INTRODUCTION:

The limited solubility of pharmaceutical active compounds presents a problem in their use as pharmacological agents; however, the requirement for a precise solubility parameter precludes any compromises. The solubility of a medicine is crucial to its formulation and bioavailability, directly influencing the efficacy of pharmacological compounds. Drugs with poor absorption encounter challenges in attaining the intended therapeutic effects, leading to inferior therapy results. The emergence of numerous freshly synthesised chemical compounds with low water solubility has rendered solubility enhancement a primary objective in pharmaceutical research and development.¹

The solubility of a medicine in a solvent is a crucial determinant of its absorption, bioavailability, and therapeutic efficacy in addressing a medical problem. The BCS framework categorises pharmaceuticals into four classes according on their solubility and permeability characteristics, with Class II compounds exhibiting low solubility but high permeability. The drug's poor solubility frequently poses considerable hurdles in its formulation, as it constrains the drug's bioavailability, particularly when taken orally. Thus, enhancing the solubility of poorly soluble pharmaceuticals has emerged as a crucial focus in the pharmaceutical sector.² The selection of an approach to enhance dissolvability is contingent upon the specific characteristics of the medicine. By employing these methodologies, pharmaceutical researchers may overcome the obstacles posed by poorly soluble medicines. Solubility denotes the amount of solute that may dissolve in a certain quantity of solvent at a particular temperature. As temperature increases, the activity of the solute and dissolvable atoms intensifies, facilitating the disruption of the forces binding the solute and promoting its dissolution. As temperature increases, solubility may decrease for certain compounds. Drugs with low solubility require greater dosages to achieve efficacy, potentially resulting in increased side effects and chronic non-compliance. The solubility of drugs is frequently influenced by their physicochemical qualities. The efficacy of the medicine can be affected by natural factors, such as proximity to the gastrointestinal tract.²

Determinants of Solubility:

Solubility denotes the capacity of a substance to dissolve in a solvent, resulting in a solution. Various factors influence the solubility of a material, including temperature, mass, and the characteristics of the solute.

1. Temperature:

The solubility of solid solutes in liquid solvents often increases with an elevation in temperature. Higher temperatures impart increased kinetic energy to solute particles, facilitating their disaggregation and interaction with solvent molecules. Sugar dissolves more rapidly in hot water than in cold water. Attempting to dissolve sugar in iced tea will reveal that it requires a prolonged duration and may not fully dissolve without extensive mixing.

Impact on Gases in Liquids: Conversely, the solubility of gases in liquids decreases with an increase in temperature. Increased temperature enables gas particles to escape more readily from the liquid, hence reducing solubility. Carbonated beverages effervesce more rapidly when left in a warm atmosphere, as the dissolved carbon dioxide escapes more readily with increasing temperature.³

2. Pressure Impact on Solids in Liquids:

Typically, the solubility of solid solutes in liquid solvents escalates with an increase in temperature. Higher temperatures impart increased kinetic energy to solute particles, facilitating their disintegration and enhancing interactions with solvent molecules, hence promoting solubility. Sugar dissolves more rapidly in hot water than in cold water. Attempting to dissolve sugar in iced tea will reveal that it requires a prolonged duration and may not fully dissolve without extensive mixing. The solubility of gases in fluids decreases with an increase in temperature. Elevated temperatures facilitate the escape of gas particles from the liquid, hence reducing solubility. For instance, carbonated beverages effervesce more rapidly when left in a warm atmosphere, as the dissolved carbon dioxide gas escapes more readily with rising temperatures.⁴

3. Characteristics of Solute and Solvent Polarity:

The principle "like dissolves like" generally holds true. Polar solvents, such as water, dissolve polar solutes, like salt, whereas non-polar solvents, such as oil, dissolve non-polar solutes, such as grease. The maximum "like dissolves like" generally holds true. Polar solvents, such as water, dissolve polar solutes, such as salt, whereas non-polar solvents, such as oil, dissolve non-polar solutes, such as grease. For instance, salt readily dissolves in water, a polar solvent, but has poor solubility in oil, a non-polar solvent. This explains the utilisation of water to dissolve salt during cooking and the application of oil to eliminate greasy streaks.⁵

4. Particle Size:

As particles decrease in size, their surface area in relation to their volume escalates. The increased surface area improves their interaction with the solvent, promoting more efficient dissolution.

