Evidence of Strong Guest-Host Interactions in Simvastatin Loaded in Mesoporous Silica MCM-41

Abstract

A rational design of drug delivery systems requires in-depth knowledge not only of the drug itself, in terms of physical state and molecular mobility, but also of how it is distributed among a carrier and its interactions with the host matrix. In this context, this work reports the behavior of simvastatin (SIM) loaded in mesoporous silica MCM-41 matrix (average pore diameter ~3.5 nm) accessed by a set of experimental techniques, evidencing that it exists in an amorphous state (X-ray diffraction, ssNMR, ATR-FTIR, and DSC). The most significant fraction of SIM molecules corresponds to a high thermal resistant population, as shown by thermogravimetry, and which interacts strongly with the MCM silanol groups, as revealed by ATR-FTIR analysis. These findings are supported by Molecular Dynamics (MD) simulations predicting that SIM molecules anchor to the inner pore wall through multiple hydrogen bonds. This anchored molecular fraction lacks a calorimetric and dielectric signature corresponding to a dynamically rigid population. Furthermore, differential scanning calorimetry showed a weak glass transition that is shifted to lower temperatures compared to bulk amorphous SIM. This accelerated molecular population is coherent with an in-pore fraction of molecules distinct from bulklike SIM, as highlighted by MD simulations. MCM-41 loading proved to be a suitable strategy for a long-term stabilization (at least three years) of simvastatin in the amorphous form, whose unanchored population releases at a much higher rate compared to the crystalline drug dissolution. Oppositely, the surface-attached molecules are kept entrapped inside pores even after long-term release assays.

Keywords: amorphous state; drug delivery development; drug release; drug-carrier multiple interactions; molecular mobility; simvastatin.

Figure A1

ATR-FTIR spectrum of neat SIM crystal polymorph I (room temperature), in the carbonyl stretching region.

Figure A2

DSC curves obtained during heating of a SIM:MCM-41 composite with loading 51% (w/w).

Figure A3

Isochronal plots of the real part of complex permittivity, ε′(T), at 10³ Hz, comparing 1st (hydrated) with 2nd (dehydrated) runs of SIM:MCM composite.

Scheme 1

Chemical structure of simvastatin: oxygen atoms numbered in red and carbon atoms numbered in black according to ref. [26].

Figure 1

Snapshot of the empty cylindrical channel carved in a pre-optimized rectangular parallelepiped matrix (71 Å × 71 Å × 36 Å) of amorphous silica (left) and filled with SIM molecules (right). The channel is completely filled with 46 SIM molecules corresponding to the density of SIM in the channel of about 0.94 g cm⁻³.

Figure 2

(a) Nitrogen adsorption/desorption isotherm for simvastatin loaded MCM-41 (blue circles); unloaded MCM-41 is included for comparison: open circles adsorption; filled circles, desorption branch. (b) Pore size distribution for the unloaded matrix (desorption branch), centered at 3 nm. The inset depicts SIM molecular structure and respective dimensions as obtained from Molecular Dynamics simulations.

Figure 3

(a) Thermogravimetric curves of SIM:MCM (composite containing ~1 mg of simvastatin; blue line), neat crystalline (mass _SIM,Crys = 0.9790 mg; black solid line), neat amorphous (mass _SIM,Amph = 0.9500 mg; olive dashed line) simvastatin, and unloaded MCM-41 silica matrix (grey line) taken at a heating rate of 5 °C min⁻¹. (b) The respective derivative plot for SIM:MCM composite and neat simvastatin (note the different vertical scales).

Figure 4

Powder X-ray diffraction patterns, at room temperature, for neat crystalline simvastatin (black line) and SIM:MCM composite (blue line). Data were displaced vertically for better visualization. The calculated diffractogram of SIM crystal Form I (Cambridge Structural Database refcode EJEQAL08) [44] is included for comparison (grey line).

Figure 5

¹³C CP/MAS NMR spectrum of SIM:MCM and main groups (see molecular structure in Scheme 1) assignment according to previous works [26,59,60].

