血根碱、白屈菜红碱离子对化合物的体外抗菌活性研究

目的通过对血根碱离子对化合物、白屈菜红碱离子对化合物的体外抗菌活性研究,寻找具有潜在开发价值的抗菌药物。方法将血根碱、白屈菜红碱与多种有机酸制备成离子对化合物,采用试管稀释法和琼脂平板扩散法测定最低抑菌浓度(MIC)和最小杀菌浓度(MBC),结合抑菌圈实验,比较制备前后化合物的抗菌效果。结果血根碱与苯甲酸、乳酸、富马酸等有机酸形成离子对化合物之后抗菌活性增强,白屈菜红碱与乙酸、丙酸形成离子对化合物之后抗菌活性增强。结论一些结合小分子有机酸形成的离子对化合物显示出良好的抗菌效果,将生物碱制备为离子对化合物的方法为寻找新的抗菌药物提供了一种思路。     

Microemulsions as topical delivery vehicles: ocular administration of timolol

The topical administration of timolol as an ion-pair with octanoate was achieved by use of an oil-in-water microemulsion containing lecithin as a surfactant. The microemulsion, a solution of the ion-pair and a solution of timolol alone were instilled in the conjunctival sac of rabbits. A rapid method for the separation and determination of timolol in aqueous humour by HPTLC was used. The bioavailability of timolol from the microemulsion and the ion-pair solution was higher than that obtained from timolol alone. The areas under the curve for timolol in aqueous humour after administration of the microemulsion and the ion-pair solution were 3.5 and 4.2 times higher, respectively, than that observed after the administration of timolol alone.     

Extraction and quantification of paraquat in liver and hemolyzed blood

A procedure for the extraction and quantification of paraquat from enzyme digested liver and hemolyzed blood is reported. Paraquat is extracted as an ion-pair with sodium dodecyl sulphate and quantified by reverse phase ion-pair high performance liquid chromatography (HPLC) with ultraviolet (UV) detection.     

Applications of the Ion-Pair Concept to Hydrophilic Substances with Special Emphasis on Peptides

Previous investigations have shown that ionic drugs with high aqueous solubilities can be lipophilized by ion-pair formation, with appropriate counter-ions. This type of association may prove promising for several biopharmaceutical, analytical and technological applications. This review examines the ion-pair concept with special emphasis on its application to peptides. The conditions for ion-pair formation of different molecules, as well as their transfer to organic solvents, are described. The use of ion-pairs to increase the permeation of various therapeutic agents, including peptidic drugs, is also discussed. Recent uses of ion-pairs in micro- and nanoencapsulation of peptides are also commented upon.     

Determination of potassium in pharmaceutical formulations by means of 18-crown-6: Extraction studies

A calorimetric method has been developed for the determination of potassium in pharmaceutical formulations. The method is based on the formation of a complex of potassium with 18-crown-6, followed by conversion to an ion-pair with picrate anion; the ion-pair is extracted with either methylene chloride or toluene—methylene chloride (80:20, v/v) and determined colorimetrically.     

Incompatibility of indometacin and benzalkonium in eye drops due to ion-pair formation

Eye drop formulations containing indometacin and benzalkonium salt often show an opalescence as a result of ion-pair formation. The insoluble ion pair was isolated and characterized by infrared and ultraviolet spectroscopy and thin layer chromatography. This ion pair is also responsible for the bad assay results of benzalkonium using the ion-pair extraction method with bromothymol blue as counterion. The distribution     

Separation and quantitation of methenamine in urine by ion-pair extraction

An ion-pair extraction technique is described for separating methenamine, a urinary tract antibacterial agent, from formaldehyde in human urine samples. Separation conditions are developed from extraction constants for the methenamine-bromocresol green ion-pair. The technique involves adsorption of the ion-pair onto a silica cartridge and elution with methylene chloride:1-pentanol (95:5). Methenamine is freed from the ion-pair by the addition of excess tetrabutylammonium iodide and converted to formaldehyde (determined spectrophotometrically) by reaction with ammonia and acetylacetone. Linear standard plots were obtained from urine containing methenamine which was diluted to 10-160 micrograms/mL. The lower limit of detection was 6 micrograms/mL of methenamine. Absolute recovery from urine was greater than or equal to 94.5%. The precision (CV) of detection of methenamine in the presence of formaldehyde was less than 2%, and less than or equal to 4.5% for the detection of formaldehyde in the presence of methenamine. No interferences were noted. The applicability of the method was demonstrated by analysis of human urine levels of both methenamine and formaldehyde following oral administration of a methenamine salt to a volunteer.     

