Ion-pair Complex Research Articles

Determination of Imatinib mesylate from Pharmaceutical Dosage Form by extractive ion pair complex colorimetric Method

Simple sensitive and accurate extractive colorimetric method was developed for the estimation of Imatinib mesylate in Pharmaceutical dosage forms. The method was based on the formation of colored ion pair complexes by the drugs with thiocynate ions. These ion pair complexes were quantitatively extracted under the experimental condition in chloroform. The absorbance values were measured at 618 respectively. The proposed method was validated statistically. A recovery of method was carried out by standard addition methods. The Beer’s law ranges were found to be 1-12μg/ml, respectively. The low values of standard deviation and percentage RSD indicate high precision of method. Hence the method is useful for routine estimation of Imatinib mesylate in tablets respectively.

Determination of Methdilazine by Extractive Colorimetric Method from Pharmaceutical Dosage Form

Simple sensitive and accurate ion pair complex formation, extractive spectrophotometric methods have developed for the estimation of methdilazine hydrochloride in pharmaceutical dosage form. The methods are based on the formation of ion paired coloured complexes by the drug with reactive dyes like Congo red, picric acid and methyl orange in acidic medium. The ion associated complexes were formed and quantitatively extracted under the experimental condition in chloroform. The absorbance values were measured at 490 nm, 400 nm, and 430 nm respectively. The proposed methods were validated statistically. Recoveries of methods were carried out by standard addition method. The linearity was found to be 1-10 μg/ml, 2-12 μg/ml, and 1-14 μg/ml for methods respectively. The low values of standard deviation and percentage RSD indicate high precision of methods. Hence these methods are useful for routine estimation of methdilazine hydrochloride in pharmaceutical dosages.

QbD Approach-Based Preparation and Optimization of Hydrophobic Ion-Pairing Complex of Lysozyme with Sodium Dodecyl Sulphate to Enhance Stability in Lipid-Based Carriers.

Hydrophobic ion pairing (HIP) complexation was found to be an efficient approach in modulating the release and enhancing the stability and encapsulation of hydrophilic macromolecules such as proteins in hydrophobic nano/microcarriers. The present work strives to develop and optimize the preparation of the HIP complex of the antimicrobial enzyme lysozyme (LYZ) with the ion-pairing agent (IPA) sodium dodecyl sulphate (SDS) relying on the quality-by-design (QbD) approach. The quality target product profile (QTPP) includes the achievement of maximal lipophilicity in a reversible manner to enable the maintenance of biological activity. The related critical quality attributes (CQAs) were defined as complexation efficacy, complex stability, enzyme recovery and activity. Three risk assessment (RA) tools were used to identify and rank the critical process parameters (CPPs) and critical material attributes (CMAs). From this assessment, the pH of the medium, LYZ:SDS molar ratio and drying conditions were determined as high-risk factors that need to be investigated. To the best of our knowledge, for the first time, electrostatic titration was used as a smart approach to determine the optimum molar ratio at different pH values. Based on the predefined CQAs, pH 8 with an LYZ/SDS molar ratio of 1:8 was found to be the optimal condition for complexation efficiency and recovery (%) of a biologically active enzyme. A cost-effective drying process based on a ventilated oven was developed, which resulted in complex qualities comparable to those obtained by the commonly used freeze-drying method. In a nutshell, the optimum conditions for the preparation of the LYZ/SDS HIP complex were efficiently facilitated by the rational application of QbD principles and the utilization of efficient electrostatic titration and ventilated oven-drying methods.

Cheap and effective potentiometric PVC sensor for the determination of imidazolium based ionic liquids in aqueous and aqua-organic media

