Spontaneously self-assembled micelles from poly(ethylene glycol)-b-poly(epsilon-caprolactone-co-trimethylene carbonate) for drug solubilization

Di-block copolymers composed of polyethylene glycol (PEG) and a second block of (co)polyesters of epsilon-caprolactone (CL) and/or trimethylene carbonate (TMC) were synthesized and characterized. Tin octoate was used as catalyst and polymerization were completed over a period of 24 h with high conversion (> 95%). Self-assembling properties in water were evaluated. All di-block copolymers behave similarly except when PCL served as the second block. Stable crew-cut micelles of about 20 nm were obtained by direct dissolution of the liquid di-block copolymers in water at room temperature. When PCL was present as the second block, no solubilization occurred. Drug encapsulation of poorly water-soluble drugs belonging to biopharmaceutics classification system (BCS) class II (ketoprofen and furosemide) was evaluated. Experimental solubility for these two drugs shows a significant enhancement such that a maximum value of 23.4 mg/ml was obtained for ketoprofen in a 10% w/v micellar solution as compared to 0.14 mg in water. In the case of furosemide, the solubility increased from 0.04 mg/ml in water to about 3.2 mg/ml in a 10% w/v micellar solution. Enzymatic degradation of diblock copolymers was also studied in the presence of Pseudomonas lipase in a phosphate buffer solution (pH 7.4). Results indicated rapid degradation of copolymers containing relatively higher amounts of CL compared to TMC suggesting the potential in vivo degradation.     

Analytical methods for assay of ellagic acid and its solubility studies

Ultra-violet (UV) spectrophotometric and high performance liquid chromatographic methods for quantitative determination of ellagic acid (EA), an antioxidant were developed. The analytical methods were validated for linearity, accuracy, intra- and inter-day variability, and precision. EA was eluted using a polyethylene glycol (PEG) column with mobile phase composed of acetonitrile and 5 mM potassium dihydrogen orthophosphate buffer pH 2.5 (80:20, v/v). The UV and high performance liquid chromatography (HPLC) methods have lower detection limits of 0.2 and 0.1 microg/ml, respectively. Because of the increasing pharmaceutical interest in phytochemicals and their solubility problems, solubility studies for EA were also carried out. Various organic solvents and surfactants were screened for assessing solubility of EA and the compound was found to be soluble in some pharmaceutically acceptable solvents like triethanolamine, polyethylene glycol 400 and N-methyl pyrrollidone (NMP). Aqueous and pH dependent solubility of EA were determined using UV and HPLC methods, respectively.     

Development of a parenteral formulation of an investigational anticancer drug, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone

The objective of this study was to develop an injectable formulation of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) suitable for intravenous infusion. The solubility of 3-AP in different solvents and pH conditions was determined. The developed formulation underwent stability assessment and compatibility testing with large volume parenteral (LVP) solutions. The aqueous solubility of 3-AP was found to be 0.1 mg/ml and could only be increased marginally by altering the pH or adding surfactants. To achieve the desired concentration (> 4 mg/ml), 3-AP was formulated at 5-10 mg/ml in a nonaqueous system consisting of 70% polyethylene glycol 300 and 30% ethanol. However, 3-AP readily precipitated from this formulation when diluted with LVP solutions. Dilution-induced drug precipitation was eliminated by acidifying the solution with citric acid. Ascorbic acid, 0.1%, was found to minimize oxidative degradation of 3-AP. Accelerated stability data indicated that the formulation is compatible with the packaging components and is chemically stable at 2-8 degrees C, and retained > 90% of 3-AP at 40 degrees C for 3 months. Simulated infusion studies showed that the citric acid formulation was compatible with LVP solutions. However, because of the potential of extraction of plasticizers from polyvinyl chloride (PVC) plastic containers, it is recommended that the formulation be diluted in glass containers prior to administration.     

