Consideration on the Formulation of Benzoyl Peroxide at Ambient Temperature: Choice of Non-Polar Solvent and Preparation of Submicron Emulsion Gels

ABSTRACT

The aim of this study performed at ambient temperature was first to determine the solubility of benzoyl peroxide in various solvents with a large range of polarity. All these solvents can be used in the dermatological field. Then, using the most suitable solvent, a new drug vehicle submicron oil-in-water emulsion was formulated. Correlation between dielectric constant (ε) and drug solubility in various solvents and different binary mixtures was verified. An original ternary diagram with surfactant–co-surfactant/oil/water was performed at low temperature to determine the regions of submicron emulsions. A dramatic change in the magnitude of benzoyl peroxide solubility occurred above a dielectric constant value of about 20. The solubility of this drug can be enhanced by the replacement of polar solvent by a vehicle of lower dielectric constant. A stable submicron emulsion gel was made with cremophor EL, glycerol, caprilic–capric triglycerides, and water in the proportion of 20–20/35/25, respectively; 1.5% benzoyl peroxide was also added. This submicron emulsion vehicle consisted of oil droplets, with a mean diameter of approximately 100–150 nm, dispersed in a continuous water phase. These studies confirm the potential of benzoyl peroxide incorporation into submicron emulsion gel and the stability of this formulation.     

Preparation and characterization of a submicron lipid emulsion of docetaxel: submicron lipid emulsion of docetaxel

Docetaxel, a widely used anticancer agent, has sparingly low aqueous solubility, thus Tween 80 and ethanol need to be added into its formulation, probably resulting in the toxic effects. In this study, we aimed to utilize submicron lipid emulsions as a carrier of docetaxel to avoid these potential toxic vehicles. Preformulation study was performed for rational emulsions formulation design, including drug solubility, distribution between oil and water, and degradation kinetics. Supersaturated submicron lipid emulsion of docetaxel was prepared by temperature elevation method. Soya oil and Miglyol 812 can incorporate docetaxel up to 1.0% (drug to lipid ratio) and were used as the oil phase of emulsions. The optimal formulation of docetaxel is composed of 10% oil phase, 1.2% soybean lecithin, 0.3% Pluoronic F68, and 0.4 or 0.8 mg/mL docetaxel, with particle size in the nanometer range, entrapment efficiency more than 90%, and is physicochemically stable at 4 and 25 degrees C for 6 months. Animal studies showed that docetaxel emulsion has significantly higher area under the curve (AUC) and C(max) in rats compared to its micellar solution. The results suggested that the submicron lipid emulsion is a promising intravenous carrier for docetaxel in place of its present commercially available docetaxel micellar solution with potential toxic effects.     

Preparation and Characterization of a Submicron Lipid Emulsion of Docetaxel: Submicron Lipid Emulsion of Docetaxel

Docetaxel, a widely used anticancer agent, has sparingly low aqueous solubility, thus Tween 80 and ethanol need to be added into its formulation, probably resulting in the toxic effects. In this study, we aimed to utilize submicron lipid emulsions as a carrier of docetaxel to avoid these potential toxic vehicles. Preformulation study was performed for rational emulsions formulation design, including drug solubility, distribution between oil and water, and degradation kinetics. Supersaturated submicron lipid emulsion of docetaxel was prepared by temperature elevation method. Soya oil and Miglyol 812 can incorporate docetaxel up to 1.0% (drug to lipid ratio) and were used as the oil phase of emulsions. The optimal formulation of docetaxel is composed of 10% oil phase, 1.2% soybean lecithin, 0.3% Pluoronic F68, and 0.4 or 0.8 mg/mL docetaxel, with particle size in the nanometer range, entrapment efficiency more than 90%, and is physicochemically stable at 4 and 25°C for 6 months. Animal studies showed that docetaxel emulsion has significantly higher area under the curve (AUC) and C_max in rats compared to its micellar solution. The results suggested that the submicron lipid emulsion is a promising intravenous carrier for docetaxel in place of its present commercially available docetaxel micellar solution with potential toxic effects.     

