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Sustainable Approaches in Pharmaceutical Sciences, First Edition. Edited by Kamal Shah, Durgesh Nandini
Chauhan, and Nagendra Singh Chauhan.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
91
5
Green Analytical Techniques Using Hydrotropy, Mixed
Hydrotropy, and Mixed Solvency
Atish S. Mundada
1
, Dipak D. Patil
2
and Rajesh K. Maheshwari
3
1
SNJBs SSDJ College of Pharmacy, Neminagar, Chandwad, Nashik, Maharashtra, India
2
K.K. Wagh College of Pharmacy, Nashik, Maharashtra, India.
3
Department of Pharmacy, SGSITS, Indore, Madhya Pradesh, India
5.1 Introduction
Analytical chemistry, a crucial branch of chemistry, provides input related to the nature of
chemical substances and their occurrence in organisms and in the environment through vari-
ous analytical measures. It is impossible to understand a product’s life cycle without chemical
analysis of its components and degradation products. The standards and specifications fol-
lowed for the use of chemicals in various industries are based on evidence obtained by analyti-
cal chemists and are further controlled by the chemical process. Sustainable development aims
at decreasing the unfavourable aftereffects of the materials that we use and produce. At the
same time, a leading concern is to change the way energy and aromatic chemicals are created
from fossil fuels to make reproducible assets. Analytical chemistry is the only field that can vali-
date the environmental friendliness of any novel method, process, or product.
The solubility of active ingredients, particularly low water solubility, poses enumerable
challenges not only during drug discovery, but also in the initial and last stages of pharma-
ceutical development. Aqueous solubility is also associated with discharge and partition of
the chemicals in the environment and thus it is considered an elementary parameter in the
CONTENTS
5.1 Introduction, 91
5.2 Green Chemistry, 92
5.3 Hydrotropes and Hydrotropy, 92
5.4 Hydrotropic Technology, 94
5.5 Pharmaceutical Analysis Using Monohydrotropy, 95
5.6 Mixed Hydrotropy, 99
5.7 Mixed Solvency, 101
5.8 Conclusion, 102
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5 Green Analytical Techniques Using Hydrotropy, Mixed Hydrotropy, and Mixed Solvency92
risk assessment of any chemical. The deployment of a combination of chemistry and high-
throughput screening techniques in the invention of drugs has propelled the formation of
high molecular weight new chemical entities (NCEs) that have greater lipid solubility.
Aqueous solubility is critical for the mixing, circulation, and performance of organic chem-
icals within experiments, analytical systems, and the environment. It is always an uphill
task to convert a poorly aqueous-soluble NCE into a final product for human use. Secondly,
how to solubilise these NCEs is a tough question to be answered by chemists and formula-
tion scientists, as solubilisation of NCEs dictates the utilisation of organic solvents.
There are many incorrect practices followed by analysts at some stage of either quantitative
or qualitative laboratory experiments that might prove harmful not only to them but also to the
environment. Foremost among these is the unrestrained dumping of organic vehicle wastes
and unfortunately numerous organic vehicles possess substantial toxicity [1]. In addition, mak-
ing use of unsafe chemical reagents has deleterious consequences on the environment. These
days, ecological anxiety has become a burning issue in laboratory experiments and hence it is
anticipated that all analytical tests should be safe and ecofriendly.
5.2 Green Chemistry
Green chemistry is the most striking notion in chemistry as it guarantees that subsequent
inventions are more sustainable compared to existing ones. Exploitation of the 12
principles
of green chemistry diminishes or eradicates the utilisation or creation of harmful
chemicals
in the planning, assembly, and functions of a chemical harvest [2]. A crucial area of green
chemistry involves the elimination of vehicles in chemical practices or finding ecologically
safe solvents as an alternative to dangerous solvents. Around 35% of synthesised drugs
have an aqueous solubility issue, which thus demands the use of organic vehicles. It is the
need of the hour to find ecofriendly and cost-effective alternatives to organic vehicles and
this has led to the formation of new and commercial approaches [3]. The initiation of sol-
vent-free processes as substitutes is obviously the first choice and if a solvent is a must for
a particular process, then choosing a solvent that will have no or limited impact on the
well-being of chemists and the environment is the best answer.
Various techniques have been exploited to solubilise poorly water-soluble medicaments
[4, 5]. The utilisation of unconventional solvents is quickly growing and ‘hydrotropy’ tech-
nology is one of the most appealing green techniques that can lead to easy swaps from the
typical universal organic solvents used in various processes.
5.3 Hydrotropes and Hydrotropy
The term hydrotropy was coined by Neuberg in 1916. Neuberg defined hydrotropes as the
organic acid salts of metal that considerably enhance the aqueous solubility of organic
substances at moderately elevated concentrations [6]. Neuberg’s hydrotropic agent
(Figure 5.1) generally has two fundamental portions: a hydrophilic portion made up of an
anionic metal ion and a hydrophobic portion consisting of an aromatic ring/ring system.
