Poorly soluble drugs in aqueous drug-delivery systems are prone to insufficient drug-loading concentrations, crystallization during storage, and precipitation after dilution with physiological fluids. Solubilizers, hydrotropes, and cosolvents can increase drug solubility through micellar incorporation, weak molecular association, and regulation of mixed-solvent polarity, respectively.

Keywords: solubilizers; hydrotropes; cosolvents; poorly soluble drugs; surfactants; micellar solubilization; hydrotropy; mixed solvents; dilution-induced precipitation; drug-delivery formulations

1 Basic Concepts of Solubilizers, Hydrotropes, and Cosolvents

1.1 Delivery Limitations of Poorly Soluble Drugs

The dissolution state of a drug in the administration medium directly affects dose uniformity, release behavior, bioavailability, and local tolerability. Increasing temperature, extending stirring, or applying ultrasonication can only accelerate the dissolution process and generally cannot produce a sustained increase in equilibrium solubility. The drug may still precipitate again after cooling, storage, or contact with physiological fluids. Therefore, formulation design should select a solubilization strategy according to the drug’s pKa, logP or logD, polymorphic form, salt form, melting point, lattice energy, and target administration concentration.

1.2 Solubilizers

Solubilizers mainly refer to surfactants capable of forming micelles or other aggregated structures in water. After the surfactant concentration reaches the critical micelle concentration, the hydrophobic segments form nonpolar regions, and poorly soluble drugs can be incorporated, adsorbed, or partitioned into the micellar core or core-shell interface, thereby increasing the apparent solubility of the system. Common solubilizers include polysorbates, polyoxyethylene fatty acid esters, polyoxyethylene castor-oil derivatives, poloxamers, bile salts, and phospholipids.

1.3 Hydrotropes

A hydrotrope is a third substance that, when added to an aqueous solution of a poorly soluble drug, increases drug solubility through weak molecular association, hydrogen bonding, aromatic-ring stacking, ionic interactions, or regulation of the hydration environment. Hydrotropes are generally highly water-soluble low-molecular-weight compounds, and the associated structures formed with drugs usually do not have fixed stoichiometric ratios. Common types include Nicotinamide, Urea, organic acids and their salts, and certain polar amide compounds.

1.4 Cosolvents

Cosolvents are water-miscible organic solvents that alter the polarity, dielectric properties, and drug-solvation environment of a mixed-solvent system. Ethanol, 1,2-Propanediol, Glycerol, and low-molecular-weight polyethylene glycols can reduce the unfavorable solvation of hydrophobic drugs in water and thereby increase drug solubility.

1.5 Functional Overlap Among the Three Material Categories

The three material categories are classified according to their predominant mechanisms, but functional overlap may occur in actual formulations. For example, Polyethylene Glycol 400 and 1-Methyl-2-Pyrrolidinone are classified as hydrotropes in some engineering systems, although their primary effects are generally associated with alteration of the solvent environment. Organic acid salts may produce hydrotropic effects while also increasing solubility through pH adjustment and enhanced drug ionization. Therefore, formulation classification cannot replace direct validation of the specific dissolution mechanism and dilution behavior.

2 Mechanisms of Action and Formulation Characteristics of Solubilizers

2.1 Micelle Formation

Surfactants contain hydrophilic and hydrophobic groups. At low concentrations, they mainly exist as monomers, whereas micelles or other aggregates form after the critical micelle concentration is reached. Further increases in surfactant concentration generally increase the number of aggregates and the drug-solubilizing capacity, but excessively high concentrations may also increase viscosity, foaming, membrane perturbation, and tolerability risks.

2.2 Drug Distribution Within Micelles

Highly hydrophobic drugs generally enter the hydrophobic micellar core. Drugs containing both aromatic rings and polar groups may be distributed at the core-shell interface, whereas more polar drugs may be located near the hydrated-chain layer. The location of the drug within the micelle affects loading capacity, the free-drug fraction, release rate, and precipitation tendency after dilution.