Preparation,solubility, and electrorheological properties of carbon nanotubes/poly(methyl methacrylate) nanocomposites by in situ functionalization

Poly(methyl methacrylate) (PMMA) nanobeads-decorated multi-walled carbon nanotubes (MWNTs) and single-walled carbon nanotubes (SWNTs) nanocomposites were prepared using two processing steps. Initially, spherical PMMA nanoparticles were synthesized using an emulsion polymerization method. Afterward, the PMMA nanobeads were decorated to MWNTs and SWNTs using benzoyl peroxide as an initiator in water during a high temperature refluxing process. The results confirmed the linkage of the nanotubes to the surrounding PMMA nanobeads via a covalent bond. The resultant nanocomposites showed high solubility in chloroform without flocculation after 24 h. In addition, the nanotubes/PMMA nanocomposites were characterized by electrical resistance measurements to analyze their electrical conductivity and examined as electrorheological (ER) materials when dispersed in silicone oil.     

Some Properties of an Ethoxylated Castor Oil and Ethoxylated Oleyl Alcohol

Ethoxylated derivates have been used as surfactants for some years. In this work, ethoxylated castor oil and ethoxylated oleyl alcohol alone and/or their I:I mixtures were used as surfactants in oil/water type of emulsion systems.

The physicochemical properties of ethoxylated castor oil (Simulsol OL 50) and ethoxylated oleyl alcohol (Simulsol 98) have been investigated.

Both of these materials have properties associated with non-ionic surfactants, although considerably soluble in water, the compounds have slight solubility in nonpolar solvents.

Surface tensions of aqueous solutions were measured over a temperature range of 20°C to 40°C. CMC were determined by surface tension measurements. pH, refractive index, conductivity and density of the two surfactants were also determined.     

Chemical characterization of crude petroleum using nanospray desorption electrospray ionization coupled with high-resolution mass spectrometry

Nanospray desorption electrospray ionization (nano-DESI) combined with high-resolution mass spectrometry was used for the first time for the analysis of the polar constituents of liquid petroleum crude oil samples. The analysis was performed in both positive and negative ionization modes using three solvents, one of which (acetonitrile/toluene mixture) is commonly used in petroleomics studies while two other polar solvents (acetonitrile/water and methanol/water mixtures) are generally not compatible with petroleum characterization using mass spectrometry. The results demonstrate that nano-DESI analysis efficiently ionizes petroleum constituents soluble in a particular solvent. When acetonitrile/toluene is used as a solvent, nano-DESI generates electrospray-like spectra. In contrast, strikingly different spectra were obtained using acetonitrile/water and methanol/water. Comparison with the literature data indicates that these solvents selectively extract water-soluble constituents of the crude oil. Water-soluble compounds are predominantly observed as sodium adducts in nano-DESI spectra indicating that addition of sodium to the solvent may be a viable approach for efficient ionization of water-soluble crude oil constituents. Nano-DESI enables rapid screening of different classes of compounds in crude oil samples based on their solubility in solvents that are rarely used for petroleum characterization providing better coverage of the crude oil composition as compared to electrospray ionization (ESI). It also enables rapid characterization of water-soluble components of petroleum samples that is difficult to perform using traditional approaches.     

In Vitro Dissolution Profile of Theophvlline Lorded Ethvl Cellulose Microspheres Preprred by Emulsificrtion Soluent Eurporrtion

Theophylline was entrapped in ethyl cellulose microspheres by a water/oil/water emulsification-solvent evaporation method. Aqueous solution of drug was emulsified into a solution of ethyl cellulose in toluene, containing polyisobutylene as protective colloid, followed by emulsification of this primary emulsion into an external aqueous phase to form a water/oil/water emulsion. Microspheres was formed after solvent evaporation and precipitation of ethyl cellulose. In vitro dissolution profile and effect of polyisobutylene on it were studied.     

