Ternary Inclusion Complex of Sinapic Acid with Hydroxypropyl-β-cyclodextrin and Hydrophilic Polymer Prepared by Microwave Technology

Abstract

Sinapic acid (SA) is a poorly water-soluble substance which could result in poor bioavailability. The aim of this study was to determine the “hydroxypropyl β-cyclodextrin (HPβCD)” solubilization of SA in the presence of the auxiliary substance hydroxypropyl methylcellulose (HPMC) and to evaluate the ternary inclusion complex prepared by microwave technology. Phase-solubility profiles showed that HPβCD exhibited the greatest solubilizing effect on SA in the presence of HPMC. The enhanced rate of SA dissolution was exhibited by a ternary complex. Outcomes of analyses such as “DSC, FTIR, NMR, and SEM” confirmed the embedding of SA into the cavity of the HPβCD and the formation of a ternary inclusion complex. The outcomes of antioxidant activity (ABTS and nitric oxide scavenging activity) demonstrated that SA ternary inclusion complex (TIC) presented strong antioxidant activity, which might be a result of the enhanced solubility of SA in the TIC prepared by microwave technology. Hence, SA-TIC formulation could be a better dosage form which may protect the body from free radical damage and oxidative stress. Microwave technology greatly boosted the interaction of SA with HPβCD and HPMC, and such findings are expected to contribute to raising the solubility of SA, thereby improving the bioavailability of SA.

1. Introduction

Drugs that are poorly water-soluble have been extensively complexed with cyclodextrins (CDs) in order to increase their solubility in water and their dissolution rate [1]. CDs’ hydrophilic properties have made them popular, because they increase drug solubility, enhance physicochemical properties, and improve chemical stability [2]. It has been observed that CDs form stable complexes with guest molecules with appropriate sizes, because they have hydrophobic central cavities [3]. In recent years, chemically modified CDs, such as “hydroxypropyl β-cyclodextrin (HPβCD)”, have gained importance due to their small cavities and hydrophilicity [4,5]. It was reported that the formation of ternary complexes can improve the solubility of drugs in aqueous solutions when some water-soluble polymer(s) is added [6,7]. As a result of the combination of CD and polymer, the process of drug solubilization was enhanced by a synergistic effect [8]. The use of water-soluble polymers aids in the stabilization of complex aggregates and pharmaceutical particle systems. In addition, they can decrease the CD mobility and increase the solubility of complexes by altering the hydration properties of CD molecules [9]. In a previous study, “hydroxypropyl methylcellulose (HPMC)” was reported to increase daidzein, vinpocetine, and piroxicam complexation with CD [10,11,12,13]. HPMC is a polymer that is soluble in water. The consequences of adding poorly soluble drugs, for instance, SA, to HPβCD/HPMC solubilization have not yet been investigated. Further, it has been also reported that CDs can improve the antioxidant properties of various agents by enhancing their release rate from the inclusion complex [14,15].

Research has shown that flavonoids can provide powerful antioxidant protection against oxidative stress and free radicals in the body [16]. Hydroxycinnamic acid is a phenolic acid that contains bioactive carboxylic acids; examples include caffeic acid, ferulic acid, and sinapic acid (SA) [17,18,19]. SA is abundant in variety of plant sources, such as berry fruits, cereals, citrus, spices, oilseed crops, and vegetables [20]. SA has a molecular weight of 224.21 g/mol, and it is a yellow-brown crystalline powder [18]. SA is considered to be poorly soluble in water, as it exhibits a poor dissolution profile, which leads to poor bioavailability. Researchers have demonstrated that SA has powerful “antioxidant, anti-diabetic, anxiolytic, antibacterial, neuroprotection, anti-inflammatory, hepatoprotection, anti-cancer, renal protection, cardioprotection properties” [17,21]. SA and its derivatives are useful in the pharmaceutical, cosmetic, and food industries due to their antioxidative properties [17,18]. Further, SA may be able to attenuate certain toxic effects that are caused by chemicals [17].

Several reports are available that demonstrate the role of SA in the management of diabetes [22,23,24,25,26]. A key characteristic of diabetes mellitus is hyperglycemia, which causes tissue damage, mediated by oxidative stress [27]. It was reported that “insulin-stimulated glucose uptake into peripheral tissues” is augmented by SA administration. Additionally, SA increases glucose uptake in primary target organs, which likely explains its insulin sensitization properties [16].

