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Comparative evaluation of dithranol-loaded nanosponges fabricated by solvent evaporation technique and melt method



Dithranol, a standard drug for psoriasis, has lured keen attention by virtue of its antioxidant, anti-proliferative and anti-inflammatory activities. However, its poor stability and solubility critically impair the formulation design, evaluation and administration. To improve these issues, dithranol was encased in β-cyclodextrin nanosponges using solvent evaporation technique. Previously, nanosponges containing dithranol were developed in our laboratory using melt technique. Herein, a comparison of nanosponges prepared by both techniques was also included.


Different nanosponge batches were engineered using diphenyl carbonate as cross-linker with β-cyclodextrin as polymer employing solvent evaporation technique. Dithranol was loaded in nanosponges via lyophilization. Fourier transform infrared spectroscopy, differential scanning colorimeter and powdered X-ray diffraction studies confirmed successful encapsulation and complexation of this drug in β-cyclodextrin nanosponges. The effect of a variable amount of cross-linker on the solubility, encapsulation efficiency, zeta potential, particle size and polydispersity index was evaluated in fabricated nanocarriers. Further, β-cyclodextrin nanosponge batches were subjected to solubility studies, photostability examination and antioxidant activity analysis and compared with previously prepared dithranol-loaded nanosponges. From the present studies results, it was concluded that dithranol-loaded nanosponges using solvent evaporation technique not only improved solubility and photostability but also preserved the antioxidant efficacy of the chosen drug.


The overall results emphasized moral guidance concerning encapsulation, evaluation and characterization and accredited dithranol solubilization, photostability and antioxidant potential. However, solvent evaporation and melt method are easy and promising methods to fabricate nanosponges for dithranol. This comparative study demonstrated the parameters which were affected by chosen techniques. Further, from the results of present studies, it was concluded that the formulation scientists should select the preparation technique based on the objective of their research work and requirement of desired features.

Graphical abstract


  • Comparative evaluation of melt and solvent evaporation techniques for synthesis of dithranol nanosponges.

  • The particle characteristics were investigated using FTIR, DSC, PXRD and surface morphology.

  • Tuning of size and crystallinity of nanosponges were achieved by tuning synthetic techniques.

  • Antioxidant and photostability properties of the dithranol nanosponges were efficiently correlated.


Nanomedicines and nanotechnology despite being extraordinarily vast research fields offer a solution for various unsolved issues of drug delivery therapeutics and represent a burgeoning branch of science [1]. In the last two decades, nanosponges have attracted an increased interest of the research community owing to their highly versatile nature, combined with very simple and cheap fabrication protocols [2]. The well-known categories of NS include polystyrene nanosponges, titanium-based nanosponges, silicon nanosponges and cyclodextrin-based nanosponges [3]. Among these, β-cyclodextrin (CD) nanosponges (NS) are nanoporous and biocompatible delivery carriers that possess the proficiency in constructing supramolecular inclusion complexes along with non-inclusion complexes, with equally hydrophilic and lipophilic moieties [4]. Since long ago, CD has been proved to possess numerous benefits in the pharmaceutical industry for increasing the solubility of drugs and masking their organoleptic attributes to upsurge its compliance [5, 6]. Howbeit, the application of natal CD for the synthesis of inclusion complexes is also impeded by obstacles, such as the easy breaking of the complex on dilution, and the typical size necessity of the drugs. Molecules having high molecular weight and aqueous solubility excluded complexation with β-CD. Although CD goes through limitations such as poor aqueous solubility, due to robust intermolecular hydrogen bonding in crystal state, cross-linking it with some suitable cross-linker is known to address this issue [7]. Hence, fabrication of β-cyclodextrin-based nanosponges (CDNS) can be recommended for reducing above-mentioned confines [8]. NS developed using β-CD has become a significant area of research in the meadow of drug delivery systems because of its low cost, high complexing capability and acceptable stability with various cross-linking agents [9, 10]. The final NS construction designs a lattice of hydrophilic channels comprising CD lipophilic orifices and carbonate bridges. Architectural evaluation of CDNS represents that the carbonyl group of cross-linker linked with 1° hydroxyl groups of CD unit as presented in Fig. 1. Additionally, nanochannels in NS architecture are created owing to the cross-linking web, and potential orifices/pockets for guests are formed for guest moieties to be encapsulated not just in nanopockets of β-CD, but also inside nanochannels of NS. In contrast to parent CD, the novel architectural chemistry of NS may be the reason for their enhanced solubility and protection capacity [11]. Some of the merits of CDNS over other solubilization technologies include their particular nature, ease of integration with other formulations, ease of production, affordable cost and a higher loading capacity [12]. Therefore, in the present investigation CDNS have been chosen as a nanocarrier for encapsulation of dithranol (DTL), an anti-psoriatic agent.

