Introduction

Methyl jasmonate (MeJa) is produced at various growth stages of plants, in general, in response to stresses, like those found in the soil by the growing seeds and roots, wind forces and herbivore attacks (Weiler et al., 1993). It is frequently referred to as volatile compound, likely because of its key odorant role at low levels on natural defense of plants against insect herbivores (Loftsson & Duchene, 2007), but its boiling point is approximately 220-225ºC at atmospheric pressure. Such a plant hormone has demonstrated to have an important anti-inflammatory (Dang et al., 2008), antioxidant (Wang, Bowman, & Ding, 2008), and antiparasitic activity (Ofer, Gold, & Flescher, 2008).

Despite the remarkable therapeutic properties of MeJa, its use as a drug in humans is limited by its low solubility in water; a drawback that has been at least partially solved by including MeJa in the central cavity of cyclodextrins (CDs) (Perassolo, Smith, Giulietti, & Talou, 2016). CDs are cyclic oligosaccharides comprised of 6, 7 ($\textcolor{red}{}\beta$-CD) or 8 glucose units that form a 3D toroidal structure with a hydrophobic cavity and an external surface that presents a hydrophilic nature (Alhassawi & Romero-Zerón, 2015; Loftsson & Duchene, 2007). The arrangement of hydroxyl groups and hydrogen/oxygen atoms are responsible for the opposed affinities of external and internal surfaces of CDs with water and make them especially attractive as hosts of non-polar drugs, as the MeJa. $\textcolor{red}{}\beta$-CD is cheap and commercially available with high purity, so it is usually preferred over the other CDs to form inclusion compounds with guest molecules for pharmaceutical purposes (Banchero, Ronchetti, & Manna, 2013). However, since it has relatively poor water solubility, modified $\textcolor{red}{}\beta$-CDs have been more extensively used as hosts to enhance the stability, aqueous solubility and bioavailability of the free guest (Yao et al., 2014).

2-hydroxypropyl $\textcolor{red}{}\beta$-cyclodextrin (HP$\textcolor{red}{}\beta$CD) is a water-soluble modified $\textcolor{red}{}\beta$-CD that presents low renal toxicity and hemolytic activity in humans. Based on these benefits, it is a Food and Drug Administration, FDA-regulated product that has been used to form inclusion compounds with ocular medications, for instance. As a host involved in the complexation of drugs, it also allows a controlled release of the bioactive guest to be achieved. Moreover, HP$\textcolor{red}{}\beta$CD is an additive that may increase the stability of thermolabile compounds in food or pharmaceutical products, as well as increase their shelf-life by protecting them against oxidation reactions that naturally take place during storage (Tan, Meng, Fan, Su, & Zhang, 2016). In summary, because of these many positive properties, HP$\textcolor{red}{}\beta$CD was chosen as the host to form inclusion compounds with MeJa in this study.

Many methods of complexation are available in the literature, such as grinding and co-precipitation with a variety of solvents (Junior et al., 2016), and freeze drying (Moyano et al., 1997). However, all these procedures are high energy-demanding operations that mostly use organic solvents. A promising alternative is the complexation by applying supercritical carbon dioxide (scCO₂). The scCO₂ method have some advantages and particular characteristics (i.e. liquid-like solvent power, gas-like viscosity and diffusivity, tunable physical properties, no traces of solvent in the final product, etc.) in comparison with the conventional chemical methods of complexation (Banchero & Manna, 2012; Banchero et al., 2013; Huang et al., 2016). It is not only believed to be a more efficient method when compared to the above mentioned ones (Rudrangi et al., 2015), but it also involves the use of a non-toxic solvent (CO₂), which can be easily removed from drugs or drug/cyclodextrin complexes after processing (Banchero & Manna, 2012; Banchero et al., 2013; Nerome et al., 2013), in addition it is an environmentally acceptable method because it uses a cheap substance as solvent (Banchero et al., 2013; Junior et al., 2017).

In this context, the present study aimed to evaluate the formation of inclusion compounds of MeJa with HP$\textcolor{red}{}\beta$CD by applying supercritical CO₂ (M₄) in comparison with the typical complexation methods of kneading (M₁), freeze drying (M₂) and co-precipitation + freeze drying (M₃). Spectral (H-NMR, FT-IR/ATR, FT-Raman, PAS) and thermal (TGA, and DSC) analyses were performed to confirm complexation. The 2,2 -diphenyl-1-picrylhydrazyl (DPPH) assay was also applied to determine the antioxidant activity of the free and complexed MeJa.

