HYDROTROPIC SOLUBILIZATION: AN EFFECTIVE TECHNIQUE FOR ENHANCING THE SOLUBILITY OF ANTIDIABETIC DRUG GLIMEPRIDE

Background and objective: Low aqueous solubility of active pharmaceutical ingredients has an effect on both formulation development and bioavailability. Nimodipine is an antihypertensive agent with low oral bioavailability, which might be attributed to the extremely poor water solubility. This study aimed to increase the solubility of nimodipine in water using hydrotropes and solid dispersion technology to increase dissolution rate compared to the marketed drug product. Methods: Solubility of nimodipine was determined separately in sodium acetate, sodium citrate, sodium benzoate, and niacinamide solutions at a concentration of 10, 20, 30, and 40% w/v using distilled water as a solvent. The highest solubility was obtained in 40% sodium benzoate solution. Mixed concentrations of hydrotropic agents were used in ratio 1:3 (niacinamide: sodium benzoate). Fourier-transform infrared spectroscopy was used to exclude any drug-hydrotropes interaction. The dissolution rate of nimodipine from solid dispersion and physical mixture were studied using USP type II dissolution test apparatus in acetate buffer (pH 4.5) as a dissolution media. Results: Hydrotropic solid dispersion of nimodipine with a blend (30% sodium benzoate and 10% niacinamide) increased the dissolution rate of the drug by 1.5 folds compared to the marketed conventional nimodipine tablet. Fourier-transform infrared analysis did not show any physicochemical interaction between drug and carriers in solid dispersion formulation. Conclusion: The hydrotrop is a novel and safe compound. It is a successful way to enhance the solubility of poorly aqueous soluble drugs. Immediate dissolution of practically insoluble drug nimodipine in dissolution media indicates that it has a great potential to solubilize the drug in biological fluids. Thus, a considerable improvement in bioavailability and onset of action of the drug can be predictable. Adding of a hydrotropic agent with nimodipine in solid dispersion increased the dissolution rate of the drug compared to the marketed conventional nimodipine tablet Keywords: Hydrotropes; Nimodipine; Solubility enhancement; Solid dispersion.

Conventional furosemide tablets are practically insoluble in water, have slow onset of action (45-60 min) and poor bioavailability (39-53%), and therefore cannot be given in emergency clinical situations like hypertension or pulmonary edema. So purpose of research was to provide a fast dissolving oral dosage form of furosemide, which can provide quick onset of action by using concept of mixed hydrotropy. Initially solubility of furosemide was determined individually in 4 hydrotropic agents namely urea, sodium acetate, sodium benzoate, sodium citrate at concentration of 10, 20, 30 and 40% w/v solutions using purified water as solvent. Highest solubility was obtained in 40% sodium benzoate solution. Then different combinations of 2, 3 and 4 hydrotropic agents in different ratios were used to determine solubility, so that total concentration of hydrotropic agents was always 40%. Highest solubility was obtained in solution of urea+sodium benzoate+sodium citrate at optimum ratio of 15:20:5. This optimized combination was utilized in preparing solid dispersions by common solvent technique using distilled water as solvent. Solid dispersions were evaluated for flow properties, XRD, DSC, SEM and were also compressed to form tablets. Dissolution studies of conventional and prepared tablets were done using USP Type II apparatus. It was concluded that the concept of mixed hydrotropic solid dispersion is novel, safe and cost-effective technique for enhancing bioavailability of poorly water-soluble drugs by dissolving drug in nonionized form. The magical enhancement in solubility of furosemide is clear indication of its potential to be used in future for other poorly water-soluble drugs in which low bioavailability is major concern.

