Investigation of the loading and release behavior of paracetamol, mesalazine, and carbamazepine utilizing Cu-and Zn(BDC) MOFs

Abstract

In this work, Cu(BDC) and Zn(BDC) metal organic frameworks were synthesized using an ultrafast ultrasound-assisted method at room temperature for loading and releasing the drugs paracetamol, carbamazepine, and mesalazine. The synthesized MOFs were characterized and identified using FT-IR, XRD, TGA, SEM, and UV-Vis analyses, and the characterization data were complemented by BET and EDX surface area measurements. BET results confirmed the porous structure of the MOFs, and EDX confirmed the complete removal of CTAB and successful drug incorporation. The loading behavior of the MOFs were evaluated using TGA, which showed efficiencies of 21.3% (paracetamol), 20.8% (carbamazepine), and 33.1% (mesalazine) for the Cu(BDC) MOF, while 25.2%, 61.1% and 36.4% were achieved for the same drugs using the Zn(BDC) MOF. Drug release studies were performed in phosphate buffer solution at 37°C, simulating physiological conditions. The results showed that the ultrasonically synthesized Cu-BDC and Zn-BDC MOFs possess stable porosity, effective drug loading capability, and distinct release behaviors. This comparison highlights their potential as tunable platforms for controlled drug delivery applications.

Introduction

Due to the rapid advancement of materials chemistry, significant efforts have been made to develop novel micro- or nanoplatforms aimed at creating controlled and intelligent drug release systems in order to increase treatment efficacy while reducing side effects¹. Using metal-organic frameworks (MOFs) is a practical way to develop novel nanoplatforms².

MOFs offer appealing alternatives in a numerous of areas, such as sensing, magnetism, gas storage, separation, and catalysis. Recently, there has been a lot of interest in the biological applications of MOFs, particularly in the areas of drug delivery and bio imaging. These compounds constitute a new class of materials and a specific therapeutic option for the treatment of diseases^2–10.

The metal centers that are present in various MOFs determine their characteristics. For MOFs to be safe and biocompatible, metal cations are crucial. Li⁺, Na⁺, Mg²⁺, Al³⁺, K⁺, Ca²⁺, Fe³⁺, Ni²⁺, Cu²⁺, Zn²⁺, etc. are the primary metal cations utilized in MOFs. According to early studies, the atomic weight of metal cations determines how toxic they are; heavier metals are typically regarded as dangerous. On the other hand, the human body may benefit from trace amounts of heavy metal cations. Trace elements, which are found in the human body at concentrations below 0.01% but are essential for sustaining normal physiological metabolism, include elements like Li, Al, Fe, Ni, Cu, Zn, Rb, Bi, and Ho. Clinical research indicates that trace amounts of Fe, Cu, and Zn are beneficial to the human immune system. Deficits in these elements may lead to decreased resistance to infections¹¹.

Notable properties of MOFs include large surface areas, resistance to heat and chemical changes, stable luminescence, high crystallinity, adjustable pore widths, and a variety of internal surface functionalities^12–16. Compared to traditional porous materials such as zeolites and activated carbon, MOFs offer clear advantages due to their inherent flexibility, stable structure, and customizable nature. Conventional porous materials, like silica and zeolites, have stable structures that restrict drug bio elimination and may have harmful effects. On the other hand, certain polymers and liposomes break down to release medications. Low adsorption capacity and uncontrolled drug release, which causes the "burst effect," are common problems with previously assessed drug delivery systems (DDS). By bridging organic and inorganic materials and enabling the gradual release of medications through structural degradation, the investigation of novel DDSs, especially MOFs, offers a promising solution to this problem^16,17. By varying some reaction process parameters, such as organic ligands, metal ions, solvents, metal-to-ligand ratios, pH levels, and reaction conditions, MOFs can exhibit a broad range of topologies, morphologies, pore sizes, volumes, and surface characteristics^13,18–21.

MOFs have long been synthesized using solvothermal methods. These processes involve dissolving metal precursors and organic linkers in an organic solvent at high temperatures and pressures. MOF crystallization is often aided by electrical heaters. However, the disadvantages of solvothermal batch processes include lengthy reaction times, low product yields and quality, and high energy consumption^22,23. To reduce the overall synthesis time, current research has focused on developing more environmentally friendly and energy-efficient methods for the synthesis of MOFs²⁴. Alternative methods like sonochemical, microwave-based, acid-free, mechanochemical, electrochemical, and water-based approaches have been investigated for the synthesis of MOFs²⁵. In this case, employing ultrasonic techniques can produce a more precise particle size distribution, a quicker reaction time, and improved phase selectivity²⁶.

Zinc is one of the most commonly used metals in biological applications due to its low toxicity and reasonable cost. Zn-MOFs have therefore recently garnered interest as potential materials for these applications. The synthesis and uses of Zn-MOF nanoparticles have been the subject of numerous published investigations²⁷.

Moreover, Cu(II)/Cu(I)-based MOFs are a suitable substitute for Zn-based MOFs due to their exceptional biocompatibility, substantial drug loading capacity, significant surface-enhanced Raman scattering (SERS) effects, and advantageous opto-thermal properties².

