Int J App Pharm, Vol 17, Issue 1, 2025, 216-223Original Article

ULTRA-FAST SYNTHESIS OF CURCUMIN-LOADED SILVER NANOPARTICLES: IMPROVED PHYSICOCHEMICAL PROPERTIES FOR DRUG DELIVERY

CHONG XUE LI1, GAMAL OSMAN ELHASSAN2, SIHAM A. ABDOUN2, RIYAZ AHMED KHAN2, MANOJ GOYAL3, MONIKA BANSAL4, JAMAL MOIDEEN MUTHU MOHAMED1*

1Faculty of Pharmacy and BioMedical Sciences, MAHSA University, Bandar Saujana Putra, 42610 Jenjarom, Selangor, Malaysia. 2Department of Pharmaceutics, College of Pharmacy, Qassim University, Buriadah, K. S. A. 3Department of Anesthesia Technology, College of Applied Medical Sciences in Jubail, Imam Abdul Rahman Bin Faisal University, Dammam, Saudi Arabia. 4Department of Neuroscience Technology, College of Applied Medical Sciences in Jubail, Imam Abdul Rahman Bin Faisal University, Dammam, Saudi Arabia
*Corresponding author: Jamal Moideen Muthu Mohamed; *Email: jamalmoideen@mahsa.edu.my

Received: 13 Sep 2024, Revised and Accepted: 16 Nov 2024

ABSTRACT

Objective: This study focused on the green synthesis of silver nanoparticles (AgNPs) using fresh garlic extract (Allium sativum-AS) as a reducing agent for the efficient delivery of curcumin (CuR), a natural anti-cancer agent used in breast cancer therapy.

Methods: The study began with the preparation of fresh AS, which was then mixed with silver nitrate (AgNO₃) solution and CuR solution under sunlight for the green synthesis of stable CuR-loaded nanoparticles (C-AgNPs). This method not only offered an eco-friendly approach to the synthesis of C-AgNPs but also highlighted the potential physicochemical characterization of AS and CuR in this context. Moreover, this study assesses the characteristics of the resulting C-AgNPs and conducts a comparative analysis with different formulations to evaluate their efficacy.

Results: The prepared C-AgNPs, characterized by Fourier-Transform Infrared Spectroscopy (FTIR), indicated that CuR, silver nitrate (AgNO₃), and AS extract were successfully incorporated, confirming the successful synthesis. The optimized preparation, referred to as AgNP1, demonstrated an entrapment efficacy of 74.24±5.87%, a drug loading of 95.99±7.81%, and a drug content of 96.11±7.82%. Additionally, the cumulative percentage of drug release was found to be 57.12±2.76% at 180 min. The drug was successfully loaded into the C-AgNPs, exhibiting physicochemical compatibility without any adverse chemical interactions with the additives used.

Conclusion: In conclusion, this study demonstrated that nanoparticle-based drug delivery systems offer a significant advancement over conventional therapies by providing controlled and efficient drug delivery, thereby improving therapeutic outcomes.

Keywords: Drug delivery, Green synthesis, Drug formulation, AgNPs, Curcumin, In vitro study, Garlic extract

© 2025 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijap.2025v17i1.52647 Journal homepage: https://innovareacademics.in/journals/index.php/ijap

INTRODUCTION

Nanotechnology is an interdisciplinary field focused on the manipulation and engineering of materials at the nanoscale, which generally spans dimensions between 1 and 100 nm. At this scale, materials display distinct properties and behaviors that are not observed at larger dimensions. The small size of nanoparticles (NPs) imparts distinctive properties, such as large surface area-to-volume ratios and quantum effects [1, 2]. These properties make NPs useful as drug delivery vehicles, particularly for cancer therapy. Owing to their diminutive size and expansive surface area, NPs carrying drugs exhibit heightened solubility, leading to improved bioavailability.

Novel Drug Delivery Systems (NDDS) are advanced techniques designed to enhance the delivery of drugs. These systems address the limitations of traditional drug delivery methods by improving bioavailability, enhancing solubility, controlling drug delivery, targeting specific sites within the body, and increasing patient compliance [3]. Additionally, NDDS enhances efficacy, reduces side effects, and increases convenience. They represent a significant evolution in the pharmaceutical industry, offering improved methods for drug administration that enhance therapeutic efficacy while minimizing side effects. Their continued development and implementation are crucial for advancing modern medicine [4].