Background: Glimepiride lowers blood sugar levels in the body, and treats type 2 diabetes mellitus. But the main problem with the drug is its low aqueous solubility. The primary purpose of this study is to increase its solubility in an aqueous medium by using amphiphilic hydrotropic agents instead of harmful, volatile organic solvents. Methodology: A solubility study of Glimepiride was carried out using various hydrotropic agents at 10%, 20%, 30%, and 40%. In mixed hydrography, 30% of the hydrotropic agents were chosen for making blends due to their highest solubility. The blend's solubility was raised more than 50 times at fixed concentrations of urea (20%) and sodium acetate (10%) in a mixed hydrotropic solution. The solubility of Glimepiride in distilled water is 0.0038 mg/ml; in 30% urea, 49.512 ug/ml; and in 30% sodium acetate, 40.43 ug/ml. The optimized blend prepared hydrotropic solid dispersions by physical mixing and solvent evaporation. It was evaluated for drug content, FTIR, SEM, X-ray diffraction, and in vitro drug release studies. Finally, the drug release profile of the prepared tablet is compared with an already available consumer product. Result: HSD-5 showed an in-vitro drug release of 84.77±0.44 at 90 min, which is higher than the remaining formulations, and no significant change was found in drug content or drug release after 15, 30, and 45 days of stability studies. Scanning electron microscopy (SEM) showed homogenous solid dispersion, crystallinity was determined using X-ray diffraction, and FTIR showed good drug compatibility with carriers. The drug release profile of the prepared tablet was higher than that of the available consumer product. Conclusion: This study revealed that hydrotropic agents can potentially increase glimepiride's solubility and drug release. This approach can effectively enhance the solubility of poorly water-soluble drugs.

The biopharmaceutics classification system places rosuvastatin calcium in class II has a low and fluctuating oral bioavailability. The research focus is to maximize rosuvastatin calcium solubility in water and dissolution rate by employing and combining various hydrotropic agents to make a solid dispersion using solvent evaporation techniques. Methodology. The experimental study was conducted at Duhok University, College of Pharmacy. Initially, assess rosuvastatin's solubility in hydrotropic agents including urea, mannitol, citric acid, sodium benzoate, and sodium salicylate at concentrations of 10, 20, 30, and 40% w/v. Then, various ratios of 2 and 3 hydrotropic agents were employed to reduce the concentration of each hydrotropic agent. By using a solvent evaporation procedure, solid dispersions were made. The solid dispersion powders underwent evaluation for their percentage drug content, percentage yield, solubility, dissolution test, XRD, DSC, SEM, and FTIR. For statistical analysis, GraphPad InStat Demo software was used to conduct a two-way analysis of variance (ANOVA). In comparison to the pure drug, the solubility of hydrotropic solid dispersions and physical mixtures of rosuvastatin with a combination of hydrotropic agents (sodium salicylate, sodium benzoate, and urea) in the ratio of 13.33 for each increased in all formulations significantly, and all manufactured formulations' drug release ranged from 98.83 to 104.78%, indicating a noticeably higher dissolution rate. The concept of mixed hydrotropic solid dispersion was shown to be an original, risk-free, and cost-effective method for enhancing the bioavailability of drugs that have a low degree of solubility in water.

Objective: Mefenamic acid (MFA) is an NSAID that exhibits anti-inflammatory analgesic and antipyretic activity. Peak plasma levels are attained in 2-4 h and the elimination half-life approximates 2 h, repetitive administration of tablets for 3-5 times a day is desired. It is supplied only in the form of tablets for oral administration. In acute conditions drug administered parenterally could give rapid relief from severe symptoms like pain. Thus, formulation of injectable formulation of MFA could be better alternative compared to conventional tablet dosage form. The low aqueous solubility of MFA precludes its use in parenteral formulation development.
 Methods: In this work attempt were made to enhance the aqueous solubility of mefenamic acid using mixed solvency technique. For that different hydrotropic agents such as Urea, Sodium acetate, sodium benzoate, sodium citrate and their blends were evaluated. Optimal concentration of hydrotropic agent in blend was determined using D-optimal mixture experimental design. The optimized bled was used to develop the aqueous injection of mefenamic acid. The developed injection was subjected for various quality control tests and stability of developed formulation was also evaluated.
 Results: The aqueous solubility in optimized blend of hydrotropic agent batches (U: SA: SB: SC, 4:4:23:9 %w/v) showed 835.71-fold compared to MFA solubility in distilled water. The quality control tests for parenteral formulation and accelerated stability study were found to be within prescribed limits and stable.
 Conclusion: The inadequate solubility of MFA was overcome, and aqueous injection was successfully developed which can be serve as cost effective treatment in various indications.

