Solubilizing Excipients in Oral and Injectable Formulations

A review of commercially available oral and injectable solution formulations reveals that the solubilizing excipients include water-soluble organic solvents (polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide), non-ionic surfactants (Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-alpha-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, Softigen 767, and mono- and di-fatty acid esters of PEG 300, 400, or 1750), water-insoluble lipids (castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil and palm seed oil), organic liquids/semi-solids (beeswax, d-alpha-tocopherol, oleic acid, medium-chain mono- and diglycerides), various cyclodextrins (alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and sulfobutylether-beta-cyclodextrin), and phospholipids (hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine, L-alpha-dimyristoylphosphatidylglycerol). The chemical techniques to solubilize water-insoluble drugs for oral and injection administration include pH adjustment, cosolvents, complexation, microemulsions, self-emulsifying drug delivery systems, micelles, liposomes, and emulsions.     

Absorption Barriers in the Rat Intestinal Mucosa. 3: Effects of Polyethoxylated Solubilizing Agents on Drug Permeation and Metabolism

Modern drug discovery chemical libraries contain a large number of molecular entities exhibiting low aqueous solubility, often necessitating the inclusion of solubilizing agents in preclinical models of absorption or metabolism. The objective of the present study was to investigate the effects of several commonly used polyethoxylated solubilizing agents on P450 (CYP) 3A and P-glycoprotein (P-gp) in the rat intestinal mucosa. Atenolol and verapamil were administered in the in situ perfused rat intestine or incubated with rat intestinal microsomes in the presence or absence of polyethylene glycol (PEG) 400 (2% or 20%, v/v) D-α-tocopheryl polyethylene glycol-1000 succinate (TPGS; 100 µg/mL), Cremophor EL® (47.5 µg/mL) or polysorbate (Tween) 80 (25 µg/mL). Effects on the absorption of unchanged drug were minimal, with the exception of Tween 80 which caused a 5.0-fold increase in paracellular absorption. Rat intestinal CYP3A was significantly inhibited by PEG-400 and in situ, exceeded inhibition observed with ketoconazole. Cremophor and TPGS increased the fraction of norverapamil in the plasma, consistent with excipient-mediated inhibition of P-gp. These results suggest that caution be exercised when these solubilizing agents are included in preclinical oral dosing solutions as the perturbation of drug absorption barriers may heighten the risk of incorrectly classifying drug candidate PK-parameters. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:1016–1027, 2010     

依托泊苷微乳相图的研究

目的确定o／w型依托泊苷微乳处方。方法选用油酸、十四酸异丙酯和十六酸异丙酯作为油相，Tween80、Cremophor EL和Cremophor RH40作为表面活性剂，乙醇、1，2-丙二醇、异丙醇、甘油和PEG400为助表面活性剂，通过滴定法绘制伪三元相图，以o／w型微乳区大小为指标筛选处方。结果确定了最终空白微乳处方为Cremophor RH40：乙醇：PEG 400：水：十四酸异丙酯=19．0：19．0：19．0：38．2：4．8（w／w）。结论所选择的微乳处方可以满足依托泊苷载药量的要求。     

Comparison of impact of the different hydrophilic carriers on the properties of piperazine-containing drug.