The effect of solvent dependent local field factor in the optical properties of CdTe quantum dots

CdTe quantum dots (QDs) are synthesized at room temperature in aqueous solvents of different dielectric constants and characterized using optical spectroscopy. Absorption spectra of the QDs obtained is used to calculate the size dependent dielectric function of the QDs using Kramers–Kronig relation and iterative matrix inversion method. Effect of solvent dielectric constant on optical properties of QDs is studied theoretically using Maxwell–Garnett effective medium theory. Direct correlation between absorption intensity and solvent dielectric constant is explained on the basis of decreasing local field factor of the solvents. Emission rates of QDs is also found to have dependence on the dielectric constant of the solvent. Spontaneous emission rates of QDs in Ionic liquid environment is studied theoretically using Maxwell–Garnett effective medium theory. Our results show that variation in dielectric constant of Ionic liquids have a significant impact on spontaneous emission properties of the QDs.     

Organic redox-initiated polymerization process for the fabrication of hydrogels for colon-specific drug delivery

Organic-redox initiated polymerization technique based on the co-initiators system comprising benzoyl peroxide and N-phenyldiethanolamine was used at ambient temperature to fabricate pH-responsive hydrogels. The effects of changes in the concentration of the co-initiators system, the ratio in which the co-initiators combined, the type of the polymerization solvent, the pH of the hydrating medium, the concentration of the cross-linking agent based on azo-bond and the pH-sensitive cross-linking agent on the properties of the hydrogels were investigated. Increasing the concentration of the co-initiators system, decreasing the concentration of the two types of cross-linking agents, and replacing DMSO by ethanol as the polymerization solvent resulted in hydrogels with increased equilibrium swelling ratio and increased molecular weight between cross-links at pH 7.4. Increasing the concentration of N-phenyldiethanolamine while keeping the concentration of benzoyl peroxide constant gave hydrogels with increased equilibrium swelling ratios. The equilibrium swelling ratios of the hydrogels at pH 2.0 were not affected by the factors investigated. The polymerization technique may be suitable for the design of drug delivery systems containing thermolabile bioactive agents like peptides and proteins.     

In Vitro Dissolution Profile of Theophvlline Lorded Ethvl Cellulose Microspheres Preprred by Emulsificrtion Soluent Eurporrtion

Abstract

Theophylline was entrapped in ethyl cellulose microspheres by a water/oil/water emulsification-solvent evaporation method. Aqueous solution of drug was emulsified into a solution of ethyl cellulose in toluene, containing polyisobutylene as protective colloid, followed by emulsification of this primary emulsion into an external aqueous phase to form a water/oil/water emulsion. Microspheres was formed after solvent evaporation and precipitation of ethyl cellulose. In vitro dissolution profile and effect of polyisobutylene on it were studied.     

Influence of Dielectric Constant of the Base on the Release of Acetaminophen from Suppositories

The dielectric constant of various polyethylene glycol suppository bases (vehicles) was investigated in relation to the release of acetaminophen as measured by dissolution. Bioavailability of the drug from the bases was also studied in the rectum of beagle dogs. Blood samples were removed at appropriate time intervals and the acetaminophen analyzed by an improved GLC method. A solubility study of acetaminophen in dioxane-water mixtures indicated that maximum solubility of the drug occured at a dielectric constant of about 14. The bioavailability results in dogs showed minimum release of drug in bases of dielectric constants near 14 and increased release characteristics in bases farther removed from this dielectric constant. The results suggest that vehicles with lower solubility for the drug tend be release acetaminophen readily and provide improved bioavailability.     

Characterization of the Enhancing Effect of a Vehicle in a Transdermal System

The percutaneous absorption of Morphine and Morphine hydrochloride is optimized using binary solvent systems as vehicle of the drugs. Release kinectics through hairless mouse skin are performed in vitro: variations of the flux, of the lagtime and of the cumulative released quantities as a function of the vehicle composition point out a synergistic effect of the two solvents (Labrafac hydrophile and Transcutol). Independant determinations of the skin/vehicle partition coefficient, of the solubility and of the diffusion coefficient are realized; the results allow us to explain the different enhancing effects of each solvent: the first one has an enhancing effect on the drug concentration in the skin, and the second one modifies the mobility of the drug in the skin

