Solubility Enhancement Techniques: Physical and Chemical Methods

Solubility Enhancement Techniques

The ability of the substance to dissolve in a solvent at a specific temperature and pressure to form a solution is called solubility. Solubility of poorly soluble or insoluble substances can be increased by the following techniques. The Process to dissolve poorly soluble or insoluble substances is called solubilization

• A. Physical methods

• B. Chemical methods

Physical methods to increase the solubility: Physical methods include size reduction of solid particles, polymorphism, drug dispersion, complexation, and use of surfactants.

• 1. Size Reduction: A decrease in particle size of the solid particles increases the surface area of the solid particles. An increase in the surface area of the particles increases the solubility of poorly soluble or insoluble drugs. However, a significant increase in solubility is achieved by the formation of microparticles or nanoparticles. For this purpose, micronization is carried out by using a colloidal mill, jet mill, or sonication. There are several methods to produce nanoparticles such as high-pressure homogenization, nanoprecipitation, emulsification-solvent evaporation, supercritical fluid technology, spray drying, sonication, etc.

• 2. Polymorphism: The ability of the drug particles to exist in multiple crystalline forms is called polymorphism. Each crystal form has different physical properties. These crystals are called polymorphs. Some polymorphs undergo transformation from one form to another form. They are called metastable polymorphs. Some polymorphs remain stable. They are called stable polymorphs. Metastable polymorphs have a high level of energy. A metastable polymorph with high solubility is selected. Thus polymorphism influences the solubility of the drug.

• 3. Amorphous forms: Amorphous drug is more soluble than crystalline drug. Amorphous drugs have high energy with a large surface area. Both contribute to increasing the solubility of the amorphous drug.

• 4. Anhydrous forms: Anhydrous drugs have no water molecules. Thus, they have a tendency to attract water molecules. Drugs with water molecules are called hydrates. Anhydrous drugs are more water soluble than hydrates.

• 5. Solid dispersion: It is a pharmaceutical technique to increase the solubility of poorly water-soluble drugs. An active pharmaceutical ingredient (API) is dispersed in the solid matrix, normally a polymer or mixture of polymers. This converts API crystalline form to anhydrous or finely dispersed form. Here API molecules shall be more readily available for dissolution. Solid dispersion has the following characteristics:

  • · Large surface area

  • · Highly porous

  • · Anhydrous/amorphous/metastable polymorph

  • · Improved water attraction which increases the wettability and dispersibility of API particle

• 6. Molecular dispersion (Solid solution): Molecular dispersion is a homogeneous mixture of two or more elements or compounds in a solid state. Molecules or atoms of the components are uniformly distributed at the molecular or atomic level under a solid state. In molecular dispersion, all components have similar crystal structures and atomic sizes. This allows them to intermix to form a homogeneous mixture.

  • Molecular dispersion increases the solubility of poorly water-soluble API. Molecular dispersion increases solubility by

  • · Producing matrix effect by one or more component

  • · Increasing the surface area of API,

  • · Forming amorphous form,

• · Breaking crystalline barriers,

• 7. Complexation: The binding of molecules or ions to a central metal ion forms a complex. This process is called complexation. Some complexes are insoluble while others are soluble in water. Complexation enhances the solubility of certain substances in solution.

• Insoluble substance reacts with soluble ingredients to form a soluble complex. For example. Iodine is poorly soluble in water. Potassium iodide is soluble in water. Iodine combines with potassium iodide in solution form to form a potassium tri-iodide complex. Potassium tri-iodide is readily soluble in water. Caffeine solubility in water is 1:50. Complex formed by the caffeine and sodium benzoate solubility in water will be 1:1.2.

• Cyclodextrin is an oligosaccharide. It is used to increase the solubility of poorly water-soluble drugs by a process called inclusion complex formation. Cyclodextrin has a hydrophobic inner cavity and hydrophilic outer surface. Poorly water-soluble API molecules enter into the hydrophilic cavity of cyclodextrin. This forms an inclusion complex. This reduces the poorly soluble API to water. The outer hydrophilic surface of cyclodextrin makes the cyclodextrin soluble in water. This increases the solubility of poorly water-soluble API.

• 8. Surfactants: The process to dissolve poorly soluble or insoluble substances in the presence of surfactant is called solubilization. Surfactants form micelles in liquids interface at critical micelles concentration (CMC). Solubilization of solutes starts at CMC. The solubility of solutes increases with an increase in the concentration of micelles. Solubilization occurs either by dissolving substances into micelles or by adsorbing solutes on the micelles.

