Cholecalciferol complexation with hydroxypropyl-β-cyclodextrin (HPBCD) and its molecular dynamics simulation

Abstract

The focus of the current study is to investigate cholecalciferol (vitamin D3) solubilization by hydroxypropyl-β-cyclodextrin (HPBCD) complexation through experimental and computational studies. Phase solubility diagram of vitamin D3 (completely insoluble in water) has an A_P profile revealing a deviation from a linear regression with HPBCD concentration increase. Differential scanning calorimetry (DSC) is the best tool to confirm complex formation by disappearance of cholecalciferol exothermic peak in cholecalciferol-HPBCD complex thermogram, due to its amorphous state by entering HPBCD inner hydrophobic cavity, similarly validated by Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). A_P solubility diagram profile can be associated with cholecalciferol-HPBCD complex instability in liquid phase requiring spray drying to bring it to a solid dispersion state (always more stable) illustrated by scanning electron microscopy (SEM). Computational studies led to a deeper understanding and clarification, at molecular level, of the interactions within cholecalciferol-HPBCD complex. Thermodynamics and geometry of the complex were investigated by molecular dynamics (MD) simulation.

Keywords: Cholecalciferol (vitamin D3); complex; hydroxypropyl-β-cyclodextrin (HPBCD); molecular dynamic (MD) simulations; molecular modeling.

Figure 1.

2D structure of a BCD molecule with hydroxyl groups labeled, which is substituted by hydroxypropyl groups in HPBCD case. Considering the symmetry, for example, substitutions on (1,2,3,4) will be similar to that on (2,3,4,5), (3,4,5,6), (4,5,6,7), (5,6,7,1), (6,7,1,2), and (7,1,2,3), thus only (1,2,3,4) will be modeled for such substitution case.

Figure 2.

Total vitamin D3 solution concentration (mM) at different HPBCD concentrations (mM) in deionized water (under vitamin D3 saturation conditions and room temperature) shows a type A_P diagram.

Figure 3.

The cholecalciferol–HPBCD complex solution 6-month stability evaluation at 25 °C/60% RH and 40 °C/75% RH. The Y-axis represents the concentration ratio of the percent cholecalciferol remaining compared to the original concentration at day 0.

Figure 4.

DSC thermograms of cholecalciferol (vitamin D3), HPBCD and spray dried cholecalciferol–HPBCD complex sample.

Figure 5.

FTIR spectrum of (A) cholecalciferol; (B) HPBCD; (C) cholecalciferol and HPBCD physical mixture (1.6:10 mole ratio); (D) spray dried cholecalciferol–HPBCD complex (1.1:20 number of moles ratio).

Figure 6.

X-ray powder diffraction pattern of (A) cholecalciferol; (B) HPBCD; (C) cholecalciferol and HPBCD physical mixture (1.6:10 mole ratio); (D) spray dried cholecalciferol–HPBCD complex (1.1:20 mole ratio).

Figure 7.

SEM micrographs of (A) cholecalciferol (vitamin D3), (B) HPBCD, (C) physical mixture of cholecalciferol and HPBCD, and (D) spray dried cholecalciferol–HPBCD complex particles.

Figure 8.

The lowest energy complex structure for both up-state (A) and down-state (B) mode selected from seven MD simulations. Cholecalciferol shown with carbon as a ball and stick representation. HPBCD shown with carbon is a light shade colored stick representation. Both top view (left) and side view (right) are present.

Figure 9.

Distances between centers of mass of cholecalciferol and HPBCD during one MD simulation for each state. Representative binding modes are shown for both up (indicated by solid arrows) and down-state (indicated by dotted arrows).