Micellar Solubilization of Timobesone Acetate in Aqueous and Aqueous Propylene Glycol Solutions of Nonionic Surfactants

The micellar solubilization of timobesone acetate, a novel topical corticosteroid, was studied in aqueous and aqueous propylene glycol solutions of 1 to 5% nonionic surfactants at 25°C. The surfactants used were polyoxyethylene (POE) sorbitan monofatty acid esters (polysorbates), fatty acid esters (Myrj), and fatty alcohol ethers (Brij), as well as sucrose monolaurate (Crodesta SL40). The increase in the solubility of timobesone acetate in the micellar solutions was dependent on the type and concentration of surfactant. The solubilizing capacity of the surfactant micelles and the distribution coefficient of timobesone acetate in aqueous micellar solutions were found (1) to increase with increasing length of the hydrophobic fatty acid group; (2) to increase according to the structure of the hydrophilic group in the order of POE sorbitan ester, sucrose ester, POE ester, and POE ether; (3) to be unaffected by the increase in POE chain length; and (4) to tend to decrease in surfactant containing unsaturated fatty acid groups. In aqueous propylene glycol solution, the solubilizing capacity increased slightly, i.e., up to 1.5-fold in 50% propylene glycol solution, for the ester-type surfactants (polysorbates and Myrj). But this increase was not observed in the ether-type surfactant (Brij) solution. The distribution coefficient decreased logarithmically with increasing concentrations of propylene glycol in the solution. This was caused by the logarithmic increase in the timobesone acetate solubility in the bulk phase, while the solubility in the micellar phase was practically unchanged. The results support the equilibrium distribution model of micellar solubilization.     

Formulation of parenteral microemulsion containing itraconazole

The aim of this study was to develop an aqueous parenteral formulation containing itraconazole (ITZ) using an o/w microemulsion system. A mixture of benzyl alcohol and medium chain triglyceride (3/1) was chosen as the oil phase. Pseudoternary phase diagrams of the microemulsion formations were constructed in order to determine the optimum ratio of oils, the concentration range of surfactant and cosurfactant and the optimum ratio between them. Consequently, the suitability of the chosen microemulsion system as a parenteral formulation was evaluated using droplet size analysis and hemolysis tests. Among the surfactants and cosurfactants screened, a mixture of polyoxyethylene (50) hydrogenated castor oil and ethanol (3/1) showed the largest o/w microemulsion region in the phase diagram. The average droplet size of the microemulsions was < 150 nm, and the hemolysis test showed this formulation to be nontoxic to red blood cells. The pharmacokinetic profiles of the ITZ-microemulsion for itraconazole and its major metabolite, hydroxyitraconazole, were compared with those of a PEG 400 solution and cyclodextrin formulations in rats. Overall, these results highlight the potential of an ITZ-microemulsion formulation for the parenteral route.     

The Influence of Liquid Crystalline Phases on Drug Percutaneous Absorption. I. Development of a Vehicle

A phase diagram approach has been used to formulate topically applied vehicles containing liquid crystalline phases. The current paper describes the construction of a major portion of the polyoxyethylene(20)cetyl ether:dodecanol:water phase diagram. Known mixtures of the three components were equilibrated and centrifuged to separate the resultant conjugate phases. These were identified and analyzed quantitatively to determine phase boundaries in relevant portions of the phase diagram. Two isotropic liquid phases, several two- and three-phase regions, a solid surfactant phase, and at least three distinct liquid crystalline phases were identified. The determination of tie lines was undertaken in a two-phase region containing an aqueous isotropic micellar solution and a liquid crystalline gel. This information will be used to prepare a number of vehicles of known phase composition and concentration for a systematic evaluation of the effect of liquid crystalline phases on transdermal drug delivery.__________________________     

Synergistic Effect of Polyvinyl Alcohol and Copovidone in Itraconazole Amorphous Solid Dispersions

Purpose

The first objective is to evaluate the feasibility of melt-extruding polyvinyl alcohol-based amorphous solid dispersions for oral drug delivery. The second objective is to investigate the miscibility between polyvinyl alcohol 4-88 and copovidone, and to characterize the properties of ternary itraconazole amorphous solid dispersions comprising both polymers.