Numerous studies have examined the use of MOFs based on zinc and copper in biological applications and drug delivery. Javabakht et al.²⁸ synthesized the Zn(BDC)@CMC framework with a yield of 50.95% and evaluated its efficacy in ibuprofen loading; these results indicated that the biopolymer CMC might improve the MOF’s in situ growth and loading capacity. In a different study, Nakhaei et al. produced three types of MOFs using the solvothermal method: MOF-5, Zn-MOF, and TMU-3, demonstrating the biological potential of zinc-based MOFs. The antibacterial efficacy of these MOFs against both Gram-positive and Gram-negative bacteria was then evaluated²⁹.

Furthermore, Nadizadeh and colleagues³⁰ used a solvent-free mechanochemical method to create a copper-based MOF and found that increasing the BDC ratio could improve drug encapsulation capability. In another study, Soltani and colleagues synthesized Cu-BTC MOF and documented the antibacterial activity of CHX@Cu-BTC nanostructure, demonstrating its exceptional stability and potency for medical applications³¹.

MOFs have recently been studied for drug delivery of a wide range of therapeutic classes, including anticancer drugs, anti-inflammatory drugs, antibiotics, and poorly soluble drugs, due to their high porosity, good stability, and controlled release capability^32,33. Among these, the small and polar chemical paracetamol has been used to study the rapid release behavior and adsorption modeling in biocompatible MOFs³⁴. Carbamazepine, a poorly water-soluble drug requiring improved bioavailability, has been extensively loaded into MOFs such as ZIF-8 and MIL-53 to evaluate the possibility of slow release and enhanced solubility³⁵. Mesalazine has also been investigated in several pH-dependent MOFs, such as ZIF-8 and MIL-100, due to its therapeutic need for targeted release in the colon and sensitivity to the gastric environment³⁶. Considering all aspects, these three drugs were chosen as models to evaluate the ability of MOFs to carry drugs that are small, poorly soluble, or require targeted release³⁷.

Cu(BDC) and Zn(BDC) MOFs were chosen based on the aforementioned factors because they have favorable properties for pharmaceutical applications, such as biocompatibility, structural stability in aqueous media, moderate metal–carboxylate coordination strength, and the capacity to form tunable pore structures that enable controlled release. These frameworks were created in this work utilizing an ultrafast cooperative-template technique, which overcomes energy-intensive constraints by drastically lowering reaction temperature and time compared to traditional MOF synthesis pathways. The resulting MOFs were quickly fabricated and then used as drug-delivery vehicles to assess their loading capacity and release behavior toward model therapeutic drugs such as mesalazine, carbamazepine, and paracetamol. This integrated strategy highlights the promise of Cu and Zn(BDC) structures as excellent platforms for rapid synthesis and successful drug delivery.

Experimental

Materials

Paracetamol, Carbamazepine, and Mesalazine (Fig.1) were obtained from Abidi Pharma and Tehran Darou Pharmaceutical (Iran), respectively. The reagents used in the experiment were sourced from Sigma-Aldrich Company and were utilized without any additional purification.

Fig. 1.

Structures of (a) Paracetamol (b) Carbamazepine (c) Mesalazine.

Fast synthesis of Cu- and Zn(BDC) MOFs under ambient conditions

The synthesis of Cu(BDC) and Zn(BDC) MOFs was conducted utilizing an ultrasonic-assisted cooperative method, following a previously established protocol³⁸. Initially, 7.2 mmol of zinc oxide (ZnO) was subjected to sonication in a blend of 36 mL N,N-Dimethylformamide (DMF) and 16 mL distilled water for a duration of 30 minutes at ambient temperature. A second solution was created by dissolving 14.4 mmol of either Copper (II) nitrate trihydrate (Cu (NO₃)₂·3H₂O) or zinc nitrate hexahydrate (Zn (NO₃)₂·6H₂O) in 36 mL of distilled water, which was subsequently introduced to the first mixture under vigorous stirring, leading to the formation of a hydroxy double salt of zinc and copper (Zn, Cu HDS). Following this, 7.2 mmol of cetyltrimethylammonium bromide (CTAB) was incorporated as a surfactant, along with 10.8 mmol of 1,4-benzenedicarboxylic acid (BDC) serving as the organic linker, into 32 mL of ethanol, and stirred for 30 minutes. This solution was then swiftly combined with the previous mixture for 1 minute and allowed to rest for 5 minutes. The resultant solid, which exhibited a pale blue hue for Cu(BDC) MOF and was colorless for Zn(BDC) MOF, was collected via filtration. To remove guest molecules, including surfactants, the product was submerged in ethanol at ambient temperature for four separate periods of 12 hours each. Ultimately, the product underwent drying overnight in a vacuum oven at 120 °C, yielding the porous Cu(BDC), and Zn(BDC) MOF synthesized through the combined effects of the hydroxy double salt (Zn, Cu HDS) and CTAB.

