One of the primary bioavailability challenges is low solubility of the drug molecule. Currently several technologies are available to address the issue of low solubility, including surfactants, nano-milling, solid dispersion, hot-melt extrusion, cyclodextrins and lipidic formulations. However, there is no ‘one size fits all’ solution. H. Leonhard Ohrem and roger Weibel, Merck Millipore, describe how the company's innovative material can improve bioavailability
SEM picture of bimodal porous silica showing macropores (approx. 2µm) and mesoporous surface
H. Leonhard Ohrem and Roger Weibel, Merck Millipore, describe how the company’s innovative material, Silver winner in the CPhI Pharma Awards, can improve the bioavailability of poorly-water soluble APIs
The pharmaceutical industry is facing a serious issue: a shortage of new drugs. Existing patents are expiring and therapeutic pipelines are shrinking as more and more drug candidates fail during development phases. Approximately 40% of the failure can be attributed to poor bioavailability.
One of the primary bioavailability challenges is low solubility of the drug molecule. To put this into perspective, take marble, which is commonly considered insoluble. Marble has a solubility of approximately 14µg/ml (CaCO3). A typical drug such as itraconazole is 14,000 times less soluble. Today, developers have to deal with such low solubilities in more than 90% of all projects.
There is no 'one size fits all' solution
Currently several technologies are available to address the issue of low solubility, including surfactants, nano-milling, solid dispersion, hot-melt extrusion, cyclodextrins and lipidic formulations. However, there is no ‘one size fits all’ solution. Every tool has its strengths and weaknesses. And for each and every drug, the approach and desired outcome is unique. As a result, many solubility problems in early drug development remain unsolved, leading to high failure rates.
Porous silica has been used in chromatography and for catalysis purposes for many years. Its use as a drug carrier was described as early as the 1980s.1 Scientific interest in this application has grown in recent years and much has been published on the use of ordered mesoporous silica.2,3
Materials such as SBA-15 (Santa Barbara Amorphous-15) or MCM-41 (Mobile Compo-sition of Matter-41) are pure silicon dioxide particles containing mesopores in an ordered structure. According to the International Union of Pure and Applied Chemistry (IUPAC), mesopores are defined in a size range of 2–50nm. Smaller pores are called micropores, which are too small to be accessible for drug molecules, and larger pores are defined as macropores. Mesopores provide a large internal surface area to material – more than 1000m²/g are possible. This area offers space for the drug molecule to be adsorbed and is crucial for the drug loading capacity.
The challenge is making this surface area accessible to a drug molecule. This is where Merck Millipore’s award winning silica innovation comes into play. The Roman Coliseum can be used to illustrate the problem-solving concept leveraged through this technology. This historic building does not contain many seats, but its open spaces and design allows people to get in and out smoothly and quickly: 50,000 can enter or leave in approximately five minutes).
Drawing on vast experience in silica engineering for chromatography combined with a deep knowledge of pharma, Merck Millipore has designed new, bimodal porous silica. The particles contain mesopores for a large surface area (around 1000m²/g) and additional macropores with a size of approximately 2µm for good access to the surface. Figure 1 shows a SEM image of this structure.
The result is an innovative material, but not a 'novel excipient'
The result is an innovative material, but not a ‘novel excipient’. This is an important distinction since the latter would lead to extraordinary regulatory efforts to register a final drug product. Chemically, the material refers to a monographed pharmaceutical excipient with GRAS status (generally regarded as safe). Such amorphous silica has been used in oral applications for decades.4 It is known to be very inert to the body and chemically compatible with most drug molecules (APIs). This leads to very high chemical and regulatory acceptability.
Application tests with a variety of poorly water-soluble drugs such as fenofibrate, ketoconazol, itraconazole, felodipine and others were performed. The drug is dissolved in organic solvent and then loaded onto the surface of the silica particles. After the solvent is completely removed, the drug substance remains on the surface in its amorphous state.
The better soluble amorphous state is one key factor for improved solubility. Therefore, the loading process is optimised to achieve this status. However, examples have shown that bimodal silica particles with the API loaded in its crystalline state also successfully enhanced the solubility of the drug. Drug loads of approximately 30% w/w could be achieved.
After loading, the performance of the loaded carrier was measured during in vitro dissolution tests according to the standard pharmacopoeial methods. The performance is benchmarked against a marketed drug with the same API strength and pure micronised API.
