A Review on “Advance Solubility Enhancement Techniques”: Significant Strategy in Development of Formulation

Abstract

In pharmaceutical formulation, solubility is essential parameter because it directly impacts the bioavailability, effectiveness and therapeutic response of drugs. Many researchers are facing obstacles in the formulation and development due to poor aqueous solubility of drug, especially for Class II and IV medications under its Biopharmaceutical Classification System (BCS). Several research papers and articles were reviewed during study for improving solubility, including hydrotropy, inclusion complexation, micronization, particle size reduction, co-solvency, pH regulation, and supercritical fluids. New methods including co-precipitation, lyophilisation, and electrospinning are also examined. The benefits, difficulties, and uses of solubility enhancement techniques are also covered in detail in this article. This review article has mainly focused on by comprehending and utilisin solubility enhancement techniques in development pharmaceutical formulations, which increases therapeutic efficacy of formulation which is responsible for sustainability of product in market.

Keywords

Introduction

SOLUBILITY:

The solute's "solubility" refers to the greatest amount that dissolves in a specific solvent volume. The quantitative definition refers to solute concentration within a soaking solution at a specific temperature. Solubility is chemical substance’s ability, referred to as solute, to dissolve in a solid, liquid, or gaseous solvent as well as form a uniform solute solution within solvent. It has been the spontaneous cooperation of two or more molecular dispersions that are comparable. A solvent is a liquid that dissolves a solute, a substance that needs to be dissolved.

A solvent is a liquid that aids in the dissolution of a substance, while a solute is a substance that has dissolved. When the solvent is water, this reaction has been referred to as hydration or solution. The term "solubility" describes a substance’s (sometimes known as solute's) ability to dissolve in a solvent that is gaseous, solid or liquid, producing a uniform solute solution inside the solvent. The solvent, temperature, or pressure fundamentally influences a substance's solubility. Because solubility happens under unique equilibrium, solubility is thought to result from the concurrent and competing phases of dissolution and precipitation (solid precipitation, for example). Under some circumstances, equilibrium solubility might be exceeded, resulting in a supersaturated solution known as metastable. (1)

UNDERSTANDING AND SIGNIFICANCE OF SOLUBILITY

Solubility should be qualitatively described as concentration of solute within a characterised quantitatively by spontaneous interaction within 2 or more compounds for creating a homogenous molecular dispersion in a saturated solution at a particular temperature. When solute or solvent reaches equilibrium, saturation occurs.

Volume fraction, mole fraction, molarity, molality, percentage, and parts can all be used to describe a medicine's solubility. In terms of temperature, pH, and stress, drug solubility is greatest quantity of medicine solute which could dissolve in a solvent. One possible indication of a static property is the drug's solubility in a saturated solution, more closely associated with the rate of bioavailability than a dynamic one. (2)

THE NEED FOR SOLUBILITY

The medication's poor membrane permeability and water solubility are the two main reasons preventing it from being absorbed from the digestive system. Before a bioactive chemical to cross the GIT, membranes and reach the circulation, it must be broken down in the stomach and/or intestinal fluids when taken orally. Increasing the oral bioavailability of dynamic operators is now the focus of pharmaceutical research in two areas: the enhancement of solubility and the pace at which less water-soluble drugs are absorbed.

The BCS may serve as a scientific foundation for categorising pharmaceutical compounds based on their intestinal permeability as well as aqueous solubility. Since solubility in stomach fluid, not absorption, is the rate-limiting factor in drug release from dose form, improving solubility progressively raises bioavailability of BCS class II or IV medications. (3)

STEPS OF SOLUBILIZATION (1)

1. In the first step of the solubilization process, when the solute's interionic or intermolecular connections are broken, the solvent molecules disperse to accommodate the solute, and the molecules or ions of the solvent and solute interact.
2. In the second step, its solid molecule separates from its bulk.
3. The third step involves integrating a solid molecule's input into the solvent's hole.

BIOPHARMACEUTICAL CLASSIFICATION SYSTEM (BCS)

The BCS stated that the scientific framework used to classify pharmacological compounds supported their intestinal permeability and water solubility. This drug research tool allows one to estimate the three primary factors that affect the medication's oral absorption: intestinal permeability, solubility, and dissolution. Due to their inadequate solubility, BCS Class II and IV medicines pose significant hurdles for formulation scientists engaged in oral pharmaceutical delivery. (1)

One of the most important factors in exhibiting a pharmacological response while reaching concentration of desired drug concentration in systemic circulation is solubility. Most medications have low aqueous solubility, and hydrophobic medications, which are mildly basic and acidic, typically need large dosages to reach therapeutic plasma levels following oral administration. (4)