5. Molecular Dimensions:

Larger and heavier molecules of a material have reduced solubility in a solvent. This occurs because the solvent molecules find it more challenging to fully encircle and decompose these larger molecules.⁶

Factors Related to Poor Drug Solubility:

1. Aqueous solubility:

Pharmaceuticals exhibiting water solubility under 100 µg/mL are classified as weakly soluble. The drug's low solubility results in poor dissolution in water, thereby restricting absorption and bioavailability. Itraconazole is an antifungal agent employed in the treatment of several fungal infections. Nevertheless, its solubility in water is exceedingly poor, which restricts its absorption in the gastrointestinal system upon oral administration.⁷

2. Low dissolution rate:

A medicine with a dissolving rate below 0.1mg/cm² inadequately dissolves in body fluids, hindering its absorption efficacy. Griseofulvin, an antifungal agent employed for the treatment of dermatophyte infections, has limited solubility in water, leading to a diminished dissolution rate and suboptimal bioavailability.

3. Self-association and aggregation:

Certain medications exhibit a propensity to self-associate or aggregate in solution, thereby diminishing their effective concentration in the solvent and further impairing solubility. Ritonavir, an antiviral medication, may agglomerate in its crystalline state, resulting in inadequate solubility. It is frequently formulated in an amorphous state to improve its solubility.⁸

4. High crystal energy:

Substances with elevated crystal energy exhibit robust intermolecular interactions inside their solid matrix, rendering them resistant to disintegration and solvation in a solvent. Elevated crystal energy constitutes a substantial impediment to solubility. Carbamazepine is an anticonvulsant and mood-stabilizing medication characterised by robust intermolecular interactions in its crystal lattice, resulting in low solubility in water.

5. Elevated molecular weight:

Pharmaceuticals with elevated molecular weight sometimes include intricate structures, complicating their solubility, particularly in aquatic conditions. Paclitaxel, an antineoplastic agent, with a considerable molecular weight and exhibits limited solubility in aqueous solutions. It is frequently combined with carriers such as Cremophor EL to enhance its solubility for intravenous delivery.⁹

Significance of Solubility:

Solubility is essential in numerous dosage forms, particularly in the context of injectable formulations. Achieving the required drug concentration in the bloodstream is crucial for obtaining the desired therapeutic effect. Drugs that exhibit low solubility in water typically require increased dosages to attain effective plasma concentrations following oral administration. The low solubility poses a significant challenge in the research and development of novel medicinal compounds and genetic materials. Water serves as the preferred solvent for liquid medications, as it guarantees that substances are presented in an absorbable form at the site of absorption. The majority of pharmaceuticals exhibit low water solubility and are typically classified as weak acids or bases.¹⁰

BCS Classification System:

The Biopharmaceutics Classification System (BCS) categorises drugs based on their solubility and permeability, facilitating predictions regarding their behaviour within the body.

Fig 1. Biopharmaceutical Classification System

Fick's first law of diffusion is articulated as follows: J = (Pw)(Cw)

Where J denotes the flux across the intestinal wall, Pw indicates the gut wall's permeability to the drug, and Cw reflects the concentration profile at the gut wall.¹¹

The process of solubilization:

1. Disrupting Inter-Ionic or Intermolecular Bonds in the Solute: The initial phase entails the cleavage of bonds present within the solute. This involves disrupting the inter-ionic bonds in ionic compounds or the intermolecular bonds in molecular compounds that maintain the integrity of the solute.

2. Separation of Solvent Molecules: The solvent molecules must separate from one another to create space for the solute particles. This step entails addressing the interactions that bind the solvent molecules.

3. Interaction between solvent and solute: Once the solute and solvent molecules are liberated, they engage with one another. This interaction may involve different forces, depending on the characteristics of the solute and solvent. Interactions such as hydrogen bonds, van der Waals forces, or ionic interactions may take place.

4. Formation of voids in the solvent: As the solute dissolves, voids or spaces are generated within the structure of the solvent. This is essential for the solute molecules or ions to occupy.

5. Integration of Solute into the Solvent: The solute molecules are ultimately integrated into the solvent. The solute molecules or ions occupy the spaces within the solvent, resulting in a uniform solution in which the solute is completely dissolved.¹²

Physical Modifications:

1. Micronization of Particle Size:

The dissolution properties of a drug are significantly influenced by its particle size; larger particles exhibit a reduced surface area, which restricts their interaction with the solvent. Reducing particle size increases the total surface area, thereby enhancing dissolution and absorption rates.

