Differentiation and quantitative determination of surface and hydrate water in lyophilized mannitol using NIR spectroscopy.

Mannitol hydrate is a metastable form produced during lyophilization. It is unstable, and therefore can undergo dehydration to release water to the surrounding environment at room temperature. The analysis of this form is challenging due to its thermodynamic instability. This study describes the development of a fast and non-invasive method to determine the mannitol hydrate and surface water content in a lyophilized product using near-infrared (NIR) spectroscopy. The mannitol hydrate was produced through lyophilization and characterized using XRPD, TGA, and NIR spectroscopy. Quantitative methods for hydrate and surface water were developed for NIR spectra with curve fitting and partial least square (PLS) regression models. The curve fitting method deconvoluted the NIR spectra into hydrate and surface water peaks and generated a calibration model by correlating pure spectra peak area to concentration. The standard error of prediction (SEP) for hydrate and surface water content were 0.65 and 0.40%, respectively. The PLS model developed for the same sample set was better than the curve fitting model; SEP = 0.50% for hydrate water and 0.22% for surface water, respectively. The methods can be used to monitor the formation and stability of mannitol hydrate in mannitol-containing formulations during the lyophilization process.