Ficaria vernaHuds. extracts and their β-cyclodextrin supramolecular systems
© Hădărugă 2012
Received: 15 January 2012
Accepted: 5 March 2012
Published: 5 March 2012
Obtaining new pharmaceutical materials with enhanced properties by using natural compounds and environment-friendly methods is a continuous goal for scientists. Ficaria verna Huds. is a widespread perennial plant with applications in the treat of haemorrhoids and to cure piles; it has also anti-inflammatory, astringent, and antibiotic properties. The goal of the present study is the obtaining and characterization of new F. verna extract/β-cyclodextrin complexes by using only natural compounds, solvents, and environment-friendly methods in order to increase the quality and acceptability versus toxicity indicator. Thus, the flavonoid content (as quercetin) of Ficaria verna Huds. flowers and leaves from the West side of Romania was determined and correlated with their antioxidant activity. Further, the possibility of obtaining β-cyclodextrin supramolecular systems was studied.
F. verna flowers and leaves extracts were obtained by semi-continuous solid-liquid extraction. The raw concentrated extract was spectrophotometrically analyzed in order to quantify the flavonoids from plant parts and to evaluate the antioxidant activity of these extracts. The F. verna extracts were used for obtaining β-cyclodextrin complexes; these were analyzed by scanning electron microscopy and Karl Fischer water titration; spectrophotometry was used in order to quantifying the flavonoids and evaluates the antioxidant activity. A higher concentration of flavonoids of 0.5% was determined in complexes obtained by crystallisation method, while only a half of this value was calculated for kneading method. The antioxidant activity of these complexes was correlated with the flavonoid content and this parameter reveals possible controlled release properties.
The flavonoid content of F. verna Huds. from the West side of Romania (Banat county) is approximately the same in flowers and leaves, being situated at a medium value among other studies. β-Cyclodextrin complexes of F. verna extracts are obtained with lower yields by crystallisation than kneading methods, but the flavonoids (as quercetin) are better encapsulated in the first case most probably due to the possibility to attain the host-guest equilibrium in the slower crystallisation process. F. verna extracts and their β-cyclodextrin complexes have antioxidant activity even at very low concentrations and could be used in proper and valuable pharmaceutical formulations with enhanced bioactivity.
KeywordsFicaria verna Huds β-cyclodextrin Supramolecular systems Inclusion compounds Molecular encapsulation Micro- and nanoparticles Flavonoids Quercetin Antioxidant activity
Ficaria verna Huds. (lesser celandine, fig buttercup) is a widespread perennial plant which is found throughout Europe, West Asia, and North America, being sometimes called "the spring messenger" due to the blossoming period starting from March. It is also called "an invasive" plant in North America due to the use of these species for specific restoration-preservation processes in native habitats [1–3]. The name is derived from the Latin ficus, which means fig, due to the resembling of the F. verna roots with these fruits. It belongs to Ranunculaceae family, comprises of 59 genera and about 1900 species [4, 5].
In folk medicine F. verna was used to treat haemorrhoids and to cure piles, being known also as pilewort. Other traditional applications were in anti-inflammatory, astringent, antibiotic, and anti-haemorrhagic treatments [4, 6, 7]. F. verna reveals a high content of vitamin C, which confer anti-scorbutic activity. The consumption of the plant before blossoming in salads, soups, or other foodstuffs, combats the fatigue which appears in spring time . Extracts and tinctures of F. verna are used especially in external treatments, but also in some oral cavity infections [6–8].
The F. verna plant contains saponosides (having oleanolic acid, ficaric acid, ficarin, anemonin as aglycone moiety), flavonoids, vitamin C, minerals, and ranunculin. From the flavonoid class the most important are kaempferol and quercetin with their 3-O- and 7-O-glycosides (e.g. rutinoside), as well as 8-C-glycosidic derivatives (vitexin, orientin, vitexin-2"-O-glucoside) [1, 4, 6, 7].