Methods

Samples were prepared using a co-rotating, twin-screw extruder. A solution precipitation study was conducted to compare the precipitation inhibition of polyvinyl alcohol against other commonly used polymers for amorphous solid dispersions. Miscibility between polyvinyl alcohol 4-88 and copovidone was determined using DSC and XRD analyses. All extrudates were characterized using DSC, XRD, and non-sink dissolution.

Results

Polyvinyl alcohol demonstrated the highest capacity for inhibiting the precipitation of itraconazole. Itraconazole was found to be more soluble in copovidone (>30%) than in polyvinyl alcohol 4-88 (<5%) in binary extrudates. Polyvinyl alcohol and copovidone are miscible when the proportion of polyvinyl alcohol 4-88 does not exceed 30% (w/w). Compared to binary extrudates, the ternary extrudate demonstrated a higher degree of supersaturation and more sustained supersaturation of itraconazole in purified water and phosphate buffer pH 6.8 solution.

Conclusion

As a surface-active material, polyvinyl alcohol was effective in inhibiting precipitation of itraconazole in aqueous media. Solubility of itraconazole in polyvinyl alcohol in solid state was limited because of the high polarity of the polymer. Ternary systems comprising a mixture of polyvinyl alcohol and copovidone demonstrated better supersaturation in aqueous media than binary systems. Ternary systems benefited from both the high solubilizing capacity of copovidone and high precipitation inhibition capacity of polyvinyl alcohol.

     

Particle size analysis of latex suspensions and microemulsions by photon correlation spectroscopy

The particle size in microemulsions and other highly dispersed systems was determined by means of photon correlation spectroscopy (PCS). As PCS cannot be applied to highly concentrated dispersed phases, the measurement accuracy was tested for its dependence on the particle concentration using latex suspensions. The data obtained by clipping and scaling were compared. The particle size determination was expected to provide information about the influence of the structure of the surfactant system on microemulsions, using a homologous alcohol series as cosurfactant and potassium oleate as surfactant. In this system the region of solubilization is characteristically divided from the region of microemulsification by a zone of instability. Furthermore, there are distinct differences in mean particle sizes between microemulsions (9-30 nm) and micellar solutions (4-6 nm).     

Effects of structural variations of non-ionic surfactants on micellar properties and solubilization: surfactants based on erucyl and behenyl (C22) alcohols

Studies on erucyl alcohol ethoxylated with 24 units and on behenyl alcohol ethoxylated with 21 ethylene oxide units gave values of 10.2 x 10(3) and 25.4 x 10(3) for the micellar weights, 74 and 203 for the aggregation number, and 134 and 106 moles water mole-1 surfactant for the micellar hydration, respectively. The solubilization of azobenzene, cortisone acetate, griseofulvin, sulphadiazine, phenylbutazone, betamethasone, tolbutamide, and menaphthone was studied in 2% solutions of the above surfactants, and in cetomacrogol. Excluding sulphadiazine, a linear relationship was found between moles solubilized/mole surfactant, and (log P)/molar volume of solubilizate.     

Study of multiple-component adsorption on the surface of activated carbon using a model system of benzyl alcohol and phenobarbital

The purpose of this work was to characterize the surface of activated carbon and to study the specificity of interactions using multicomponent adsorption. The competition between phenobarbital and benzyl alcohol was studied by conducting multicomponent-adsorption experiments. Benzyl alcohol and phenobarbital were combined to form a bisolute system. The adsorption of the bisolute system from simulated intestinal fluid (without pancreatin) by activated carbon was studied by using the rotating bottle method. The concentrations, both before and after the attainment of equilibrium, were determined with the aid of an HPLC system using a reversed-phase column. The modified competitive Langmuir-like model was fit to the data. A good correlation was obtained between the experimental and the calculated data, which indicates that benzyl alcohol and phenobarbital are competing for the same binding sites. The competition between benzyl alcohol and phenobarbital was not expected, and it suggests that benzyl alcohol is not interacting with the site having the theoretically highest enthalpy of interaction (carbonyl group on the activated carbon surface), due to the blockage of this site by the solvent (water). This unexpected result also indicates that the hydroxyl group is likely to be the most important group when the adsorption occurs from aqueous solution.     

