Cosolvency of Dimethyl Isosorbide for Steroid Solubility

Dimethyl isosorbide (DMI), which is currently under investigation for its potential use as a pharmaceutical vehicle and drug permeation enhancer, is a water-miscible liquid with relatively low viscosity. The solubilization behavior of DMI as a cosolvent for nonpolar drugs was characterized via dielectric constant measurements of binary solvent systems containing DMI and either water, propylene glycol (PG), or polyethylene glycol (PEG). Evidence from the dielectric constant profiles and NMR studies suggest that DMI undergoes complexation with water and PG, but not with PEG, through hydrogen bonding interactions. The solvent complexation exhibited a major effect on the solubilities of prednisone, dexamethasone, and prednisolone in the mixed solvent systems. Maximum solubility of each drug was found to occur near a DMI/water or DMI/PG concentration ratio of 1:2. In the DMI–PEG mixed system, while there is no apparent interaction between DMI and PEG molecules, the solubility of prednisone was found to increase with decreasing dielectric constant.     

Solubility prediction of clonazepam in aqueous mixtures of ethanol,polyethylene glycol 200 and propylene glycol at 30 °C

Solubility of clonazepam in aqueous binary mixtures of ethanol, polyethylene glycol 200 and propylene glycol was determined at 30 °C using the shake flask method. The maximum solubility of clonazepam was observed at volume fraction of 0.90 of ethanol, whereas for aqueous mixtures of polyethylene glycol 200 and propylene glycol, the maximum values were observed in the neat cosolvents. The generated data was fitted to the Jouyban-Acree model and its constants were computed, then the back-calculated solubilities were compared with the corresponding experimental values by calculating the mean percentage deviation (MPD) in which the overall MPD for three cosolvent systems was 7.0 %. The solubility data in cosolvent + water mixtures was predicted using previously trained versions of the Jouyban-Acree model and the prediction MPDs were 13.4, 54.2 and 24.9 %, respectively for ethanol, polyethylene glycol 200 and propylene glycol mixtures and the overall MPD was 30.8 %.     

Transdermal Delivery of Isoproterenol HC1: An Investigation of Stability,Solubility, Partition Coefficient,and Vehicle Effects

Effects of solubility, partition coefficient, and selected adjuvants (propylene glycol and Azone) on percutaneous penetration of isoproterenol HC1 have been investigated using human cadaver skin. Isoproterenol was found to be stable (<1% decomposition) for 24 hr at 22 ± 0.5°C in the pH range 1 to 7 in the following solvents: water, normal saline, propylene glycol and a series of propylene glycol–water mixtures (10, 20, 40, and 60%; v/v); however, decomposition was significant beyond pH 8. In normal saline, the rate of decomposition increased significantly with an increase in temperature to 37°C. The solubility of isoproterenol HC1 decreased and its skin/vehicle partition coefficient increased with increasing proportions of propylene glycol in the vehicle, while the product of the solubility and partition coefficient appeared to plateau at 20% propylene glycol in water. Optimal penetration enhancing effects of Azone were seen when incorporated at a concentration of 1% (v/v) in the 20% (v/v) propylene glycol–water blend and, more significantly, when skin was pretreated with pure Azone for 60 min prior to application of the drug formulation.     

A new definition of solubilization power of a cosolvent

The solubilization power of a cosolvent is defined based on the maximum solubility of a solute in the water-cosolvent mixtures (X(m,max)) and the corresponding solvent composition (f(c,max)) predicted by trained versions of the Jouyban-Acree model. The applicability of the proposed definition was checked using solubility data of three cosolvent systems where the solubilization power was ordered as: dioxane > ethanol > polyethylene glycol 400. Using this definition, one could select the most appropriate cosolvent for solubilization of a poorly water soluble drug. There are linear relationships between the solubilization power of a cosolvent and the solute's logarithm of partition coefficients.     

Optimization of cosolvent concentration and excipient composition in a topical corticosteroid solution.

Physicochemical factors involved in the development of a topical solution of a novel corticosteroid, tipredane (1), are described. A cosolvent system consisting of polyethylene glycol 400 (PEG 400), propylene glycol, and water was used to dissolve the concentration (0.1% w/w) of 1 required for the formulation. The solvent mixture was also nonirritating to the skin. Buffering agent, antioxidant, and metal-chelating agent were required to stabilize the drug. Solubilities of hydrophilic and lipophilic excipients were ensured by careful adjustment of their concentrations, as well as that of PEG 400. Two formulations, one containing potassium citrate and the other tromethamine as the buffering agents, were identified. Upon storage, sodium metabisulfite, an antioxidant used in the formulation, oxidized to form K2SO4 in the formulation containing potassium citrate. Potassium citrate decreased the solubility and resulted in the precipitation of K2SO4 by exerting a common ion effect. Lowering of the concentrations of potassium citrate, sodium metabisulfite, and PEG 400 ensured the solubility of K2SO4 formed. There was no such precipitation of K2SO4 in the formulation buffered with tromethamine, thus indicating that tromethamine is a good buffering agent in cosolvent systems.     