The rate of the drug release is usually optimized increasing the drug activity in the donor in relation with the solubility variation. With transdermal system (matrix, film) a more accurate approach is to increase the skin permeation of the drug (1) (2). This effect is commonly attempted with enhancers contained in the system, but a particular vehicle can act as an enhancer and as a solvent (3-7). In this case, we optimize the permeation coefficient, P = (K D/e), where K is the skin/vehicle partition coefficient, D is the diffusion coefficient and e is the skin thickness. The partition coefficient allows variation of the drug concentration in the skin, while the diffusion coefficient represents the mobility of the drug in the skin

The aim of this presentation is to analyze, on experimental data, the variation of the permeation to identifie, to localize, and to explain the role of a such vehicle. We studied the morphine permeation through hairless mouse skin with a binary solvents system. The solvents used are a diethylene glycol monoether (T) and a glycolysed ethoxylated glyceride (L). We propose to analyze the influence of the mixture composition on the partition and diffusion coefficient of morphine. We used an hydrophilic specie, morphine hydrochloride (MHCl), and a lipophilic specie, basic morphine (M), assuming that their routes of penetration are different: etheir hydrophilic inter or intra cellular route, or lipidic intercellular route. We suppose that each solvent can modifie the physical or chemical structure of these routes and consequently, the permeation of one particular specie of morphine     

Some Properties of an Ethoxylated Castor Oil and Ethoxylated Oleyl Alcohol

Abstract

Ethoxylated derivates have been used as surfactants for some years. In this work, ethoxylated castor oil and ethoxylated oleyl alcohol alone and/or their I:I mixtures were used as surfactants in oil/water type of emulsion systems.

The physicochemical properties of ethoxylated castor oil (Simulsol OL 50) and ethoxylated oleyl alcohol (Simulsol 98) have been investigated.

Both of these materials have properties associated with non-ionic surfactants, although considerably soluble in water, the compounds have slight solubility in nonpolar solvents.

Surface tensions of aqueous solutions were measured over a temperature range of 20°C to 40°C. CMC were determined by surface tension measurements. pH, refractive index, conductivity and density of the two surfactants were also determined.     

High drug loading self-microemulsifying/micelle formulation: design by high-throughput formulation screening system and in vivo evaluation

Purpose: To design a high drug loading formulation of self-microemulsifying/micelle system. Methods: A poorly-soluble model drug (CH5137291), 8 hydrophilic surfactants (HS), 10 lipophilic surfactants (LS), 5 oils, and PEG400 were used. A high loading formulation was designed by a following stepwise approach using a high-throughput formulation screening (HTFS) system: (1) an oil/solvent was selected by solubility of the drug; (2) a suitable HS for highly loading was selected by the screenings of emulsion/micelle size and phase stability in binary systems (HS, oil/solvent) with increasing loading levels; (3) a LS that formed a broad SMEDDS/micelle area on a phase diagram containing the HS and oil/solvent was selected by the same screenings; (4) an optimized formulation was selected by evaluating the loading capacity of the crystalline drug. Aqueous solubility behavior and oral absorption (Beagle dog) of the optimized formulation were compared with conventional formulations (jet-milled, PEG400). Results: As an optimized formulation, d-α-tocopheryl polyoxyethylene 1000 succinic ester: PEG400?=?8:2 was selected, and achieved the target loading level (200?mg/mL). The formulation formed fine emulsion/micelle (49.1?nm), and generated and maintained a supersaturated state at a higher level compared with the conventional formulations. In the oral absorption test, the area under the plasma concentration-time curve of the optimized formulation was 16.5-fold higher than that of the jet-milled formulation. Conclusions: The high loading formulation designed by the stepwise approach using the HTFS system improved the oral absorption of the poorly-soluble model drug.     

