  Like any solid form transformation, the speed at which it will happen remains an unknown variable in the process.  Introducing the temperature as a variable in the study may help to speed up the process but is no guarantee for success.  If hydration is confirmed in these studies more sophisticated approaches such as Dynamic Vapor Sorption (DVS) and variable humidity and temperature XRPD analysis may shed further light on the actual process of hydration and dehydration.

For poorly aqueous soluble APIs and for APIs for which the anhydrous and hydrated forms are kinetically stable, the previous described methods might not trigger hydrate formation. A rapid method to determine the relative physical stability of an anhydrous vs hydrated form is the solvent mediated phase transformation containing mixtures of both crystal forms in various organic/aqueous systems with known water activities. The slurries are done at different temperatures to investigate variations in the solid form upon temperature/water activity conditions. This method will shed more light on the relative humidity (water activity range) under which the hydrate is the more thermodynamically stable from over the anhydrous crystal form.  This approach introduces the concept of water activity in relation to hydrate formation.

The water activity (aw) of the crystallization solvent plays an important role in hydrate formation. Depending on the aw of the crystallization solvent, the anhydrous or hydrate crystal form might be the most thermodynamically stable form. To establish a proper ratio of organic solvent in water for the crystallization of a hydrate it is crucial to investigate the influence of aw of the water/organic solvent system on the physical stability of the solid form, especially when at least one anhydrous and one hydrated form are known of the same drug substance.  The solubilities of both crystal forms should be determined in a wide range of water activities of a certain water/organic solvent system at various temperatures and the residual solid phase characterized by XRPD. From this experiment a equilibrium diagram of the two forms can be plotted as presented in Figure 1.

Figure 1. Physical stability study of the anhydrous and hydrated crystal form of a drug substance at various temperature and water activities

Hydrate investigations are part of all screens carried out at Crystallics.  Crystallics has also designed a specific hydration screen which focus on investigating the hydration behaviour of drug substances. Where hydrated forms are newly discovered, the thermodynamically stability of the anhydrous vs hydrates is determined in a certain range of temperature and humidity to define phase boundaries between anhydrous and hydrated forms in water/solvent systems.