Curcumin (CuR) is a natural polyphenol compound derived from the turmeric plant (Curcuma longa) with potential anticancer and anti-inflammatory properties. Additionally, CuR acts as a powerful antioxidant, scavenging free radicals and protecting cells from oxidative stress and DNA damage. Its ability to modulate cell cycle progression and induce apoptosis in cancer cells contributes to its anticancer effects. However, its clinical application is hampered by challenges related to low solubility, limited bioavailability, and rapid degradation [5, 6]. Hence, nanoparticle-based drug delivery systems have emerged as a solution to these challenges, facilitating enhanced stability, controlled release, and targeted delivery of therapeutic agents.

Garlic (Allium sativum-AS) has a long history of medicinal use, attributed to its bioactive compounds such as allicin, ajoene, and various sulfur-containing compounds. Renowned for its medicinal properties and rich bioactive content, AS offers a natural and sustainable avenue for creating nanoparticles (NPs). The decision to utilize AS stems from its abundance, biocompatibility, and the eco-friendly nature of green synthesis methods [7]. As a versatile source of bioactive compounds, AS not only serves as a stabilizing and reducing agent in NP synthesis but also provides antioxidant and therapeutic properties [8]. This dual role of AS in green synthesis aligns with the principles of sustainability, minimizing environmental impact and offering a promising pathway for the development of NPs with diverse applications, making AS an attractive candidate for NP formulation through a green synthesis approach [9].

The convergence of CuR and AS within the framework of NPs holds the promise of synergistic anticancer effects. Both CuR and AS compounds have individually demonstrated anticancer activities, and their combined potential, when encapsulated in NPs, is an uncharted territory that demands exploration [10]. This study aims to pioneer the green synthesis of CuR-loaded AS nanoparticles (C-AgNPs) and subsequently comprehensively characterize these NPs. Furthermore, the study seeks to evaluate the in vitro drug release and physicochemical properties of these NPs, specifically through Fourier-Transform Infrared Spectroscopy (FTIR), offering insights into their potential as effective therapeutic agents.

The green synthesis approach is a key aspect of this research, underscoring the commitment to environmentally sustainable practices. Traditional methods of nanoparticle (NP) synthesis often involve the use of harsh chemicals and energy-intensive processes, contributing to environmental degradation. In contrast, green synthesis methods utilize natural resources and environmentally benign techniques, minimizing ecological impact and promoting sustainable technologies [11]. The incorporation of AS in this synthesis not only aligns with the green synthesis ethos but also highlights the inherent medicinal properties of AS compounds.

MATERIALS AND METHODS

The curcumin (CuR) used was obtained from Sisco Research laboratories Pvt. Ltd., (Maharashtra, India). Fresh garlic (Allium sativum-AS) cloves were purchased from the local market of Bandar Saujana Putra (Selangor, Malaysia). Silver nitrate (AgNO3), ethanol and distilled water procured from Merck, Germany. All the experiments utilised double distilled water. Analytical-grade substances and components were used throughout.

Preparation of calibration curve

CuR concentration was estimated using the UV spectrophotometric technique. CuR was dissolved in ethanol, and the appropriate volume was added to prepare a stock solution of 1 mg/ml. Double-distilled water was used to further dilute this stock solution to obtain a concentration of 10 µg/ml. Aliquots of these solutions were placed into a quartz cell and subjected to a UV spectrophotometer (SECOMAM UviLine 9400, Selangor, Malaysia) to measure λmax in the 200–800 nm range, using double-distilled water as a blank. Plotting concentration against absorbance produced the standard calibration curve, with various CuR solution concentrations constructed in the range of 1–10 µg/ml [12].