The objective of this study was to determine the impact of a series of nonionic surfactants on the solubility of piperazine-containing drug (meclizine, MZ) in comparison to that of natural cyclodextrins (alpha-CD and beta-CD) and dimethyl-beta-cyclodextrin (DM-beta-CD). The solubility of the drug was studied in either CDs solutions or nonionic surfactant solutions. Three classes of nonionic surfactants were used namely; polyoxyethylene (POE) sorbitan fatty acid esters (polysorbates), POE fatty acid esters (Myrjs) and polyethylene oxide (PEO) fatty alcohol ethers (Brijs and Eumulgins). The solubility of MZ was increased linearly with the increasing surfactant concentration, indicating that micellar solubilization follows the partition model. It was found that the longer the hydrocarbon chain in a homologous series, the more efficient is the solubilizing power of surfactant. For example, polysorbate 80 (Tween-80) is a more efficient solubilizer than polysorbate 20 (Tween-20), indicating that the drug was incorporated in the core of micelle more than the capsular region of the micelle. On the other hand, in case of POE fatty acid esters, the solubilizing power increased with decreasing polyoxyethylene chain as Myrj 53 was more efficient than Myrj 59. In class of PEO fatty alcohol ethers, the shorter the hydrophilic chain and longer lipophilic chain, the more efficient was the solubilizing capacity. Thus, Brij 58 was more efficient solubilizer than Brij 35 and Eumulgin C1000 was more active than Eumulgin C1500. Comparatively, Eumulgin C1000 had the highest solubilizing power for MZ among the studied PEO fatty alcohol ethers and other groups of surfactants. The solubility action of surfactants toward MZ was increased by raising the temperature of the surfactant solutions from 30 to 45 degrees C. Hydrophilic macromolecules (PEG 1000 and PEG 6000) or cosolvents (glycerol and propylene glycol) have a very slight effect on the solubility of MZ and confirm the predominance of hydrophobic interaction between the drug and nonionic surfactants. A(L)-type phase solubility diagrams were obtained for the drug with alpha-, beta- and DM-beta-CDs showing that the solubility of MZ was enhanced through inclusion complexation. Comparatively, DM-beta-CD had the highest solubilizing efficiency for the drug among the investigated CDs, which could be attributed to its larger hydrophobic cavity size.     

Influence of tensides on the release of medical agents from hydrophilic gels, part 2: The influence of selected tensides on hydrocortisone release from xerogels

With the increase of polysorbates 20 and 21 concentration in xerogels, in the presence of 1,2-propylene glycol and PEG 200, hydrocortisone half-release periods from these preparations become longer while the half-release periods for polysorbate 80 and propylene glycol, and polysorbate 21 and PEG 200 are proportionally shortened. The concentration of tensides has no significant impact on the half-release periods of hydrocortisone with polysorbate 81 added to xerogels in the presence of propylene glycol and polysorbate 20 and 80 with PEG 200.     

The effects of common solubilizing agents on the intestinal membrane barrier functions and membrane toxicity in rats

The use of solubilizing agents to improve the solubility of poorly water-soluble drugs often results in an alteration of intestinal membrane barrier function and intestinal membrane damage. In this study, 5(6)-carboxyfluorescein (CF) and fluorescein isothiocyanate-labeled dextran (MW 4400, FD4) were used as model compounds to examine the effects of twelve common solubilizing agents, sodium taurocholate (NaTC), Labrasol, polyethylene glycol 400 (PEG 400), Transcutol P, propylene glycol, Gelucire 44/14, HCO-60, ethanol, Cremophor EL, Tween 80, 2 hydroxypropyl-β-cyclodextrin (2HP-β-CyD) and dimethylsulfoxide (DMSO), on intestinal membrane barrier function and membrane toxicity in rats. Intestinal transport and absorption of CF were examined using an in vitro diffusion chamber and an in situ closed-loop technique. The in vitro diffusion chamber study showed that only 5 and 10% (w/v) NaTC significantly increased the transport of CF across the intestinal membrane. The in situ closed-loop study showed a remarkable increase in the absorption of CF and a bioavailability of more than 30% in the presence of 5 and 10% (v/v) Labrasol, 5 and 10% (w/v) NaTC and 10% (v/v) Transcutol P. Furthermore, we evaluated the effect of NaTC and Labrasol on the intestinal absorption of FD4, a high molecular weight compound. The results indicated that the absorption of FD4 also increased in the presence of 5 and 10% (w/v) NaTC and 10% (v/v) Labrasol, suggesting that these concentrations of NaTC and Labrasol may alter the intestinal membrane barrier functions in rats. We measured the release of protein and lactate dehydrogenase (LDH) from the intestinal membrane to examine the safety of solubilizing agents in the intestine. 5 and 10% (w/v) NaTC and 5 and 10% (v/v) Gelucire 44/14 significantly increased the presence of these toxicity markers compared to the control. The LDH level was also increased in the presence of 10% (v/v) of Cremophor EL. These findings suggest that the solubilizing agents at these concentrations except for NaTC, Gelucire 44/14 and Cremophor EL are considered safe and do not cause intestinal membrane damage. In conclusion, this study provides a basic approach in screening and predicting the effects of solubilizing agents for intestinal absorption studies using drugs poorly soluble in water.     

