Technical Review Article | Open Access | Published 29th September 2026
Hydrotropic Solublization Technique: a Potential Approach to Improve Solubility of Poorly Soluble Drugs
Patel Sonali, Gupta Ashish*, Darwhekar Gajanan - Acropolis Institute of Pharmaceutical Education & Research, India | EJPPS | 313 (2026)| https://doi.org/10.37521/ejpps31313
Abstract
Hydrotropic solubilization is a method for improving the solubility of poorly soluble drugs by adding a hydrotrope, which enhances their aqueous solubility. Effective hydrotropes include sodium citrate, sodium benzoate, and urea. This technique is advantageous due to its cost-effectiveness, eco-friendliness, and lack of need for chemical modifications or organic solvents. Hydrotropes are employed in various dosage forms to enhance the therapeutic efficacy and bioavailability of drugs. The review explores hypotheses related to hydrotropic mechanisms, although many are unproven, and examines factors influencing solubilization. Hydrotropes also serve as extraction agents, separation agents in pharmaceutical analysis, and improve chemical reaction rates. The article discusses mixed hydrotropy's role in solubility enhancement and outlines future applications of hydrotropes in innovative drug delivery systems.
Keywords: Hydrotropic solubilization, Poorly soluble drugs, Drug delivery, Mixed Hydrotropy, Solubilizing agent, Mechanisms of hydrotropes, Application of Hydrotropes, Solubility, Bioavailability enhancement.
Introduction
Hydrotropes, or hydrotropic agents, are substances that enhance the solubility of poorly soluble solutes in solvents.1 The process of solubilization involves complex molecular interactions influenced by salting-in and salting-out techniques. The salts participating in salting-in are known as hydrotropic salts, which enhance solubility through weak interactions without exhibiting colloidal properties.2 Hydrotropes behave similarly to surfactants, improving the aqueous solubility of sparingly soluble solutes at room temperature, and have potential for industrial applications. Research primarily focuses on interactions between hydrotropes and solutes, indicating that solubilization results from complexation.3 Common hydrotropic agents include tetra alkyl ammonium halides, urea, and sodium thiocyanate.4 Hydrotropes can either increase or decrease solute solubility and have been shown to effectively enhance the solubility of drugs with poor aqueous profiles.5 They may serve as additives due to their surfactant-like properties in various phases and have a unique capacity to form aggregated structures through non-covalent bonding.6 Hydrotropes are amphiphilic, consisting of a polar and a smaller non polar part, distinguishing them from typical surfactants.7 The strategy of mixed hydrotropy has emerged due to the cost- effectiveness, non-toxicity, and eco-friendliness of combining various hydrotropic agents, which leads to significant solubility enhancement.8 This review emphasizes the mechanisms by which hydrotropes aid drug solubility, their characteristics, and their relevance in the pharmaceutical industry, alongside discussing their advantages and disadvantages. The solubilization of poorly soluble pharmaceuticals poses significant challenges in drug development, as evidenced by the Indian and US Pharmacopoeias which catalogue many drugs with low water solubility. This issue can lead to inadequate bioavailability, making solubility a critical physicochemical property in drug formulation.9 Traditional organic solvents such as methanol and chloroform are often employed for solubilization but face limitations due to cost, volatility, and toxicity.10 In contrast, hydrotropic agents, identified since Neuberg's work in 1916, provide a safer, environmentally friendly, and cost-effective alternative.11 These agents, which include sodium benzoate and sodium salicylate, enhance the aqueous solubility of solutes when added in large quantities.12 Hydrotropic agents are mainly anionic organic salts characterized by an anionic group and a hydrotropic aromatic ring, contributing to their effectiveness in increasing solubility.13
Solubility