In the present investigation, newly developed mixed hydrotropic solid dispersion (HSD) technology precludes the use of organic solvent and also decreases the individual concentration of hydrotropic agents, simultaneously decreasing their toxic potential. ‘Mixed-hydrotropic solubilization’ technique is the phenomenon to increase the solubility of poorly water- soluble drugs in the aqueous solution containing blends of hydrotropic agents, which may give synergistic enhancement effect on solubility of poorly water-soluble drugs and to reduce concentrations of each individual hydrotropic agent to minimize their toxic effects due to high concentration of hydrotropic agents. Maheshwari has made HSD of paracetamol using urea. In the present study, the aqueous solution of hydrotropic blend (20% urea and 10% sodium citrate) has been found to increase aqueous solubility of poorly water-soluble drug, aceclofenac. This mixedhydrotropic blend was used to prepare solid dispersion of aceclofenac. The prepared solid dispersions have been characterized by IR and XRD studies. They have been studied for dissolution rate enhancement effect. The prepared solid dispersions were found very stable (chemically).

Etodolac is a non-steroidal anti-inflammatory drug used in the treatment of mild to moderate pain, osteoarthritis or rheumatoid arthritis and it is basically available in the market only as tablet dosage form for human use. The present study was investigated with an intention to develop a stable and effective parenteral formulation, containing Etodolac for acute pain management. Etodolac is a Biopharmaceutical Classification System (BCS) class II drug and it is insoluble in water hence solubility and dissolution rate enhancement was carried out by using various hydrotropic blends.. Etodolac was blended in different proportion with various hydrotropic agents like sodium acetate, sodium benzoate, sodium citrate etc and other co-solvents. The drug was formulated in injectable dosage form using a optimized hydrotropic blend as solvent. The optimized batches of Etodolac injection formulation were subjected to various evaluation tests and accelerated stability study. Amongst all trial batches, formulation containing 15% sodium benzoate and 25% solvent system S (Blend C) and 10% sodium acetate, 5% sodium citrate and 25% solvent system S (Blend O) were found to be more stable and passed all tests satisfactorily.

Low aqueous solubility is a major problem faced during formulation development of new drug molecules. Lurasidone HCl (LRD) is an antipsychotic agent specially used in the treatments of schizophrenia and is a good example of the problems associated with low aqueous solubility. Lurasidone is practically insoluble in water, has poor bioavailability and slow onset of action and therefore cannot be given in emergency clinical situations like schizophrenia. Hence, purpose of this research was to provide a fast dissolving oral dosage form of Lurasidone. This dosage form can provide quick onset of action by using the concept of mixed hydrotropy. Initially, solubility of LRD was determined individually in nicotinamide, sodium citrate, urea and sodium benzoate at concentration of 10, 20, 30 and 40% w/v solutions using purified water as a solvent. Highest solubility was obtained in 40% sodium benzoate solution. In order to decrease the individual hydrotrope concentration mixed hydrotropic agents were used. Highest solubility was obtained in 15:20:5 ratio of Nicotinamide + sodium benzoate + sodium citrate. This optimized combination was utilized in the preparation of solid dispersions by using distilled water as a solvent. Solid dispersions were evaluated for X-ray diffraction, differential scanning calorimetry and Fourier-transform infrared to show no drug-hydrotropes interaction has occurred. This solid dispersion was compressed to form fast dissolving tablets. Dissolution studies of prepared tablets were done using USP Type II apparatus. The batch L3 tablets show 88% cumulative drug release within 14 min and in vitro dispersion time was 32 min. It was concluded that the concept of mixed hydrotropic solid dispersion is novel, safe and cost-effective technique for enhancing the bioavailability of poorly water-soluble drugs. The miraculous enhancement in solubility and bioavailability of Lurasidone is clear indication of the potential of mixed hydrotropy to be used in future for other poorly water-soluble drugs in which low bioavailability is a major concern.

