Ion-pair Complex Research Articles

Synthesis of (R)-(6-Methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methanol Tetraphenylborate Ion-Pair Complex: Characterization, Antimicrobial, and Computational Study.

The (R)-(6-Methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methanol (quinine)-tetraphenylborate complex was synthesized by reacting sodium tetraphenyl borate with quinine in deionized water at room temperature through an ion-pair reaction (green chemistry) at room temperature. The solid complex was characterized by several physicochemical methods. The formation of ion-pair complex between bio-active molecules and/or organic molecules is crucial to comprehending the relationships between bioactive molecules and receptor interactions. The complex under study was examined for antimicrobial activity. All theoretical calculations were carried out in vacuum and water using the B3LYP level 6-311G(d,p) levels of theory. The theoretical computation allowed for the prediction and visualization of ionic interactions, which explained the complex's stability. The results of energy optimization showed that the Q-TPB complex is stable with a negative complexation energy. The obtained geometries showed that the boron (B-) and nitrogen (N+) in piperidine of the two molecules tetraphenylborate and quinine are close to each other, which makes it possible for ions to interact. The modest energy gap between HOMO and LUMO showed that the compound was stable. The computation of the electron transitions of the two models by density functional theory (TD-DFT) in the solvent at the theoretical level B3LYP/6-311G(d,p) allowed for the detection of three UV/visible absorption bands for both models and the discovery of a charge transfer between the host and the guest. The UV absorption, infrared, and H NMR are comparable with the experimental part.

EXTRACTIVE SPECTROPHOTOMETRIC METHODS FOR THE ASSAY OF OSELTAMIVIR PHOSPHATE, FAMCICLOVIR AND ACYCLOVIR IN PURE AND DOSAGE FORMS

For the determination of oseltamivir phosphate (OSP), acyclovir (ACL), and famciclovir (FMV) medicines in pure form and their formulations, quick, accurate, and simple spectrophotometric procedures have been established. The procedures were relied on the formation of ion-pair complexes between the drugs and anionic dyes (OSP with bromothymol blue (BTB), ACL with methyl red (MTR) and FMV with methyl orange (MTO)) in an acidic medium, separately. The yellow OSP-bromothymol blue complex, orange ACL-methyl red complex and orange-yellow FMV-methyl orange complex formed were quantitatively extracted with chloroform and their absorbance measured at 416, 416 and 488 nm wavelengths, respectively. The limits of detection and quantification were found to be 0.5, 1.5, 1.0 µg mL-1 and 1.7, 5.0 and 3.3 µg mL-1 for the OSP, ACL and FMV, respectively. The linearity was established from 1-5, 2-12 and 5-14 µg mL-1 for OSP, ACL and FMV, respectively. R2 (regression coefficient) values were above 0.996 for all the three drugs. Recovery (accuracy) results were found within 98.0 % to 102 %. The developed methods comply with the ICH guidelines. The developed methods were successfully used to measure OSP, ACL and FMV in both their pure and in formulation forms.

Acriflavine: an efficient green fluorescent probe for sensitive analysis of aceclofenac in pharmaceutical formulations

Acriflavine is a multipurpose drug that shows antibacterial, antiviral, antimalarial, and antifungal activities. The remarkable native fluorescence of acriflavine is exploited in analytical chemistry field as an efficient probe for analysis of pharmaceutical and biological compounds. The fluorescent probe action of acriflavine is based on the remarkable fluorescence turning-off via formation of ion-pair complexes with acidic drugs at a specific pH. Herein, the acidic drug aceclofenac is analysed for the first time using acriflavine as a fluorescent probe. Aceclofenac can form an ion-pair complex with acriflavine at pH 8.5, and hence it partially turns off the fluorescence intensity of acriflavine over a concentration range of 1–20 µg/mL. The fluorescence quenching was monitored at 502 nm following an excitation at 265 or 451 nm. The reaction stoichiometry between acriflavine and aceclofenac was found to be 1:1 using limiting logarithmic method. The type of quenching was confirmed to be static using Stern–Volmer plot. The method showed low values of quantitation limit (0.89 µg/mL) and detection limit (0.29 µg/mL). Moreover, the method was linear (r = 0.9999), accurate, precise (RSD < 1.7%), robust, and specific. The proposed method was successfully employed to analyse aceclofenac in its dosage forms with high %recovery (98–101%). Additionally, GAPI and AGREE approaches were used to guarantee the suggested techniques' greenness, and the findings showed an excellent level of greenness.

