A Review on Solubility Enhancement of Poorly Soluble Drugs by Using Hydrotrophic Agents

Harshada Padwal, Snehal Kashid, Purva Katore, Madhavi Tirkhunde, Rutuja Thorat, Dr. Vrushali Tambe,

doi:10.5281/zenodo.15099654

Review Paper | Open Access
Volume 03 | Issue 03 | Article Id IJPS/250303242

A Review on Solubility Enhancement of Poorly Soluble Drugs by Using Hydrotrophic Agents
Harshada Padwal* Snehal Kashid Purva Katore Madhavi Tirkhunde Rutuja Thorat Dr. Vrushali Tambe
PES Modern College of Pharmacy (For Ladies), Moshi, Pune.

Abstract

Solubility enhancement of poorly water-soluble drugs remain a significant challenge in pharmaceutical formulation development. Drug solubility is a quite common issue and affects the bioavailability of a drug in the body. Various methods can accommodate to improve solubility of poorly soluble drugs. Hydrotropy is one of the unique technique which can be used to enhance the solubility of poorly water-soluble drugs with many folds by using hydrotropes like sodium citrate, urea, sodium benzoate, etc. Hydrotropes typically contain both a hydrophilic and a hydrophobic component which help to form micelle like structure. Hydrotropic solubilization has emerged as a valuable technique in pharmaceutical formulations, offering a promising solution to enhance the solubility of poorly soluble drugs. This method leverages the ability of hydrotropic agents to disrupt intermolecular interactions between drug molecules, thereby increasing their aqueous solubility. This technique has several advantages like doesn’t require chemical modification of hydrophobic drugs, addition of emulsifying agent, use of minimum organic solvent. This review, mainly focus on hydrotropy, mechanism of hydrotropy and its applications in pharmaceutical formulation.

Keywords

Solubility enhancement, Hydrotropy, Hydrotropic agents, Bioavailability.

Introduction

The preparation of a poorly water-soluble drugs is facing a challenging issue by pharmaceutical industry, and it is expected to increase because around 40% or more of the new chemical substances being generated by drug discovery programs are poorly water-soluble drugs. (1) Orally dispense drugs totally absorb only when they show equitable solubility in gastric environment and such drugs show good bioavailability but other unequitable drugs or API needs to be soluble properly to show good bioavailability. A number of techniques are used to improve solubility of such poorly water-soluble drug and also improve its bioavailability. (2)

Solubility:

Solubility is a property of substances in a particular solvent. In quantitative terms it is concentration of dissolved solute in a saturated solution at a specific temperature. It is measured as maximum amount of solute dissolved in an appropriate solvent equilibrium. (3) Solubility is an important parameter to attain desired concentration of the drug to show specified pharmacological response.(4) The solubility of drug can be expressed as percentage, parts, molality, molarity, mole fraction and volume fraction. (5) The solubility of the drug in water is a fundamental attribute that must be scrutinized. The pharmacokinetic outline is dominant, especially for drugs with low solubility. Most of the BCS class II drugs has poor aqueous solubility and also high permeability. Biopharmaceutical Classification system was invented by the United state Food and Drug Administration. It helps to distinguish drug into four classes according to permeability and solubility. Solubility obstacles are mostly look forward in the Class II and Class IV of the Biopharmaceutical classification system facing dissolution as the rate limiting factor for absorption of drug due to low solubility. (3)

The descriptive solubility terms are noted in Table 1.

Table 1: Expression for approximate solubility (3)

Descriptive terms	Relative amounts of solvents to dissolve 1 parts of solute
Very soluble	<1
Freely soluble	From 1 -10
Soluble	From 10 -30
Sparingly soluble	From 30 -100
Slightly soluble	From 100 -1000
Very slightly soluble	From 1000 -10000
Insoluble or practically insoluble	>10000

There are different techniques introduced for enhancing solubility of the poorly water-soluble drugs such as hydrotropy, solid dispersion, PH modification, co-solvency, co-crystallization, Cyclodextrin complexation, Dendrimers, Nano- suspensions, Self emulsifying drug delivery system.

