solubility-MM.pptx

solubility-MM.pptx

• 1.
  Unit 1:Solubility ofdrugs By Mariyambibi A. Mandarawala Department of Pharmaceutics Krishna School of Pharmacy & Research, KPGU
• 2.
  Solubility of drugs •Solubility expressions, • Mechanisms of solute solvent interactions, • Ideal solubility parameters
• 3.
  • Solubility ofdrugs: Solubility expressions, mechanisms of solute solvent interactions, • ideal solubility parameters, solvation & association, quantitative approach to the factors influencing solubility of drugs, diffusion principles in biological systems. • Solubility of gas in liquids, solubility of liquids in liquids, (Binary solutions, ideal solutions) • Raoult’s law, real solutions. Partially miscible liquids, Critical solution temperature and applications. • Distribution law, its limitations and applications
• 4.
  Definition • Solubility isdefined in quantitative terms as the concentration of a solute in a saturated solution at a certain temperature • Saturated solution: It is a solution that contains the solute at the limit of its solubility at any given temperature and pressure. • In qualitative terms it is defined as spontaneous interaction between two or more substance to form a homogeneous molecular dispersion.
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  SOLUBILITY EXPRESSIONS • g/ml: Most commonly used method of expressing solubility. It is the number of grams of solute that dissolves in one ml of the solvent. • Molarity : It is the number of moles (gram molecular weight) of the solute in 1 litre of the solvent. • Normality : It is the gram equivalent weight of the solute in 1litre of the solution.
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  SOLUBILITY EXPRESSIONS • %w/w: It is the weight in grams of solute dissolved in 100 g of solution. • %w/v : It is the weight in grams of solute dissolved in 100 ml of solution. • %v/v : It is the volume of the solute in ml dissolved in 100 ml of the solvent
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  SOLVENT-SOLUTE INTERACTIONS • Theinteraction between the solute and the solvent depends on the chemical, structural and electrical properties of both the solute as well as solvent. • Both, the attractive as well as the repulsive forces play a role in these interactions. • Repulsive forces : ​Astwo molecules are brought together, opposite charges in the two molecules being closer than the like charges, causes the molecules to attract each other. When both the molecules come so close that their electronic clouds touch each other, they repel each other like rigid elastic bodies. • Attractive forces: Van der Waals force
• 8.
  SOLVENT-SOLUTE INTERACTIONS (Hydrogen bond) •Hydrogen bond is a strong type of dipole-dipole interaction that occurs between a molecule containing a hydrogen atom and a strongly electronegative atom such as fluorine, oxygen, or nitrogen • In order to create the bond, the hydrogen atom must be covalently attached to another electronegative atom. • A perfect example of hydrogen bond is water. • Hydrogen bonds can also exist between alcohol molecules, carboxylic acids, aldehydes, esters, and polypeptides.
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  • In awater molecule, the hydrogen lone electron is pulled by the covalently attached oxygen atom, creating a naked nucleus on the side of the hydrogen atom facing away (partial positive charge) • This side of the hydrogen atom can get close to neighbouring oxygen atom (with a partial negative charge) and interact strongly with it. SOLVENT-SOLUTE INTERACTIONS (Hydrogen bond)
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  • “Like dissolveslike.” • Polar solvent dissolves polar solute • Non-polar solvent dissolves non-polar solute SOLVENT-SOLUTE INTERACTIONS
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  SOLVENT-SOLUTE INTERACTIONS (Polar solvents) •Polar solvents dissolve ionic solutes and other polar substances. • Accordingly, water mixes in all proportions with alcohol and dissolves sugars and other polyhydroxy compounds. • Ability of the solute to form hydrogen bonds is responsible • Water dissolves phenols, alcohols, aldehydes, ketones, amines, and other oxygen- and nitrogen containing compounds that can form hydrogen bonds with water • When additional polar groups are present in the molecule, as found in propylene glycol, glycerin, and tartaric acid, water solubility increases greatly
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  SOLVATION • ​Theprocess ofattracting and associating the molecules of solvents towards molecules or ions of the solute is called as solvation. • The larger the ion, the more solvent molecules surround it and the more they are solvated. • Solvation depends on factors such as hydrogen bonding and Van der Waals forces.