There are two ways to characterize solubility: quantitatively and qualitatively. It can be quantified as the solute's concentration in a saturated solution at a particular temperature. Qualitatively, it describes a substance's propensity to disintegrate on its own. The process by which two or more elements come together to form a homogenous molecular combination is known as solubility. When the solute and solvent are in balance, the solution is said to be saturated. When quantitative data is available, solubility can be stated in a variety of ways in pharmaceutical sciences. Parts, molarity, normalcy, formality, mole fraction, percent solution, volume fraction, and molality are some of the often-used units to describe solubility. The highest concentration of medication solute that may dissolve in a particular solvent under particular circumstances, such as temperature, pH, and pressure, is referred to as drug solubility. A drug's solubility in a saturated solution is thought to be a static characteristic, whereas the drug's rate of dissolution is thought to be a dynamic characteristic that is more strongly associated with the rate of bioavailability.14
Need of Solubility
The most significant of these issues is the drug molecule's insufficient water solubility and membrane permeability, which can impede the absorption of medications from the gastrointestinal (GI) tract.15 An active medication must dissolve in gastric and/or intestinal fluids before penetrating the gastrointestinal walls and entering the bloodstream in order to be administered orally. Therefore, increasing the oral bioavailability of active drugs by increasing their solubility and rate of dissolution is a top priority in two distinct fields of pharmaceutical research. A scientific framework called the Biopharmaceutics Classification System (BCS) is used to classify medicinal compounds according to their intestinal permeability and water solubility. Rather than the absorption process, the release of the drug from the dosage form and its solubility in stomach fluid are the rate-limiting steps for BCS class II and IV medications. Therefore, improving these medications' solubility may result in an increase in their bioavailability.16
Table 1: BCS Classification of Drug.
Class | Solubility | Permeability | Characteristics |
I | High | High | High absorption: absorption is not limited by solubility or permeability (e.g., paracetamol, amantadine). |
II | Low | High | Absorption is limited by the dissolution rate. |
III | High | Low | Absorption is limited by membrane permeability. (e.g., atenolol and metformin). |
IV | Low | Low | Poor oral bioavailability: absorption is limited by both solubility and permeability (e.g., furosemide). |
Hydrotropic Solubilization
The pharmaceutical industry faces difficulty in finding ways to make pharmaceuticals more water-soluble because over 70% of newly identified medication candidates have low water solubility. A drug's bioavailability, which is mostly influenced by the drug moiety's solubility, determines its therapeutic efficacy. Oral bioavailability can currently be increased by a variety of formulation strategies that improve solubility and dissolution.17 Hydrotropy is a well-known method for resolving solubility-related problems in addition to these developments. To help researchers explore hydrotropy for the creation of medicine delivery, this study will build a number of hypothetical systems, analyze them, and identify the geometric properties of hydrotropic chemicals. Most corticosteroid medications fall within class II (BCS) of the biopharmaceutics classification system. These medications have limited oral bioavailability due to their low solubility in bodily fluids.18
Hydrotropy
In the hydrotropy solubilization procedure, a third solute's water solubility is increased by adding a sizable quantity of a second solute. Solubilization is the term for this process. To improve solubility, hydrotropic compounds including sodium alginate, sodium acetate, sodium benzoate, and urea interact weakly with poorly soluble medications through a process called complexation. Complexification and this process are more closely related. It is brought on by the abundance of salts with large anions or cations that are very soluble in water. "Salting in" is the term for this phenomenon. Because hydrotropic solutions are non-colloidal and have a weak bond between the hydrotropic agent and the solute, they are not regarded as colloids.19
Mechanism of Action of Hydrotrope
The mode of action of hydrotropes is still up for debate and far from definitive. Numerous researchers have offered their own theories regarding the potential mechanism of hydrotrope. The following three theories have been proposed to explain hydrotropic activity:
(a) Solute- hydrotrope complex forming,
(b) Water molecules' tetrahedral complex disintegrating or shattering, and
(c) Hydrotropes self-associating.20
However, they haven't provided evidence to support the hydrotropes' mechanism. To comprehend the mechanism of hydrotropes, different researchers proposed a number of theories, some of which are described below:
Hydrotrope Self-aggregate Formation:
According to this theory, the hydrotropes' molecules self-aggregate, creating structured clusters in the hydrophilic fluid. Additionally, it was proposed that solute hydrophilicity is increased when solute molecules become stuck in these ordered clusters. The Minimum Hydrotropic Concentration (MHC) is the critical concentration at which hydrotropes start to assemble. It was assumed that the hydrotropes' molecular structure contains planar aromatic rings that stack on top of one another to facilitate aggregation.21 Similar to the micellization process, aggregation occurs concurrently in the aqueous solvent when hydrophobic chemical solubilization begins. Hydrotropes' self-aggregation has been seen as a prerequisite for a number of uses in diverse fields, including medication solubilization. Enthalpy, entropy, and free energy all alter as hydrotropes aggregate.22
Alteration of the Water Structure:
According to Frank and Evans' theory, hydrotropes damage the structure of water, preventing the development of icebergs, rather than directly binding with weakly or sparingly soluble solutes.23
Solute-hydrotrope Complex Formation:
Higher aqueous solubility is the outcome of weak complexation between the hydrotrope and the non-polar molecule, which causes solubilization. According to these complexation hypotheses, hydrotropy originates from low stoichiometry complexes like1:1or 1:2.24
Hydrotrope Build Up Surrounding the Medication:
Through various experimental investigations using additives, several compounds have been used to ascertain the mechanism of hydrotrope. These investigations have shown a strong interaction between the solute and the additive, resulting in the formation of micelles that act as a bridge and concentrate around hydrophobic solutes without interaction.25 Other mechanisms include:
a) Compound formation between hydrotropes and the dissolved solute,
b) Molecule complex formation at low hydrotrope concentration,
c) Hydrotrope molecular aggregation caused by donor-acceptor type electrostatic forces between hydrotropes and solute molecules, and
d) Stake-type aggregation.26
Importance of Hydrotropy
Due to its affordability, ease of handling, non-toxicity, and environmental friendliness, hydrotrope solutions might be considered green solvents. Avoiding the use of organic solvents is one step closer to increasing the solubility in hydrotropes; aqueous solutions of hydrotropes showed the special qualities of an alternative reaction medium for organic synthesis because organic solvents were commonly used, which may be sources of pollution, some of which may be toxic, and more expensive. However, inaccuracies might also result from volatility.27
Advantages of Hydrotropy and Mixed Hydrotropy:
Compared to another organic solvent, this one is less dangerous.
Because it just involves combining the drug material and particular hydrotropes with the solvent, using hydrotropes for solubilization is a simple and affordable technique. In a wide range of commercial and pharmaceutical applications, this can offer solutions to solubility issues.
Hydrotropes are frequently used into today's more complex formulae.
The hydrotropic technique's ability to maintain the drug's active ingredients' chemical activity is one of its key advantages.
Hydrotropes are a cheap, environmentally friendly solvent with a wide range of formulation, compatibility, and efficacy.
Hydrotropy is recommended as a safe, inexpensive, straight forward, accurate, and exact procedure due to its great selectivity over alternative solubilization techniques.
The use of an organic solvent to avoid issues is prohibited by mixed hydrotropy.
One of the best methods for optimum criteria is mixed hydrotropy.
Hydrotropy has a part in extraction and separation in science.
Hydrotropes have some advantageous characteristics, such as excellent selectivity, pH- independent solvent character, and lack of emulsification.
Simple dilution makes it easy to recover the solute from hydrotrope solutions.
A combination of agents can reduce the individual concentration that should be effective and less hazardous, which is one of the primary advantages of mixed hydrotropy.
Mixed hydrotropy has a synergistic effect on the solubility of medications that are poorly soluble in water. 28-29
Disadvantages of Hydrotropy and Mixed Hydrotropy:
The hydrotropic agent and medications may interact weakly. Water cannot be completely removed since it is utilized as a solvent.