METHOD DEVELOPMENT AND VALIDATION OF SIMULTANEOUS ESTIMATION OF PREGABALIN AND ETORICOXIB IN BULK AND PHARMACEUTICAL DOSAGE FORM BY UV-VISIBLE SPECTROSCOPY

A simple, accurate, precise and economical method has been developed for the simultaneous estimation of pregabalin and etoricoxib in combined dosage form by using double point standardization method. Methanol is used as the solvent and chromogenic agent added was bromocresol green. Bromocresol green is only reactive with pregabalin form a green colour ion pair complex. l max of pregabalin and etoricoxib was at 618 nm and 235 nm, respectively. The method was found to be linear in the range of 6-22 µg mL-1 for pregabalin and 4.8-17.6 µg mL-1 for etoricoxib. Validation parameters was performed and method was found to be linear, accurate, precise, rugged and robust.

Carbazole diester strapped calix[4]pyrrole: Synthesis, anion binding and self-assembly based on ion pair recognition

A new carbazole strapped calix[4]pyrrole 1 has been synthesized and ion binding properties was investigated using 1H NMR, isothermal titration calorimetry and single crystal X-ray diffraction analyses. Compared to the parent octamethyl calix[4]pyrrole 2, receptor 1 showed enhanced binding towards halide anions. Solid state structural analysis revealed that receptor 1 is capable of binding various halide salts showing different binding modes depending on the bound ion pairs. Interestingly, complexes of tetrabutyammonium (TBA+), tetraethylammonium (TEA+) and tetramethylammonium (TMA+) salts of chloride anion displayed three distinctly different binding geometries in the solid state. As a result, the linear supramolecular polymers seen in the crystal lattices are also dramatically different for these three chloride complexes of 1. Combination of 1H NMR and solid state studies revealed that binding of anion in one condition do not translates to another completely. Receptor 1 also found to form 1/1 complexes with CsCl, CsBr and CsI salts and 1D coordination polymer chains are stabilized in the solid state. Overall, construction of four different 1D linear chains are described for chloride anion based on ion pair recognition. In addition, the solid state structure of ion pair complex with CsI salt is unprecedented in the calix[4]pyrrole chemistry. Moreover, under solid-to-liquid extraction condition, receptor 1 is able to solubilise CsF and CsCl ion pairs in chloroform in which these salts are otherwise insoluble.

Unraveling the role of counter anions on optical and microwave absorption characteristics of flexible copolymers

Engineering the structural architecture of materials is critical for the transmittance of visible light and absorb microwave radiation in various stealth and electronic applications. Transparent copolymers comprising of methyl methacrylate (MMA) and 2-(dimethylamino)ethyl methacrylate (DMAEMA) were synthesized at different compositions using reversible addition-fragmentation chain transfer (RAFT) polymerization. The copolymers exhibited a high percentage of light transmittance (>90%) within the visible range owing to the majority fraction of MMA units. The amine functionalities in the synthesized copolymers were ionized at room temperature by treating with dilute acids such as hydrochloric acid (HCl), trifluoroacetic acid (TFA), nitric acid (HNO3), tetrafluoroboric acid (HBF4), and hexafluorophosphoric acid (HPF6). The quaternization of the side-chain amine groups have resulted in a series of copolymer salts with an ion-pair complex. The investigation of the counter anion effect on the conductivity of the materials has been carried out to produce the highly transparent and conductive MMA-based copolymers. The presence of partially mobile Cl⁻ counter anions in the copolymers can result in conductance as high as 0.939 mS cm−1. Moreover, the optically transparent MMA-based copolymer salts have witnessed a high microwave absorption due to multiple reflections from structural and physical anisotropies.

