Active Pharmaceutical Ingredient Ionic Liquid Research Articles

Active pharmaceutical ingredient-ionic liquids assisted follicular co-delivery of ferulic acid and finasteride for enhancing targeted anti-alopecia

Androgenetic alopecia (AGA) is the primary hair loss with impairing patients’ quality of life. Finasteride (FIN) is an SRD5A2 inhibitor for AGA treatment, but oral FIN causes systemic adverse effects. Topical FIN delivery is anticipated to overcome this problem. Ferulic acid (FA) is a natural phenolic acid with vascular remodeling and anti-inflammatory effects. Herein, an active pharmaceutical ingredient ionic liquid (API IL) based on choline and FA (CF-IL) is for the first time constructed to load FIN for fabricating FIN CF-IL. CF-IL aims to act as carriers and cargos and enhance hair follicle (HF) co-delivery of FA and FIN for synergistic anti-alopecia. Thermal and spectroscopic analysis combined with quantum chemistry calculations and molecular dynamics confirm the formation of CF-IL. The CF-IL simultaneously increases the solubility of FA (∼648-fold) and FIN (∼686-fold), enhances the permeation and retention of FIN and FA through the follicular pathway, and promotes cellular uptake. FIN CFIL regulates the abnormal mRNA expressions in dihydrotestosterone-irritated hDPCs, and promotes hair regrowth in AGA mice in a combined manner with FIN and FA. These findings suggest that FA-based API IL is a promising approach for percutaneously co-delivering FA and FIN to HF, providing an enhanced targeting treatment for AGA.

Ionic Liquids: New Forms of Active Pharmaceutical Ingredients with Unique, Tunable Properties.

This Review aims to summarize advances over the last 15 years in the development of active pharmaceutical ingredient ionic liquids (API-ILs), which make up a prospective game-changing strategy to overcome multiple problems with conventional solid-state drugs, for example, polymorphism. A critical part of the present Review is the collection of API-ILs and deep eutectic solvents (DESs) prepared to date. The Review covers rules for rational design of API-ILs and tools for API-IL formation, syntheses, and characterization. Nomenclature and ionic speciation, and the confusion that these may cause, are highlighted, particularly for speciation in both ILs and DESs of intermediate ionicity. We also highlight in vivo and in vitro pharmaceutical activity studies, with differences in pharmacokinetic/pharmacodynamic depending on ionicity of API-ILs. A brief overview is provided for the ILs used to deliver drugs, and the Review concludes with key prospects and roadblocks in translating API-ILs into pharmaceutical manufacturing.

Tuning pharmaceutically active zein-based formulations for additive manufacturing

Zein, a biopolymer from corn, was plasticized by glycerol and an Active Pharmaceutical Ingredient-Ionic Liquid (API-IL) for its melt processing at 130 °C. In order to enhance the rheological properties of the formulation for 3D printing, the ratio of glycerol to API-IL was adjusted while maintaining a consistent addition of 20% plasticizer. A 50/50 ratio allowed obtaining an initial melt viscosity suitable for extrusion-based processes, at approximately 1 kPa.s at a shear rate of 10 s−1, with a shear thinning behavior. This viscosity remained stable during a processing window of about 6 min, before zein proteins start to aggregate, leading to an apparent gelation phenomenon for long residence times. The processability of this formulation containing API-IL for the printing of tablets for potential therapeutic applications was confirmed by tests on a 3D printer. Nonetheless, in comparison to a reference formulation containing only glycerol, the printing accuracy experienced a decrease. This was ascribed to slower viscous sintering kinetics in presence of API-IL, evidenced by monitoring fusion-bonding during dynamic X-ray tomography trials carried out at Synchrotron SOLEIL.