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.     

Solubilization of flavopiridol by pH control combined with cosolvents, surfactants, or complexants.

This study investigates the roles of both ionized and un-ionized species of flavopiridol in solubilization by complexation, micellization, and cosolvency. Control of pH was used in combination with surfactants (polysorbate 20 and polysorbate 80), cosolvents (ethanol and propylene glycol), as well as uncharged and anionic complexing agents [hydroxypropyl beta-cyclodextrin (HPbetaCD) and sulfobutyl ether beta-cyclodextrin (SBEbetaCD)] to solubilize flavopiridol. These combined techniques increase not only the solubility of the un-ionized flavopiridol but also the solubility of the ionized drug. This study confirms that previously developed equations effectively characterize the roles of pH, pK(a), and either complexation constant, micelle partition coefficient, or cosolvent solubilizing power in determining drug total aqueous solubility.     

Investigation of the solubility relationships of polar,semi-polar and non-polar drugs in mixed co-solvent systems

The solubility relationships of a non-polar (tioconazole), polar (oxfenieine) and semi-polar (caffeine) drug have been investigated in aqueous ethanol, propylene glycol and polyethylene glycol 400 (PEG 400) binary co-solvent systems. A semi-empirical equation was deduced to describe the relationship between the amount of drug dissolved and the volume fraction of co-solvent employed. The data for tioconazole and oxfenicine followed the expected semi-logarithmic relationship between solubility and fraction co-solvent. However, the semi-polar drug, caffeine followed this relationship only with PEG 400; the other two co-solvents yielded parabolic relationships.Using the binary solubility data, multiple linear regression was used to deduce an equation for the solubility of tioconazole in ternary ethanol, propylene glycol and PEG 400 co-solvent systems. The derived relationship gave excellent prediction of the drug solubility throughout the complete volume fraction range. This allowed a graphical representation of the drug solubility-co-solvent fraction relationship to be established. This visualization of are drug solubility relationship was then used to demonstrate its utility to optimize drug solubility within the competing constraints of the pharmaceutical system.     

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.     

Melt granulation using a twin-screw extruder: a case study

The purpose of this study was to use a twin-screw extruder for melt granulation. Polyethylene glycols (PEG 400 and 4000) were used as binders for the development of a drinking water formulation with immediate drug release. The effect of drug content, PEG 400/4000-ratio, surfactant (type and concentration) and granulation temperature on granule properties and dissolution characteristics was determined. The granulation temperature had an important influence on the granule formation. High yield (95% of the granules <1400 microm) was obtained only at a temperature near the melting point of PEG 4000. During granulation the drug of BCS class II was finely dispersed in the PEGs, creating a micro-environment around the drug particles enhancing the dissolution rate. To obtain complete drug release within 10 min for a formulation containing 10% drug, the addition of 2% (w/w) surfactant (polysorbate 80 or Cremophor RH40) was required. At a higher drug content (20%), the PEG 4000 concentration had to be increased to 20% to improve granule properties and 4% polysorbate 80 was required to obtain 100% drug release. X-ray diffractograms showed distinct peaks of crystalline drug, the crystallinity of the drug did not change after 50 days, independent of the storage conditions.     

Characterization of itraconazole/2-hydroxypropyl-beta-cyclodextrin inclusion complex in aqueous propylene glycol solution

The interaction of itraconazole, a triazole antifungal agent, with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) in water and 10% v/v propylene glycol/water solution at pH 2.0 was investigated by the solubility method and ultraviolet and 1H-nuclear magnetic resonance (NMR) spectroscopies. The solubility of itraconazole in water significantly increased as the concentrations of HP-beta-CyD were augmented, showing an AP type phase solubility diagram. The upward curvature closely corresponded to the simulation curve which was calculated on the basis of the 1:2 (guest:host) complexation model. The 1:2 complex was formed even in the presence of 10% v/v propylene glycol, although the co-solvent system made the interaction with HP-beta-CyD weaker due to the competitive inclusion. The ultraviolet spectroscopic studies also supported the 1:2 complex formation of itraconazole with HP-beta-CyD in 10% v/v propylene glycol/water solution at pH 2.0. The 1H-NMR spectroscopic studies suggested that the triazole and triazolone moieties of itraconazole are involved in the 1:2 inclusion complexation.Copyright     

