Solubility Enhancement Techniques: A Comprehensive Review of Approaches for Poorly Soluble Drugs

Abstract

Aqueous solubility is one of the crucial factor that affect drug’s bioavailability. In order to achieve the intended pharmacological action, it is crucial to attain the the optimal concentration of the drug in the bloodstream. Almost 50% of the newly discovered drugs are found to be insoluble during the screening phase. Delivery of drugs and formulation development are restricted by poor solubility. Diverse techniques have been explored to improve the drug's water solubility. Since majority of drugs are poorly soluble, this review article focuses mostly on those that fall within classes II and IV of the Biopharmaceutical Classification System (BCS). Several techniques are described to improve the solubility of poorly soluble drugs, including solid dispersions, inclusion complexation, dendrimers, nano-suspensions, co-solvency, pH modification approach, self-emulsifying drug delivery system, hydrotrophy, co-crystallization, and ionic liquid creation.

Keywords

Introduction

Solubility is defined as the ability of a solute to dissolve in a particular solvent to form a uniform mixture, resulting in a formation of a solution. A substance's solubility is mostly dependent on the solvent used, temperature, and pressure.A solute's extent of solubility in a particular solvent can be measured using the saturation concentration. (1)

 For many years, researchers have been searching for the ideal approach to make drug more soluble, which increases their bioavailability. Low aqueous solubility is a significant factor affecting bioavailability of more than 40 % of newly discovered compounds.  This is because, in order for the drug to be able to partition across the membrane of an epithelial cell, it must be present in the solution form in the aqueous intestinal fluid (passive diffusion).(2)

Solubility and permeability are two important aspects of drug absorption. The Biopharmaceutical Classification System is used to classify drugs based on their solubility and permeability.(3) BCS  divides the drugs based on their solubility & permiability into four classes. Low solubility characteristic of  both class II and IV compounds, but poor permeability is an additional problem for class IV compounds. A drug is considered to have high soluble when its maximum dose strength dissolves in 250 millilitres or less of aqueous medium at 37°C and a pH range of 1-7.5.(4)

Figure 1: BCS CLASSIFICATION

Importance of solubility

Solubility plays a crucial role in any formulation to achieve therapeutic drug concentration for obtaining maximum pharmacological response. Drugs having very low aqueous solubility require higher dose be in to reach therapeutic drug concentration after oral administration. Drug must be in an aqueous solution form for absorption. Water serves as the main solvent when working with liquid formulations.(5)

        Most of the weekly acidic and basic drugs have very limited aqueous solubility. Over 40% of new discovered molecules have less water solubility.  These poorly soluble drugs are slowly absorbed, cause gastrointestinal mucosal damage and result in insufficient and inconsistent bioavailability. Solubility is the most crucial factor limiting the rate at which oral drugs can reach in appropriate concentration in the blood stream for systemic action. (6)

3. Techniques for Solubility Enhancement     There are various procedures to improve solubility, which can be divided into three categories: physical modification, chemical modification of the drug, and miscellaneous methods.

Figure 2: Hot-melt extrution

Figure 3: Inclusin Complexation

(C) Co-solvency method:

      Co-solvency is a method that involves blending a drug with a water-miscible solvent to increase its solubility.(20) Co solvents are water-miscible solvents that are frequently employed for solubilization in the pharmaceutical industry.(21)

The most often used co-solvent  are propylene glycol,ethanol,glycerin and polyethylene glycol.Dimethyl sulfoxide and dimethyl acetomide are common solvent with relative low toxicity and high solubility capacity for poorly soluble drugs.(1)

Co-solvent improves the solubility by following mechanism:

1. Polarilty adjustment: Co-solvent alter the polarity of solvent system.This is useful when solute is very poorly soluble in primary solvent(e.g.,water)(21)

2. Hydrogen bonding disruption:In aqueous In a aqueous system co-solvent such as ethanol or propylene glycol can disrupt the structured hydrogen bonding network of water. This reduce the cohesive forces of water ,making it easier for nonpolar or weakly polar solutes to dissolve.(21)

3. Reduction in dielectric constant: Co-solvent reduces the dielectric constant of the solvent mixture, which can enhance solubility of non-polar or hydrophobic drugs by lowering the solvent’s polarity.(21)

Using four distinct cosolvents, the study assessed and evaluated the solubility enhancement of rofecoxib and meloxicam. PEG 400 has proven to be the most effective solubilizing cosolvent and an acceptable cosolvent in terms of side-effect profile, increasing solubility by 778 fold for rofecoxib and about 21 fold for meloxicam at 80% v/v cosolvent level.(22)

