Porous Iron Framework Achieves High Loading Efficiency for Codeine Drug Delivery

A research team has synthesized an iron(III)-tricarboxylate metal-organic framework formulated as [Fe3(btc)2] and established its functional capacity as a porous host carrier for the encapsulation of the opiate analgesic codeine. Utilizing a room-temperature solvent synthesis combining iron(III) nitrate nonahydrate with 1,3,5-benzene tricarboxylic acid, the investigators prepared the coordinated material and evaluated its physical, structural, and chemical properties through analytical characterization and computational modeling. The experimental findings revealed that the synthesized coordination architecture encapsulated codeine with an efficiency of ninety-one percent, accommodating approximately two hundred forty-nine milligrams of the therapeutic agent per two hundred milligrams of dehydrated framework material. The porous carrier demonstrated stable host-guest immobilization through non-covalent interactions without framework degradation, presenting an empirical model for the deployment of iron-based coordination polymers in targeted pharmaceutical immobilization.

Developing advanced drug delivery systems remains a significant focus in biomedical science to enhance the bioavailability of therapeutic compounds within biological environments while minimizing carrier toxicity. Conventional pharmaceutical platforms, including inorganic polymers and organic assemblies like liposomes and micelles, have encountered clinical limitations related to inadequate encapsulation rates and unpredictable payload release resulting from a lack of tunable cavities. In contrast, porous coordination polymers and metal-organic frameworks offer distinctive structural advantages over rigid nanoparticles, including exceptionally high surface areas, extensive porous networks, and customizable functional groups along their internal walls. Metal-organic frameworks can incorporate biocompatible metals like iron, calcium, copper, or zinc alongside non-toxic linkers like trimesic acid, creating customizable interior environments where cavity dimensions and surface chemistries interact favorably with specific drugs.

Within this material landscape, iron-based metal-organic frameworks have emerged as promising candidates for physiological delivery due to low toxicity, economic accessibility, and proven chemical stability. Prior investigations into frameworks like Fe-MIL-88A, Fe-MIL-101, and Fe-MIL-100 demonstrated favorable toxicological profiles and effective drug encapsulation, including successful loadings of antitumor agents and ibuprofen. The present study evaluated [Fe3(btc)2] specifically for the accommodation of codeine, a 3-methylmorphine opioid alkaloid naturally occurring in Papaver somniferum and synthetically derived from morphine for use as an antitussive and analgesic agent. Because improper dosing, dependence, and uncontrolled release of codeine in the bloodstream present significant therapeutic challenges, identifying an absorbent carrier system capable of stabilizing this hydrophobic narcotic under physiological conditions addresses an essential objective in formulation science.

The synthetic protocol executed by the researchers employed an accessible, one-step solution pathway designed for material scalability. The authors dissolved nine millimoles of 1,3,5-benzene tricarboxylic acid in fifty milliliters of deionized water and ten millimoles of iron(III) nitrate nonahydrate in fifty milliliters of ethanol before combining the two mixtures under stirring at room temperature for twenty-four hours. The resulting reddish-brown precipitate was filtered, washed three times with thirty-milliliter portions of deionized water and ethanol, dried at one hundred fifty degrees Celsius for ten hours, and stored in a desiccator. This process produced five grams of purified [Fe3(btc)2], achieving an eighty-four percent yield. The compound exhibited a melting point of two hundred forty-one degrees Celsius and an elemental composition of forty-six point eighty-four percent carbon, three point zero four percent hydrogen, and two point sixty-eight percent nitrogen.

Initial structural verification of the pristine framework was conducted using powder X-ray diffraction and Fourier-transform infrared spectroscopy. The diffraction pattern obtained using copper K-alpha radiation closely matched the simulated crystalline profile cataloged under Cambridge Structural Database entry 640536, displaying prominent high-intensity peaks at nine point ninety-eight degrees two-theta. Infrared spectroscopy confirmed coordination between the organic linker and iron centers, marked by the shift of the carbonyl stretching vibration from seventeen hundred twenty reciprocal centimeters in pure trimesic acid to seventeen hundred thirteen reciprocal centimeters in the framework. The spectrum also recorded a broad hydroxyl band at thirty-three hundred seventy-three reciprocal centimeters, an aromatic carbon-carbon double bond vibration at fourteen hundred fifty-one reciprocal centimeters, a coordinated water band at six hundred fifty-nine reciprocal centimeters, and an iron-oxygen vibration at five hundred twenty reciprocal centimeters confirming metal-linker bonding.

To assess drug encapsulation, the framework was thermally activated overnight at one hundred twenty degrees Celsius to evacuate guest solvent from the pore system. Immobilization experiments were performed by suspending two hundred milligrams of activated [Fe3(btc)2] in thirty milliliters of an aqueous solution containing three hundred milligrams of codeine, establishing an initial concentration of ten thousand milligrams per liter. The codeine uptake was tracked over contact intervals from zero point one to thirty hours at thirty-two degrees Celsius using ultraviolet-visible spectroscopy based on a calibration curve prepared from serial dilutions between zero point zero one and zero point zero four molar concentrations. Spectroscopic analysis confirmed that the framework reached an uptake capacity of two hundred forty-nine point four milligrams of codeine per gram of dehydrated carrier, reflecting an encapsulation efficiency of ninety-one percent.