Preparation of C-AgNPs

Preparation of AS extract

20 cloves of AS were used, with the outer skins manually removed. The AS cloves were then washed with sterile distilled water and allowed to air dry at room temperature for 1 h [13]. An aqueous fresh AS extract was prepared by grinding the cloves with 50 ml of double-distilled water using a Trio Blender, Chopper and Miller (Malaysia). The mixture was then filtered through Whatman filter paper (11 µm) to eliminate solid particles. The resulting filtrate was stored in the refrigerator at 4 °C for about 1 h while preparing the CuR and AgNO₃ solutions to maintain stability for subsequent use.

Green synthesis of silver nanoparticles (AgNPs)

For the synthesis of C-AgNPs, table 1 presents the appropriate quantities of CuR and AgNO₃. CuR was dissolved in 0.5 ml of ethanol and 0.5 ml of double-distilled water to form a CuR solution, while AgNO₃ was dissolved in 18 ml of distilled water to create an aqueous AgNO₃ solution. An appropriate quantity of aqueous AS extract was then added to the CuR solution and mixed well. Subsequently, 18 ml of the AgNO₃ solution was added to the mixture, which was continuously stirred (650 rpm) using a flat spin magnetic stirrer (Dragon Lab, Flatspin Magnetic Stirrer 8030184000, Selangor, Malaysia) and exposed to sunlight for the silver ion reduction process (35 °C under dry and hot conditions). After a few seconds (within 3 sec), the yellowish solution turned reddish-brown, indicating the formation of silver colloids [14]. The color intensity increased over time and plateaued after 15 min. Lastly, the sample was placed in a freeze dryer (ScanVac CoolSafe 110-4, Selangor, Malaysia) and allowed to freeze-dry for 36 h to obtain the final products. The procedure was repeated for the preparation of blank AgNPs; however, the formulation of AgNPs (B) was adjusted to use 100 mg of CuR and 50 mg of AgNO₃.

Drug assay and yield

Following a 2 ml ethanol dilution, pure CuR, AgNPs, and C-AgNPs equivalent to the weight of CuR were sonicated. Double-distilled water was used for further dilutions, and UV absorbance was recorded. A standard calibration curve at a wavelength of 423 nm was used to quantify the drug content, and the material balance was computed in relation to that content [15]. The following formula was used to calculate the yield percentage based on the initial amount.

…….. (1)

Table 1: Various preparation of C-AGNPs

S. No. Ingredients Codes
C-AgNP1 C-AgNP2 C-AgNP3
1 CuR (mg) 50 100 75
2 AgNO3 (mg) 100 50 50
3 AS extract (mL) 0.5 1 1.5

Drug loading (DL)

The freeze-dried C-AgNPs were dissolved in 0.5 ml of ethanol and an appropriate quantity of distilled water for dilution. The solution was then filtered through a 0.45 µm membrane filter, and the concentration was measured at 423 nm using a UV-Vis spectrophotometer [15]. The following equation was used to quantify the drug loading (DL) capacity from C-AgNPs.

……….. (2)

Percentage drug entrapment efficiency (%EE)

The CuR % encapsulation efficiency (%EE) in C-AgNPs was determined based on the supernatant collected during the nanoparticle formulation. The clear supernatant was obtained after centrifugation at 6000 rpm for 15 min and analyzed using UV-visible spectroscopy at 423 nm. The following equation (3) was used to calculate the drug %EE [16].

……….. (3)

Fourier-transform infrared spectroscopy (FTIR) study

FTIR was used to confirm the formation of C-AgNPs and to determine the functional groups of CuR. Two milligrams of CuR, blank AgNPs, and C-AgNPs were scanned using an FTIR spectrometer (FTIR Perkin Elmer, Spectrum Two, Selangor, Malaysia) in the range of 4000–400 cm⁻¹ with the settings of 20 scans and a resolution of 4 [16].

In vitro cur release

The dialysis bag method was used for the in vitro drug release investigation. A small quantity of PBS dissolving media was introduced to a cellulose dialysis bag (Molecular cutoff: 12,000 KDa) containing nanocrystals equivalent to 5 mg of the drug. The bag was sealed at both ends and placed in a beaker with 1x PBS and pH 6.4. At each time interval, 5 ml aliquots were removed and replaced with fresh dissolving media until 180 min. A UV spectrophotometer was used to test the samples at 423 nm [17].