Development of parenteral formulations and evaluation of the biological activity of the trypanocide drug benznidazole

Chagas disease, caused by Trypanosoma cruzi, is a major public health problem in Latin America. According to the World Health Organization, around 20 million people are infected and another 40 million are at risk of acquiring the disease. One of the drugs most frequently used for the treatment of Chagas disease is benznidazole (BZL). It is practically insoluble in water (0.4 mg/ml), which precludes the preparation of liquid dosage forms, in particular, parenteral formulations. Thus, the aim of this work was to investigate the solubilization of BZL at two pH values using various cosolvents such as ethyl alcohol, propylene glycol, polyethylene glycol 400, benzyl alcohol, diethylene glycol monoethyl ether (Transcutol) and surfactants such as polysorbates (Tween) 40 and 80, and sodium dioctyl sulfosuccinate (AOT). Solvent systems based on PEG 400, with the addition ethyl alcohol and/or potassium biphthalate buffer solution, increased the BZL solubility up to 10 mg/ml. These alcoholic vehicles showed no toxicity against parasite when assayed at 1%. Physical and chemical stability studies showed that the formulations were stable for at least 1.5 years. In agreement with the biological activity results, the selected formulations are suitable for further clinical studies. Moreover, increasing the aqueous solubility of BZL reduced the problems in vitro testing techniques and bioassays leading to more reliable results and/or reproducibility.     

Vorinostat with sustained exposure and high solubility in poly(ethylene glycol)-b-poly(dl-lactic acid) micelle nanocarriers: Characterization and effects on pharmacokinetics in rat serum and urine

The histone deacetylase inhibitor suberoylanilide hydroxamic acid, known as vorinostat, is a promising anticancer drug with a unique mode of action; however, it is plagued by low water solubility, low permeability, and suboptimal pharmacokinetics. In this study, poly(ethylene glycol)‐b‐poly(dl‐lactic acid) (PEG‐b‐PLA) micelles of vorinostat were developed. Vorinostat's pharmacokinetics in rats was investigated after intravenous (i.v.) (10 mg/kg) and oral (p.o.) (50 mg/kg) micellar administrations and compared with a conventional polyethylene glycol 400 solution and methylcellulose suspension. The micelles increased the aqueous solubility of vorinostat from 0.2 to 8.15 ± 0.60 and 10.24 ± 0.92 mg/mL at drug to nanocarrier ratios of 1:10 and 1:15, respectively. Micelles had nanoscopic mean diameters of 75.67 ± 7.57 and 87.33 ± 8.62 nm for 1:10 and 1:15 micelles, respectively, with drug loading capacities of 9.93 ± 0.21% and 6.91 ± 1.19%, and encapsulation efficiencies of 42.74 ± 1.67% and 73.29 ± 4.78%, respectively. The micelles provided sustained exposure and improved pharmacokinetics characterized by a significant increase in serum half‐life, area under curve, and mean residence time. The micelles reduced vorinostat clearance particularly after i.v. dosing. Thus, PEG‐b‐PLA micelles significantly improved the p.o. and i.v. pharmacokinetics and bioavailability of vorinostat, which warrants further investigation.     

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.     

Solubilization of valsartan by aqueous glycerol, polyethylene glycol and micellar solutions

To increase the solubility of valsartan in aqueous solutions was considered of interest. This study therefore investigated the solubilization of valsartan by cosolvency and micellization. Of the solubilization agents used, sodium lauryl sulfate was found to be the most effective. The increase in solubility at the maximum concentration studied was in the following order: sodium lauryl sulfate > polysorbate-80 > polyethylene glycol 400 > glycerol. The effect of propylene glycol on the solubility of valsartan in a 2% w/v polysorbate-80 solution was also investigated and was found that propylene glycol decreased the solubilizing power of polysorbate-80 at the concentrations studied.     

Solubilization and stability of bumetanide in vehicles for intranasal administration, a pilot study.

The solubility of bumetanide in vehicles of various polarities, suitable for intranasal administration in acute situations, has been investigated. The solubility at 4 degrees C in glycofurol and polyethylene glycol 200 was high (167 and 143 mg/mL, respectively), decreasing exponentially with addition of phosphate buffer or coconut oil. Vehicles containing coconut oil and glycofurol did not seem to improve the solubility relative to mixtures between glycofurol and buffer. Adequate solubility (approximately 50 mg/mL) was achieved in vehicles containing about 80% cosolvent. The stability of bumetanide was studied at 5 degrees C and 57 degrees C. No degradation was observed at low temperature. At high temperature, bumetanide decomposes in nonaqueous vehicles with half-lifes ranging from 69 to 400 days, but sufficient stability may be obtained by adjustment of pH to 7.4. It may be concluded that it is possible to prepare a clinically relevant formulation for intranasal delivery of bumetanide.     

