Solubility and Solutions

• Solubility refers to the amount of a substance that dissolves to establish equilibrium at a constant temperature, forming a saturated solution

Objectives

• Explain concentration and its expressions, including conversion and manipulation of concentration calculations
• Describe the solubility of solids in liquids, liquids in gases, liquids in liquids, and solids in solids
• List factors affecting the solubility of solids in liquids
• Understand Raoult's Law for liquid miscibility
• Draw and explain eutectic mixture diagrams and their relevance in medicine

Definitions

• Solution: A mixture of two or more components forming a single, homogenous phase at the molecular level
• Solvent: Determines the phase of the solution and is the largest part of the system
• Solute: Other components in a solution. These components exist as dispersed molecules or ions

Solubility States

• Saturated Solution: Balance between the solute in solution and any excess undissolved substance
• Sub-saturated Solution: Contains less solute than is needed for equilibrium
• Super-saturated Solution: Contains more solute than needed for equilibrium

Concentration Expressions

• Quantity per quantity: Volume or weight of solute in a given volume/weight solvent (kg m⁻³)
• Percentages: Weight and volume ratios (% v/w, % w/v, % v/v, % w/w)
• Parts: Used in pharmacopoeias for approximate solubility
• Molarity: Moles of solute per liter of solution (mol L⁻³)
• Molality: Moles of solute per kg of solvent (mol kg⁻¹)
• Mole fraction: Moles of solute divided by total moles of solute and solvent
• Milliequivalents: One-thousandth of the gram equivalent of an ion
• Normal solutions: Contains the equivalent weight of solute in grams per liter of solution

Qualitative Solubility Descriptions

• Very soluble requires less than 1g of solvent to dissolve 1g of solute
• Freely soluble requires between 1 and 10g of solvent to dissolve 1g of solute
• Soluble requires between 10 and 30g of solvent to dissolve 1g of solute
• Sparingly soluble requires between 30 and 100g of solvent to dissolve 1g of solute
• Slightly soluble requires between 100 and 1,000g of solvent to dissolve 1g of solute
• Very slightly soluble requires between 1,000 and 10,000g of solvent to dissolve 1g of solute
• Practically insoluble requires more than 10,000g of solvent to dissolve 1g of solute
• Pharmacopoeias often use these to express solubility

Solubility of Solids in Liquids

• Use pure solvents and solutes
• Saturated solution creation: Add excess solute to solvent at the specified temperature while stirring. Some undissolved solute must remain after cooling
• Filtering is used to remove undissolved matter. Perform at temperature with minimal adsorption of solute
• Ways to determine solute amount : gravimetric analysis, UV spectrophotometry or chromatography (HPLC, UPLC)

Factors Affecting Solid Solubility in Liquids

• Complex formation and solubilizing agents
• Molecular structure of solute and temperature
• Cosolvents, pH, and particle size
• Common ion effect, addition of electrolytes or non-electrolytes

Temperature and Molecular Structure

• Increasing heat increases solubility (↑ 10°C = 2x solubility), endothermic
• Molecular changes influence solubility
• Changing poorly soluble drugs (acids/bases) to salts increases dissolution

Modifying Aqueous Solubility

• Reduction in aqueous solubility: Necessary for taste masking or protecting the drug from stomach acid
• Esterification can be used to achieve reduction in aqueous solubility

Cosolvents, pH, Particle Size, and Common Ion Effect

• pH impacts drug absorption
• Cosolvents are employed to improve solubility
• Smaller particle size increases solubility
• Saturated solutions exist in equilibrium, AB ↔ A+ + B-, and are reversible

Polymorphism

• Polymorphs are different crystalline forms altering crystal alignment
• Different properties, polymorphic form
• Metastable polymorphs increase dissolution, while conversions to stable forms are typically slow
• Amorphous powder leads to ↑ drug solubility compared to its crystalline form

Solvation and Hydration

• Solvation= incorporation of solvent molecules into a crystal lattice
• Process increases aqueous solubility
• Increased solvent length decreases aqueous solubility
• Hydration: Water is the solvating molecule, that get water combined in the crystal lattice
• This will decrease energy released when a solid dissolves and decreases aqueous solubility

Electrolytes and Non-electrolytes

• Indifferent electrolytes: Increases solubility in sparingly soluble electrolytes if they don't share ions
• Non-electrolytes: Impact electrolyte solubility as they affect dielectric constant
• Electrolytes on Non-electrolytes: Soluble electrolytes compete with the non-electrolyte for water and can break water bonds

Other Solubility Factors

• Solubilizing agents form aggregates or micelles above certain concentrations
• Organic phases can increase the solubility of organic solutes in aqueous solutions, known as solubilisation
• Complex Formation: Formation of intermolecular complexes with a solute. Example: PVP-Iodine (Betadine Solution)

Gas Solubility in Liquids

• Amount of gas dissolving depends nature, temperature, and pressure
• Henry's Law: At a constant temperature, gas solubility in a liquid is directly proportional to the gas's pressure
• Most gases' solubility decreases as temperature rises
• Used to remove from injections CO₂ or air

Liquid Solubility

• Ideal solutions: all intermolecular forces are equal
• Raoult's Law: Partial pressure equals vapor component times mole fraction
• Positive deviation: stronger cohesion between like molecules (Ethanol-Hexane)
• Negative deviation: A-B cohesion exceeds A-A and B-B cohesion (Acetone-Water)

Solids Solubility

• Achieved by melting and solidifying the mixture or dissolving in solvents
• Components end as one-component solid solutions or two mixture

Solid Solubility: Solid Solutions

• Component molecules mix molecularly together
• They result in the solution of one component (solute) in the other (solvent).
• Complete miscibility requires similar size, smaller solute fit solvent crystalline lattice structure resulting in interstitial impact

Solid Solutions: Eutectic Mixtures

• Eutectic mixtures (easily melted) show lowest melting points (lower than components)
• Drug administration uses readily water-soluble
• Carrier dissolves, and drug releases in a fine state
• Components are miscible in liquid and immiscible in solid

Two Component Eutectic Region

• One liquid phase is salol and thymol
• Solid salol and a conjugate liquid phase occurs
• Solid thymol in equilibrium with conjugate liquid phase
• The point has liquid coexist with solid salol and thymol
• Lowest existing liquid is 13C, in 34% thymol and salol mixtures