A) Micronization: Entails the process of transforming a solid material into minuscule particles, akin to the method of grinding a substance into an exceptionally fine powder. This technique is frequently utilised to improve the solubility of drugs, facilitating their more efficient dissolution within the body. Techniques including freeze-drying, crystallisation, spray drying, and milling are employed to produce micron-sized drug particles, especially for BCS Class II medications. This is achieved through

a) Milling and grinding: Envision utilising a highly efficient blender or grinder to finely pulverise the material into minute fragments.

b) Jet Milling: This process involves utilising high-velocity air to collide particles with one another, resulting in their reduction to a significantly smaller size.

B) Nanosuspension: A "nanosuspension" is a liquid containing small particles known as nanoparticles dispersed within it. These particles are minuscule, necessitating a microscope for observation, and they may possess unique features due to their diminutive scale. Preparation of Nanosuspension: Bottom-Up and Top-Down Technologies Nanosuspensions, comprising sub-micron colloidal dispersions of pure drug particles, can be produced using two primary methodologies: bottom-up and top-down methods. Both methods offer distinct benefits and are efficient in improving the solubility and bioavailability of poorly soluble medicines.¹³

Fig2. Bottom-Up and Top-Down Process of Nanosuspension

C) Bottom-Up Technology: This approach entails dissolving the medication in a solvent and subsequently precipitating nanoparticles. Methods such as antisolvent precipitation, microprecipitation, and solvent evaporation are included in this category. Bottom-up methodologies are optimal for regulating particle dimensions and attaining uniform dispersion.

D) Top-down Technology: Commences with bigger drug particles that are then reduced to nanoparticles. Prevalent methods encompass high-pressure homogenisation and grinding. These approaches are particularly beneficial for medications that are challenging to dissolve and necessitate mechanical effort to diminish particle size.¹⁴

2. Alteration in Crystal Morphology Crystalline Structures:

Polymorphism- refers to the ability of a substance to crystallise in several forms, termed polymorphs. Although these crystalline forms are chemically equivalent, they exhibit distinct physicochemical features such as melting temperature, texture, density, solubility, and stability. The amorphous form of a medication is typically more advantageous than its crystalline counterpart due to its greater surface area and elevated energy levels. Polymorphs can profoundly affect the drug's properties and efficacy.

Pseudo polymorphs- entails the inclusion of solvent molecules within the crystal lattice of a solid, resulting in the formation of solvates. These solvates display distinct crystalline structures referred to as pseudo polymorphs. Despite being chemically equivalent, these forms exhibit variations in physicochemical qualities such as melting point, texture, density, solubility, and stability. Amorphous forms frequently possess advantages over crystalline forms owing to their increased surface area and elevated energy levels. The hierarchy of solid drug forms is generally: Amorphous > Metastable polymorphs > Stable polymorphs.¹⁵

3. Drug Dispersion in carriers:

Eutectic Compositions The combination of two or more substances generally does not produce a homogeneous product. At specific ratios, the components may impede one another's crystallisation, leading to a mixture with a melting point lower than that of the separate components.

Solid Dispersion:

Involves the incorporation of a hydrophobic medication into a hydrophilic matrix, which can be either crystalline or amorphous. The medicine might be distributed at the molecular level as amorphous aggregates or as crystalline particles. This method improves the solubility and bioavailability of poorly soluble pharmaceuticals.

i) Solvent Evaporation Method:

This technique is extensively employed for the fabrication of polymeric nanoparticles and nanocapsules. The method involves dissolving the polymer and the medication in a volatile organic solvent, thereafter emulsifying them in an aqueous phase with a surfactant. The organic solvent is subsequently evaporated, leading to the creation of nanoparticles or nanocapsules. Recent improvements seek to enhance the comprehension of nanoparticle formation mechanisms and optimise synthesis from novel structures or polymers.¹⁶

ii) Fusion Process:

Techniques such as hot melt extrusion (HME) and KinetiSol® technologies are significant for enhancing the solubility of poorly soluble pharmaceuticals.

a) Hot Melt Extrusion (HME):

involves the fusion of the medication with the polymer, followed by the extrusion of the mixture to generate a solid dispersion. HME is acknowledged for enhancing the bioavailability of poorly soluble active pharmaceutical ingredients and facilitating an efficient, continuous production process. It is employed in the manufacture of diverse dosage forms, including tablets, capsules, and granule-filled sachets, as well as innovative formulations such as dry powder inhalers, nano extrusion, 3D printing, and amorphous solid dispersions.