Owing to the extensive research on imidazolium based ionic liquids; the present study aims to design a potentiometric sensor for alkyl methylimidazolium ion. For this, poly(vinyl chloride) PVC membrane based on the neutral ion-pair complexes of cetylpyridinium chloride and sodium dodecyl sulfate (CPy+DS−) has been developed. The synthesized ion selective electrode (ISEs) have been found to show linear response with near-Nernstian slope for CnMeImCl (C10MeImCl, C12MeImCl and C14MeImCl). The proposed ISEs show quick response (5–6 s) and provide wide pH range for working. The influence of various ions on the performance of ion-selective electrode is investigated in terms of potentiometric selectivity coefficients, which were determined by separate solution method. The performance of synthesized ISE in examining the critical micellar concentration (cmc) of CnMeImCl in aqueous, aqua-organic media and in the presence of amino acids (glycine, L-glutamic acid and L-phenylalanine) has been found to be satisfactory and confirmed through conductivity and fluorescence measurements. This emphasizes its worth for in-situ analysis of alkyl methylimidazolium ions, during an organic reaction, and hence possible reaction mechanism evaluation. Different thermodynamic parameters such as Standard Gibbs energies of micellization (ΔGm∘), degree of counterion dissociation (α), amphiphile tail transfer Gibbs free energy (ΔGm,trans∘) have been evaluated. Further, the analytical application of synthesized electrode as end point indicator in the potentiometric titration of C14MeImCl with SDS has also been explored, which compared well with improved two-phase titration method. The current study is novel as it involves the use of a cheaper material (CPyCl) as ionophore and that the same electrode can be used for different chain alkyl methylimidazolium ions simply by changing the internal reference solutions.

Thermodynamic studies on the formation of ion-pair cobalt complexes in acetone–water mixtures

Dicarboxylic acids are stronoger acids than moncraboxylic acids and more soluble in water due to the presence of two carboxylic (–COOH) groups which are industrially important in producing polyester, polyamides, and polyols and as a pioneer to pharmaceutical additives. Succinic acid is one of the most prosperous chemicals that can be generated from renewable resources which can be used in the industries of antiseptics, cosmetics, sutures, drugs, solvents, detergents, herbicides, fungicides, synthetic resins, and inks. The ion–pair formation is very important in diferent applications, used widely for inorganic analysis by liquid chromatography and used for the heavy metal removal from waste water, so studing the ion-pair association constant (KA) formed between chloropentamminecobalt(III) cation [CpX2+] and a different ligands of dicarboxylate anions (AC2-), have been determined by EMF technique in different compositions of acetone aqueous media (0–44.20 wt% acetone) for succinic acid and for the other dicarboxylic acids (Maleic, Malonic and Malic) in the same solvent composition (40 wt% acetone) with in temperature range (30 – 60 °C). The thermodynamic association properties (ΔGA°, ΔHA° and ΔSA°) have been estimated and discussed. Extra thermodynamic correlations like ΔHA°- ΔSA° and ΔGA°- ΔGI(orII)° (where I and II are mentioned for the first and second dissociation constant of the dicarboxylic acids) in different compositions of acetone aqueous media for succinic acid and in fixed solvent composition for the other dicarboxylic acids were examined in order to give more information about the behavior of solvent molecules and its effect on formation of the ion-pair molecules. In addition, The Gibbs free energy of transfer for the association process ΔGA°(t) from water to acetone mixed solvents were calculated for succinic acid in order to indicate the spontaneous nature and the stabilization of the ion-pair by increasing the acetone weight percent in the mixed acetone – aqueous media. The linear correlation between pKD values and the relative permittivity of acetone aqueous medium is in accordance to Born’s equation.

Direct fluorescence and spectrophotometric-based detection of azithromycin using fluorescein isothiocyanate: Method development and comparative analysis

New methods for the analysis of azithromycin (AZM) have been devised, employing direct fluorescence and spectrophotometric techniques. This research focused on the development and validation of these methods, especially based on the formation of an ion-pair complex with fluorescein isothiocyanate (FITC). The resulting complex enhanced the fluorescence intensity at a wavelength of 520 nm and the absorbance at 480 nm. The impact of different solvent compositions was investigated, with methanol and a 1:1 mixture of methanol and Milli-Q proving to be the most sensitive. The optimal FITC concentration was determined as 50 µg/ml, and the molar ratio of the AZM-FITC ion-pair complex was determined to be 1:1. Notably, an instantaneous increase in fluorescence intensity was observed, eliminating the need for incubation. The developed methods were validated for sensitivity, accuracy, and precision, with the fluorescence-based method demonstrating superior sensitivity and precision compared to the spectrophotometric method. Under optimum conditions, the fluorescence-based method achieved a linear range of 0–31.25 µg/ml with a limit of detection (LOD) of 0.41 µg/ml and a limit of quantification (LOQ) of 1.23 µg/ml., In contrast, the spectrophotometric method had an LOD of 0.82 µg/ml and an LOQ of 2.49 µg/ml. Additionally, the fluorescence-based method exhibited a narrower recovery range in artificial urine samples, suggesting higher precision in complex matrices. Overall, these methods offer rapid and sensitive AZM analysis with potential applications in diverse matrices such as biological samples post-extraction.