Validated and selective potentiometric analysis of anti-coagulant edoxaban via a screen-printed electrode: green assessment by Eco-Scale and Complex-GAPI

AbstractThromboembolism because of coronavirus infection (COVID-19) resulted in increasing the number of sudden deaths after recovery. So, patients were switched to edoxaban tosylate monohydrate (EDTM) therapy after low molecular weight heparin to shorten the hospitalization period. In response to increase the demand for EDTM, we developed a home-made screen-printed electrode to determine EDTM in its pure form and pharmaceutical dosage form. Optimized conditions were achieved with a screen-printed electrode utilizing EDTM-Phosphotungstic acid (EDTM-PTA) as an ion pair complex and a plasticizer dibutyl phthalate with a Nernstian slope of 58.78 ± 0.1 mV decade−1 at the concentrations ranging from 5.0 × 10–6 to 1.0 × 10–2 M EDTM (R2 = 0.9985). The detection limit was 4.3 × 10–6 M. Our method was proven to be eco-friendly after assessment by Eco-Scale and Complex-GAPI. The results obtained were validated according to ICH guidelines and were found to agree with those gained from the reference method.

Ion-Pair Complex of Trimethoprim with Alizarin Yellow and its Determination and Extraction by LLE and DLLME

For the analysis of trimethoprim medication in its pure form and pharmaceutical formulations, precise and accurate microextraction techniques with UV-Vis measurement have been developed and confirmed. In this study, LLE and DLLME procedures were utilized for the separation, pre-concentration, and evaluation of trimethoprim in pure form and pharmaceutical preparations by UV-Vis spectroscopy at 390 nm. The method was validated and applied to the evaluation of trimethoprim in pharmaceutical formulations. Several experimental factors containing the type of dispersive and extraction solvents and their volumes, pH, temperature, and centrifuging time were carried out. Under the ideal conditions, the procedures were linear in the range of 2–45 and 1-10 mg/L, with a coefficient of determination (R2) of 0.9961 and 0.9992 for LLE and DLLME, respectively. The limit of detection (LOD) was 1.52 and 0.21 mg/L. Recovery of the target analyte in pharmaceutical formulations was 99.3%-104.9%.

Green-adapted spectrophotometric determination of fostemsavir based on selective bromophenol blue extraction; reduction of hazardous consumption using computational calculations

A computationally-assisted and green spectrophotometric method has been developed for the determination of fostemsavir, a recently FDA-approved drug used in combination with antiretroviral drugs to treat multidrug-resistant HIV-1 infection. The method was developed using computational studies and solvent selection based on green chemistry principles. The density functional theory method was employed to identify bromophenol blue as the preferred acid dye for efficient extraction of fostemsavir. The solvent selection process involved a careful evaluation of the green ranking of solvents, which led to the use of water as the solvent. The method involved the extraction of fostemsavir with bromophenol blue to form a yellow ion-pair complex, which exhibited maximally sharp peaks at 418 nm, enabling sensitive visible spectrophotometric determination of fostemsavir in bulk and pharmaceutical preparations. The extraction procedures were optimized, and the method was demonstrated to be sensitive over the concentration range of 2–12 μg/mL fostemsavir. Furthermore, the method was evaluated with respect to green chemistry principles using the analytical eco-scale, the green analytical method index, and analytical greenness metric approach, all of which confirmed that the data obtained by the proposed method were environmentally acceptable.

An Innovative Selective Fluorescence Sensor for Quantification of Hazardous Food Colorant Allura Red in Beverages Using Nitrogen-Doped Carbon Quantum Dots

An innovative simple, sensitive, and selective method has been developed and validated for quantification of hazardous Allura red (AR, E129) dye in beverages. Allura red (AR) is a synthetic dye that is commonly used in the food industry to give foods a bright and appealing color. The method is based on microwave-assistant nitrogen-doped carbon quantum dots (N@CQDs) from a very cheap source with a high quantum yield equal to (36.60%). The mechanism of the reaction is based on an ion-pair association complex between AR and nitrogen-doped carbon quantum dots (N@CQDs) at pH 3.2. The reaction between AR and N@CQDs led to a quenching effect of the fluorescence intensity of N@CQDs at 445 nm after excitation at 350 nm. Moreover, the quantum method’s linearity covered the range between 0.07 and 10.0 µg mL− 1 with a regression coefficient is 0.9992. The presented work has been validated by ICH criteria. High-resolution transmission electron microscopy (HR-TEM), X-ray photon spectroscopy (XPS), Zeta potential measurements, fluorescence, UV-VIS, and FTIR spectroscopy have all been used to fully characterize of the N@CQDs. The N@CQDs were successfully utilized in different applications (beverages) with high accuracy.