Material and methods

Chemicals

MeJa (purity ³ 94.5%, MW = 224.3 g moL^-1) and HP$\textcolor{red}{}\beta$CD (MW = 1380 g moL^-1) were purchased from Wacker Chemie AG (Burghaunsen, Germany). DPPH, and 6-hydroxy-2,5,7,8-tetramethylch-roman-2-carboxylic acid (Trolox) were from Sigma-Aldrich (purity ³ 90.0, Saint Louis, MO, USA). Ethanol 98% purity was from Anidrol (Diadema, State São Paulo, Brazil), and CO₂ technical grade from White Martins (Rio de Janeiro, State Rio de Janeiro, Brazil). All of them were used as received.

Complexation

M₁ (grinding method of complexation) is the simplest among the investigated methods of complexation. It basically consisted of grinding a dry mixture of MeJa (formed inclusion compounds) and HP$\textcolor{red}{}\beta$CD in a crucible for 15 min at ambient temperature and atmospheric pressure. The molar ratio of the guest to the host was unity (Junior et al., 2017).

To include MeJa in HP$\textcolor{red}{}\beta$CD by freeze-drying (M₂ - freeze drying method of complexation), a 1:1 molar mixture and 50 mL distilled water were initially added in a beaker, kept under agitation for 30 min. The dispersion was transferred to a freeze-dryer (L 101, Liotop, São Carlos, Brazil) to be lyophilized at 1.3 Pa and -54oC (temperature of the condenser) for 36 hours. M₂ was according to the procedure of complexation by freeze-drying suggested by da Rosa et al., (2013); Vajna et al., (2011).

M₃ (co-precipitation + freeze drying method of complexation) was carried out at the same molar ratio between the guest and host already assumed for M₁ and M₂ (Mangolim et al., 2014). HPβCD was diluted in distilled water, while separately, MeJa was diluted in ethanol (98% purity), making two different solutions, respectively. Both solutions were prepared under stirring at a controlled temperature of 40°C and a concentration of 1 M. Thereafter, still under stirring and separately, the solutions were cooled in a controlled manner to 25°C for 4 hours in order to visually inspect the formation of precipitates. In the rotary evaporator, the two solutions were then mixed under a stirring condition of 120 rpm and a temperature of $\approx$78°C (the boiling point of ethanol at the atmospheric pressure) for approximately 90 min. This operation promotes the formation of the MeJa/HPβCD complex. Then the complex formed is frozen and lyophilized at 1.3 Pa and -54°C for 36 hours.

M₄ (complexation of MeJa with HP$\textcolor{red}{}\beta$CD by applying supercritical CO₂) was based on analogous procedures available in the literature (Banchero et al., 2013). The pressure of the employed scCO₂ apparatus can be set up to 200 bar and enables the temperature control of the sample. In this work, the chosen operating conditions were 90 bar, 40°C, and 60 min. To avoid degradation of MeJa, the temperature of M₄ methodology was fixed at 40°C. Pressure condition set to 90 bar resulted in low density (e.g., 0.29 g cm^-3). The most soluble compounds present the essential oils are extracted using these operational conditions (Reverchon & De Marco, 2006). Such conditions were tested in a previous work and revealed to be very satisfactory in complexation of drugs with cyclodextrins (Junior et al., 2017). In summary was fed into a packed bed formed by a 1:1 molar mixture of MeJa and HP$\textcolor{red}{}\beta$CD. Stagnant CO₂ at the desired temperature and pressure was left in the bed for further 60 min. before removal by simple system depressurisation.

