The Analysis of the Physicochemical Properties of Benzocaine Polymorphs

Abstract

The study was a pioneering attempt to assess the influence of the structural polymorphism (forms I, II, III) of benzocaine on its solubility, apparent solubility, and chemical stability, which are vital parameters for preformulation and formulation work. The impact of differences in the solubility of selected polymorphs of benzocaine on their permeability through artificial biological membranes (PAMPA system) was evaluated. The polymorphs of benzocaine were obtained by means of techniques commonly used for the preparation of various pharmaceutical dosage forms: ball milling, micro milling, and cryogenic grinding, which allowed for the appearance or preservation of form III, the initial conformation of benzocaine. Ball milling resulted in the conversion of form III to I, whereas micro milling yielded form II. As a result of cryogenic grinding, form III of benzocaine was preserved. The identification of all polymorphic forms of benzocaine was confirmed via X-ray powder diffraction (PXRD) supported by FT-IR spectroscopy coupled with density functional theory (DFT) calculations. The differences in solubility, dissolution, and permeability through artificial biological membranes resulting from the polymorphic forms of benzocaine were established by using chromatographic determinations. Accelerated stability tests indicated that all polymorphic forms were chemically stable at a required level.

A new high-pressure benzocaine polymorph — towards understanding the molecular aggregation in crystals of an important active pharmaceutical ingredient (API)

“…The current state of knowledge on the relationship between four BZC polymorphs was mapped in Scheme 1. Methods for ambient-pressure crystallization of polymorphs (I)-(III) are cited after previous reports (Sinha & Pattabhi, 1987;Lynch & McClenaghan, 2002;Chan et al, 2009;Paczkowska et al, 2018).…”

“…Even slight changes in the hydrogenbonding pattern supporting the crystal structure, as observed between polymorphs, can result in varied properties of different solid forms of the same compound (Braga et al, 2009). In fact, it was recently reported that polymorphs (I)-(III) of BZC differ in solubility and permeability (Paczkowska et al, 2018). Until now three polymorphs of BZC were known.…”

“…On cooling to 150 K, polymorph (II) undergoes a solid-to-solid phase transition to polymorph (III) of monoclinic symmetry, space group P112 1 (Chan et al, 2009). Depending on the milling protocol, polymorph (III) can transform to polymorph (I) (ball milling) or polymorph (II) (micro milling; Paczkowska et al, 2018). In all reported forms of BZC, molecules are hydrogen-bonded via N-HÁ Á ÁO hydrogen bonds into ribbons, and a similar positioning of soformed ribbons in respect to each other is observed.…”

Amine-Grafted Mesoporous Carbons as Benzocaine-Delivery Platforms

“…The characteristic bands in the range of ~450–1750 cm –1 and ~2770–3080 cm –1 were primarily considered. At ~850 cm –1 , the wagging vibrations of C–H bonds present in the benzene ring were identified [ 42 ]. Contrastingly, at 1102 cm –1 , the stretching vibrations of C–C bonds of the ring itself are noticed, which correspond to the breathing mode.…”

“…Furthermore, the bands centered at ~2895 and 2985 cm –1 assigned to the symmetric stretching vibrations of C–H from –CH 3 and the asymmetric stretching vibrations of C–H from –CH 2 are clearly visible. The pronounced three bands in the benzocaine FT-IR spectra at 3218, 3347, and 3427 cm –1 can be attributed to the symmetric and asymmetric stretching vibrations of N–H [ 42 ]. In the FT-IR spectra of all mesoporous carbon samples registered after the adsorption of benzocaine, some new bands derived from the active substance become visible, especially in the wavenumber range of ~450–1750 cm –1 .…”