The Stability of Hydrogen-Bonded Ion-Pair Complex Unexpectedly Increases with Increasing Solvent Polarity.

The generally observed decrease of the electrostatic energy in the complex with increasing solvent polarity has led to the assumption that the stability of the complexes with ion-pair hydrogen bonds decreases with increasing solvent polarity. Besides, the smaller solvent-accessible surface area (SASA) of the complex in comparison with the isolated subsystems results in a smaller solvation energy of the latter, leading to a destabilization of the complex in the solvent compared to the gas phase. In our study, which combines Nuclear Magnetic Resonance, Infrared Spectroscopy experiments, quantum chemical calculations, and molecular dynamics (MD) simulations, we question the general validity of this statement. We demonstrate that the binding free energy of the ion-pair hydrogen-bonded complex between 2-fluoropropionic acid and n-butylamine (CH3CHFCOO-…NH3But+) increases with increased solvent polarity. This phenomenon is rationalized by a substantial charge transfer between the subsystems that constitute the ion-pair hydrogen-bonded complex. This unexpected finding introduces a new perspective to our understanding of solvation dynamics, emphasizing the interplay between solvent polarity and molecular stability within hydrogen-bonded systems.

Green spectrophotometric and spectrofluorimetric determination of biperiden hydrochloride using erythrosine B sensing probe.

Erythrosine B (EB) is a food colorant antiviral xanthene dye that has many applications as a color additive in pharmaceuticals and cosmetics. Its use as a sensor for spectrofluorimetric and spectrophotometric analysis of amine-based pharmaceuticals renders many advantages because of its availability, low cost, rapid labeling, and high sensitivity. Herein, two fast and sensitive spectrofluorimetric and spectrophotometric methods were established for the estimation of the anti-Parkinson drug, biperiden (BIP) hydrochloride (HCl), in its raw material and tablet forms. The proposed methods depended on the interaction between the phenolic group of EB and the tertiary amino group of the studied analyte to form an ion-pair complex at pH4 using the Britton Robinson buffer. The spectrofluorimetric method is based on the measurement of the quenching power of BIP HCl on the fluorescence intensity of EB at λex/em= 527.0/550.9nm. This method was rectilinear over the concentration range of 0.1-1.0μg/mL with a limit of detection (LOD) = 0.017 μg/mL and a limit of quantification (LOQ) = 0.05 μg/mL. Meanwhile, the colorimetric method involved monitoring the absorbance of the formed ion-pair complex at 555 nm, showing a linearity range of 0.4-5.0μg/mL with LOD = 0.106 μg/mL and LOQ = 0.322 μg/mL. The proposed methods were assessed for the greenness, indicating the greenness of the developed methods.

Spectrophotometric Estimation of Donepezil Hydrochloride in pure and dosage forms via ion-pair complex with Erythrosine Dye.

Spectrophotometric Estimation of Donepezil Hydrochloride in pure and dosage forms via ion-pair complex with Erythrosine Dye.

Spectrophotometric Determination of Remdesivir Using the Ion Pair Complex Method Using through Alizarin Red S Dye

The research included the development of a simple and practical spectroscopic method for the estimation of remdesivir (RDV) by the ion-pair method, which is based on the interaction of RDV with Alizarin Red S (ARS) at laboratory temperature. Using water as a medium for the reaction, a product Red in color was formed, with a linear relation ranging from 1 to 25 ?g/ml. It gave the highest absorption at wavelength 524 nm, and the complex completed its reaction after an hour, as the value of the sample was a relative standard deviation of no more than 1%, the recovery rate is 100.2429%, and high sensitivity to low concentrations, where she was the values of limit of detection, limit of quantitation were 0.0198, 0.0602 ?g/ml, respectively, detection limit of 0.0139 ?g/mL, and a quantitation limit of 0.0422 ?g/mL. The molar absorptivity is 51340.668 L/mol/cm, and Sandell?s sensitivity value is 0.0117 ?g.cm-2. The recovery values ranged from 99.3088% to 100.5184%, with a relative standard deviation not exceeding 0.7886% for RDV. The method was successfully applied for the estimation of pharmaceutical preparations using both direct and standard addition methods.. KEYWORDS :Alizarin red S, Ion pair, Remdesivir, Spectrophotometric estimation.

