4 October 2019

Challenges in the development and manufacturing of hydrates in the pharmaceutical industry- part 1/2

Pharmaceutical hydrates have a significant impact on the bioavailability of active pharmaceutical ingredients (APIs).

A comprehensive understanding of the thermodynamic and kinetic parameters of the crystallisation of various types of hydrates, as well as the control of hydrate formation is extremely important in drug development and formulation processes, especially during crystallisation, lyophilisation, spray drying, wet granulation, aqueous film-coating and storage.

It has been estimated that at least every third small organic molecule of an API can form a hydrate.

Polpharma also has many hydrates in its portfolio.

Hydrates can be obtained through crystallisation from a sufficient amount of water or exposure of water vapor. The incorporation of water molecules in a crystal lattice of active pharmaceutical ingredients affects the level of intermolecular interactions, packing arrangement and crystalline disorder which influences free energy, thermodynamics parameters, solubility, dissolution rate and bioavailability, as well as the solid-state stability of APIs.

Usually, water adducts crystallise more easily than anhydrous forms, because the hydrogen bonding sites of the API molecules are often better supplied by intermolecular interaction with water molecules than with the molecule itself.

The low Gibbs free energy of hydrates is responsible for a lower solubility and dissolution rate compared to anhydrates. However, hydrates are more thermodynamically stable than anhydrates because water activity is above the critical water activity for hydrate formation. Moreover, the formation of hydrates can also affect mechanical properties such as flow properties or compatibility.

The physical and chemical stability of hydrates are dependent on temperature, water vapor pressure and absolute hydrate formation or dehydration, which may affect the biological activity of the final drugs.  Therefore, it is important to understand and control the anhydrate-hydrate phase transformation of pharmaceutical compounds to avoid unexpected phase changes during the production or storage of the product.

In general, hydrates are susceptible to dehydration during routine drying or storage, which can lead to the formation of hydrates with a lower or higher water content, with anhydrous or amorphous forms. On the one hand, water molecules are often present in the pharmaceutical manufacturing environment; for example, ambient humidity cannot be avoided or aqueous solutions are needed in processing or subsequent processing steps involve heat and may lead to dehydration of the hydrate.

The rehydratation-dehydratation system can result in an unstable product due to variations in the hydrate content and an uncontrolled hydrate formation or dehydration process. This phenomenon needs a thorough understanding of the structural aspects of hydrates, as well the hydrate formation mechanism.

Dorota Pogoda is a Technology Specialist in the R&D Division of the Polpharma API Plant. She is currently preparing to defend her PhD thesis at Wroclaw University of Science and Technology in the field of Solid-state Chemistry.


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