The metal ion portion boosts the water solubility, although the type of anion or metal ion
in the hydrotrope usually demonstrates a trivial influence on this. Conversely, the
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5.3 Hydrotropes and Hydrotropy 93
planarity of the non-hydrophilic aromatic ring has been suggested as an imperative facet in
the solubilisation process using a hydrotropic agent.
In 1985, Saleh and El-Khordagui explained that hydrotropes could be positively charged,
negatively charged, or neutral, inorganic or organic, and non-micelle-forming molecules
that may be solid or liquid in nature. Hydrotropes contain a very small hydrophobic por-
tion compared to the surfactant and the equilibrium between the water-loving and the
water-hating part controls the efficiency of hydrotropic solubilisation. The hydrotropic
agents (solubilisers, additives, or enhancers) are ionic organic salts.
Hydrotropy is a molecular phenomenon wherein the water solubility of poorly soluble
material is enhanced by incorporating a second solute (a hydrotrope) [7]. In simple terms, it
is a solubility enhancement technique that augments the solubility of one solute by the pres-
ence of a large quantity of another solute [8, 9]. Hydrotropy not only assists in the segregation
of a narrow boiling point isomeric agent from its mixture, but also enhances the speed of
diverse reactions [10–13]. The phenomenon of hydrotropy is considered an exceptional and
revolutionary solubilisation strategy as it shows effortless recovery of hydrotropes from the
liquefied solute and the possibility of recycling such hydrotropic solutions [8].
5.3.1 Advantages of Hydrotropy
● Owing to its pH-independent solvent character, high solute selectivity, and non-require-
ment of an emulsification step, hydrotopy is considered as a better choice over alterna-
tive solubilisation processes like micellar solubilisation [14], co-solvents [15], and the
salting-in method [16].
● The only requirement in hydrotropic solubilisation is mixing of the drug with the hydro-
tropic agent in water [17].
● Hydrotropy requires neither chemical alteration of an inadequately water-soluble
medicament nor the use of any organic vehicle [17].
● Hydrotropy is a financially viable, harmless, and easy-to-use technique [17].
5.3.2 Classification of Hydrotropic Agents
The literature suggests that numerous hydrotropic agents could be employed for solubility
augmentation of inadequately soluble medicaments. All these materials used as hydro-
tropes could be put up into the following categories [18–21]:
● Urea and its derivatives: e.g. urea and ethyl, butyl, and N,N-dimethyl derivatives of urea.
● Organic metal salts and acids: e.g. sodium salicylate, sodium glycinate, sodium ascorbate,
sodium acetate, sodium and potassium citrate, sodium benzoate, benzoic acid.
Hydrophilic (Metal ion/
anion) part has minor
inuence on hydrotropy
Achieving Balance between
counteracting parts
Hydrophobic (aromatic
ring) part has major
inuence on hydrotropy
Figure 5.1 Hydrotropic agent.
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5 Green Analytical Techniques Using Hydrotropy, Mixed Hydrotropy, and Mixed Solvency94
● Aromatic alcohols: e.g. resorcinol, pyrogallol, catechol, α and β-naphthols.
● Aromatic anionics: e.g. sodium xylene sulfonate, sodium benzene sulphonate, sodium
p-toluene sulfonate, sodium benzoate, sodium cinnamate, sodium salicylate, sodium-
3-hydroxy-2-naphtholate, nicotinamides, p-amino benzoic acid hydrochloride, N,N-
diethyl nicotinamide, N,N-dimethyl benzamide.
● Aromatic hydrotropes: e.g. caffeine, nicotinamides, N,N-dimethyl benzamide.
● Aromatic cationics: p-amino benzoic acid hydrochloride, caffeine, procaine HCl.
● Aliphatic and linear compounds: e.g. sodium alkanoate, urea, N,N-dimethyl urea, tertiary
butyl alcohol.
● Surfactants: e.g. diacids, sodium dodecyl sulfate, dodecylated oxidibenzene, and many
other anionic, cationic, non-ionic, and amphoteric surface-active agents.
5.3.3 Mechanism of Hydrotropic Solubilisation
In 1996, Coffman and Kildsig studied a riboflavin–nicotinamide mixture to understand
the way a hydrotrope works and on the basis of spectral characters, established that there
is no complex formation reaction involved between the drug and the hydrotropic agent
[22]. Later it was shown that hydrotropes could be acting as a solubility-enhancing agent
in the presence of their critical hydrotrope concentration, similar to surfactants but with
a
non-micellar property [23]. Various theoretical and experimental set-ups were tried to
elucidate the mechanisms of hydrotropic solubilisation. The available projected ways can
be
summarised under three designs [20, 24]:
● Self-aggregation potential: e.g. sodium salicylate, sodium p-toluene sulfonate, sodium
xylene sulfonate, etc.