Rivastigmine-DHA ion-pair complex improved loading in hybrid nanoparticles for better amyloid inhibition and nose-to-brain targeting in Alzheimer’s

Rivastigmine hydrogen tartrate (RIV-HT) is given orally for Alzheimer's disease. However, oral therapy shows low brain bioavailability, short half-life and gastrointestinal-mediated adverse effects. RIV-HT intranasal delivery can avoid these side effects, but its low brain bioavailability remains challenging. These issues could be solved with hybrid lipid nanoparticles with enough drug loading to enhance RIV-HT brain bioavailability while avoiding oral route side effects. The RIV-HT and docosahexaenoic acid (DHA) ion-pair complex (RIV:DHA) was prepared to improve drug loading into lipid-polymer hybrid (LPH) nanoparticles. Two types of LPH, i.e., cationic (RIV:DHA LPH(+ve)) and anionic LPH (RIV:DHA LPH(-ve)) were developed. The effect of LPH surface charge on in-vitro amyloid inhibition, in-vivo brain concentrations and nose-to-brain drug targeting efficiency were investigated. LPH nanoparticles showed concentration dependant amyloid inhibition. RIV:DHA LPH(+ve) demonstrated relatively enhanced Aβ1-42 peptide inhibition. The thermoresponsive gel embedded with LPH nanoparticles improved nasal drug retention. LPH nanoparticles gel significantly improved pharmacokinetic parameters compared to RIV-HT gel. RIV:DHA LPH(+ve) gel showed better brain concentrations than RIV:DHA LPH(-ve) gel. The histological examination of nasal mucosa treated with LPH nanoparticles gel showed that the delivery system was safe. In conclusion, the LPH nanoparticle gel was safe and efficient in improving the nose-to-brain targeting of RIV, which can potentially be utilized in managing Alzheimer's.

Unraveling the dependence of proton transfer on solvent polarity in ion pairs of carbamates and dithiocarbamates with nitrogen‐based counterions

AbstractSmall, but important, differences in the structure–property relationships between ionomers composed of amidinium or imidazolinium groups with alkylcarbamate or alkyldithiocarbamate counterions have been examined experimentally by us previously. To unravel the sources of these differences, DFT calculations are conducted here for ion‐pair complexes (IPs) of these systems and their corresponding uncharged base and acid components (NPs). Calculations include IPs and NPs in which the amidine/amidinium and imidazoline/imidazolinium groups are anchored to a dimethylsiloxane pentamer. A surprising dependence of proton transfer on the dielectric constant (ε) of the medium is found for the systems: Whereas interconversion between the NPs and IPs is strongly dependent on medium dielectric in systems with an alkylcarbamate, none of the initial IP forms with an alkyldithiocarbamate transforms to an NP. Although the calculations do not include individual solvent–solute molecular interactions, they do probe how the components sense their bulk environments. The lack of detectable reversible proton transfer from the amidinium or imidazolinium cations to the dithiocarbamates is consistent with the “principle of proton affinity/pKa equivalence”: Because the acidity of dithiocarbamates is higher than that of carbamates, the gap between their proton affinities (ΔPA) is decreased, favoring stronger electrostatic‐based H‐bonds in the ion‐pair complexes of the dithiocarbamates. The differences can also be estimated from the Deuri–Phukan nucleophilicity index scale, which is based on DFT calculations and suggests a strong dependence of proton transfer on the nucleophilicity of the base and the dielectric constant of the solvent. Predictions from these calculations on some important experimental systems are mentioned.