The solubility of 17 beta-oestradiol in aqueous polyethylene glycol 400

The solubility of 17 beta-oestradiol (E2) in aqueous solutions of polyethylene glycol (PEG) 400 has been measured at 35 degrees C. Up to 80% w/w PEG the solubility data conform to a log linear equation ln S = ln Sw + f sigma where S is the E2 concentration in the water/cosolvent mixture, Sw is E2 solubility in water, f is the weight fraction of PEG 400 and sigma is a parameter representing the solubilizing power of the cosolvent for the drug. Above 80% PEG the relationship becomes less convincing, with significant deviation from anticipated values. Reasons for these aberrations are discussed. It is suggested that conformational changes may be induced in the PEG by the addition of small quantities of water. Deviations noted for the melting point, viscosity and density data of PEG 400-water solutions may also confirm this suggestion.     

Bioavailability enhancement of a poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture

Oral bioavailability of a poorly water-soluble drug was greatly enhanced by using its solid dispersion in a surface-active carrier. The weakly basic drug (pK(a) approximately 5.5) had the highest solubility of 0.1mg/ml at pH 1.5, < 1 microg/ml aqueous solubility between pH 3.5 and 5.5 at 24+/-1 degrees C, and no detectable solubility (< 0.02 microg/ml) at pH greater than 5.5. Two solid dispersion formulations of the drug, one in Gelucire 44/14 and another one in a mixture of polyethylene glycol 3350 (PEG 3350) with polysorbate 80, were prepared by dissolving the drug in the molten carrier (65 degrees C) and filling the melt in hard gelatin capsules. From the two solid dispersion formulations, the PEG 3350-polysorbate 80 was selected for further development. The oral bioavailability of this formulation in dogs was compared with that of a capsule containing micronized drug blended with lactose and microcrystalline cellulose and a liquid solution in a mixture of PEG 400, polysorbate 80 and water. For intravenous administration, a solution in a mixture of propylene glycol, polysorbate 80 and water was used. Absolute oral bioavailability values from the capsule containing micronized drug, the capsule containing solid dispersion and the oral liquid were 1.7+/-1.0%, 35.8+/-5.2% and 59.6+/-21.4%, respectively. Thus, the solid dispersion provided a 21-fold increase in bioavailability of the drug as compared to the capsule containing micronized drug. A capsule formulation containing 25 mg of drug with a total fill weight of 600 mg was subsequently selected for further development. The selected solid dispersion formulation was physically and chemically stable under accelerated storage conditions for at least 6 months. It is hypothesized that polysorbate 80 ensures complete release of drug in a metastable finely dispersed state having a large surface area, which facilitates further solubilization by bile acids in the GI tract and the absorption into the enterocytes. Thus, the bioavailability of this poorly water-soluble drug was greatly enhanced by formulation as a solid dispersion in a surface-active carrier.     

Evaluation of new propofol aqueous solutions for intravenous anesthesia

The aim of this study was to evaluate the potential of using three new aqueous formulations of propofol for intravenous (i.v.) anesthesia. The first formulation can be prepared by using hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD) as a solubilizer. Phase-solubility analysis showed a linear increase in the solubility of propofol to a maximum of 16.6 mg/ml in 30% (w/v) HP-gamma-CD. Moreover, phase-solubility studies demonstrated that 18% (w/v) HP-beta-CD or SBE-beta-CD and 24% HP-gamma-CD solutions, respectively, are required to dissolve 10mg of propofol in 1 ml of the vehicle; the corresponding solutions, however, are slightly hypertonic. Autoclaving the 10 mg/ml CD-based formulations for 15 min at 121 degrees C caused a change in pH which was more evident for the HP-beta-CD-based formulation while, in any case, no detectable fall in propofol concentration was observed. The second formulation herein evaluated is a co-solvent mixture (i.e., propylene glycol:water (1:1), v/v) which is able to dissolve 10 mg/ml of the anesthetic agent. However, although it is simple to prepare, the stability of this formulation is limited. The third aqueous formulation can be prepared by using the prolinate ester of propofol and its water-soluble derivative dissolved in water at equimolar concentration. The efficacy of all these formulations as i.v. anesthetic agents was assessed using a pharmacodynamic measure (onset and duration of loss of the righting reflex, LORR), and compared with that of the commercial propofol formulation (Diprivan, 10 mg/ml) in rats. It was found that minimizing the amount of cyclodextrin in all CD-based formulations, anesthetic effects comparable to those of propofol in Diprivan were still observed. Moreover, the prolinate ester constituted an effective i.v. anesthetic formulation with the same duration of action but with a longer induction time than Diprivan.     