An insight into the advances in ionic liquids and its applications in medicine

Ionic liquids (ILs) are intriguing non-molecular compounds of sole ions and have been emerging as major players with a wider application spectrum in the science and technological domains of nanoscience, synthesis, catalysis, extraction, analytics, electrochemistry, and biotechnology due to their highly customizable nature, outstanding capabilities, and greener alternative to conventional organic solvents. Aside from physical and chemical features and potentials, ionic liquids have higher biological activities that excite the curiosity of researchers, biochemists, ecologists, and medical professionals towards innovations and smart procedures. The evidence of ionic liquids' biological activity, including their antibacterial and cytotoxic capabilities, has been further explored and examined in light of their potential uses in drug production and drug delivery systems. The biological actions and their prospective applications, such as a revolutionary active pharmaceutical ingredient, ionic liquid (API-IL), in medicine, have been gaining special attention. The primary goal of this review is to elaborate on the enticing potential of chemical and biological characteristics and their advancements in ionic liquids for pharmaceutics and medicinal applications.

Active pharmaceutical ingredient ionic liquid in natural deep eutectic solvents – Influence of solvent composition

In this work, the mixture of the active pharmaceutical ingredient ionic liquid (API-IL) benzocainium ibuprofenate and natural deep eutectic solvents (NADESs) of menthol:decanoic acid with the molar ratios 1:2, 1:1 and 2:1 were prepared, and nature of interactions in these systems was investigated for the first time. These systems of hydrophobic API-IL-NADES are mixtures that are compatible and offer an opportunity for the topical application of ionic liquids, which are in a liquid state above room temperature and do not dissolve in water well. Ionic liquid and NADESs with different molar ratios were synthesized and characterized using infrared and nuclear magnetic resonance spectroscopy and differential scanning calorimetry. The densities, speeds of sound, and viscosities of the studied mixtures were measured in the temperature range from T = (293.15 to 318.15) K at different API-IL molalities. From obtained thermodynamic properties, it was discussed how the mole fraction of the NADES components influences the molecular and solvent performance.

Structural, electronic, and thermochemical properties of salicylic acid-containing ionic liquids as active pharmaceutical ingredients

Active pharmaceutical ingredient ionic liquids have recently been developed as a new generation of ionic liquids. In this study, the geometrical and electronic structures of six imidazolium-based ionic liquids containing salicylic acid in the cation or/and anion are studied by performing density functional theory calculations. Molecular electrostatic potential surfaces of the cation and anion fragments are obtained to elucidate those sites at which they are most likely to interact. The magnitude of the cation–anion interaction energies is calculated. The natural bond orbital method is performed to analyze the cation–anion interactions. The standard enthalpies of formation of the studied ionic liquids are calculated using the atomization approach. The results indicate a relationship between the enthalpies of formation and the structure of the studied ionic liquids.

Release kinetics of [lidocainium][ibuprofenate] as Active Pharmaceutical Ingredient-Ionic Liquid from a plasticized zein matrix in simulated digestion

An in vitro approach is proposed to study the release of an Active Pharmaceutical Ingredient-Ionic Liquid (API-IL) from a natural biopolymer matrix based on zein, a maize storage protein. Zein can be processed in the molten state with 20 w% [Lidocainium][Ibuprofenate] added as API-IL also acting as plasticizer and potentially co-plasticized by glycerol. The thermal stability of the matrix is checked, as well as the in vivo biological activity of the API-IL confirming anesthetic and anti-inflammatory activities. Model tablets are thermomolded at 130 °C (∅20 mm, 0.2 mm thick) and submitted to simulated digestion based on the INFOGEST static protocol of gastrointestinal food digestion at 37 °C (2 h under gastric conditions followed by 2 h under intestinal ones). The release of the API-IL is evaluated by HPLC-UV to dissociate lidocainium, that shows a progressive release (35 % after 2 h and 60 % after 4 h digestion), from ibuprofenate, that is mainly released under intestinal conditions due to low solubility in acidic conditions. The monitoring of the tablets reveals release mechanisms based on diffusion without noticeable erosion of the matrix. These results demonstrate the interest of this thermoplastic material to provide a relevant drug delivery system.

