Solubility and Distribution Phenomena PDF

Solubility and Distribution Phenomena By: Asnake W. (B.Pharm, & MSc in Pharmaceutics) Outline ❖ Solubility Phenomena ❖Terminologies (solute, solvent, solution, solubility) ❖Solubility expressions ❖Solute-solvent interactions ❖Solubility of gases in liquids ❖Sol...

Solubility and Distribution Phenomena By: Asnake W. (B.Pharm, & MSc in Pharmaceutics) Outline ❖ Solubility Phenomena ❖Terminologies (solute, solvent, solution, solubility) ❖Solubility expressions ❖Solute-solvent interactions ❖Solubility of gases in liquids ❖Solubility of liquids in liquids ❖Solubility of solids in liquids ❖ Distribution Phenomena. Solubility Phenomena  Solubility phenomena  Solubility phenomena refer to the processes and principles governing the dissolution of a solute in a solvent to form a homogeneous solution.  It involves the interaction of solute and solvent molecules, leading to the distribution of solute particles uniformly within the solvent.  Solubility is a fundamental concept that describes how much of a solute can dissolve in a solvent at a specific temperature and pressure.  Key aspects include: Molecular Interaction: Solubility depends on the nature of interactions between the solute and solvent molecules, such as hydrogen bonding, van der Waals forces, and ionic interactions. Temperature and Pressure: Solubility varies with temperature (e.g., most solids are more soluble at higher temperatures) and pressure (e.g., gases are more soluble at higher pressures in liquids). Nature of Solute and Solvent: The principle "like dissolves like" implies that polar solutes dissolve in polar solvents, while non-polar solutes dissolve in non-polar solvents. Quantitative Measure: Solubility is often expressed as the maximum amount of solute that can dissolve in a given amount of solvent at a specific temperature and pressure.  Introduction  A fundamental understanding of factors affecting solubility  is important to the pharmacist, ◼ not only because many drugs are formulated as solution dosage forms, ◼ but also, because, regardless of dosage form a drug must be in solution form to be biologically active.  Thus, an understanding of the forces responsible for  solubility and the  rate of dissolution are very important concepts in pharmacy.  Terminologies  Solute: is the dissolved agent(less abundant part of the solution ).  Solvent : is the component in which the solute is dissolved (more abundant part of the solution).  A Solution: is a mixture of two or more components that form a homogenous mix. Cont’d,… Solubility:  In a quantitative way: it is the concentration of solute in a saturated solution at a certain temperature.  It is intrinsic property of solute.  In a qualitative way: it is the spontaneous interaction of two or more substances (solute & solvent)  to form a homogeneous molecular dispersion.  Importance of Solubility ❖ Solubility of a substance serves as a standard test for purity ❖Select the best solvent for a drug or a mixture of drugs ❖Overcome problems arising during preparation of pharmaceutical solutions ❖Drug molecules are required to present in dissolved form, in order to be transported across biological membranes. Solubility Expressions  The solubility of a substance can be expressed in a number of ways: – Percentage, molarity and molality  In the pharmaceutical field, three concentration terms are often used these are:  Percent weight by weight (%w/w) ◼ which is the number of grams of solute dissolved in 100 grams of solution.  Percent volume by volume (%v/v) ◼ which is the number of mL of solute dissolved in 100 mL of solution.  Percent weight by volume (%w/v) ◼ which is the number of grams of solute dissolved in 100 mL of solution. Cont’d,…  Molarity  is defined as the number of moles (or gram molecular weight) of solute dissolved in 1liter(1000ml) of solution.  Molality  is defined as the number of moles of solute dissolved in 1kg (1000g) of solvent.  USP defines the solubility of drugs by stating the volume of solvent required to dissolve a specific amount of solute. ❖ The USP lists the solubility of drugs as:  the number of ml of solvent in which 1g of solute will dissolve. E.g. 1g of boric acid dissolves in 18 mL of water and in 4 mL of glycerin.  