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42 May 2017 Tablets & Capsules The evolution of silica in drug delivery Many of the early investigations into using silica as a drug delivery material were done on novel, ordered mesoporous forms. Use of these materials to improve the dissolution of poorly soluble compounds was first reported in the 1970s [3, 4]. These original mesoporous silica materials— synthesized for use as catalysts—dif- fered from other silicas because they had ordered pore structures. The most common synthesis was an organic template upon which sil- ica was condensed to form a three- dimensional silica framework. The template was then removed by calci- nation or dissolved by organic sol- vent to create the final structure [5]. In this form, the pores were uniform, dimensionally aligned, and channel- like. Further research demonstrated that the material was useful in improving the bioavailability of poorly soluble APIs. How it works The mechanism of silica-based drug delivery is based on pore-size suppression of recrystallization. That is, after an API is loaded into the pores of amorphous silica particles, the limited space within the pores restricts the API's ability to recrystal- lize. Typically, the API is loaded into the pores using an volatile organic sol- vent. First, the API is dissolved in the solvent and that solution is loaded into the silica pores by an "incipient wetness" technique. The solvent is then removed by evaporation. To effectively suppress recrystallization, the silica must be processed under tightly controlled conditions to ensure the pores are only a few times larger than the critical diameter of the API molecule [6]. The loaded silica can then be formulated into an appro- priate dosage form. Once the drug formulation enters the gastrointestinal tract, capillary action drives water into the pores of the silica. Subsequently, the strong affinity of silica's surface for water provides the mechanism for drug release. This strong absorptive action displaces the amorphous API from the surface of the pores, which causes the API to release quickly. In this way, highly bioavailable, amor- phous forms of APIs are readily deliv- ered into the gastrointestinal tract to provide the intended therapeutic effect. To ensure silica-based solid dispersions are stable, API loading should be limited to about 40 to 50 percent. The formulation and scaleup of finished dosage forms, however, have yet to attain the optimal API loading and therapeutic efficiency. Alternatives and advances In 2012, my company and Formac Pharmaceuticals began studying how to use novel ordered mesoporous sil- ica to deliver poorly soluble APIs in humans. In one study, we succeeded in administering fenofibrate to humans in a way that improved bioavailability over that of a commer- cial formulation [7]. Ordered meso- porous silicas are the most extensively studied silicas for drug delivery, and they have demonstrated that they can enhance bioavailability. Given the promise of ordered silicas, both researchers and pharmaceutical com- panies have continued to develop sil- ica-based products and to investigate techniques for using silica as a plat- form for drug delivery. There is also an alternative silica- based drug delivery method that works with current compendial "non- ordered" silica excipients. Success with this technology requires judi- ciously selecting the properties of the compendial silica and carefully engi- neering the particles. Since the pores of these materials are non-ordered and random, tight control of the porosity during manufacture is key to ensuring these excipients can enhance an API's bioavailability. The flexibility of the process used to manufacture non- ordered silica makes that possible. As a result, these silicas enable formula- tors to create stable amorphous dis- persions for a majority of poorly solu- ble APIs and API candidates. My company's SilSol technology is one means of producing these excipients [8]. The process synthe- sizes silica gel (silicon dioxide, NF) to create particles of various sizes that all have tightly controlled intra- particle pores. The benefit of SilSol technology is that it takes advantage of a portfolio of readily available and well understood compendial silicas. These excipients are available for use in oral pharmaceutical dosage formu- lations in order to enhance the solu- bility of BCS II compounds. As technologies that use compen- dial silica excipients advance, formu- lators will have access to potentially expedited approaches to bioavailabil- ity enhancement. And, as formulators gain more experience with these techniques and products through clinical trials, new tools for creating solid dispersions may emerge and mature, thus creating more efficient drug products and dosage forms. Figure 1 Solid dispersion of 20 percent intraconazole with non-ordered silica (SilSol) improves API solubility and storage stability % API Spout 0 20 40 60 80 100 120 70 60 50 40 30 20 10 0 Pure API 20% w/w intraconazole/SilSol 6m; 25/60; open 6m; 25/60; closed