Flavonoids such as quercetin and rutin are responsible for the anti-inflammatory and other biological activities of F. verna extracts, but these polyphenolic compounds are not very stable due to their susceptibility to oxidation. In order to protect them against environmental degradation factors (air/oxygen, light, humidity) and to obtain formulations with controlled release properties molecular encapsulation can be used. Some of the better matrices for molecular encapsulation (host-guest supramolecular systems or inclusion compounds) are cyclodextrins, which are naturally occurring cyclooligosaccharides mainly containing 6-8 glucopyranose moieties (α-, β-, and γ-cyclodextrin, αCD, βCD, and γCD, respectively), and having a hydrophobic inner cavity with a capacity to enclose (partial or total) small organic molecules [9–14]. The presence of primary and secondary hydroxyl groups to the exterior increase the water solubility of these compounds and the corresponding host-guest complexes. Some studies on the complexation and properties of flavonoids and other similar derivatives in cyclodextrins were done [13, 15–17].
Materials and methods
All F. verna Huds. plants were collected from the West side of Romania (Banat county) in April 2010, when these plants were in blossoming period; the raw flowers and leaves were separated and stored in sealed flasks at -20°C until extraction. In the extraction and complexation processes ethanol 96% (v/v) from Chimopar (Bucharest), was used. Quercetin and β-cyclodextrin (purity > 98%) were achieved from Fluka Chemie AG and DPPH (2,2-diphenyl-1-picryl-hydrazyl, 99% purity) was obtained from Sigma-Aldrich. Titrant 5 apura®, Solvent apura®, and Water standard 1% apura®, used for two-component Karl Fischer water titration, were purchased from Merck&Co., Inc.
Obtaining of Ficaria vernaHuds. extracts
Conditions and results for obtaining Ficaria verna Huds. ethanolic extracts, "EE_Fv" ("Fl"-flower, "Lf"-leaf); "a-c"-replicates
Sample weight (g)
Volume of ethanol (mL)
Extraction time (min)
No of cycles
Volume of extract (mL)
Obtaining of Ficaria vernaHuds. extract/β-cyclodextrin complexes by crystallisation method
Obtaining of new supramolecular systems containing F. verna extracts were realized by complexation in natural β-cyclodextrin. The first method used for obtaining these complexes was the controlled crystallisation from the ethanol-water solution. The study of the complexation parameters were studied and published elsewhere for similar supramolecular systems [23, 27]; only optimal parameter values were used in this study. Thus, 0.5 mmoles of β-cyclodextrin was dissolved in 4 mL distilled water in a 10 mL complexation reactor, equipped with a thermostatic jacket and a dropping funnel. The βCD solution was heated to 50°C and a volume of the F. verna concentrated extract corresponding to a molar ratio of 4:1 between βCD and flavonoids (expressed as quercetin) was added to the βCD solution under magnetic stirring in 15 minutes. The suspension was stirred at 50°C for another 15 minutes and after that the slow controlled cooling of the reactor was started, with a cooling rate of 7.5°C/hour. The suspension of complex crystals obtained after 4 hours was stored over night at 4°C in a refrigerator. The suspension was filtered in vacuum, washed with 1 mL 96% ethanol and dried in exicator at 40°C until constant mass. The complex recovering yield was calculated as the ratio between the complex mass and the sum of the starting materials (βCD and flavonoids as quercetin). The obtained F. verna extract/βCD complex was analyzed by scanning electron microscopy, Karl Fischer water titration, and spectrophotometry in order to evaluate the flavonoid content and antioxidant activity [see Additional file 1].
Obtaining of Ficaria vernaHuds. extract/β-cyclodextrin complexes by kneading method
The F. verna extract/βCD complexes were obtained also by using the kneading method [31, 32]. βCD and F. verna extract in the above mentioned quantities were kneaded for 15 minutes in a mortar in the presence of a small volume of water (a ratio of 2:1 between extract and water, by volume) at the constant temperature of 50°C. The viscous mixture was filtered in vacuum, washed with 1 mL 96% ethanol (in order to remove the non-complexed compounds-flavonoids and partially β-cyclodextrin), and dried until constant mass. The cyclodextrin complex was grinded and sieved through 0.25 mm sieve. The resulted βCD complexes were analyzed in the same manner as in the case of complexes obtained by crystallisation method [see Additional file 1].
Karl Fischer water titration (KFT)
Karl Fischer water titration of βCD complexes and commercial βCD was carried out by using a Karl Fischer 701 Titrando apparatus from Metrohm; a Metrohm 10 dosing system and 703 Ti Stand mixing systems were also used. The two-component technique was used for water determination (Component 1: Titrant 5 apura® and Component 2: Solvent apura®). The titer of component 1 was performed by using Water standard 1% apura®, standard for volumetric Karl Fisher titration (a titer of 4.4849 mg/mL was determined). The sample amount was ~0.05 g. The method parameters were: I(pol) of 50 μA, end point and dynamics at 250 mV, maximum rate of 5 mL/min, drift was used as stop criterion, with a stop drift of 15 μL/min. The extraction time was 300 s. All determinations were done at least in triplicate [see Additional file 2].