The effect of surfactant on drug-plastic sorption phenomenon in solution

Abstract— The sorption of calcitriol into PVC from an injectable formulation containing Tween 20, a nonionic surfactant, was studied. The amount of drug sorbed by the plastic decreased as the concentration of the surfactant increased. The apparent partition parameter of the drug between PVC strips and the solution was experimentally determined at three different concentrations of the surfactant. A physical model was developed to describe mathematically the partition equilibrium of the drug between the plastic solid phase, the micellar phase of the surfactant, and the aqueous phase of the solution. This model also allowed the calculation of the drug/plastic and drug/micelle partition parameters using the experimentally determined apparent partition parameters.     

Solubilization of hydrocortisone, dexamethasone, testosterone and progesterone by long-chain polyoxyethylene surfactants.

Solubility and dialysis methods were used to study the solubilization of hydrocortisone, dexamethasone, testosterone and progesterone in aqueous long-chain polyoxyethylene non-ionic surfactant solutions. Partition coefficients, Km, between micellar and aqueous phases were calculated between 10-50 degrees. Km decreased with temperature and polyoxyethylene chain length but increased with decrease in steroid polarity. The standard free energy change, deltaGOS, for the solubilization of the steroids decreased with decrease in steroid polarity and surfactant hydrophilic chain length but was essentially independent of temperature. The enthalpies and entropies for the process were determined from the variation of Km with temperature. deltaHOS and deltaSOS increased with decreasing steroid polarity but were essentially independent of temperature and polyoxyethylene chain length.     

Micelle Formation and Phase Separation of Poloxamer 188 and Preservative Molecules in Aqueous Solutions Studied by Small Angle X-ray Scattering

Multi-injection pharmaceutical products such as insulin must be formulated to prevent aggregation and microbial contamination. Small-molecule preservatives and nonionic surfactants such as poloxamer 188 (P188) are thus often employed in protein drug formulations. However, mixtures of preservatives and surfactants can induce aggregation and even phase separation over time, despite the fact that all components are well dissolvable when used alone in aqueous solution. A systematic study is conducted here to understand the phase behavior and morphological causes of aggregation of P188 in the presence of the preservatives phenol and benzyl alcohol, primarily using small-angle x-ray scattering (SAXS). Based on SAXS results, P188 remains as unimers in solution when below a certain phenol concentration. Upon increasing the phenol concentration, a regime of micelle formation is observed due to the interaction between P188 and phenol. Further increasing the phenol concentration causes mixtures to become turbid and phase-separate over time. The effect of benzyl alcohol on the phase behavior is also investigated.     

