Why hydrate formation must be accounted for at all stages of drug development and manufacturing?

Pharmaceutical solids have the tendency to crystallize in multiple crystal forms and the significance of this phenomenon, polymorphism, has been demonstrated through the years. Like polymorphs, the hydrates of an active pharmaceutical ingredient or of an excipient may differ in key properties such as solubility, dissolution rate, stability, and particle habit. Water plays an important role, no matter where it is present, in the active ingredient, excipients, or the atmosphere. Water can induce phase transitions, dissolve soluble components, and increase interactions between the drug and excipients.  All this can affect the physical and chemical stability of the drug substance to the detriment of drug product performance. Therefore it must be accounted for at all stages of drug development and manufacturing.

Unlike polymorphs, hydrates represent different chemical entities as defined by the stoichiometry of water with respect to the active compound. Depending upon the nature of the hydrate, the water content may change over time with ambient humidity, temperature, or other processing conditions. Hydrates may be stoichiometric or nonstoichiometric.

Stoichiometric hydrates show step like type of sorption/desorption isotherms characterized by a fixed water content over a defined relative humidity (RH) range. In general, the stoichiometric hydrates convert upon dehydration to a distinct phase, either crystalline or amorphous. The crystallization water usually play a crucial role in stabilizing the molecular structure of a stoichiometric hydrate. 

Nonstoichiometric hydrates have a continuously variable composition within a certain relative humidity (RH) range that is not associated with a significant change in the crystal lattice. Dehydrating a nonstoichiometric hydrate may result in an isomorphic dehydrate (desolvate), a one-component phase that exhibits the main structural features of its parent phase. Desolvated solvates are usually metastable and easily take up the original solvent or sometimes other solvents to minimize free volume (void space) in the crystal structure. There are only few known cases, where nonstoichiometric hydrates lose crystallinity and become amorphous in extreme drying conditions.

The hydration, dehydration and rehydration processes of a compound can be complex and difficult to control at large scale. Hygroscopicity, a measure of the water vapor uptake of a solid by moisture sorption analysis should be routinely evaluated, typically, at the earliest stages of drug product development. The mechanism by which the water is taken up by a solid will definitely help to understand the impact that water molecules will have on the properties of the compound. Hydrates are generally expected to be thermodynamically more stable, hence less soluble and slower to dissolve than anhydrate forms above the critical water activity for hydrate formation. However, as particle size/shape distribution, specific surface area, and other surface properties heavily affect dissolution, and therefore a hydrate may dissolve faster than an anhydrate. Some hydrates are intrinsically more soluble (less stable) in water than neat forms. For example, Norfloxacin is considered unusual because its more soluble hydrates are zwitterionic and at least one of its anhydrates is charge neutral. In this case, the higher solubility of the hydrate can be attributed to the stronger hydration of the highly charged zwitterions relative to the uncharged molecule in the anhydrous form.

As water adversely affects the physical and chemical stability of a drug substance, it must be accounted for at all stages of drug development and manufacturing. The starting point should be the solubility determination of the different hydrated/anhydrated forms of a compound. The Crystal16 instrument may be used to determine the kinetic solubilities of hydrated/anhydrated forms of a compound in different solvent systems. In order to determine the solubility of a compound, one should start with a suspension of the investigated compound in a solvent system. The advised heating/cooling rates are between 0.1° and 0.5°C/min. The heating/cooling rates need to be adapted in order to avoid phase transformation. The temperature at the point the suspension becomes a clear solution upon heating, called also a “clear point” should be considered as the saturation temperature of the measured sample with known concentration.

Last but not least, in order to make sure that solvent-mediated transformations had not occurred during the measurements, residual solids should be analyzed by secondary analyses such as XRPD (X-ray powder diffraction), DSC (differential scanning calorimetry), TGMS (thermal gravimetric mass spectroscopy), etc. A variety of different solid-state analytical and spectroscopic techniques must be applied in order to understand the complex phase transition behavior of a hydrate compound. Processes need to be developed for drying, sieving and micronization by jet-milling for example in order to avoid non-desired phase transitions (over-drying effects) into other hydrate or anhydrate forms. Special methods need to be established to minimize, monitor and control the formation of amorphous content during the particle size reduction steps. Only by optimizing all production parameters it is possible to produce large scale batches with suitable physical quality.


If you would like to learn more about this topic, please check the references below and the Crystal16 instrument:
(1)    Newman, A. W.; Reutzel-Edens, S. M.; Zografi, G. Characterization of the ″hygroscopic″ properties of active pharmaceutical ingredients. J. Pharm. Sci. 2008, 97 (3), 1047−1059.
(2)     Griesser, U. J. The importance of solvates. In Polymorphism: In the Pharmaceutical Industry, Hilfiker, R., Ed.; Wiley-VCH: Germany, 2006; pp 211−233.
(3)    Vippagunta, S. R.; Brittain, H. G.; Grant, D. J. W. Crystalline solids. Adv. Drug Deliver. Rev. 2001, 48 (1), 3−26.
(4)    Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G. Solid-State Chemistry of Drugs; second ed.; West Lafayette, IN: SSCI, Inc.1999, West Lafayette, IN.
(5)    Zhu, H.; Yuen, C.; Grant, D. J. W. Influence of water activity in organic solvent + water mixtures on the nature of the crystallizing drug phase. 1. Theophylline. Int. J. Pharm. 1996, 135 (1,2), 151−160.
(6)    Fucke, K.; McIntyre, G. J.; Lemee-Cailleau, M. H.; Wilkinson, C.; Edwards, A. J.; Howard, J. A. K.; Steed, J. W. Insights into the Crystallisation Process from Anhydrous, Hydrated and Solvated Crystal Forms of Diatrizoic Acid. Chem. - Eur. J. 2015, 21 (3), 1036−1047.
(7)    Jeffrey, G. A. Water structure in organic hydrates. Acc. Chem.Res. 1969, 2 (11), 344−352.
(8)    Clark, J. R. Water molecules in hydrated organic crystals. Rev.Pure Appl. Chem. 1963, 13, 50−90.
(9)    Brittain, H. G.; Morris, K. R.; Boerrigter, S. X. M. Structural aspects of solvatomorphic systems. In Polymorphism in Pharmaceutical Solids, Brittain, H. G., Ed.; Informa Healthcare: New York, 2009; pp 233−281.
(10)    Authelin, J. R. Thermodynamics of non-stoichiometric pharmaceutical hydrates. Int. J. Pharm. 2005, 303 (1−2), 37−53.
(11)    Stubberud, L.; Arwidsson, H. G.; Graffner, C. Water-solid interactions: I. A technique for studying moisture sorption/desorption. Int. J. Pharm. 1995, 114 (1), 55−64.
(12)    Roberts, A. The design of an automatic system for the gravimetric measurement of water sorption. J. Therm. Anal. Calorim. 1999, 55 (2), 389−396.
(13)    Stephenson, G. A.; Groleau, E. G.; Kleemann, R. L.; Xu, W.; Rigsbee, D. R. Formation of Isomorphic Desolvates: Creating a Molecular Vacuum. J. Pharm. Sci. 1998, 87 (5), 536−542.