4. Solubility.pptxProbability sampling technique

Editor's Notes

• #6: Reversed phase HPLC- uses non-polar stationary phase and polar mobile phase
• #17: A logical starting point for approaching formulation development is “ideal solubility” , de -fined as the solubility of a solute in the perfect solvent, for which there is no energy penalty associated with the dissolution process. This definition of ideal doesn’t cover cases where there are specific chemical reactions (i.e., acid-base) or ionic effects (in water) associated with dissolution. The ideal solubility depends only on the energy penalty needed to break the crystalline structure of the API – the API has to “melt” before it can dissolve. If the enthalpy of fusion, the melting point and heat capacities are known, the ideal solubility can be calculated. An ideal solution is defined as a solution in which there is no change in the properties of the components other than dilution, when they are mixed to form a solution. Thus molecules in ideal solution experiences or exhibits complete freedom of motion and randomness of distribution in the solution. In this process no heat is absorbed or evolved during mixing of the components and the final volume of the solution is simply the sum of the volumes of its constitutes. There is no expansion or contraction when they are mixed. Ideal solution are formed by mixing substance having similar properties. 50 ml methanol is mixed with 50ml of ethanol=100ml of solution.
• #18: There is actually no such thing as an ideal mixture! However, some liquid mixtures get fairly close to being ideal. These are mixtures of two very closely similar substances. Commonly quoted examples include: hexane and heptane, benzene and methylbenzene (toluene), propan-1-ol and propan-2-ol, ethyl bromide and ethyl iodide, chlorobenzene and bromo benzene In a pure liquid, some of the more energetic molecules have enough energy to overcome the intermolecular attractions and escape from the surface to form a vapour. The smaller the intermolecular forces, the more molecules will be able to escape at any particular temperature. If you have a second liquid, the same thing is true. At any particular temperature a certain proportion of the molecules will have enough energy to leave the surface. In an ideal mixture of these two liquids, the tendency of the two different sorts of molecules to escape is unchanged. If the red molecules still have the same tendency to escape as before, that must mean that the intermolecular forces between two red molecules must be exactly the same as the intermolecular forces between a red and a blue molecule. If the forces were any different, the tendency to escape would change. Exactly the same thing is true of the forces between two blue molecules and the forces between a blue and a red. They must also be the same otherwise the blue ones would have a different tendency to escape than before. If you follow the logic of this through, the intermolecular attractions between two red molecules, two blue molecules or a red and a blue molecule must all be exactly the same if the mixture is to be ideal. This is why mixtures like hexane and heptane get close to ideal behaviour. They are similarly sized molecules and so have similarly sized van der Waals attractions between them. However, they obviously aren't identical - and so although they get close to being ideal, they aren't actually ideal.
• #19: X2 is the ideal solubility of solute expressed as a mole fraction, T0 is the melting point of the solid solute in Kelvins and T is temperature of the solution . This equation will no longer be applicable if the temperature of the solution is greater than melting temperature, above T0 the solid exists as liquid and in an ideal solution the liquid solutes are miscible in all proportion of the solvent. In ideal solution, solubility of the solute does not depend on the nature of the solvent. From a practical perspective, estimating the ideal solubility is worthwhile as it will prompt the formulator to investigate alternate formulation methods rather than spend time attempting to develop a solubilizing formulation approach when the ideal solubility is too low for the intended application. One can’t fight the laws of thermodynamics.
• #20: When you make any mixture of liquids, you have to break the existing intermolecular attractions (which needs energy), and then remake new ones (which releases energy). If all these attractions are the same, there won't be any heat either evolved or absorbed. That means that an ideal mixture of two liquids will have zero enthalpy change of mixing. If the temperature rises or falls when you mix the two liquids, then the mixture isn't ideal.
• #23: When stronger solute-solvent interactions occur, heat is released upon dissolving ( ∆ H soln< 0). A non-ideal solution is a solution that does not abide to the rules of an ideal solution where the interactions between the molecules are identical (or very close) to the interactions between molecules of different components. That is, there is no forces acting between the components: no Van-der-Waals nor any Coulomb forces. We assume ideal properties for dilute solutions.
• #25: When weakersolvent-solute interactions occur, heat is removed upon dissolving ( ∆ Hsoln> 0)
• #27: An electrolyte is a compound which forms ions in solution. A strong electrolyte is nearly completely dissolved as ions (> 99 %) and not as an associated unionized compound (< 1 %).
• #28: The reaction is neither exothermic nor endothermic(=0) e.g NaCl , in this case the solubility is not affected by temperature
• #33: More of the salt will then pass from the undissolved to dissolved state until the solubility product constant is reached and the equilibrium is re-established.
• #34: This relationship between pH and the solubility of ionized solutes is extremely important with respect to the ionization of weakly acidic and basic drugs as they pass through the gastrointestinal tract and expe-rience pH changes between about 1 and 8. This will affect the degree of ionization of the drug molecules, which in turn influences their solubility and their ability to be absorbed.
• #43: The increase in solubility with decrease in particle size ceases when the particles have a very small radius, and any further decrease in size causes a decrease in solubility. It has been postulated that this change arises from the presence of an electrical charge on the particles and that the effect of this charge becomes more important as the size of the particles decreases.
• #46: It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice. Different crystalline forms are called polymorphs. so that the occurrence of polymorphism has important formulation, biopharmaceutical and chemical process implications.
• #47: Eg. Introduction of the hydrophilic group in hydrophobic substance may improve solubility. Like aldehydes and ketones, they are polar molecules and so have dipole-dipole interactions as well as van der Waals dispersion forces. However, they don't form hydrogen bonds, and so their boiling points aren't anything like as high as an acid with the same number of carbon atoms.
• #49: a solute will distribute itself between two immiscible solvents so that the ratio of its conc. in each solvent is equal to the ratio of its solubility in each one
• #55: Log P = 1 means 10:1 Organic:Aqueous Log P = 0 means 1:1 Organic:Aqueous Log P = -1 means 1:10 Organic: AqueousIt is worth noting that this is a logarithmic scale, therefore, a log P = 0 means that the compound is equally soluble in water and in the partitioning solvent. If the compound has a log P = 5, then the compound is 100,000 times more soluble in the partitioning solvent. A log P = –2 means that the compound is 100 times more soluble in water, i.e., it is quite hydrophilic. In general, Drugs having values if P much greater than 1 are classified as lipophilic, whereas those with partition coefficient much less than 1 are indicative of a hydrophilic drug.