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  Solubility parameter • Solventpower of a liquid is influenced by its intermolecular cohesive forces and that the strength of these forces can be expressed in terms of a solubility parameter • The solubility parameter is a numerical value that indicates the relative solvency behavior of a specific solvent. • It is derived from the cohesive energy density of the solvent, which in turn is derived from the heat of vaporization
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  Dielectric constant • Dielectricconstant of solvent is also responsible for solubility • The dielectric constant is a measure of the ability of molecule to resist charge separation. • Water (78.5), chloroform (4.8) • The capacitance of the condenser filled with some material, Cx , divided by the reference standard, C0, is referred to as the dielectric constant, ε: • ε = Cx/C0
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  ASSOCIATION • When specificinteractions occur between like molecules of one of the components in a solution, the phenomenon is called as association • e.g. dimerisation of benzoic acid where two molecules of benzoic acid undergo association in a non- polar solvent (benzene) to form a dimer.
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  Polar solvents • Dueto high dielectric constant, polar solvent decrease force of attraction between oppositely charged ions in crystals such as sodium chloride. • ​Polar solvents break covalent bonds of potentially strong electrolytes by acid base reactions. • Polar solvents are capable of solvating molecules and ions through their hydrogen bond formation leading to solubility of a solute.
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  Non-Polar solvents • Non-polarsolvents are unable to reduce the attractions of ions between strong and weak electrolytes. • Because these solvents have a low dielectric constant. Nor can they break covalent bonds and ionise weak electrolytes, since they are aprotic solvents (don’t release H+ ion). • Hence ionic or polar solutes are not soluble or slightly soluble in non-polar solvents. • However non-polar solvents dissolve non-polar solutes through induced dipole-induced dipole interactions. The solute molecules are kept in solution by weak Van der Waals type or London type of forces • Example: Oils and fats dissolve in carbon tetrachloride, benzene
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  ideal solutions vsnon-ideal solutions • Mixing substances with similar properties forms ideal solutions. For example, when 100 mL of methanol is mixed with 100 mL of ethanol, the final volume of the solution is 200 mL, and no heat is evolved or absorbed. The solution is nearly ideal. • When 100 mL of sulfuric acid is combined with 100 mL of water, however, the volume of the solution is about 180mL at room temperature, and the mixing is attended by a considerable evolution of heat; the solution is said to be nonideal, or real.
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  FACTORS AFFECTING SOLUBILITY Temperature •Temperature: If the process of dissolution is exothermic then increase in temperature decreases the solubility. • If the process of dissolution is endothermic then increase in temperature increases the solubility. • Solubility curves are used to indicate effect of temperature on solubility • Generally solubility curves are straight curves except in a few cases like Na2SO4
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  FACTORS AFFECTING SOLUBILITY Temperature •Solubility curve of Na2SO4 • Its solubility therefore increases with rise in temperature until 32.5°C is reached. Above this temperature the solid is converted into the anhydrous form Na2SO4, and the dissolution of this compound is an exothermic process. • The solubility therefore exhibits a change from a positive to a negative slope as the temperature exceeds the transition value.
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  FACTORS AFFECTING SOLUBILITY Natureof the solvent • Nature of the solvent The solubility of the solute in the solvent depends on the polarity of both the solvent as well as the solute • 'Like dissolves like', i.e. a polar substance will dissolve in a polar solvent and a non-polar solute will dissolve in a non-polar solvent. • Such a generalization should be treated with caution, because the • intermolecular forces involved in the process of dissolution are influenced by factors other than the polarity of a molecule; • For example, the possibility of intermolecular hydrogen-bond formation between solute and solvent may be more significant than polarity.