Effect of propylene glycol,Azone and n-decylmethyl sulphoxide on skin permeation kinetics of 5-fluorouracil

The effect of propylene glycol (PG), azone (LDA) and n-decylmethyl sulfoxide (LDB) on the permeation course of fluorouracil through the hairless mouse skin was studied. Steady-state fluxes and permeability coefficients were measured in buffer solutions and in systems containing the enhancing agents. The permeation rates of fluorouracil have been shown to be highly pH dependent in the pH range of 5–9, the rate decreases with an increase in pH. The solubility of fluorouracil in pure propylene glycol at equilibrium measured by the solubility method was found to be 2.2 mg · ml^?1 at 25°C which is a relatively low value as compared to the solubility in water. The effect of various concentrations of propylene glycol in aqueous donor solutions on the drug permeation rate was examined at pH's 5.7 and 9.0. It was found that propylene glycol decreases the permeation flux when increasing concentrations are added to the aqueous pH 5.7 system; however, at pH 9, a strong enhancement effect was shown. PG was also found to decrease the drug reservoir in the hairless mouse skin e.g. 8.4 and 2.8 mg · (mg skin)^?1 for buffer pH 9 and PG/aqueous solution pH 9 systems, respectively. The concentration dependent enhancement effects of azone and n-decylmethyl sulfoxide have been measured. Both have been found to be potent enhancing agents. However, at relatively low concentrations such as 5%, Azone induced a 50-fold and n-decylmethyl sulfoxide only a two-fold enhancement of the drug steady-state flux. At high concentrations as much as 40%, n-decylmethyl sulfoxide appears to be more effective than Azone. The fluxes measured with these systems were 0.21, 0.17 and 0.003 mg · cm^?2 · h^?1 for the n-decylmethyl sulphoxide, Azone and PG/H₂O systems, respectively.     

LC separation of calcipotriol from its photodegradation products and protection possibilities using adjuvants.

Mobile phase optimization and reversed-phase column characteristics were used to separate photodegradation products from the parent compound, 24-cyclopropyl-9-,10-secochola-5,7,10(19),22-tetraene-1alpha,3beta,24-triol (calcipotriol). Separation between calcipotriol and its degradation products was obtained with an acetonitrile/water (53:47, v/v) mobile phase on a C(18) Hypersil ODS column (250 mm length, 4.6 mm id, 5 microm particle size) and a flow rate of 1 ml/min. Using this system, the influence of commonly used solvents in dermatology on degradation was studied. The addition of a UV filter in two concentrations was also evaluated for its possible protective effect to light exposure. Propylene glycol and polyethylene glycol 400 decreased the speed of degradation. The sunscreen 2-hydroxy-4-methoxybenzophenone affords a protection proportional to the filter concentration used in the study.     

Water migration from soft gelatin capsule shell to fill material and its effect on drug solubility

The bioavailability of some poorly water-soluble drugs was reported to increase due to a change in dosage form from a tablet to a solution encapsulated in soft gelatin capsules. However, the objective of increasing the bioavailability may be defeated if the drug crystallizes from a solution inside the capsule. In this study, a water-insoluble drug [alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; REV 5901] was solubilized in both polyethylene glycol 400 (PEG 400) and a 6:1 mixture of Gelucire 44/14:PEG 400. The solutions were then encapsulated in soft elastic gelatin capsules with a fill weight of 700 mg (drug, 125 mg), and water migration from the capsule shell into the fill material and its effect on the solubility of the drug were investigated. Gelucire 44/14 is a mixture of hydrogenated fatty acid esters with a mp of 44 degrees C; PEG 400 was added to reduce the mp of solution to approximately 36 degrees C for easier encapsulation. After equilibration of capsules at ambient condition, the amount of water in the PEG 400 solution was 6.3%. This reduced the solubility of the drug by 45%, resulting in drug crystallization. The solubility decreased exponentially with the increase in water content. The water in the encapsulated Gelucire:PEG solution was only 1.1%, which did not affect the solubility significantly.     