Table: Terms to approximate solubility expressions Term Parts of solvent required for one part of solute. Very soluble less than 1 part Freely soluble 1 to 10 parts Soluble 10 to 30 parts Sparingly soluble 30 to 100parts Slightly soluble 100 to 1000 parts Very slightly soluble 1000 to 10,000 parts Practically insoluble or insoluble more than 10,000 parts Solvent - Solute Interactions In pre or early formulation, selection of the most suitable solvent is based on the principle of “like dissolves like”  That is, a solute dissolves best in a solvent with similar chemical properties. Or  two substances with similar intermolecular forces are likely to be soluble in each others.  Polar solutes dissolve in polar solvents. E.g salts & sugar dissolve in water.  Non polar solutes dissolve in non polar solvents. Eg. Naphtalene dissolves in benzene. Types of solubility i. Solubility of Gases in liquids ii. Solubility of Liquids in liquids iii. Solubility of Solids in liquids  Solubility of Gases in liquids  The solubility of a gas in a liquid  It refers to the amount or concentration of gas that is dissolved in the liquid when the system reaches a state of equilibrium.  At equilibrium, some of the gas is dissolved in the liquid, while some of it remains in the gas phase above the liquid (in contact with the liquid surface)..  Pharmaceutical solutions of gases include:  hydrochloric acid and effervescent preparations containing carbon dioxide that are dissolved & maintained in solution under positive pressure.  Aerosol products in which the propellant is either carbon dioxide or nitrogen, ◼ some of which is dissolved under pressure. Factors affecting the solubility of gases in liquids ❑ The solubility of gases in liquids depends on: 1. The mass of gas molecules 2. Pressure 3. Temperature 4. Presence of salt Cont’d,… 1. The Mass of Gas Molecules  The solubility of gas molecules typically increases with increasing mass of the gas molecules.  The larger the mass of gas molecules, the stronger London forces between gas and solvent molecules. Cont’d,… 2. Pressure  When the pressure above the solution is released (decreases), the solubility of the gas decreases.  Increasing the pressure results in more collisions of the gas molecules with the surface of the solvent (more solvation); and => hence greater solubility. Cont’d,…  The pressure of a gas above the solution is an important consideration in gaseous solutions ▪ because it changes the solubility of the dissolved gas in equilibrium with it. Henry's law  The effect of the pressure on the solubility of a gas is expressed by Henry's law  Henry's law states, ‘Solubility is directly proportional to partial pressure of gas at a constant temperature’. S= KP , k solubility coefficient  Cont’d,… 3. Temperature  Temperature also has a marked influence on the solubility of a gas in a liquid.  As the temperature increases, the solubility of gases decreases  to the greater tendency of the gas to expand.  Increasing temperature causes an increase in kinetic energy of gas molecules which  leads to breakdown of intermolecular bonds and gas escaping from solution.  E.g. Carbon dioxide gases escape faster from a carbonated drink as the temperature increases.  Eg. Take a look figure below. How temperature decrease the solubility of gas in the liquid.  Cont’d,…  Solutions of gases are potentially dangerous when exposed to warm temperature  because of the libration and expansion of dissolved gas ◼ which may cause the container to burst.  The pharmacist exercise caution in opening containers of gaseous solutions in warm climates & under other conditions of temperatures.  A vessel containing a gaseous solution or a liquid with a high vapor pressure such as ethyl nitrite and strong ammonia solution ▪ should be immersed in ice or cold water for some time ▪ to reduce the temperature & pressure of the gas before opening the container. Cont’d,… 4. Presence of Salts  Dissolved gases are often liberated from solutions  by the introduction of an electrolyte (e.g. NaCl) and  sometimes by a non electrolyte (e.g. sucrose) ◼ This phenomenon is known as SALTING OUT.  The salting out effect can be demonstrated by adding a small amount of salt to a “carbonated” solution, example add salt in soft drinks like coca cola. Cont’d,…  The resultant escape of gas is due to the attraction of salt ions or the highly polar non electrolyte like sucrose for the water molecules which reduces the density, structure and dynamics of the aqueous environment adjacent to the gas molecules and therefore, Reduce the solubility of the gas. Applications  Dissolved gases are removed by heating the solution.  