Effect of commonly used vehicles on gastrointestinal, renal, and liver function in rats

INTRODUCTION: Solubility is often a limiting factor when testing new compounds in animal experiments. Various solubilizing agents may be used, but each have their own pharmacological effects. We investigated the effects of selected vehicles having different chemical characteristics on gastrointestinal, renal, and liver function. METHODS: Rats were treated orally, intravenously or intraperitoneally and gastric emptying, intestinal transit, renal, and liver function were investigated. RESULTS: Gastrointestinal motility was influenced by hydroxyethylcellulose, hydroxypropyl-beta-cyclodextrin (HPbetaCD), HPgammaCD, DMSO, polyethylene glycol 400 (PEG 400), fat emulsion, and the corresponding emulsifier. Liver function was affected by HPbetaCD, HPgammaCD, DMSO, PEG 400, Polysorbate 80, Cremophor RH 40, and fat emulsion. An increase in liver enzymes was observed after PEG 400 and Polysorbate 80. DMSO interfered with clinical chemistry measurements in serum. Urinary function was modified by HPgammaCD, DMSO, PEG 400, and Polysorbate 80, while enhanced urine enzyme excretion was observed after HPbetaCD, HPgammaCD, DMSO, PEG 400, and Polysorbate 80. DISCUSSION: Most of the investigated vehicles changed gastrointestinal, renal, and/or liver parameters after application of a certain threshold dose for each assay. No "best" vehicle could be identified that may be used in each test system. Thus, vehicles must be selected not only on their chemical characteristics but also on their potential pharmacological activity in a given test system.     

Preparation and evaluation of microemulsion of vinpocetine for transdermal delivery

Poorly soluble vinpocetine was selected as the model drug to prepare a microemulsion in order to increase solubility and in vitro transdermal delivery of the drug. Oleic acid was chosen as the oil phase due to its excellent solubilizing capacity. PEG-40 hydrogenated castor oil (Cremophor RH40) was employed as a surfactant (S) and purified diethylene glycol monoethyl ether (Transcutol P) was used as a cosurfactant (CoS). The effects of diverse types of oil, different weight ratios of surfactant to cosurfactant (S/CoS) on the solubility and permeation rate of vinpocetine were investigated. The optimized microemulsion consisted of 1% vinpocetine, 4% oleic acid, 20% Cremophor RH40, 10% Transcutol P and 65% distilled water (w/w), in which drug solubility was about 2,100 fold compared to that in water and the apparent permeation rate across the excised rat skin was 15.0 +/- 2.5 microg/cm2/h. Finally the physicochemical properties of the optimized microemulsion including pH, viscosity, refractive index, conductivity and particle size distribution were examined, which showed stable behavior after more than 12 months at ambient temperature. The irritation study showed that optimized microemulsion was a safe transdermal delivery system.     

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.     

Studies on the In-vitro Percutaneous Penetration of Indomethacin from Gel Systems in Hairless Mice

The influence of co-solvents on the in-vitro percutaneous penetration of indomethacin from gel systems was studied using a simplex lattice experimental design. Gel formulations were prepared by gelling the vehicle mixture of water, either alcohol or isopropanol and either propylene glycol or PEG 400 with 1% w/w Carbomer 940. Hairless mouse skin was employed as the barrier in a Franz-type diffusion cell. The penetration rates at steady state for seven formulations were fitted to a polynomial equation based on this simple lattice method and a three-dimensional plot was constructed. The formulation having the maximal penetration rate was determined to be the vehicle with a solvent ratio of water: alcohol: propylene glycol equal to 15:33:52, and which possessed a solubility parameter of 15 and a drug solubility of around 10 mg mL^?1. When the solubility parameter of the vehicle was > 15, the drug solubility increased. However, the penetration rate decreased with an increasing solubility parameter. For those vehicles with a solubility parameter < 15, both the drug solubility and the penetration rate decreased with a decrease in the solubility parameter. There was shown to be an approximately 20-fold increase in the relative enhancement factor when using both alcohol and isopropanol, but only a threefold increase for both propylene glycol and PEG 400, when compared with water.     

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.     

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.     

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.     

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.