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.
Highlights
The increasing prevalence of poorly water-soluble drugs has driven the field of pharmaceutical technology to develop modern approaches for formulation development
The appearance of mesoporous silica formulations remained consistent over the duration of the 3 month study
It has been demonstrated that mesoporous silica can be used to successfully stabilize compounds of poor amorphous stability that are unsuitable for formulation in standard polymer-based amorphous solid dispersions
Summary
The increasing prevalence of poorly water-soluble drugs has driven the field of pharmaceutical technology to develop modern approaches for formulation development. A well-established technique is to formulate the drug in an amorphous form, which results in an increase in apparent solubility, dissolution performance, and subsequent oral bioavailability [1,2]. Such an approach comes with difficulties related to thermodynamic instability of the amorphous state, which can lead to recrystallization and negation of the aforementioned formulation advantages [3]. The classification was developed for undercooled melts, which can be directly related to hot melt extrusion (HME), it has proven to be accurate for solvent evaporation processes as well [7] This is a relevant consideration for mesoporous silica systems, given that drug loading is driven by solvent penetration into pores and subsequent evaporation [8]
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