Degradation of O6-Benzylguanine in Aqueous Polyethylene Glycol 400 (PEG 400) Solutions: Concerns with Formaldehyde in PEG 400

The degradation of O⁶-benzylguanine (BG) in aqueous polyethylene glycol (PEG) 400 solution at room temperature had been investigated using chromatographic and spectrometric methods. The degradation of BG in this solvent appeared to arise from a reaction between BG and formaldehyde. The formaldehyde was present as an impurity in PEG 400 and probably formed through air oxidation of PEG 400. The major product of this reaction was believed to be a methylene-bridged compound containing two BG molecules. This was probably produced via an intermediate imine, a schiff base between one BG molecule and formaldehyde. This degradation reaction was the only observable reaction in the 40% PEG/water solvent (pH 8.0) i.e. degradation of the drug via hydrolysis was minimal under these conditions.     

Benzoyl Peroxide Solubility and Stability in Hydric Solvents

Saturated solubility and reaction rate constants for the decomposition of benzoyl peroxide in solution and suspension were determined for use in formulation development. The solvents studied included ethanol, propylene glycol, and cosolvent mixtures of PEG 400 and water. The solubility of benzoyl peroxide was inversely related to the solvent polarity, with greater solubility occurring with semipolar solvents. The stability of benzoyl peroxide in solution was dependent on the solvent, concentration of benzoyl peroxide, and temperature. The compound was least stable in PEG 400. Stability was improved when water was added to PEG 400. Similar solvent effects were observed in suspension. In benzoyl peroxide suspensions of PEG 400 and PEG 400/water blends, benzoyl peroxide stability was dependent on solubility, with improved stability occurring in blends where the benzoyl peroxide was least soluble. Thus, solution formulations of benzoyl peroxide in pharmaceutically acceptable solvents are unlikely to show good stability; however, suspension formulations should be reasonably stable if the vehicle is selected to provide low benzoyl peroxide solubility.     

Influence of solute structure on deviations from the log-linear solubility equation in propylene glycol:water mixtures

The solubilities of the methyl, ethyl, propyl, and butyl esters of p-hydroxy- and p-aminobenzoates have been determined in propylene glycol:water mixtures. The log of the observed solubility data in propylene glycol:water mixtures was examined for deviations from the following equation: In Xi = f In (Xc) + (1 - f) In (Xw), where Xi is the calculated mole fractional solubility of the solute, f is the volume fraction of cosolvent, Xc is the observed mole fractional solubility in the neat cosolvent, and Xw is the solubility in water. In each case, the deviations from the predicted solubilities demonstrated a characteristic pattern. Positive deviations were observed at high volume fractions of cosolvent, while negative deviations were observed at low volume fractions. The magnitude of the deviations at low volume fractions of cosolvent was related to the carbon chain length within each group of esters. A similar phenomenon was not observed at high volume fractions of cosolvent; however, the magnitude of the deviations was dependent on the nature of the polar group on the ester. The data are interpreted in terms of the possible effects of solvent structure on the solubility of the solutes.     

Behavior of erythrocytes in ternary solvent systems.

The effect of ternary solvent systems on erythrocytes was investigated. Hemolysis experiments were run at 37degree in solutions containing various amounts of water, two nonaqueous solvents, and 0.9% sodium chloride. The nonaqueous solvents were propylene glycol, polyethylene glycol 400, dimethyl sulfoxide, dimethylformamide, and tetramethylurea. Ternary diagrams based on the critical hemolytic compositions of the various ternary systems are presented.     

