Opportunities for Successful Stabilization of Poor Glass-Forming Drugs: A Stability-Based Comparison of Mesoporous Silica Versus Hot Melt Extrusion Technologies

Abstract

Amorphous formulation technologies to improve oral absorption of poorly soluble active pharmaceutical ingredients (APIs) have become increasingly prevalent. Currently, polymer-based amorphous formulations manufactured by spray drying, hot melt extrusion (HME), or co-precipitation are most common. However, these technologies have challenges in terms of the successful stabilization of poor glass former compounds in the amorphous form. An alternative approach is mesoporous silica, which stabilizes APIs in non-crystalline form via molecular adsorption inside nano-scale pores. In line with these considerations, two poor glass formers, haloperidol and carbamazepine, were formulated as polymer-based solid dispersion via HME and with mesoporous silica, and their stability was compared under accelerated conditions. Changes were monitored over three months with respect to solid-state form and dissolution. The results were supported by solid-state nuclear magnetic resonance spectroscopy (SS-NMR) and scanning electron microscopy (SEM). It was demonstrated that mesoporous silica was more successful than HME in the stabilization of the selected poor glass formers. While both drugs remained non-crystalline during the study using mesoporous silica, polymer-based HME formulations showed recrystallization after one week. Thus, mesoporous silica represents an attractive technology to extend the formulation toolbox to poorly soluble poor glass formers.

Keywords: amorphous stability; glass forming ability; hot melt extrusion; mesoporous silica; supersaturation.

Figure 1

Haloperidol (top) and carbamazepine (bottom) hot melt extrusion (HME) before (left) and after (right) 7 days accelerated stability conditions as specified in the materials and methods section.

Figure 2

SEM images for carbamazepine loaded silica (a) and HME (b) showing particle size and morphology at 0 days (top) and 90 days stability (bottom) as specified in the materials and methods section.

Figure 3

SEM images for haloperidol loaded silica (a) and HME (b) showing particle size and morphology at 0 days (top) and 90 days stability (bottom) as specified in the materials and methods section.

Figure 4

Powder X-ray (PXRD) patterns for carbamazepine loaded silica (top) and carbamazepine HME (bottom) showing crystalline carbamazepine (a), pure Parteck MXP^® (PVA) (b), unstressed carbamazepine formulation (c) and stressed carbamazepine formulations at 30 (d), 60 (e), and 90 (f) days. The arrows indicate crystalline peaks in the diffractograms.

Figure 5

PXRD patterns for haloperidol loaded silica (top) and haloperidol HME (bottom) showing crystalline haloperidol (a), pure PVA (b), unstressed haloperidol formulation (c) and stressed haloperidol formulations at 30 (d), 60 (e), and 90 (f) days. The arrows indicate crystalline peaks in the diffractograms.

Figure 6

¹³C Solid-state nuclear magnetic resonance spectroscopy (SS-NMR) spectra for crystalline haloperidol (c), HME formulation at 0 days (b) and 90 days (a).

Figure 7

¹³C SS-NMR spectra for crystalline carbamazepine (c) and carbamazepine HME formulation at 0 days (b) and 90 days (a).

Figure 8

Fasted Simulated Intestinal Fluid (FaSSIF) mini-dissolution curves for carbamazepine loaded silica (left) and carbamazepine HME formulation (right) showing crystalline carbamazepine (♦), unstressed carbamazepine formulation (●), and stressed carbamazepine formulations at 30 (▪), 60 (X), and 90 (▲) days.

Figure 9

FaSSIF mini-dissolution curves for haloperidol loaded silica (left) and haloperidol HME formulation (right) showing crystalline haloperidol (♦), unstressed haloperidol formulation (●), and stressed haloperidol formulations at 30 (▪), 60 (X), and 90 (▲) days.