Spectral analyses (FT-IR/ATR, FT-Raman)

Spectroscopy techniques (FT-IR/ATR, FT-Raman) were also applied, requiring no procedure of sample preparation, to analyze the guest, host and products of complexation (i.e.; dry powder was used in these cases). FT-IR/ATR and FT-Raman spectra were recorded from commercial spectrometers, so the procedures of absorbance reading are presented in a summarized way. In particular, FT-IR/ATR spectra with 128 scans each were monitored in the wavelength range between 4000 and 400 cm^-1 at a resolution of 2 cm^-1 by using a spectrometer (model Vertex 70v, Bruker, Ettlingen, Germany) coupled to an attenuated total reflectance (ATR) cell (model Platinum, Bruker, Ettlingen, Germany). FT-Raman absorbances with 500 scans per sample at wavelengths from 4000 to 4 cm^-1 (resolution = 4 cm^-1) were instead measured with the same Vertex 70 v spectrometer equipped with a Raman module and a Germanium detector. The excitation source was a 1064 nm laser whose power could be varied from 5 to 200 mW.

Thermal analyses (DSC and TGA)

Both the responses emerged from thermal treatments of 2 mg powder samples placed in platinum crucibles taken to the furnace of a thermogravimetric analyzer (model STA 409 PC, Netzsch, Selb, Germany). The temperature of the sample was increased from 25 to 600°C at a constant heating rate of 10°C min.^-1 and under a N₂ stream of 50 mL min.^-1, respectively.

Antioxidant activity

The measured antioxidant activity (AA - antioxidant activity [%]) of MeJa in the free- and in the complexed forms (from different tested methodologies of complexation) was based on the well-known DPPH assay (Brand-Williams, Cuvelier, & Berset, 1995). It is a standard assay that involves a homogeneous reaction between DPPH as a stable free radical (0.004 mM) and the examined samples (3´10^-3 M) with ethanol as solvent. In the current case, it took place in a glass vessel, involving a mixture of 3.6 mL of the first solution and 0.4 mL of the second, under dark room conditions for approximately 1 hour. The AA of the samples was given absorbance of the reaction products was measured at 517 nm with a spectrophotometer (model UV-1203, Shimadzu, Kyoto, Japan). The control was a mixture of 3.6 mL of a DPPH ethanol solution (0.004 mM) and 0.4 mL of a Trolox ethanol solution (0.05 mM). The AA of the samples were given by Equation 1:

where:

A (absorbance of solutions of ethanol and MeJa, in a free and complexed form) and A_c (absorbance of control) are the absorbances of the samples and that of the control, respectively. All the experiments were performed in triplicate.

Results and discussion

Spectral analyses (FT-IR/ATR, FT-Raman)

The similarities between the FT-IR/ATR spectra of free HP$\textcolor{red}{}\beta$CD and those of the formed inclusion compounds observed in Figure 1a. is another indication of complexation of MeJa with HP$\textcolor{red}{}\beta$CD by the four different methods of inclusion (Sambasevam, Mohamad, Sarih, & Ismail, 2013; Yuan, Lu, & Jin, 2014).

Changes in intensity and wavenumber of some peaks in the complexes when compared to the same ones found in the free MeJa spectrum (e.g., at 1733, 2960, 1436 cm^-1), as well as the identification of absorption peaks characteristic of free MeJa in all the formed complexes (e.g.; at 1733 cm^-1) also support that the guest was included into the cavity of the HP$\textcolor{red}{}\beta$CD.

However, there are some differences between the FT-IR/ATR spectra of the inclusion compounds obtained by applying M₁-M₂ and M₃-M₄. For instance, from Figure 1a it is clear that the intensity of absorption at 3006 and 2960 cm^-1, characteristics of vibrations of = C-H and -C-H groups in the MeJa structure, are observed in the complexes obtained by applying the methods M₁ and M₂. However, they were no longer found (the one at 3006 cm^-1), or were shifted (the one at 2960 cm^-1), in the spectra of the inclusion compounds formed by applying co-precipitation + freeze-drying (M₃) and scCO₂ (M₄). This indicates the difference in the complexation mechanism between the methods M₁-M₂ and M₃-M₄.

The FT-Raman spectra of all the examined samples of free and inclusion compounds are illustrated in Figure 1b. To support complexation from these data, attention was given to changes in absorbance intensity and position of characteristics bands of MeJa at 1737, 1656 and 1272 cm^-1 also detected in the spectra of MeJa/HP$\textcolor{red}{}\beta$CD complexes.