Physicochemical properties of a nonpeptide cyclic urea HIV protease inhibitor (DMP 323)

DMP 323 ([4R-(4α, 5α, 6β, 7β)]-hexahydro-5,6-bis(hydroxy)-1,3-bis ([(4-hydroxymethyl)phenyl]methyl)-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one), a potent inhibitor of HIV protease and HIV replication, is a white irregular-shaped nonhygroscopic crystalline material. Differential scanning calorimetry revealed a single melt peak at 195.7°C. DMP 323 was practically insoluble in water at 10 µg/ml (pH 8.1) at 25°C. The aqueous solubility was unaffected by changes in pH. The logarithm of the solubility of DMP 323 is a linear function of the percentage of water miscible cosolvents. The highest solubility values of DMP 323 were 272 mg/ml in 95% (v/v) ethanol in water, 160 mg/ml in propylene glycol, 144 mg/ml in polyethylene glycol 400, 65.5 mg/ml in 70% (w/w) polyethylene glycol 1450 in water, 64.2 mg/ml in polyoxyethylene sorbitan monooleate, and 1.61 mg/ml in glycerin. DMP 323 was stable as a function of pH with no loss observed at pH 3, 5, 7, 9 and 12.7 in aqueous buffers containing 5% (v/v) methanol after eight weeks at 40°C. In polyethylene glycol 400 solutions, the degradation of DMP 323 was approximated with apparent first order kinetics at elevated temperatures. Butylated hydroxytoluene and butylated hydroxyanisole were effective antioxidants in reducing the degradation in polyethylene glycol 400 solutions while citric acid afforded no protection from the degradation. Argon flushing was effective at reducing the oxidative degradation in polyethylene glycol 400 solutions stored at room temperature. Consistent with the oxidative degradation, DMP 323 degraded to the mono- and dibenzaldehyde, the monobenzoic acid, and the monobenzaldehyde monobenzoic acid derivatives.     

Effect of Polyethylene Glycol 400 on the Intestinal Permeability of Carbamazepine in the Rabbit

Because of the limited solubility of carbamazepine, aqueous solutions are usually prepared using glycols as cosolvents. This research focuses on the effect of varying the composition of polyethylene glycol 400 (PEG-400) in aqueous solutions on rabbit intestinal permeability of carbamazepine in the duodenojejunum and the ascending colon using an in situ perfusion technique. In both segments the intestinal permeability varied inversely with the percentage of PEG-400, when the concentration of carbamazepine in the perfusing solution was maintained constant. The decreased permeability may be explained by a reduction in the thermodynamic activity of carbamazepine with increased concentrations of PEG-400, as well as by reverse solvent drag because of the hyperosmolarity of the perfusing solutions.     

Permeation enhancement of ketoprofen using a supersaturated system with antinucleant polymers

Permeation enhancement of ketoprofen (KP) from supersaturated systems and the effects of antinucleant polymers on both stability and permeation of supersaturated KP were investigated using silicone membrane as a skin model. The supersaturation was prepared by the cosolvent technique with water and propylene glycol (PG). Saturated solubility of KP in water/PG cosolvent increased markedly with an increase in PG percentage. The time-profiles of the cumulative amount of released KP from supersaturated solutions through the membrane increased linearly, and this KP flux had a significant correlation with the degree of saturation (DS) in 80 : 20, 60 : 40, 50 : 50, and 40 : 60 (v/v) water/PG cosolvent systems. The influence of 1% solutions of antinucleant polymers, hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), and sodium carboxymethylcellulose (SCMC) on the DS and the stability of supersaturated KP was examined in 60 : 40 (v/v) water/PG cosolvent. The remaining DS for 24 h after mixing the solvents increased in the presence of HPMC and SCMC but not PVP. In the presence of SCMC, the physical stability of supersaturated KP was higher, however, the KP flux was lower than that in the control and in the presence of the other polymers. In conclusion, the supersaturation system can be applied to achieve higher transmembrane permeation of KP, and appropriate antinucleant polymers such as HPMC can optimize the physical stability and permeability of KP.     

Development of oral liquid dosage forms of acetazolamide

Two oral liquid dosage forms of acetazolamide have been developed. Using the solubility profiles, polyethylene glycol 400 (7%, v/v) was used as the solubilizing agent and propylene glycol (53%, v/v) as the cosolvent to keep acetazolamide in solution. Because of the bitter taste of acetazolamide, sweetening agents (simple syrup, sorbitol solution, and artificial sweeteners) and flavors (raspberry, sweet, and menthol) were added to the final formulations. A buffer (either phosphate or citrate) solution was used to maintain a pH value of 4 (pH of maximum stability as reported earlier) to minimize hydrolysis. The final dosage forms were stable for at least 90 days at 37 degrees C (loss of potency of 5%). According to FDA guidelines, a tentative expiry date of 2 years at 25 degrees C is justifiable.     

