The relationship between hydrogen-bonded ion-pair stability and transdermal penetration of lornoxicam with organic amines

Ion pair is an effective chemical approach to enhance skin penetration of drugs. The aim of this work was to investigate the skin enhancement mechanism of ion pairs for lornoxicam (LOX) with organic amines from the standpoint of ion-pair stability. Various organic amines, triethylamine (TEtA), diethylamine (DEtA), N-(2'-hydroxyethanol)-piperdine (NP), diethanolamine (DEA) and triethanolamine (TEA), were employed as the counter ions for enhancing LOX across the rabbit skin in vitro. Intermolecular interaction between LOX and organic amines was confirmed by IR and (1)H NMR spectroscopy in solution. All the amines, especially TEtA, provided an obvious enhancing effect for LOX. Spectra data proved that the presence of organic amines led to ion pair formation in solution which was associated with proton transfer of hydroxyl group of LOX. The stability parameter of ion pairs, ion-pair lifetimes (T(life)), was calculated from the NMR data. The results demonstrated that the stability of ion-pair complexes was closely related with the basicity of organic amines and exhibited a great contribution on skin permeation of LOX.     

Bioanalysis of picomole amounts of acetylcholine by ion-pair partition chromatography applied to rat sciatic nerve.

A method for determination of acetylcholine in small, discrete biological objects by use of ion-pair technique has been developed. Acetylcholine is extracted as an ion pair with 3,5-di-t-butyl-2-hydroxybenzenesulphonate and separated from co-extracted components by ion-pair partition chromatography with picrate as the counter ion and porous cellulose as support. The quantitative evaluation is made from the acetylcholine peak in the chromatogram obtained by ultraviolet detection. Acetylcholine has been analysed in 1 cm large pieces of rat sciatic nerve containing about 60 pmol (10 ng). The overall recovery of the method is 100 +/- 10% at the 120 pmol level of acetylcholine in a sample.     

苯扎溴铵选择性电极的研制

The PVC membrane selective electrode for benzalkonium bromide was studied. It is based on the use of benzalkonium tetraphenylborate ion pair complex as the active material. The PVC membrane electrode showed Nernstian response over the concentration range from 10^-3 mol/L to 5×10^-6mol/L with a slope of 53～57 mV/pC, and the detection limit was found to be 3×10^-6 mol/L. The electrode showed rapid response and good reproducibility. The selectivity coefficients of 16 substances were determined. Using direct potentiometric determination, the recovery of pure benzalkonium bromide was 101.8%. The present method is more rapid and simpler than the volumetric method given in the Chinese Pharmacopoeia.     

Determination of mangafodipir trisodium and related impurities in bulk substance and pharmaceutical formulation by ion-pair high-performance liquid chromatography

The development of an ion-pair liquid chromatographic method for determination of mangafodipir trisodium and related impurities is described. Good resolution was obtained when using a polymeric reverse-phase column and a mobile phase of pH* 10.5 composed by borate buffer, acetonitrile, and tetrabutylammonium hydrogensulphate as ion pair agent. Validation of the method showed good selectivity, precision, accuracy and linearity, and detection limits of 0.1--0.2 microg/ml.     

Effect of the stability of hydrogen-bonded ion pairs with organic amines on transdermal penetration of teriflunomide

The aim of this work was to investigate the effect of the stability of hydrogen-bonded ion pairs with organic amines on transdermal penetration of teriflunomide (TEF). Five organic amines, diethylamine (DEtA), triethylamine (TEtA), diethanolamine (DEA), triethanolamine (TEA), and N-(2'-hydroxyethanol)-piperdine (NP), were chosen to form ion pairs with TEF separately, and the passage of each TEF ion pair through the rabbit skin was evaluated in vitro. FTIR and (1)H NMR spectroscopy were performed to confirm the formation of ion pairs between TEF and organic amines in solution. The stability parameter of ion pairs in terms of ion-pair lifetimes (T(life)) was calculated from the NMR data. TEF could form ion pairs with these amines via hydrogen bond. The formation of ion pairs enhanced the percutaneous absorption of TEF except TEF-DEA. It was found that, for most studied organic amines, the longer the ion-pair lifetime, the higher the flux of skin permeation. The stability of TEF ion pairs was a pivotal factor influencing the skin permeation of TEF.     

The stoichiometric interaction and influence of ionic strength on the organic-aqueous distribution behaviour of a tetrazole ion pair

Physicochemical measurements have been carried out on drug-pairing ion systems. The stoichiometric solubility product, K_s was used to define the complexation between a novel tetrazole derivative with quaternary ammonium and phosphonium compounds. The stoichiometry of interaction was unity which suggested that the solute transport occurred as a 1 : 1 complex and not as the predicted 2 : 1 species. The behaviour of the ion-pair species was examined by a conditional extraction constant. This constant increased with increasing weight of the interacting cation counterion. However, the presence of an inorganic electrolyte, sodium chloride was shown to inhibit the transfer of the ion pair from an aqueous phase to an organic phase. A salting-in effect was described.     