Materials characterization

The XRD patterns were obtained using an Inel X-Ray Diffractometer (EQUINOX 3000), which utilized Cu Kα radiation at 60 kV and 60 mA. The sample was held at a fixed angle of 6 degrees relative to the incoming X-ray, while the detector was moved through a 2θ angle range of 5° to 80°, at a scanning speed of 10° (2θ) per minute. Additionally, crystal behaviors were analyzed using Xpert High Score software. SEM images were obtained with a Zeiss-Leo 1430 VP Scanning Electron Microscope. Energy dispersive X-ray spectroscopy (EDAX) images were obtained using a field emission scanning electron microscope (FE-SEM, TESCAN Mira 3) integrated with an energy-dispersive X-ray spectrometer (EDX). Elemental analysis with atomic absorption spectrophotometry (AAS) was performed on an AA-6800 Shimadzu. The specific surface area was determined from the N₂ isotherms (Quantachrome, QDS-MP-30) using the Brunauer Emmett-Teller (BET) theory. TGA was performed using a TGA-DTA (Linseis STA PT 1000: Combined TG-DSC instrument). FTIR spectra were collected with a Bruker-Tensor27 FT-IR Spectrometer, covering a range of 400–4000 cm⁻¹ with KBr. The UV-Vis spectrum was examined with an Agilent Technologies-Cary 60 UV-vis Spectrophotometer to assess UV–vis absorption spectra.

Drug loading and release studies

The drug loading process employed a simple impregnation method. First, 100 mg each of paracetamol, carbamazepine, and mesalazine were mixed with 5 mL of the appropriate solvent while stirring continuously. Subsequently, 50 mg of the MOF was added to the mixture, which was then agitated for 24 hours at ambient temperature. To eliminate any drugs that were attached to the surface, the samples underwent a filtration process three times and were subsequently rinsed with distilled water. The drug-loaded MOF was then subjected to drying in a vacuum oven at a temperature of 60 °C for a duration of 4 hours.

In order to evaluate the drug release from MOFs, 5 mg of the drug-encapsulated MOF samples were immersed in 100 mL of phosphate-buffered saline (PBS). pH was controlled using 0.1 M phosphate buffer saline (PBS, pH = 7.4), and when required, slight adjustments were made using 0.1 M HCl or NaOH at a temperature of 37°C. Samples were obtained at predetermined time intervals utilizing an incubator-shaker operating at 50 rpm, and the concentration of the released drugs was quantified through UV-visible absorption spectroscopy.

Results and discussion

Investigating the mechanism synthesis of Cu(BDC), Zn(BDC) MOFs

The synthesis of Cu(BDC) and Zn(BDC) MOFs in this work follows a cooperative templating mechanism that integrates hydroxy double salts (HDS), surfactant-assisted self-assembly, and ultrasonic irradiation. Consistent with the mechanism proposed by Koshy et al., the rapid formation of Zn(BDC) MOF can be rationalized by the generation and transformation of Zn-based HDS intermediates. When ZnO is dispersed in nitrate solution, layered Zn–HDS structures are produced, in which the cationic plates (Zn²⁺/Cu²⁺ coordinated with NO₃⁻) exhibit high anion-exchange reactivity toward organic linkers. Ultrasonic cavitation further accelerates this process by creating localized high-temperature and high-pressure microdomains that enhance ZnO dissolution, promote the conversion of HDS into reactive coordination nuclei, and significantly increase the nucleation rate of the MOF.

Simultaneously, CTAB molecules undergo self-assembly to form positively charged micelles that interact electrostatically with the (Zn, Cu)–HDS layers. This cooperative templating effect organizes the BDC²⁻ linkers around the micelles and provides preferential sites for ligand exchange, thereby guiding the oriented crystallization of the framework. The auxiliary template not only accelerates anion substitution of NO₃⁻ by BDC²⁻ but also stabilizes pre-organized domains that direct growth at the micelle–HDS interface. The dimensions of these micelles, therefore, play a crucial role in defining the resulting pore structure. Removal of CTAB during the final stages of crystallization produces ordered mesoporous channels^38,39.

FT-IR analysis

Examination of FT-IR spectra related to Cu(BDC) MOF and drug-loaded MOFs

The analysis of the samples using FT-IR spectroscopy was conducted within the range of 400–4000 cm⁻¹ in KBr (Fig. 2). The absorption peaks observed at 935 cm⁻¹ and 1022 cm⁻¹ correspond to the stretching vibrations of C-O-Cu. The occurrence of double peaks near 733 cm⁻¹ can be ascribed to the positioning of Cu on the benzene ring. The two absorption bands identified at 3568 cm⁻¹ and 3442 cm⁻¹ within the Cu(BDC) MOF are associated with the C-H stretching vibrations of BDC. Furthermore, the absorption bands ranging from 833 cm⁻¹ to 1022 cm⁻¹ can be linked to the symmetric and asymmetric O-C=O stretching vibrations, as well as the C-O stretching vibration of BDC, which may indicate a reacted state. The bands between 468 cm⁻¹ and 833 cm⁻¹ are related to the in-plane and out-of-plane bending vibrations of the aromatic ring. The peaks observed are in agreement with findings from similar studies^38,40.

Fig. 2.

FT-IR Spectra of Cu(BDC) MOF and drug-loaded MOFs.