Hydrotrope:

Carl Neuburg was the first scientist to describe the term hydrotropic agents in 1916. It explains the rise in the solubility of the solute by adding equitably high concentration of salts of alkali metals of different organic acids. Hydrotrope is a mixture which has fundamental formation of a hydrophilic part and hydrophobic part. (6) In comparison to surfactants, they contain too small hydrophobic fraction. The competence of Hydrotrope solubilization technique relay upon the equilibrium between hydrophobic and hydrophilic part of Hydrotrope. Hydrotrope is a chemical that dissolves hydrophobic substances in aqueous solutions. Hydrotropes typically contain both a hydrophilic and a hydrophobic component (surfactants), but the hydrophobic component is usually too tiny to induce spontaneous self-aggregation. Hydrotropes have an ideal concentration above which self-aggregation 'suddenly' begins (as observed in micelle- and vesicle-forming surfactants, that, although a not necessarily anionic, can act as a hydrotropic agent, CMC and CVC, respectively). However, particular hydrotropes self-aggregate in stages, progressively enhancing agglomeration size. Still, several hydrotropes are unable to self-aggregate unless a solubilizer is added.

Hydrotropy:

Hydrotropy is a solubilization procedure in which an addition of significant quantities of a second substance increases the water-based dissolution of another solute. The solute comprises of salts of alkali metals with different organic acids. Hydrotropic agents are referred to as ionic organic salts. Chemical compounds or salts that improve the solubility of an individual medium are referred to as "salt in" the solute, whereas salts that decrease the solubility are referred to "salt out". Various salts possessing big anions or cations that are especially soluble in water cause the "salting in" of non-electrolytes called "hydrotropic salts," a phenomenon termed "hydrotropism." Hydrotropic solutions do not exhibit colloidal features and have a minimal contact with both the hydrotropic substance with the solute. Hydrotropy refers to an enhancement of solubility for water caused by adding a significant quantity of chemicals. The method by which it increases dissolvability is much more closely connected to complexation, which involves a weak contact with hydrotropic agents such as sodium benzoate, sodium acetate, sodium alginate, and urea and weakly soluble medicines. (7)

Mechanism of Hydrotrope:

Hydrotrope enhances water solubility by molecular self-association and the binding of hydrotrope particles to the solute. Despite their widespread application in a variety of industrial sectors, little is known about the mechanisms underlying hydrotropism. Several hypotheses and investigations are being conducted to clarify the processes of hydrotrope. Three approaches exist for reducing the available proposed mechanisms:

1. Self-aggregation potential

2. Structure breakers and structure makers

3. Ability to produce micelles-like structures.

1.Self-Aggregation Potential:

The minimum hydrotropic concentration (MHC) is the critical concentration for hydrotrope molecules to aggregate, indicating their self-aggregation potential. Hydrotropic agents' solubilization capacity depends on their hydrophilic-lipophilic characteristics and the solute particle composition. Hydrotropes have volume-fraction-dependent solubilization potential. Initially, hydrotrope molecules establish a pairwise initial association, which is followed by successive stages to produce trimers, tetramers, and so on, and these complexes (trimers, tetramers) may lead to greater water solubility. These findings were derived via fluorescence emission methods, crystallographic analysis, molecular dynamics replication, and thermodynamic solubility studies. Aside these, they can also act as bridging agents, lowering the Gibbs energy and increasing the dissolution of a solute. Simply put, the composition of the hydrotrope-water combination around the drug molecule holds the key for comprehending the basis of the self-aggregation capacity.

Diagrammatic representation of mechanism of hydrotropy: Hydrotropic agents with planar hydrophobic part and hydrophilic part.

Fig.1 Mechanism of hydrotrope

2. Structure-breakers and Structure-maker:

In hydrotropic solubilization procedure, an electrostatic charge of the donor-acceptor atom has a critical function; thus, they are also referred to as a structure-breaker. Hydrotropic compounds, such as urea, increase solubility by affecting the solvent's capacity to build structures via hydrogen bonding between molecules. Structure-breaker hydrotropes (chaotropes) and structure-maker hydrotropes (kosmotropes) affect solubility in various ways. Kosmotropes diminish the critical micelle concentration (CMC) by strengthening hydrophobic interactions, resulting in larger micelles and less hydration.