Acipimox's solubility in four different solvents like—water, methanol, acetone, and acetonitrile—as well as their aqueous solutions have been determined using the isothermal saturation method at atmospheric pressure and temperatures between 283.15 and 318.15 K. The, the solubility reached its maximum at 80% mass fraction in methanol and acetone aqueous solutions and 60% in acetonitrile aqueous solutions.(23)

(E) Hydrotrophy:

Hydrotrophy is a solubility enhancement technique of poorly water-soluble drug in which large quantity of second solute improve the aqueous solubility of another solute. Different concentrated hydrotropic solution like sodium benzoate, sodium salicylate, urea, nicotinamide, sodium citrate and sodium acetate are observed that improve the aqueous solubility of liphophilic drugs.(24)

Various hypothetical mechanism by which hydrotropes can form:

(I) Self aggregation potential:

Hydrotropes interact strongly with solute and form a complex and these complex would have improved solubility. Hydrotropes also reduce gibbes energy to improve the solubility of solute.

(II) Structure-breaker and structure-maker

A electrostatic force play important role for hydrotropic solubilization for donor-acceptor molecules. Solute which have hydrogen donating and acceptance nature improve the solubility.

Solutropic agent by changing the nature of solvent alter the solvent’s ability to structure formation., Urea.

(III)Miceller formation:

It is based on a self-association hydrotropes with a solute which form a micelles. It reduces repulsion between the head group and form a stable micelles.(25)

Classification of hydrotropic agent:

1.organic acid and their metal salts    2.urea and its derivatives   3.Alkaloids

4.Phenolic derivatives            5. Surfactants        6.Aromatic cations(26)

By using the 8M urea as a hydrotropic agent be 8-fold increase in solubility of ibuprofen that Can be analysed by titrimetric method.(27)

E.x:

1.By using 15%Sodium Salicylate 5% Niacinamide,5% Sodium Acetate 5% Sodium Citrate as a hydrotropic agent 33 fold increase in solubility of furosemide that Can be analysed by titrimetric method.(28)

2.Metronidazole having low solubility & absorption by using urea as a hydrotropic agent &drug in ratio of (15:1) there was 2 fold increase in solubility.(29)

 (F)Mixed Hydrotrophy

When two hydrotropic chemical substances are combined there will be combined effect of substances that leads to improve the solubility of drug these phenomena known as mixed Hydrotropy. R.K. Maheshwari created mixed hydrotropy as a solubilization method by using the spectrophotometric examination of a drug having very low aqueous solubility. By using mixed hydrotropic method, the Aceclofenac’s solubility was improved 20-40 times   in comparison to its solubility in the aqueous phase in solutions containing 45% urea & 45% sodium citrate solution (SCS). Aceclofenac solubility has been improved more than 700 times in a mixed hydrotropic solution with 22.5 percent urea & 22.5 percent sodium citrate. Drugs that are low aqueous solubility that can be dissolved using the mixed hydrotropic solution approach.(30)

Since the hydrotropic technique eliminates the need for emulsion system preparation, organic solvent use, and chemical modification of the drug, it is a promising strategy with tremendous potential for poorly soluble medications. This study's main goal was to boost the oral bioavailability of furosemide by making it more soluble with hydrotropes and their combinations.(31)

Lurasidone HCl is a antipsychotic used in treatment of schizophrenia which having low aqueous solubility. Different hydrotropic agent like nicotinamide, sodium citrate, urea and sodium benzoate at concentration of 10, 20, 30 and 40% w/v solution using water as a solvent.(31)

For decreasing the individual concentration of hydrotropes mixed hydrotropic technique is used. By using mixed hydrotropic agent Nicotinamide + sodium benzoate + sodium citrate in 15:20:5 ratio highest solubility was obtained.(32)

(G)Self-Emulsifying Drug Delivery System:

Self-emulsifying drug delivery system was developed to improve the solubility.SEDDS are isotropic mixture of natural or synthetic oils, solid or liquid surfactant & one or more hydrophilic solvent/co-surfactant.

There are basically two type of SEDDS:

1.Lipid soluble component system: These system is isotropic mixture of lipid and surfactant having HLB value less than 12 that self-emulsify to form fine oil in water emulsion in aqueous medium.

2.Water soluble component system: This system formulated by using hydrophilic surfactant like ethanol, Propylene Glycol & Polyethylene glycols having HLB value greater than 12.