● Structure-breaker and/or -maker: chaotropes, e.g. urea, guanidium chloride; or kosmo-
tropes, e.g. polyhydric alcohol, trehalose, glycine, betaine, proline, etc.
● Forming a micelle-resembling structure: e.g. alkyl benzene sulfonate, alkyl sulfates, etc.
It is presumed that hydrotropic agents flock into the less rigid non-covalent congregation
of non-polar microdomains to enhance the solubility of the hydrophobic candidates. Some
scientists have commented that hydrotropic solubilisation resembles complexation, with a
weak contact offered between solute and hydrotropic agent. In short, it can be said that the
hydrotropic technique is a combined molecular event involving a mutual intermolecular
interface and many complementary molecular pulls [25].
5.4 Hydrotropic Technology
Applications of hydrotropic agents in the field of pharmacy have been put into two groups
on the basis of their use:
● Monohydrotropy or single hydrotropy, concerned with the application of single hydro-
tropic agents.
● Mixed hydrotropy, wherein two or more than two hydrotropic agents are used.
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5.5 Pharmaceutical Analysis Using Monohydrotropy 95
5.5 Pharmaceutical Analysis Using Monohydrotropy
Though the utilisation of a single hydrotropic agent appears to be easy and uncomplicated,
the decision on the selection of the appropriate material may be intricate. The documented
evidence suggests that monohydrotropic agents have been successfully used for the con-
current evaluation of drug pairs. The method of analysis to be selected depends on the
conditions for the experiment and the category of the drug. The concept of hydrotropic
solubilisation has been exploited by Maheshwari and his group in the estimation of numer-
ous poorly aqueous-soluble drugs and the research findings have been well documented.
5.5.1 Thin-Layer Chromatography
Numerous non-polar organic vehicles like alkanes (hexane, heptane), aromatics (xylene, tolu-
ene, benzene), chloroform, ether, dichloromethane, cyclohexane, and polar solvents like ace-
tone, ethyl acetate, butanol, and ethanol are being utilised for carrying out thin-layer
chromatography (TLC) of a variety of drugs. Some organic solvents in that list are costly and
generate poisons, and hence are considered to be toxic not only to the chemist but also to the
environment. Hydrotropic solutions can be used as a mobile phase replacing these toxic organic
solvents to perform TLC analysis of many poorly water-soluble compounds. The application of
hydrotropic agents like urea and sodium benzoate has been shown to improve the solubility of
some poorly water-soluble medicaments by Maheshwari et al. [26, 27]. Mangal et al. [28] proved
the use of a 5.0 M solution of sodium salicylate as a
hydrotropic agent in TLC analysis of ome-
prazole, whereas Jayronia et al. [29] effectively developed a novel, ecofriendly, simple, safe, and
inexpensive TLC technique for model drugs like norfloxacin, erythromycin, and ciprofloxacin
using sodium salicylate, sodium benzoate, and urea as hydrotropic agents in a mobile phase.
5.5.2 Titrimetric Analysis
The principle of hydrotropic solubilisation has been successfully exploited in titrimetric estima-
tion to preclude the use of harmful organic solvents. Moreover, it has been observed and docu-
mented that organic solvents demonstrate inaccurate results in spectrophotometric evaluation
of many medicaments due to the volatility of these solvents. Thus, the application of hydrotropy
not only helps in overcoming this drawback, but also improves the solubility of certain poorly
water-soluble drugs. The numerous titrimetric investigations of poorly aqueous-soluble drugs,
in bulk as well as in solid dosage forms, carried out using a hydrotropic agent and thus avoiding
the use of harmful and toxic organic solvents, have been summarised in Table 5.1.
5.5.3 Spectrophotometric Analysis
Today, about 35–40% of frequently used substances are found to have an aqueous solubility
of less than 10 µM or 5 mg/mL at pH 7, which creates problems in the analytical evaluation
or formulation of these types of drugs. Organic solvents that are expensive, toxic, as well as
harmful to the environment are frequently employed for the spectrophotometric analysis
of water-insoluble moieties. Furthermore, exposure to these organic solvents leads to
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5 Green Analytical Techniques Using Hydrotropy, Mixed Hydrotropy, and Mixed Solvency96
Table 5.1 Summary of hydrotropic agents used in titrimetric analysis.