The FT-IR spectrum of Cu(BDC) MOF that containing paracetamol exhibits alterations in the peak patterns compared to the original MOFs. The peaks observed at 3566 cm⁻¹ and 3422 cm⁻¹ are likely indicative of the O-H and N-H functional groups of paracetamol present within the framework. The peak at 2923 cm⁻¹ is associated with the aliphatic C-H stretching vibrations originating from the CH₃ groups of the drug. Furthermore, the peak at 1575 cm⁻¹ corresponds to the stretching carbonyl group found in both the drug and the ligand, while the peaks at 1400 cm⁻¹ and 1507 cm⁻¹ are related to the C=C aromatic vibrations of the benzene ring from both components. The FT-IR spectrum of Cu(BDC) MOF loaded with carbamazepine also demonstrates significant changes in peak patterns, with a broad peak ranging from 2541 cm⁻¹ to 3571 cm⁻¹ indicating the overlap of functional groups from the drug and the aromatic C-H stretching vibrations of BDC, thereby confirming the successful integration of carbamazepine. Similarly, the FT-IR spectrum of mesalazine-loaded Cu(BDC) MOF shows remarkable changes, with a broad peak from 2400 cm⁻¹ to 3300 cm⁻¹ attributed to the overlapping functional groups and aromatic C-H stretching vibrations. Additionally, the peaks at 1650 cm⁻¹ and 1450 cm⁻¹, which correspond to mesalazine, further validate the successful incorporation of the drug into the Cu(BDC) MOF structure.

Examination of FT-IR spectra related to Zn(BDC) MOF and drug-loaded MOFs

In the Zn(BDC) MOF complex, two weak bands in the region of 3603 cm⁻¹ and 3546 cm⁻¹ correspond to the aromatic C-H stretching vibration of BDC (Fig. 3.). The bands located at 1158 cm⁻¹ and 1150 cm⁻¹ are associated with the residual C-O stretching vibration of the carbonyl group of BDC, as well as the skeletal C-C vibration of the aromatic ring. A prominent band at 1369 cm⁻¹ is attributed to the C-O stretching vibration. Furthermore, the absorption band spanning from 818 cm⁻¹ to 1145 cm⁻¹ is linked to both symmetric and asymmetric O-C=O stretching vibrations, along with the C-O stretching vibrations of BDC, which remain unreacted and in a reacted state. Bands ranging from 1656 cm⁻¹ to 1818 cm⁻¹ are indicative of in-plane and out-of-plane bending vibrations of the aromatic ring. Zn-O stretching vibrations, which pertain to the metal-linker bond, were detected between 1485 cm⁻¹ and 1625 cm^−138–44. Alterations in the FT-IR spectrum of paracetamol-loaded Zn(BDC) MOF were observed, with peaks in the range of 3000-3500 cm⁻¹ indicating the presence of O-H and N-H groups from paracetamol. The peak at 2923 cm⁻¹ corresponds to the aliphatic C-H stretching of CH₃ groups present in the drug. Peaks ranging from 1574 cm⁻¹ to 1678 cm⁻¹ are associated with carbonyl group stretching vibrations from both the drug and the ligand, while peaks at 1389 cm⁻¹ and 1504 cm⁻¹ relate to C=C aromatic vibrations from the benzene ring of both components. In the FT-IR spectrum of carbamazepine-loaded Zn(BDC) MOF, significant peak alterations were noted. A broad peak spanning from 2400 cm⁻¹ to 3600 cm⁻¹ indicates the overlap of functional groups from the drug and the aromatic C-H stretching of BDC within the MOF. Furthermore, peaks between 400 cm⁻¹ and 1685 cm⁻¹ either appeared or shifted, confirming the incorporation of carbamazepine into the Zn(BDC) MOF structure. The FT-IR spectrum of mesalazine-loaded Zn(BDC) MOF also exhibited changes, with a broad peak between 2400 cm⁻¹ and 3300 cm⁻¹ attributed to the overlap of functional groups from the drug and the aromatic C-H stretching of BDC. The emergence of peaks at 1645 cm⁻¹ and 1488 cm⁻¹, linked to mesalazine, further substantiates the drug’s incorporation into the Zn(BDC) MOF structure.

Fig. 3.

FT-IR Spectra of Zn(BDC) MOF and drug-loaded MOFs.

XRD analysis

Examination of the X-ray diffraction pattern of Cu(BDC) MOFs and drug-loaded MOFs

Fig. 4 illustrates the XRD spectra of Cu(BDC) MOF across a 2θ range of 5 to 80 degrees. The presence of sharp peaks signifies the elevated crystallinity of the synthesized MOF, which corresponds with the XRD patterns documented in references^38,40,41. To ascertain the crystal size, the Debye-Scherrer equation (Equation 1) was utilized:

1

Fig. 4.

XRD Spectra of Cu(BDC) MOF and drug-loaded MOFs.

