Eye on Excipients: The Silica Solution

Silica is well known in the pharmaceutical industry as an excipient. While pure silica, SiO2, is common, there are silicates of calcium, magnesium, and aluminum that are widely used as anti-caking agents, glidants, opacifiers, and viscosity modifiers. These silicas are considered bulk solids and come in many forms, including flakes, pellets, granules, and even nanoparticles. There is another class of silica excipients that are of interest in pharmaceuticals: porous silica (poSi). 

PoSi, as the name implies, is simply silica that has some level of pores throughout the solid body. These poSi materials are typically categorized by pore size, where silica with pores of less than 2 nanometers (nm) are considered microporous, and silica with pores 2 to 50 nm are mesoporous, and when the pores exceed 50 nm, they are called macroporous. Sometimes the bulk of these three categories are more generally called “nanoporous,” which indicates pores smaller than 100 nm. The pore size, as well as the level of porosity, are important to the silica’s functionalization and applications. 

Applications in Product Identification 

Pharmaceutical and nutraceutical companies have focused on product identification (PI) to reveal and deter counterfeiting and product diversion. This is done through track-and-trace technologies. To date, the majority of PI has been at the package level, using barcodes, holograms, and other proprietary security features on the bottle or printed on the label. However, because packaging has proven to be relatively easy to counterfeit, there is great interest in using a PI technology at the dose (tablet, capsule) level. For dose-level PI, companies have relied on composition-measurement technologies, which seek to determine what is in the dose under examination. 

Oftentimes, however, there is no way to confirm the production details (lot number, date of manufacture, location of manufacture) nor to identify diverted products in a case of goods in which authentic drug products are discovered in unexpected or unsanctioned channels or territories. Because of the limitations of current package-level and dose-level identification, and industry demand for more advanced dose-level solutions, the FDA published a Guidance in 2011 on incorporating on-dose anti-counterfeiting technologies, referred to as physical chemical identifiers (PCIDs), for use in solid oral dosage forms (SODFs)¹. 

The approach outlined in the Guidance is to introduce a trace amount of an inactive ingredient to an SODF product so it can be detected to authenticate the product and thus identify counterfeits. This Guidance has helped to accelerate the development of poSi-based materials and technologies. SiO2 is affirmed as Generally Recognized as Safe (GRAS) by the FDA, so it is considered edible and can be added at substantial levels (2 percent w/w, according to the FDA). 

Moreover, as noted above, silica has been used extensively in the pharmaceutical and nutraceutical industries, so it is well-accepted as a common excipient, making these poSi particles excellent candidates for use in pharmaceutical and nutraceutical products as unique identifiers. 

Optical microtags are a promising poSi PCID technology that has recently been developed. These are fabricated using a silicon wafer anodization technique that is well understood and, therefore, allows for easy control of the formation of poSi materials on a large scale. And because they are manufactured from high-purity, semiconductor-grade silicon wafers, the impurity profile is similarly well understood and controlled, typically within the low ppm or ppb level. 

Microtag identification technology is based on fundamental optical filter technology. The pores can be etched into the silicon wafer in such a way that, when illuminated by white light, a specific, pre-selected optical reflectance peak (color) results. This specific color reflectance can easily be discerned by a spectrometer, or even your eye. The entire wafer surface is etched identically, after which the surface layer is removed and broken into fine particles, thereby producing millions of microtags from each etched layer, with each of those micro-particles reflecting the same color pattern. 

As you can imagine, a single color of reflected light is not particularly secure since one could use any material with a unique color reflectance (e.g., glitter) and replicate that effect. The poSi microtag security feature comes from other elements of the poSi product, whereby multiple reflectance peaks—from ultraviolet to infrared—are etched into the microtags, thereby creating a unique, multicolor, optical “signature.” 

This feature is analogous to the number of bits in encrypted data. The more bits there are, the more combinations exist and the more difficult it is to crack the encryption. Depending on the level of security needed for a given application, you can specify the number of color reflectance peaks the microtag will include. In addition to the optical peaks encoded in the poSi microtags, other characteristics of the reflectance (optical spectrum, amplitude, dispersion), as well as the application (location, density) can be included to provide multiple levels of security, making this technology virtually impossible to counterfeit. 

The application of the optical microtags to SODF products is done using existing methods, such as pan coating for tablets and blending and encapsulation for capsules. Because the number of tags required to accurately verify a single dose is low, there is virtually no impact on the product’s manufacturing process, dosage form, function, or elegance. 