Scanning electron microscopy (SEM) analysis
For morphological and dimensional evaluation of the F. verna extracts/βCD complexes the scanning electron microscopy (SEM) technique was used. An Inspect S SEM apparatus, with a voltage of 25 kV, 300× to 3000× magnitude level, and focusing of 10-14.1 mm was used. Prior to examination, samples were gold sputter-coated, to render them electrically conductive.
Spectrophotometric analysis and antioxidant activity evaluation
The presence of flavonoids containing phenolic OH groups (such as quercetin) confers to the Ficaria verna extracts antioxidant character. The antioxidant activity of F. verna extracts as well as of their βCD complexes was evaluated by using DPPH spectrophotometric method (UV-VIS CamSpec 501 apparatus); the acquisition and handling of the data were realized with the UV-vis Analyst program, ver. 4.67. Thus, the sample cuvette contains 2 mL ethanol (96%, v/v), 0.5 mL F. verna extract (undiluted or diluted), quercetin or βCD complex solutions, and 0.5 mL DPPH ethanolic solution (concentration of 1 mM). The spectrophotometric analysis was realized at 517 nm for 15 minutes. Ethanol was used as reference solvent. The same apparatus was used in order to quantify the flavonoid content of F. verna extracts and their βCD complexes (as quercetin) [see Additional file 1].
Results and discussion
Obtaining and analysis of Ficaria vernaHuds. extracts
Flavonoid concentrations (expressed as quercetin) from the Ficaria verna Huds. ethanolic extracts, "EE_Fv", and plant parts ("Fl"-flower, "Lf"-leaf); "a-c"-replicates
Absorbance (@256 nm)
Flavonoid concentration (in extract) (mg/100 mL)
Flavonoid concentration (in raw plant) (mg/100 g)
104.5 ± 16.3
202.0 ± 16.4
90.1 ± 16.1
223.3 ± 33.0
Obtaining and analysis of Ficaria vernaHuds. extract/β-cyclodextrin supramolecular systems
F. verna extract/βCD complexes were obtained by using two methods: controlled crystallisation from ethanol-water solution and kneading methods, both in a molar ratio of 1:4 for the calculated flavonoid content (as quercetin) and βCD. In the case of crystallisation method the complex recovering yield was 59.3 ± 0.3% for the F. verna flower extract/βCD complex and 49.0 ± 2.6% for the F. verna leaf extract/βCD complex. The second method conduct to a better complex recovering yield, higher for the F. verna flower/βCD complex (91.7 ± 4.3%) and with 5% lower for the F. verna leaf/βCD complex (86.9 ± 0.4%). These differences between the recovering yields are due to the water solubility of βCD and the corresponding F. verna extract/βCD complexes; in the crystallisation method the association-dissociation of the biocompounds-βCD equilibrium tend to be attained. This equilibrium depends on the water solubility of βCD and its complexes; further, the separation process (filtration, washing, and drying) allow to partially loose βCD and complexes. In the case of kneading method only some volatile substances and ethanol-soluble compounds from extracts as well as the complex recovering process influences the global yield. As a result, the recovering yield in the kneading method is 32-38% higher than in the case of crystallisation method.
The analysis of the βCD complexes was performed by using scanning electron microscopy (SEM) in order to evaluate the morphology and approximate dimensions of micro/nanoparticles. Karl Fischer titration (KFT) was used in order to establish the water content of βCD complexes. Finally, the spectrophotometric analysis was used for evaluation of the encapsulated biocompounds and for antioxidant activity evaluation of extracts and their βCD complexes (see below).