A reliable quantitative procedure to verify whether inclusion took place, still based on FT-IR/ATR spectroscopy, involves the estimation of absorbance band areas characteristics of functional groups of the guest (Aigner, Berkesi, Farkas, & Szabó-Révész, 2012; Valentini et al., 2015). In other words, such groups are those whose bands are exhibited in the spectrum of MeJa, but not in the one of HP$\textcolor{red}{}\beta$CD. In this case, the Gaussian function (dashed lines in Figure 2) with parameters tuned on the recorded absorbance (solid lines in Figure 2) was used to describe the absorbance bands of these particular groups at 1734 and 1701 cm^-1.

Coefficients of determination (R²) close to unity corroborated the reliability of such a model, thus, in order to compute the areas, the Gaussian curves (dashed lines in Figure 2) were simply integrated. The sum of the computed areas from the MeJa spectrum (23.76 + 3.93 = 27.69 au) (Figure 2b) and those from the spectra of MeJa/HP$\textcolor{red}{}\beta$CD complexes close to the aforementioned frequencies (4.52 + 2.24 = 6.76 au; 0.85 + 0.67 = 1.52 au; 1.39 + 0.32 + 0.58 = 2.29 au; 0.41 + 0.38 + 0.11 = 0.90 au) (Figure 2, c to f) are markedly diverse. In summary, such an analysis also supports the formation of inclusion compounds of MeJa with HP$\textcolor{red}{}\beta$CD.

An additional remarkable finding from Figure 2 is that A₁ + A₂ for the free MeJa minus A₁ + A₂ for the MeJa/HP$\textcolor{red}{}\beta$CD complex by M₁ gives the lowest variation of area ($\textcolor{red}{}\approx$20.93 au) among those computed. Such a change is associated with a minor degree of complexation by grinding. Because M1 is the only inclusion method performed at mild conditions of temperature and pressure, it is naturally supposed that complexation at T and P close to normal ambient conditions does not contribute positively to include the guest into the host. The presence of a new absorbance band in the FT-IR/ATR spectra shown in Figure 2 (e and f) between 1600 and 1700 cm^-1 confirms that the more drastic conditions of T and P by M₃ and M₄ favor inclusion.

Thermal analyses (TGA and DSC)

The results of loss of mass from the TG analyses in Figure 3a are discussed in view of three endothermic energy phenomena observed in Figure 3b (DSC data) in the temperature ranges 20-110, 110-305 and 305-700oC.

For instance, the decrease in mass between 20 and 110oC is an endothermic transition due to the evaporation of compounds with low boiling point (Bruylants, Wouters, & Michaux, 2005). Water is often the most common, so such a stage is usually referred to as dehydration (Yang et al., 2013). The free CD's are often produced by crystallization with water as solvent, so their cavities present a high content of water ($\textcolor{red}{}\approx$ 8.56 %) that was completely removed when the HP$\textcolor{red}{}\beta$CD was thermally treated up to 110^oC (Frijlink, Eissens, Schoonen, & Lerk, 1990). The differences of water loss among the complexes obtained by the different methods of inclusion are basically attributed to the distinct temperature and pressures at which they were produced. For example, M₁ involved a T close to 25^oC and a P that was the atmospheric one, so almost all the water naturally found in the HP$\textcolor{red}{}\beta$CD was not removed during inclusion ($\textcolor{red}{}\approx$ 8.54%), but only when heated in the oven of the thermogravimetric analyzer.

From a rapid analysis of the loss of mass in Figure 3a from 110 to 305^oC, it is possible to infer that the free HP$\textcolor{red}{}\beta$CD is thermally stable at this temperature range, that is, the loss of mass for HP$\textcolor{red}{}\beta$CD was only 0.57%. Therefore, the higher decay of mass of formed complexes may be only associated with the boiling point of MeJa (220-225oC). This suggests that M₃ and M₄ are the best methods in terms of formation of thermally stable complexes. The highest temperature of the endothermic peak for the MeJa/HP$\textcolor{red}{}\beta$C$\textcolor{red}{}∆$ complex by M₄ (311.11 °C) supports it (see Figure 3b).

A sharp fall of mass of all the examined compounds is observed in Figure 3a by increasing the temperature of the samples above 305^oC. According to Udrescu et al., (2014), the endothermic peak for free HP$\textcolor{red}{}\beta$CD at 301.67^oC in Figure 3b could be the melting point of the host. However, the loss of mass of HP$\textcolor{red}{}\beta$CD started at this temperature, in Figure 3a, may not be explained by this phenomenon, but only by the evaporation or thermal decomposition of this compound, as it was already inferred for another cyclodextrin (Junior et al., 2017).