In this context, D denotes the size of the crystal, λ signifies the wavelength of the X-ray, K represents a constant shape factor, β indicates the full width at half maximum (FWHM) in radians, and θ is defined as half of the peak angle. The sizes of the crystals were determined for the significant peaks at 2θ = 33.4, yielding a size of 34.6 nm, and at 2θ = 25.1, resulting in a size of 37 nm. The incorporation of paracetamol into the structure resulted in alterations to the XRD spectrum. Specifically, the introduction of paracetamol into the Cu(BDC) MOF framework led to structural modifications. Following the loading of paracetamol, peaks beyond 30 degrees were absent from the XRD spectrum, suggesting the elimination of certain planes from the structure. The variations observed in other peaks, in comparison to the state prior to drug loading, can be attributed to the positioning of the drug within the MOF structure and the resultant changes in crystallinity, which stem from the occupation of the MOF pores by the drug. An analysis of the XRD spectrum for the carbamazepine-loaded Cu(BDC) MOF was also conducted. A comparison of the XRD peaks before and after drug loading indicated alterations in both peak intensity and presence, reflecting changes in crystallinity and the incorporation of the drug. Peaks located between 10 and 20 degrees correspond to those associated with carbamazepine. In the case of the mesalazine-loaded Cu(BDC) MOF, a unique XRD peak was detected. The analysis of the XRD patterns before and after drug loading demonstrated a reduction in the peak intensity of Cu(BDC) MOF, attributed to the incorporation of the drug into MOF’s pores, leading to a decrease in its crystallinity.

Examination of the X-ray diffraction pattern of Zn(BDC) MOFs and drug-loaded MOFs

XRD analysis of Zn(BDC) MOF was conducted over an angular range of 5 to 80 degrees (Fig. 5). The distinct peaks observed in the XRD pattern signify a high level of crystallinity, which is consistent with findings from prior research^38,40. The Debye-Scherrer equation was used to determine particle sizes, yielding crystal dimensions of 30.2 nm and 31.4 nm for the prominent peaks at 2θ = 8.5 and 2θ = 27.8, respectively.

Fig. 5.

XRD Spectrum of Zn(BDC) MOF and drug-loaded MOFs.

The XRD pattern of the drug-loaded Zn(BDC) MOF showed changes in peak intensities exhibiting variations in peak intensities when compared to the unloaded MOF. While the drug did not induce significant shifts in peak positions, changes in crystallinity were noted. The peak at 2θ=19° may suggest the incorporation of paracetamol. For the Zn(BDC) MOF loaded with carbamazepine, a reduction in peak intensity in the 2θ =10° region indicated successful drug entrapment within the MOF cavities. A notable reduction in peak intensities was also observed in the 10–20-degree range, with a significant peak at 17° likely corresponding to carbamazepine. In the case of mesalazine-loaded Zn(BDC)MOF, a reduction in peak intensity was observed following drug incorporation, indicating the integration of mesalazine into the MOF pores and a decrease in crystallinity. Conversely, peaks in the 10–20° range increased, indicating the presence of mesalazine within the MOF structure.

Due to the presence of multiple reported polymorphs for Zn(BDC) and Cu(BDC) MOFs, a single crystallographic reference pattern is not available for these phases, particularly under ultrasonic-assisted synthesis conditions. Therefore, the XRD profiles were compared with experimentally reported patterns from structurally similar BDC-based MOFs, which showed good agreement with the characteristic reflections. As can be seen in Figures 4 and 5, with the loading of drugs into the MOF pores, some of the main planes were slightly displaced, causing differences in the height and position of the patterns. Considering the sharp peaks and the good peak matching, it can be said that the structure of the original MOFs is completely preserved. Therefore, the drugs are located in the pores.

TGA analysis

Examination of the TGA of Cu(BDC) MOFs and drug-loaded MOFs

TGA analysis on Cu(BDC) MOF in a nitrogen gas environment up to 700 °C showed initial weight reduction due to water removal up to 100 °C (2.32%) and N,N-Dimethylformamide solvent elimination up to 250 °C (Fig. 6). Significant weight loss between 300–350°C was attributed to BDC ligand decomposition, indicating good thermal stability up to 300°C. The residue after decomposition was identified as CuO³⁸.

Fig. 6.

TGA analysis of Cu(BDC) MOF and drug-loaded MOFs.

TGA was performed on Cu(BDC) MOF loaded with paracetamol, as shown in Fig. 6. The examination indicated a preliminary weight reduction attributed to the evaporation of water and leftover DMF solvent prior to the loading of paracetamol. A significant weight reduction followed, indicating the release of paracetamol and degradation of the BDC ligand, resulting in a 70% decrease in weight. The drug loading efficiency was calculated using equation 2 quantify the percentage of the added drug that is successfully incorporated into the MOF, yielding 21.36% for Cu(BDC) MOF.

2

The TGA of Cu(BDC)MOF loaded with carbamazepine was performed (Fig. 6). The results of the TGA were compared before and after drug loading. First, up to a temperature of approximately 240 °C, the weight loss is attributed to the removal of N,N-Dimethylformamide, and water from the pores of the Cu(BDC)MOF structure. In the next step, due to the degradation temperature of carbamazepine, the drug is removed from the MOF structure, resulting in a weight loss of approximately 13%. The subsequent steps involve removing the BDC ligand and the remaining ligand from the structure, a process similar to the analysis of the MOF prior to drug loading. Finally, the residual material from thermal degradation is CuO. The drug loading efficiency was calculated using Equation 2, and its value was obtained as about 20.87%.