2.3 Effects of Surfactant Structure

Hydrophobic-chain length, the number of hydrophilic chains, hydrophilic-lipophilic balance, hydration of polyoxyethylene chains, and aggregate size can all affect solubilizing capacity. Polysorbates generally form nonionic micelles, polyoxyethylene castor-oil derivatives provide relatively large hydrophobic aggregation regions, and poloxamers consist of polyoxyethylene and polyoxypropylene blocks whose micellization behavior is sensitive to temperature and concentration.

2.4 Effects of Coexisting Components

Buffer salts, electrolytes, sugars, proteins, cosolvents, and other surfactants may alter the critical micelle concentration, micelle size, and drug partitioning. Solubilizers should not be evaluated only in purified water but under conditions approximating the final formulation composition, pH, and ionic strength.

2.5 Total Drug and Free Drug

Micellar solubilization increases the total drug concentration in the system, whereas the drug capable of diffusing across biological membranes, binding to targets, or distributing into tissues is generally the free drug. When the interaction between the surfactant and drug is excessively strong, total solubility may increase while the free-drug fraction and membrane permeability decrease.

2.6 Micelle Dissociation After Dilution

After administration, surfactants are diluted by gastrointestinal fluids, blood, or tissue fluids. When the concentration approaches or falls below the critical micelle concentration, the number of micelles decreases, and the drug is released from the micelles into a supersaturated state. If nucleation and crystal-growth rates are sufficiently high, the drug may precipitate in the administration medium.

2.7 Major Limitations of Solubilizers

Surfactants may cause foaming, turbidity, adsorption to filters, extraction of packaging materials, and oxidative degradation of drugs. Injectable administration also requires evaluation of hemolysis, vascular irritation, complement activation, and hypersensitivity reactions. Oral administration requires attention to gastrointestinal irritation, intestinal-barrier alterations, and effects on drug transporters.

3 Mechanisms of Action and Formulation Characteristics of Hydrotropes

3.1 Weak Drug-Hydrotrope Association

Hydrotropes can form weak, water-soluble associations with drugs through hydrogen bonding, dipole interactions, aromatic-ring stacking, and hydrophobic interactions. Because this process generally does not form stable complexes with fixed stoichiometry, hydrotropic effects may exhibit threshold behavior or nonlinear changes with increasing hydrotrope concentration.

3.2 Regulation of the Hydration Environment

Hydrophilic small molecules such as Nicotinamide and Urea can alter the water structure, hydrogen-bond network, and hydrophobic hydration surrounding a drug, thereby reducing the free energy required for the drug to enter the aqueous phase. Hydrotropic solubilization usually requires relatively high hydrotrope concentrations, so osmolality, local irritation, and drug chemical stability should be evaluated simultaneously.

3.3 Nicotinamide Hydrotropic Systems

Nicotinamide can increase the solubility of certain aromatic drugs through pyridine-ring interactions, hydrogen bonding, and changes in the hydration environment. Its hydrotropic effect depends on drug structure, Nicotinamide concentration, temperature, and pH. The high aqueous solubility of Nicotinamide itself cannot be used to infer that it will produce the same effect for all drugs.

3.4 Urea Hydrotropic Systems

Urea can regulate the hydrogen-bond network and hydrophobic hydration of the aqueous phase and produce hydrotropic effects for certain poorly soluble drugs. High Urea concentrations may affect protein conformation, system osmolality, and packaging compatibility, making Urea more suitable for mechanistic research and specific formulation screening.

3.5 Organic Acid Salt Hydrotropic Systems

Citrate, Benzoate, Salicylate, and related salts may increase the apparent solubility of certain drugs through ionic interactions, weak association, and changes in the hydration environment. However, organic acid salts commonly affect pH and ionic strength simultaneously, so equal-pH and equal-ionic-strength controls should be included.

3.6 Polar Amide Materials

1-Methyl-2-Pyrrolidinone and N,N-Dimethylacetamide have strong polarity and hydrogen-bond-accepting capacity and can increase the solubility of various hydrophobic drugs. Their effects generally include substantial cosolvent contributions, and the final concentration must be determined according to the administration route, dose, administration rate, and tolerability.