3.Ability to Form Micelle-like Structures:

Hydrotropes can increase solubility by generating micelle-like structures through self-association with solutes. This lowers the electrostatic repulsion between solute molecules. Examples include alkyl-benzene sulfonates, alkyl sulphates, lower alkanoates and aromatic anionic hydrotropes such as nicotinamide and sodium salicylate. Aromatic anionic hydrotropic compounds, like nicotinamide, boost the dissolving ability of riboflavin by a self-association mechanism, resulting in micellar formations. In contrast, anionic hydrotropes such as sodium salicylate enhance the solubility of poorly water-soluble chemicals such as phenazopyridine (PMZ) by producing stable, mixed micelles. This mixed micellization lowers electrostatic repulsion between PMZ's head groups, enhancing its solubility.(8–10)

Mixed hydrotropy:

Mixed hydrotropic solubilization method is the phenomenon that enhances the solubility of poorly water-soluble medications in the mixture of hydrotropic agents, which can give incredible synergistic enhancement impacts on the solubility of weakly water-soluble substances, utilization of it in the formulation of certain dosage forms of water insoluble drugs, and to minimize the concentration of individual hydrotropic agent to reduce the adverse effects instead of using an excessive amount of one hydrotrope, a combination of, say, five hydrotropes can be used in 1/5th concentrations, lowering their individual toxicities. (8)

Advantages of Mixed Hydrotropic Solubilization:

It is a novel, easy, cost-effective, secure, precise, reliable, and ecologically sound approach for analyzing poorly water-soluble medicines (titrimetric and spectrophotometric), which does not require any kind of organic solvents.
It is possible to decrease the huge total amount of hydrotropic agents required to provide a modest rise in solubility by using a combination of agents at smaller amounts.
It prohibits the usage of organic solvents, so avoiding residual toxicity, volatility-induced mistake, pollution, cost, and further damage. (7)

Pharmaceutical applications of hydrotropic solubilization:

1. Enhance bioavailability: By increasing the solubility of poorly soluble drugs, hydrotropic agents can improve their absorption and bioavailability.

2. Improve formulation flexibility: Hydrotropic solubilization enables the development of various formulations, including tablets, capsules, and injectables.

3. Reduce toxicity: By enhancing solubility, hydrotropic agents can help reduce the toxicity associated with poorly soluble drugs.

4. Facilitate drug delivery: Hydrotropic solubilization can aid in the design of targeted drug delivery systems, enabling more efficient and effective treatment outcomes.

5. Improved sensitivity and accuracy: Hydrotropic solubilization enables the accurate determination of poorly water-soluble drugs, even at low concentrations.

6. Reduced interference: Hydrotropic solubilization can reduce interference from excipients and other components, enabling the accurate determination of the active pharmaceutical ingredient. (11)

7. Quantitative estimation by spectrophotometry: Poorly water-soluble drugs can be easily analyzed by using spectrophotometric analysis in hydrotropic solubilization such as Rosiglitazone, cephalexin, etc. (12,13)

8. Quantitative estimation by titrimetric analysis: Poorly water-soluble drugs can be easily analyzed by using titrimetric analysis in hydrotropic solubilization such as ibuprofen, flurbiprofen and naproxen using sodium benzoate. (14)

9. Preparation of hydrotropic solid dispersions of poorly water- soluble drugs precluding the use of organic solvents. Such as felodipine using poly-ethylene glycol 6000 and poly-vinyl alcohol. (15)

Table 2: Different hydrotropic solubilization studies for various poorly water-soluble drug with respect to formulation development