This study examined the influence of the ternary inclusion complex of HPβCD/HPMC on SA’s aqueous solubility and dissolution rate, as well as its antioxidant activity. Microwave irradiation (MI) was used to prepare the ternary inclusion complex of SA with HPβCD + HPMC. A phase solubility study was conducted to establish the stability constant of the ternary mixture. Further, the prepared TPM and SA-TIC were compared with SA alone in terms of their dissolution characteristics. In addition, the solid-state properties of pure SA, HPβCD, HPMC, and SA-TIC were characterized by “Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), and Scanning electron microscopy (SEM)”. Furthermore, “ABTS (2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)” radical cation and nitric oxide scavenging activity were used to determine the antioxidant activity of prepared SA-TIC and compared with pure SA.

2. Materials and Methods

2.1. Materials

SA was obtained from “Carbosynth Limited, Berkshire, UK”. HPMC and HPβCD were procured from “Sigma-Aldrich, St. Louis, MO, USA”. Ethanol and methanol were purchased from “Scharlab S. L., Sentmenat, Spain and Fisher Scientific UK, Limited, Loughborough, UK”, respectively. Other materials of analytical reagent grade were used.

2.2. Experimental Analysis of Phase Solubility

A phase solubility analysis was performed to determine the stability constant and complexation efficiency of the ternary mixture containing SA/HPβCD/HPMC. In this study, an excess quantity of SA was added into aqueous solutions containing HPβCD (2–10 mM), with and without HPMC (5%) [28]. At 25 °C, the flasks containing samples were repeatedly shaken for 72 h. Supernatants of the samples were carefully pipetted out and filtered across the membrane filter (0.45 µm), then the filtrate was spectrophotometrically analyzed at 322 nm [29,30]. In Equation (1), the stability constant (K_c) is determined by the slope of the phase solubility plot [31,32,33,34]. Equation (2) was used to assess each sample’s complexation efficiency (C_e) [32,35]. S₀ is the solubility of SA in water at equilibrium [36,37,38].

(1)$K_c=\frac{Slope}{Intercept \left(1-Slope\right)}$

(2)$C_e=S_0{K}_c$

2.3. Preparation of Physical Mixture and Inclusion Complex

The SA-ternary physical mixture (SA-TPM, 1:1) was prepared by proper mixing of each component of SA-TPM [SA: HPβCD: HPMC (5%)] with a mortar and pestle. The prepared TPM mixture was stored in a desiccator for dissolution testing. In this study, SA-TIC was prepared by adding the precise amount of SA to ethanolic water (7:3 v/v) along with HPMC. Following the addition of the HPMC to this mixture, the mixture was then placed in a microwave oven which was programmed to emit 600 W of microwave radiation “(Samsung ME0113M1; Malaysia)” [2,39,40]. Samples that had been irradiated were collected and cooled. Following the drying process, the dried mass was ground using a mortar and pestle and then passed through a #80 mesh sieve. A well-sealed desiccator was used to store the prepared dried ternary complex.

2.4. Dissolution Study

The test was carried out using the “USP dissolution apparatus II paddle system” for in vitro dissolution studies. For the assessment of dissolution profiles for SA, TPM, and TIC samples (equivalent to 100 mg of SA) were placed in a dissolution test vessel. The dissolution media, “phosphate buffered with pH 6.8 (900 mL), was kept at 37 °C ± 0.5 °C” and the paddle rotation speed was fixed at 50 rpm. The sample (5 mL) was withdrawn from the dissolution test vessels at every time point up to 60 min, and at the same time refilled with an equivalent volume of dissolution media. The filtered pipetted samples (4 mL) were then assessed for drug concentration using a UV spectrophotometer at 322 nm [29,30].

2.5. Differential Scanning Calorimetry

“DSC, Perkin Elmer, Pyris 6 System, Shelton, CT, USA” was used to assess the thermal analytical determinations of pure SA, HPβCD alone, HPMC alone, and TIC. The test sample of 5 mg was placed in an aluminum pan that had been crimped, and an empty aluminum pan was considered as a standard. During the testing process, a steady rate of 10 °C/min was applied to the DSC system during its operation at a temperature range of 50 °C to 300 °C [41].