Release kinetics

The dissolution release kinetics of the prepared C-AgNPs were calculated using first-and zero-order equations. Higuchi, Hixson-Crowell, Korsmeyer-Pappas, and release exponent (n) equation models were then used to further characterize the drug release mechanism [12]. To determine the pattern of release from the C-AgNPs, other parameters and the regression coefficient (R²) were computed.

Statistical analysis

The data derived from three measurements taken in triplicate are reported as mean values and standard deviations. Statistical analysis was conducted using Student’s t-test after performing a one-way analysis of variance (ANOVA), with the analyses carried out using SPSS software.

RESULTS AND DISCUSSION

The λmax of CuR was determined first by scanning solution of CuR in a UV spectrophotometer (fig. 1a) and the λmax was found to be 423 nm as shown in fig. 1a and the calibration curve of CuR was plotted as shown as fig. 1b.

Drug content and yield

The amount of CuR present in the prepared C-AgNPs ranges from 92.23±8.41 to 96.11±7.82 % and the material loss concerning the CuR content was estimated to be 2.79± 0.81 to 4.86±0.93 % of the material (fig. 2). After obtaining the product, the higher material loss was observed with C-AgNPs3>C-AgNPs2>C-AgNPs1 due increased the concentration of AS extract according to the previous study [18].

Fig. 1: (a) UV scan (at the concentration 5 µg/ml in the range of 200 to 800 nm) and (b) standard calibration curve of CuR, each value signifies mean±SD, n = 3

EE and DL

The C-AgNPs exhibited ideal drug loading (>60%). However, to increase drug loading, other factors such as reaction time, temperature, and the drug-to-Ag precursor ratio may need to be further considered and optimized. The percentages of encapsulation efficiency (EE) and drug loading (DL) of C-AgNPs varied from 58.56±4.18% to 74.24±5.87% and from 89.23±6.14% to 95.99±7.81% (fig. 2). Approximately 90% of the total output was due to the highest absorption of C-AgNPs, which occurred between 200 and 400 nm, with a peak observed at 423 nm (p>0.05). This measurement indicates that the EE was between 95% and 105% of CuR, which is the reference (label amount) range [19]. Due to its smaller size and maximum DL (95.99±7.81%) and EE (74.24±5.87%), CAgNP1 was chosen as the best formulation for this investigation. The lipophilic property of CuR (log P = 3.29) and the CuR: AgNO₃ ratio of C-AgNP1 were found to be 1:2. This suggests that incorporating a positively charged carrier, such as Ag⁺, could enhance EE [20].

FTIR outcome

Fig. 3 displays the FT-IR spectra of AS extracts, pure CuR, AgNO₃, AgNPs, and CAgNPs that were used to prepare the nanoparticles (NPs). The wavenumbers for each spectrum and the characteristics of the functional bands observed are listed in table 2. The peak in the CuR spectrum at 3440.22 cm⁻¹, corresponding to −OH (alcohol) stretch vibrations, was present, suggesting the existence of a hydroxyl group. It was evident from the peaks at 1739.88 and 1631.29 cm⁻¹ that the structure contained C=O (carbonyl) groups, indicative of the presence of a conjugated ketone group in the compound. According to an earlier investigation published by Mohamed et al. (2022), the C–H (alkane) stretch vibrations at 2931.01 and 2851.09 cm⁻¹ and the C=C (aromatic) stretch vibrations at 1589.87 and 1510.23 cm⁻¹ were also noticeable [21].

Fig. 2: (a) % EE and (b) % DL of prepared C-AgNPs. * Each value signifies mean±SD, n = 3