温度、浓度对水/乙醇混合溶剂中壳聚糖溶液黏度的影响

研究了溶解于水/乙醇混合溶剂中的壳聚糖溶液黏度随温度和浓度的变化规律。混合溶剂中,乙醇是壳聚糖的不良溶剂,而水是壳聚糖的良溶剂,将乙醇与水按一定比例混合,再加入1%的乙酸,配制成水/乙醇混合溶剂。实验使用乌氏黏度计测量溶液黏度,通过分析黏度随温度、浓度的变化规律,揭示了混合溶剂对壳聚糖溶液黏度的影响规律。研究发现,壳聚糖溶液黏度随着温度的升高而降低;恒定温度,壳聚糖溶液黏度随浓度的增加而增加。而随着温度的升高,壳聚糖在良溶剂中产生的增比黏度变化率要比其在不良溶剂中高;随着浓度的增加,壳聚糖溶液产生的增比黏度的变化率也相应增加。当浓度极稀时,壳聚糖溶液的(ηsp/C)/C曲线会出现反常现象——体系黏度随着浓度的减小而急剧上升。     

High drug loading self-microemulsifying/micelle formulation: design by high-throughput formulation screening system and in vivo evaluation

Purpose: To design a high drug loading formulation of self-microemulsifying/micelle system.

Methods: A poorly-soluble model drug (CH5137291), 8 hydrophilic surfactants (HS), 10 lipophilic surfactants (LS), 5 oils, and PEG400 were used. A high loading formulation was designed by a following stepwise approach using a high-throughput formulation screening (HTFS) system: (1) an oil/solvent was selected by solubility of the drug; (2) a suitable HS for highly loading was selected by the screenings of emulsion/micelle size and phase stability in binary systems (HS, oil/solvent) with increasing loading levels; (3) a LS that formed a broad SMEDDS/micelle area on a phase diagram containing the HS and oil/solvent was selected by the same screenings; (4) an optimized formulation was selected by evaluating the loading capacity of the crystalline drug. Aqueous solubility behavior and oral absorption (Beagle dog) of the optimized formulation were compared with conventional formulations (jet-milled, PEG400).

Results: As an optimized formulation, d-α-tocopheryl polyoxyethylene 1000 succinic ester: PEG400?=?8:2 was selected, and achieved the target loading level (200?mg/mL). The formulation formed fine emulsion/micelle (49.1?nm), and generated and maintained a supersaturated state at a higher level compared with the conventional formulations. In the oral absorption test, the area under the plasma concentration-time curve of the optimized formulation was 16.5-fold higher than that of the jet-milled formulation.

Conclusions: The high loading formulation designed by the stepwise approach using the HTFS system improved the oral absorption of the poorly-soluble model drug.     

Characterization of the Enhancing Effect of a Vehicle in a Transdermal System

Abstract

The percutaneous absorption of Morphine and Morphine hydrochloride is optimized using binary solvent systems as vehicle of the drugs. Release kinectics through hairless mouse skin are performed in vitro: variations of the flux, of the lagtime and of the cumulative released quantities as a function of the vehicle composition point out a synergistic effect of the two solvents (Labrafac hydrophile and Transcutol). Independant determinations of the skin/vehicle partition coefficient, of the solubility and of the diffusion coefficient are realized; the results allow us to explain the different enhancing effects of each solvent: the first one has an enhancing effect on the drug concentration in the skin, and the second one modifies the mobility of the drug in the skin

The rate of the drug release is usually optimized increasing the drug activity in the donor in relation with the solubility variation. With transdermal system (matrix, film) a more accurate approach is to increase the skin permeation of the drug (1) (2). This effect is commonly attempted with enhancers contained in the system, but a particular vehicle can act as an enhancer and as a solvent (3–7). In this case, we optimize the permeation coefficient, P = (K D/e), where K is the skin/vehicle partition coefficient, D is the diffusion coefficient and e is the skin thickness. The partition coefficient allows variation of the drug concentration in the skin, while the diffusion coefficient represents the mobility of the drug in the skin

The aim of this presentation is to analyze, on experimental data, the variation of the permeation to identifie, to localize, and to explain the role of a such vehicle. We studied the morphine permeation through hairless mouse skin with a binary solvents system. The solvents used are a diethylene glycol monoether (T) and a glycolysed ethoxylated glyceride (L). We propose to analyze the influence of the mixture composition on the partition and diffusion coefficient of morphine. We used an hydrophilic specie, morphine hydrochloride (MHCl), and a lipophilic specie, basic morphine (M), assuming that their routes of penetration are different: etheir hydrophilic inter or intra cellular route, or lipidic intercellular route. We suppose that each solvent can modifie the physical or chemical structure of these routes and consequently, the permeation of one particular specie of morphine     