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  FACTORS AFFECTING SOLUBILITY Particlesize • Smaller the particle size of the solute, more will be the surface area available for dissolution and hence more will be the solubility. • The solubility of a substance to increase with decreasing particle size due to increase interfacial free energy as per equation • 𝑙𝑜𝑔 𝑆 = 𝑆0 2.303 𝑅𝑇𝜌𝑟 2𝛾 𝑀 • Where, • S is the solubility of small particles of radius r, • S0 is the normal solubility (i.e. of a solid consisting of fairly large particles), • y is the interfacial energy, • M is the molecular weight of the solid, p is the density of the bulk solid, • R is the gas constant and • T is the thermodynamic temperature
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  FACTORS AFFECTING SOLUBILITY Crystalstructures & polymorphism • Crystal structures : The amorphous forms of drugs are more soluble than the crystalline forms. • The different crystalline forms of the same substance are known as polymorphs • The more soluble polymorphs are metastable but they convert to the stable form; the rate of such conversion is often slow hence metastable form are useful in pharmaceutical point of view. • Crystalline material may be altered by incorporation of solvent molecules. The processes is solvation and the resultant solid is known as solvates. If the solvent is water then the it is termed as hydrate. These hydrated crystals show lower aqueous solubility than their unhydrated forms
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  FACTORS AFFECTING SOLUBILITY Molecularstructures • Molecular structures : Presence of hydrophilic or hydrophobic groups within the molecular structure greatly affects the solubility of the compound. • Introduction of a hydrophilic hydroxyl group can produce a large improvement in water solubility • Phenol is 100 times more soluble than benzene
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  FACTORS AFFECTING SOLUBILITY Molecularstructures Reduction in solubility may provide a suitable method for: • Masking the taste of a parent drug, e.g. chloramphenicol palmitate is used in paediatric suspensions rather than the more soluble and very bitter chloramphenicol base; • Protecting the parent drug from excessive degradation in the gut, e.g. erythromycin propionate is less soluble and consequently less readily degraded than erythromycin;
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  FACTORS AFFECTING SOLUBILITY pH •pH : pH has a great influence on the solubility of ionic compounds for e.g. in case of acidic drugs higher the pH (in alkaline range) more will be their ionization. • Acidic drugs are unionised in acidic pH. Hence, precipitation may occur if pH is reduced of the solution of acidic drug. • But the acedic drug undergo ionisation if pH is increased (to basic range i.e. above 7) • Henderson Hasselbalch equation a • pH = pK + log [𝑆𝑎𝑙𝑡] [𝐴𝑐𝑖𝑑 ]
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  FACTORS AFFECTING SOLUBILITY Commonion effect • Whenever a solution of an ionic substance added to another ionic compound with a common ion, the solubility of the ionic substance decreases significantly • The common ion effect can be explained by Le Chatelier’s principle of chemical equilibrium
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  Diffusion principles inbiological systems • ​Diffusion is the process of movement of the solute from a region of higher concentration to the region of a lower concentration. • ​The transport of a drug across a biological membrane can occur by two processes, passive diffusion and active transport, of which passive diffusion is the predominant mechanism. • Thus absorption of the drug through the GI tract, skin etc. occur by the process of diffusion.
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  Diffusion • Diffusion isspontaneous movement of molecules from higher concentration region to lower concentration region till equilibrium is established
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  Diffusion through biologicalmembranes
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  • Diffusion throughlipoidal membrane (BBB) is known as transcellular diffusion • Paracellular diffusion occurs through the space between cells • In addition to drugs, nutrients also pass through biological membranes Diffusion through biological membranes
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  • Membrane transportersare specialized proteins that facilitate drug transport • Active transport • Facilitated diffusion Diffusion through biological membranes
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  • Energy dependentcarrier mediated diffusion through biological membrane (Active transport) • Energy independent carrier mediated diffusion through biological membrane (Facilitated diffusion) Diffusion through biological membranes
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  Diffusion principles inbiological systems • GASTROINTESTINAL DRUG ABSORPTION : • ​Adrug taken orally must dissolve first in the GI fluid followed by its absorption into the blood stream. • ​For drug absorption, it needs to pass through the GI membrane at various locations. • The GI membrane acts as a barrier and it is composed of double layer of phospholipids surrounded by protein molecules. • Drug absorption through this membrane occurs by passive diffusion, pore transport, facilitated diffusion, active transport, etc. • ​Passive diffusion : ​It is a process in which molecules spontaneously diffuse from a region of higher concentration to a region of lower concentration.