A critical and rate-limiting phase in oral bioavailability drug release is for medications with low solubility as well as high permeability, such as BCS Class II medicines. To reduce negative effects and boost bioavailability, BCS Class II drugs can have their drug release profile changed. (5)

The BCS provides a scientific basis for pharmaceutical classification as per their soluble properties, permeability, or dissolution characteristics. The BCS uses the following categories to classify drug compounds:

• Class I: High permeability as well as solubility
• Class II:  High permeability as well as Low solubility
• Class III: Low permeability as well as High solubility
• Class IV: Low permeability as well as solubility

METHOD TO ENHANCE SOLUBILITY

Physical Modification

• Particle Size Reduction:

Drug solubility and particle size are frequently inextricably linked; as particle size decreases, the surface area to volume ratio rises. A greater surface region facilitates more contact with the solvent, enhancing solubility. (3)

• Micronization:

The traditional method of micronization reduces particles to the micrometer or nanometer range. By increasing particle surface area, micronization speeds up drug dissolution and, in turn, increases the bioavailability of poorly soluble active pharmaceutical ingredients.

Micronization decreases particle size and enhances drug crystals' amorphous characteristics and structural disorder. Three mechanical methods for micronizing pharmaceuticals are air jet mills, fluid energy mills, and rotor stator colloidal mills. (6)

Chemical Modification

• Co-solvency/ Solvent Blending:

Is a method for making prescription drugs more soluble in water by mixing an organic solvent with water in a safe and non-toxic way. Cosolvents like polyethylene glycols, glycerin, propylene glycol, ethanol, and glycofural are commonly used in the pharmaceutical industry. The co-solvency of solvent combinations, particularly non-water-based ones, affects viscosity, surface tension, acid dissociation constants, and drug stability. Co-solvency models come in three varieties: theoretical, semi-empirical, and empirical. (7)

• Hydrotrophy:

When a second solute is added in large amounts, a solubilization process called hydrotropy occurs. The solute comprises alkali metal salts of different organic acids, which elevates the water solubility of the solute. "Hydrotropic agents" refers to ionic organic salts. When a solute is "salted in" by salts or additives that make a substance more soluble in a certain solvent, it is referred to be "salted out" by salts that decrease its solubility. Water-soluble cations or large anions in many salts lead non-electrolytes to "salt in," a process called "hydrotropism."(1)

• Inclusion Complexation:

The method by which A non-covalent bond is created when two or more molecules combine complex that is more soluble than the drug is known as complexation. Cyclodextrin inclusion complexes have improved the stability and solubility of medications categorized under the Biopharmaceutical Classification System II. In recent years, cyclodextrins have become more widely used in the food, chemical, pharmaceutical, agricultural, and environmental engineering industries. Piroxicam is a famous nonsteroidal anti-inflammatory medication having analgesic, antipyretic, and anti-inflammatory effects. (8)

• pH Adjustment

A change in pH can cause a drug that isn't very soluble to dissolve in water. Determining the solubility of this approach requires careful consideration of buffer capacity and pH tolerance. Soluble excipients, which increase the ambient pH inside the capsule, alkalizing excipients, or weakly acidic medications, increase the solubility of such medicines to a range greater than the pKa. May improve the solubility of weakly basic medications. (1)

• Supercritical Fluid (SCF) Process (9)

Additionally, numerous technologies and applications utilising supercritical fluids have increased rapidly. The ability of supercritical fluids (SCFs) to dissolve non-volatile solvents has been understood for over a century. The most popular SCF is carbon dioxide, which has a critical point. It is affordable, safe, and good for the environment. Pharmaceutical research finds SCFs appealing because of their low working conditions (temperature and pressure). A single phase is called an SCF below its critical temperature (Tc) also pressure (Pc). Because SCFs are in the middle of pure liquid and gas, they have properties that are useful for product processing, such as more diffusivity than liquids, density similar to a liquid, as well as compressibility and viscosity similar to a gas. Additionally, there are noticeable differences in density, transport properties (like viscosity and diffusivity), along with additional physical characteristics with minor adjustments to the operating pressure, temperature, or both (e.g., polarity or dielectric constant) at the critical points. As a result, it is feasible to combine the qualities required for a particular application precisely.

Recently, SCFs' distinctive processing abilities, which have long been acknowledged and used in the food industry, have been modified for use in medicinal applications. Supercritical solvents frequently used include water, n-pentane, ethylene, propylene, propane, carbon dioxide, nitrous oxide, ethanol, and ammonia. The drug particles may recrystallise at significantly smaller particle sizes after becoming soluble in SCF. Drug particles may be micronized within a limited range of particle sizes, frequently to sub-micron levels, owing to SCF's adaptability and precision. Techniques. It has been shown that current SCF procedures may produce nano suspensions of particles with a diameter of 5–2,000 nm.