Determination of sennoside A in oriental pharmaceutical decoctions containing Rhei Rhizoma by ion-pair high-performance liquid chromatography]

A simple method using ion-pair high-performance liquid chromatography was established for the rapid and precise determination of sennoside A in oriental pharmaceutical decoctions containing Rhei Rhizoma. This method was compared with other two methods, i.e. ion-suppression and phosphate buffer methods. Sennoside A was eluted without interference in this ion-pair method, while the determination of sennoside A was interfered by co-existing components in the other two methods.     

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.     

Enhancing effects of ion-pair complexes on skin permeation of cromolyn in vitro

Lipophilic ion-pair complexes of 3-dl-alpha-tocopherylcarbonyl-1-n-alkyl-pyridinium-cromolyn (TAP-CG) were designed to enhance the percutaneous absorption of cromolyn (CG), and the effect of n-alkyl chainlength of the ion-pair complexes on the CG permeation through hairless mouse skin was evaluated in vitro. The permeation rates of CG were examined in isopropyl myristate (IPM) suspension using static Keshany-Chien type diffusion cells at 32 degrees C. The permeation parameters, steady-state flux, diffusion coefficient, partition coefficient between skin and IPM, and permeability coefficient were determined. Steady-state fluxes of CG increased linearly with the increasing n-alkyl chain-length of TAP-CG, and 3-dl-alpha-tocopherylcarbonyl-1-n-hexyl-pyridinium-cromolyn (THP-CG) produced the highest CG flux (0.62 +/- 0.11 nmol.cm-2.h-1), which was 14-fold greater than that of CG.Na in IPM suspension and more than 480-fold greater than that of CG.Na in aqueous solution due to increasing lipophilicity. In the case of TAP-CG with longer n-alkyl chainlength than THP-CG, however, the steady-state fluxes of CG decreased due to the high molecular weight and/or the high lipophilicity of the ion-pair complexes. It is suggested that lipophilic ion-pair complexes, especially THP-CG, are effective in absorption of cromoglicate through the skin. The results would be useful for studies on the role of each counterion in the lipophilic ion-pair complexes.     

Development of a standardized analysis strategy for basic drugs using ion-pair extraction and high-performance liquid chromatography - I. Philosophy and selection of extraction technique

The first of a series of papers on the development of a standardized analysis strategy for basic drugs explains the possible advantages and philosophy of the strategy. The scheme uses ion-pair extraction with direct injection of the extracts into an HPLC system emanating, from two previously-selected systems. The extraction efficiency of sodium-n-octylsulphate as the ion-pairing reagent is compared with that of di(2-ethylhexyl) phosphoric acid (previously shown to be generally applicable to the extraction of basic drugs). Direct injection of the ion-pair extracts into an HPLC system is possible because retention behaviour is independent of whether the basic drugs are injected as an ion-pair or as a base.     

宝塔糖中盐酸左旋米唑的离子对萃取分光光度测定法

盐酸左旋米唑糖锭剂(宝塔糖)中的左旋米唑与溴甲酚绿形成离子对,用氯仿萃取后在420nm 处测定,回收率为100.2%,变异系数为0.26%。该法操作简便,分析速度快,灵敏度高。     

Formation of ion-pairs in aqueous solutions of diclofenac salts.

In this work we studied the ability of the diclofenac anion to form ion-pairs in aqueous solution in the presence of organic and inorganic cations: ion-pairs have a polarity and hydrophobicity more suitable to the partition than each ion considered separately and can be extracted by a lipid phase. The cations considered were those of the organic bases diethylamine, diethanolamine, pyrrolidine, N-(2-hydroxyethyl) pyrrolidine and N-(2-hydroxyethyl) piperidine; the inorganic cations studied were Li(+), Na(+), K(+), Rb(+), Cs(+). Related to each cation we determined the equilibrium constant (K(XD)) for the ion-pair formation with the diclofenac anion in aqueous solution and the water/n-octanol partition coefficient (P(XD)) for each type of ion-pair formed. Among the alkali metal cations, only Li(+) shows some interaction with the diclofenac anion, in agreement with its physiological behaviour of increasing clearance during the administration of diclofenac. The influence of the ionic radius and desolvation enthalpy of the alkali metal cations on the ion-pair formation and partition was briefly discussed. Organic cations promote the formation of ion-pairs with the diclofenac anion better than the inorganic ones, and improve the partition of the ion-pair according to their hydrophobicity. The values of the equilibrium parameters for the formation and partition of ion-pairs are not high enough to allow the direct detection of their presence in the aqueous solution. Their formation can be appreciated in the presence of a lipid phase that continuously extracts the ion-pair. Extraction constants (E(XD)=P(XD) times K(XD)) increase passing from inorga to organic cations. This study could help to clarify the mechanism of the percutaneous absorption of diclofenac in the form of a salt, a route where the formation of ion-pairs appears to play an important role.     