Effect of Nonionic Surfactant on Transport of Model Drugs in Emulsions

Purpose. To investigate the influence of excess surfactant on transport kinetics in emulsions, using phenylazoaniline (PAA), benzocaine, benzoic acid and phenol as model drugs. Mineral oil was chosen as the oil phase and the nonionic surfactant, polyoxyethylene oleyl ether (Brij 97) as the emulsifier. Methods. Model drug transport in emulsions was investigated using side by side diffusion cells mounted with hydrophilic dialysis or hydrophobic membranes. A novel method, involving a combination of a membrane equilibrium technique and surface tension measurement (Wilhelmy plate method), was developed to determine surfactant critical micelle concentration (CMC) in the presence of O/W emulsions. Emulsion stability was determined by droplet size analysis as a function of time, temperature and dilution using photon correlation spectroscopy and a light blockage technique. Model drug mineral oil/water partition coefficients and aqueous solubilities were determined in the presence of surfactant. Results. The emulsion CMC value was used to calculate micellar phase concentration. The transport rates of PAA and benzocaine in emulsions increased with increase in Brij 97 micellar concentration up to 1.0 % w/v and then decreased at higher surfactant concentrations. The transport rates of the more hydrophilic compounds, benzoic acid (ionized form, pH 7.0) and phenol, were not affected by the presence of micellar phase. Conclusions. Excess surfactant affected the transport rates of the model drugs in the emulsions depending on drug lipophilicity. Transport rates measured using side by side diffusion cells appeared to be governed by model drug partitioning rates from the oil to the continuous phases and by membrane type.     

Effects of structural variations of non-ionic surfactants on micellar properties and solubilization: surfactants based on erucyl and behenyl (C22) alcohols

Studies on erucyl alcohol ethoxylated with 24 units and on behenyl alcohol ethoxylated with 21 ethylene oxide units gave values of 10·2 times 10³ and 25·4 times 10³ for the micellar weights, 74 and 203 for the aggregation number, and 134 and 106 moles water mole^?1 surfactant for the micellar hydration, respectively. The solubilization of azobenzene, cortisone acetate, griseofulvin, sulphadiazine, phenylbutazone, betamethasone, tolbutamide, and menaphthone was studied in 2% solutions of the above surfactants, and in cetomacrogol. Excluding sulphadiazine, a linear relationship was found between moles solubilized/mole surfactant, and (log P)/molar volume of solubilizate.     

Solubilisation of Drugs in Micellar Systems Studied by Eluent Gel Permeation Chromatography

Purpose. The purpose of the study was to investigate the potential of a chromatographic method which is based on elution gel chromatography (EGPC) in the study of solubilisation of drugs in micellar solutions. Methods. The EGPC method differs from conventional GPC in the use of a solution of the associating surfactant as eluent (rather than solvent) and the injection of a small volume of solution of different concentration (or alternatively injection of solvent alone) to probe the association equilibrium in the eluent. The technique was applied to a study of the solubilisation of selected drugs in aqueous micellar solutions of a triblock copolymer (Synperonic-PE F127) composed of oxyethylene [E, OCH₂CH₂] and oxypropylene [P, OCH₂CH(CH₃)] units with nominal molecular formula E₉₈P₆₇E₉₈. Results. EGPC curves were obtained showing vacancy peaks at the elution volumes of the drugs, clearly demonstrating their solubilisation. In addition, the micelle-molecule equilibrium of the copolymer surfactant could be monitored at all times. Quantitative determination of the partition of solute between micelles and solvent phase was not possible due to the incomplete conversion of molecules to micelles in solutions of the selected copolymer. Conclusions. The EGPC technique provides evidence for the solubilisation of the drugs in aqueous solutions of Synperonic F127; a more thorough assessment of its potential for quantitative measurement of solubilisation requires the use of a surfactant which is wholly (or at least mainly) in the micellar state under the conditions of use.     

胺类药物的胶束色谱研究

以十二烷基硫酸钠(SDS)和溴化十六烷基三甲胺(CTAB)两者的胶束水溶液为流动相,利用高效液相色谱法,研究了七种具有典型分配率的胺类药物和有机弱酸的胶束色谱保留机理,以及胶束溶液在不同pH值时对溶质保留值的影响,提出了胶束色谱保留机理的指数模型公式。该公式可用于估计溶质的胶束色谱类型,对溶质与三相(胶束相、表面活性剂修饰的固定相及总水相)的静电作用、疏水作用对溶质保留值的影响做了合理的解释。     

In vitro permeation characteristics of moxifloxacin from oil drops through excised goat, sheep, buffalo and rabbit corneas