Two green and sensitive spectrofluorimetric approaches for determination of Ambroxol and guaifenesin in their single and combined pharmaceutical formulations.

Ambroxol hydrochloride (AMX) and guaifenesin (GFN) are approved drugs utilized to treat coughs through their potent mucolytic and expectorant properties. Due to their massive, combined administration in many illnesses, there is a persistent need for their concurrent estimation in different pharmaceutical formulations. Two sensitive, environmentally friendly spectrofluorimetric methods were developed. AMX was determined using the first method (I) without interference from GFN. This method depends on the quenching of Erythrosine B (EB) native fluorescence at 552 nm after excitation at 527 nm due to the formation of a non-fluorescent AMX-EB ion-pair complex in Britton-Robinson buffer (BRB) solution pH (3.5). The concentration plot is linear over the 0.25-5.0μg/mL range, with a mean percent found value of 99.74%. Method (II) depends on measuring the native fluorescence of aqueous GFN solution at two analytical wavelengths, either 300 or 600 nm, after excitation at 274 nm. Relative fluorescence intensity (RFI)-concentration plots are linear over the ranges of 0.02-0.5 and 0.1-2.0μg/ml, with mean percent found at 99.96% and 99.91% at dual wavelengths, respectively. The proposed methods were successfully applied to assay both drugs in raw materials and different single and combined pharmaceutical formulations. These methods have been thoroughly validated following International Committee on Harmonisation (ICH) guidelines. National Environmental Methods Index, Analytical Eco-Scale, and Green Analytical Procedure Index were used to prove greenness, thereby enhancing their applicability. The proposed techniques provide straightforward, precise, and cost-effective solutions for routine formulation analysis in quality control laboratories.

Quality-by-Design Based Development of Doxycycline Hyclate-Loaded Polymeric Microspheres for Prolonged Drug Release.

This study explores a novel approach to address the challenges of delivering highly water-soluble drug molecules by employing hydrophobic ion-pairing (HIP) complexes within poly (lactic-co-glycolic acid) (PLGA) microspheres. The HIP complex, formed between doxycycline hyclate (DH) and docusate sodium (DS), renders the drug hydrophobic. The development of the microspheres was done using the QbD approach, namely, Box-Behnken Design (BBD). A comprehensive characterization of the HIP complex confirmed the successful conversion of DH. DH and the HIP complex were effectively loaded into PLGA microspheres using the oil-in-water (O/W) emulsion solvent evaporation method. Results demonstrated significant improvements in percentage entrapment efficiency (% EE) and drug loading (% DL) for DH within the HIP complex-loaded PLGA microspheres compared to DH-loaded microspheres alone. Additionally, the initial burst release of DH reduced to 3% within the initial 15min, followed by sustained drug release over 8days. The modified HIP complex strategy offers a promising platform for improving the delivery of highly water-soluble small molecules. It provides high % EE, % DL, minimal initial burst release, and sustained release, thus having the potential to enhance patient compliance and drug delivery efficiency.

Spectrophotometric quantification of amitriptyline hydrochloride in pharmaceutical tablets: method development and validation

The development and validation of two uncomplicated, selective, and non-extraction-based visible spectrophotometric methods was carried out for the quantification of a tricyclic antidepressant amitriptyline hydrochloride as pharmaceutical tablets as well as in its pure form. The methods rely on the formation of ion pair complexes between amitriptyline base and two acidic dyes, bromothymol blue and bromocresol purple, which were subsequently measured at 410 and 400 nm, respectively. The developed methods included numerous reaction variables that were examined and improved. Beer's law is applicable under optimal conditions for the bromothymol blue and bromocresol purple methods, respectively, over concentrations from 0.5 to 12.5 μg mL−1 and from 0.5 to 10.0 μg mL−1 amitriptyline hydrochloride. The computed values of molar absorptivity were 1.79 × 104 and 2.32 × 104 L.mol−1.cm−1 for bromothymol blue and bromocresol purple methods, respectively, with Sandell’s sensitivity values of 0.0155 and 0.0119 μg cm−2. Both detection limits and quantification limits were computed and determined to be 0.55 and 1.67 μg mL−1 for bromothymol blue method, and 0.49 and 1.49 μg mL−1 for bromocresol purple method, respectively. The developed methods were successfully applied to estimate the concentration of amitriptyline hydrochloride in bulk form and commercial pills. Therefore, these methods demonstrate promising potential for testing this drug in labs for quality control.Graphical abstractSpectrophotometric quantification of amitriptyline hydrochloride in pharmaceutical tablets: method development and validation

Iodine-PEG as a unique combination for the metal-free synthesis of flavonoids through iodonium-triiodide ion-pair complexation.