Analysis of absorption kinetics demonstrated that codeine immobilization proceeded rapidly during initial contact before gradually approaching equilibrium as available host sites diminished. This rapid uptake corresponded to the widespread availability of unoccupied void pore cavities within the freshly activated framework, whereas the subsequent deceleration reflected progressive site saturation within the internal microenvironment. Quantitative measurements indicated that loading was practically complete after twenty-two hours of continuous stirring, beyond which immobilized drug content stabilized and remained constant up to thirty hours. Throughout this extended immersion, the characteristic reddish-brown coloration of the [Fe3(btc)2] crystals remained unaltered. Researchers attributed this exceptional uptake capacity to the high internal porosity of the framework and a pore microenvironment chemically suited to accommodate the hydrophobic molecular structure of the codeine guest.

Textural analysis performed via nitrogen gas physisorption at seventy-seven Kelvin provided clear physical confirmation that codeine molecules penetrated into the internal pore network. For the pristine [Fe3(btc)2] material, Brunauer-Emmett-Teller analysis recorded an initial surface area of eight hundred forty-nine point sixty-three square meters per gram and a pore volume of zero point two hundred ninety cubic centimeters per gram. Following the encapsulation of codeine, the measured Brunauer-Emmett-Teller surface area dropped to two hundred three point four square meters per gram, while the pore volume decreased to zero point zero fifty-nine cubic centimeters per gram. This substantial reduction in both surface area and internal pore volume verified that guest codeine molecules occupied the inner pore cavities rather than adhering loosely to outer particle surfaces.

Complementary characterization of the drug-loaded framework via diffraction, spectroscopy, and electron microscopy corroborated the retention of the encapsulated analgesic. Post-loading diffraction patterns revealed decreases in intensities and peak alterations at ten, fifteen, twenty, and thirty degrees two-theta, reflecting partial loss of crystallinity resulting from pore filling, alongside newly emerged peaks at forty, forty-five, and eighty-five degrees corresponding to codeine. Infrared spectra of the loaded material demonstrated the appearance of a carbon-nitrogen vibrational band at thirteen hundred twenty-three reciprocal centimeters originating from codeine, accompanied by vibrational shifts in hydroxyl and aromatic modes. Furthermore, scanning electron micrographs documented a marked change in particle morphology: the smooth, crystalline, and loosely packed exterior surface of pristine [Fe3(btc)2] transitioned into a densely packed, roughened surface after codeine encapsulation.

To clarify the molecular mechanics governing this host-guest association, the investigators executed induced-fit molecular docking using the OPLS4 force field within the Schrödinger computational environment. Comparative docking evaluations performed between the geometry-optimized [Fe3(btc)2] framework and guest analytes revealed a significantly stronger host binding affinity for codeine compared to diatomic nitrogen. Specifically, the framework-codeine complex yielded a favorable Glide docking score of negative four point three hundred forty-nine kilocalories per mole, compared to negative two point six hundred thirty-two kilocalories per mole for nitrogen. Structural visualization demonstrated that while the nitrogen complex lacked significant secondary interactions, codeine established robust non-covalent contacts consisting of prominent hydrogen bonding and pi-cation interactions with the iron-carboxylate framework, underpinning the superior thermodynamic stability and preferential binding affinity observed experimentally.

The dynamic behavior and durability of the framework-codeine assembly were subsequently evaluated through a one hundred nanosecond molecular dynamics simulation conducted under simulated physiological conditions. The simulation utilized the Desmond platform with a single point charge water model in a triclinic cell containing zero point fifteen molar sodium chloride, maintaining a temperature of three hundred Kelvin and a pressure of one point zero thirteen bar. Throughout the one hundred nanosecond runtime, codeine remained stably confined within the [Fe3(btc)2] binding cavity, anchored primarily by persistent hydrogen bonds and pi-cation interactions. Furthermore, trajectory analysis revealed that surrounding water molecules formed transient bridging hydrogen bonds with both the framework and codeine. These solvent-mediated interactions actively enhanced complex stability, confirming that physiological solvation supports structural retention during controlled drug accommodation.

Quantum chemical descriptors derived from density functional theory calculations using parametric method six in Scigress software provided electronic insight into complexation. Computations revealed that [Fe3(btc)2]@COD exhibited an electrophilicity of ten point eighty-three electronvolts, designating it as an electron acceptor, alongside a reduced hardness of two point ten electronvolts compared to trimesic acid and codeine at four point seventy-nine and four point forty-five electronvolts. The frontier orbital gap narrowed from five point three electronvolts in the bare framework to four point nineteen electronvolts in the loaded complex, while the lowest unoccupied orbital dropped from negative zero point ninety-two to negative four point sixty-four electronvolts. Orbital distributions confirmed that the highest occupied orbital localized on codeine while the lowest unoccupied orbital resided on trimesic acid linkers, demonstrating that codeine acts as an electron donor creating stable charge separation.

Subject of Research: Iron-based metal-organic framework synthesis and characterization for codeine drug encapsulation

Article Title: Iron(III)-Tricarboxylate Metal-Orgonic Framework (MOF) as drug carrier in the loading of codeine

Article References: Ologe, M. O., Olatunji, S. J., Ademola, E., Obiyenwa, G. K., Adimula, V. O., Clayton, H. S., Adeyeni, E. G., Gordon, A. T., & Tella, A. C. (2025). Iron(III)-Tricarboxylate Metal-Orgonic Framework (MOF) as drug carrier in the loading of codeine. Discover Molecules, 2(1), Article 26. https://doi.org/10.1007/s44345-025-00031-x

Image Credits: AI Generated

DOI: 10.1007/s44345-025-00031-x

Keywords: Metal-Organic Frameworks, Drug Delivery, Codeine, Coordination Chemistry, Molecular Dynamics, Density Functional Theory, Adsorption, Nanoporous Materials, Iron, Tricarboxylate, Metal-Orgonic, Framework