Identification and Characterization
of Stoichiometric and Nonstoichiometric Hydrate Forms of Paroxetine
HCl: Reversible Changes in Crystal Dimensions as a Function of Water
Absorption
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Abstract
Paroxetine hydrochloride (HCl) is an antidepressant drug,
reported to exist in the anhydrous form (form II) and as a stable
hemihydrate (form I). In this study, we investigate the hydration
behavior of paroxetine HCl form II with a view to understanding both
the nature of the interaction with water and the interchange between
forms II and I as a function of both temperature and water content.
In particular, we present new evidence for both the structure and
the interconversion process to be more complex than previously recognized.
A combination of characterization techniques was used, including thermal
(differential scanning calorimetry (DSC) and thermogravimetric analysis
(TGA)), spectroscopic (attenuated total reflectance Fourier transform
infrared spectroscopy (ATR-FTIR)), dynamic vapor sorption (DVS) and
X-ray powder diffraction (XRPD) with variable humidity, along with
computational molecular modeling of the crystal structures. The total
amount of water present in form II was surprisingly high (3.8% w/w,
0.8 mol of water/mol of drug), with conversion to the hemihydrate
noted on heating in hermetically sealed DSC pans. XRPD, supported
by ATR-FTIR and DVS, indicated changes in the unit cell dimensions
as a function of water content, with clear evidence for reversible
expansion and contraction as a function of relative humidity (RH).
Based on these data, we suggest that paroxetine HCl form II is not
an anhydrate but rather a nonstoichiometric hydrate. However, no continuous
channels are present and, according to molecular modeling simulation,
the water is moderately strongly bonded to the crystal, which is in
itself an uncommon feature when referring to nonstoichiometric hydrates.
Overall, therefore, we suggest that the anhydrous form of paroxetine
HCl is not only a nonstoichiometric hydrate but also one that shows
highly unusual characteristics in terms of gradual unit cell expansion
and contraction despite the absence of continuous channels. These
structural features in turn influence the tendency of this drug to
convert to the more stable hemihydrate. The study has implications
for the recognition and understanding of the behavior of pharmaceutical
nonstoichiometric hydrates