The objective of present investigation was to study the in vitro permeation characteristics of moxifloxacin from oil drops through freshly excised goat, sheep, buffalo and rabbit corneas. Moxifloxacin, 0.043 to 0.048% (w/v) ophthalmic solutions with or without (0.5% v/v) benzyl alcohol were made in arachis, castor, cottonseed, olive, soybean, sunflower and sesame oils. Permeation studies were conducted by putting 1 ml oil formulation on cornea (0.50 cm2) fixed between donor and receptor compartments of an all glass modified Franz diffusion cell and measuring the drug permeated in receptor (containing 10 ml bicarbonate ringer, pH 7.4 at 37 degrees C under stirring) by spectrophotometry at 291 nm, after 120 min. Post permeation corneal hydration was measured to assess corneal damage. The study was designed with paired corneas i.e. one cornea of an animal received formulation without benzyl alcohol while the contralateral cornea received formulation with benzyl alcohol. Moxifloxacin ophthalmic solution in castor oil showed maximum permeation with all the corneas. Addition of benzyl alcohol, a preservative, to oil drops reduced permeation of moxifloxacin from each oil drop, with corneas of all the species. Partition experiments with moxifloxacin oil drops and phosphate buffer (pH 7.4) indicated higher partitioning of drug in the oil phase, in presence of benzyl alcohol. Thus results of permeation are consistent with the partition characteristics of drug between oil and aqueous phase. Corneal hydration obtained with all the formulations was between 75 to 80% indicating no corneal damage.     

Interaction of substituted benzoic acids with polysorbate 20 micelles.

Equilibrium solubilities of a series of substituted benzoic acids in different concentrations of polysorbate 20 at controlled pH were measured. The maintenance of pH was achieved using a pH-stat assembly. A linear relationship was found between the amount of benzoic acid solubilized and surfactant concentration. As solubilizate polarity increased, the amount solubilized also increased. Solubility data were analyzed, and the interaction between solubilizate molecules and micelles was calculated in terms of partition coefficients of ionized and unionized molecules between aqueous and micellar phases. A linear relationship between pi values (log partition coefficients) of functional groups and aqueous-micellar partition coefficient was found.     

Partitioning of halofantrine hydrochloride between water, micellar solutions, and soybean oil: Effects on its apparent ionization constant

Recent studies in a conscious dog model demonstrated intestinal lymphatic transport to be a significant contributor to the bioavailability of the highly lipid-soluble free-base of halofantrine (Hf), and surprisingly, also the poorly lipid-soluble hydrochloride salt (Hf. HCl). Partial conversion of solubilized Hf. HCl to Hf base within the intestinal lumen prior to the lymphatic uptake seemed to be the most likely explanation for these results. This hypothesis was supported by studies exploring the partitioning behavior of Hf. HCl between soybean oil (SBO) and aqueous micellar solutions containing different ionic and nonionic surfactants. Mixed micelles prepared from sodium taurodeoxycholate (NaTC) and lecithin (PC) were chosen to represent fed-state intestinal fluids. The apparent ionization constants derived from the partitioning versus pH profiles showed marked shifts when compared with the likely aqueous pK(a) value. In the present paper, the apparent pK(a) values of Hf in aqueous micellar phases, without a coexisting oil phase, were investigated to further probe the mechanisms underlying the effect of micellar media on the apparent ionization equilibrium, and subsequently, on its partitioning behavior in the triphasic systems. Another aim of this study was to further evaluate the aqueous pK(a) value of Hf. The results indicate that the aqueous pK(a) of Hf is most probably in the range approximately 8-9, and that the ionization equilibrium is highly dependent on the solution environment. For example, marked pK(a) shifts of several units were observed for Hf in the presence of different micellar species and SBO. The apparent ionization equilibrium depends not only on interaction of Hf with the micelles, but also on its partitioning into the oil phase.     