Antioxidant activity

Figure 4 illustrates the variation of measured AA of free MeJa and of formed complexes over time.

A first-order kinetic model given by Equation 2 was able to describe correctly the experimental results at all the examined circumstances (R² $\textcolor{red}{}\ge$ 0.97).

Such a model allows a simplified and clear view of the kinetic results because it summarizes the several kinetic data per method of inclusion in only two model parameters (k and AA_e). k is the antioxidant activity constant rate of the examined sample (min.^-1), while AA_e represents the antioxidant activity at equilibrium (%). These parameters were tuned on the measured AA reported in Figure 4 to minimize the sum of the squared residues by applying the Levenberg-Marquardt method.

A comparison among the parameters of this model for the different kinetic curves shown in Figure 4 is an accurate procedure to evaluate the effect of complexation and inclusion methods on AA in terms of kinetics and equilibrium. As may be more explicitly noticed in Table 1 than in Figure 4, there is no difference among the kinetics of AA of all the examined samples (free MeJa or complexes formed by M₁ to M₄) for a confidence level equal to 0.05.

However, except for M₁, the influence of complexation on AA at equilibrium is noticeable (Stražišar, Andrenšek, & Šmidovnik, 2008). The negligible role of complexation by grinding on AA is in accordance with previous evidences reported in the literature (Folch-Cano, Jullian, Speisky, & Olea-Azar, 2010; Stražišar, Andrenšek, & Šmidovnik, 2008). In terms of results of AA_e, Table 1 reveals that M₃ and M₄ are the best methods of inclusion among those currently considered.

Conclusion

The spectroscopy measurements demonstrated that inclusion compounds were obtained by all the considered methods, but the inclusion took place in a different way by M₃-M₄ and M₁-M₂. Because of this, the positive effect of complexation on thermal stability and AA of MeJa (analyses TGA/DSC and DPPH assay) was more markedly noticed when the complexes were formed by combining (M₃) and by applying (M₄). Although M₃ being similar to M₄, concludes that the use of cheap, non-toxic and low energy-demanding method of inclusion with scCO₂ is more advantageous than those currently considered to form complexes of MeJa with HP$\textcolor{red}{}\beta$CD.

Acknowledgements

The authors are thankful to the Brazilian Agencies Capes and CNPq, for their financial support to this work.

References

Aigner, Z., Berkesi, O., Farkas, G., & Szabó-Révész, P. (2012). DSC, X-ray and FTIR studies of a gemfibrozil/dimethyl-β-cyclodextrin inclusion complex produced by co-grinding. Journal of Pharmaceutical and Biomedical Analysis, 57, 62–67. https://doi.org/10.1016/j.jpba.2011.08.034

Alhassawi, H., & Romero-Zerón, L. (2015). Novel Surfactant Delivery System for Controlling Surfactant Adsorption onto Solid Surfaces. Part III: Oil Displacement Tests. Canadian Journal of Chemical Engineering, 93(9), 1539–1546. https://doi.org/10.1002/cjce.22231

Banchero, M., & Manna, L. (2012). The use of lysine to enhance the supercritical complexation of ketoprofen and cyclodextrins. Journal of Supercritical Fluids, 67, 76–83. https://doi.org/10.1016/j.supflu.2012.03.010

Banchero, M., Ronchetti, S., & Manna, L. (2013). Characterization of Ketoprofen / Methyl- β -Cyclodextrin Complexes Prepared Using Supercritical Carbon Dioxide, 2013. https://doi.org/10.1155/2013/583952

Brand-Williams, W., Cuvelier, M. E., & Berset, C. (1995). Use of a free radical method to evaluate antioxidant activity. LWT - Food Science and Technology, 28(1), 25–30. https://doi.org/10.1016/S0023-6438(95)80008-5

Bruylants, G., Wouters, J., & Michaux, C. (2005). Differential Scanning Calorimetry in Life Science: Thermodynamics, Stability, Molecular Recognition and Application in Drug Design. Current Medicinal Chemistry, 12(17), 2011–2020. https://doi.org/10.2174/0929867054546564

da Rosa, C. G., Borges, C. D., Zambiazi, R. C., Nunes, M. R., Benvenutti, E. V., Luz, S. R. Da, … Rutz, J. K. (2013). Microencapsulation of gallic acid in chitosan, β-cyclodextrin and xanthan. Industrial Crops and Products, 46, 138–146. https://doi.org/10.1016/j.indcrop.2012.12.053