Hydrotropic agent used Drug References
2.0 M sodium benzoate Aspirin [26]
Frusemide [30, 31]
Ketoprofen [32]
Aceclofenac [33, 34]
Flurbiprofen [35]
Ibuprofen [35]
Benzoic acid [36]
2.0 M sodium salicylate Benzoic acid [36]
Aceclofenac [37]
Frusemide [38]
Ketoprofen [39, 40]
0.5 M ibuprofen sodium Frusemide [41]
Aspirin [42]
Aceclofenac [43]
1.25 M sodium citrate Aspirin [26]
Salicylic acid [33]
Ketoprofen [39]
8.0 M urea Salicylic acid [33]
Norfloxacin [44]
1.0 M calcium disodium edetate Salicylic acid [45]
0.5 M ibuprofen sodium Salicylic acid [45]
1.5 M metformin HCl Aspirin [46]
2.0 M Nicotinamide Salbutamol [47]
2.0 M niacinamide Aspirin [48]
2.0 M sodium salicylate Theophylline [49]
2.0 M sodium saccharin Salicylic acid [50]
2.0 M sodium acetate Ketoprofen [33]
4.0 M sodium acetate Aspirin [26]
adverse effects like skin inflammation, eye irritation, nausea, headache, and sedation.
Prolonged exposure may even lead to various harsh consequences like neurological disor-
ders, mutagenic disorders, liver damage, chronic renal failure, and necrosis.
Researchers are persistently working in this direction to get an ecological solution for
this issue and fortunately these harmful solvents can be substituted by some other ecof-
riendly sources. The spectrophotometric estimation of numerous poorly aqueous-soluble
drugs precluding the employment of toxic organic vehicles has been carried out by
Maheshwari and group as well as other researchers, and has been summarised in Table 5.2.
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Table 5.2 Summary of hydrotropic agents used in spectrophotometric analysis.
Hydrotropic agent used Drug References
0.1 M citric acid Lercanidipine [51]
Pioglitazone HCL [52]
7.5 M N,N-dimethyl urea Diclofenac sodium [53]
Gatifloxacin [54]
Naproxen [55]
1.5 M metformin hydrochloride Aspirin [46]
Gatifloxacin [56]
Famotidine [57]
2.0 M niacinamide Naproxen [58]
Indomethacin [59]
Nalidixic acid [27]
Norfloxacin
Tinidazole
4.0 M sodium acetate Lovastatin [60]
Cefixime [61]
Ketoprofen [32]
Tinidazole [23]
Amlodipine besylate [62]
2.0 M sodium benzoate Naproxen [63]
Ofloxacin [26]
Gatifloxacin [56]
Hydrochlorothiazide [64]
Indomethacin
Frusemide [65, 66]
Tinidazole [23]
Piroxicam [67]
Riluzole [68]
Lornoxicam [69]
Etoricoxib [70]
1.25 M sodium citrate Salicylic acid [71]
Cefixime [61]
Tinidazole [23]
Naproxen [72]
5.0 M urea Fluvoxamine [73]
Dextro-methorphan [74]
Amlodipine besylate [62]
Acyclovir [75]
Cefadroxil [76]
Lomefloxacin [77]
Ciprofloxacin [78]
(Continued)
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5 Green Analytical Techniques Using Hydrotropy, Mixed Hydrotropy, and Mixed Solvency98
Hydrotropic agent used Drug References
8.0 M urea Cefixime [61]
Tinidazole [23]
Cephalexin [79]
Diclofenac sodium [80]
Terconazole [81]
10 M urea Hydrochlorothiazide [82]
Amoxicillin [83]
Paracetamol [84]
1.0 M calcium
disodium edetate
Benzoic acid [85]
1.5 M ibuprofen sodium Piroxicam [86]
1.0 M lignocaine
hydrochloride
Tinidazole [87]
2.0 M potassium acetate Ketoprofen [88]
5.0 M potassium acetate Amoxicillin [89]
2.0 M sodium salicylate Nifedipine [90]
5.5.4 Simultaneous Spectrophotometric Estimation
A handful of investigations are known in the area of concurrent spectrophotometric esti-
mation of poorly aqueous-soluble drugs. It has been well documented that a hydrotropic
solubilisation technique has been successfully utilised and the outcomes of these analyses
have been summarised in Table 5.3.
Table 5.2 (Continued)
Table 5.3
Summary of simultaneous spectrophotometric estimation using hydrotropy.
Drug molecule(s) Hydrotropic agent used References
Norfloxacin and tinidazole Urea [91]
Atenolol and amlodipine besylate [92]
Cefixime trihydrate and Oonidazole [93]
Ciprofloxacin hydrochloride and
tinidazole
[94]
Levofloxacin hemihydrate and
ambroxol hydrochloride
[95]
Paracetamol and diclofenac sodium [96]
Metronidazole and norfloxacin [97]
Diclofenac sodium and
rabeprazole sodium
[98]
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