The toxicity of several hydrotropic agents limits their use.28-29
These are the limits of hydrotropic agents:
Sodium benzoate: Parenterally delivered drugs may contain up to 0.5%benzoicacid, as may oral medications.30
Nicotinamide (NAD): Research found that taking up to 900 mg of nicotinamide mononucleotide orally, which increases blood NAD concentrations, is safe and well- tolerated. According to blood NAD concentration and physical performance, the therapeutic efficacy seems to peak at a daily oral intake of 600 mg.31
Potassium citrate: The treatment aims to elevate the urine pH to between 6.0 and 7.0and return urine citrate levels to normal (above 320 mg/day and as close to the average normal value of 640 mg/day). A daily dose of 100 mEq of Urocit®-K is advised, as greater doses have not been investigated.32
Sodium citrate: Commonly used in the medical field to stop kidney stones from forming. Adults should usually take 10–30 mL, diluted in up to 6 oz of water or juice, orally after meals and at bedtime as needed.33
Sodium acetate: USP Sodium Acetate Injection (2 mEq/mL) is utilized. It is a concentrated solution of sodium acetate in water that is sterile and non-pyrogenic for injection. For safety reasons, the solution is given after being diluted.34
Caffeine: Most healthy persons can safely consume up to 400 milligrams (mg) of caffeine per day.35
Urea: The normal range of urea concentrations in human blood is 6 to 20 mg/Dl (2.1 to 7.1 mmol/L). Urea is the major end product of protein metabolism and is primarily excreted by the kidney in the urine over the course of a 24-hour period. Urea creatinine normally ranges from 0.59 mg/dl to 1.35 mg/dl.36
Approach
By the application of several solubilization techniques, including molecular, thermodynamic, and solid dispersion methods that improve solubility. In pharmacognosy, for example, hydrotropes are used as a solvent for drug extraction. In the analytical field, mixed hydrotropes aid in identification, spectrometric analysis, HPLC, and many other instrumental approaches, and in pharmaceutical science, hydrotropes are used in formulation and estimation processes.37 The majority of hydrotropes and mixed hydrotropes are useful in chemistry for a variety of applications related to thermodynamics, mass coefficient, temperature studies, concentration phenomena, green solvents, pH-dependent research, micelle production, etc. However, in the pharmaceutical industry, hydrotropes are used for "green synthesis" in the formulation of dosage forms and various approaches in the formulations of dosage forms (e.g., parenteral, oral, transdermal, nasal, etc.). This is completely different from the industrial scenario of hydrotropes, which were used in the formulation of cleaning and personal care products.38
Pharmaceutical application:
Hydrotropes have been utilized in pharmaceutical research to both prepare and stabilize medication formulations. Hydrotropes are used in the production of oral, topical, parenteral, and innovative drug delivery systems. They are mostly used for medications with problems with solubility.39
Analytical application:
This method is used in analytical chemistry to improve the sample's aqueous solubility and avoid or prevent the usage of organic solvents. Hydrotropes have been employed in a number of techniques, including:
Thin-layer chromatography,
Spectrophotometric analysis, and
Titrimetricanalysis.40
Chemistry application:
Hydrotropes are used in the extraction process, solubility increase, compound separation, etc. Additionally, hydrotrope is used for green synthesis due to its eco-friendliness. For instance, hydrotropes are utilized to determine the activity in microemulsions and the initial principles of statistical thermodynamics of hydrotropes are determined by the Gibbs phase rule.41
Pharmacognosy application:
Hydrotropes-assisted extraction increases the percentage yield of the active ingredients in a variety of extraction processes used in pharmacognosy. For example, adding a hydrotropic agent to the solvent raised the yield of reserpine, which is extracted from the roots of Rauwolfia vomitoria, to that of conventional extraction. Reserpine was extracted at the same concentration using three distinct hydrotropes: Na-CS, Na-PTS, and NBBS. There were two methods used: a traditional method and a modified method.42
Computational application:
Using computer stimulations, software is used to estimate the mechanism by which hydrotropes increase solubility. The results are most likely predicted based on the traditional molecular dynamic stimulation technique.43
Artificial Neuronal application:
Artificial Neural Networks (ANNs), which are computational models created by applying machine learning, are quite essential in the pharmaceutical sciences for determining and predicting the quantitative evaluation of different hydrotrope physicochemical features. In order to determine the role of hydrotropes in improving the solubility of weakly water-soluble drugs, a computational model and artificial neural network (ANN) are used for the application of hydrotrope-enhanced properties.44
Current and future prospects
Current Prospects of Hydrotropic Solubilization