Additionally, TGA was carried out on Cu(BDC) MOF samples after drug loading of mesalazine. The initial stage of weight loss associated with the removal of water and DMF solvent remaining within the Cu(BDC)MOF structure. In the next stage, the drug mesalazine is removed from the structure, resulting in a weight loss of approximately 22%. The following stages involve the removal of BDC ligand. Finally, after the destruction of CuO, the drug loading efficiency was calculated using Equation 2, yielding a value of 33.1%.

Examination of the TGA of Zn(BDC) MOFs and drug-loaded MOFs

The TGA of Zn(BDC)MOF (Fig. 7) was performed under nitrogen gas flow up to 700°C. The results obtained indicate that the initial weight loss can be attributed to the removal of water molecules up to approximately 100 °C and N,N-Dimethylformamide solvent up to approximately 250 °C from the structure, which may have been trapped through surface adsorption or within the pores of the MOF during synthesis. In the next step, from a temperature of about 200 to 300 °C, a weight loss of about 18% occurred, which can be attributed to the removal of the BDC ligand from the MOF structure. Additionally, during the subsequent steps, in the range of 300 to 500 °C, approximately 40% weight loss occurred, which can be attributed to the removal of the remaining BDC ligand from the MOF structure. This indicates a relatively good thermal stability of the synthesized MOF up to about 300°C. The residual material from the thermal decomposition of this MOF is ZnO.

Fig. 7.

TGA analysis of Zn(BDC) MOF and drug-loaded MOFs.

TGA analysis of paracetamol-loaded Zn(BDC) MOF revealed weight loss to 180 °C, attributed to the elimination of solvent and water. The release of paracetamol resulted in a 35% weight decrease, while ligand degradation led to the formation of ZnO. The drug loading efficiency was calculated at 25.28%. TGA was performed on a Zn(BDC) MOF sample containing carbamazepine to compare results before and after drug loading. Initially, the MOF was treated to remove water and residual DMF. The analysis indicated that drug release began around 180 °C, resulting in a 40% weight loss. Before drug loading, weight loss stages were linked to BDC ligand degradation and MOF structural breakdown. After thermal decomposition, the remaining material was confirmed to be ZnO, with a drug loading efficiency of 61.1%. Furthermore, thermal analysis of Zn(BDC) MOF was conducted after mesalazine loading, revealing weight loss up to 242 °C attributed to the elimination of residual water and DMF. The decomposition and release of the mesalazine drug resulted in a 37% weight loss from the MOF structure, followed by the elimination of the BDC ligand and byproducts, leaving ZnO as the final residue.

SEM image

The SEM image of Cu(BDC) MOF (Fig. 8a) shows nearly spherical nanoparticles (<40 nm), which is in good agreement with the morphologies reported for Cu–BDC systems synthesized under similar conditions³⁸. This consistency supports the successful formation of the expected framework. In contrast, the Zn(BDC) MOF (Fig. 8b) exhibits a needle-like morphology with particle sizes below 50 nm, which has also been reported as a standard feature in Zn–BDC structures prepared via rapid or surfactant-assisted routes. The observed morphologies therefore fall within the expected range for these materials, confirming the validity of the synthesis.

Fig. 8.

SEM Images of (a) Cu(BDC) MOF, and (b) Zn(BDC) MOF.

BET analysis

According to the BET results summarized in Table 1, both Zn(BDC) and Cu(BDC) MOFs synthesized in this study, confirm the presence of mesoporous structures. The BJH pore-size distribution (8–10 nm) and cumulative pore volume indicate the formation of interconnected mesopores, which is consistent with the templated growth mechanism induced by CTAB and ultrasound. When compared with the BET characteristics reported by John et al.³⁸, who also observed hierarchical porosity in their ultrasonically synthesized MOFs, the materials obtained in this study show comparable mesopore sizes and pore volume ranges, despite being prepared similarly. As a result, the textural properties obtained here offer a favorable balance of mesoporosity and framework integrity, making these MOFs suitable for applications that benefit from facilitated guest-molecule diffusion, including drug loading and controlled release studies.

Table 1.

Porosity values of Cu(BDC) and Zn(BDC)MOFs.

	Cu(BDC)MOF	Zn(BDC)MOF
Surface area
Single point surface area at p/p° = 0.300000000 (m2/g)	7.9570	10.5115
BET surface area (m2/g)	11.1949	11.1340
t-Plot external surface area (m2/g)	18.0422	16.0986
BJH adsorption cumulative surface area of pores between 1.7000 nm and 300.0000 nm width (m2/g)	27.801	26.696
Pore volume
Single point adsorption total pore volume of pores less than 40.4123 nm width at p/p° = 0.950000000 (cm3/g)	0.024669	0.025192
BJH adsorption cumulative volume of pores between 1.7000 nm and 300.0000 nm width (cm3/g)	0.057587	0.056064
Pore size
Adsorption average pore diameter (4V/A by BET) (nm)	8.81446	9.05038
BJH adsorption average pore width (4V/A) (nm)	8.2856	8.4004

EDAX analysis

The EDAX spectra of the synthesized Zn(BDC) and Cu(BDC) MOFs (Figs. 9, 10) showed no detectable Br or N signals, confirming the complete removal of CTAB during purification. Following the loading of paracetamol, carbamazepine, and mesalazine, the emergence of nitrogen and the marked increase in carbon content clearly indicate the successful incorporation of the drug molecules into the MOF structures. A slight reduction in the relative Zn/Cu percentages is consistent with partial surface coverage of the MOFs by the adsorbed drugs. These observations, summarized in Table 2, collectively support the effective loading of the drugs into the MOFs.