Distilled water is maintained at 80°C in order to make it convenient for parenteral use, ◼because gases cannot dissolve in water at that temp.  Dissolved air influences boiling of liquids.  Dissolution of gaseous anesthesia in blood influenced by factors mentioned.  Solubility of liquids in liquids ❖ Frequently two or more liquids are mixed together in the preparation of pharmaceutical solutions. ❖ For example:  Alcohol is added to water to form hydroalcoholic solutions  Volatile oils are mixed with water to form dilute solutions known as aromatic waters  Volatile oil are added to alcohol to yield spirits and elixirs  Various fixed oils are blended into lotions, sprays and medicated oils. RAOULT’S LAW Raoult's Law, which describes the relationship between the partial pressures of components in a liquid solution and their mole fractions. “The partial pressure (Pi) of each component in a solution equal to the mole fraction of the component & the vapour pressure of the pure component”. Pi = Px Or P = PA0 xA + PB0 xB Where PA and PB are the partial vapor pressures of the constituents over the solution  when the mole fraction concentrations are XA and XB.  The vapor pressures of the pure components are PA0 and PB0 respectively. Ideal and Real solution Ideal solutions  An ideal solution is a solution in which:  there is no attraction between solute and solvent molecules.  No Change in Properties Other Than Dilution ◼ there is no change in the properties of the components, other than dilution, when they are mixed to form the solution.  No Heat Evolved or Absorbed During Mixing  Stated another way, no shrinkage or expansion occurs when the substances are mixed. Cont’d,… Uniformity of intermolecular forces. Irrespective of the volume of the solute and solvent they are miscible to each other Obey Raoult’s law over the whole range of composition. Mixtures of ◼benzene + ethylene chloride and ◼ ethyl bromide + ethyl iodide are commonly mentioned systems that exhibit ideal behavior.  Real (Non ideal) solutions  In real solutions, the behavior deviates from the ideal behavior described by Raoult's Law.  These deviations occur due to differences in intermolecular forces between the solute and solvent molecules compared to the forces between like molecules  In real solutions,  the "cohesive“ force of attraction between A for A exceeds the "adhesive" force of attraction existing between A and B. Alternatively,  the attractive forces between A and B may be greater than those between A and A or B and B.  This may occur even though the liquids form solution in all proportions. Such mixtures are real or non-ideal.  They do not adhere to Raoult’s law over entire range of composition”. Solubility of solid in liquid  Systems of solids in liquids include the most frequently encountered and probably the most important type of pharmaceutical solutions.  Pharmaceutical solutions consists of a wide variety of solutes and solvents. Ideal solution  Ideal solubility is approached when solute and solvent are involved in similar intermolecular interactions.  If the IMFs of attraction are the same type and equal strength,  the solvent and solute molecules randomly mix. ◼ A homogeneous solution results, and => an ideal solution. – “like dissolves like”  Cont’d,…  Ideal solution: has no change Interactions b/n solvent molecules A-A; solute molecules B-B; solvent and solute enthalpy; ∆Hsoln = 0 and This molecules A-B. means that no heat is absorbed or released during the mixing process. Solute  As a result certain properties are predictable from the properties of the solution components.  In general, ideal solutions are rare. Solvent All same  Solutions of non-polar solutes in non-polar solvents  usually come close to being ideal.  Non-Ideal solution  If the IMFs of attraction b/n unlike Interactions b/n solvent molecules A- A; solute molecules B-B; solvent and molecules exceed those of like solute molecules A-B. molecules, a solution still forms. =>A non-ideal solution results. Solute  Non-ideal solution: here ∆Hsoln < 0 Force dominates (exothermic) and the properties of the solution components cannot easily predicted. Solvent  Cont’d,…  Eg;  H-bonding b/n CHCl3 (chloroform) and (CH3)2CO (acetone) molecules  produces forces of attraction b/n unlike molecules that exceed those b/n like molecules.  