The Effects of pH and PEG 400–Water Cosolvents on Oxytetracycline–Magnesium Complex Formation and Stability

The effects of pH and PEG 400 on the stoichiometry, conformation, and stability of the magnesium–oxytetracycline (Mg⁺²–OTC) complex were evaluated. Circular dichroism (CD) and HPLC were used to investigate Mg⁺²–OTC complex formation and determine the stability of the complexes formed. The stoichiometry of the complex was determined to be a 1:1 molar ratio of Mg⁺² to OTC regardless of changes in pH, in the range 7–10, and regardless of the percentage of polyethylene glycol (PEG) 400 in solution. CD showed that the conformation assumed by Mg⁺²–OTC complex is sensitive to changes in pH, however, little to no effect was found when the PEG 400 concentration was varied. PEG 400 was found to effect the magnitude of complexation as evident by the dependence of CD peak intensity on the cosolvent concentration in solution. The Job's method confirmed that the formation of this complex increased with increasing PEG 400 concentration and was most favored at pH 8. HPLC analyses of OTC solutions at pH 9 revealed the formation of multiple degradation products after storage at 50°C. The incidence and magnitude of OTC degradation products were reduced in the presence of Mg⁺² and PEG 400. Despite the HPLC results of maintained OTC stability in magnesium-complexed solutions over time, visual inspection showed these solutions to have darkened, indicating that an oxidative process is responsible for initial degradation of OTC. Therefore, the need for additional measures (i.e., antioxidants) was established to ensure the long-term stability of OTC in solution.     

Degradation of fenprostalene in polyethylene glycol 400 solution

The kinetics of degradation of fenprostalene (I) in polyethylene glycol 400 solution was examined using HPLC. The degradation of I at 80 degrees C was shown to depend on the presence of oxygen and a large number of polar products were produced, as evidenced by using 3H-labeled I. Evidence that autoxidation of the polyethylene glycol 400 was concurrent with degradation of I was found from a drop in the apparent pH. Antioxidants were very effective in retarding the rate of degradation in the presence of oxygen. Degradation of I in polyethylene glycol 400 appears to arise from a reaction between the drug and reactive peroxide intermediates formed through air-oxidation of polyethylene glycol 400. This is supported by the finding that I reacts exclusively by a slow transesterification reaction in diethylene glycol, a solvent that is stable to autoxidation.     

Solution stability of salmon calcitonin at high concentration for delivery in an implantable system

Abstract: Salmon calcitonin solutions (50 mg/mL and 100 mg/mL) were placed on stability at 37°C for 1 year in a variety of solvent systems including water, ethanol, glycerol, propylene glycol (PG) and dimethyl sulfoxide (DMSO). Calcitonin degradation was monitored by RP‐HPLC and size‐exclusion chromatography. DMSO and pH 3.3 solutions provided optimum stability. Conformational stability was also monitored by FTIR over the 1 year time course and compared with chemical and physical stability. After 12 months at 37°C, four major conformations were observed: a β‐sheet conformation (pH 3.3, pH 5.0, 70% DMSO and 70% glycerol), an aggregate conformation (pH 7.0 water), a strong α‐helical conformation (70% EtOH, 70% PG) and a weak α‐helical conformation (100% DMSO). No correlation between structure and chemical stability was observed in which both the β‐sheet structure (pH 3.3, water) and a loose α‐helical structure (100% DMSO) demonstrated good stability. However, some correlation was observed between structure and physical stability, where co‐solvents inducing an α‐helical structure resulted in a decrease in gelation. These two structural states associated with improved stability and minimal gelation, indicated that gelation can be reduced or eliminated by the use of pharmaceutically acceptable co‐solvents. Finally, salmon calcitonin (50 mg/mL) was formulated in 100% DMSO and delivered from a DUROS® implant over 4 months. Delivery at a target dose of 18 µg/day calcitonin at 37°C was confirmed.     