By increasing drug solubility in aqueous formulations, hydrotropic solubilization may improve the effectiveness of drug administration. The greater solubility often leads to better drug distribution and absorption inside the body, increasing its therapeutic efficacy. Oral solutions, suspensions, and injectable formulations are only a few of the pharmaceutical dosage forms in which hydrotropic drugs can be used.45 This approach's versatility allows pharmaceutical companies to develop drugs that better suit patients' unique needs and preferences. Improving drug solubility using hydrotropic solubilization may speed up the drug development process, saving money and time. By using pre-existing APIs (active pharmaceutical ingredients) in more soluble forms, researchers may be able to avoid the need to create completely new pharmacological compounds, which is an expensive and time-consuming process. Hydrotropes that are biodegradable and biocompatible are commonly used in hydrotropic solubilization, making them a more environmentally friendly option than other solubilizing techniques that depend on dangerous solvents.46
Future Prospects of Hydrotropic Solubilization
Researchers may find new and better hydrotropic agents if they get a deeper comprehension of the basic mechanisms and interactions involved in hydrotropic solubilization. This may lead to additional improvements in medication delivery and solubility. To create innovative and focused drug delivery systems, combination therapies combine hydrotropic solubilization with other drug delivery techniques such as liposomes or nanoparticles.47 Combining these two approaches could revolutionize pharmacological therapy and open up new therapeutic avenues. Pharmaceutical companies are likely to include hydrotropic solubilization into their drug development pipelines as more research and positive results accumulate. A higher number of pharmaceuticals with improved solubility and bioavailability could be produced as a result of the improvement of medication commercialization brought about by higher acceptance rates. The approval and assessment of hydrotropic formulations' efficacy and safety by regulatory bodies is a prerequisite for the continued viability of hydrotropic solubilization. The pharmaceutical industry may use these formulations more frequently if these organizations provide clear rules and all-encompassing support.48
Conclusion
This review provides an extensive examination of hydrotropes and their mechanisms in enhancing the solubility of compounds with poor aqueous solubility. It outlines the numerous advantages and disadvantages associated with hydrotropic techniques, illustrating their potential as a replacement for traditional methods in pharmaceuticals. Hydrotropes not only facilitate the development of dosages for poorly soluble drugs but also improve the extraction of phyto constituents with pharmacological activities. The advantages of hydrotropes include their role as green solvents that generate less pollution, are environmentally friendly, and are generally more economical than organic solvents. The paper highlights applications in pharmacognosy, where hydrotropes can replace organic solvents, thereby increasing the yield during the isolation, separation, and characterization of compounds. In pharmaceutics, these agents enhance the aqueous solubility and bioavailability of both synthetic and isolated compounds. The review discusses proposed mechanisms by which hydrotropic agents interact with poorly water-soluble drugs, ultimately enhancing their solubility and bioavailability. Furthermore, the ability of hydrotropic agents to enhance the solubility of medicinal substances allows for the development of various dosage forms, including oral solutions, suspensions, and injectables, thus increasing the adaptability of drugs for specific patient needs. The method is not only cost-effective and time-efficient but also circumvents the arduous task of developing new pharmaceutical compounds, thereby reducing costs and accelerating drug development timelines. The hydrotropic agents exhibit biodegradability and biocompatibility, making them a promising, ecologically sound alternative to harmful solvent- dependent methods. They are also suggested for use in combination therapies that integrate hydrotropic solubilization with other drug delivery systems, such as nanoparticles or liposomes, potentially recalibrating pharmacological therapy and offering innovative therapeutic solutions. Despite the promising aspects of hydrotropic solubilization, it is considered a relatively new field that requires further research to fully understand the mechanisms and interactions involved. Additionally, the widespread application of hydrotropic methods in pharmaceuticals is contingent upon regulatory approvals from health authorities, which could shape future developments in this area.
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Authors
Patel Sonali, Gupta Ashish*, Darwhekar Gajanan
Corresponding Author: Gupta Ashish
Acropolis Institute of Pharmaceutical Education & Research,
Indore MP India 453771
Email: ashishgupta@acropolis.edu.in
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