3.7 Major Limitations of Hydrotropes

Hydrotropes generally require relatively high concentrations to produce substantial effects and may increase osmolality, local irritation, and systemic excipient exposure. After hydrotropes are diluted by physiological fluids, weakening of drug-hydrotrope associations may also cause drug precipitation.

4 Mechanisms of Action and Formulation Characteristics of Cosolvents

4.1 Regulation of Mixed-Solvent Polarity

Water has strong solvation capacity for ionic and highly polar molecules but limited solvation capacity for hydrophobic drugs. Addition of a water-miscible organic solvent alters the dielectric constant, cohesive energy, and hydrogen-bonding environment of the system, thereby strengthening interactions between the drug and solvent.

4.2 Ethanol Systems

Ethanol can substantially reduce the polarity of mixed solvents and has low viscosity and convenient handling characteristics. It is commonly combined with water, Propylene Glycol, or Polyethylene Glycol. Excessively high Ethanol proportions may cause evaporative loss, local irritation, permeation through packaging, and administration-tolerability problems.

4.3 1,2-Propanediol Systems

1,2-Propanediol is miscible with water and Ethanol and has lower volatility than Ethanol. It can improve drug solubility while maintaining relatively favorable formulation fluidity. Increasing its proportion may increase osmolality and local irritation. Injectable use also requires consideration of the administered dose and clearance capacity.

4.4 Glycerol Systems

The cosolvent capacity of Glycerol is generally weaker than that of Ethanol and Propylene Glycol, but it can simultaneously regulate viscosity, humectancy, and palatability. High proportions of Glycerol may affect injectability, drug diffusion, and gastrointestinal tolerability and are more suitable as auxiliary components in combined cosolvent systems.

4.5 Low-Molecular-Weight Polyethylene Glycol Systems

Polyethylene Glycol 200, Polyethylene Glycol 300, and Polyethylene Glycol 400 are all miscible with water, and their viscosity and solvation capacity vary with average molecular weight. Low-molecular-weight polyethylene glycols can be combined with Ethanol, Propylene Glycol, or surfactants to reduce the proportion of any single excipient and expand the formulation window.

4.6 Dilution-Induced Precipitation

After administration of a cosolvent system, the solvent proportion rapidly decreases because of dilution with physiological fluids, and the drug may transition from a dissolved state to a supersaturated state and crystallize. The precipitation rate is affected by the dilution factor, mixing rate, drug polymorph, nucleation time, and temperature.

4.7 Volatility and Packaging Compatibility

Volatile cosolvents such as Ethanol may undergo concentration changes during preparation, filling, and storage, altering the dissolution state of the drug. Cosolvents may also cause swelling of plastics, rubber stoppers, or coatings and increase the risk of extractables and leachables.

5 Comparison of Solubilization, Hydrotropic, and Cosolvent Strategies

6 Empirical Concentration Ranges in Animal-Dosing Formulations

6.1 Surface-Active Solubilizers

6.2 Polar Hydrotropes and Cosolvents

The concentrations listed above are mainly used for prescreening single-dose formulations in mice or rats. The mass- or volume-based definition of each percentage should be specified in the individual protocol, and these values should not be directly regarded as clinical-use concentrations or universal safety limits.

7 Products

7.1 Surface-Active Solubilizer Products

7.2 Hydrotrope and Polar Solubilizing Material Products

7.3 Cosolvent Products

Solubilized formulations should be based on the minimum effective excipient proportion required to achieve the target drug concentration, and their suitability should be confirmed through physiological-fluid dilution, crystallization, stability, and administration-tolerability testing.

References

[1] Li P, et al. Developing early formulations: practice and perspective. Int J Pharm. 2007;341(1-2):1-19.

[2] Koikawa K, Kibe S, Suizu F, et al. Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy. Cell. 2021 Sep 2;184(18):4753-4771.e27.

[3] Cao B, Zhao RY, Li HH, Xu XM, Cui H, Deng H, Chen L, Wei B. Oral administration of asparagine and 3-indolepropionic acid prolongs survival time of rats with traumatic colon injury. Mil Med Res. 2022 Jul 6;9(1):37.

For more related articles, please see below:

[1] Polyethylene Glycol (PEG): Properties, Applications Across Multiple Fields, and Product Selection Guide