8 October 2019

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

Due to the variety of pharmaceutical compounds, water molecules can be incorporated into the crystal lattice in several ways.

Hydrates can be divided into three maim classes.

  • The first category is called isolated site hydrates, which form hydrogen bonds or van der Waals interactions with the drug molecules. These hydrates show sharp dehydration endothermic peaks on thermograms, determined by differential scanning calorimetry (DSC) and sharp -OH bands in spectrum determined by infrared spectroscopy (IR).
  • The second class is channel hydrates, where crystalline water molecules form chains along a given axis of the crystal lattice. These structures have also sharp -OH bands in infrared spectrum, but at relatively low frequency. They demonstrate broad endothermic peaks in a DSC thermogram. The dehydration temperature of a channel hydrate is usually lower compared to an isolated hydrate. Channel hydrates can be divided into two subclasses: planar hydrates, where the water creates a two-dimensional network and expanded channels, which have additional water in a non-stoichiometric amount.
  • The third category is called ion-associated hydrates, which contain ion-coordinated water. This class demonstrates high dehydration temperatures.

On the basis of the hydrate-dehydrate mechanism or moisture sorption-desorption behaviour, hydrates can also be divided into two main categories – stoichiometric and non-stoichiometric hydrates.

  • Stoichiometric hydrates contain a stoichiometric water content in a given relative humidity (RH) and the water molecules are an integral part of the crystal network, which interact strongly with the APIs molecules or each other. In this case, dehydration involves a significant rearrangement of the molecules, that result in the instability of the crystal lattice, which collapses and remains as an amorphous state or recrystallises as a crystalline form with a lower content of water.
  • Non-stoichiometric hydrates are generally problematic because the water molecules are weakly bound, which means they can interact with other components that threaten performance formulation and stability. They usually contain water in open structural voids that permit the reversible release/uptake of water without significant changes to the crystal network. So, the amount of water in the crystal network depends on the environmental condition, especially moisture and temperature. As previously mentioned, the non-stoichiometric behaviour of hydrates is also observed in channel hydrates.

Identification of the type of hydrate requires several analytical methods, including thermal (differential scanning calorimetry with thermogravimetric analysis), spectroscopic (infrared and Raman spectroscopy), X-ray powder diffraction with variable temperature and humidity, single crystal X-ray diffraction, critical water activity and dynamic vapor sorption.

Knowledge about the absorption of water vapor and the influence of moisture on the physical and chemical properties of drug stability is a key issue in the development of medical products to minimise or avoid problems during the production, formulation or storage of the drugs. At Polpharma, we guarantee you Experts in above mention areas.

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