Fig. 1
figure 1

Schematic representation of synthesis and interaction between dithranol and β-cyclodextrin-based nanosponges

Psoriasis is an autoimmune chronic dermal disease distinguished by scaly, itchy and disfiguring skin abrasions. This disorder is evidenced by modified neovascularization, hyperproliferation, keratinocyte differentiation and enhanced epidermal size [13, 14]. Considerable data have been provided in the literature that DTL impedes cellular proliferation in psoriatic skin, by limiting cellular movement or restricting the run of neutrophils, and so, it exhibits an anti-inflammatory action [15]. Despite being effective, benefits of this moiety are hampered by burning, staining, irritating and necrotizing expressions on normal and diseased skin [16]. Further, it also exhibits challenges in the preparation of nanoformulations, which have been attributed to its higher lipophilicity and sensitivity toward photodegradation, as it easily gets photo-oxidized [17]. DTL oxidation increases in daylight and it is vulnerable to air, ultraviolet light and higher temperature [18]. The degradation by-products, such as dithranol dimmer and danthron, are anticipated to give unwanted results and found less active or inactive [16, 19]. The currently available commercial formulations are not only unsuccessful to diminish the unwanted effects of DTL but also not able to enhance its photochemical stability [20]. As per literature reports, several endeavors have been attempted to synthesize novel DTL formulations to improve its solubility and stability such as liposomes/niosomes [20], hydrophilic silica aerogels [21], solid lipid nanoparticles [22], phospholipid microemulsions [17], nanoemulsions [23], hyperbranched dendritic nanocarriers [24], solid lipid dispersions [16], solid lipid nanoparticles [22], lipid-core nanocapsules [25] and dendrimer entrapped microsponges gels [26]. Although each reported novel system have addressed a few concerns of DTL, there are certain inherent limitations associated with each carrier.

Numerous synthetic processes have been investigated and reported for fabrication of CDNS, such as ultrasound synthesis, melt method, solvent evaporation technique and microwave-assisted synthesis to entrap a vast number of moieties with a wide range of applications [1, 6, 8, 12, 14, 27,28,29,30,31,32,33,34,35]. Among all these, melt method and solvent evaporation technique have been reported as the most popular and successful approaches [35, 36]. Hitherto, in-depth scientific reports and studies signifying the effect of the fabrication technique of CDNS are lacking [35]. Bearing this in mind, we chose to fabricate DTLNS via solvent evaporation technique. Previously, dithranol-loaded nanosponges have been synthesized in our laboratory via melt method [37]. The solvent evaporation method primarily includes a dispersion of cyclodextrin (polymer) in dimethyl sulfoxide or dimethylformamide (aprotic solvent). Herein, diphenyl carbonate (DPC) was selected as a cross-linker and dimethylformamide (DMF), as the internal solvent, for its capability of dissolving both CD and DPC [34]. For comparison purposes, we have kept the cross-linker and polymer as well as their ratio the same in both studies. Simple chemistry of polymers and cross-linkers, make this technology easy to scale up [38]. Besides routine characterizations, solubility study, photostability study and antioxidant activity were carried out. As focus of this investigation is to compare this technique with melt method, line of characterization and evaluation studies were kept similar to our previous investigation using this moiety. It is worth mentioning that this is the first-ever study regarding the comparison of solvent evaporation and melt techniques for fabrication of CDNS.

Materials and method


Dithranol was received from Himedia (India). β-CD was provided by Roquette (France). DPC was purchased from Sigma-Aldrich (India), and DMF was acquired from Finar (India). All other reagents and chemicals employed were of analytical grade.


Fabrication of cyclodextrin nanosponges (CDNS)

β-CD (MW 1135 g/mol) NS were fabricated as earlier reported by Singireddy et al., 2019 with minor alterations [35]. Briefly, 20 mL of anhydrous DMF was poured into a flask and 3.78 g of anhydrous β-CD has been added to obtain complete dissolution. Later, 0.713 g of DPC was added and the solution was left for 4 h at 100 °C to react. Next to condensation polymerization, the transparent block of hyper-cross-linked CD was roughly grounded and washed with distilled water. Lastly, residuals of unreacted reagents or by-products were fully cleared using acetone in Soxhlet extraction. The obtained white powder was dried the whole night in a hot air oven (at 60 °C) and grounded in a mortar. The cyclodextrin: DPC molar ratios were varied (i.e., 1:2, 1:4, 1:6, 1:8 and 1:10) and named NS2, NS4, NS6, NS8 and NS10 as presented in Table 1.

Table 1 Composition of engineered nanosponges

Engineering of DTL-loaded nanosponges (DTLNS)

Dithranol-loaded CDNS were synthesized using the lyophilization method as reported earlier by Rezaei et al., 2019 with some modifications. Accurate weights of CDNS were dispersed in distilled water (50 mL) by continuous stirring followed by an excess quantity of DTL, and the suspensions were sonicated for ten minutes, then kept under stirring for 24 h. The mixture was centrifuged (2000 rpm) for 10–15 min to remove the unbound DTL settled beneath the colloidal supernatant. The obtained supernatant was lyophilized on a freeze dryer (Alpha 2-4 LD Plus, Germany) operating pressure of 0.110 mbar and at − 20 °C temperature [12]. The resultant DTL formulations were stored in a desiccator and named DTLNS2, DTLNS4, DTLNS6, DTLNS8 and DTLNS10, depending on the ratio of polymer and cross-linker as displayed in Table 1.