2.6. Fourier Transform Infrared Spectroscopy

Further, the FTIR spectra of the pure SA, HPβCD alone, HPMC alone, and TIC sample were analyzed by “Alpha FTIR spectroscopy (Bruker, Karlsruhe, Germany)”. All samples were determined across a spectral range between 400 and 4000 cm⁻¹ [42].

2.7. Nuclear Magnetic Resonance Spectroscopy

The test specimens of the neat SA, HPβCD, and HPMC, as well as the SA-TIC, were solubilized in acetone-d6. Measurements of ¹H NMR were conducted by “Bruker NMR spectroscopy”. The values for the spectrum and chemical shift (δ) were reported as ppm [43,44].

2.8. Scanning Electron Microscopy

A SEM microscope (“EVO LS10, Carl Zeiss, Oberkochen, Germany”) was used for the analysis of surface features of pure SA, pure HPβCD, and HPMC, as well as the prepared complex SA-TIC. A SEM scan of the all samples was performed, and they were photographed under magnification and electronically captured [38,45].

2.9. ABTS Radical Cation and Nitric Oxide Scavenging Activity

The SA-TIC radical scavenging activity against the radical cation of ABTS was calculated [46]. Separately, a potassium persulfate solution (2.45 mmol/L) and an ABTS solution (7 mmol/L) were prepared in water. Both solutions were mixed 1:1 and stored at room temperature in the dark for 6 h. This period was marked by the production of the ABTS radical. An aliquot (0.1 mL) of SA-TIC was mixed with 2.9 mL of diluted ABTS radical cation solution. An absorbance measurement at 734 nm was taken after incubating the reaction for 20 min at 30 °C. The potency of the test sample to quench the ABTS free radical was assessed in accordance with Equation (3).

(3)$Scavenging activity (\%)=\frac{A_{control-}{A}_{test }}{A_{control}}\times 100$

Nitric oxide radical inhibition was estimated using Griess Illosvory reaction [47,48]. The nitric oxide scavenging activity of SA-TIC was estimated by using Equation (3) [49].

2.10. Statistical Analysis

“The findings of phase solubility and dissolution study were assessed statistically via one-way ANOVA followed by Dunnett test and Tukey test, whereas the unpaired t-test was performed for evaluating the significance of antioxidant efficacy. Analyses were conducted by GraphPad InStat^® 3.06 (GraphPad Software, Inc., San Diego, CA, USA) and *^{, $} p < 0.05 was considered significant”.

3. Results and Discussion

3.1. Phase Solubility

Analyses of phase solubility were performed on SA’s solubility in HPβCD with HPMC. It can be seen that SA solubility was augmented in increments in the concentration of HPβCD (Figure 1).

The solubility of SA was found to be 3.67 times higher in water in the presence of HPβCD/HPMC. The K_c and C_e values were found to be 961.90 M⁻¹ and 2536.56, respectively. Antecedent reports have revealed that a K_c value between 50 and 5000 M⁻¹ was found to be most suitable for improving the stability and solubility of poorly water-soluble drugs [28,50,51,52,53,54]. In our case, the K_c value was found to be 961.90 M⁻¹; an assessment concluded that the preparation of a SA/HPβCD/HPMC complex was stable [55]. Furthermore, HPMC increased the stability constant of the mixture, which led to enhanced SA solubilization. The outcomes advocating for a strong interaction between SA and HPβCD/HPMC have been accomplished, and this is evident from the higher K_c value.

3.2. Dissolution Study

In Figure 2, the dissolution profiles for SA, SA-TPM, and SA-TIC are illustrated. It was noted that the lowest rate of dissolution of the pure SA (27.63 ± 2.44%) was observed at 60 min compared to the rest of the formulations, such as SA-TPM and SA-TIC.

It has been speculated that this may be a result of SA’s poor solubility. Both the TPM and TIC formulations greatly enhanced the rate of dissolution of SA. During the dissolution study, it was found that approximately 47.27 ± 4.65% of the SA was released from TPM at 60 min. SA-TIC further improved the release of SA by a considerable amount compared with the pure SA and TPM. A maximum release of 77.56 ± 5.25% of SA was observed at 60 min from prepared complex SA-TIC (Figure 2). Recently, Ahad et al. developed a binary inclusion complex of SA with HPβCD using the solvent evaporation process. Authors stated that 2.59 times better solubility of SA in water was measured in the existence of HPβCD, and 46.27% drug release was reported for the prepared inclusion complex [56]. Another study evaluated SA-loaded “SNEDDS (self-nanoemulsifying drug delivery systems)” formulation. Comparing SNEDDS with SA suspension, the dissolution of SA was substantially improved. A considerable difference in efficacy was observed between SA suspension and SA in SNEDDS in in vivo anti-inflammatory studies in animal models [57].