Sr. No	Drug	Hydrotropic agents	Outcome	Reference
1	Lurasidone Hydrochloride	Nicotinamide, Sodium benzoate, Sodium Citrate	Immediate dissolution of insoluble drug Lurasidone Hydrochloride in the aqueous dissolution media	(16)
2	Naproxen	0.5% ibuprofen sodium solution	350 times improvement in aqueous solubility	(17)
3	Aceclofenac	Urea 20% & sodium citrate 10%	Improvement in vitro dissolution. Improved in solubility more than 250 folds	(18)
4	Mefenamic Acid	PEG 4000	Enhance the release of low soluble drugs from its dosage form	(19)
5	Furosemide	15:20:5 Urea, Sodium Benzoate, Sodium citrate	Improvement in the solubility of furosemide	(20)
6	Griseofulvin	Trisodium citrate, urea, sodium acetate, sodium benzoate, sodium salicylates	Solubility and dissolution enhancement of poor water-soluble drugs.	(21)
7	Nevirapine	Citric acid 10% & urea 20%	Enhancement in solubility of nevirapine	(22)
8	Telmisartan	5.0 M urea solution &1.0 M citric acid solution	15737 folds improve solubility	(23)
9	Dexamethasone	Sodium benzoate and sodium Salicylate	Improvement in the Solubility of Dexamethasone	(24)
10	Cefprozil	Potassium acetate, Potassium citrate, Sodium acetate, Sodium citrate, Urea	Solubilization of cepfrozil enhances by using different hydrotropic agents	(25)
11	Chartreusin	Hydroxybenzoate	Aqueous solubility of water insoluble cytotoxic agent, chartreusin, increased at PH 7 by using hydroxybenzoate as a hydrotropic agent.	(26)
12	Zaltoprofen	Urea, sodium benzoate	Improved in solubility more than 600-fold	(27)
13	Aceclofenac	0.5 M Ibuprofen Sodium	Improvement in solubility of Aceclofenac	(28)
14	Riboflavin	Caffeine & Nicotinamide	Two hydrotropic agents lead to increase in the solubility of vitamin	(29)
15	Etodolac	Sodium benzoate, Sodium acetate	sodium benzoate and sodium acetate were found to be more stable	(30)
16	Nimesulide	Piperazine, sodium benzoate, Sodium Ascorbate, Sodium Salicylate	Improved in solubility using piperazine as Hydrotrope was developed	(31)
17	Ofloxacin	Sodium citrate, sodium benzoate, urea, Sodium Acetate, Niacinamide, Lignocaine HCL, PEG 6000, PEG 400	Aqueous injection of drug was prepared for antimicrobial effectiveness and stability	(32)
18	Halofantrine	Caffeine, nicotinamide	Solubility is increased to a greater extent in the presence of caffeine	(33)
19	Ibuprofen	Sodium acetate, Sodium benzoate, Sodium toluene sulfonate, Sodium salicylate and Sodium toluate	Improvement in solubility of Ibuprofen by using various hydrotropes. sodium benzoate was more powerful Hydrotrope	(34)
20	Ketoprofen	2.0 M Potassium Acetate	Enhance the solubility of Ketoprofen using hydrotopic Agent	(35)
21	Naproxen	Niacinamide	The solubility of Naproxen using Niacinamide solution was more than 110 fold	(36)
22	Piroxicam	Ibuprofen sodium	The solubility of piroxicam using Ibuprofen sodium was more than 50 folds	(34)
23	Olanzipine	Sodium benzoate, sodium acetate, sodium bicarbonate, sodium chloride, sodium gluconate, thiourea, trisodium citrate, Urea	Enhance solubility of drug using hydrotopic agents was more than 6, 19, 22, 74, 12, 89, 59 % 98 folds	(37)
24	Lornoxicam and Paracetamol	Urea	Enhance solubility of Lornoxicam and paracetamol	(38)
25	Theophyllin	7.5 M Sodium Salicylate & 5.5 M Resorcinol	2 fold increase in solubility with respect to the sodium salicylate and 1.3 fold increase in the solubility with respect to the Resorcinol	(39)
26	Sparfloxacin	Sodium Benzoate	Enhancement in the solubility of Sparfloxacin	(40)
27	Glipizide	tri-sodium citrate and urea solution	Hydrotropic solubilization is an effective technique in the enhancement of solubility of Glipizide	(41)
28	Escitalopram	Niacinamide	Improvement in solubility of Escitalopram using Hydrotrope	(42)
29	Chlorobenzene	Citric acid, sodium benzoate and urea	Solubility of chlorobenzene increases 53.98 times in the presence of urea as hydrotrope	(43)