Generalized theory for two- phase ion- pair and complexometric titrations

A systematic theoretical treatment of the two-phase titration based on ion-pair and metal-complex formation is presented. Equations for the titration curve, accuracy, equivalence point and choice of the indicator are derived. Much attention is paid to the parameters determining the titratabilityviz. extraction constant, distribution constant, phase volume ratio and the concentration of the analyte. Special attention is given to the role of intermediate ion-pair and metal-complex formation in the, aqueous phase. The ion-pair formation in aqueous solution is examined closer by means of the relationship between the association constant in water, the degree of dissociation of the ion pair () and the concentration of the counter ion. The merits of this theoretical treatment are illustrated with literature examples.     

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 pH_max (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 (> 300^οC), 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.     

Effect of benzalkonium chloride on percutaneous absoption of antisense phosphorothioate oligonucleotides

The effect of benzalkonium chloride on skin permeability of partially modified antisense phosphorothioate oligonucleotides (PS-ODN), which are designed as scar formation inhibitor, was investigated using Franz Diffusion Cell. When the concentration ratio of PS-ODN-quarternary ammonium salt complex is more than 1∶100, the apparent partition coefficient (APC) of each complex was increased in the following order; tetraphenyl phosphonium chloride (TPP)<cetyltrimethyl ammonium bromide (CTAB)<benzalkonium chloride (BZ). The permeability of PS-ODN through the rat skin increased in the presence of BZ. The fluxs of PS-ODN with BZ were increased by addition of Pluronic F 68 or Triton X-100 to phosphate buffered saline (PBS), respectively. When the mole ratio of PS-ODN to BZ is 1∶10, the fluxs penetrated of PS-ODN with BZ was greatest. The increase of the permeability in the presence of BZ might be due to the formation of lipophilic ion-pair complex between PS-ODN and BZ. By regulation of mole ratio of PS-ODN to BZ, the development of topical dosage forms using PS-ODN as scar formation inhibitor will be possible with minimal systemic exposure.     

Facilitated transfer of cationic drugs across a lipoidal membrane by oleic acid and lauric acid

The transfer of four β-adrenoceptor blocking agents of different lipophilicity across an artificial lipid membrane was measured using the rotating diffusion cells (RDC). A facilitated transport mechanism was established when oleic acid and lauric acid were incorporated in the membrane, using an appropriate pH gradient. The diffusion of metoprolol, oxprenolol and to a lesser extent propranolol was enhanced by an ion-pair mechanism in the presence of the fatty acids. The transfer of atenolol, the most hydrophilic of the drugs under investigation, was not enhanced. The results are useful in understanding the way in which charged molecules may be transported across biological membranes by ion pair mechanisms and also for the development of solid supported liquid membranes in separation technology.     

Flow injection potentiometric determination of amantadine HCl

New amantadine (Am) ion selective plastic membrane electrodes of both conventional and coated graphite types based on the ion-pair of amantadinium tetraphenylborate (Am-TPB) ion-pair are prepared. The conventional type electrode was fully characterized in terms of membrane composition, life span, pH, ionic strength and temperature. It was applied to potentiometric determination of amantadine in pure state and pharmaceutical preparation under batch and flow injection conditions. The selectivity of the electrode toward a large number of inorganic cations, sugars and amino acids was tested. The solubility product of the ion-pair and the formation constant of the precipitation reaction leading to the ion-pair formation were determined conductimetrically.     

Simple spectrophotometric determination of cinnarizine in its dosage forms

A direct, extraction-free spectrophotometric method has been developed for the determination of cinnarizine in pharmaceutical preparations. The method is based on ion-pair formation between the drug and three acidic (sulphonphthalein) dyes; namely bromocresol green (BCG), bromocresol purple (BCP) and bromophenol blue (BPB) which induces an instantaneous bathochromic shift of the maximum in the drug spectrum. Conformity to Beer's law enabled the assay of dosage forms of the drug. Compared with a reference method, the results obtained were of equal accuracy and precision. A more detailed investigation of the cinnarizine-BCG ion pair complex was made with respect to its composition, association constant and free energy change. In addition, this method was also found to be specific for the analysis of cinnarizine in the presence of some of the co-formulated drugs, such as pyridoxine hydrochloride and digoxin.     

离子对高效液相色谱法检测洗液中苯扎溴铵含量

目的建立测定洗液中苯扎溴铵含量的离子对高效液相色谱法。方法色谱柱采用AgilentXDB-C18柱（150mm×4．6mm,5μm）,以0．02mol／L庚烷磺酸钠溶液（含0．1％三乙胺,pH为3．45±0．1）-乙腈（35：65）为流动相,检测波长210nm,柱温30℃。结果苯扎溴铵质量浓度在0．005-0．1μg范围内与峰面积线性关系良好（r=0．9997）。结论所用方法灵敏、准确、简便,适合于洗液中微量苯扎溴铵的含量测定。     

Retention model for ion-pair chromatography based on double-layer ionic adsorption and exchange

Previous work has demonstrated the validity of an electrical double-layer model for sorption of sample ions onto low capacity ion exchangers. In the present work it is shown how this model can be used in describing the chromatographic retention of sample ions in so-called reversed-phase ion-pair chromatography. The pairing ion added to the mobile phase is sorbed onto the reversed-phase sorbent, creating an electrical double layer and a surface electrical potential psi(o). Sample counterions undergo both ion exchange for electrolyte ions in the diffuse part of the double layer and surface adsorption. The latter depends on the magnitude of psi(o), which can be calculated from the Stern-Gouy-Chapman theory. The model predicts virtually all of the phenomena that have been described in the literature on ion-pair chromatography.     