Figure 2: Comparison of in vitro dissolution results of API loaded bimodal silica (blue line; 30% drug load) with marketed drugs (TriCor 48mg, LipidilTer 160mg) and micronised pure fenofibrate (testing conditions: 900mL Fed State Simulated Intestinal Fluid (FeSSIF), USP II apparatus at 75 rpm, 37±0.5°C)
Figure 2 shows a case study with fenofibrate, where the loaded silica exceeded the dissolution performance of the marketed drug, which used other solubility enhancement techniques. The large surplus of dissolved drug compared with the pure micronised crystalline fenofibrate is due to supersaturation.
The same effect was observed in other case studies. Bimodal silica either matched or exceeded the performance of marketed drugs in vitro. However, the only reliable measurement of a drug’s bioavailability can be performed in vivo. Therefore, pharmacokinetic studies have been carried out in rats, comparing the loaded silica with marketed drug and pure crystalline drug. Again, the loaded silica could match or exceed the respective performance measured as AUC (area under the curve).
Another important aspect of drug development is stability. Both the amorphous state of the drug and the chemical stability of the API are critical. To achieve this, stability testing for the loaded bimodal silica was performed according to ICH guidelines. Storage conditions ranging from refrigeration to accelerated conditions (40°C, 75% relative humidity) in closed vials were used. Frequent measurements of the crystallinity (by XRD and DSC), chemical purity and dissolution performance have shown perfect stability for a period of six months. This is particularly remarkable in view of the low melting point of fenofibrate (79°C), which makes the stability of the amorphous state at storage conditions of 40°C rather unlikely.
The loaded silica was tested as a granulate (particle size 5–25µm) and also as a tablet formed with Parteck ODT in direct compression. Dissolution tests with such a tablet (640mg) showed no significantly different dissolution behaviour when compared with the granules.
Dr Leonhard Ohrem, Portfolio Manager, (left) and Roger Weibel, Head of Bioavailability Enhancement, Pharm Chemicals Solutions, Merck Millipore
In summary, bimodal silica is a very promising drug carrier for bioavailability enhancement of poorly-water soluble drugs. Improved performance was shown for numerous APIs in both in vitro and in vivo studies (data not shown). Such a material is now available in GMP quality from the world’s largest producer of high performance silica for chromatography.
This will benefit development projects of new chemical entities (NCEs) facing solubility problems. As the loading procedure is based on organic solvents, this NCE should be soluble in and compatible with an organic solvent. The application study can take place in an early preformulation phase or in the development of final formulation of the new drug development. As more drug patents expire, reformulation of currently marketed drugs will greatly enhance lifecycle management. With bimodal silica as a new formulation tool many drug molecules will have the opportunity to be repositioned.
Bimodal silica will also be a game-changer for the pharmaceutical industry
Bimodal silica will also be a game-changer for the pharmaceutical industry as this new tool can be used to recover former drug candidates which failed due to low solubility.
It is not enough just to develop a technology. Application and regulatory support are essential. Feasibility studies with customers are offered that include API optimisation of the loading procedure, tailoring the silica structure, characterisation of the loaded silica and performance tests of the dissolution behaviour in vitro.
This allows access to first-hand experience in the loading procedure and the full range of silica modification competence and speeds up the development process. Support in the final formulation of the tablet is offered. For the registration process, the DMF and CEP filing of the excipient are very helpful to speed up the time to market of a new formulation. Merck Millipore provides all these services along with EMPROVE, which offers customers full regulatory documentation and support.
1. Unger K. Rupprecht H. Valentin B. Kircher W. Drug Development and Industrial Pharmacy (1983) 9:1-2 (69-91).
2. Van Speybroeck M. Barillaro V. Thi T.D. Mellaerts R. Martens J. Van Humbeeck J. Vermant J. Annaert P. Van Den Mooter G. Augustijns P. Journal of Pharmaceutical Sciences (2009) 98:8 (2648-2658).
3. Shen S.-C. Ng W.K. Chia L. Dong Y.-C. Tan R.B.H. Journal of Pharmaceutical Sciences (2010) 99:4 (1997-2007).
4. Morishige T. Yoshioka Y. Inakura H. Tanabe A. Yao X. Tsunoda S. Tsutsumi Y. Mukai Y. Okada N. Nakagawa S. Pharmazie (2010) 65:8 (596-599).