In further steps of this study, samples of SA, HPβCD, HPMC, and SA-TIC were evaluated for solid state characterization.

3.3. Differential Scanning Calorimetry

DSC analysis is an important tool to determine the formation of an inclusion complex. In the DSC thermogram of the inclusion complex, the absence of an endothermic peak of the drug signifies that the guest molecule has melted, and this indicates that the complex has formed.

According to Figure 3, a notable absorption peak for SA can be found at 193.07 °C. In another study, Torrisi et al. concluded that the absorption peak is caused by the melting of SA [58]. The sample of HPβCD has a wide endothermic response, ranging from 50 to 100 °C, that can be linked to the water loss from the structure of the HPβCD [59]. It is interesting to note that as opposed to pure SA, the DSC curve of the TIC does not show any endothermic peak of SA at 193 °C. In this way, the disappearance of the endothermic drug peak could be interpreted as an indicator of SA/HPβCD/HPMC ternary complex formation.

3.4. Fourier Transform Infrared Spectroscopy

Character absorption peaks of SA and HPβCD were founded at 621.53, 1109.20, 1258.81, 1658.46 cm⁻¹, 1021.94, and 3344.17 cm⁻¹, respectively (Figure 4), while the stretching vibration at 1049.05 cm⁻¹ was the main noticeable peak for HPMC.

In this study, it was found that the inclusion complex spectrum differed significantly when compared with the FTIR spectra of pure SA. In addition, substantial decreases in intensity and expanded peak shapes were observed in the FTIR spectra of SA-TIC. This could be due to an interaction that had transpired between SA, HPβCD, and HPMC, resulting in a decrease in peak intensity and displacement. As shown in Figure 4, the characteristic peaks of SA at 621.53 to 1658.46 cm⁻¹ were nearly absent in the inclusion complex spectrum. All such changes in the spectra effectively demonstrated the inclusion of SA into the hydrophobic interior of HPβCD.

3.5. Nuclear Magnetic Resonance Spectroscopy

The proton NMR spectrum of SA in acetone-d6 showed a distinct singlet at 7.62 ppm, which was attributed to the Ar-CH = CH group. The singlet OH and OCH3 peak for the SA was also observed at 𝛿 6.41 and 3.91 ppm, respectively [60,61], while the structure of HPβCD exhibited triplet and duplet peaks at 𝛿 values of 2.07 and 2.09 ppm, respectively (Figure 5). One singlet peak was observed at 𝛿 value 2.06 ppm, and two distinct peaks were also seen at 𝛿 2.86 and 2.90 ppm in the NMR spectra of HPβCD. However, in the NMR spectra of HPMC, distinct peaks were seen at 𝛿 2.06, 2.86, and 2.89 ppm (Figure 5).

NMR spectra of the prepared complex SA-TIC portrayed changes in the 𝛿 values, which were observed to be different from the NMR spectra of pure SA, HPβCD, and HPMC. The ¹H NMR values of SA-TIC demonstrated that peaks of HPβCD and HPMC showed considerable shifting. Some additional peaks were also detected in SA-TIC samples that could be attributed to the HPβCD and HPMC, demonstrating the development of TIC. The NMR spectroscopic findings depicted evidence of the interaction between the pure SA and HPβCD and HPMC, which contributes to the development of inclusion complexes.

3.6. Scanning Electron Microscopy

As shown in Figure 6, TIC, HPβCD, and HPMC were characterized using SEM. The surface of SA gives the impression of being fairly smooth and compact. HPMC appears to be elongated, thin, crumpled, and slightly distorted. The HPβCD sample has a rough surface and a thick appearance.

In micrographs of TIC, however, SA crystals and HPβCD exhibit different characteristic patterns. No evidence of SA’s compact solid appearance could be found in the TIC complex. When the sample of TIC was observed, it appeared as if HPMC was layered on the surface of SA/HPβCD. The formation of the inclusion complex is strongly supported by the changes in both the crystal structure and morphology observed in TIC sample.