Study on the interactions of tetradecylpyridinium dl-mandelic acid and cetylpyridinium dl-mandelic acid with some small biomolecules in aqueous solution

Interactions of two active pharmaceutical ingredient ionic liquids (API-ILs) tetradecylpyridinium dl-mandelic acid ([TetPy][MAN]) and cetylpyridinium dl-mandelic acid ([CetPy][MAN]) with some small biomolecules have been studied by using conductometric, density and UV–vis spectroscopic techniques. The chosen small biomolecules are glycine, l-alanine, l-valine, l-leucine and glycylglycine (AAGG). The critical micelle concentration (cmc) of [TetPy][MAN] and [CetPy][MAN] in aqueous AAGG solution is calculated from the measured conductance values, thus yielding some thermodynamic parameters of the micellization, such as the standard Gibbs energy change (ΔGm0), the standard enthalpy change (ΔHm0) and the standard entropy change (ΔSm0). On the basis of the experimental densities of ternary solutions of (AAGG + API-ILs + water), apparent molar volume at infinite dilution (V2,φ0), apparent molar expansibility at infinite dilution (Eφ0), transfer partial molar volume (ΔtV0) and hydration number (nH) of AAGG in aqueous API-ILs solution were calculated. The dominant hydrophobic-hydrophilic and hydrophobic-hydrophobic interactions were involved in the investigated systems. The binding constant (Kb) between AAGG and API-ILs has been calculated from UV–vis spectroscopic data. Effect of some factors including concentration, temperature, molecular structure, etc. on the aforementioned parameters and the existing solvent–solute interaction has been discussed.

Active Pharmaceutical Ingredient-Ionic Liquids (API-ILs): Nanostructure of the Glassy State Studied by Electron Paramagnetic Resonance Spectroscopy.

Active Pharmaceutical Ingredient-Ionic Liquids (API-ILs) draw increasing interest as a particular class of ILs that possess unusual physicochemical properties along with simultaneous potentials for pharmaceutical applications. Although nanostructuring phenomena were actively investigated in common ILs, their studies in API-ILs are scarce so far. In this work, using the complex methodology of Electron Paramagnetic Resonance (EPR) and dissolved spin probes, we investigate nanostructuring phenomena in a series of API-ILs: [Cnmim][Ibu], [Cnmim][Gly], and [Cnmim][Sal] with n = 2, 4, and 6, respectively. We reveal similar trends for API-ILs and common ILs, as well as peculiarities inherent to the studied API-ILs. Unusual behavior observed for [Cnmim][Ibu] has been assigned to the presence of a non-polar fragment in the [Ibu]− anion, which leads to the formation of more complex nanostructures around the radical compared to common ILs. Understanding general trends in the formation of such self-organized molecular structures is of fundamental interest and importance for applying API-ILs.

Physicochemical study on molecular interactions of the active pharmaceutical ingredient ionic liquid domiphen salicylate with amino acids at different temperatures

The molecular interactions between the active pharmaceutical ingredient ionic liquid domiphen salicylate ([Dom][Sal]) and some amino acids (glycine, L-alanine, L-valine, L-leucine) in aqueous solution were studied. In order to accomplish this objective, the volume, conductivity and UV–vis spectroscopy of ternary systems were measured at different temperatures. The infinite dilution apparent molar volume, V2,φ0, transfer volume, ΔtV0, hydration number, nH and infinite dilution apparent molar expansibility, Eφ0 of amino acids in aqueous [Dom][Sal] solution were derived from the measured density data. Side chain contributions to V2,φ0 have been estimated. Critical micelle concentration, cmc, and thermodynamic properties of micellization (ΔGm0, ΔHm0,ΔSm0) for [Dom][Sal] in aqueous amino acids solutions were calculated using electrical conductivity data. The binding constant Kb of the amino acid with [Dom][Sal] was estimated based on the maximum absorbance data of the UV–vis spectroscopy. The impacts of temperature, concentration and the length of aliphatic chain of amino acids on these parameters were discussed. The mentioned parameters was employed to unveil the solute–solvent interactions in ternary systems.

Application of 3D printing technology for generating hollow-type suppository shells.