Table 2: FTIR spectrum and its wavelength of prepared C-AGNPs

Formulation Absorption (cm−1) Chemical groups Compound class
C-AgNPs 3011.38 Weak O-H stretching Alcohol
1508.23 C-H bending Alkane
1225.14 Strong C-H stretching Amine salt
1205.44 Strong S=O stretching Sulfonamide
963.06, 807.90 C=C bending Ester
AgNPs 3272.57 N-H stretching Primary amine
2936.72 C-H stretching Alkane
1507.09 C=N stretching Imine/oxime
1428.16 Strong S=O stretching Sulfonamide
1232.92, 1205.66 Strong C-O stretching Ester
963.33, 855.81 C=C bending Ester
Pure CuR 3322.14, 3020.22 O-H stretching Alcohol
2931.01, 2851.09 C=C stretching Aromatic
1739.88, 1631.29 C=O stretching Carbonyl
1589.87, 1510.23 C-C stretching Aromatic
AgNO3 3419.23 O-H stretching Alcohol
1752.91, 1642.89 C=O stretching Esters
1308.07 C-H bending Amine salt
1044.23 S=O stretching Sulfoxide
829.89, 799.12 N-O bending Nitro compound
AS Extract 3235.22 O-H stretching Alcohol
1741.12, 1625.29 C=O bending Carbonyl
1534.87 C-C stretching Aromatic
934.32 C=C bending Ester

The FTIR spectrum of C-AgNPs (fig. 3) showed a peak at 3011.38 cm⁻¹, which indicated the presence of aromatic C–H stretching groups in CuR. The peaks at 1275.14 cm⁻¹ and 1205.44 cm⁻¹ corresponded to the stretching vibrations of the phenolic C–O bond in CuR. Additionally, the FTIR spectrum also showed a peak at 1508.23 cm⁻¹, indicating the presence of an aromatic ring in the AS extract, which acted as a reducing agent for the nanoparticles (NPs). CAgNPs with a higher concentration of CuR showed greater intensity of peaks for the aromatic ring and phenolic hydroxyl groups [22].

The FTIR spectrum of AgNO₃ showed a peak at 800.69 cm⁻¹, reflecting the symmetric stretching of N–O bonds. AgNO₃ itself does not exhibit distinct peaks in the FTIR spectrum because it is a salt and lacks characteristic functional groups that produce strong IR absorptions. The FTIR spectrum of AS extract exhibited C–S stretching vibrations at 1098.67 cm⁻¹, indicating the presence of sulfur-containing compounds in AS, such as allicin. The peaks at 3331.14 cm⁻¹ and 3020.22 cm⁻¹, corresponding to −OH (alcohol) stretch vibrations, suggest the existence of two hydroxyl groups. It was evident from the peaks at 1739.88 cm⁻¹ and 1631.29 cm⁻¹ that the structure contained C=O (carbonyl) groups.

Fig. 3: FTIR spectrum of (a) Pure CuR, (b) AgNO3, (c) AS extract, (d) AgNPs, and (e) C-AgNP1 were obserbed at 1500 – 3500 cm–1

In vitro CuR release

Fig. 4 displays the cumulative CuR release profiles from C-AgNPs. As a control, pure CuR in 1X PBS was employed. For the in vitro release of CuR, a pH of 6.8 in PBS was selected, as it is similar to the physiological conditions of human tissues. The pH, which has been shown to be a crucial factor in many therapies, influences how the drug is released. Normal tissue has a different pH than disease-induced tissues and organs, depending on the pathological processes occurring in those tissues [23, 24]. Under the pH 6.8 condition, pure CuR release was sustained, and no early burst release was observed, suggesting a potentially advantageous use of the phytogenic C-AgNPs for topical and intravenous delivery.

The rate of CuR release was found to be half that of pure CuR in the pH 6.8 and internal gastrointestinal (GIT) environments. C-AgNPs demonstrated slower, more prolonged, and regulated drug release (sustained release). Maintaining the physiological pH of the body at 6.8 is beneficial, as the average amount of CuR released from C-AgNPs at that pH reduces the toxicity of CuR to normal tissue. Mohamed et al. (2022) also found that isoniazid (INH)-AgNCs exhibited a controlled and prolonged release (up to 180 min) of the drug; in pH 5.7 (weakly acidic) and pH 7.2 (neutral) conditions, the release rate was observed to be 3 to 4-fold lower than that of free INH [25].

Release kinetics

The Korsmeyer-peppas model (0.999±0.10) provided a better explanation for the in vitro release of CuR from C-AgNPs compared to the first-order (0.993±0.07) release kinetics, as displayed in table 3. The Korsmeyer-Peppas model is a mathematical equation used to describe drug release from polymeric matrices.