Dang, H. T., Lee, H. J., Yoo, E. S., Hong, J., Bao, B., Choi, J. S., & Jung, J. H. (2008). New jasmonate analogues as potential anti-inflammatory agents. Bioorganic and Medicinal Chemistry, 16(24), 10228–10235. https://doi.org/10.1016/j.bmc.2008.10.050

Folch-Cano, C., Jullian, C., Speisky, H., & Olea-Azar, C. (2010). Antioxidant activity of inclusion complexes of tea catechins with β-cyclodextrins by ORAC assays. Food Research International, 43(8), 2039–2044. https://doi.org/10.1016/j.foodres.2010.06.006

Frijlink, H. W., Eissens, A. C., Schoonen, A. J. M., & Lerk, C. F. (1990). The effects of cyclodextrins on drug absorption II. In vivo observations. International Journal of Pharmaceutics, 64(2–3), 195–205. https://doi.org/10.1016/0378-5173(90)90269-A

Huang, Y., Zu, Y., Zhao, X., Wu, M., Feng, Z., Deng, Y., … Wang, L. (2016). Preparation of inclusion complex of apigenin-hydroxypropyl-β-cyclodextrin by using supercritical antisolvent process for dissolution and bioavailability enhancement. International Journal of Pharmaceutics, 511(2), 921–930. https://doi.org/10.1016/j.ijpharm.2016.08.007

Junior, O. V., Dantas, J. H., Barão, C. E., Zanoelo, E. F., Cardozo-Filho, L., & de Moraes, F. F. (2016). Formation of inclusion compounds of (+)Catechin with β-Cyclodextrin in different complexation media: spectral, thermal and antioxidant properties. The Journal of Supercritical Fluids. https://doi.org/10.1016/j.supflu.2016.06.005

Loftsson, T., & Duchene, D. (2007). Cyclodextrins and their pharmaceutical applications. International Journal of Pharmaceutics, 329(1–2), 1–11. https://doi.org/10.1016/j.ijpharm.2006.10.044

Mangolim, C. S., Moriwaki, C., Nogueira, A. C., Sato, F., Baesso, M. L., Neto, A. M., & Matioli, G. (2014). Curcumin–β-cyclodextrin inclusion complex: Stability, solubility, characterisation by FT-IR, FT-Raman, X-ray diffraction and photoacoustic spectroscopy, and food application. Food Chemistry, 153, 361–370. https://doi.org/10.1016/j.foodchem.2013.12.067

Moyano, M.J., Arias-Blanco, J.M., Ginés, F. (1997). Solid-state characterisation and dissolution characteristics of gliclazide-b-cyclodextrin inclusion complexes. Journal of Chemical Information and Modeling, (148), 211–217. https://doi.org/10.1017/CBO9781107415324.004

Nerome, H., Machmudah, S., Wahyudiono, Fukuzato, R., Higashiura, T., Youn, Y. S., … Goto, M. (2013). Nanoparticle formation of lycopene/β-cyclodextrin inclusion complex using supercritical antisolvent precipitation. Journal of Supercritical Fluids, 83, 97–103. https://doi.org/10.1016/j.supflu.2013.08.014

Ofer, K., Gold, D., & Flescher, E. (2008). Methyl jasmonate induces cell cycle block and cell death in the amitochondriate parasite Trichomonas vaginalis. International Journal for Parasitology, 38(8–9), 959–968. https://doi.org/10.1016/j.ijpara.2007.12.008

Perassolo, M., Smith, M. E., Giulietti, A. M., & Talou, J. R. (2016). Synergistic effect of methyl jasmonate and cyclodextrins on anthraquinone accumulation in cell suspension cultures of Morinda citrifolia and Rubia tinctorum. Plant Cell Tiss Organ Cult, 319–330. https://doi.org/10.1007/s11240-015-0896-y

Reverchon, E., & De Marco, I. (2006). Supercritical fluid extraction and fractionation of natural matter. Journal of Supercritical Fluids, 38(2), 146–166. https://doi.org/10.1016/j.supflu.2006.03.020