b) Kinetisol® Technology:

Similar to HME, it employs strong shear pressures to amalgamate the medication and polymer without required elevated temperatures. It is appropriate for heat-sensitive pharmaceuticals and expedited processing. This technology is very beneficial for formulating poorly soluble medicines, improving their bioavailability and therapeutic effectiveness. Optimising equipment and processes can be intricate.¹⁷

The spray drying process involves the atomisation of the liquid input (solution, suspension, or emulsion) into a fine mist via a nozzle or rotary atomiser. Desiccation occurs as droplets are swiftly evaporated in a heated gas stream, typically air, leading to the creation of solid particles. Collection: The desiccated particles are gathered with cyclones or filter bags.¹⁸

Techniques for the formation of inclusion complexes

Blending Method:

The kneading process rapidly amalgamates high-performance materials (HPs) with a polyethyleneimine (PEI) polymer solution, producing a "dough" that facilitates the formation of stable suspensions in aqueous solutions. This technology enables pharmaceutical researchers to diminish particle size, producing small, spherical, and readily flowing particles of poorly soluble active pharmaceutical ingredients (APIs), hence minimising unwanted needle-like morphologies. Factors affecting the kneading process encompass duration, temperature, pace, aeration, and water content, all of which must be regulated to enhance the dough's rheology and resulting characteristics.

Co-precipitation Method:

Co-precipitating amorphous solid dispersions (ASDs) entails the amalgamation of drug molecules with excipients at the concluding stage of chemical processing, hence augmenting the functional attributes of proteins. Titanium with nanotubular structures can be anodised and infused with penicillin-based antibiotics using a co-precipitation method, wherein the drug molecules precipitate alongside calcium phosphate crystals in simulated physiological fluid.¹⁹

4. Lyophilization (Spray Freeze Drying Method):

Entails the removal of water from a frozen material through sublimation and desorption. This procedure, which includes freezing, primary drying, and secondary drying, influences the quality of the final product. Cryopreservation, a crucial method for preserving biological products, entails the spray freeze-drying of polymeric and lipid nanoparticles by dispersing them into cold air infused with cryoprotectants, succeeded by freeze-drying.²⁰

5.Microwave Irradiation Technique:

Microwave irradiation in solid-phase peptide synthesis enhances product purity and reduces reaction duration. This approach enhances reaction efficiency by augmenting product recovery while minimising by-product formation and energy consumption. Microwave technique enhances drug-polymer interactions and modifies dissolution properties, providing advantages including superior product quality, energy efficiency, and reduced processing durations.

6. Surfactant-Induced Solubilisation:

Microemulsion: A thermodynamically stable isotropic dispersion consisting of a polar solvent, oil, surfactant, and co-surfactant. Microemulsions spontaneously develop and stabilise via mixed-film formation at surfaces. They improve the dissolving rate of poorly water-soluble medicines by solubilising them in the oil phase. 39Self-Micro Emulsifying Drug Delivery Systems (SMEDDS) facilitate emulsion formation in the gastrointestinal tract using a blend of oil, surfactant, co-surfactant, hydrophilic solvent, and co-solvent. These methods enhance the solubility and absorption of lipophilic medicines by generating fine emulsions or micro-emulsions upon dilution in the gastrointestinal tract. Although they are easily scalable and manufacturable, elevated surfactant concentrations may irritate the gastrointestinal tract.²¹

Chemical Alteration:

Solubility can be improved by including polar functional groups (e.g., carboxylic acids, ketones, amines) to reinforce hydrogen bonding and augment water interaction. Methods encompass salt production, co-crystallization, co-solvency, hydrotropy, the application of new solubilizers, and nanotechnology.

1. Synthesis of Salt:

The application of salt synthesis methods aims to enhance the solubility and dissolution of medicinal compounds. This technique is utilised to monitor any chemical response or alteration in various pharmaceuticals. Salt is generated when the medication experiences ionisation. The procedure encompasses multiple methodologies, including physiochemical qualities that influence the stability, biological availability, filtration, and manufacturability of the medication. The creation of salts has long been a favoured method to enhance the solubility of poorly soluble therapeutic candidates. This approach pertains to the methodology for assessing responses to various drugs or chemicals. Salt is generated when the medication is in an ionised state. It possesses an exceptional approach for physicochemical properties and effects Stability, bioavailability, purification, and manufacturability of the pharmaceutical compound. Salt production has been utilised for various periods to enhance solubility. For example, Aspirin, Theophylline, Barbiturates, etc.²²

