Pharmaceutical hydrates

Khankari RK, Grant DJW. 1995. Pharmaceutical hydrates. Thermochim. Acta 248 62-79. 

Giron, D., Goldbrown, Ch., Mutz, M., Pfeffer, S., Piechon, Ph., and Schwab, Ph. (2002), Solid-state characterization of pharmaceutical hydrates, J. Therm. Anal. Calor., 68, 453 165. 

Han, J. Gupte, S. Suryanarayanan, R. Applications of pressure differential scanning calorimetry in the study of pharmaceutical hydrates. II. ampicillin trihydrate. Int. J. Pharm. 1998, 170, 63-72. 

While DSC may be used to study pharmaceutical hydrates, the most useful thermal method is undoubtedly TGA. Hydrates are materials whereby molecules of water are incorporated into the lattice structure of that solid at specific ratios, hence a monohydrate has one molecule of water for each molecule of drug, a dihydrate two molecules of water etc. The stoichiometry may also be fractional. Hydrates are again extremely important pharmaceutically as the physical properties differ from the anhydrous form, the former having, for example, a lower water solubility. Many drugs are marketed as hydrate forms, often due to their greater physical stability than the anhydrous form which may convert to the hydrate over a period of time if exposed to water vapor. 

Khankari RK and Grant DJW, Pharmaceutical Hydrates. Thermochim Acta 1995 248 61-79. 

Bettini R, Bertolini G, Casini I, Rossi A, Gazzaniga A, Pasquali I, Giordano F. Interaction of pharmaceutical hydrates with supercritical CO2. AAPS Pharm Sci 2002 4(4). 

Examples of Studies Involving Pharmaceutical Hydrates and Solvates... 

Pharmaceutical examples of studies involving solvates are often linked with investigations into polymorphism hence, there is some overlap with the previous section. In addition, the chapter on thermogravimetric analysis in this book also deals with this subject. The examples given here have been chosen specifically on the basis of their illustrating the use of DSC, rather than outlining the properties of pharmaceutical hydrates in general. 

The majority of studies on drugs and excipients involving TGA have used the technique as a means of identifying and characterizing pharmaceutical hydrates. The method presents several opportunities in this respect. In the first instance, the presence of a hydrate (as opposed to sorbed water) is usually easily discerned by the sharpness of the instrumental response corresponding to the water loss process. More specifically, loss of water of hydration usually occurs for pharmaceuticals over a range of approximately 5 to 20°C, depending on the experimental conditions used,... 

The potential pharmaceutical impact of changes in hydration state of crystalline drug substances and excipients exists throughout the development process. The behavior of pharmaceutical hydrates has become the object of increasing attention over the last decade, primarily due (directly or indirectly) to the potential impact of hydrates on the development process and dosage form performance. Substances may hydrate/dehydrate in response to changes in environmental conditions, processing, or over time if in a metastable thermodynamic state [1]. 

The characterization of pharmaceutical hydrates must be sufficient to provide confidence that the behavior of the material is predictable and reproducible. This requires the application of considerable molecular level intuition along with the available data. Data from all the techniques discussed are not always available, so in the absence of a complete data set the gaps must be filled using the types of energetic and structural principles described in the earlier chapter [1], When the available data are consistent with what is expected from these relation-... 

Han J, Suryanarayanan R (1999) A method for the rapid evaluation of the physical stability of pharmaceutical hydrates. Thermochimi Acta 329 163-170. 

Han, J. Influence of Environmental Conditions on the Dehydration of Pharmaceutical Hydrates. Ph.D. thesis. Department of Pharmaceutics, University of Minnesota, Minneapolis, 1998, pp. 162-180. 

Khankari RK, Law, and Grant DJW (1992) Determination of water in pharmaceutical hydrates by differential... 

In situ thermal transitions were also described by Taylor et al., who examined the isothermal dehydration behavior of trehalose dihydrate [29]. For small particle size fractions (<45 fjLm), heating at 80°C caused loss of peak definition until, at 210 min, amorphous material was present. In contrast, a larger particle size fraction (>425 fim) converted to the crystalline anhydrous form of the material. The kinetics of this conversion was probed from the Raman data using peak height ratios with time a two-stage rearrangement was indicated. A broader consideration of pharmaceutical hydrates, including their characterization by several techniques (NMR, Raman spectroscopy, and isothermal calorimetry) can be found in the literature [30] as can a review of the use of spectroscopic techniques for the characterization of polymorphs and hydrates [31]. 

LS Taylor, AC Williams, P York. Particle size dependent molecular rearrangements during the dehydration of trehalose dihydrate—in situ FT-Raman spectroscopy. Pharm Res 15 1207-1214, 1998. RK Khankari, DJW Grant. Pharmaceutical hydrates. Thermochim Acta 248 61-79, 1995. 

---