In Vitro-In Vivo Myotoxicity of Intramuscular Liposomal Formulations

Purpose. The first objective was to study the in vitro myotoxicity of empty liposomes and to examine whether liposome size, charge and fluidity affect liposome myotoxicity. The second objective was to investigate the effect of liposomal encapsulation on the in vitro and in vivo myotoxicity of loxapine compared to the loxapine commercial preparation (Loxitane^®). Methods. The in vitro myotoxicity of empty liposomes and loxapine liposomes was evaluated by the cumulative efflux of the cytosolic enzyme creatine kinase (CK) from the isolated rat extensor digitorum longus (EDL) muscle over a 2 hour period. In the in vivo studies, the area under plasma CK curve over 12 hours was used to evaluate muscle damage. Results. The in vitro myotoxicity for all empty liposomal formulations was not statistically different from negative controls (untreated control muscles and normal saline injected muscles). However, these empty liposomal formulations were significantly less myotoxic than the positive controls (muscles injected with phenytoin and muscle sliced in half). In vitro-in vivo studies showed that the liposomal encapsulation of loxapine resulted in significant (P < 0.05) reduction in myotoxicity (80% in vitro and 60% in vivo) compared to the commercially available formulation which contains propylene glycol (70% V/V) and polysor-bate 80 (5% W/V) prepared at equal concentration. Conclusions. Results indicate that empty liposomes do not induce myotoxicity. Furthermore, liposomal size, charge and fluidity do not affect myotoxicity. In addition, in vitro and in vivo studies have demonstrated that liposomal encapsulation of loxapine can reduce myotoxicity compared to a formulation containing organic cosolvents.     

Percutaneous Penetration Enhancement in Vivo Measured by Attenuated Total Reflectance Infrared Spectroscopy

A novel application of attenuated total reflectance IR Spectroscopy (ATR-IR) was used to monitor the outer several microns of the stratum corneum (SC) and, thereby, demonstrate enhanced percutaneous absorption in vivo in man. 4-Cyanophenol (CP) as a model permeant yielded a unique IR signal, distinct from those of the stratum corneum and the vehicle components. CP was administered for 1, 2, or 3 hr as a 10% (w/v) solution either in propylene glycol or in propylene glycol containing 5% (v/v) oleic acid. The absorbance at 2230 cm^–1, which corresponded to CN bond stretching, diminished significantly faster when CP was codelivered with oleic acid. An IR absorbance due primarily to propylene glycol at 1040 cm^–1 (C–O stretching) also disappeared more quickly following application of the enhancer-containing solution. In addition, only the formulations with oleic acid induced a higher wavenumber shift in the frequency of the asymmetric C–H bond stretching absorbance. This change indicates increased lipid-chain disorder, the mechanism by which oleic acid is believed to cause enhanced drug transport across the stratum corneum. Therefore, ATR-IR permits one to examine noninvasively the kinetics, extent, and mechanism of percutaneous penetration enhancement in vivo in human subjects.     

Oxidative Degradation of a Sulfonamide-Containing 5,6-Dihydro-4-Hydroxy-2-Pyrone in Aqueous/Organic Cosolvent Mixtures

Purpose. To predict the oxidative stability of a sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrone in lipid-based delivery systems, N-(3-{1[(3,6R)-4-hydroxy-2-oxo-6-phenyl-6-propyltetrahydro-2H-pyran-3-yl]propyl}phenyl)-5-(trifluoromethyl)-2-pyridinylsulfonamide (DHP) was oxidized by peroxides and peroxyl radicals in binary mixtures of water and organic cosolvents. Methods. DHP was oxidized by hydrogen peroxide, t-butylhydroperoxide, or peroxyl radicals derived from the thermal decomposition of 2,2-azobis(2-amidinopropane) dihydrochloride (AAPH) in 40% (v/v) organic cosolvent and 5 mM buffer at or near 40°C. Interactions between DHP and ]propane sulfonic acid and imidazole) and DH^– were assessed by ¹H-NMR spectroscopy. The formation of CO likely involves a free radical mechanism. Results. The reaction of DHP with peroxides in 40% (v/v) acetonitrile yields epimeric monohydroxylation products, R-OH and S-OH, at C-3 of the pyrone ring, and a keto-derivative (CO). Hydroxylation rates depend on the protonation state of DHP, and the nature of buffer and the organic cosolvent. Organonitriles accelerate the oxidation through formation of peroxycarboximidic acid. Peroxyl radicals do not yield significant amounts of R/S-OH or CO. Conclusions. The hydrogen peroxide-induced degradation of DHP in the presence of acetonitrile involves two reactions, hydroxylation and carbonyl formatin. Hydroxylation proceeds via nucleophilic attack by the monodeprotonated form of DHP (DH^–) on peroxycarboximidic acid. The oxidation rate is slowed by ion pairing between nitrogen-containing buffers ([3-N-morpholino]propane sulfonic acid and imidazole) and DH^–. The formation of CO likely involves a free radical mechanism.     