油水相界面张力对乳化炸药性能的影响

采用白金环法测定了乳化炸药复合油相与硝酸铵水溶液的界面张力,并研究了乳化剂质量分数、温度、分子结构和热值对油水相界面张力的影响以及界面张力对乳胶基质微观结构和储存稳定性的影响。结果表明,随着乳化剂质量分数的升高,界面张力先下降后保持恒定;随着温度升高,界面张力呈线性下降趋势;复合蜡组分的异构化烷烃含量越高,环状化合物越少,热值越低,油水相界面张力越低。随着界面张力和临界质量分数的降低,乳胶基质的粒径减小。乳胶基质的储存稳定性随着油相材料界面张力的降低而增强。     

Preparation Methods of Biodegradable Microspheres on Bovine Serum Albumin Loading Efficiency and Release Profiles

The solvent evaporation and multiple phase methods for preparing poly-(d, l) lactide microspheres of bovine serum albumin (BSA) were compared. The effects of poly (vinyl alcohol) concentration and external aqueous phase temperature on the loading efficient of BSA microspheres prepared by multiple phase emulsion method were evaluated as well. The BSA loading efficient of microspheres by multiple phase emulsion method was much higher than that by solvent evaporation method. The high aqueous solubility of BSA contributes to the low loading efficieny in the solvent evaporation method, suggesting that this method is inappropriate for proteins with high water solubility. The loading efficieny of microspheres, whcih were prepared by multiple phase emulsion method, increased with PVA concentration but decreased with external aqueous phase temperature. The burst phenomenon of release profiles of microspheres was influenced by poly (vinyl alcohol) concentrations and the external aqueous phase temperature. Considering the duration sustained release, 0.5% w/v of poly (vinyl alcohol) is most appropriate among the concentrations tested for preparing BSA microspheres by multiple phase emulsion method.     

Medium effect (transfer activity coefficient) of methanol and acetonitrile on beta-cyclodextrin/benzoate complexation in capillary zone electrophoresis

Association constants, Kc, were derived from the electrophoretic mobilities of the anionic solutes (seven benzoates with hydroxy or chloro substituents) by capillary zone electrophoresis in different solvent systems, consisting of binary mixtures of water with up to 20% (v/v) methanol or acetonitrile, respectively. The association constants expectedly are found to decrease with increasing organic solvent concentration. The effect of organic solvents on the Kc of the benzoates with beta-cyclodextrin was analyzed applying the concept of the transfer activity coefficient (or the medium effect). This concept enables the evaluation of the significance of the contributions of the individual species involved in the complexation equilibrium in the different solvents: the benzoate ion, beta-cyclodextrin, and the anionic benzoate-beta-cyclodextrin complex. The medium effect on benzoate was calculated from the change in acidity constant of benzoic acid in the different mixed solvents and the corresponding transfer activity coefficients of the proton and the molecular acid. The transfer activity coefficients for beta-cyclodextrin results from its solubility at saturation in the different solvents. In this way, an estimation of the standard free energy of transfer, deltaG(t)0, of each species involved in the complexation equilibrium was possible for the transfer from water into the respective mixed solvent. It was found that the organic solvents do not significantly affect deltaG(t)0 for the benzoate anion. However, the organic solvents play a different role concerning the stabilization of beta-cyclodextrin and the complex anion: whereas the addition of acetonitrile has nearly no influence on deltaG(t)0 of the anionic complex, the reduction in Kc is caused by the enhanced stabilization of beta-cyclodextrin (reflected by its better solubility). Addition of methanol, on the other hand, lowers the solubility of beta-cyclodextrin, thus giving positive values for deltaG(t)0. Thus, the overall effect on Kc in methanolic solutions must be related to the pronounced destabilization of the benzoate-beta-cyclodextrin complex.