Simple cloud point microextraction based on indophenol dye formation for mesalazine determination in pharmaceutical and biological samples

An efficient, sensitive, and environmentally friendly technique for determining mesalazine concentrations in pure drug dosage forms and blood serum using room temperature cloud point microextraction (RT-MCPE) is proposed in this study. The procedure relies on the formation of a blue indophenol dye in an alkaline medium that occurs due to an oxidative coupling reaction between mesalazine and syringic acid. The resultant dye can shift from blue to pink by forming an ion-pair complex with the acetate buffer (pH 3) used. To separate the dye from the surrounding aqueous environment, sodium sulfate (Na2SO4) and a nonionic surfactant, Triton X-114, were added to the solution, allowing the dye molecules to form micelles around the surfactant at room temperature. After using NaOH to restore the blue colour of indophenol, the solution was diluted and its absorbance at 635 nm was measured using a visible spectrophotometer, with all the experimental parameters optimised. The calibration curve exhibited linearity in the range of 0.25–10 μg mL−1 mesalazine, with a limit of detection of 0.04 μg mL−1. The method allowed for the accurate determination of the mesalazine content in drug dosage forms and serum, with an average recovery rate of 99.2% and a preconcentration factor of approximately 20. It yielded comparable results to traditional HPLC measurements, suggesting that it can serve as a reliable alternative or supplementary method for mesalazine determination.

Determination of doxepin hydrochloride in spiked human plasma and capsule after derivatization with eosin Y using resonance Rayleigh scattering, second-order scattering and frequency doubling scattering methods.

Doxepin hydrochloride (DOX) is a tricyclic antidepressant drug. Three sensitive spectrofluorimetric methods, namely resonance Rayleigh scattering (RRS), frequency doubling scattering (FDS) and second-order scattering (SOS), were developed and validated for their estimation of doxepin in spiked human plasma and formulation using liquid-liquid extraction method through the formation of an ion pair complex with eosin Y at a pH of4.5. Various factors affecting fluorescence intensity were optimized, and the reaction kinetics was determined using the Arrhenius equation method. Different scattering methods such as RRS, FDS and SOS were developed at maximum scattering wavelengths λex /λem = 567/567 nm for RRS, 720/360 nm for SOS and 260/520 nm for FDS, respectively. The methods exhibited high sensitivities, and the detection limits for DOX were found to be 0.82, 1.20 and 1.03 ng/ml for RRS, FDS and SOS methods, respectively. The FDS method exhibited the highest sensitivity. The methods were validated using the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines and applied to determine DOX in capsule and spiked human plasma samples.

Surface Confinement of Finite-Size Water Droplets for SO3 Hydrolysis Reaction Revealed by Molecular Dynamics Simulations Based on a Machine Learning Force Field

As an important source for sulfuric acid in the atmosphere, hydrolysis of sulfur trioxide (SO3) takes place with water clusters of sizes from several molecules to several nanometers, resulting in various final products, including neutral (H2SO4)-(H2O) clusters and ionic (HSO4)--(H3O)+ clusters. The diverse products may be due to the ability of proton transfer and the formation of hydrated ions for water cluster of finite sizes, especially the sub-micrometer ones. However, the detailed molecular-level mechanism is still unclear due to the lack of available characterization and simulations tools. Here, we developed a quantum chemistry-level machine learning (ML) model to simulate the hydrolysis of SO3 with water clusters of sizes up to nanometers. The simulation results demonstrate diverse reaction paths taking place between SO3 and water clusters of different sizes. Generally, neutral (H2SO4)-(H2O) clusters are preferred by water clusters of ultra-small size, and a loop structure-mediated mechanism with SO3(H2O)n≤4 structures and a non-loop structure-mediated mechanism with structure relaxation are observed. As the water cluster size increases to (H2O)8, a (HSO4)--(H3O)+ ion-pair product emerges; and the Eigen-Zundel ion conversion-like proton transfer mechanism takes place and stabilizes the ion pairs. As the water cluster sizes further increase beyond several nanometers ((H2O)n≥32), the (SO4)2-[(H3O)+]2 ion-pair product appears. The reason could be that the surface of these water clusters is large enough to screen Coulomb repulsion between two tri-coordinated ion-pair complexes. These findings would provide new perspectives for understanding SO3 hydrolysis in the real atmosphere and sulfuric acid chemistry in atmospheric aerosols.