Fig. 9.

EDAX analysis (a) Cu(BDC) MOF, (b) Cu(BDC)MOF/Paracetamol, (c) Cu(BDC)MOF/Mesalazine, and (d) Cu(BDC)MOF/Carbamazepine.

Fig. 10.

EDAX analysis (a) Zn(BDC) MOF, (b) Zn(BDC)MOF/Paracetamol, (c) Zn(BDC)MOF/Mesalazine, and (d) Zn(BDC)MOF/Carbamazepine.

Table 2.

EDAX analysis of Cu(BDC) and Zn(BDC) before and after drug loading.

ELT	Cu(BDC)MOF			Cu(BDC)MOF/Paracetamol		Cu(BDC)MOF/Carbamazepine		Cu(BDC)MOF/Mesalazine
	W%		A%	W%	A%	W%	A%	W%	A%
C	25.92		41.43	38.43	48.08	55.23	63.90	45.47	54.04
O	40.30		48.36	51.09	47.99	34.45	29.92	43.91	39.17
Cu	33.79		10.21	8.74	2.07	5.26	1.15	5.08	1.14
N	-		-	1.74	1.87	5.07	5.03	5.54	5.65

ELT	Zn(BDC)MOF			Zn(BDC)MOF/Paracetamol		Zn(BDC)MOF/Carbamazepine		Zn(BDC)MOF/Mesalazine
	W%	A%		W%	A%	W%	A%	W%	A%
C	29.89	44.69		42.99	52.02	54.57	62.97	46.49	54.64
O	42.51	47.72		49.67	45.13	35.93	31.13	43.59	38.46
Zn	27.61	7.59		5.84	1.30	4.49	0.95	3.90	0.84
N	-	-		1.50	1.55	5.00	4.95	6.01	6.06

Examination the results of drug release

To investigate drug release, a drug-loaded MOF was placed in a PBS solution mimicking human body conditions (37°C, pH 7.4, 0.1 M). For drug-loaded MOFs, at the maximum absorbance value was substituted into the calibration equations to determine the drug concentration at specific times (maximum absorbance value 240 nm for paracetamol, 284 nm for carbamazepine, and 332 nm for mesalazine). The outcomes of the drug loading process are presented in Table 3.

Table 3.

The loading percentage of paracetamol, carbamazepine, and mesalazine in Cu(BDC) MOF and Zn(BDC)MOF.

Zn(BDC)MOF	Cu(BDC)MOF	Drug loading yield
25.28	21.36	Paracetamol
61.1	20.87	Carbamazepine
36.5	33.1	Mesalazine

The proportion of paracetamol released from Cu(BDC) MOF has steadily risen over time. After a duration of 36 hours, the release percentage of the drug reached 39.37%. The graphical representation of the paracetamol release percentage from the MOF is visualized in Fig. 11. Notably, the release process exhibited a gradual pace and attained its peak value within 36 hours. The release of carbamazepine from the Cu(BDC) MOF increased over 36 hours, reaching 53.63%. The mezalazine release from Cu(BDC) MOF data showed that the drug release percentage increased over time, but the actual amount of drug released remained low, reaching 11.26% in 36 hours. This level of release may be suitable for sustained release over a longer period, but further investigation is needed.

Fig. 11.

Drug release behavior of drug loaded Cu(BDC) MOF.

For paracetamol loaded- Zn(BDC) MOF, over time, there has been a consistent increase in the rate of drug release, 26.83. This trend is further illustrated in Fig. 12, where it is evident that the peak percentage of drug release is achieved within 24 hours. Interestingly, the drug released remains relatively constant after the initial 12-hour mark. Moreover, the carbamazepine release from Zn(BDC) MOF shows that the drug release increased over time. The release profile of mesalazine from Zn(BDC)MOF is provided in Fig.12. The drug’s release from this MOF exhibited a minimal quantity. This issue may be attributed to the drug’s molecular structure and the entrapment of drug molecules within the framework of Zn(BDC)MOF. Table 4 presents findings of the drug release from Cu(BDC) and Zn(BDC) MOFs.

Fig. 12.

Drug release behavior of drug loaded Zn(BDC) MOF.

Table 4.

The release percentage of paracetamol, carbamazepine, and mesalazine in Cu(BDC)MOF and Zn(BDC)MOF.

Zn(BDC)MOF			Cu(BDC)MOF			Time
Mesalazine	Carbamazepine	Paracetamol	Mesalazine	Carbamazepine	Paracetamol
8.67	0.09	9.00	3.88	7.48	14.70	2
1.263	2.42	20.16	6.62	9.76	19.10	6
12.962	4.56	26.54	9.8	15.42	32.53	12
12.99	11.98	26.93	1.51	48.98	38.48	24
12.66	13.48	26.83	11.26	53.63	39.37	36

As shown in Table 5, Cu- and Zn(BDC)-based MOFs have been widely applied for loading a variety of therapeutic agents, including anticancer and anti-inflammatory drugs, using diverse synthesis routes and functional modifications. This comparison highlights the versatile drug-carrier potential of BDC-based MOFs across different conditions.

