Mechanochemical Synthesis and Crystal Structure of the Lidocaine-Phloroglucinol Hydrate 1:1:1 Complex

Abstract

Molecular complexation is a strategy used to modify the physicochemical or biopharmaceutical properties of an active pharmaceutical ingredient. Solvent assisted grinding is a common method used to obtain solid complexes in the form of cocrystals. Lidocaine is a drug used as an anesthetic and for the treatment of chronic pain, which bears in its chemical structure an amide functional group able to form hydrogen bonds. Polyphenols are used as cocrystal coformers due to their ability to form O-H···X (X = O, N) hydrogen bond interactions. The objective of this study was to exploit the ability of phloroglucinol to form molecular complexes with lidocaine by liquid assisted grinding. The formation of the complex was confirmed by the shift of the O-H and C=O stretching bands in the IR spectra of the polycrystalline ground powders, suggesting the formation of O-H···O=C hydrogen bonds. Hydration of the complexes also was confirmed by IR spectroscopy and by powder X-ray diffraction. The molecular structure was determined by single crystal X-ray diffraction.

Mechanochemical Synthesis of a Cocrystal of Two Supramolecular Hydrogen-Bonded Aggregates of 1,3,6,8-Tetraazatricyclo[4.3.1.13,8]undecane (TATU) with 4-tert-Butylphenol Bearing Different Hydrogen Bonding Interactions

“…The compound 1,3,6,8-tetraazatricyclo[4.3.1.1 3,8 ]undecane (TATU, 1) was synthesized as described in the literature [14]. The melting point was determined with an electrothermal apparatus (Cole-Parmer Lab Apparatus, Stone, Staffordshire, UK) using an open capillary tube, which was uncorrected.…”

“…A mixture of 1,3,6,8-tetraazatricyclo[4.3.1.1 3,8 ]undecane (TATU) (154 mg, 1 mmol) and 4-tert-butylphenol (4TBP) (300 mg, 2 mmol) was ground in a mortar at room temperature for 15 min as required to complete the reaction. The mixture was recrystallized from n-hexane solution to obtain colorless crystals that are suitable for X-ray analysis, m.p.…”

“…Many methods and techniques are used for the preparation of cocrystals. Nowadays, the solid-state grinding, which is also known as mechanochemical synthesis, has developed as an interesting alternate method/technique for cocrystal synthesis [7][8][9][10]. We previously reported [11][12][13] that grinding a 1:1 mixture of 1,3,6,8-tetraazatricyclo[4.3.1.1 3,8 ]undecane (TATU, 1, Scheme 1) and different phenols (4-nitrophenol, 4-chlorophenol and 4-chloro-3,5-dimethylphenol) at room temperature for 15 min affords phenol-aminal 2/1 cocrystals in excellent yields, which have been assembled through hydrogen-bonding interactions.…”

Structure of Bis(lidocaine) Tetrachloridocuprate(ii)

“…According to the values of the corresponding torsion angles, the amide group is twisted out from the plane of the aromatic ring by ~116, ~83, ~113 and ~98 o in cations 1, 2, 3 and 4, respectively. For all four cations the aromatic ring and the oxygen atom adopt a synperiplanar (С) conformation with respect to the carboxamide N-C bond, the amido and amino nitrogen atoms adopt staggered antiperiplanar (T) conformation excluding the formation of an intramolecular hydrogen bond N-H•••N noted in the lidocaine free base and its molecular complex, when the nitrogen atoms adopt a C conformation [25].…”

Rational Coformer Selection in the Development of 6-Propyl-2-thiouracil Pharmaceutical Cocrystals

“…Evidence on the prevention of diseases by polyphenols has raised the interest of food and pharmaceutical industries in these molecules [ 17 , 18 , 19 ]. In fact, they are included in the “Substances Added to Food” list [ 20 ] and have already been used as coformers in the design of multicomponent pharmaceutical solids with different APIs due to their ability to form O-H···O and O-H···N H-bonds, improving their physicochemical properties [ 21 , 22 , 23 , 24 , 25 , 26 ].…”