An efficient metal-free single-step protocol has been developed for the direct synthesis of flavones from 2-hydroxyacetophenone and substituted benzaldehydes. This chemical transformation is exclusively promoted by the iodonium-triiodide ion couple formed through iodine and PEG-400 complexation. The triiodide anion not only helps in the abstraction of a proton from the acetophenone but also promotes the cyclization of intermediate chalcone to the corresponding flavones. The flavones were obtained in very high yields without using any toxic metal catalysts or harsh reaction conditions. The reaction mechanism was established through a series of test reactions and entrapping of reaction intermediates. The developed protocol provides direct access to flavones in high yields under milder reaction conditions with great substrate compatibility, including hydroxylated derivatives.

New spectrophotometric determination sulfamethoxazole drug via various analytical methods in pharmaceutical formulation

For the determination of sulfamethaxazole (SMZ) in pure and pharmaceutical formulations, new simple sensitive spectrophotometric methods have been devised. The first technique involved forming an ion pair complex between the basic nitrogen of the SMZ medication and Eriochrome black (EBT) in an acidic buffer solution, and extracting the created complex with chloroform to get a persistent reddish-orange colored dye with a maximum wavelength of 490 nm. Beer's law was followed, and 0.9998 was the correlation coefficient., 0.471×104L. mol-1.cm-1was the molar absorptivity, and the detection limit was 0.177 g/mL. Dispersive liquid-liquid extraction (DLLE) is a second method for estimating a trace amount in an aqueous solution product using an ion pair and a UV-visible spectrophotometer with a maximum wavelength of 490 nm. The concentration range was 0.5-6 g/mL, with a correlation coefficient of 0.9995, 0.889×105 L.mol-1.cm-1, a molar absorptivity of ,the detection limit of 0.013 g/L, and a pre-concentration factor of 25 and an enrichment factor of 18.20. Sulfamethaxazole in pharmaceutical formulations was successfully determined using the provided methodology
 

Spectrofluorimetric Protocol for Estimation of Commonly Used Antispasmodic Drotaverine. Fluorescence Quenching Study.

A fast, simple, accurate, precise, and cheap fluorimetric protocol has been proposed for analysis of aphosphodiesterase-IV inhibitor, namely drotaverine hydrochloride. Fluorimetric protocol is based on estimating the decrease in the eosin Y fluorescence intensity by quantitative addition of drotaverine at pH 3.1 (acetate buffer). An ion pair complex is formed, which leads to quenching in the fluorescence intensity of the dye without need of prior extraction at 534 nm (λex. 339 nm). Different reaction perimeters which influence the production of complex (ion pair between drotaverine and eosin) were deeply investigated and optimized. The developed fluorimetric protocol is capable for quantitative estimation of drotaverine in linear range of 0.4 to 2.5 µg mL-1. After method validation in respect to ICH guidelines, it was applied to determinedrotaverinein its commercial preparation. By comparing with other reported method, the developed and validated fluorimetric protocol is capable for estimation of drotaverine in commercial preparation with good accuracy and excellent precision.

Unprecedented enantio-selective live-cell mitochondrial DNA super-resolution imaging and photo-sensitizing by the chiral ruthenium polypyridyl DNA "light-switch".