Rapid determination of benzalkonium chloride in pharmaceutical preparations with flow injection liquid-liquid extraction

Benzalkonium chloride was assayed by on-line extraction of the benzalkonium ion with picrate to chloroform. The absorbance of picrate was measured. The extractions were performed with a home-made flow injection extraction unit. Calibration curves (1.5-180 x 10(-4)% w/v) were straight lines (r = 0.9993) and the relative standard deviation of a series of injections was less than or equal to 2%. Pharmaceutical benzalkonium preparations, containing xylometazoline, timolol, phenylephrine or carbachol could also be assayed. The method was compared with a modified HPLC assay.     

阳、阴离子型药物电位滴定通用电极的比较研究

磷钨酸十六烷基三辛基铵电极可用于多种阳离子型及阴离子型药物的电位滴定,分别用四苯硼钠及硫酸作滴定剂,电位突跃可达150～400 mV,最低测定浓度可达10^-5mol/L左右,经过短时转化,即可改用于不同药物的滴定。季磷、季钟盐型电极或其它阴离子型电极性能较差。电活性物显示烃基加重效应。电极结构无显著影响。表面活性剂苯扎溴铵可加速活化。     

建立电感耦合等离子体质谱分析法测定滴眼液中的苯扎溴铵

目的:建立了电感耦合等离子体质谱分析(ICP-MS)测定滴眼液中苯扎溴铵的含量:.方法:采用ICP-MS技术,检测苯扎溴铵中的溴元素,建立了滴眼液中苯扎溴铵的含量测定方法,并进行了完整的方法学验证.结果:苯扎溴铵在0.163 2～2.725μg· mL-1范围内线性关系良好(r=0.999 9),平均回收率为101.5...     

Ion-pair formation of Bi(III)–iodide with some nitrogenous drugs and its application to pharmaceutical preparations

A systematic spectrophotometric study on the ion-pair formation of Bi(III)–iodide with amineptine hydrochloride, piribedil and trimebutine maleate is carried out. The optimal experimental conditions pH, concentration of Bi(III) nitrate, potassium iodide; and the nature and amount of organic solvent have been studied. The ion pairs are soluble in 1,2-dichloroethane and the optimum pH range is 2.0–2.8. By application of the methods of Sommer and Job involving non-equimolar solutions, the conditional stability constant (log K′) of the Bi(III)–piridedil ion pair (1:1) at the optimum pH of 2.4 and an ionic strength (μ) 0.1 M, was found to be 5.436. The validity of Beer's law has been tested in the concentration range 5–50 μg ml⁻¹ in the organic layer, the relative standard deviation is less than 1%. The method is applied to the determination of these drugs in tablets without interference.     

Determination of ambroxol hydrochloride in pure solutions and some of its pharmaceutical preparations under batch and FIA conditions

New ambroxol (Amb) ion selective plastic membrane electrodes of both conventional and coated graphite types based on the ion-pair of ambroxolium tetraphenylborate (Amb-TPB) ion-pair are prepared. The conventional type electrode was fully characterized in terms of membrane composition, life span, pH, ionic strength and temperature. It was applied to potentiometric determination of ambroxol in pure solutions and pharmaceutical preparations under batch and flow injection conditions. The potentiometric determination was used in the determination of ambroxol in muco syrup in four batches of different expiry dates, also the amounts of ambroxol released after 1, 8 and 16 h from the muco sustained release type (S.R.) capsules were also assayed. The selectivity of the electrode toward a large number of excipient like inorganic cations, sugars and amino acids was tested. The solubility product of the ion-pair and the formation constant of the precipitation reaction leading to the ion-pair formation were determined conductimetrically.     

盐酸左氧氟沙星滴眼液抑茵剂添加及包装材料相容性研究

目的研究7个生产企业的65批盐酸左氧氟沙星滴眼液的现行质量标准以及苯扎溴铵、苯扎氯铵、羟苯乙酯、三氯叔丁醇4种抑菌剂的添加状况和包装材料的相容性,为提高其质量标准提供参考。方法对盐酸左氧氟沙星滴眼液的现行6个质量标准及常用的苯扎溴铵、苯扎氯铵、羟苯乙酯、三氯叔丁醇4种抑菌剂的测定方法进行研究,建立HPLC法对抑茵剂苯扎溴铵、苯扎氯铵、羟苯乙酯的含量进行测定,并对不同包装材料相容性进行考察。结果现行6个质量标准不统一,有的未对抑菌剂进行控制,包装材料对抑茵剂三氯叔丁醇存在吸附作用,有些抑茵剂与其包装材料搭配存在缺陷。结论现行质量标准有待统一,应加强对抑茵剂的控制,建议改进包装材料。