Flupirtine is an amino pyridine derivative that functions as a centrally acting non-opioid, non-steroidal analgesic. It is a selective neuronal potassium channel opener that also has NMDA receptor antagonist properties. Its muscle relaxant properties make it popular for back pain and other orthopedics uses. In the present investigation, recently developed mixed hydrotropic solid dispersion technology precludes the use of organic solvent and also decreases the individual concentration of hydrotropic agents, simultaneously decreasing their toxic potential. Mixed-hydrotropic solubilisation technique is the experience to increase the solubility of poorly water soluble drugs in the aqueous solution containing blends of hydrotropic agents, which may give synergistic enhancement effect on solubility of poorly water-soluble drugs and to reduce concentrations of each individual hydrotropic agent to minimize their toxic effects due to high concentration of hydrotropic agents. The Flupirtine loaded solid dispersion was prepared by a solvent evaporation technique using sodium benzoate and a niacinamide hydrotropic mixture. The prepared solid dispersions were valuated regarding their solubility, mean particle size, in-vitro drug release. The prepared solid dispersions were found very stable (chemically). The superior dissolution rate due to its reduced particle size may have contributed to the increased oral bioavailability. This study demonstrated that mixed-solvency may be an alternative approach for poorly soluble drugs to improve their solubility and oral bioavailability.
 Keywords: Flupirtine, Solid dispersion, Mixed-hydrotropic solubilisation, Solvent evaporation technique, Sodium benzoate, Niacinamide

Solubility is a crucial characteristic for achieving the appropriate drug concentration in the systemic circulation and demonstrating pharmacological response. Poor water solubility can severely limit drug efficacy, and some medications can even cause negative effects as a result of their poor solubility. Enhancing water solubility can be done through several of methods. Increased water solubility can thus be a beneficial technique for enhancing therapeutic effectiveness and/or reducing side effects. This is true for solutions that are given intravenously, topically, or orally. Increasing the aqueous solubility of drugs that are weakly water soluble can be done in a variety of techniques. Hydrotropy is a solubility enhancement technique that uses hydrotropes such as sodium benzoate, sodium salicylate, sodium citrate, urea, ibuprofen sodium, and niacin amide to improve the solubility of poorly water-soluble drugs. Hydrotropic solubilization was employed in this study to solubilize weakly water-soluble drug like Dexamethasone utilizing hydrotropic agents like sodium benzoate (2M) and sodium salicylate (2M). Dexamethasone has maximum absorbance at 272.05nm, when sodium benzoate is used as a hydrotropic agent. In the 5-25 µg/ml concentration range, this substance follows the beers law. Dexamethasone shows maximum absorbance at 317.10nm, when sodium salicylate is used as a hydrotropic agent. In the concentrations ranging from 5 to 25µg/ml, this substance follows the beers law. The findings of studies have been statistically confirmed, as well as by re-examination studies. According to the ICH guidelines, validation parameters such as linearity, range, and assay were investigated.

SummaryAccurate prediction of the solubility of chemical substances in solvents remains a challenge. The sparsity of high-quality solubility data is recognized as the biggest hurdle in the development of robust data-driven methods for practical use. Nonetheless, the effects of the quality and quantity of data on aqueous solubility predictions have not yet been scrutinized. In this study, the roles of the size and the quality of data sets on the performances of the solubility prediction models are unraveled, and the concepts of actual and observed performances are introduced. In an effort to curtail the gap between actual and observed performances, a quality-oriented data selection method, which evaluates the quality of data and extracts the most accurate part of it through statistical validation, is designed. Applying this method on the largest publicly available solubility database and using a consensus machine learning approach, a top-performing solubility prediction model is achieved.

Dexibuprofen, is a practically water-insoluble nonsterodial anti-inflammatory drug which has a better anti-inflammatory effect than ibuprofen. A mixed hydrotropic solubilization technique was applied in order to improve the aqueous solubility and dissolution rate of dexibuprofen. Nine formulae were prepared using different concentrations of hydrotropic agents (sodium citrate dihydrate and urea). The prepared formulae were inspected visually for color and odor. Hygroscopicity, micromeretic properties, solubility, and pH for 1% aqueous solutions were determined. In-vitro dissolution studies of the different prepared formulae were performed adopting the USP XXII dissolution method type I basket apparatus method. The prepared formulae were characterized by infrared (IR) spectroscopy and differential scanning calorimetry (DSC). The prepared formulae were a white color, odorless, slightly hygroscopic and exhibited good flow properties. Formulae containing higher amounts of hydrotropic agents exhibited an increase in the pH, solubility, rate and amount of dexibuprofen released from the dissolution medium. The highest dissolution rate was achieved from the F9 formula at drug:sodium citrate dihydrate:urea ratio (1:3:7.5). IR and DSC thermograph of dexibuprofen, hydrotropic agents and prepared formulae indicated the presence of intermolecular interaction between drug and hydrotropic agents which increased solubility and dissolution rate of drug, also, there is no chemical interaction confirming the stability of the drug with hydrotropic agents.