• For pan-coating applications, the microtags are blended directly into the tablet’s outer coating formulation for integration via the spray coating process. 
• For addition to capsules, the microtags are blended into the formulation just prior to encapsulation and are filled directly into the capsules. 

These microtags are covert, can be incorporated into or onto SODF products as well as bulk powder products, and their use levels are far less than 1 percent, making them easy to integrate into existing products and processes while remaining cost-effective for the manufacturer. Furthermore, because each batch or lot of SODF products can have a unique signature, and because the microtags on secured products can be scanned and decoded in seconds, countermeasures can be initiated immediately. This can prevent potentially harmful counterfeit products from reaching consumers and allow law enforcement to more quickly identify the perpetrators. 

The development of these optical microtags using excipient-grade silica provides a low-cost, highly secure on-dose identification solution. It offers manufacturers a new tool to combat the pandemic of pharmaceutical counterfeiting and diversion, and protects patients from potentially tragic consequences. 

Application to Drug Delivery 

Enhancing the solubility of APIs 

PoSi has been shown to improve oral bioavailability of poorly water-soluble APIs. Because oral administration is a preferred method of drug delivery, it is critical that APIs achieve systemic absorption when ingested. That means it must be present in solution in the gastro-intestinal tract so it can be absorbed by the intestinal walls. Unfortunately, many APIs have low solubility in water, which poses a significant challenge to making it available for absorption. By depositing such APIs onto poSi particles, it is possible to improve the dissolution rate of many of these low-solubility molecules. 

Intercellular nanoparticles

Mesoporous silica nanoparticles are another area of interest because they can be taken in by individual cells through endocytosis, and deliver their payload there. The benefits of such delivery are potentially huge since the particles, once inside the cell, can be functionalized to target specific cellular organelles. These materials are typically introduced into the bloodstream by intravenous injection. While functionalizing poSi at a nanoparticle level is still an immature technology, it holds tremendous promise in applications such as antitumor therapies. 

Sustained delivery

Mesoporous silica particles have also been used in sustained-release drug delivery applications. Benefits of sustained drug delivery include significantly less frequent treatments, which can reduce costs and risks from treatment complications, especially when drug products are administered by injection. In sustained-release applications, the poSi particles are loaded with one or more APIs, which adsorb on the outer surface and the internal pore surfaces. The API release profile is affected by the balance between surface adsorption and how the API molecule interacts with the dissolution medium. The stronger the adsorption to the surface, the slower the release. Some studies have shown that the release, or elution, profile follows a well-known model defined by the Higuchi equation.

Others have shown a two-step elution profile, whereby there is an initial release burst followed by a slower release profile. The initial elution burst is thought to come from API molecules that are adsorbed on the outer particle surfaces and the near-surface regions of the pores, where the dissolution medium can reach the API relatively unobstructed. Then, as the near-surface API material dissolves, the dissolution medium must diffuse further into the nanometer-scale pores to reach more API molecules, thus hindering dissolution and reducing the rate of elution. 

One promising application is treating age-related macular degeneration (AMD), which affects an estimated 11 million people in the USA and is the leading cause of irreversible blindness and visual impairment in the world. Current treatment regimens require intraocular injections about every 4 to 8 weeks. With each injection comes a level of pain and discomfort, as well as injection-related risks such as endophthalmitis and retinal detachment.

Unfortunately, because the treatment only retards further vision degeneration while the API is present, treatments must be continued indefinitely to prevent further deterioration. It’s not surprising that patient compliance is a challenge, as is the impact on the ophthalmologists who administer the treatments. 

Available solutions

At TruTag Technologies, we have developed state-of-the-art, cGMP-compliant poSi manufacturing lines to fabricate optical microtags for product identity and precision micro-particles for sustained drug delivery. For product identity, we combine our silica microtag technology with our proprietary optical readers to create a fully integrated solution for pharmaceutical and nutraceutical manufacturers to use in combating drug product counterfeiting and diversion. And we are now partnering with a drug delivery biotech firm to use our poSi micro-particles to address the growing AMD treatment market.

Conclusion 

Silica as an excipient has been around for decades in food and pharmaceutical products that we consume every day. With new, advanced technologies being developed in silica material technologies, many new and exciting tools are being created for addressing major challenges such as counterfeiting, product diversion, therapy effectiveness, and patient compliance. 

Reference 

1. Guidance for Industry: Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting. October 2011.