2. pH Modification:

Pharmaceuticals with low aqueous solubility may dissolve in water via pH alteration. It is essential to evaluate buffer capacity and acceptable pH levels. Solubilising excipients that modify the pH of the dosage form to exceed the pKa of weakly acidic medicines can improve solubility. For weakly acidic pharmaceuticals, a decreased pH induces an un-ionized, insoluble precipitate, whereas an elevated pH produces an ionised, more soluble variant. In contrast, for weakly basic medicines, a decreased pH induces ionisation and enhanced solubility, while an elevated pH results in a unionised, insoluble precipitate.

3. Co-Crystallization:

Enhancing the solubility of molecular crystals requires the alteration of their surface characteristics and molecular arrangement. Enhanced solubility is a trait of unstable/metastable polymorphic forms that retain their molecular structure, exhibiting reduced crystal lattice energy and increased thermodynamic solubility. This approach has revealed that polymorphic modification affects the dissolving rate and bioavailability of pharmaceutical compounds, as evidenced in the pharmaceutical co-crystals of carbamazepine (Tegretol).²³

4. Hydrotropy:

Hydrotropy involves enhancing the saturation solubility of a chemical in water with the addition of organic salts or non-electrolytes that must be physiologically suitable for medicinal applications. Hydrotropic agents enhance the quantity of hydrogen bonds in water clusters by association or chemical complexation, rendering water more hydrophobic and a superior solvent for non-polar pharmaceuticals. Nonetheless, the application of hydrotropic agents such as sodium benzoate, nicotinamide, urea, caffeine, and sorbitol are constrained by marginal enhancements in saturation solubility at elevated excipient concentrations and the absence of isotonicity.

5. Cosolvency:

Co-solvents, consisting of water and one or more water-miscible solvents, improve the solubility of poorly soluble substances. They can enhance solubility by multiple orders of magnitude compared to solubility in water alone. Examples comprise dimethyl sulfoxide (DMSO) and dimethylacetamide (DMA), recognised for their substantial solubilisation ability and minimal toxicity. Weak electrolytes and nonpolar molecules exhibit enhanced solubility in solvent mixtures, a phenomenon referred to as co-solvency.

6. Nanotechnology:

Nanotechnology has impacted solubility enhancement by modifying the properties of nanoparticles utilised in nano-formulations, nutritional supplements, and the food sector. Nanomaterials, due to their small size and elevated surface-to-volume ratio, are highly effective in improving solubility, oral bioavailability, stability, and controlled release. Methods such as grinding, high-pressure homogenisation, vacuum deposition, and high-temperature evaporation produce nanoparticles. Nanotechnology has significantly enhanced the anticancer efficacy of drugs such as resveratrol in both experimental and in vivo environments.²⁴

Novel Solubility Enhancement Strategy:

1. Liquisolid Method:

Numerous pharmaceuticals are lipophilic and exhibit poor solubility in water, complicating their absorption by the body. The liquisolid technology addresses this issue by converting liquid pharmaceuticals into dry, free-flowing, and compressible powders. This is accomplished by combining the liquid medication with certain excipients referred to as carriers or coating agents.

2. Spherical Agglomeration:

This technique, referred to as spherical crystallisation, transforms crystals into compact spherical shapes during their formation. This technique minimises tablet size by decreasing the necessity for fillers and enhances the flow and compressibility of the medication powders.

3. Melt Sono Crystallisation

This approach alters the physical and chemical features of medicines, such as rosiglitazone, enhancing their efficacy. It enhances the responsiveness of adipocytes to insulin, functioning as an insulin sensitiser through its interaction with the PPAR receptor.

4. Prodrug Strategy:

Prodrugs are inactive drug forms that activate upon entering the body. This method, however challenging to implement, has the potential to enhance the characteristics of both novel and existing pharmaceuticals.

5. Approaches in Nanotechnology:

Transforming medications into nanoparticles enhances their solubility and dissolution rate. In solid forms, these minute particles are stabilised on polymer substrates. They can also be converted into a liquid suspension for oral or injectable administration.²⁵

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Received on 25.02.2025 Revised on 05.04.2025

Accepted on 10.05.2025 Published on 10.07.2025

Available online from July 17, 2025

Asian J. Pharm. Res. 2025; 15(3):309-315.

DOI: 10.52711/2231-5691.2025.00048

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.