Pharmaceutical nanotechnology
Flavonoid nanocrystals produced by ARTcrystal®-technology

https://doi.org/10.1016/j.ijpharm.2014.11.008Get rights and content

Abstract

ARTcrystal®-technology is a novel technique for a more efficient production of nanocrystals. It consists of a high speed stirring (HSS) step as pre-milling and subsequent high pressure homogenization (HPH) at reduced pressure and cycle numbers. In this study, three antioxidants, rutin, hesperidin and apigenin, were processed by ARTcrystal®-technology, the results were compared to sizes obtained for the production of nanocrystals produced by classical HPH. By using the ARTcrystal®-process, all three substances could be transformed into nanosuspensions with mean sizes and PdIs of 431 nm/0.27, 717 nm/0.21 and 262 nm/0.31, respectively. Depending on the properties of the raw material the ARTcrystal®-technology revealed similar or even better results than classical HPH. Further optimization of the setup of the HSS process might lead to an optimized process with higher efficacy than classical HPH.

Introduction

Flavonoids, e.g., rutin, hesperidin and apigenin possess many positive biological effects. They scavenge reactive oxygen species, such as hydroxyl radicals and superoxide radicals, thus preventing biological and chemical substances from oxidative damage. These radicals can come into existence by UV-radiation. Furthermore, rutin has antiplatelet, antiviral and antihypertensive effects (Ghiasi and Heravi, 2011). Flavonoids have a light tumor growth inhibition potential (Deschner et al., 1991). Due to their manifold benefits, flavonoids have a great potential for supporting various disease treatments, thus being interesting substances in the pharmaceutical and nutraceutical field. However, a limiting factor is their poor solubility, restricting their full antioxidative potential as well as their bioavailability. To overcome this problem the solubility of the actives needs to be increased.

During the last decades different ways to enhance the solubility of poorly soluble actives were developed. Examples are soluble drug salts, co-solvents or cyclodextrins (Frömming and Frömming, 1993). However, one of the most successful methods is the production of nanocrystals. Nanocrystals consist of 100% pure drug, only being stabilized by a small amount (1–2% (w/w)) of stabilizer and possess a mean crystal size below 1000 nm, typically between 200 and 500 nm (Keck and Müller, 2006). In contrast to larger crystals, nanocrystals possess a higher curvature. According to the Ostwald–Freundlich equation, this leads to a higher dissolution pressure and thus to a higher kinetic saturation solubility (Wu and Nancollas, 1998). Furthermore, nanocrystals possess a larger surface area. Thus, according to the Noyes–Whitney equation this leads to an increased dissolution velocity. Finally, the greater surface-to-mass ratio enables mucosal adherence of nanocrystals, allowing them to stay in the upper parts of the gastrointestinal tract until complete dissolution is ensured. As a consequence, the possibility of a fast gastrointestinal passage and fecal elimination of undissolved crystals is reduced and bioavailability is increased (Müller et al., 2011). In fact, the production of nanocrystals is the most elegant way to overcome poor solubility and to increase to bioavailability of poorly soluble actives.

There are two main approaches of nanocrystal production, the bottom-up and the top-down approach. While the bottom-up process focuses on in situ forming of nanocrystals by precipitation, top-down processes produce nanocrystals by grinding large crystals into the nanoscale. Common top-down techniques are high pressure homogenization (HPH) and bead milling (Müller et al., 2011). Newer processes combine a pre-treatment step with subsequent HPH. Examples are freeze drying and HPH or bead milling and HPH (Salazar et al., 2014). These combination techniques aim at achieving smaller crystal sizes.

Recently another combination process was introduced. This process is called the ARTcrystal®-technology and aims at a faster and more economic nanocrystal production compared to traditional top-down techniques. It combines an effective rotor–stator high speed stirring (HSS) process with subsequent HPH at reduced numbers and cycles (Keck, 2011). Recent studies investigated the major process parameters of the HSS process, such as in process temperature and HSS pretreatment efficacy depending on raw material properties (Scholz et al., 2014) for the flavonoid rutin.

To further prove the efficacy of the ARTcrystal®-technology, this study aimed at investigating the efficacy of the HSS process in comparison to the classical pre-milling step of HPH and to apply the method to different materials, i.e., to other flavonoids with different physicochemical properties. Finally, it was aimed at comparing the results obtained by ARTcrystal®-technology to the results obtained by classical HPH.

Section snippets

Materials

Coarse rutin (Art.-No. 907861) and jet-milled rutin (Art.-No. 900313) were purchased from Denk Ingredients, Munich, Germany. Apigenin and hesperidin were purchased from Exquim, S.A., Barcelona, Spain. As stabilizer Plantacare® 2000 (decyl glucoside, BASF, Ludwigshafen, Germany) was used. Distilled water was obtained from a WDA 25 distillation unit (QVF PILOT-TEC, Jena, Germany). All other chemicals were used as received.

Methods

In the first part of the study, the efficacy of the high speed stirring

Comparison of diminution efficacy of high speed stirring (HSS) vs. classical pre-milling

Classical pre-milling was performed by rendering a coarse rutin suspension with a rotor–stator pre-mixing step (39,000 rpm, 1 min) and subsequent HPH (2 cycles at 250 bar, 5 cycles at 500 bar). ARTcrystal®-technology was applied by applying HSS for 5 min at 24,000 rpm, followed by 5 cycles of HPH at 500 bar. The results obtained are shown in Fig. 1.

HSS was found to be more efficient than the classical pre-mixing. Whereas the HSS led to a suspension with a d(v) 0.50 of 3.68 μm and a d(v) 0.99 of 28.6 μm (

Conclusion

ARTcrystal®-technology combines HSS as pre-treatment step and HPH at reduced pressures. In this study, the HSS pretreatment step of the ARTcrystal®-technology was shown to be more effective than the classical pre-milling, typically applied for HPH. By applying the ARTcrystal®-process different flavonoid nanosuspensions could be produced. Particles obtained possess lower PdI values and mean sizes similar or smaller to suspensions produced by classical HPH. Similar to HPH, the diminution efficacy

Acknowledgement

This project was supported by “Zentrales Innovationsprogramm Mittelstand” (ZIM), Förderkennzeichen: KF2161906CS2.

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