Mechanism for benzyl alcohol-induced aggregation of recombinant human interleukin-1 receptor antagonist in aqueous solution

Benzyl alcohol, an antimicrobial preservative, accelerates aggregation and precipitation of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) in aqueous solution. The loss of native monomer during incubation at 37 degrees C was determined by analysis of sample aliquots with size exclusion high performance liquid chromatography (SE-HPLC). Benzyl alcohol caused minor perturbation of the tertiary structure of the protein without changing its secondary structure, documenting that the preservative caused a minor shift in the protein molecular population toward partially unfolded species. Consistent with this conclusion, in the presence of benzyl alcohol the rate of H-D exchange was accelerated and the fluorescence of 1-anilinonaphthalene-8-sulfonic acid in the presence of rhIL1ra was increased. Benzyl alcohol did not alter the free energy of unfolding based on unfolding experiments in urea or guanidine HCl. With differential scanning calorimetry it was determined that benzyl alcohol reduced the apparent Tm of rhIL-1ra, but this effect occurred because the preservative lowered the temperature at which the protein aggregated during heating. Isothermal calorimetry documented that the interaction of benzyl alcohol with rhIL-1ra is relatively weak and hydrophobically driven. Thus, benzyl alcohol accelerates protein aggregation by binding to the protein and favoring an increase in the level of partially unfolded, aggregation-competent species. Sucrose partially inhibited benzyl alcohol-induced aggregation and tertiary structural change. Sucrose is preferentially excluded from the surface of the protein, favoring most compact native state species over expanded aggregation-prone forms.     

Study of partition of nitrazepam in bile salt micelles and the role of lecithin

The effect of trihydroxy (sodium cholate and sodium glycocholate) and dihydroxy (sodium deoxycholate and sodium glycodeoxycholate) bile salt micelles on the spectrophotometric properties and on the solubility of nitrazepam in aqueous solution, at 25.0 degrees C and at ionic strength 0.1 M in sodium chloride, has been assessed. From the results obtained it was possible to calculate the partition coefficients (Kp) of nitrazepam between aqueous and micellar phases. The partition coefficients of nitrazepam have also been determined in mixed micelles of cholate or deoxycholate with lecithin (egg yolk phosphatidylcholine), which were used as a model of the gastrointestinal tract. Drug partition was found to depend on the bile acid (number of hydroxyl groups and conjugation with glycine), and our data indicate further that addition of lecithin to bile salt micelles decreases the values of the partition coefficients in the mixed micelles at physiological pH.     

Solvent Effects on the Solubility and Physical Stability of Human Insulin-Like Growth Factor I

Purpose. The solubility and physical stability of human Insulin-like Growth Factor I (hIGF-I) were studied in aqueous solutions with different excipients. Methods. The solubility of hIGF-I was determined by UV-absorption and quantification of light blocking particles. The physical stability of hIGF-I was studied with differential scanning calorimetry (DSC) and circular dichroism (CD) spectroscopy. Results. Human IGF-I precipitated at low temperature in the presence of 140 mM benzyl alcohol and 145 mM sodium chloride. CD data showed that the tertiary structure of hIGF-I during these conditions was perturbed compared to that in 5 mM phosphate buffer. In the presence of benzyl alcohol 290 mM mannitol stabilized hIGF-I. Sodium chloride or mannitol by themselves had no effect on either the solubility or the tertiary structure. Benzyl alcohol was attracted to hIGF-I, whereas sodium chloride was preferentially excluded. The attraction of benzyl alcohol was reinforced by sodium chloride leading to salting-out of hIGF-I. The CD-data indicated interactions of benzyl alcohol with phenylalanine in hIGF-I. Thermal denaturation of hIGF-I occurred in all solutions with sodium chloride, whereas mannitol or benzyl alcohol had no effect on the thermal stability. The thermal stability of hlGF-I was thus decreased in 145 mM sodium chloride although it was excluded from hIGF-I. Conclusions. The self-association and thermal aggregation of hIGF-I is driven by hydrophobic interactions. Benzyl alcohol is attracted to hIGF-I and induces changes in the tertiary structure causing hydrophobic attraction of the protein at low temperatures.