3.7. ABTS Radical Cation and Nitric Oxide Scavenging Activity

Antioxidant activity is more readily recognized using the ABTS assay. This might be due to its more rapidly reaction kinetics and more potent reaction time to antioxidants [62,63]. Nithya and Subramanian found that SA exhibits 86.5% and 88.6% ABTS radical scavenging and superoxide scavenging activity at 50 μM concentration, and this clearly demonstrates its antioxidant potential. The findings of our investigation are consistent with those of the preceding literature, providing evidence that SA strongly scavenges free radicals [64].

SA’s ABTS radical scavenging activity was strongly influenced by the complexation with HPβCD and HPMC. It was demonstrated that the SA-TIC is able to scavenge the ABTS radical cation to a higher extent than pure SA (Figure 7).

The antioxidant capacity of pure SA was noted to be 94.47% at 100 µg/mL concentration, and it has been found to be significantly higher for SA TIC (96.31%). There was also a substantial difference in nitric oxide scavenging activity between the pure SA and the SA-TIC sample. The sample of SA-TIC demonstrated 73.80% scavenging activity at 100 μg/mL concentration, in contrast to pure SA, which showed 63.28%. The outcomes of ABTS radical cation and nitric oxide scavenging activity demonstrated that the SA-TIC presented strong antioxidant activity. This might be a result of the enhanced solubility of SA in TIC.

Based on the outcomes of present study, it can be concluded that CDs can be used as excipients in SA-loaded formulations, since they form inclusion complexes with SA, showing improvements in physicochemical properties compared to free SA. Further, this study showed improvement in the aqueous solubility of SA without the addition of the organic solvents, surfactants, or lipids. This further increases the dissolution rate, and could contribute to ameliorating the oral bioavailability of SA. In addition to this, SA-TIC exhibited better antioxidant activity compared to SA alone. Hence, SA-TIC formulation could be a better dosage form to protect the body from free radical damage and oxidative stress.

4. Conclusions

It was demonstrated in the present study that the microwave irradiation method was successful in preparing SA ternary inclusion complex with HPβCD/HPMC. Outcomes of phase solubility exhibited that HPβCD/HPMC caused solubilization of SA. Compared to water, SA’s solubility was 3.67 times higher in the presence of HPβCD/HPMC. The formulation of SA-TIC greatly enhanced the rate of dissolution of SA. A release of 77.56% of SA was observed at 60 min from the prepared complex SA-TIC. Further analysis viz. DSC, FTIR, NMR, and SEM confirmed the embedding of SA into the cavity of the HPβCD and the formation of the ternary inclusion complex. Moreover, the SA/HPβCD/HPMC ternary inclusion complex substantially augmented the antioxidant activity of SA. The inclusion complex of SA with HPβCD/HPMC depicted a high dissolution rate and, consequently, it is an excellent candidate for developing pharmaceutical formulations of SA. It is anticipated that the formation of inclusion complexes with CDs may improve the properties of SA formulations, ameliorating the antioxidant effectiveness for future applications.

Author Contributions

“Conceptualization, A.A. and F.I.A.-J.; formal analysis, A.A.; funding acquisition, Y.A.B.J.; writing—original draft, A.A.; writing—review and editing, F.I.A.-J., A.M.A.-M., Y.A.B.J. and M.R. All authors have read and agreed to the published version of the manuscript.”

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data generated from the experiments have been presented in the results.

Acknowledgments

“The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project no. (IFKSURG-2-235).”

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Figure 1. (A) Phase solubility profile of SA in presence of HPβCD and HPMC (5%) and (B) SA solubility enhancement ratio in presence of HPβCD and HPMC (5%), * p < 0.05 as compared to S0.

Figure 2. Dissolution profile of SA, TPM, and TIC, * p < 0.05 as compared to SA, $ p < 0.05 as compared to TPM.

Figure 3. DSC thermograph of SA, HPβCD, HPMC, and TIC.

Figure 4. FTIR spectra of SA, HPβCD, HPMC and TIC.

Figure 5. NMR spectra of SA, HPβCD, HPMC, and TIC.

Figure 6. SEM graph of SA, HPβCD, HPMC, and TIC.

Figure 7. (A) ABTS and (B) nitric oxide scavenging activity of SA and TIC, * p < 0.05, as compared to SA.

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