• Solubilization is widely used in the pharmaceutical industry, especially for insoluble substances. Micellar solubilization forms a clear solution. This solution shall be thermodynamically stable. Examples are solubilization of fat-soluble vitamins A, D, E, K, aspirin, antibiotics, alkaloids, glycosides, griseofulvin, etc.

• 9. Co-solvency: Cosolvency is a technique to use cosolvent to increase the solubility of the drug in water. In co-solvency, an organic solvent is used which is miscible with water and which solubilizes the drug readily. This organic solvent is called co-solvent. “Solvent added in a solution to increase the solubility of solute is called co-solvent”. Alcohol, glycerin, propylene glycol, etc are used as co-solvent to increase the solubility of solutes in water.

• 10. Hydrotrophy: Enhancement of solubility of water insoluble drug or poorly water-soluble drug by adding any other substance that is not a surface active agent is called hydrotrophy. A substance that is not a surface active agent and increases the solubility of water-soluble insoluble substances or poorly water-soluble substances is called a hydrotrope. The exact mechanism of Hydrotrophy is not clear. The mechanism might be an increase in their dispersibility in water.

• 11. Micronisation: The reduction of the size of the particles to a micrometer or submicrometer is called micronization. Micronization is carried out to improve the solubility of the drug or the rate of dissolution of the drug. It is useful for poorly water-soluble drugs. Micronization increases solubility by increasing the surface area of the solid particles, enhancing the dissolution rate, and preventing agglomerates of the drug particles.

• 12. Sonication is a process to reduce particle sizes into microparticles or nanoparticles by using ultrasound waves of 20kHz to 5MHz. The formation of nanoparticles also increases the solubility of the drug. This is called nanonization. Nanonisation forms nanocrystals, nanosuspension, nanoemulsion, etc.

• 13. Lyophilization (Freeze drying): Lyophilization is a technique to remove water molecules from the product. The lyophilization process involves freezing, primary drying (sublimation), secondary drying (Desorption), sealing of the container, and storage. This process removes all water molecules and forms porous structure in the drug product. This results in a significant reduction in particle size, increased surface area, and increased tendency to attract water molecules. This improves the solubility of pharmaceuticals.

• 14. Supercritical Fluid Process: A substance that exists at a temperature and pressure above its critical point is called supercritical fluid. The critical point is the combination of temperature at which liquid and gas phases of a substance become indistinguishable. Beyond this substances are in a supercritical stage that exhibits the properties of both a liquid and a gas.

• The supercritical fluid process is a technique to enhance the solubility of drugs by utilizing supercritical fluid. Supercritical carbon dioxide is the most commonly used solvent to enhance the solubility of poorly soluble drugs. The critical temperatures for carbon dioxide exist at a temperature of 31.1 degrees C (87.98 degrees F) and a pressure of 73.8 atmosphere

Chemical methods to increase the solubility:

The following chemical methods are used to increase the solubility of poorly soluble APIs.

• 1. pH modification: Weak acidic or weak basic API solubility is affected by the change in pH of the water medium. Ionization of the Weak acidic or weak basic APIs depends upon the pH of the water medium. Ionized APIs are more soluble in water than unionized APIs. Weak acidic APIs remain ionized in the high pH medium and shall be soluble and vice versa. Similarly, weak basic APIs remain ionized in the low pH and shall be soluble and vice versa.

• 2. Buffering agents: Buffering agents are used to stabilize solution pH. This helps to prevent the precipitation of dissolved APIs by stabilizing the pH of the solution during storage. The selection of a buffering agent depends upon the stability of APIs and excipients in the buffer, compatibility between buffering agents and container, and suitability of acid-base for use in oral liquid. All buffering agents are not suitable for oral liquid dosage forms like boric acid buffer not used due to its toxicity. pH of some buffering agents changes with a change in temperature. For examples. The pH of acetate buffer increases with an increase in temperature. pH of boric acid buffer decreases with an increase in temperature. Some drugs act as buffers in the solution. For example salicylic acid with base acts as a buffering agent. Ephedrine with acid acts as a buffering agent. Buffers containing carbonate, citrate, tartrate, and phosphate may react with calcium ions to form sparingly soluble salts in liquid preparation. Thus buffering solutions containing any one of these are not used in liquid dosage form containing calcium ions.

• 3. Prodrug: Prodrugs are inactive or less active drugs that are converted into active form within the human body through metabolic processes. Prodrugs are designed to change the physiochemical properties of the drug. These prodrugs may be more soluble than its active form.

• 4. Salt formation: Drugs are converted into salt by reacting them with acid or base. The salt of the drug may be more soluble than the parent drug. For example, Alkaloids are poorly soluble in water. However, Alkaloidal salts are freely soluble in water. It is the most commonly used technique to increase the solubility of the drug.

Alok Bains