Solid-State NMR Characterization of Mefloquine Resinate Complexes Designed for Taste-Masking Pediatric Formulations

Abstract

Mefloquine (MQ) is an antimalarial medication prescribed to treat or malaria prevention.. When taken by children, vomiting usually occurs, and new doses of medication frequently need to be taken. So, developing pediatric medicines using taste-masked antimalarial drug complexes is mandatory for the success of mefloquine administration. The hypothesis that binding mefloquine to an ion-exchange resin (R) could circumvent the drug's bitter taste problem was proposed, and solid-state ¹³C cross-polarization magic angle spinning (CPMAS) NMR was able to follow MQ-R mixtures through chemical shift and relaxation measurements. The nature of MQ-R complex formation could then be determined. Impedimetric electronic tongue equipment also verified the resinate taste-masking efficiency in vitro. Variations in chemical shifts and structure dynamics measured by proton relaxation properties (e.g., T1ρ^H) were used as probes to follow the extension of mixing and specific interactions that would be present in MQ-R. A significant decrease in T1ρ^H values was observed for MQ carbons in MQ-R complexes, compared to the ones in MQ (from 100-200 ms in MQ to 20-50 ms in an MQ-R complex). The results evidenced that the cationic resin interacts strongly with mefloquine molecules in the formulation of a 1:1 ratio complex. Thus, ¹³C CPMAS NMR allowed the confirmation of the presence of a binding between mefloquine and polacrilin in the MQ-R formulation studied.

Keywords: 13C NMR; CPMAS NMR; T1ρH relaxation time; electronic tongue; ion-exchange resin; mefloquine; taste masking.

Figure 1

Structural formulas for racemic, (+), and (−) of mefloquine. HCl (Adapted from ref. [19]).

Figure 2

Structural formula of potassium polacrilin—‘2-Propenoic acid, 2-methyl-, potassium salt (1:1), polymer with diethenylbenzene’ (adapted from ref. [20]).

Figure 3

Optimized ¹³C CPMAS NMR spectrum obtained for MQ. Optimized conditions: NS-512, D1—20 s, contact time—10,000 μs. Asterisks denote spinning sidebands. The carbon signals are numbered following the MQ structure presented in Table 1.

Figure 4

¹³C chemical shifts variation (D chemical shift = d_MQ–R − d_MQ) observed for MQ carbon skeleton in DMSO-d₆ solution (green), and in the solid state (orange). The change for higher frequency (deshielding) is denoted by the positive bar; the shift for lower frequency (shielding) is denoted by the negative bar. DMQ chemical shifts (±1 ppm interval) for each carbon signal are indicated by the horizontal lines in blue.

Figure 5

¹³C CPMAS NMR spectra of the samples: polacrilin resin (R, Φ); mefloquine hydrochloride (MQ, Ω); physical mixture MQ + R; and mefloquine–resin complex (MQ–R). * Denotes spinning sidebands.

Figure 6

Distribution of T_1ρ^H for the carbons of mefloquine hydrochloride, MQ (blue); MQ–R (orange); and resin R (grey).

Figure 7

Variation of the intensity of carbon C2 signal with the cross-polarization contact time (tc, s) for samples of mefloquine hydrochloride (MQ, pink) and mefloquine resinate (MQ–R, blue). The curve obtained for polacrilin carbons at 47 ppm (R, black) was included for comparison. The vertical scale is arbitrary.

Figure 8

The dissolution test for mefloquine resinate in simulated salivary conditions was performed using the impedance method, measured through the conductivity difference between MQ–R (|Z|) and R (|Z₀|).

Figure 9

The taste-masking efficiency was determined with an electronic tongue analysis. (A) IDMAP plot points to the clusters formed by the mefloquine (MQ), the resin (R), and the mefloquine resinate (MQ–R). (B) Dendrogram with the Euclidean distances and similarities between the clusters formed.