Different oil used for preparing SEDDS like corn oil, olive oil, sesame oil, soyabean oil etc.(33)

Mechanism:

SEDDS when comes into contact with aqueous fluids (e.g., Gastrointestinal fluid, that leads system undergoes spontaneous emulsion formation without need of external energy. This process forms a stable oil-in-water microemulsion or nano emulsion.(34)

There was two main factors small particle size & polarity of oil droplet determine drug release from SEDDS.(35)

Resveratrol is a non-flavonoid having low solubility by preparing SEDDS using various oils, surfactants, and cosurfactants there was increase the solubility. SEDDS prepared from olive oil, Tween 80, and propylene glycol in the ratio 200:266.7:533.3 (in mg) ratio having very increased solubility for oral delivery of resveratrol.(36)

(H)Co-crystals:

Two or more chemically different molecules organized in a stoichiometric ratio to form a multicomponent molecular crystal known as a cocrystal. This type of crystal can be created by modifying drug   to change their solubility or other physical characteristics without changing the drugs pharmacological effect.(37)

Mechanism:

The cocrystal having drug and conformer held together in a single crystalline structure via non-covalent interactions. This crystal lattice having lower lattice energy than pure drug enabling faster disruption of the lattice in presence of solvent.(38)

Examples:

• Carbamazipine-saccarin cocrystal: It having significantly improved the solubility of carbamazepine approximately 1.5 to 2 times higher than pure drug. Pure drug having 200ug/ml solubility where as cocrystal having 350-400ug/ml solubility was determined. (39)
• Atorvastatin calcium co-crystals were prepared and characterized utilizing a liquid-assisted grinding process with co-formers such as nicotinamide and citric acid to improve solubility. Atorvastatin calcium's solubility was improved by the co-crystallization approach by employing a liquid-assisted grinding method.(40)

Telmisartan (TMS) an angiotensin-II Receptor antagonist used in treatment of hypertension, dissolves slowly in water due to its low solubility. The telmisartan water solubility and rate of dissolution was increased through the production of TMS-OXA co-crystals.(41)

(I)pH-modification technique

It is possible to change the microenvironment pH at the diffusion area by incorporating a pH-modifying excipient into the formulation. If drug shows pH-dependent solubility it may dissolve more readily if the pH of the microenvironment is adjusted, which could result in improved oral absorption.(42) (43)

      An effective way to modify pH for ionizable drugs is through Adjusting the pH. When ionizable drugs contain basic groups (like amines) or acid groups (like carboxylic acids), they can be protonated or deprotonated, respectively. For an additional boost in solubility, pH adjustment is commonly paired with co-solvents.(42)

       Phenytoin injection (Epanutin® ready mixed, Pfizer) 50 mg/ml with propylene glycol 40% and ethanol 10% (1.1 mmol Na+ per 5 ml ampoule) is one example of a commercially available product that has been formulated using the pH adjustment approach.(43)

(J)Ionic liquid formation:

     Ionic liquid (ILs) has played an important role in polymer chemistry, which possess the desirable property of hydrophobicity/hydrophilicity. A hydrophobic associating polymer   was transformed with a polymerizable ionic liquid using free-radical polymerization.
The polymer containing ionic liquids demonstrated superior rheological and solubility characteristics compared to the traditional hydrophobic   polymer. Moreover, the hydrophilic ionic liquid might improve the rheological characteristics and polarity of the polymer solution.(44)

E.x: A novel ionic liquid solvent was created Using tryptophan as the anion and choline as the cation. After some study, the drug's mechanism for improving solubility was shown not due to pH increase in the medium. The formation of hydrogen bonds and the π–π interaction between aromatic rings are the most important mechanisms responsible for the rise in glibenclamide solubility.(45)

It has been demonstrated that ionic liquids are a suitable solvent for solubilizing an extensive variety of sparingly soluble or insoluble drugs for use in formulations or administration. Many of the disadvantages of solid-state medications, like polymorphism and low solubility, stability, and bioavailability, can also be addressed by the use of ILs. Nevertheless, the primary obstacle to creating IL-based medication formulations and drug delivery methods is that many ILs are intrinsically hazardous.(46)

(K)Dendrimers:

Three distinct elements determine the structure of dendrimers, which are large, highly branched polymers:

 (I)  initiator core;

 (II) internal layer, which consists of repeated generations (units) connected to the initiator core; and

 (III) External functional surface

   By using a divergent technique, Buhleier et al. (1978) synthesized the first dendrimer. Due to solubility enhancing nature of dendrimer researchers are more motivated to comprehend potential dendrimer-drug interactions.(47)

     Due to the high degree of specificity of dendrimer structure, which includes size, branching, density, and surface functioning, dendrimers are perfect for enhancing the aqueous solubility of drugs. Many commercially availabledrugs, including poly(amidoamine) (PAMAM), poly (propylene imine) (PPI or DAB), and poly(etherhydroxylamine) (PEHAM), have been effectively synthesized with dendrimers to exhibit anticancer, anti-inflammatory, and antibacterial properties.(48)

