Valsartan
(VAL) is an antihypertensive drug marketed in an amorphous
form. Amorphous materials can have different physicochemical properties
depending on preparation method, thermal history, etc., but the nature
of such materials is difficult to study by diffraction techniques.
This study characterizes two different amorphous forms of valsartan
(AR and AM) using solid-state NMR (SSNMR) as a primary investigation
tool, supported by solution-state NMR, FT-IR, TMDSC, and dissolution
tests. The two forms are found to be clearly distinct, with a significantly
higher level of structural arrangement in the AR form, as observed
in 13C, 15N, and 1H SSNMR. 13C and 15N NMR indicates that the fully amorphous material
(AM) contains an approximately equal ratio of cis–trans conformers about the amide bond, whereas
the AR form exists mainly as one conformer, with minor conformational
“defects”. 1H ultrafast MAS NMR shows significant
differences in the hydrogen bonding involving the tetrazole and acid
hydrogens between the two materials, while 15N NMR shows
that both forms exist as a 1,2,3,4-tetrazole tautomer. NMR relaxation
times show subtle differences in local and bulk molecular mobility,
which can be connected with the glass transition, the stability of
the glassy material, and its response to aging. Counterintuitively
the fully amorphous material is found to have a significantly lower
dissolution rate than the apparently more ordered AR material.
Ionic liquids (ILs) and deep eutectic mixtures (DEMs) are potential solutions to the problems of low solubility, polymorphism, and low bioavailability of drugs. The aim of this work was to develop and investigate ketoprofen (KET)-based ILs/DEMs containing an ester local anesthetic (LA): benzocaine (BEN), procaine (PRO) and tetracaine (TET) as the second component. ILs/DEMs were prepared via a mechanosynthetic process that involved the mixing of KET with an LA in a range of molar ratios and applying a thermal treatment. After heating above the melting point and quench cooling, the formation of supercooled liquids with Tgs that were dependent on the composition was observed for all KET-LA mixtures with exception of that containing 95 mol% of BEN. The KET-LA mixtures containing either ≥ 60 mol% BEN or 95 mol% of TET showed crystallization to BEN and TET, respectively, during either cooling or second heating. KET decreased the crystallization tendency of BEN and TET and increased their glass-forming ability. The KET-PRO systems showed good glass-forming ability and did not crystallize either during the cooling or during the second heating cycle irrespective of the composition. Infrared spectroscopy and molecular modeling indicated that KET and LAs formed DEMs, but in the KET-PRO systems small quantities of carboxylate anions were present.
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