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.     

Contribution of Ion-Pair Complexation with Bile Salts to the Transport of Organic Cations Across LLC-PK1 Cell Monolayers

Purpose. To examine the effect of ion-pair complexation with endogenous bile salts on the transport of organic cations (OCs) across LLC-PK1 cell monolayers. Methods. The transport of tributylmethyl-ammonium (TBuMA) and triethylmethylammonium (TEMA) across the cell monolayer was measured in the presence of taurodeoxycholate (TDC), an endogenous organic anion that forms an ion-pair complex with TBuMA, but not with TEMA. Results. Under proton gradient conditions (i.e., pH 6.0 apical/pH 7.4 basal), the above OCs exhibited similar transport charactersistics, consistent with the well-established OC/H⁺ antiporter, and the presence of TDC had no measurable effect on the transport of these OCs. Under pH-equilibrated conditions (i.e., pH 7.4 apical/pH 7.4 basal); however, basal to apical transport of TBuMA, not that of TEMA, was increased in the presence of TDC, probably as a result of the formation of a lipophilic ion-pair complex between TBuMA and TDC. The transport and efflux of the TBuMA-TDC complex across the apical membrane of the cell was inhibited by representative substrates of the P-glycoprotein (P-gp), indicating the involvement of P-gp in this process. The increased affinity of the ion-pair complex to P-gp is consistent with a mechanism involving increased transport. Conclusion. In cases where there is no proton gradient between the plasma and urine, the formation of lipophilic ion-pair complexes in the kidney with endogenous bile salts might be involved in the in vivo urinary excretion of large Mw OCs, such as TBuMA.     

Quantitative analysis of trimethobenzamide hydrochloride by ion-pair column chromatography and semiquantitative analysis of 3,4,5-trimethoxybenzoic acid by thin-layer chromatography

An ion-pair column chromatographic/UV spectrophotometric method for assaying trimethobenzamide hydrochloride in capsules and injections is presented, as well as a method for the detection of 3,4,5- trimethoxybenzoic acid in trimethobenzamide hydrochloride bulk drug and dosage forms. Results obtained by the USP XX, Pharmacopeial Forum, and ion-pair column assay procedures are compared, and results of a collaborative study of the proposed assay and impurity detection methods are presented.     

Functional group contribution of bile salt molecules to partitioning of a quaternary ammonium N,N-dimethyl derivative of propranolol

A quaternary ammonium N,N-dimethyl derivative of propranolol was extracted from pH 7.4 phosphate buffer into 1-octanol as ion-pairs with 12 different bile salts. The binding number, n, and the extraction constant, Ke, were determined. To obtain group contribution values of the bile salt molecule from the ion-pair extraction data, multiple linear regression analysis by the Free-Wilson technique was applied. The results showed that the fundamental premise of the functional group's contribution to the ion-pair extraction is valid. The functional groups of counterions contribute to the partitioning of the ammonium compound independently and additively in this system.     

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.     

Identification of 3,N4-propanodeoxycytidine 5'-monophosphate formed by the reaction of acrolein with deoxycytidine 5'-monophosphate

Acrolein reacts with deoxycytidine 5'-monophosphate at physiological pH to form one major adduct. A second minor adduct can be detected when a 3-fold excess of acrolein is present in the reaction mixture. The products were separated by ion-pair HPLC on two reverse-phase columns connected in series using triethylammonium formate as ion-pair reagent. The major adduct was characterized as 3-(5'-monophospho-2'-deoxyribosyl)-7,8, 9-trihydro-7-hydroxy-pyrimido [3,4-c]pyrimidin-2-one (3,N4-propanodeoxcytidine 5'-monophosphate). This mixture of diastereomers was formed by addition of C1 of acrolein to the exocyclic amino group at the 4-position of cytidine, followed by ring closure between C3 of acrolein and N3 of the heterocyclic ring. In order to address the utility of 32P postlabeling for the detection of this exocyclic adduct in acrolein-modified nucleic acids, an acrolein-deoxycytidine 3'-monophosphate reaction mixture was subjected to 32P postlabeling. 3-Dephosphorylation with nuclease P1 and the 3'-phosphatase activity of T4 polynucleotide kinase yields a nucleotide 5'-[32P] monophosphate which cochromatographs with 3,N4-propanodeoxycytidine 5'-monophosphate. These data indicate that 32P postlabeling and 3'-dephosphorylation can be used in conjunction with ion-pair HPLC for the detection and quantitation of acrolein-modified nucleotides.     

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.