Discriminative stimulus effects of intravenous l-nicotine and nicotine analogs or metabolites in squirrel monkeys

Squirrel monkeys were trained to emit one response after IV administration of l-nicotine (0.4 or 0.2 mol/kg) and a different response after IV administration of saline. After stable discriminative performances were established, subjects were tested with cumulative doses of l-nicotine (0.02–2.2 mol/kg), d-nicotine (0.02–19.7 mol/kg), l-nornicotine (0.2–12.0 mol/kg), l-cotinine (56.8–567.5 mol/kg), and dl-anabasine (0.6–19.7 mol/kg). All of the drugs produced dose-related increases in the percentage of drug-appropriate responses emitted, from predominately saline-appropriate responses after low doses, to predominately drug-appropriate responses at the highest doses studied. Relative potency comparisons indicated that l-nicotine was 28 times more potent than d-nicotine, 29 times more potent than l-nornicotine, and approximately 2000 times more potent than l-cotinine. Each of the drugs also produced decreases in rates of responding, with potency order similar to that obtained for the discriminative effects. The effects of l-cotinine may be attributed to trace amounts of l-nicotine, which existed within the l-cotinine. The effects of dl-anabasine were lethal in one subject and were consequently not studied in the other subjects.     

一次性无菌注射器的浸出有机物研究

目的:研究一次性无菌注射器(简称一次性注射器)与有机助溶剂接触后的浸出有机物,确定其结构并测定含量。方法:采用含橡胶活塞的三件式一次性注射器及不含橡胶活塞的二件式一次性注射器与注射剂中常用的乙醇、丙二醇、聚乙二醇400及甘油等有机助溶剂接触,采用高效液相色谱-二极管阵列检测器、质谱确定浸出有机物的结构;模拟已上市注射剂处方,以高效液相色谱法定量测定一次性注射器分别与5%²0%乙醇溶液、20%20%乙醇溶液、20%⁶0%丙二醇溶液及20%60%丙二醇溶液及20%⁶0%聚乙二醇400溶液接触后浸出有机物的含量。结果:三件式一次性注射器与甘油接触后无明显浸出有机物;与乙醇、丙二醇及聚乙二醇400接触后有有机物浸出,其中乙醇中浸出量最高;二件式一次性注射器与上述有机助溶剂接触均无浸出物出现。浸出有机物来源于注射器中的橡胶活塞,为增塑剂邻苯二甲酸二异辛酯(DEHP)。一次性注射器与不同浓度的有机助溶剂接触5 min以内,浸出的DEHP含量均低于1.5μg/ml,远低于人体可耐受的日摄入量。结论:采用一次性注射器注射含有机助溶剂的注射剂,短时间内使用安全性风险较低。     

The effects of pH and mixed solvent systems on the solubility of oxytetracycline

The solubility of oxytetracycline (OTC) in aqueous and mixed solvent systems was studied. The effects of pH and cosolvent composition on the solubility and apparent dissociation constants (pKa') of OTC were determined by a solubility method. The pKa' values of OTC in each mixed solvent system were estimated and used to generate expressions for predicting drug solubility in each cosolvent as a function of pH. Cosolvent systems of PEG 400, propylene glycol, glycerin, and 2-pyrrolidone were studied in the pH range of 2.5-9. Solubility results showed increased solubility with increased cosolvent concentration, especially in 2-pyrrolidone solvent systems. These results also showed that cosolvents enhanced drug solubility through either their effects on polarity of the solvent medium or complex formation with OTC. Aqueous and mixed solvent systems at lower pH values resulted in higher OTC solubilization because the drug existed primarily in its cationic form. A mass balance equation including all ionic species of OTC allowed for estimation of the intrinsic solubilities and pKa' values in each solvent system. pKa' values and intrinsic solubility of the OTC zwitterion increased with increasing cosolvent content. These parameters allowed prediction of drug solubility within the pH range and cosolvent concentrations used in this study.     

自制复方特比萘酚软膏渗透促进剂的研究

目的 筛选并确定自制复方特比萘酚软膏中的渗透促进剂.方法 采用体外经皮渗透试验,使用立式Franz扩散池,接收液为60％聚乙二醇400-40％生理盐水,渗透膜为SD大鼠腹部皮肤,筛选最适渗透促进剂.结果10％丙二醇对复方特比萘芬软膏的促渗作用明显大于15％丙二醇,对比氮酮和丙二醇的促渗效果,10％丙二醇优于3％氮酮.结...