Wednesday, 02 July 2014 00:00

Nanocrystals - from fast dissolution and improved solubility to controlled release applications

Written by Leena Peltonen
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SEM figure of itraconazole nanocrystals stabilized by poloxamer F127 and produced by wet milling. SEM figure of itraconazole nanocrystals stabilized by poloxamer F127 and produced by wet milling.

Problems related to low oral bioavailability due to poor solubility of new drug candidates are an increasing challenge in pharmaceutical research and formulation development. One efficient way to improve solubility is the utilization of nanocrystallization techniques: pharmaceutical nanocrystals are solid drug particles covered by a stabilizer layer with approximated size typically between 100 and 500 nm. Nanocrystal studies have been conducted since the beginning of the 1990’s and the first product entered the market after 10 years of intensive research. At first, nanocrystals were utilized purely for improved dissolution, but today also controlled release applications are in use.   

 

Applications

The most important benefit with nanocrystals is the increased surface area, which speeds up the dissolution [1]. Another, but often forgotten impact is the higher saturated solubility with nanosized particles [2]. Accordingly, nanocrystals are mostly utilized for improved dissolution of poorly soluble drug materials [3]. However, during the last years utilization of nanocrystals in controlled drug release applications has been studied more and more [4]. Controlled release with nanocrystals can be reached for example by tailoring the particle size of very poorly soluble drug material or by attaching nanocrystals inside a matrix structure.   

Production 

Nanocrystals can be produced by top-down methods, e.g. milling or high-pressure homogenization of larger particles or by bottom-up techniques, e.g. building up larger particles molecule by molecule. In our research group we are mainly producing nanocrystals by wet ball milling [5], though we have also utilized anti-solvent precipitation in some studies [4]. In our laboratory, we have the capability to produce small scale batches containing drug material from 100 mg to 8 g.

Challenges

Often nanocrystals are easy to produce, and instead the stability and state after further processing  are the main challenges [6]. The smaller the nanocrystals are, the higher their tendency for aggregation. Another challenge is to successfully turn the in vitro enhancement in drug release to improved bioavailability in vivo [7].  The selection of stabilizer is also a crucial step, as well as the overall composition of the formulation.

Future work

The research with nanocrystals in Helsinki is mainly focused in two areas: 1) interactions between the drug and stabilizer material in order to rationalize the selection method for a successful stabilizer for a certain drug, and 2) the role of stabilizer in improving the bioavailability of nanocrystalline formulations. 

References

[1] Sarnes, A., Østergaard, J., Smedegaard Jensen, S., Aaltonen, J., Rantanen, J., Hirvonen, J., Peltonen, L. (2013). Dissolution study of nanocrystal powders of a poorly soluble drug by UV imaging and channel flow methods. European Journal of Pharmaceutical Sciences, 50, 511-519.

[2] Peltonen, L., Hirvonen, J., Laaksonen, T. (2013). Drug nanocrystals and nanosuspensions in medicine. In Handbook of Nanobiomedical Research, Vol. 1, Materials for Nanomedicine, Ed. Torchilin, V., World Scientific Publishing Company, 2014.

[3] Santos, H.A., Peltonen, L., Limnell, T., Hirvonen, J. (2013). Mesoporous materials and nanocrystals for enhancing the dissolution behavior of poorly water-soluble drugs. Current Pharmaceutical Biotechnology, 14, 926-938.

[4] Valo, H., Arola, S., Laaksonen, P., Torkkeli, M., Peltonen, L., Linder, M.B., Serimaa, R., Kuga, S., Hirvonen, J., Laaksonen, T. (2013). Drug release from nanoparticles embedded in four different nanofibrillar cellulose aerogels. European Journal of Pharmaceutical Sciences, 50, 69-77. 

[5] Tuomela, A., Liu, P., Puranen, J., Rönkkä, S., Laaksonen, T., Kalesnykas, G., Oksala, O., Ilkka, J., Laru, J., Järvinen, K., Hirvonen, J., Peltonen, L. (2014). Brinzolamide nanocrystal formulations for ophthalmic delivery: reduction of elevated intraocular pressure in vivo. International Journal of Pharmaceutics, 467, 34-41.

[6] Peltonen, L., Hirvonen, J. (2010). Pharmaceutical nanocrystals by nanomilling: critical process parameters, particle fracturing and stabilization methods. Journal of Pharmacy and Pharmacology, 62, 1569-1579.

[7] Sarnes, A., Kovalainen, M., Häkkinen, M.R., Laaksonen, T., Laru, J., Kiesvaara, J., Ilkka, J., Oksala, O., Rönkkö, S., Järvinen, K., Hirvonen, J., Peltonen, L. (2014). Nanocrystal-based per-oral itraconazole delivery: superior in vitro dissolution enhancement versus Sproranox® is not realized in in vivo drug absorption. Journal of Controlled release, 180, 109-116. 

PSSRC Facilities

The nanocrystallization research group in Helsinki headed by docent Leena Peltonen has strong know-how in physicochemical characterization of nanocrystals and systematic understanding of process parameters on the milling outcome. We are mainly studying the milling process for nanocrystal production. Recently, we have started studies with impact of different stabilizers on cell uptake and permeability properties and we are utilizing some new techniques, like CARS, in co-operation with Professor Clare Strachan in this research area.  

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