New Spectrophotometric Gliclazide Determination in Tablets Formulations by Charge Transfer Complexation

Rapid useful and easy spectrophotometric method for quantitative analysis of Gliclazide(GLZ)in raw material and tablets pharmaceutical formulation has been described. This method is based on the formation of yellow ion-pair complex between (GLZ) and Bromocresol purple (BCP) in Toluene medium. Different parameters affecting the reaction such as: effect of solvents, time, reagent concentration, correlation ratio, etc. were optimized. The absorbance of the formed complex GLZ-BCP was measured by visible spectrum at absorption maximum 415 nm. The range of linearity was(4.85 – 113.19) µg/mL,regression analysis had a good correlation coefficient R2 = 0.9999. The limit of detection (LOD)and limit of quantification (LOQ)were to be 0.47µg/mL and 1.44µg/mL respectively. The average percent recovery of (GLZ) was found to be (99.73 – 100.41)%. The method was successfully applied for the determination of (GLZ) in tablets pharmaceutical formulations in Syrian pharmaceutical products: UNICRON. The proposed method is simple, direct, and sensitiveand does not require any pre-extractionprocess. Thus, the method could be ready to apply in routine analysis and quality control.

ANALYTICAL METHOD DEVELOPMENT AND VALIDATION FOR THE ESTIMATION OF FOSFOMYCIN TROMETAMOL IN ITS BULK AND PHARMACEUTICAL DOSAGE FORM

The goal of the current study is to develop and validate a new chromatographic method for Fosfomycin Trometamol's determination in both pure form and pharmaceutical formulation. In the present study, a pre chromatographic derivatization of Fosfomycin Trometamol was done by forming an ion-pair complex of Heterocyclic nitrogen using the acidic dye methyl orange and phthalate buffer of pH-6. The yellow ion-pair complex was extracted with chloroform and it was further extracted with aqueous solution of 0.01M HCL. The ion-pair complex of Fosfomycin Trometamol and methyl orange obeyed Beer's law in the range of 30 -70 μg/ml with a correlation coefficient (r2) of 0.9946. A Liquid chromatography system equipped with an Agilent ACE C18 column (250 X 4.6mm, 5μm) was used as a stationary phase in this work. The developed method was validated according to ICH guidelines. For determining the medication in bulk and formulation, the devised approach was proven to be accurate, sensitive, and repeatable

Modeling of adsorptive removal of azithromycin from aquatic media by CoFe2O4/NiO anchored microalgae-derived nitrogen-doped porous activated carbon adsorbent and colorimetric quantifying of azithromycin in pharmaceutical products

Herein, it was aimed to optimize the removal process of Azithromycin (Azi) from the aquatic environment via CoFe2O4/NiO nanoparticles anchored onto the microalgae-derived nitrogen-doped porous activated carbon (N-PAC), besides developing a colorimetric method for the swift monitoring of Azi in pharmaceutical products. In this study, the Spirulina platensis (Sp) was used as a biomass resource for fabricating CoFe2O4/NiO@N-PAC adsorbent. The pores of N-PAC mainly entail mesoporous structures with a mean pore diameter of 21.546 nm and total cavity volume (Vtotal) of 0.033578 cm3. g−1. The adsorption studies offered that 98.5% of Azi in aqueous media could remove by CoFe2O4/NiO@N-PAC. For the cyclic stability analysis, the adsorbent was separated magnetically and assessed at the end of five adsorption-desorption cycles with a negligible decrease in adsorption. The kinetic modeling revealed that the adsorption of Azi onto the CoFe2O4/NiO@N-PAC was well-fitted to the second-order reaction kinetics, and the highest adsorption capacity was found as 2000 mg. g−1 at 25 °C based on the Langmuir adsorption isotherm model at 0.8 g. L−1 adsorbent concentration. The Freundlich isotherm model had the best agreement with the experimental data. Thermodynamic modeling indicated the spontaneous and exothermic nature of the adsorption process. Moreover, the effects of pH, temperature, and operating time were also optimized in the colorimetric Azi detection. The blue ion-pair complexes between Azi and Coomassie Brilliant Blue G-250 (CBBG-250) reagent followed Beer's law at wavelengths of 640 nm in the concentration range of 1.0 μM to 1.0 mM with a 0.94 μM limit of detection (LOD). In addition, the selectivity of Azi determination was verified in presence of various species. Furthermore, the applicability of CBBG-250 dye for quantifying Azi was evaluated in Azi capsules as real samples, which revealed the acceptable recovery percentage (98.72–101.27%). This work paves the way for engineering advanced nanomaterials for the removal and monitoring of Azi and assures the sustainability of environmental protection and public health.