Aim: The main aim of this present investigation is to apply the hydrotropic solubilization phenomenon for spectroscopic analysis of poorly water-soluble drugs to avoid the use organic solvents which may be costlier, toxic to environment, volatile, and pollutant. Materials and Methods: A simple ultra violet spectroscopic method was used for the content analysis by diluting the drug cefixime with various hydrotropic agents. In this study, 20% solutions of sodium salicylate (SS), sodium citrate (SC), sodium acetate (SA), and sodium benzoate (SB) were used as hydrotropes for the analysis of cefixime. Results and Discussion: The drug cefixime showed the linearity of 0.5-2 μg/mL in SS, 5-30 μg/mL in SC, 5-50 μg/mL in SA, and 0.05-0.30 μg/mL in SB solution. Then the proposed methods were validated with respect to accuracy and precision as per International Conference of Harmonization guidelines Q2 (R1), November 2005 (Validation of Analytical Procedures: Text and Methodology). The drug showed less limit of detection (LOD) and limit of quantification (LOQ) values (LOD = 0.0225471 μg/mL and LOQ 0.0683246 μg/mL) to SB solution and it obeyed the Beer's law at very low concentration range (0.05-0.30 μg/mL) which proved that the drug has high sensitivity with SB solution. Conclusions: Finally, it was concluded that the all proposed methods were simple, cost-effective, safe to environment, rapid, reproducible, and highly sensitive with SB solution.

Furosemide is a high ceiling diuretic that exhibits antihypertensive activity and also used in treatment of edema associated with congestive heart failure, liver cirrhosis, renal disease, including nephrotic syndrome. It is practically insoluble in water. The effect of hydrotropes such as urea, sodium citrate, sodium benzoate, sodium acetate and blends on the solubility of furosemide was investigated. The enhancement in the solubility of furosemide was up to 200.46 fold in 40% sodium benzoate solution, 14.81 fold in 40% urea solution, 11.85 fold in 40% sodium citrate solution and 9.35 fold in 40% sodium acetate solution compared to its solubility in distilled water. The solubility of drug was raised up to 357.87 fold in blend BUC (containing sodium benzoate, urea and sodium citrate in the ratio of 13.3:13.3:13.3) which was about 1.35 times more than the solubility in the blend BU (containing sodium benzoate and urea in the ratio of 20:20). This proved a synergistic enhancement in solubility of a poorly water soluble drug due to mixed hydrotropy. Combination of hydrotropic agents giving synergistic solvent action can minimize the amount of hydrotropic agents employed, minimizing the chances of their individual toxicities. Aqueous injection of furosemide, using the mixed hydrotropic solubilization technique, was developed. The developed formulation was studied for physical and chemical stability. The prepared formulation was unaffected in respect of color stability. There was no color change or precipitate was found in the developed formulation. In the freeze thaw study there was no precipitation and no turbidity in the developed parenteral formulation at the end of the testing. Chemical stability showed that there was no appreciable loss of furosemide in the formulation stored for 30 days at different temperatures. So it can be assumed that the formulation will have sufficient chemical stability at room temperature.

Solubilisation of poorly soluble drugs is encountered as a challenge in screening studies of new chemical entities as well as its formulation development is obstacle. A number of methodologies can be adapted to improve solubility of poor water soluble drug and its bioavailability. Hydrotropes possess the ability to increase the solubility of sparingly soluble and poorly soluble drugs in water. It is a molecular phenomenon, adding a second solute (i.e. hydrotrope) helps to increase the aqueous solubility of poorly soluble drug. The presence of a excess quantity of one solute enhances the solubility of another solute. Various organic solvents are used for the development of analytical methods for poorly water soluble drugs. The major drawback of such solvents is cost, toxicity and environmental hazards. To overcome these issues less costly hydrotropic agents have gain wide application for the development of analytical methods for routine analysis of marketed dosage form and developed dosage forms. The mixed hydrotropy approach suggests the minimum amount of the hydrotropic agents as a blend of two or more agents. Such blends results in lesser quantity as that of single hydrotropic agents. Similarly the hydrotropic agents are now days widely used to develop dosage forms as solid dispersion, mouth dissolving tablets, injections to improve therapeutic effectiveness and bioavailability for poorly water soluble drugs.