30	L-Tyrosine	Caffeine, Nicotinamide, Sodium salicylate and Sodium Benzoate	Solubility of L-Tyrosine increases with increase in Hydrotrope concentration and varying temperature	(44)
31	Amino-nitrobenzene	Sodium benzoate, sodium saccharin, dimethyl benzamide	Solubility of amino-nitrobenzene increases with increase in concentration of hydrotrope	(45)
32	Methyl benzoate	Citric acid, urea and nicotinamide	Increase the solubility of methyl benzoate by 26.66 times in the presence of citric acid.	(46)
33	Furfural	Urea, tri-sodium citrate, sodium toluate and sodium benzoate	Solubility of furfural has been increased in the existence of urea	(47)
34	Acetylsalicylic acid	Sodium salicylate, sodium benzoate, nicotinamide and urea	Hydrotropic agents enhance the solubility of Acetylsalicylic acid	(48)
35	m/p-Amino-acetophenone	Diethyl nicotinamide, sodium pseudocumene sulfonate and sodium thiocynate	Sodium thiocynate was identified to be a best hydrotrope for enhancement of solubility of m/p Amino acetophenone	(49)
36	Hydro-chlorothiazide	niacinamide, sodium acetate, sodium benzoate, sodium citrate and urea	There was enhancement in solubility of hydrochlorothiazide in hydrotropic solution	(50)
37	Gatifloxacin	2 M sodium benzoate solution and 1.5 M metformin hydrochloride solution.	Solubility of gatifloxacin in 2 M sodium benzoate solution was more than 230 times and in 1.5 M metformin hydrochloride solution was more than 18-fold as contrasted to solubility in the distilled water.	(51)
38	Carbamazepine	urea and nicotinamide	By using either urea or nicotinamide as a hydrotropic agent, solubility of the carbamazepine can dramatically increase.	(52)
39	Glipizide	Sodium acetate, Sodium Benzoate and salicylate	Enhancement in the solubility of glipizide	(53)
40	Lornoxicam	2M sodium benzoate	Enhancement in the solubility of Lornoxicam	(54)
41	empagliflozin	Ammonium acetate and sodium citrate	Successful development and validation of a method of assessment of empagliflozin using hydrotopic phenomenon	(55)
42	Meloxicam	Sodium Benzoate	Significant enhancement in solubility with the highest increment of sodium benzoate	(56)
43	Ezetimibe	2M Ammonium Acetate & 2M Sod. Citrate	Enhancement of solubility of Ezetimibe by hydrotopic agents	(57)
44	Diacerein	Sodium Acetate	Enhancement in the solubility of Diacerein	(58)
46	Rosuvastatin calcium	Sodium Benzoate, urea, Mannitol, Sodium Salicylate	Sodium Citrate is useful to enhance the solubility of Rosuvastatin	(59)

CONCLUSION

This study concludes that solubility is the most essential physical attribute of a medicine for bioavailability, formulation, the development of multiple dosage forms for various drugs, and quantitative analysis. Solubility can be increased by numerous approaches, among which hydrotropy is highly important. To overcome solubility constraints, numerous enhancing techniques are employed, with hydrotropy being the most important. Hydrotropy is the use of hydrotropic chemicals that self-assemble with poorly soluble medications, increasing solubility and simplifying formulation development. The advantages of hydrotropes have been demonstrated in numerous disciplines because of their exceptional characteristics such as water solubilization, that makes it a better solvent, inflammability, which at first eliminates any risk, and high electrical conductivity, leading to greater acceptability. However, there are still many more issues that must be addressed. As a result, it is suggested that the value of hydrotropes be investigated in order to anticipate improved drug administration of poorly water-soluble pharmaceuticals and drug moieties with limiting therapeutic applications, as well as to explain their successful structure-based mechanism. ((8,60)

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