Cont’d,…  If the IMFs of attraction b/n unlike Interactions b/n solvent molecules is some what weaker than molecules A-A; solute molecules B-B; solvent those of like molecules, and solute molecules A-B  a non-ideal solution may still result. Stronger  Non ideal solution: here ∆Hsoln > 0 (endothermic) and the properties of the solution components cannot easily predicted. Weaker  Cont’d,… Interactions b/n solvent  If the IMFs of attraction b/n unlike molecules A-A; solute molecules is significantly weaker than molecules B-B; solvent and those of like molecules, solute molecules A-B.  the components remain segregated in a heterogeneous mixture.  Dissolution does not occur to any significant extent. Think: Water and gasoline Solubility and Heat of solution  As a solid solute dissolves,  it takes in energy to break apart the crystal lattice structure and ◼ separate it into ions or molecules to get to the individual ion or molecule necessary to form a solution.  The solvent-water-takes in energy to break apart its hydrogen bonds  to allow the solute to come in contact with adjacent molecules of water.  When the solute and the solvent come together,  energy is released.  Cont’d,…  The overall energy exchange is called the Heat of solution – The amount of heat energy absorbed or released when a solute dissolves in a specific amount of a solvent.  Steps of solid going into solution 1. Step 1: Hole open in the solvent. Pure solvent => separated solvent molecules, ΔHa > 0 (endo) 2. Step 2: One molecule of the solid breaks away from the bulk. Molecule solute => separated solute molecules, ΔHb > 0 (endo) 3. Step 3: The solid molecule is enter into the hole in the solvent. Separated solvent and solute molecules dissolve => solution, ΔHc < 0 (exo) Overall: Pure solvent + pure solute = > sol. ΔH = ΔHa + ΔHb + ΔHc Solubility of strong electrolytes  A rise in T increases the solubility of a solid that absorbs heat (endothermic process) when it dissolves and the flask gets cold (more common). Eg KNO3 , KBr  The reaction may be exothermic when heat is released as a result of solubility process, and the flask gets warm (less common). Eg Calcium hydroxide , calcium acetate , => in this case solubility decreases as T rises.  Cont’d,…  NaCl does not absorb or evolve an appreciable amount of heat when it dissolves in water;  thus, its solubility is not altered much by a change of T.  Sodium sulfate exists in hydrated form, Na2SO4. 10H2O, up to a T of 32 oC  the solution process is endothermic and  solubility increases with increase in T.  Above this point the compound exists as anhydrous salt, Na2SO4 ,  the dissolution is exothermic and  solubility decreases with an increase in T  Cont’d,…  Plots of solubility versus temperature, which are referred to as solubility curves,  are often used to describe the effect of temperature on a given system. 32 oC  Common ion effect ❖ Common ion effect ❖ can reduce the solubility of slightly soluble electrolytes. according to Le Chatelier’s Principle.  If an ion in common with AgCl,  Ag+ or Cl-, is added to the solution of silver chloride, ◼Eg: the addition of NaCl increases the concentration of Cl-  so that momentarily [Ag+ ] [Cl-] > Ksp (solubility product constant)  some of the AgCl precipitates from the solution until equilibrium is , [Ag+ ] [Cl-] =Ksp, re-established  Solubility of weak electrolytes  A weak electrolyte forms only a few ions (< 1 %) in solution with most of the compound staying in a non-ionic form (> 99 %).  Many important drugs belong to the class of weak acids and bases.  The solubility of weak electrolytes is strongly influenced by  pH of the solution.  The solubility of a compound, at a given pH,  is a function of the solubility of the ionized form and  the limiting solubility of the neutral molecule.  Cont’d,…  If the pH of a solution of either a weakly acidic drug or a salt of such a drug is reduced then the proportion of unionized acid molecules in the solution increases.  Precipitation may therefore occur because the solubility of the unionized species is less than that of the ionized form.  Conversely, in the case of solutions of weakly basic drugs or their salts precipitation is favoured by an increase in pH.  Example: 1% solution of phenobarbital sodium is soluble at pH values high in the alkaline range.  The soluble ionic form is converted into molecular phenobarbital as the pH is lowered, and below 9.3, ◼ the drug begins to precipitate from solution at room temperature. Strong vs. weak acids and bases 1. Strong – ionized at all pHs. 2. Weak – only ionized at certain pHs (most drugs are weak acids or weak bases. 