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Microwave assisted nanonization of poorly water-soluble curcumin Nayak P. Aditya, Ian E Hamilton, John Noon, and Ian T. Norton ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b06377 • Publication Date (Web): 11 May 2019 Downloaded from http://pubs.acs.org on May 12, 2019
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ACS Sustainable Chemistry & Engineering
Microwave assisted nanonization of poorly water-soluble curcumin
Nayak P Aditya*, Ian E Hamilton., John Noon., Ian T Norton School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
N.P Aditya: School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Ian E Hamilton: Global Snacks Discovery and Disruption PepsiCo, R&D , Beaumont Park, 4 Leycroft Road, Leicester, LE4 1ET, UK John Noon: School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Ian T Norton: School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
*Corresponding Address: School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Telephone: +44 (0) 121 414 5296. E-mail:
[email protected] 1
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Abstract Nanonization is a technology that is often used to enhance the aqueous solubility and thus improve bioavailability of poorly soluble molecules.
This improvement in
bioavailability is due to change in physico-chemical properties such as surface/volume ratio, wettability etc. In this work, material specific coupling and volumetric heating properties of microwaves was utilized to achieve a high degree of supersaturation and nucleation by rapidly and uniformly evaporating the solvent from the binary mixture of solvent and anti-solvent. This resulted in the formation of nanosized curcumin nanoparticles suspended in the anti-solvent. Nanonization resulted in the formation of curcumin nanoparticles which were ~160 nm size. The spherical shape of nanoparticles was visually confirmed by Scanning Electron Microscopes. By applying this approach, we managed to convert large polydispersed curcumin crystals into nanoparticles with considerably decreased crystallinity. This was demonstrated by the decrease in the curcumin’s characteristic sharp peaks in the spectral line from 10–30° (2θ) in the XRD studies and reduced enthalpy of melting as observed by DSC studies. As a consequence of this increased bioavailability of curcumin, it potentially increases its use in both food and pharmaceutical products and should lead to a step change in the development of sustainable nanotechnology for food and pharmaceutical application.
Key Words Supersaturation, nucleation, dielectric heating, food, drug
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ACS Sustainable Chemistry & Engineering
Introduction In pharmaceutical industry, more than 50% of the drug compounds under development have poor water solubility1, 2. Similarly, food bioactives such as polyphenols and flavonoids (e.g. curcumin, quercetin etc.), which are known for their health promoting and disease-preventing activities, also lack the desired solubility within aqueous media3. Low aqueous solubility results in low oral bioavailability, bioaccessibility and toxicity4, 5. Thus, developing a novel strategy to overcome the problem of poor aqueous “solubility” is of the utmost importance for both the food and pharmaceutical industries. Reduction in particle size (nanonization) provides a wide scope to overcome solubility limited bioavailability by altering their physico chemical properties such as surface/volume ratio, wettability and polymorphism6, 7. For example, according to Noyes-whitney equation, increasing surface/volume ratio has the potential to enhance the dissolution velocity and apparent solubility by decreasing the diffusion distance between particle surface and surrounding water (hydrodynamic boundary)
8, 9.
Similarly, according to the Kelvin equation, conversion of crystalline particles into amorphous particles during nanonization increases the dissolution velocity of the compound more than crystalline particles due to an increase in surface energy (Gibbs’ free energy) and a more random arrangement of molecules or atoms 10. This increase in solubility results in proper mixing of compounds with gastro intestinal fluids in the Gastro Intestinal Tract (GIT). This enhances their absorption, which leads to enhanced bioavailability. Thus, to obtain maximum benefit, in terms of oral bioavailability, a particle needs to be nanosized (~200nm), monodispersed and amorphous 11, 12.
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Nanonization can be achieved either by a top-down approach (e.g. high pressure homogenization, microfluidization, media milling etc.) or bottom-up approach (e.g. precipitation using an anti-solvent; precipitation using supercritical fluids and precipitation by solvent removal)
13, 14.
However, between these two approaches,
bottom-up approach allows to obtain the nanosuspensions, which are monodispersed and nanosized, because, it allows to build the particles from the molecular level15. In addition, top-down approach is associated with drawbacks such as limited size reduction capacity, formation of crystalline particles, long processing time and residual metal contamination 9, 16. That said, even currently established bottom-up approaches lack control over key phenomenon such as degree of supersaturation, nucleation and crystal growth that control particle characteristics such as size, shape etc.,
12, 13, 17, 18.
This compromises
the quality of the formed particles, for example, size, polydispersity, size distribution and physical stability. In general, for currently established bottom-up approaches that are widely referred to as precipitation methods, solvents are evaporated using conductive (thermal) heating (e.g., evaporative crystallization, anti-solvent (non-solvent) evaporation). However, most of the solvents and anti-solvents e.g. water, ethanol, ethyl ether etc., which are used to precipitate solutes (actives) have low thermal conductivity (diffusivity)19. This lower diffusivity makes it difficult to obtain high degree of supersaturation and nucleation. This leads to the formation of substandard nanosuspensions which have a high degree of polydispersity and instability. Furthermore, these approaches are associated with scalability and toxicity issues e.g. metal contamination from instruments during sonication12. Therefore, the development of scalable, nontoxic and
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environmentally friendly nanonization technology via a bottom-up approach is highly desirable. Herein, for the first time, under vacuum condition, volumetric and material specific heating properties of microwave has been tactically investigated to fabricate the nanosuspensions of poorly water-soluble compounds by anti-solvent precipitation technique. Such process involves dissolving the solute (hydrophobic compound) in the solvent (e.g. ethanol) and adding this solvent to anti-solvent (e.g. water) in which the solvent is miscible but solute is insoluble. Subsequently, solvent is evaporated swiftly and uniformly from the binary mixture of solvent and anti-solvent under vacuum condition by utilizing the specific microwave-coupling ability of dielectric heating to a specific polar solvent (e.g., ethanol has favourable dielectric properties over water such that it can be selectively heated during dielectric heating)
20-23.
This
has led to the high degree of supersaturation and nucleation, which finally resulted in the formation of stable, monodispersed and nanosized particles that are suspended in anti-solvent as nanosuspensions. The process is exemplified using a model poorly water-soluble compound curcumin. Curcumin has been chosen because it can be considered both as a bioactive to use in food products and also as a drug compound to treat diseases 5, 24, 25. In addition, it can be classified under BCS class II compounds due to its physicochemical properties. For example curcumin has MW