Mitochondrial DNA (mtDNA) is known to play a critical role in cellular functions. However, the fluorescent probe enantio-selectively targeting live-cell mtDNA is rare. We recently found that the well-known DNA 'light-switch' [Ru(phen)2dppz]Cl2 can image nuclear DNA in live-cells with chlorophenolic counter-anions via forming lipophilic ion-pairing complex. Interestingly, after washing with fresh-medium, [Ru(phen)2dppz]Cl2 was found to re-localize from nucleus to mitochondria via ABC transporter proteins. Intriguingly, the two enantiomers of [Ru(phen)2dppz]Cl2 were found to bind enantio-selectively with mtDNA in live-cells not only by super-resolution optical microscopy techniques (SIM, STED), but also by biochemical methods (mitochondrial membrane staining with Tomo20-dronpa). Using [Ru(phen)2dppz]Cl2 as the new mtDNA probe, we further found that each mitochondrion containing 1-8 mtDNA molecules are distributed throughout the entire mitochondrial matrix, and there are more nucleoids near nucleus. More interestingly, we found enantio-selective apoptotic cell death was induced by the two enantiomers by prolonged visible light irradiation, and in-situ self-monitoring apoptosis process can be achieved by using the unique 'photo-triggered nuclear translocation' property of the Ru complex. This is the first report on enantio-selective targeting and super-resolution imaging of live-cell mtDNA by a chiral Ru complex via formation and dissociation of ion-pairing complex with suitable counter-anions.

Validation of Molnupiravir by Application of Reactive Dyes from Pharmaceutical Dosages

Simple sensitive and accurate ion pair complex formation with reactive dyes, extractive spectrophotometric methods have developed for the estimation of molnupiravir in pharmaceutical dosage form. The methods are based on the formation of ion paired coloured complexes by the drug with reactive dyes like Congo red, eriochrome black T and methyl orange in acidic medium. The ion associated complexes were formed and quantitatively extracted under the experimental condition in chloroform. The absorbance values were measured at 490nm, 500nm, and 430nm respectively. The proposed methods were validated statistically. Recoveries of methods were carried out by standard addition method. The linearity was found to be 4.0-24.0μg/ml, 2-12μg/ml, and 2-16μg/ml for methods respectively. The low values of standard deviation and percentage RSD indicate high precision of methods. Hence these methods are useful for routine estimation of molnupiravir in pharmaceutical dosages.

Mucus-penetrating and permeation enhancer albumin-based nanoparticles for oral delivery of macromolecules: Application to bevacizumab

The oral administration of therapeutic proteins copes with important challenges (mainly degradation and poor absorption) making their potential therapeutic application extremely difficult. The aim of this study was to design and evaluate the potential of the combination between mucus-permeating nanoparticles and permeation enhancers as a carrier for the oral delivery of the monoclonal antibody bevacizumab, used as a model of therapeutic protein. For this purpose, bevacizumab was encapsulated in PEG-coated albumin nanoparticles as a hydrophobic ion-pairing complex with either sodium deoxycholate (DS) or sodium docusate (DOCU). In both cases, complex formation efficiencies close to 90% were found. The incorporation of either DS or DOCU in PEG-coated nanoparticles significantly increased their mean size, particularly when DOCU was used. Moreover, the diffusion in mucus of DOCU-loaded nanoparticles was significantly reduced, compared with DS ones. In a C. elegans model, DS or DOCU (free or nanoencapsulated) disrupted the intestinal epithelial integrity, but the overall survival of the worms was not affected. In rats, the relative oral bioavailability of bevacizumab incorporated in PEG-coated nanoparticles as a complex with DS (B-DS-NP-P) was 3.7%, a 1000-fold increase compared to free bevacizumab encapsulated in nanoparticles (B-NP-P). This important effect of DS may be explained not only by its capability to transiently disrupt tight junctions but also to their ability to increase the fluidity of membranes and to inhibit cytosolic and brush border enzymes. In summary, the current strategy may be useful to allow the therapeutic use of orally administered proteins, including monoclonal antibodies.Graphical

A Personal Account on Inorganic Reaction Mechanisms.

The presented Review is focused on the latest research in the field of inorganic chemistry performed by the van Eldik group and his collaborators. The first part of the manuscript concentrates on the interaction of nitric oxide and its derivatives with biologically important compounds. We summarized mechanistic information on the interaction between model porphyrin systems (microperoxidase) and NO as well as the recent studies on the formation of nitrosylcobalamin (CblNO). The following sections cover the characterization of the Ru(II)/Ru(III) mixed-valence ion-pair complexes, including Ru(II)/Ru(III)(edta) complexes. The last part concerns the latest mechanistic information on the DFT techniques applications. Each section presents the most important results with the mechanistic interpretations.