Mesoporous Silica: for solubility enhancement of challenging compounds
Mesoporous Silica: An Emerging Solubility Enhancement Technology
Mesoporous silica refers to any number of a variety of materials synthesised to produce a SiO2 mesoporous structure1. Mesoporous silica can be ordered or non-ordered2, 3. The former include classic structures such as SBA-15 and MCM-414, whilst the latter include novel, proprietary excipients manufactured by drug delivery specialists, such as Parteck® SLC5,6. It has been widely reported that mesoporous silica can act as a solubility enhancer by adsorbing and stabilizing active pharmaceutical ingredients (APIs) in the amorphous form within the porous network5, 6, 7, 8, 9, 10.
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Loading APIs onto Mesoporous Silica
There are various methods of loading crystalline API onto mesoporous silica, which can be grouped into three broad categories: solvent-based5, mechanical activation11 and vapour-mediated (e.g. via sc-CO2)12. Although a wide variety of methods are present in the literature; generally speaking, the solvent-based approach is most commonly employed (Figure 2). These solvent approaches can be sub-grouped into two main categories: solvent impregnation and incipient wetness. During the solvent impregnation loading approach, API is dissolved in organic solvent (thus removing any crystal lattice) and added to mesoporous silica. Adsorption of API onto the silica is then initiated through mechanical agitation or sonication of the slurry. Finally, solvent is removed, which can be achieved using a number of methods including vacuum drying, spray drying, lyophilization or rotary evaporation5, 13, 14, 15. The second approach, incipient wetness, involves the steady addition of small volumes of concentrated API solution onto the heated silica. As a result, the full amount of solvent is adsorbed into the network and then rapidly evaporated, leaving the API within the pores6, 9. Both methods result in an API-loaded silica, in which the previously crystalline API is now amorphous or molecularly dispersed. Success can then be confirmed with analytical methods such as DSC or PXRD.
Recently, efforts by mesoporous silica manufacturer Merck KGaA, Darmstadt, Germany and contract development and manufacturing company Hovione FarmaCiencia SA, Lisboa, Portugal have described the commercial-scale loading of ibuprofen onto mesoporous silica. This was achieved in a 100 kg batch using standard manufacturing equipment and to a high degree of control.
Dissolution and Bioavailability Enhancement with Mesoporous Silica
Upon contact with aqueous medium, API loaded in mesoporous silica is released. As the drug is in the amorphous form, supersaturation can be generated, which can enhance oral bioavailability6. Due to the very high energy associated with the supersaturated state, mesoporous formulations are often coupled with precipitation inhibitors, (Figure 3). This is the basis of the spring and parachute model first proposed by Guzman, and is common when considering formulations that generate supersaturation16.
In this, the mode of action of mesoporous silica is analogous to spray dried dispersions (SDDs) and hot melt extrusion (HME). However, the entire loading process can be achieved with common-place laboratory equipment and does not require expensive spray driers or extruders, this makes for a very attractive formulation option from an industrial perspective5. Furthermore, scaling of this technology is feasible and offered by commercial-scale CDMO companies.
Unparalleled Amorphous Stability
One of the potential benefits of mesoporous silica relative to alternative amorphous formulations, is the high stabilities that are achievable. This is due to the energetic favorability of the loaded system; the very small environment of the mesoporous network (so-called ‘nano-confinement’)17 and complimentary interactions (yet to be fully resolved) with the silica surfaces, which lower the free energy of the system further18. API-loaded silica can often be stored in open containers and at elevated temperatures and pressures, though this too can be API-dependent. Muller and co-workers demonstrated stability of the amorphous form at ambient and accelerated conditions for 30 different formulations of API-loaded silica, exceeding the requirements for regulatory stability studies19. This could be particularly used for compounds that have high tendency to re-crystallise (poor glass-formers)19.1, where stability problems may arise with alternative formulations such as SDDs4, 20, 21.
This is underlined in the physical chemistry of drug adsorption of APIs to mesoporous silica. Crucially, it has been shown in various scientific papers that this process reduced the types of molecular mobility associated with re-crystallization. For example, it was demonstrated how menthol could be successfully loaded onto mesoporous silica in the amorphous form due to a reduction in beta relaxation. Menthol is especially unstable in the amorphous form, with a glass transition temperature of -54.3°C, an extremely poor glass former22. This was also observed with the small molecule, ibuprofen, where nanoconfinement in mesoporous silica substantially reduced all types of molecular mobility even in the presence of elevated temperatures and moisture.
Nanoconfinement and reduction of molecular mobility make mesoporous silica the prime candidate to stabilize extremely unstable compounds, poor glass formers, in the amorphous form. Recent work by Ditzinger and Price demonstrated this application of mesoporous silica experimentally. In their study, the two poor glass formers haloperidol and carbamazepine were formulated with both mesoporous silica and polymeric amorphous solid dispersion. These formulations were then stored under accelerated stability conditions, where it was observed that both APIs remained amorphous when formulated with mesoporous silica. For HME, on the other hand, re-crystallization was observed after only one month22.1.
Summary
In conclusion, mesoporous silica is an exciting prospect to add to the formulator’s toolbox when considering poorly soluble APIs. Mesoporous silica has particular advantages in pre-clinical development due to the low capital investment requirements and relatively accessible loading method. The loading of mesoporous silica can be achieved using simple laboratory equipment and scaled to commercial batches using regular manufacturing equipment. Finally, recent developments have established mesoporous silica as a best-in-class excipient for stabilization of poor glass forming APIs. This has solidified mesoporous silica’s future as an excipient to formulate poorly soluble molecules that are challenging to stabilize with standard amorphous technologies.
Illustrative Blog Post for pharmaexcipients.com – Prepared by Merck KGaA, Darmstadt, Germany by Daniel Joseph Price. The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. — All Rights Reserved
Daniel Joseph Price is technical product manager for Merck Life Science’s SAFC(R) portfolio of solubility enhancement and sustained release excipients with profound expertise in mesoporous silica and thermodynamics of amorphous systems.
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