Evaluation and characterization of CDNS formulations

Solubility study

The solubility of CDNS (NS2–NS10) was examined for the solubility enhancement capacity of these batches. An excess quantity of DTL was mixed with 20 mg of NS in MilliQ water. The containers were positioned on a mechanical shaker (50 rpm) at room temperature. After 24 h, solutions were centrifuged (10 min at 10,000 rpm) to remove the free DTL and colloidal supernatant. The above supernatant was extracted using methanol for DTL entrapped in CDNS. This solution was then examined by calibration curve plotted previously for DTL concentrations by UV spectrophotometer (UV-1800, Shimadzu UV Spectrophotometry) at λmax 233 nm [30].

% Entrapment efficiency (%EE) and drug content

Weighed quantities of loaded DTLNS were mixed with methanol and sonicated for 10 min to split the complex. The suspensions were filtered via Whatman filter paper, diluted appropriately and then observed by UV spectrophotometer at 233 nm to find out the concentration of loaded DTL [8, 39]. The experiment was performed in triplicate. % EE was computed employing the following formula:

$${\text{EE}}\,{ }\left( {\text{\% }} \right){ } = \frac{{{\text{Weight }}\;{\text{of}}\;{\text{DTL}}\;{\text{in}}\;{\text{CDNS}}}}{{{\text{Weight }}\;{\text{of}}\;{\text{DTL}}\;{\text{taken}}\;{\text{initially}}}} \times 100$$

Particle size, polydispersity index (PDI) and zeta potential (ZP) analysis

The particle size of all fabricated DTLNS batches was analyzed by Malvern Instruments Ltd, Worcestershire, UK, to estimate the uniformity in particle size distribution and size range of the CDNS. The CDNS were appropriately diluted with distilled water before each analysis. The ZP of the same formulations was observed by a Zetasizer, Malvern Instruments Ltd, Worcestershire, UK. The device has functioned at a constant room temperature employing a clean disposable zeta cell. The average size, PDI and ZP of the CDNS were evaluated and averaged after three observations [6, 40].

Fourier transform infrared spectroscopy (FTIR)

FTIR spectrums were analyzed employing a PerkinElmer Spectrum BX II, USA, spectrophotometer to carry out the interaction in DTL and CDNS, and also to assure the DTLNS formation. Approximately 1–2 mg of the formulation was blended with dry KBr (potassium bromide; 50 mg) and examined in transmission mode in 4000–400 cm−1 wave number range [6].

Differential scanning colorimetry (DSC)

To determine the thermal nature of DTL, blank NS and DTLNS4, DSC was analyzed. The principle is to measure the heat flow across the reference and sample for the controlled temperature cycle period. About 10 mg of the formulation was taken and sealed in an aluminum pan at a 10 °C/min heating rate, in a 25–300 °C temperature range in the process of nitrogen (flow rate of 100 mL/min), and DSC thermogram for samples was identified using DSC-4000 PerkinElmer Thermal Analyzer, USA [38].

Powder X-ray diffraction (PXRD)

To investigate the interactions of DTL and the formulation and configuration of resulting nanosponges, a PXRD study was conducted. DTL, blank CDNS and DTLNS were examined under PXRD by X-ray powder diffractometer (Bruker D8 Advance) [4].

Surface morphology

The surface analysis of blank CDNS and DTLNS4 was observed using an analytical scanning electron microscope (Model JSM6100 (Jeol) with image analyzer, elemental analyzer for CHN (Thermo Scientific). The nanoformulations were softly sprinkled upon a double adhesive tape stuck to a stub of aluminum. The stub was then layered with gold to a 10 A˚ thickness in an argon atmosphere with a gold sputter module under a high vacuum evaporator. The stub with coated formulations was established in the scanning electron microscope assembly and analyzed [30, 39].

A thorough morphology of blank was analyzed using a park system N*10 Atomic Force Microscope (Mikromash Si tips, Au-backside, k = 15 N/m, alternate contact mode) having a 50 lm scanner with three piezo electrodes for three axes in a non-contact mode. The tips of silicon furnished with dual scope DS 95-50 camera. The outcomes were observed by XEI software. The samples (01%w/v) were developed using distilled water and dropped a drop onto a glass slice (2 × 2 cm). The slice was dried under HEPA filter, followed by an analysis of the dried region [41, 42].

Photostability studies

Dithranol photodegradation studies were conducted by employing a UVA lamp having a short wavelength range. The samples under investigation were the suspension of DTL and DTLNS4 in methanol. 10 mL of each sample was held 10 cm away from the light and irradiated by keeping them under regular stirring. At fixed time intervals of 10 min, over 1 h of total irradiation, 1 mL of every sample was taken and diluted using methanol for spectrophotometric analysis [41].