DRUG DISPERSION IN CARRIER

SOLID DISPERSION (8)

A solid dispersion is a collection of solid goods containing at least 2 different ingredients. It mainly consists of a hydrophilic matrix containing a hydrophobic medication. Amorphous and crystalline matrixes are the two varieties. Medication can be dispersed in three different ways: crystalline, amorphous, or molecular.

TYPES OF SOLID DISPERSIONS:(8)

• Continuous solid solutions
• Solid solution
• Glass solution & suspensions
• Eutectic mixtures
• Substitutional solid dispersions
• Discontinuous solid solutions
• Interstitial solid solutions
• Amorphous precipitation in crystalline matrix

ADVANTAGES OF SOLID DISPERSION:(10)

• Better Wettability of Particles
• Reduced Particle Size Particles
• The Higher Porosity Particles
• The amorphous condition of the drug

DISADVANTAGES OF SOLID DISPERSION (9)

• Because they transform into less soluble crystalline forms when stored in moisture, amorphous medicines are not commonly used as commercial products. This is because the increased drug mobility can cause phase separation and instability.
• Expensive preparatory techniques hinder large-scale production.
• It is not possible to ensure reproducibility.
• It can be difficult to incorporate SDs into various dose formulations.

SELECTION OF CARRIER (11)

The development of solid dispersions depends on carriers, which can be hydrophilic or hydrophobic, swell in water, and function as release enhancers or retardants based on their properties.

Moreover, the kind of carrier affects how well medication molecules dissolve. When choosing a carrier, the following criteria are taken into account:

• It should be water soluble or swellable and dissolve in various solvents.
• It should be pharmacologically inactive, non-toxic, and reasonably priced.
• It must have heat stability.
• Chemically compatible with the drug.

POLYMERS USED IN SOLID DISPERSION

• Polyethylene glycol (PEG): For solid dispersions and solutions, polyethylene glycols (PEGs) have a viscosity that rises with their molecular weight (MW). PEGs resemble Vaseline in viscosity and are waxy, hard, brittle, and fluid. (8)
• Polyvinylpyrrolidone (PVP): The result of vinylpyrrolidone polymerization is polyvinylpyrrolidone (PVP), which has a molecular weight between 2500 and 3000000. Fikentscher's equation can be used to determine the K value, which can be used to categorize these. The moisture content of a PVP affects its temperature in addition to its MW. The temperature at which glass transitions (Tg) is often high. (12)
• Phospholipids: The components were dissolved in filtered water to create blends of polymer-phospholipid and polymer-xylitol. Using different concentrations of phospholipid and xylitol, the plasticizing impact was assessed. The amount of excipient needed for a glass transition at 120°C was calculated. The combination was lyophilized, freeze-dried, and ground into a mill powder. (13)

METHODS OF PREPARATION OF SOLID DISPERSION

1. Lyophilization Techniques
2. Kneading Method
3. Electrospinning Method
4. Super Critical Fluid Technology
5. Melting or Fusion method
6. Solvent evaporation method
7. Co-Precipitation Method

• Melting method or Fusion Method

Low melting point, heat-stable materials are best suited for melting techniques. These techniques entail melting the medication and carrier, combining them, and then chilling them to produce a uniform solid dispersion. They lower formulation hazards and toxicities and are inexpensive and simple to employ. (13)

• Solvent evaporation method

The development of solvent evaporation techniques for heat-unstable components has led to using carriers with high melting points. These techniques include mixing drug as well as carrier in a solvent, agitating, even evaporating mixture to create a solid dispersion. (14)

• Super Critical Fluid Technology

Supercritical fluid technology (SFT) has many benefits in SD formulation. The SFT is acknowledged as an environmentally friendly, safe, green, and sustainable approach. Furthermore, since the SFT has been used for many years in the food and textile sectors and standards for the tools and procedures needed for Good Manufacturing Practice (GMP) have already been established, it might be readily adopted in the pharmaceutical industry. By using the SFT, the drawbacks of procedures that rely on the application of natural solvents or melting are eliminated. Primary benefit with the SFT is that it does not affect the process and should not be used in conjunction with the polymers' compatibility and miscibility at high temperatures, nor does it depend on the thermostability of the API. (1)

• Electrospinning Method

Nanotechnology and SD technologies are combined in the electrospinning process. A millimeter-scale nozzle delivers a stream or melt of polymeric fluid to create solid fibers. The benefits of this approach are its affordability and ease of use. PVA (polyvinyl alcohol): ketoprofen (1:1, w/w) nanofiber has been generated using the electrospinning technique, an effective method for making nanofibers and controlling drug release. This nanofiber dissolved far more readily than ketoprofen alone (p < 0.05). In another work, PVP was used as the carrier in the electrospinning process for creating an amorphous formulation of indomethacin along with griseofulvin. In a desiccator, this formulation remained stable for eight months. (15)