Water content of Ficaria verna Huds. extract/β-cyclodextrin complexes and commercial β-cyclodextrin, determined by Karl Fischer titration ("Cr"-crystallisation method, "Kn"-kneading method, "Fl"-flower, "Lf"-leaf; "a-d"-replicates)
Sample weight (g)
Volume of the titrant (mL)
Water content (%)
15.27 ± 0.15
11.32 ± 0.02
10.91 ± 0.17
12.95 ± 0.59
13.24 ± 0.16
The concentration of cyclodextrin encapsulated compounds from F. verna extracts (principally flavonoids expressed as quercetin) was evaluated by using the same spectrophotometric method. This determination was performed on 2% aqueous solutions of F. verna extract/βCD complexes, by using the same calibration curve for quercetin. The concentration of encapsulated biocompounds from F. verna extracts were higher in the case of βCD complexes obtained by crystallisation method (0.50 ± 0.06% for the case of flower extracts and 0.46 ± 0.23% for the case of leaves extract), while this concentration was almost at a half in the case of kneading method (0.28 ± 0.01% for the case of flower extracts and 0.25 ± 0.04% for the case of leaves extract) [see Additional file 1]. Theoretically, the molar ratio between biocompounds from F. verna extracts (expressed as quercetin) and cyclodextrin was 1:4, which could conduct to a percent concentration of 4.3% flavonoid in cyclodextrin complexes, but the higher hydrophilic properties of flavonoids demonstrate that the hydrophobic interaction with the inner cavity of cyclodextrin is poor; this observation is demonstrated by the final concentration of these compounds in the studied complexes: ~0.5% by crystallisation method and a half for kneading method. This difference can be explained by the possibility to attain the flavonoid-cyclodextrin equilibrium, which is better performed in the crystallisation method (slow crystallisation of the complex), while a high quantity of biocompounds (uncomplexed ones) were removed.
Antioxidant activity of Ficaria vernaHuds. extracts and their β-cyclodextrin complexes
Antioxidant activity of F. verna extracts and their β-cyclodextrin complexes was evaluated by using the radical scavenging property of DPPH (2,2-diphenyl-1-pycryl-hydrazyl). Generally, antioxidants act as radical trapping compounds (i.e. peroxy radicals resulted by auto-oxidation of fatty acids), and the antioxidant activity could be evaluated by using such as radicals; DPPH is one of the most stable organic radical, which can be used as radical trapping.
A large class of antioxidants (even synthetic or natural) is hindered phenols; these compounds easily react with free radicals (i.e. peroxy radicals) and generate phenoxy radicals. As a consequence the neutralization of the first dangerous ones take place. Phenoxy radicals resulted from the hindered phenol antioxidant compounds regenerate the starting phenols and also furnish quinone or quinone methides, which have limited stability and react to yield a complex mixture of products. The role of free radicals could be taken by DPPH and the overall antioxidant activity could be evaluated spectrophotometrically due to the fact that DPPH have a maximum absorbance at 517 nm. The above mentioned reaction can be monitored by measuring this absorbance in the presence of samples containing antioxidants.
Where AA represents the antioxidant activity, Abs.(t) represents the absorbance of the reaction mixture (solution of flavonoid sample and DPPH) at the time t (measured at the wavelength of 517 nm), while Abs.(t = 0) represents the initial absorbance of this mixture in the same conditions. A higher value of AA indicates a higher antioxidant activity of the sample.
Four quercetin standard solutions with concentrations of 1600 μM, 160 μM, 16 μM, and 1.6 μM were prepared and analyzed spectrophotometrically for evaluation the antioxidant activity. Antioxidant activities of these standard samples, evaluated according to the above mentioned equation after 300 s in the presence of DPPH, are 89% for the most concentrated solution, followed by 49% for the second one. The last two quercetin solutions have lower but important antioxidant activities (9% and 5%, respectively).
The antioxidant activity was evaluated in the same manner for the F. verna extracts and their βCD complexes, for both raw and diluted samples (5- and 25-fold dilutions). Thus, all studied samples (extracts and aqueous βCD complex solutions) show antioxidant activity by means of decreasing the absorbance of the sample-DPPH mixture at 517 nm; this decreasing is more significant in the case of undiluted samples and remains important also in the case of diluted ones. The same aspect was observed in the case of the corresponding F. verna/βCD complexes (2% aqueous solution), but less significant (resembling to 25-fold diluted extracts) due to the concentration of the bioactive compounds. The antioxidant activity of the 25-fold diluted F. verna extract (both flower and leaf) is approximately the same: 13.2 ± 2.5% and 12.9 ± 2.8% for flower and leaf extracts, respectively. These values are placed between the antioxidant activity of quercetin standard solutions with concentrations of 160 μM and 16 μM. The antioxidant activity of the corresponding βCD complexes was little bit lower: 5.1 ± 1.2% and 5.6 ± 2.8% for the F. verna flower and leaf/βCD complexes obtained by crystallisation method; in the case of F. verna flower and leaf/βCD complexes obtained by kneading method these values were 4.5 ± 2.5% and 7.9 ± 1.2%. Higher antioxidant activity values were obtained in the case of F. verna leaf extract/βCD complexes for both complexation methods (5.6% for crystallisation method and 7.9% for kneading method) [see Additional file 1]. These values resemble with the quercetin standard solutions with concentrations of 160 μM and 16 μM.