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  Diffusion principles inbiological systems • Drug moves down the concentration gradient. • ​Thetransport process depends on the surface area of the GI membrane. Thus more drug is absorbed from the intestine than the stomach. • ​It depends on partition coefficient of the drug. Thus drugs that have high value of K are lipophilic and diffuse easily across the lipoidal GI membrane. • Unionised forms, being lipoidal, diffuse easily as compared to the ionic form.
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  Diffusion principles inbiological systems • PERCUTANEOUS DRUG ABSORPTION : • Percutaneous penetration, or absorption through skin, involves: (i)​Drug dissolution in its vehicle. (ii)​Drug diffusion from vehicle to skin surface. (iii)​Drug penetration through skin layers. • ​Theskin consists of three layers: the epidermis, dermis and subcutaneous fat layers. • The epidermis consists of outermost layer of stratum corneum which is composed of dead, keratinized cells. • The stratum corneum is the main barrier to drug diffusion and once it is overcome, it can easily enter the dermis and the systemic circulation. • The process of drug penetration in the stratum corneum is passive diffusion, which depends on different factors such as hydration of the stratum corneum, drug properties such as its partition coefficient, pH, etc.
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  Solubility of gasin liquids
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  SOLUBILITY OF GASIN LIQUIDS • Solubility of gas in liquids is the concentration of dissolved gas in the liquid when it is in equilibrium with the pure gas above the solution. • The example of gas in liquid includes effervescent preparations containing dissolved carbon dioxide, ammonia water and hydrochloride gas. • Aerosol products containing nitrogen or carbon dioxide as propellant are also considered to be solution of gases in liquids.
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  Factors Affecting Solubilityof Gas in Liquids: The solubility of gas in liquids depends on • Pressure, • Temperature, • Concentration of Salt • Chemical reaction • Micellar solubilization.
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  Pressure: • Liquids andsolids do not show any change of solubility with changes in pressure. • But, solubility of gases in liquids, depends on the pressure of the gas in contact with the liquid • At higher gas pressure, more gas is dissolved in liquids Solubility of Gases at Different Pressures
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  Pressure: • For example,the soda bottle is packed at high pressure of carbon dioxide before sealing. • When the cap of bottle is opened, the pressure above the liquid is reduced to 1 atm and the soda fizzes. • This fizzing is just carbon dioxide that was dissolved in soda, is getting released. • Therefore, if lower is the pressure less carbon dioxide is soluble
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  Pressure: • The effectof pressure on the solubility of gas is given Henry’s law which states that in dilute solution the mass of gas which dissolves in each volume of liquid solvent at constant temperature is directly proportional to partial pressure of gas. Henry law Sg = KHPg Where, • Sg is solubility of gas, expressed as mol/L; • KH is Henry law constant which is different for each solute-solvent system • Pg is partial pressure of the gas in mmHg
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  Temperature : • Temperature: As the temperature increases the solubility of most gases decreases due to increased tendency of gas to expand.
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  Salting out • Saltingout : Gases are liberated from the solution in which they are dissolved by the introduction of an electrolyte such as sodium chloride and non electrolyte such as sucrose. • This phenomenon is called as “salting out”. • The resultant escape of gas is due to attraction of salt ions or highly polar non electrolytes for water molecules which decreases the density of aqueous environment adjacent to gas molecules.