• Lyophilization Techniques

Lyophilization, an alternative technique to solvent evaporation, which creates a lyophilized molecular dispersion by dissolving medication and carrier in a solvent and then freezing the mixture in liquid nitrogen. Thermolabile goods that are stable in dry state for extended storage times but unstable in aqueous solutions are usually treated with this technique. To assess physicochemical and in vitro properties, nifedipine and sulfamethoxazole SD were synthesized using Solu plus and PEG 6000 as carriers in a prior work. (16)

• Kneading Method

This procedure turns the carrier into a paste by dispersing in water. The medication has been then added as well as carefully kneaded. The final kneaded formulation has been dried as well as sieved (if needed). The kneading procedure was used to manufacture cefixime SD with β-CD as the carrier. According to results, Cefixime's dissolution rate from the SD had been 6.77times higher than the pure medication, which may indicate an improvement in BA. In domperidone SD, HP-β-CD had been carrier in a different investigation. Domperidone from SD had much better saturation solubility as well as in vitro dissolution (3-fold) than pure medication. (16)

• Co-Precipitation Method

This approach involves dissolving the carrier in a solvent to create a solution, then stirring the medication into the solution to create a homogenous mixture. For precipitation, dropwise addition of water to homogeneous mixture. After filtering and drying the precipitate, a silymarin SD was made employing HPMC E15LV as carrier as well as various techniques, that includes spray-drying, co-precipitation as well as kneading. When compared to other 2 approaches, the silymarin SD produced via co-precipitation demonstrated noticeably (p<0.05) improved solubility. Also, compared to traditional medication, solubility of silymarin from SD made via co-precipitation enhanced by a factor of 2.5.(17)

CHARACTERIZATION OF SOLID DISPERSIONS. (13)

• Analysis of Thermo-Gravimetric
• Polarized Light Microscopy in Hot Stage
• Infrared Spectroscopy Using Fourier Transformation
• X-Ray Diffractometry at Wide Angles
• Calorimetry via Differential Scanning
• Dissolution Studies
• Scanning Electron Microscopy
• High-Performance Liquid Chromatography

CONCLUSION

A key component of pharmaceutical formulation is improving drug solubility has a direct impact on bioavailability, therapeutic efficacy, as well as patient outcomes.  For improving the dissolving profiles of weakly water-soluble pharmaceuticals, a variety of solubility enhancement approaches have been thoroughly investigated. These techniques include inclusion complexation, micronization, co-solvency, hydrotropy, pH modification, particle size reduction, micronization, and supercritical fluid technology.  Solid dispersion has become a viable approach among these because of its capacity to increase drug porosity, decrease particle size, and improve wettability. Modern developments like co-precipitation, lyophilization, and electrospinning keep improving solubility improvement methods and provide creative ways to formulate BCS Class II and IV medications. Large-scale industrial usage, however, requires addressing difficulties including repeatability, scalability, and stability. Future studies should concentrate on refining these techniques, creating new carriers, and incorporating nanotechnology-based strategies to improve medication solubility and therapeutic efficacy even more. Drug delivery systems can be greatly enhanced by the pharmaceutical industry by utilizing these developments, which will ultimately improve patient care and treatment results. (9).

Ethics

This review article is based on a comprehensive analysis and synthesis of previously published literature. No new studies involving human participants or animals were conducted by the authors for the purposes of this work. All sources of information have been properly cited to acknowledge the contributions of original authors. The manuscript adheres to ethical standards in scholarly publishing, including honesty, integrity, and transparency. The authors affirm that there is no plagiarism, data fabrication, or unethical manipulation of citations. Any potential conflicts of interest have been disclosed.

ACKNOWLEDGEMENT

The authors express sincere gratitude to all researchers whose valuable contributions have formed the basis of this review. The support and insights from mentors, colleagues, and institutions involved in facilitating access to relevant resources are also gratefully acknowledged.

Conflicts of Interest

The authors declare that there is no conflict of interest.

Funding

No funding required.

Data access

The data that support the findings of this study are mentioned in the references.

ACKNOWLEDGEMENT

The authors express sincere gratitude to all researchers whose valuable contributions have formed the basis of this review. The support and insights from mentors, colleagues, and institutions involved in facilitating access to relevant resources are also gratefully acknowledged.

Conflicts of Interest

The authors declare that there is no conflict of interest.

Authorship Statement:

Nadeem A. Farooqui: Abstract

Introduction, Method: Saransh Jain, Deepika Bhawsar

Referencing: Deepika Bhawsar

Editing: Nadeem A. Farooqui, Nimita Manocha.

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