Dendrimer solubility  behavior is impacted by the covalent and non-covalent complexes they form with drug molecules and hydrophobes. The stability, controlled release, large drug payload, and decreased toxicity of the entrapped drug or drugs are the advantages of dendrimer-mediated complexation. There is an abundance of research on the non-covalent interactions between dendrimers and drugs in terms of solubilization. In contrast to covalent conjugation, non-covalent complexation frequently results in lower drug encapsulation and complex stability.(49)

E.X:Ketoprofen is  a NSAID is not freely soluble in water(0.0165 mg/ml) by using polyamidomide  dendrimer concentration (10 mg/ml) there was also  increase in solubility of ketoprofen 10 mg/ml.(50)

Figure 4: Basic Stacture of Dendrimer:

(L)Prodrug Aproach:

prodrug is a drug that has been chemically modified to increase its water solubility. After being taken, the prodrug is broken down by the body to release the active ingredient. This method is frequently applied to drugs that are low solubility in lipid and water. One way to change a hydrophobic drug is to transform it into a hydrophilic ester prodrug, which dissolves better in aqueous solution.(51)

     These approaches are employed in drug design to enhance the solubility, stability, bioavailability, and targeting, among other pharmacokinetic and pharmacological aspects of APIs. Prodrugs of several kinds, such as bio precursor and carrier linked prodrugs, were utilized to solubilize drug which having very poor aqueous solubility.(51)

Mechanism of conversion:

1. Enzymatic conversion: Prodrugs are often created to act as substrates for particular enzymes found in the organs' intended tissues. The prodrug becomes the active drug when it comes into contact with the enzyme. As an example, the liver's esterase can break the ester bond and release the drug.(52)

2. Chemical Conversion: Certain prodrugs are made to release the active medication by non-enzymatic hydrolysis or other chemical events that take place in the physiological environment.(52)

E.x:

1.Palmarumycin is drug which having low aqueous solubility 0.1 mg/ml but when these converted into prodrug ester form there will be 7 fold increase in  solubility(0.7mg/ml).

2.Acyclovir is a antiviral drug having poor solubility &bioavailability by converting amide prodrug there was 17 fold increase in solubility.(53)

Prodrugs must possess sufficient stability to hold their form both in storage and when they get to the intended tissue or location of action. Unintentional early conversion may result in higher Toxicity or decreased efficacy.(53)

 (M)Super-critical fluid Technology:

A sophisticated and adaptable method called supercritical fluid technology is used to increase the aqueous solubility, and bioavailability of drugs having low aqueous solubility. carbon dioxide most commonly used for supercritical fluid. The ability of this approach to manufacture small drugs particles with better solubility is gaining in the pharmaceutical sector.(54)

Principle of Supercritical fluid technology:

Drugs are processed by SCFT in a variety of methods, including as reducing particle size, solubilizing, and forming solid dispersions, by utilizing the unique characteristics of supercritical fluid.

      Solvent power: SCFs can change their solvating power in response to variations in temperature and pressure. It allows possible for extraction and selective solubility of compounds.(55)

Method using SCF to improve solubility:

1.Supercritical Anti-solvent  2.Rapid Expansion of Supercritical solution

3.Supercritical fluid extraction of Emulsion(56)

SCF improve solubility by different mechanism:

1. SCFs can be utilized to create ultra-fine medicine particles or nanoparticles by the use of Gas Anti-Solvent (GAS) methods or Rapid Expansion of Supercritical Solutions (RESS).(56)
2. SCFs can solubilize drugs and co-precipitate them with excipients or carriers due to their unique solvent characteristics, particularly scCO?.(56)
3. Highly porous drug particles can be produced using SCF processing.A greater porosity facilitates better  penetration in a dissolution medium, which increased drug release.(57)

E.x:Grisiofulvin having low aqueous solubility(15ug/ml) so by using supercritical fluid trifluromethane in micronization process there was increase in solubility of grisiofulvin in 100 times much  more compare to pure drug.(58)

Challenges and Considerations:

High pressure   Requirements: The high pressure need for equipment is required can lead the cost and complexity of procedure.

Drug Compatibility: All drugs are not compatible with supercritical fluids, particularly those that do not dissolve well in SC-CO2.

Process optimization: Optimal conditions (temperature, pressure, flow rates) for each drugs achieving can be challenging and require extensive experimentation.(58)

CONCLUSION

Improving solubility would be a highly effective way to increase bioavailability for BCS class II drugs. Solubility problems often delay the development of newly produced API. There are numerous methods for improving solubility, and each one enhance the solubility by different mechanism. To increase the drug's solubility, the numerous techniques discussed above can be used alone or in combination with one another.

The benefits and drawbacks of each technique must be considered while choosing the best approach for the drug selection. To reduce the likelihood of errors, it is essential to select the appropriate technique. Academic and corporate research has improved our understanding of how to make drug more soluble through various techniques; this science will help to0 produce effective drug formulations for poorly soluble drugs.

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