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  Raoult’s law & Azeotropicbinary solutions (mixture)
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  Concept • Mole fraction •Solution = 20% component A + 80% component B • Solution = 0.2 A + 0.8 B • Partial pressure = Pressure exerted by one component (e.g. component A) when it is in solution • Vapour pressure = Pressure exerted by one component (e.g. component A) when it is 100% pure
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  Vapour Pressure ofsolution
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  Raoult’s law • Inideal solutions partial vapor pressure of each volatile constituent is equal to the vapor pressure of the pure constituent multiplied by its mole fraction in the solution. • Thus, for two constituents A and B • in which ƤA and ƤB are the partial vapor pressures of the constituents over the solution when the mole fraction concentrations are XA and XB respectively
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  Deviation from Raoult’sLaw Negative deviation Positive deviation
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  Negative deviation from Raoult’sLaw • Negative deviation: When the "adhesive" attractions between molecules of different species exceed the "cohesive" attractions between like molecules, the vapor pressure of the solution is less than that expected from Raoult's ideal solution law, and negative deviation occurs • E.g. Chloroform + Acetone
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  Negative deviation fromRaoult’s Law • The vapor pressure-composition relationship of the solute(Chloroform) cannot be expressed by Raoult's law, but instead by an equation known as Henry's law (Chloroform + Acetone) •Ƥsolute = ksolute Xsolute • Henry’s law applies to the solute and Raoult's applies to the solvent in dilute solutions of real liquid pairs
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  Positive deviation from Raoult’sLaw • When the interaction between A and B molecules is less than that between molecules of the pure constituents (A-A or B-B), the presence of B molecules reduces the interaction of the A-A molecules correspondingly reduce the B- B interaction. • Accordingly, the dissimilarity of polarities or internal pressures of the constituents results in a greater escaping tendency of both the A and the B molecules. The partial vapor pressure of the constituents is greater than that expected from Raoult's law, and the system is said to be positive deviation. • E.g. Benzene + Ethyl Alcohol
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  Azeotropic binary solutions(mixture) • It is the mixture of liquids that has a constant boiling point because the vapor has the same composition as the liquid mixture. • The boiling point of an azeotropic mixture may be higher or lower than that of any of its components. • The components of the solution cannot be separated by simple distillation
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  Solubility of liquidsin liquids, (Binary solutions, ideal solutions)
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  Solubility of Liquidin Liquid 59 • Frequently two or more liquids are mixed together in the preparation of pharmaceutical products (e.g. aromatic waters, spirits, elixirs, lotions, sprays, and medicated oils).
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  Solubility of Liquidin Liquid 60 Liquid–liquid systems can be divided into two categories according to the solubility of the substances in one another: 1. Complete miscibility 2. Partial miscibility.
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  Solubility of Liquidin Liquid Complete Miscibility 61 • Polar and semipolar solvents, such as water and alcohol, alcohol and acetone, are said to be completely miscible because they mix in all proportions. • Nonpolar solvents such as benzene and CCl4 are also completely miscible. • These liquids are miscible because the broken attractive forces in both pure liquids are re-established in the mixture.
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  Solubility of Liquidin Liquid Partial Miscibility • When water and phenol are mixed, two liquid layers are formed each containing some of the other liquid in the dissolved state. 62
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  Solubility of Liquidin Liquid Partial Miscibility • Miscibility is the common solubilities of the components in liquid- liquid systems. • Partial miscibility occurs is when the substances only mix partially. • When mixed, there are two layers formed each layer containing some of both liquids. • Of these two mixed layers, each layer contains some of both the liquids for example, phenol and water
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  Solubility of Liquidin Liquid Partial Miscibility Conjugate solutions • If water be added to phenol and the mixture shaken, solution will form up to a certain point; beyond this point further addition of water result in the formation of two liquid layers, • one consisting of a saturated solution of water in phenol and the other a saturated solution of phenol in water. • These two mutually saturated solutions in equilibrium at a temperature are called conjugate solutions • A conjugate system has two partially miscible liquids in contact with each other
• 63.