In vitro antioxidant activity by DPPH radical scavenging test

The DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) radical scavenging activity of DTLNS4 was examined and compared with the DTL as described earlier with some modifications [43, 44]. Various concentrations of DTL and DTLNS4 (5–100 μg/mL) were developed. 0.1 mL of methanolic solution of DPPH (0.1 mM) mixed with either DTL or DTLNS4 (2 mL) solution. Afterward, the solution was incubated for 30 min and evaluated by UV–visible spectrophotometer at λmax 517 nm. Methanol was taken as control and outcomes were correlated with ascorbic acid (AA) as a positive standard [45]. The % scavenging assay was evaluated by the following formula.

$${\text{Radical}}\;{\text{ scavenging}}\; {\text{activity}}\, \left( \% \right) = 1 - \frac{{ {\text{Abs}}_{{{\text{sample}}}} }}{{{\text{Abs}}_{{{\text{Blank}}}} }} \times 100$$

where Absblank denotes the absorbance of DPPH (standard) and Abssample represents the absorbance of the drug.

Statistical analysis

All the studies were performed in triplicate and the findings were described as mean ± SD. The calculated results were statistically evaluated by GraphPad Prism software version 5.0 (GraphPad Software Inc., La Jolla, CA, USA). The variations were considered statistically significant at p < 0.05.


Evaluation and characterizations of NS formulations

Solubility study

The solubility of all CDNS batches and β-CD was examined and measured with the solubility of DTL in distilled water at room temperature. Modification in the molar ratio of β-CD to DPC is detected to be a pivotal factor, affecting the capacity of CDNS to enhance the solubility of the drug. Dithranol is poorly water-soluble (< 2 mg/mL) moiety. The higher log p value (log p = 2.3) of DTL indicates its hydrophobic nature [17]. All the formulation batches of CDNS (NS2, NS4, NS6, NS8 and NS10) improved the solubility of DTL in comparison with free DTL (0.336 ± 0.198) in water as depicted in Fig. 2. Among these, NS4 (0.655 ± 0.128) exhibited maximum solubilization efficiency followed by NS6 (0.481 ± 0.065), in comparison with native DTL and β-CD (0.385 ± 0.239). Low concentration of cross-linker DPC in NS2 with a 1:2 ratio comes up with the presence of the unbound complex, decreasing the cross-linking sites accessible to encapsulate the drug, resulting in lower solubility. This had been well documented in the literature [10, 39]. Moreover, the 1:6 and 1:4 ratios of CDNS consist of a less dense matrix, as compared to the 1:8 ratio; however, it may consist of a larger affinity to form inclusion complexes, henceforth showing an overall solubility, more than the 1:8. The higher amount of cross-linking in CDNS with 1:8 and 1:10 ratio brings about hyper-cross-linking of CD and impairs the single units of CD intermolecular hydrogen-bond network, restricting the interaction of DTL with the pockets and encasing in CDNS due to torturous and complex nanostructures. In addition, the higher degree of cross-linking in these ratios resulted in impeded growth of the nanopolymeric architecture but caused enhanced branching of β-CD units. This resulted in a very porous configuration making a mesh-type web, as a consequence decreasing the solubilization efficiency. The results also showed the superiority of DTL solubilization with NS over plain β-CD. The enhanced solubilization of the drug was perhaps due to the formation of the inclusion complex of DTL as well as its encapsulation in the NS matrix. Hence, the encasing of DTL in CDNS might be ended with its enhanced solubility. Similar solubilization efficiency results have been reported recently in the literature by Suvarna et al., 2021 [46].

Fig. 2
figure 2

Solubilization of DTL (dithranol), β-CD (β-cyclodextrin) and NS2 + DTL, NS4 + DTL, NS6 + DTL, NS8 + DTL and NS10 + DTL (different nanosponge batches with dithranol) in distilled water. All the values are presented in triplicate (mean ± SD); *Indicates p < 0.05 analyzed by one-way ANOVA, followed by Tukey’s test for multiple comparisons

% Encapsulation efficiency (%EE) and drug content

In the present investigation, payload efficiency of DTLNS (all batches) for DTL delivery was calculated and compared. The encapsulation efficiencies of DTLNS batches were observed to be lying between 58.77 ± 0.53 andd 83.59 ± 1.45 (Table 2). The loading efficiency of all batches of NS is presented in Fig. 3. As reported and traced in the literature [8, 12], among different cross-linker ratios fabricated, the DTNS4 ratio demonstrated high encapsulation efficacy and drug content (17.11%) in comparison with other ratios. DTLNS4 presented 83.59 ± 1.45% encapsulation efficiency, albeit reduced DTL content has been found in other batches. Indeed, fabrication under similar conditions with a minor changes in cross-linker concentration affected the encapsulation efficiencies of various batches. This was followed by DTLNS6  > TLNS8  >  DTLNS10  >  DTLNS2. Similar results were observed for drug content as well with various molar ratios of developed CDNS. The data demonstrated that the degree of cross-linking affects the complexation behavior of NS. In DTLNS2, cross-linking with CD was incomplete and decreased sites were available for the complexation of the drug. However, in DTLNS8 and DTLNS10, the larger amount of cross-linker might have resulted in a hyper-cross-linking of β-CD and could hamper the interaction of DTL with cyclodextrin cavities. Earlier researches also certify our findings. As described by Allahyari et al., 2021, CDNS (ratio 1:4) indicated high flutamide loading (56.5% and 9.4%) in comparison with the 1:2 weight ratio of 36.05% and 6.0% weight ratio prepared by solvent evaporation method [8]. These outcomes demonstrated that our fabricated CDNS had greater cross-linking which gives high drug loading. As mentioned in the prior analysis, the degree of cross-linking in CDNS belongs to the design of polymer matrix which, further to inclusion complexes, can entrap drugs and increase solubility [30, 44].