Rudrangi, S. R. S., Bhomia, R., Trivedi, V., Vine, G. J., Mitchell, J. C., Alexander, B. D., & Wicks, S. R. (2015). Influence of the preparation method on the physicochemical properties of indomethacin and methyl-β-cyclodextrin complexes. International Journal of Pharmaceutics, 479(2), 381–390. https://doi.org/10.1016/j.ijpharm.2015.01.010

Sambasevam, K. P., Mohamad, S., Sarih, N. M., & Ismail, N. A. (2013). Synthesis and characterization of the inclusion complex of β-cyclodextrin and azomethine. International Journal of Molecular Sciences, 14(2), 3671–3682. https://doi.org/10.3390/ijms14023671

Stražišar, M., Andrenšek, S., & Šmidovnik, A. (2008). Effect of β-cyclodextrin on antioxidant activity of coumaric acids. Food Chemistry, 110(3), 636–642. https://doi.org/10.1016/j.foodchem.2008.02.051

Tan, J., Meng, N., Fan, Y., Su, Y., & Zhang, M. (2016). Hydroxypropyl- β -cyclodextrin – graphene oxide conjugates : Carriers for anti-cancer drugs. Materials Science & Engineering C, 61, 681–687. https://doi.org/10.1016/j.msec.2015.12.098

Udrescu, L., Sbârcea, L., Fulias, A., Ledeti, I., Vlase, G., Barvinschi, P., & Kurunczi, L. (2014). Physicochemical Analysis and Molecular Modeling of the Fosinopril β-Cyclodextrin Inclusion Complex. Journal of Spectroscopy, 2014. https://doi.org/10.1155/2014/748468

Vajna, B., Farkas, I., Farkas, A., Pataki, H., Nagy, Z., Madarász, J., & Marosi, G. (2011). Characterization of drug-cyclodextrin formulations using Raman mapping and multivariate curve resolution. Journal of Pharmaceutical and Biomedical Analysis, 56(1), 38–44. https://doi.org/10.1016/j.jpba.2011.05.005

Valentini, S. R., Fenelon, V. C., Nogueira, A. C., Sato, F., Medina, A. N., Baesso, M. L., … Matioli, G. (2015). Insulin complexation with hydroxypropyl-beta-cyclodextrin: Spectroscopic evaluation of molecular inclusion and use of the complex in gel for healing of pressure ulcers. International Journal of Pharmaceutics, 490(1–2), 229–239. https://doi.org/10.1016/j.ijpharm.2015.05.037

Wang, S. Y., Bowman, L., & Ding, M. (2008). Methyl jasmonate enhances antioxidant activity and flavonoid content in blackberries (Rubus sp.) and promotes antiproliferation of human cancer cells. Food Chemistry, 107(3), 1261–1269. https://doi.org/10.1016/j.foodchem.2007.09.065

Weiler, E. W., Albrecht, T., Groth, B., Xia, Z.-Q., Luxem, M., Liß, H., … Spengler, P. (1993). Evidence for the involvement of jasmonates and their octadecanoid precursors in the tendril coiling response of Bryonia dioica. Phytochemistry, 32(3), 591–600. https://doi.org/10.1016/S0031-9422(00)95142-2

Yang, X., Zhao, Y., Chen, Y., Liao, X., Gao, C., Xiao, D., … Yang, B. (2013). Host – guest inclusion system of mangiferin with β -cyclodextrin and its derivatives. Materials Science & Engineering C, 33(4), 2386–2391. https://doi.org/10.1016/j.msec.2013.02.002

Yao, Y., Xie, Y., Hong, C., Li, G., Shen, H., & Ji, G. (2014). Development of a myricetin/hydroxypropyl-β-cyclodextrin inclusion complex: Preparation, characterization, and evaluation. Carbohydrate Polymers, 110(0), 329–337. https://doi.org/http://dx.doi.org/10.1016/j.carbpol.2014.04.006

Yuan, C., Lu, Z., & Jin, Z. (2014). Characterization of an inclusion complex of ethyl benzoate with hydroxypropyl-β-cyclodextrin. Food Chemistry, 152, 140–145. https://doi.org/10.1016/j.foodchem.2013.11.139

Author notes

osvaldo.valarinijr@gmail.com