  Solubility of Liquidin Liquid Partial Miscibility Conjugate solutions • Phenol-water solution is characterized by increasing mutual solubility with rise of temperature. • Thus, when phenol is added to water at the ordinary temperature, a homogeneous liquid is produced. • When the concentration of the phenol in the solution has risen to about 8 %, the addition of more phenol results in the formation of a second liquid phase, which may be regarded as a solution of water in phenol
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  Phenol Water System
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  Solubility of Liquidin Liquid Partial Miscibility Consulate temperature • The temperature at which the two layers become identical in composition and are in fact one layer is known as the critical solution temperature or the consulate temperature of the system. • Upper consulate temperature • Lower consulate temperature
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  Solubility of Liquidin Liquid Partial Miscibility • Partially miscible liquids are influenced by temperature. The two conjugate phases changed to a homogenous single phase at the critical solution temperature (or upper consolute temperature). • Some liquid pairs (e.g. trimethylamine and water) exhibit a lower consolute temperature, below which the two members are soluble in all proportions and above which two separate layers form. 68
• 67.
  Solubility of Liquidin Liquid Partial Miscibility • Few mixtures (e.g. nicotine and water) show both an upper and a lower consolute temp. with an intermediate temp. region in which the two liquids are only partially miscible. • A final type exhibits no critical solution temperature (e.g. ethyl ether and water shows partial miscibility over the entire temperature range at which the mixture exists. 69
• 68.
  Distribution Partition coefficient
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  NERNST’S Distribution law/PARTITIONLAW • When an excess amount of solute is added to two immiscible liquid phases, it distributes itself between these phases until saturation, if mixed by shaking vigorously. • If insufficient amount of solute is added it distributes in a definite ratio. • The term partition coefficient is commonly refers to the equilibrium distribution of single substance between two immiscible solvent phases separated by a boundary.
• 70.
  Partition coefficients • Partitioncoefficients’ are sometimes called distribution coefficient • Partition coefficient is a measure of drugs lipophilicity • It is commonly determined using octanol (oil) and water (aq.)
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  Partition coefficient • The partitioncoefficient is defined as the ratio of unionized drug distributed between organic phase and aqueous phase at equilibrium. • Ko/w = Co/Cw
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  Limitations of DistributionLaw • The selected solvent liquid pair must immiscible with each other. Any mutual solubility must not affect distribution of solute if left aside for enough time to separate. • The experimental temperature must be maintained constant. As temperature has effect on solubility of solute, any change in temperature during determinations may change the findings. • The solute in question should be in same molecular state in both the solvents. If any chemical change is observed the concentration of species common to both solvents only should be considered. • Solute must present in both the solvent at low concentrations. At high concentrations of solutes Nernst’s distribution law does not hold good. • Samples should be withdrawn for analysis only after achievement of equilibrium. Early equilibrium attainment can be possible by vigorous shaking.
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  Applications • Solubility ofdrugs in water and other solvents can be predicted. • Drug absorption, bioavailability, toxicity, bioaccumulation and metabolism. • Since biological membranes are lipoidal in nature the rate of drug transfer for passively absorbed drugs is directly related to the lipophilicity of the molecule. • Effect on dissolution rate, pKa and solubility on absorption • hydrophobic drug receptor interactions. • preservative action of weak acids and determination of its optimum concentration for the effectiveness of action. • Drug absorption in vivo can be predicted. • SAR for a series of drugs can be studied. • Release of drugs from ointments and creams can be predicted. • Partition principle is used in partition chromatography to separate organic substances from mixtures.
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  Applications • extraction ofdrugs from mixtures such as blood, urine and crude plant extracts • drug separation by partition chromatography • structure activity relationship for series of compounds • To study release of drug from gels, ointments and creams partition coefficient is a very important consideration.