Table 2 Particle size, zeta potential (ZP), polydispersity index (PDI) and % encapsulation efficiency (%EE) of dithranol nanosponges (n = 3, mean ± SD)
Fig. 3
figure 3

Encapsulation efficiency of nanosponges formulations. All data are expressed as mean ± standard deviation (n = 3). Data were analyzed by one-way ANOVA, followed by Bonferroni’s multiple comparison test. a indicates ***p < 0.0001 versus DTLNS2, b indicates *p < 0.05 versus DTLNS2, c indicates **p < 0.001 versus DTLNS4, d indicates ***p < 0.0001 versus DTLNS4, e indicates *p < 0.05 versus DTLNS6 and f indicates ***0.0001 versus DTLNS6. Abbreviations: DTLNS stands for dithranol-loaded nanosponges

Particle size, polydispersity index (PDI) and zeta potential (ZP) analysis

The particle size of all the fabricated DTLNS batches ranged from 379 to 978 nm as presented in Table 2. ZP of all DTLNS batches was also analyzed to observe the surface charge. The outcomes of ZP are presented in Table 2. The ZP or particle charge is also called the electrokinetic potential. ZP is the shear plane of a particle revolving in an electric field [47]. The ZP measurements are generally analyzed by the electrophoretic light scattering and can be negative or  positive. However, a ZP of − / + 30 mV is usually taken as a stability threshold [48]. Elevated ZP demonstrated that the porous DTLNS would be stabilized owing to a greater magnitude of repulsive forces, bringing about a reduction in their capacity to aggregate. The narrow range of PDI represents that the prepared nanoformulations are homogenous and stable by nature. The prepared DTLNS batches were obtained as light yellowish free-flowing powders.

It was observed a small increment of cross-linker promoted variation in the average size values and surface charge of DTLNS. The DTLNS presented mean size values of 379.2 ± 7 nm, 470.55 ± 16 nm, 911.95 ± 63 nm and 978.35 ± 85 nm for DTLNS4, DTLNS6, DTLNS8 and DTLNS10, respectively. For DTLN4, lower cross-linker content resulted in negatively charged nanosponges (Fig. 4). Despite this, the nanoformulations showed a monomodal distribution of particle size which was also supported by the PDI outcomes (0.537 ± 0.19 to 0.833 ± 0.24), authenticating the existence of a polydispersion. In the present study, the observed sizes revealed that the NS produced were lying in the desired size range.

Fig. 4
figure 4

Representative particle size and zeta potential graphs of DTLNS4 obtained during analysis

Based upon the particle size, solubility and %EE studies, formulation NS4 and DTLNS4 were chosen for further experiments.

Fourier transform infrared spectroscopy (FTIR)

FTIR spectra of the porous NS4, pure drug, DTLNS4 have been recorded (Fig. 5). NS4 complexes showed a characteristic peak at 1741 cm−1 confirming the formation of the carbonate ester group, characteristic peak of NS4 which have been fabricated using diphenyl carbonate cross-linker. Further, NS exhibited characteristic C–H stretching at 2930 cm−1 and C–H bending at 1400 cm−1; FTIR peaks at 1159 cm−1 have been assigned to C–O–C absorption bands and those at 1022 cm−1 have been attributed to C–O stretching vibration of primary alcohol. In the FTIR spectrum of DTLNS4, all the characteristic bands related to NS4 have been visualized. The characteristic FTIR peaks of DTL show C=O (1601 cm−1), C–H (722, 774 and 1461 cm−1) and C–OH (2973 cm−1), as presented in Fig. 5. The results are in agreement with the findings of Gambhire et al., 2011 wherein DTL showed identical outcomes as achieved in its FTIR spectra [22] illustrated in Fig. 5. Among the above-mentioned DTL peaks, the peak at 722 cm−1 was masked, whereas peaks at 2928, 1483 and 752 cm−1 were shifted on complexation with NS4. Hence, complexion and interactions between CDNS and drug were confirmed by such shifting in FTIR peaks. The results of the present investigation not only confirm the successful incorporation of DTL in the formulation but also the preservation of its structural features needed for its functional attributes. In another similar study, such interactions and shifting in peaks evidenced the complexation of curcumin with NS [41].