The application of 3D printing technology for generating tablets is attracting the attention of the pharmaceutical industry following approval of a 3D printed tablet (Spritam) by the US Food and Drug Administration. Here we focused on hollow-type suppository formulations typically prepared as suppository shells by pharmacists in hospitals. We used a fused deposition modeling-type 3D printer and polyvinyl alcohol filament as a water soluble material to print suppository shells with various thicknesses and different inner structures by changing the printing conditions for the 3D designed objects. The hardness of the suppository shell was dependent on the thickness and designed inner structure. An active pharmaceutical ingredient ionic liquid, a novel type of liquid drug formulation, was loaded in the suppository shells. The drug dissolution profile of the suppository formulations differed depending on the type of suppository shell. Composite suppository formulations (two drugs in separate compartments in the suppository shell) were prepared as a model tailored medicine for pediatric patients. Our findings suggest that 3D printing technology is applicable to the preparation of hollow-type suppository formulations and may be compatible with on-site hospital production.

Ionic Liquids for Therapeutic and Drug Delivery Applications.

Ionic liquids (ILs) are ionic compounds with highly tunable and remarkable properties which make them an important candidate in multiple domains such as extraction, synthesis, analytics, catalysis, biotechnology, therapeutics as well as pharmaceutical sciences. This review systematically highlights the classification, properties and toxicity of ionic liquids. It focuses on exploring the biological activity of ionic liquids, which includes antimicrobial and anticancer property along with an emphasis on the concept of Active Pharmaceutical Ingredient- Ionic Liquids (API-ILs) for explaining the emulsifier and solubility enhancement property of ILs. An elaborative discussion on the application of ILs for the development of oral, transdermal and topical drug delivery systems has also been presented with suitable literature support. Ionic liquids possess exceptional potential in the field of medicine, biology and chemistry.

Polyvinylidene fluoride–Hyaluronic acid wound dressing comprised of ionic liquids for controlled drug delivery and dual therapeutic behavior

To improve the efficacy of transdermal drug delivery systems, the physical and chemical properties of drugs need to be optimized to better penetrate into the stratum corneum and to better diffuse into the epidermis and dermis layers. Accordingly, dual-biological function ionic liquids composed of active pharmaceutical ingredients were synthesized, comprising both analgesic and anti-inflammatory properties, by combining a cation derived from lidocaine and anions derived from hydrophobic nonsteroidal anti-inflammatory drugs. Active pharmaceutical ingredient ionic liquids (API-ILs) were characterized through nuclear magnetic resonance, cytotoxicity assay, and water solubility assay. All properties were compared with those of the original drugs. By converting the analgesic and anti-inflammatory drugs into dual-function API-ILs, their water solubility increased up to 470-fold, without affecting their cytotoxic profile. These API-ILs were incorporated into a bilayer wound dressing composed of a hydrophobic polyvinylidene fluoride (PVDF) membrane to act as a drug reservoir and a biocompatible hyaluronic acid (HA) layer. The prepared bilayer wound dressing was characterized in terms of mechanical properties, membrane drug uptake and drug release behavior, and application in transdermal delivery, demonstrating to have desirable mechanical properties and improved release of API-ILs. The assessment of anti-inflammatory activity through the inhibition of LPS-induced production of nitric oxide and prostaglandin E2 by macrophages revealed that the prepared membranes containing API-ILs are as effective as those with the original drugs. Cell adhesion of fibroblasts on membrane surfaces and cell viability assay confirmed improved the viability and adhesion of fibroblasts on PVDF/HA membranes. Finally, wound healing assay performed with fibroblasts showed that the bilayer membranes containing dual-function API-ILs are not detrimental to wound healing, while displaying increased and controlled drug delivery and dual therapeutic behavior. Statement of significanceThis work shows the preparation and characterization of bilayer wound dressings comprising dual-biological function active pharmaceutical ingredients based on ionic liquids with improved and controlled drug release and dual therapeutic efficiency. By converting analgesic and anti-inflammatory drugs into ionic liquids, their water solubility increases up to 470-fold. The prepared bilayer wound dressing membranes have desirable mechanical properties and improved release of drugs. The prepared membranes comprising ionic liquids display anti-inflammatory activity as effective as those with the original drugs. Cell adhesion of fibroblasts on membrane surfaces and cell viability assays show improved viability and adhesion of fibroblasts on PVDF/HA membranes, being thus of high relevance as effective transdermal drug delivery systems.

