Article,
Vibrational and thermal analyses of multicomponent crystal forms of the anti-HIV drugs lamivudine and zalcitabine
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, (2015)
DOI: 10.1016/j.jpba.2015.03.004
Abstract
The vibrational and thermal characterizations of four multicomponent
molecular crystals of lamivudine, namely, lamivudine hydrochloride
anhydrate (1), lamivudine hydrochloride monohydrate (2), lamivudine
duplex I(3), with a 8:2:2:1:4 lamivudine:maleic
acid:HCl:(CH3)(2)CHOH:H2O stoichiometry, being all three more soluble in
water than the commercial solid form of lamivudine, and lamivudine
maleate (4), have been performed here by infrared (IR) and Raman
spectroscopy, differential scanning calorimetry (DSC), and
thermogravimetry (TG). Furthermore, the vibrational spectra of
zalcitabine hydrochloride (5), isostructural to 1 but with a methylene
moiety in the 3'-position of the five-membered ring instead of sulfur in
lamivudine, have also been measured in order to point out the role of
this molecular substitution and conformation in the vibrational modes of
the salts. In fact, scattering bands at the high frequency range
relative to CH stretching modes are not superimposable in the Raman
spectra of I and 5, even though these crystal forms are assembled with
the same molecular conformation and intermolecular packing. At the same
time, the structural similarity between 1 and 5 can be reflected in
their IR spectra, as in the carbonyl and iminium stretching bands
shifted to lower frequencies as consequence of their hydrogen bonding
engagement. Furthermore, a scattering band at 3057 cm(-1) is observed
only in the Raman spectra of crystal forms present with their 5'-CH2OH
moiety in-gauche conformation, namely, 2-4. It is absent in the Raman
spectra of 1 and 5 whose 5'-CH2OH moiety adopts (+)gauche conformation.
In-gauche conformation, the 5'-OH oxygen is pointed toward one of the
two aromatic CH hydrogens. Consequently, there is formation of an
intramolecular hydrogen bond between them, shifting the aromatic CH
stretching band to a lower frequency. The DFT calculations have also
revealed in-phase and out-of-phase couplings of the two aromatic CH
stretchings in the Raman spectra of 1, which is without intramolecular
hydrogen bond due to (+)gauche conformation of 5'-CH2OH moiety. Both
coupled vibrational modes are observed in the corresponding experimental
spectrum as a single peak because of their similar frequencies. On
contrary, aromatic CH stretching modes are not coupled in 2 due to the
intramolecular hydrogen bond, resulting in resolution of the Raman
bands. Thermal events in DSC and TG curves of 1 and 2 are also in
agreement with crystal stoichiometry as observed from single-crystal
X-ray diffraction analysis. (C) 2015 Elsevier B.V. All rights reserved.