Fig. 5
figure 5

FTIR spectrum of DTL (dithranol), NS4 (nanosponges formulation) and DTLNS4 (dithranol nanosponges)

Differential scanning calorimeter (DSC)

DSC analysis investigated the physical state of DTL after its encapsulation in NS4 as well as pure DTL and native NS4. DSC thermograms (Fig. 6) indicated the melting points with corresponding enthalpies. The enthalpy demonstrates the absolute heat uptake, which is shown by the area under the transition peak. Since DTL is crystalline, its DSC spectra (Fig. 6) depicted a sharp endothermic peak at 181 °C, with corresponding enthalpy − 76.379 J/g. These findings are in agreement with the study of Carlotti et al., 2009 available in the literature for DTL solid lipid nanocarriers [15]. However, a significant difference was evident between the DSC peaks of native NS4 and DTLNS4. The endothermic peak of DTL was found suppressed in DTLNS4, suggesting partial protection due to encapsulation of the drug within hydrophobic cavities of NS4. The lack of endothermic peak in DTLNS4 also suggested a reduced percent of plain crystalline DTL. Therefore, it can be concluded that DTL is successfully encapsulated in DTLNS4. If partial complexation takes place, drug peak is expected to be reduced in the complex owing to its interaction with CDNS. Further, it was observed that CDNS have not been degraded up to 300 °C, indicating the stable nature of the prepared nanosponges as this temperature is far beyond storage temperature for pharmaceuticals in various setups [49].

Fig. 6
figure 6

DSC thermogram of DTL (dithranol), NS4 (nanosponges formulation) and DTLNS4 dithranol nanosponges)

Powder X-ray diffraction (PXRD)

PXRD spectra of plain DTL, NS4 and DTLNS4 further evidenced complexation. The intensity of PXRD patterns of DTLNS4 was found reduced than plain DTL and NS4, confirming the formation of the inclusion complex (Fig. 7). The PXRD pattern of DTL exhibited sharp and intense peaks at 12.16, 14.23, 17.56, 25.04 and 26.91 2θ values which indicated the crystalline nature of DTL as presented in Fig. 7. The PXRD of CDNS did not exhibit any characteristic peaks and these results also validate their amorphous characteristic. The masking of characteristic peaks 10.48, 12.55, 19.86 and 24.84 2θ values of DTL in DTLNS4 indicated a loss in crystallinity of the drug and its consequent amorphization after its encapsulation inside the CDNS. Such shreds of evidence further suggested the development of an inclusion complex as well. Rao and Shrisath have also reported similar results in their studies for efavirenz NS using diphenyl carbonate as a cross-linker reported that reduced intensity in PXRD spectra is an indicative measure of inclusion complexation [50]. Further, it is well documented in the literature that the broadening of peaks in X-ray spectra and reduction in peak intensities are indicative of inclusion complexion [30, 39, 51].

Fig. 7
figure 7

PXRD diffraction analysis of DTL (dithranol), NS4 (nanosponges formulation) and DTLNS4 (dithranol nanosponges)

Surface morphology

From the SEM images of NS4 and DTLNS4, their porous nature and internal cavities are confirmed (Fig. 8). Further, a prominent change was observed in the surface morphology of DTLNS4 (Fig. 8B, D), as the drug partially filled pores which was clear in blank nanosponges (Fig. 8A, C). As mentioned before, the porous NS4 were developed as a consequence of the cross-linking of the cross-linker and polymer in the presence of a solvent. Similar morphology was described by Zainuddin et al., 2017 for rilpivirine HCL with an identical cross-linker as well as preparation technique as used in the present investigation [49]. The rough porous surface of NS4 is further authenticated by atomic force microscopy (AFM) (Fig. 9). AFM of NS4 illustrated the size of nanosponges in the nanorange (25–400 nm). The recorded images showed the prominent crystal planes on crystalline CDNS an approximate height of 400 nm. Additionally, particle size by AFM correlated well with those obtained using a Zetasizer. Swaminathan et al., [52]. Pushpalatha et al., [41] too reported similar highly porous and rough surface morphology of DPC-NS using SEM and AFM.

Fig. 8
figure 8

SEM images of blank nanosponges, NS4 (A, C) and dithranol-loaded nanosponges, DTLNS4 (B, D)

Fig. 9
figure 9

AFM images of blank nanosponges (NS4)