Formation - Extraction of Ion Pair Complexes of [PdI4]-2 and[BiI4]-1 with Trifluoperazine Hydrochtoride (TFPri) Drug andDetermination by Molecular Absorption Spectroscopy

This Study includes the determination of (TFPH) drug via the formation of ion association pair with [pdly]? and with [Bily]" in aqueous phase . The analytical results obtained are as follow: the optimum pH is 5 and 4, reaction time is immediate and 5 minutes, mixing time 3 and 4 minutes for the two ion pair respectively. The statistical and other analytical results for the first ion pair in the concentration range (6- -40ppm) were as follow: the detection limit is 0.228 ppm, molar absorption coefficient is 2.3635x10* liter mole™ em™ at 297nm . For Bily — TFPH ion pair at 292 nm, the results in the concentration range (0.2-18ppm) ere as follow: detection limit is 0.0030 ppm , and molar absorption coefficient is 3.747 x 10° liter mole” cm™ . This method was applied to Salabid pharmaceutical preparation with percentage recovery of not less than 98.5%

Enhancing Oil Solubility of BCS Class II Drug Phenytoin Through Hydrophobic Ion Pairing to Enable High Drug Load in Injectable Nanoemulsion to Prevent Precipitation at Physiological pH With a Potential to Prevent Phlebitis

This work investigates the micellar titration of phenytoin (a weakly acidic drug) with cetyltrimethylammonium hydroxide (CTAH) to form a hydrophobic ion-pair to enhance oil solubility of phenytoin, followed by an effort to formulate nanoemulsion that could potentially prevent precipitation of phenytoin at physiological pH. The ion-pair formulated in nanoemulsion was evaluated for in vitro precipitation during serial dilution at physiological pH. The formation of ion-pair during titration was explained in context of pH-solubility data. The mathematical model successfully integrated ionization and micellization equilibria to reflect on dominant mechanisms for solubilization. The micellar phenomenon during titration was confirmed using Dynamic Light Scattering (DLS). The phase changes of the excess undissolved solids during titration were evident from X-Ray Powder Diffraction (XRPD) and Fourier Transform Infrared Spectroscopy (FTIR). This analysis confirmed the conversion of phenytoin into ionized state and its subsequent ionic interaction with CTAH forming hydrophobic ion-pair complex (HIP). The complete ion pair formation was evident at pHmax (8.8 to 9.2), and its 1:1 stoichiometry was confirmed using HPLC (Phenytoin and CTAH) and H1 NMR, hence could also be called as a lipophilic salt. The ion-pair (salt) was insoluble in water and showed remarkably high partition coefficient (log P) in octanol/water. As characterized by Hot Stage Microscopy (HSM), the melting point of the ion-pair complex was lowered to 150.8⁰C compared to the free acid (> 300οC), this was even further lowered to 81.1 °C when evaluated in castor oil. This led to approximately eight-fold higher solubility of hydrophobic ion pair (HIP) in castor oil compared to the free acid form. The high miscibility in castor oil was suitable to formulate a high drug load injectable dispersed system. This was successfully achieved with lecithin and polysorbate as emulsifiers without leaching drug into continuous phase at pH 7.4. This nanoemulsion (<300 nm, and > +30 mV zeta potential) remain stable when evaluated over a period of one month. A serial dilution study of the nanoemulsion was performed in PBS buffer, microscopic observations suggested no birefringence despite incubation at 25°C for several hours. This result indicated that Phenytoin remained strongly partitioned within dispersed oily phase with a higher drug loading when ion-paired phenytoin was used. The higher drug load could enable a small volume slow bolus injection to meet 50 mg/min or lower delivery rate criteria for Phenytoin in the clinical set up. This provided a pathway to further explore potential injectable nano-emulsion formulations that could alleviate typical phlebitis issue associated with the injectable phenytoin solution administration at physiological pH.