Where Δc DPPH is the variation of the DPPH concentration on the studied range and Δt is the time interval. The rate results from the slope value of the Concentration vs. Time linear correlation for the studied time range. Thus, three time ranges were identified for antioxidant activity evaluation time of maximum 900 s: v 1 for the time range of 0-50 s, v 2 for the time range of 50-300 s, and v 3 for the time range of 300-900 s. Thus, the mean DPPH reaction rate of the F. verna flower 25-fold diluted extracts decrease from 0.3 μM/s for the first interval to 0.05 μM/s for the second one, and finally to 0.01 μM/s for the last interval. Little bit lower decrease was observed in the case of F. verna leaf extracts, at the same dilution (from 0.18 μM/s to 0.03 μM/s, and finally to 0.01 μM/s). In the case of cyclodextrin complexes this decrease of the DPPH reaction rate is lower than in the case of non-encapsulated F. verna extracts: in the first and second intervals the DPPH reaction rate in the presence of cyclodextrin complex solutions is 5-fold and 3-fold lower than in the case of non-encapsulated flower and leaf samples, respectively. In the last interval only 2-fold lower DPPH reaction rate was calculated for the cyclodextrin complexes in comparison with non-encapsulated extracts [see Additional file 1]. Further, the ratios between the mean DPPH reaction rates from different time ranges could indicate the controlled release properties of cyclodextrin complexes (further studies will be needed). This aspect is evident in the case of complexes obtained by crystallisation method, where the ratio between v 2 and v 3 is lower than in the case of non-encapsulated samples (v 2 /v 3 of 5.6 and 4.5 for non-encapsulated and βCD encapsulated F. verna flower extracts, 3.2 and 2.8 for the corresponding leaf extracts, respectively). These observations reveal also that the host-guest inclusion process is better achieved by using the crystallisation method in comparison with kneading method.
The following conclusions among the extraction and analysis of bioactive compounds from Ficaria verna Huds. species as well as the cyclodextrin complexation and antioxidant activity evaluation of non-encapsulated and encapsulated extracts can be drawn: (1) the content of flavonoids and other resembling compounds (expressed as quercetin) of Ficaria verna Huds. from the West side of Romania (Banat county) is approximately the same in flowers and leaves (harvested in blossoming period), being situated at a medium value among other studies (1-3.5 mg/g) [4, 6, 7]; (2) β-cyclodextrin complexes of F. verna extracts are obtained with lower yields by crystallisation than kneading methods, but the flavonoids (as quercetin) are better encapsulated in the first case most probably due to the possibility to attain the host-guest equilibrium in the slower crystallisation process; (3) water content of cyclodextrin complexes is an indirect parameter which demonstrate the quality of the host-guest interaction-the water concentration in cyclodextrin complexes is lower in comparison with the commercial cyclodextrin due to the replacing of water molecules by more hydrophobic bioactive flavonoids from F. verna extracts. However, the differences between water content values of cyclodextrin and complexes are not very high due to the fact that flavonoids and especially flavonosides or saponins (which are evaluated as quercetin) have a lower hydrophobicity (the explanation is the great number of hydroxyl groups); as a result, the van der Waals interactions with the inner cavity of cyclodextrins are relatively poor. These observations correlates with the flavonoid content of complexes obtained by these two methods; (4) both F. verna extracts and their β-cyclodextrin complexes have antioxidant activity even at very low concentrations. Antioxidant activity (which is related with the above mentioned biological activities) can be better monitored by means of the reaction rate of the model radical species.
This work was supported by Ministry of Education, Research, Youth, and Sports from Romania, PN2_ID_PCCE_140/2008. The author is grateful to Professor Heinz-Dieter Isengard (Hohenheim University, Germany) for the help in Karl Fischer water titration and to Dr. Ioan Grozescu (INCDEMC Timişoara, Romania) for the permission to evaluate the particle dimensions by scanning electron microscopy.
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