The effect of pharmaceutically active ionic liquids, 1-methyl-(3-hexyl or octyl) imidazolium ibuprofenate on the thermodynamic and transport properties of aqueous solutions of glycine at T = 298.2 K and p = 0.087 MPa

The influence of two innovative ionic liquids consisting ibuprofenate anion as active pharmaceutical ingredient ionic liquids (API-ILs) on the volumetric, ultrasonic, viscometric, conductometric and refractometric properties of aqueous solutions of glycine has been surveyed. To reach this purpose, the densities, sounds velocity, viscosities, electrical conductivities and refractive indices of ternary solutions of (glycine + API-ILs, 1-methyl-3-hexylimidazolium ibuprofenate [C6mim][Ibu] or 1-methyl-3-octylimidazolium ibuprofenate, [C8mim][Ibu] + water) have been determined at different concentrations of API-ILs and T = 298.2 K. The experimental data have been employed to calculate the properties such as partial apparent molar volume Vϕ0, partial molar volume of transfer ΔtrVϕ0, partial molar isentropic compression κφ0, ion association constant KA, molar refraction RD, viscosity B-coefficients, and hydration number nH. All of these properties were discussed in the terms of the competitive interactions existing between glycine-[C6mim][Ibu] or [C8mim][Ibu] in aqueous media and the hydration properties of glycine.

Electrical Conductivity Studies of 1-Butyl-3-methylimidazolium Salicylate as an Active Pharmaceutical Ingredient Ionic Liquid (API-IL) in Aqueous Amino Acids Solutions

The molar conductivity data of 1-butyl-3-methylimidazolium salicylate, [BMIm][Sal] as an active pharmaceutical ingredient ionic liquid (API-IL) have been determined in water and aqueous solutions of amino acids, glycine and L-alanine at T= (288.15 to 318.15) K. The molar conductivity data were analyzed by low concentration Chemical Model (lcCM) and limiting molar conductivities ), ion association constants ( K _A and standard Gibbs energies (∆ G _A ^° ) of the ion association process were calculated. The obtained values of and decrease with increase in the amino acid concentration. Moreover, the values of increase from glycine to L-alanine solutions due to the stronger solvation of the ions of [BMIm][Sal] by (COO− /NH3+) zwitterionic centers of glycine relative to L-alanine but this trend is vice versa for . The more negative values of (∆ G _A ^° ) for [BMIm][Sal] in glycine relative to L-alanine solutions is indicative of the more spontaneously and feasibility of the association process in this amino acid.

Thermodynamic Study of L-alanine in Aqueous Solutions of 1-Hexyl-3-Methylimidazolium Ibuprofenate as an Active Pharmaceutical Ingredient Ionic Liquid (API-IL)

The present work reported density, viscosity, speed of sound, electrical conductivity and refractive index data of L-alanine in the aqueous solutions of 1-hexyl-3-methylimidazolium ibuprofenate at T= 298.15 K. Using the measured data, partial molar volume of transfer ( ), partial molar isentropic compressibility of transfer ( ), viscosity B-coefficient of transfer (∆traB), ion association constant (KA) and molar refraction (RD) quantities were calculated. The obtained parameters provide the information about the solvation properties of aqueous solutions of L-alanine in the presence of [HMIm][Ibu]. The positive values of , and ∆traB are indicative of the ion-polar and polar-polar interactions between [HMIm][Ibu] and L-alanine. In addition, decreeing the KA values with addition of L-alanine to the [HMIm][Ibu] solutions suggests that the ion pair formation don’t proceed spontaneously at higher concentration of amino acid.