Fig. 4: In vitro CuR release from C-AgNPs prepared using AS as the reducing agent at 37 °C and pH 6.8. The control was 1X PBS containing pure CuR, *Each value signifies mean±SD, n = 3

Table 3: In vitro CuR release kinetics of free CuR and various C-AgNPs

Correlation coefficient (r2) Release exponent (n)
Codes Zero-order First order Higuchi Hixon Crowell Korsmeyer-peppas
Free CuR 0.887±0.05 0.982±0.09 0.872±0.03 0.962±0.02 0.870±0.08 0.421±0.04
C-AgNP1 0.989±0.06 0.993±0.07 0.966±0.08 0.712±0.09 0.999±0.10 0.773±0.02
C-AgNP2 0.883±0.14 0.989±0.08 0.892±0.12 0.954±0.18 0.997±0.05 0.672±0.09
C-AgNP3 0.891±0.09 0.979±0.08 0.971±0.05 0.941±0.21 0.980±0.06 0.681±0.09

*Each value signifies mean±SD, n=3.

The release mechanism was complex, involving both diffusion and other factors. The release rate is between Fickian and case II transport. This could be advantageous for controlled-release systems with a balance of rapid and sustained release fig. 5. Compared to free CuR, the release of CuR from C-AgNPs may be more effectively diffusion-controlled with a prolonged release. It relates the amount of drug released to time and a release exponent (n). This exponent provides insights into the mechanism of drug release. 0.5<n<1.0 (0.773±0.02), suggests anomalous diffusion. The drug release from C-AgNPs releases as a combination of Fickian diffusion and such as relaxation of the cross-linking complex with CuR with AgNO3 chains [26].

By understanding the release exponent, researchers can tailor the properties of nanoparticles and polymeric matrices to achieve desired drug release profiles for various therapeutic applications [27].

Fig. 5: Mechanism of CuR release kinetics of various models such as (a) zero-order, (b) first order, (c) Higuchi model, (d) Korsmeyer-Peppas model, and (e) Hixson-Crowell release from C-AGNP1

CONCLUSION

In summary, the ultra-fast synthesis of CuR-loaded silver nanoparticles has demonstrated significant advancements in the physicochemical properties critical for effective drug delivery. The study highlights the successful enhancement of drug loading capacity and entrapment efficiency, as evidenced by FTIR analysis and other characterization techniques. The in vitro drug release profiles indicate a controlled release mechanism, which can potentially improve therapeutic outcomes. These findings suggest that the developed silver nanoparticles not only enhance the bioavailability of CuR but also hold promise for applications in targeted drug delivery systems. Future studies should explore the in vivo efficacy and safety of these nanoparticles to further validate their potential in clinical settings. Additionally, future research should include particle size analysis to fully characterize the size distribution of the nanoparticles, which is crucial for optimizing their performance in drug delivery applications.

FUNDING

Nil

AUTHORS CONTRIBUTIONS

All authors contributed equally to that manuscript regarding design of experiments, experimental work, preparing and reviewing the manuscript before submission. All the authors contributed significantly to this manuscript, participated in reviewing/editing and approved the final draft for publication. Conceptualization (Jamal Moideen Muthu Mohamed); methodology (Jamal Moideen Muthu Mohamed and Chong Xue Li); software (Gamal Osman Elhassan); validation (Jamal Moideen Muthu Mohamed); formal analysis (Jamal Moideen Muthu Mohamed and Chong Xue Li, Riyaz Ahmed Khan); investigation (Gamal Osman Elhassan and Chong Xue Li); resources (Jamal Moideen Muthu Mohamed, Siham A. Abdoun and Gamal Osman Elhassan) data curation (Jamal Moideen Muthu Mohamed and Gamal Osman Elhassan); writing—original draft preparation (Manoj Goyal and Siham, Monika Bansal, A. Abdoun); review (Siham A. Abdoun and Riyaz Ahmed Khan); visualization (Jamal Moideen Muthu Mohamed and Riyaz Ahmed Khan); supervision (Jamal Moideen Muthu Mohamed); project administration (Manoj Goyal); funding acquisition (Gamal Osman Elhassan, Manoj Goyal and Monika Bansal).

CONFLICT OF INTERESTS

The authors have no conflicts of interest

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