3. Ionized drugs are not very lipid soluble - only non ionized form of drug crosses membrane readily. 4. Percent ionization is pH dependent 5. Weak acids become highly ionized as pH increases. 6. Weak bases become highly ionized as pH decreases.  PASSIVE DIFFUSION  Water soluble drug (ionized or polar) is readily absorbed via  aqueouschannels or pores in cell membrane.  Lipid soluble drug (non ionized or non polar) is readily absorbed via  cell membrane itself. Factors influencing solubility 1-Temperature  Generally, an increase in the temperature of the solution increases the solubility of a solid solute.  A few solid solutes are less soluble in warm solutions.  For all gases, solubility decreases as the temperature of the solution increases.  For effect of T on solubility we have to take consider two criteria:  If the solution process absorbs energy then the solubility will be increased as the temperature is increased.  If the solution process releases energy then the solubility will decrease with increasing temperature. 2- PH  is one of the primary influences on the solubility of most drugs that contain ionizable groups.  Solubility depends on the degree of ionization.  Degree of ionization depends on the Ph. 3- Particle size (surface area)  As the PS decreases solubility increases  due to increase in the surface area ◼ meaning more of the solid is in contact with the solvent.  But after very small PS decrease in PS will decreases solubility  due to formation of agglomerates. 4- Crystal properties  Solids exist as either  Non crystalline or amorphous compounds or  Crystalline compounds depending on internal structure of the compounds.  Crystalline compounds are characterized by repetitious spacing of constituent atom or molecule in three dimensional array( lattice).  Cont’d,…  When substances exists in more than one crystalline form, the different form are designated as polymorphs and the phenomenon as polymorphism.  Polymorphs are two crystals that have the same composition , but different arrangement of molecules or crystal packing.  Polymorphs have the same chemical structure but different physical properties, such as  Melting point  Solubility  Density and  Stability ◼ General there is a correlation between the melting point of the different polymorphs and solubility.  Polymorphs with high melting points have low solubility. Cont’d,…  Amorphous forms are, by definition, non-crystalline materials,  i.e., they do not have well defined molecular structure.  In amorphous form atom or molecule are randomly placed.  A drug that exists as an amorphous form (non crystalline form)  generally dissolves more rapidly than the same drug in crystalline form. Cont’d,…  5- Boiling and Melting Point  Both reflect the strengths of interactions between the molecules in the pure liquid or the solid state.  In general, aqueous solubility decreases with  increasing boiling and melting point. 6- Molecular size  Molecular size will affect the solubility.  The larger the molecule or the higher its molecular weight the less soluble the substance.  In the case of organic compounds the amount of carbon branching will increase the solubility  since more branching will reduce the size (or volume) of the molecule and make it easier to solvate the molecules with solvent 7-The influence of Surfactants  Surfactants are termed as surface-active agents also wetting agents, emulsifying agents or suspending agents depending on its properties and use.  Surface-active agents are substances which, at low concentrations, adsorb onto the surfaces or interfaces of a system and  alter the surface or interfacial free energy and the surface or interfacial tension.  Surfactants are monomers, it has a characteristic structure possessing both  hydrophobic groups / non-polar regions (their "tails") and  hydrophilic groups / Polar Regions(their heads).  Therefore, they are soluble in both organic solvents and water, so they called amphiphilic.  Cont’d,…  The functional groups such as alcoholic (-OH), carboxylic acid (-COOH), sulphate (- SO4) & quaternary ammonium(NH4+) contribute to hydrophilic portion. alkyl chains contribute to lipophilic nature of molecules  The polar end is oriented towards the water and the non polar end is projected upwards to space.  8-Complexation as solubility enhancing mechanism  It is reversible association of a substrate and ligand molecule.  The most common complexing ligands are  cyclodextrins , caffeine, urea, polyethylene glycol, N -methyl glucamide.  