Photostability studies

Degradative products of DTL in the influence of light, heavy metals, oxygen and basic pH develop free radicals, which are harmful to the biological tissues and irritate those deeply [18]. Also, it has been proposed that these free radicals further exhibit desired effect by preventing psoriasis. Besides this, the produced superoxide anions can exert an adaptable mechanism for enhanced capacity of drug [53]. Instead, the oxidized products of danthron and dithranol dimer have the dark brownish appearance, which stains clothes and skin and is ineffective in psoriasis [26]. Dithranol in the UV region displayed a peak around 233 nm and its affinity was found to impede over UVA irradiation showing photolysis. As DTL is very light sensitive, it seemed mandatory to characterize its degradation under exposure to light. To perform the photodegradation evaluation, it was observed that DTL-loaded NS were higher photostable than free drug under same conditions (Fig. 10a). DTL alone showed 97.4% degradation within 60 min due to the direct influence of UV light. Indeed, it was authenticated from the findings of this study that DTLNS4 (36.14% degradation) demonstrated better protection from UV light. This could be attributed to the entrapment of the drug in NS cavities, which showed improved photostability (Fig. 10a) and provided a physical barrier to the drug in contrast to UV-induced deterioration. It was also analyzed that degradation of DTL from the NS was rapid which begins from 10 min only. This might be a result of free DTL present on the surface of NS. In agreement with the present findings, Sunderarajan et al., 2017 observed the enhanced photostability of chrysin NS-inclusion complex synthesized via melt method using DPC as a cross-linker [45].

Fig. 10
figure 10

a Residual content (%) of dithranol (DTL) and dithranol-loaded nanosponges (DTLNS4) after photodegradation study. All data are expressed as mean ± standard deviation (n = 3). Data were analyzed by two-way ANOVA, followed by Bonferroni’s posttest (***). Statistically significant difference (***p < 0.001). b 2,2-Diphenyl-1-picryl-hydrazyl-hydrate radical scavenging activity of ascorbic acid (AA), dithranol (DTL) and dithranol-loaded nanosponges (DTLNS4). All data are expressed as mean ± standard deviation (n = 3). Data were analyzed by two-way ANOVA, followed by Bonferroni’s posttest (***). Statistically significant difference (***p < 0.001)

In vitro antioxidant activity by DPPH radical scavenging test

Dithranol is highly susceptible to oxidation and has poor permeability through the horny layer of skin [26]. DTL oxidation is increased by UV light, daylight, contact with molecular oxygen/air and increased temperature [18]. DTL oxidized and resulted in degraded products, which are found to exhibit unwanted results and are less active or inactive in psoriasis (a significant application of DTL) [16]. Hence, the evaluation of antioxidant activity was performed via DPPH assay, which allows the evaluation of antioxidant responses of a given sample based on concentration. DTL shows an antioxidant effect mainly, owing to the phenolic hydroxyl groups present. Antioxidant activity of all samples under study was found increased with an increase in the concentration, which exhibited dose dependent nature of DTL moiety. Percent inhibition for DPPH for chosen samples is presented in Fig. 10b. A perusal of the data showed that at a concentration of 100 µg/mL, all samples individually exhibited maximum percent inhibition: DTL (83.82%), DTLNS4 (89.74%) and ascorbic acid (92.68%; standard). From these results, it is clear that NS-embedded DTL showed higher percent inhibition at the same concentration in comparison with native DTL (Fig. 10b). The greater antioxidant assay of DTL-laden NS can be due to its increased solubility with NS; thus, it readily supplied protons to DPPH. The findings are in accordance with other reports in the literature. Recently, Dhakar et al., 2019 have reported that kynurenic acid-loaded NS demonstrated a higher reduction in DPPH concentration when compared to free kynurenic acid [44].


As mentioned above, the present work is an extension of previous work conducted on DTLNS. The purpose of this attempt was to compare characteristics as well as the photostability and antioxidant performance of DTLNS fabricated via solvent evaporation and melt technique. The synthesis of DTLNS involved 2 steps: first one to prepare CD-based blank nanosponges via optimum cross-linking of polymer and cross-linker, followed by drug encapsulation into blank nanosponge by lyophilization. Herein, blank NS were synthesized using solvent evaporation technique taking β-CD as polymer, DMF as solvent and DPC as cross-linker. For nanosponge synthesis, the ratio of polymer to cross-linker plays a crucial role. This ratio should be optimized such that neither high nor less cross-linking occurs and results in the formation of rigid and stable nanosponges having nanopores. Hence, an optimum balance of the two is expected to produce nanosponges with superior drug entrapment and other best possible characteristics. Further, a change in fabrication method may also lead to variation in physicochemical attributes of prepared NS. The interactions of functional groups in CD with drug vary depending on the selected fabrication technique. Hence, the importance of degree of substitution of polymer depends on the ultimate amount of cross-linker and preparation technique used. Taking into consideration the underlying facts, trial-and-error experiments and available literature, the two techniques (solvent evaporation and melt techniques) were selected and compared in this study. For comparison purpose, drug polymer, cross-linker, as well as their ratios, were kept the same in both experimental works.