Figure 6

ATR-FTIR spectra at room temperature in the hydroxyl (OH) band (left-hand panels) and carbonyl (CO) band region (right-hand panels) of neat simvastatin (crystal form I and bulk amorphous, respectively, panels (a,b) and (d,e)) and SIM:MCM composite (panels (c,f)).

Figure 7

(a) DSC curves of SIM:MCM (taking in account the weight % of SIM+water in the composite) and neat SIM crystal (form I) during heating at 10 °C min⁻¹. (b) DSC curves of SIM:MCM (taking in account the weight % of SIM in the composite) and bulk SIM amorphous during heating at 30 °C min⁻¹ (after previous cooling at 30 °C min⁻¹ of the dried composite and melt neat SIM). (c) Temperature derivative of heat flow curves shown in (b).

Figure 8

(a) Comparison of dehydrated SIM:MCM (blue symbols; right-hand axis) with bulk amorphous SIM (olive symbols; left-hand axis) in terms of the imaginary part, ε″(T), at four frequencies (see caption inside figure). In the inset, the ε´´(T)-trace at 10⁵ Hz for bulk SIM, where the different dielectric processes, γ, β, α, and conductivity (σ_dc) are identified; the conductivity tail of bulk SIM was removed from the ε″(T)-trace in the main figure. ε″(f) isothermal plots of SIM:MCM: (b) compared with bulk SIM at −50 °C and −20 °C; (c) between −20 °C and 30 °C. The inset displays the temperature evolution of β relaxation times (−log(τ) vs. 1/T) of SIM in the composite (blue circles) and bulk SIM (olive circles); (d) compared with bulk SIM at 10 °C.

Figure 9

Simvastatin´s dissolution (grey circles) and release from MCM (blue circles) normalized for the total quantity used in the trial (averaged over three trials; error bars are of the order of the data point symbol): (a) As monitored for 56 days (solid lines are a guide for the eyes). (b) scale up of the first 10 h evidencing the superior releasing rate of loaded amorphous SIM compared with the neat crystalline drug dissolution.

Figure 10

Radial density function of confined SIM at T = 300 and 600 K. The distance r from the pore center is calculated based on the center of mass position of the SIM molecules. Dashed line indicates the expected average density of SIM in the pore (0.94 g cm⁻³) considering the volume of the pore of cylindrical shape and the number of molecules.

Figure 11

Zoom of the simulation cell obtained by MD simulations of simvastatin confined in a cylindrical pore of 3.5 nm diameter that mimics MCM-41 mesoporous materials, illustrating the interaction of one simvastatin with the silanol groups of the MCM matrix through (a) three hydrogen bonds and (b) five hydrogen bonds identified by the white arrows. The snapshots illustrate well that the surface-anchored SIM molecules adopt a conformation that leaves a hydrophobic part towards the center of the pore.

Figure 12

Distribution $P\left(\varphi \right)$ of the angles $\varphi$ of the SIM molecules present in the pore volume or the pore surface at T = 300 and 600 K. $\varphi$ corresponds to the angle formed between the SIM dipole moments $\overrightarrow{\mu }$ and the vector perpendicular to the pore surface (See Scheme 2). $\varphi =0$ corresponds to a situation where the dipole moment of the SIM molecule is radial, i.e., pointing along the direction perpendicular to the pore surface. At $\varphi =\pm 180°,$ the dipole moment of the SIM molecule is parallel or antiparallel to the pore surface. The horizontal dashed line indicates the expected value for a distribution of randomly orientated dipoles as expected in the bulk.

Scheme 2

Schematic representation of the plane (OXY) perpendicular to the pore cylindrical channel. The direction OZ is orientated along the channel. ϕ represents the angle between the SIM dipole moment $\overrightarrow{\mu }$ and the vector normal to the pore surface $\overrightarrow{N}$. $\overrightarrow{N}$ is connecting the pore center and the center of mass of the SIM molecule.