Design of Etched- and Functionalized-Halloysite/Meloxicam Hybrids: A Tool for Enhancing Drug Solubility and Dissolution Rate

Abstract

The study focuses on the synthesis and characterization of Meloxicam-halloysite nanotube (HNT) composites as a viable approach to enhance the solubility and dissolution rate of meloxicam, a poorly water-soluble drug (BCS class II). Meloxicam is loaded on commercial and modified halloysite (acidic and alkaline etching, or APTES and chitosan functionalization) via a solution method. Several techniques (XRPD, FT-IR, ¹³C solid-state NMR, SEM, EDS, TEM, DSC, TGA) are applied to characterize both HNTs and meloxicam-HNT systems. In all the investigated drug-clay hybrids, a high meloxicam loading of about 40 wt% is detected. The halloysite modification processes and the drug loading do not alter the structure and morphology of both meloxicam and halloysite nanotubes, which are in intimate contact in the composites. Weak drug-clay and drug-functionalizing agent interactions occur, involving the meloxicam amidic functional group. All the meloxicam-halloysite composites exhibit enhanced dissolution rates, as compared to meloxicam. The meloxicam-halloysite composite, functionalized with chitosan, showed the best performance both in water and in buffer at pH 7.5. The drug is completely released in 4-5 h in water and in less than 1 h in phosphate buffer. Notably, an equilibrium solubility of 13.7 ± 4.2 mg/L in distilled water at 21 °C is detected, and wettability dramatically increases, compared to the raw meloxicam. These promising results can be explained by the chitosan grafting on the outer surface of halloysite nanotubes, which provides increased specific surface area (100 m²/g) disposable for drug adsorption/desorption.

Keywords: dissolution tests; drug–nanoclay composites; halloysite nanotubes; meloxicam; poorly soluble drugs.

Scheme 1

Molecular structure of meloxicam.

Figure 1

XRPD patterns of (a) MEL, (b) H, (c) MH, (d) MH_NaOH_0.5M, (e) MH_A, and (f) MH_C.

Figure 2

FT-IR spectra of (a) H, (b) APTES, (c) H_A, (d) CTS, and (e) H_C in 4000–2000 cm⁻¹ (I), and 2000–650 cm⁻¹ (II) wavenumber range.

Figure 3

FT-IR spectra of (a) MEL, (b) MH, (c) MH_NaOH_0.5M, (d) MH_A, and (e) MH_C in 4000–2000 cm⁻¹ (I), and 2000–650 cm⁻¹ (II) wavenumber range.

Figure 4

SEM images at 20 kX magnification of (a) H, (b) H_NaOH_0.5M, (c) H_A, (d) H_C.

Figure 5

SEM images of MEL at (a) 3 kX and (b) 10 kX magnification.

Figure 6

SEM images of (a) MH, (b) MH_NaOH_0.5M, (c) MH_A, (d) MH_C at 10 kX magnification.

Figure 7

TEM images at 100 kX magnification of (a) H, (b) H_NaOH_0.5M, (c) H_A, (d) H_C.

Figure 8

TEM images at 100 kX magnification of (a) MEL, (b) MH, (c) MH_NaOH_0.5M, (d) MH_A, (e) MH_C.

Figure 9

DSC curves of (a) MH_C, (b) MH_A, (c) MH_NaOH_0.5M, (d) MH, (e) MEL, and (f) H (magnified in the inset).

Figure 10

Dissolution profiles of MEL, MH, MH_HCl_2M, MH_HCl_4M, and MH_NaOH_0.5M in the different fluids considered. All samples contain 7.5 mg of the drug.

Figure 11

Dissolution profiles of MEL, MEL loaded on commercial H, MH, and functionalized Halloysites, MH_A, and MH_C in the different fluids considered. All samples contain 7.5 mg of the drug.

Figure 12

Contact angle, θ, of MH_C compared to MEL alone in the four fluids considered: HCl pH 1.0, phosphate buffers, pH 4.5 and 7.5, and deionized water.