Cyclodextrins are unique  since they increase the water solubility of poorly soluble drugs ◼ by fitting them into the hydrophobic cavity of the cyclodextrin molecule.  These cyclodextrins have the ability to form molecular inclusion complexes with hydrophobic drugs having poor aqueous solubility. Cont’d,…  These are formed by the insertion of the non polar molecule or the non polar region of one molecule into the cavity of another molecule or group of molecules.  The most commonly used host molecules are cyclodextrins. Hydrophillic Hydrphobic 9- The influence solvents on the solubility of drugs  Substances like weak electrolytes and non-polar molecules are poorly soluble in water  The solubility of these substances can be enhanced by the addition of water miscible solvents in which the drug has good solubility.  The nonelectrolytes and the undissociated molecules of weak electrolytes more soluble in a mixture of solvents than in one solvent alone.  This phenomenon is known as cosolvency, and Cont..  the solvents that, in combination, increase the solubility of the solute are called cosolvents.  This technique is mainly used in the formulation of parenterals.  Commonly used co-solvents are  Ethanol, Sorbitol, Glycerin, Polyethylene glycol, propylene glycol etc Cont’d,…  The solubilizing effect by co-solvency depends on the polarity of the drug with respect to solvent and co-solvent.  That means more non-polar the solute the greater is the solubilization achieved by the added solvents.  Mechanism responsible for solubility enhancement through co-solvency is  by reducing the interfacial tension predominantly between the aqueous solution and hydrophobic solutes and  by reducing the contact angle between the solid and liquid. Cont’d,…  Co-solvents increases the solubility by reducing the difference between the polarity of the drug and water system Ex. For co-solvency  The solubility of Diazepam can be increased by using 10% ethanol and 40% propylene glycol.  Phenobarbitone is relatively insoluble in water but its solubility can be increased by using mixture of solvents like water, alcohol and glycerin. Distribution Phenomena Partition Coefficient (K) Definition  If a substance which is soluble in both components of a mixture of immiscible liquids is dissolved in such a mixture  when equilibrium is attained at constant temperature, it is found that – the solute is distributed between the two liquids in such a way that the ratio of the concentration of the substance in each liquid is a constant. ◼ This is known as the Nernst distribution law or partition law.  Cont’d,… Co is molar conc. in organic layer Cw is molar conc. in aqueous layer Kd is partition coefficient , distribution constant or distribution ratio.  Partition coefficient(p)  Partition Coefficient (oil/ water) is a measure of a drug’s lipophilicity and  an indication of its ability to cross cell membranes. ❖ Molecules of the solute will distribute in each phase until equilibrium is established. It is defined as the ratio of unionized drug distributed between the organic and aqueous phases at equilibrium. Log P =[Un-ionized Cpd]org [Un-ionized Cpd]aq. Cont’d,…  The most common method for determining partition and distribution coefficients is the shake flask method.  In this technique, the candidate drug is shaken between  octanol (previously shaken together to pre saturate each phase with the other) and  water layers, from which an aliquot is taken and analyzed using UV absorption, HPLC or titration. Octanol was chosen as the model lipid phase because it most closely simulates the properties of biological membranes. Interpretation  P > 1 or Log P > 0  implies that the drug has affinity for lipid membranes  P = 1 or Log P = 0  there is equal distribution between the water and oil layer.  P < 1 or Log P < 0  the drug has affinity for water or hydrophilic layer. ❖ Structure affect the value of partition coefficient P  The substituent that increase P value are -alkyl, -aryl, halogens  The substituent that decrease P value are -COOH, -NH2, -O, -CO , -OH Application of distribution concepts  Knowledge of partition is important to the pharmacist because the principle is involved in several areas of current pharmaceutical interest. These include: 1. Preservation of oil–water systems. 2. The absorption and distribution of drugs throughout the body. 3. Extraction of active ingredients from crud drugs. Thank You!!!!