Table 5.

Comparison of BDC-based MOFs in drug loading and release.

MOF	Drug	Method	Loading%	Releasing %	Refs.
Cu(BDC)MOF/Chondroitin sulfate (ChS) Nanocomposite	Methotrexate	Solvothermal	70.8 ± 0.5 %	70 % Acidic 20 % physiological	45
Cu-MOF	Doxorubicin	Solvothermal 24 h at 120 ◦C	60.2 ±0.5 %	Lower than Cu(BDC)/Hep	46
Cu(BDC)MOF/Hep	Doxorubicin	Solvothermal 24 h at 120 ◦C	65.5 ±0.5 %	at pH 5 (>90 % on 96 h, 41 ◦C pH 7.4 (<10 % on 96 h, 37 ◦C	46
Zn(BDC) MOF @CMC (Carboxy methyl Cellulose)	Ibuprofen	Solvothermal 120 ◦C for 25 h	50.95%	11% and 82% over 240 h at pH 1.2 and 7.4	29
Zn(BDC)	Ibuprofen	solvothermal at 120 ◦C for 25 h	31.26%	90%	29
Zn2(BDC)2(DABCO)-MOF	Imatinib mesylate	Ball milling	4 wt%, 8.1 wt and 17.5 wt%	95% of drug after 24 h.	47
Cu(BDC)MOF	Paracetamol	Ultrafast ultrasonic assisted	21.3%	39.37%	This work
	Carbamazepine		20.8%	53.63%
	Mesalazine		33.1%	11.26%
Zn(BDC)MOF	Paracetamol	Ultrafast ultrasonic assisted	25.2%	26.83%	This work
	Carbamazepine		61.1%	13.48%
	Mesalazine		36.4%	12.66%

Proposed mechanisms of drug loading and release

The loading of paracetamol, carbamazepine, and mesalazine into the Cu(BDC) and Zn(BDC) MOFs is primarily driven by pore confinement and a series of weak host–guest interactions. The mesoporous channels (8–10 nm) allow efficient diffusion of the drug molecules into the framework, while hydrogen bonding between the drug functional groups (–OH, –NH₂, –COOH) and the carboxylate linkers, along with π–π interactions between aromatic components, contribute to their stabilization within the pores. The higher carbon and nitrogen signals, along with the slight reduction in metal percentages, observed in the EDX spectra of the drug-loaded samples, are consistent with a combined pore-filling and surface-adsorption mechanism.

The release process is governed mainly by diffusion through the mesoporous network and the reversible nature of the non-covalent interactions responsible for drug loading. Upon immersion in the release medium, solvent molecules progressively weaken hydrogen bonding and other host–guest interactions, enabling the drug molecules to diffuse outward from the pores. Thus, the overall release profile reflects a diffusion-controlled mechanism coupled with the gradual disruption of weak intermolecular interactions between the MOF structure and the encapsulated drugs.

Conclusion

In this study, Cu(BDC)MOF and Zn(BDC)MOF were synthesized via a rapid, ultrasound-assisted route at room temperature, offering a significantly faster and milder alternative to the conventional solvothermal methods typically employed for these frameworks. Structural analyses (FT-IR, XRD, and TGA) confirmed the successful formation of both MOFs as well as the incorporation of paracetamol, carbamazepine, and mesalazine. BET measurements confirmed that the mesoporous character of the materials was preserved after synthesis. At the same time EDX analysis indicated the complete removal of CTAB, supporting the successful loading of drug molecules, as evidenced by the increase in carbon and nitrogen signals and slight changes in metal ratios. The loading experiments demonstrated that Zn(BDC)MOF generally achieved higher drug-loading efficiencies (25.28% for paracetamol, 61.09% for carbamazepine, and 36.49% for mesalazine) compared to Cu(BDC)MOF (21.36%, 20.87%, and 33.11%, respectively). Despite this, Cu(BDC)MOF displayed comparatively faster release for paracetamol and carbamazepine, whereas Zn(BDC)MOF provided slower and more sustained release- particularly for mesalazine- indicating that their structural distinctions enable different release profiles. The results of AAS measurements of zinc and copper elements from the reaction solution after drug loading and also after drug release indicate the stability of the synthesized compounds under experimental conditions and no metal elements were observed in the solutions.

Importantly, this work represents the first application of these ultrasonically synthesized Cu- and Zn-BDC MOFs for the loading and release of paracetamol, carbamazepine, and mesalazine, as well as the first direct comparison of their delivery performances. The combined results demonstrate that both frameworks possess suitable structural stability, porosity, and drug-interaction characteristics, making them promising candidates for controlled-release drug-delivery systems.

Author contributions

Author contributions: Golnaz Zahabi and Roya Nayebi designed research, Roya Nayebi and Abdollah Fallah Shojaei wrote the main manuscript text and Roya Nayebi prepared figures. All authors reviewed the manuscript.

Data availability

The datasets generated and/or analyzed during the current study are not publicly available due to the non-public nature of the data, but are available upon reasonable request from the corresponding author.

Declarations

Competing interests

The authors declare no competing interests.