Firstly, solubilization efficacy was found slightly higher for DTLNS synthesized via melt method (4.54 fold) than solvent evaporation technique (1.7 fold). This may be accredited to variations in the size of NS, which were found 374.2 and 274.6 nm (for optimized batches) fabricated via solvent evaporation technique and melt method, respectively. Concerning % DTL encapsulation via melt method, it was ~ 83%, whereas for solvent evaporation technique, % EE was found to be 83.59%. Thus, % EE via both techniques was found similar. Polymer cross-linker ratio as well as the particle size of crafted NS plays a significant role in drug encapsulation. Along with these parameters, resultant pore size of obtained NS cannot be overlooked. Pore size directly depends on polymer and cross-linker interactions, which eventually depend on their ratios. It is noteworthy that for melt technique, the NS6 batch (1:6 ratio; β-CD and cross-linker) was chosen; however, for solvent evaporation method, NS4 batch (1:4 ratio; β-CD and cross-linker) was selected for further evaluation based on solubility, % encapsulation efficiency and particle size. FTIR, DSC, PXRD and SEM results of these optimized batches verified the preparation of the inclusion complex of dithranol with nanosponges employing chosen techniques. Solvent evaporation method leads to the formation of amorphous NS with a small size distribution, whereas melt method produces NS of crystalline nature. This property plays a significant role in solubility and drug release which in turns affect the efficacy of entrapped drug.

Photostability evaluation implied that photostability of DTL was enhanced for both nanoformulations prepared via solvent evaporation and melt techniques [37]. However, enhancement in photostability was slightly higher for NS fabricated via melt technique. Results of antioxidant potential assessment showed that DTLNS synthesized via solvent evaporation process were highly superior in imparting antioxidant efficacy. The difference in activities of DTLNS might have occurred due to different polymer to cross-linker ratios and variable particle size. Of course, the preparation technique might have played a chief role in these findings, as interactions of drug and nanosponge complexes have been governed by process conditions and process variables of the selected techniques. Undoubtely, this comparative study demonstrated the parameters which were affected by chosen techniques. Not only this, the findings of this study advocated the significance of DTL-loaded NS (fabricated via solvent method) for addressing the challenges of DTL. Besides photoprotection, the incorporation of DTL in the prepared nanosponges can enhance its solubility as well as antioxidant efficacy. Furthermore, it is assumed that entrapment of DTL in these nanostructures may also help in reducing its staining effect and other side effects such as erythema, irritant dermatitis, pigmentation, irritation and instability in the presence of light. Hence, CDNS may prove as an appropriate system for improving the therapeutic efficacy of this drug.

Therefore, based on the outcomes of current and previous studies, preparation technique should be carefully chosen for fabrication of CDNS depending on the desired characteristic features, which ultimately affects the therapeutic efficacy of resultant formulation. However, our study lacked in vitro anti-psoriatic comparative studies to show the effect of both (solvent evaporation and melt method) dithranol-loaded nanosponges on psoriasis-affected skin.


This investigation advocated the successful preparation of dithranol-loaded nanosponges having photostability and antioxidant potential through the solvent evaporation process. Despite an increase in technological usage of nanosponges, various queries regarding the fabrication techniques and their effects on physicochemical attribute are still open. Most importantly, cyclodextrin to cross-linker ratio may be optimized during their fabrication to enhance the drug entrapment and solubility. Slight changes during synthesis bring about variations in properties of encapsulated drug. Alterations in synthesis of DTL-loaded NS resulted in an anomalous characteristics with respect to morphology, physicochemical properties and solubility of dithranol. Besides, satisfactory findings from characterization of DTLNS, uniform-size nanosponges were obtained with desired particle size distribution and higher encapsulation efficiencies. The photostability data indicated that nanosponges prompted dithranol protection when compared to pure dithranol. Further, the antioxidant activity of selected batches suggested that the functionality of dithranol was preserved in NS and was observed maximum in DTLNS4 synthesized by the solvent evaporation method. These results unveiled the successful fabrication of dithranol nanosponges by solvent evaporation technique as an effective mode of delivery, by preserving desired functionality of the drug. While comparing the melt method and solvent evaporation technique, it was observed that the formulation scientists should select the preparation technique based on the objective of their research work and requirement of desired features. The present investigation, no doubt, will provide valuable information to the formulation scientists working with this profound delivery system.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author, upon reasonable request.









Diphenyl carbonate




Dithranol-loaded nanosponges


Particle size distribution


Polydispersity index


Zeta potential analysis


% Entrapment efficiency




Fourier transform infrared spectroscopy


Differential scanning colorimetry


Powder X-ray diffraction


Atomic force microscopy


Scanning electron microscopy




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We would like to thank Dr. Rajesh Thakur, Department of Bio and Nanotechnology, Guru Jambheshwar University of Science and Technology, Hisar, Haryana, for providing AFM facility and other instrumental support. The authors are grateful to A P J Abdul Kalam Central Instrumental Laboratory and Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar, Haryana, for the instrumental and infrastructural facilities.


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VK, PD, SK and RR contributed to the design of the study; VK and PD collected the samples; VK and SK performed the experiments and analysis the data; VK, AK and RR drafted the paper. All authors read and approved the final manuscript.

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Correspondence to Rekha Rao.

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Kadian, V., Dalal, P., Kumar, S. et al. Comparative evaluation of dithranol-loaded nanosponges fabricated by solvent evaporation technique and melt method. Futur J Pharm Sci 9, 13 (2023).

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