Study of interactions between l-alanine and 1-octyl-3-methylimidazolium salicylate or 1-octyl-3-methylimidazolium ibuprofenate using the thermophysical properties at T = 298.15 K

The effect of 1‑octyl‑3‑methylimidazolium salicylate, [OMIm][Sal] and 1‑octyl‑3‑methylimidazolium ibuprofenate, [OMIm][Ibu] as active pharmaceutical ingredient ionic liquids (API-ILs) on the solvation properties of l-alanine in aqueous media have been investigated by thermophysical properties determination. The partial molar volume of transfer (ΔtraVϕ0), partial molar isentropic compressibility of transfer (Δtraκϕ0), viscosity B-coefficient of transfer (∆traB), ion association constant (KA) and molar refraction (RD) quantities have been calculated using the measured density, speed of sound, viscosity, electrical conductance and refractive index data. The results showed that the ion-polar and polar-polar interactions between API-ILs and l-alanine are dominant.

Thermophysical Properties of 1-Hexyl-3-methylimidazolium Salicylate as an Active Pharmaceutical Ingredient Ionic Liquid (API-IL) in Aqueous Solutions of Glycine and l-Alanine

The effect of 1-hexyl-3-methylimidazolium salicylate, [HMIm][Sal] as an ionic liquid form of active pharmaceutical ingredient (API-IL) on the thermodynamic behavior of two simple amino acids, glycine and l-alanine have been investigated. The densities, speeds of sound, viscosities, and refractive indices of the amino acids in the mixtures of ([HMIm][Sal] + water) have been determined at T = 298.15 K. Moreover, the electrical conductivities of the studied API-IL in water and aqueous mixtures of the amino acids have been calculated using the measured specific conductivities. The measured data were utilized to compute the partial molar volume of transfer (ΔtraVϕ0), partial molar isentropic compressibility of transfer (Δtraκϕ0), viscosity B-coefficient of transfer (ΔtraB), ion association constant (KA), and molar refraction (RD) quantities. The increase in the positive values of ΔtraVϕ0, Δtraκϕ0 and ΔtraB with an increase in the API-IL concentration indicates that the ion–polar and polar–polar interactions be...

Interaction Between an Active Pharmaceutical Ingredient Ionic Liquid Benzalkonium Salicylate and Small Biomolecules in Aqueous Solution: UV Absorption, Conductivity, and Volumetric Study

UV absorption spectroscopy, electrical conductivity and density experiments have been used to investigate the interactions of some small biomolecules (amino acids/dipeptides) with an active pharmaceutical ingredient in ionic liquid form (API-IL), benzalkonium salicylate (BaSal), in aqueous solution. A number of useful parameters, such as critical micellar concentration (cmc), aggregation number (Nagg) and limiting molar conductivity (Λ0) of BaSal, standard partial molar volumes (\(V_{2,\phi }^{ \circ }\)), corresponding volumes of transfer from water to aqueous BaSal solutions (ΔtrVo), standard partial molar expansibilities (\(E_{\phi }^{ \circ }\)), hydration number (nH) of small biomolecules, as well as the binding constants (Kb) for small biomolecule–BaSal complexes have been evaluated. The dependence of the properties on concentration, temperature and alkyl chain length of amino acids/dipeptides is examined. The results are used to identify the solute–solvent physicochemical interactions occurring in the studied systems.

Studies on the interactions of some small biomolecules with antibacterial drug benzethonium chloride and its active pharmaceutical ingredient ionic liquid (API-IL) benzethonium L-proline at varying temperatures

From the conductivity, density and spectroscopy measurements, the interactions of benzethonium chloride ([BTC]) and its active pharmaceutical ingredient in ionic liquid format benzethonium L-proline ([BT][PRO]) with some amino acids and glycyl dipeptides have been examined. A number of useful parameters, such as standard partial molar volume (V2, ϕo), partial molar transfer volume (ΔtVo), standard partial molar expansibility (Eϕo) of these small biomolecules, critical micelle concentration (cmc), aggregation number (Nagg), thermodynamic micellization parameters of [BTC]/[BT][PRO], as well as binding constant for small biomolecule-drug complex have been evaluated. Group contributions of charged end group (NH3+, COO−), CH2 and (CH2CONH) groups of amino acids/dipeptides to V2, ϕo values have also been perceived. These parameters are helpful to study the structure making capacity of small biomolecules, solvation behavior of [BTC]/[BT][PRO] and various interactions present in the studied ternary solution. The interaction difference of [BTC] and [BT][PRO] with small biomolecules was studied.