Use of an in Vitro Model for the Assessment of Muscle Damage from Intramuscular Injections: in Vitro-in Vivo Correlation and Predictability with Mixed Solvent Systems

The potential of binary mixtures of propylene glycol–water, ethanol–water, and polyethylene glycol 400–water to cause skeletal muscle damage (myotoxicity) following intramuscular injection was examined with an in vitro model using the isolated rat muscle. At moderate concentrations (20–40%, v/v) of the organic cosolvent, the order of myotoxicity was propylene glycol > ethanol polyethylene glycol 400. The in vitro results were then compared with in vivo toxicity in rabbits after injection of normal saline, 40% (v/v) polyethylene glycol 400, 40% (v/v) propylene glycol, indocyanine green in normal saline, and indocyanine green in 40% (v/v) propylene glycol. Employing the area under the creatine kinase activity curve from 0 to 72 hr as the index of skeletal muscle damage, an excellent in vitro–in vivo correlation was observed. The basic myotoxicity relationships obtained from the binary cosolvent systems were then used to examine the myotoxicity of ternary organic cosolvent mixtures. Several mixed solvent systems with the same theoretical molar solubilization power for a model compound, diazepam, were selected to determine (1) if myotoxicity can be reduced by changing the composition of the ternary mixtures and (2) if myotoxicity of the individual components is additive. For the solvent systems containing propylene glycol, ethanol, and water, the total myotoxicity equaled the sum of the individual myotoxicity of each component. In contrast, for the solvent systems containing polyethylene glycol 400, the total myotoxicity was only half of the sum of individual toxicities. These results suggest that polyethylene glycol 400 in mixed cosolvent systems might have a protective effect on the myotoxicity generated by intramuscular injections.     

Drug permeability across a phospholipid vesicle-based barrier: 4. The effect of tensides, co-solvents and pH changes on barrier integrity and on drug permeability

In this study the integrity of the recently developed phospholipid vesicle-based permeability barrier in the presence of a variety of co-solvents and tensides has been investigated. Also included are studies of the influence of these additives on drug permeation and the effect of pH changes on the permeability of ionogenic drug compounds. Permeability experiments using the hydrophilic model compound calcein together with polysorbate 80 (Tween 80), polyoxyl 35 castor oil (Cremophor EL), macrogol lauryl ether (Brij 35), sorbitan monolaurate (Span 20), polyethylene glycol 400 (PEG 400), ethanol and dimethylsulphoxide (DMSO) were performed to determine whether the barriers were affected by the presence of these additives in the donor compartment. It was found that the integrity of the phospholipid vesicle-based barriers did not seem to be influenced by Span 20 up to a concentration of 5mg/ml, PEG 400 up to a concentration of 40mg/ml and ethanol and DMSO up to a concentration of 20mg/ml, respectively. Brij 35, Tween 80 and Cremophor EL were however found to be incompatible with the model at all concentrations as the barriers became leaky. Appearance of phospholipid in the donor chamber in presence of these three tensides indicated that the loss of integrity was due to partial dissolution of the phospholipid vesicles from the barrier. The permeability of testosterone was not significantly improved by the presence of the different co-solvents, except for 40 mg/ml PEG 400 and 20 mg/ml DMSO where the permeability was increased. In the pH study the permeability of metoprolol and naproxen was shown to decrease with increasing degree of ionisation according to the pH partition hypothesis. This renders the permeability model suitable for using pH-shift as a factor to influence solubility of drugs as well as to predict segmental absorption in the gastrointestinal tract.     

The impact of co-solvents and the composition of experimental formulations on the pump rate of the ALZET osmotic pump

The water-miscible co-solvents polyethylene glycol 400 (PEG400), N-methyl-2-pyrrolidone (NMP), and N, N-dimethylacetamide (DMA) exhibit the potential to increase the solubility of poorly water-soluble compounds and therefore they represent promising vehicles for compound delivery using osmotic pumps in early discovery experiments. Thus, the selected co-solvents were investigated for their compatibility with the interior of ALZET osmotic pumps. Moreover, 1-week pumps were filled with mixtures of either the co-solvents with water (60:40, v/v), with neat PEG400, or with PEG400/water mixtures of different concentrations. It was determined whether the composition of an experimental formulation could have an impact on the overall pump rate with 14C-mannitol being used as the model compound. It was found that neat PEG400 was compatible with the reservoir material, whereas NMP and DMA were tolerable only in aqueous solutions up to 60%. PEG400, NMP, and DMA mixtures with water (60:40) resulted in release rates comparable to those of water and PEG400/water mixtures of lower co-solvent concentration. Moreover, as demonstrated using the various PEG400/water mixtures, the amount of co-solvent in the formulation had no significant impact on the overall release profile. By contrast, the use of neat PEG400 resulted in a significant decrease in the pump rate.