IDM - Water Solubility

1. what does water solubility mean: -measure of the amount of chemical substance that can dissolve in water at a specific temperature 2. why is water solubility important for drugs: - because we needs to know a drugs ability to dissolve in water - drugs must be dissolved in water before it is able to cross biological membranes,reach its pharmacological target and elicit a therapeutic effect - since many drugs are given in the solid form, their solubility in water is critical 3. what is a solution: - one phase system (usually liquid) which consists of solute molecules dissolved within a solvent vehicle 4. what is a solute: - a substance (drug) which is dissolved in solution. - a solute is present at a lesser quantity than the solvent 5. what is a solvent: - substance that is used to dissolve a solute ( a chemically different solid, liquid or gas) - the solvent is the component which is present in greater quantity 6. what is dissolution: the process of dissolving - the prep of a solution by mixing together a solute (solid) and solvent until homogenous liquid (solution) is obtained 7. what is a saturated solution: a mixture that contains as much dissolved solute as is possible at a given temperature - if the solubility limit is exceeded, solid particles of solute (drug) will be present which are in equilibrium with those in the solution phase 8. what is an unsaturated solution: a solution in which more solute can be dissolved at a given temperature (hasn't reached saturated solution) - also known as sub-saturated solution 9. what is a supersaturated solution: a solution that contains more solute than it can theoretically hold at a given temperature - this is done by altering the temp, volume or pressure 10. what is a crystalline solid vs an amorphous solid: crystalline: solid that is made up of crystals in which particles are arranged in a regular, repeating 3D pattern amorphous: a solid that lacks the ordered characteristics of a crystal (non-crystalline solid) 11. what is solubility: a tug-of-war between two opposing properties: hydrophilicity and hydrophobicity - the nature of the compound determines which property is dominant and whether it will be soluble in water (polar) or a non-polar solvent 12. what does hydrophilicity mean: - the affinity of a compound to water - water loving 1 / 10 13. what does hydrophobicity mean: - the repulsion of a compound from water - water fearing 14. what is the maximum solubility: - the max amount of a solute that can be dissolved in a solvent under specific conditions (temp, pressure, pH) - equilibrium is reached between the solute in solution and excess undissolved solute, forming a saturated solution - also known as equilibrium solubility 15. explain the solubilisation process: 1. a solute molecules i removed from its bulk structure. its bonds are broken 2. a cavity for this molecule is created in the solvent 3. the solute molecule inserts itself into this cavity and interacts with the solvent molecules forming bonds 16. explain the difference of breaking bonds in the solubilisation process between crystal and amorphous structures: - crystal structures are highly ordered and tightly packed and have strong intermolecular bonds which requires more energy to break apart than amorphous - crystals display higher melting points and lower solubility than amorphous solids 17. how is solubility quantitatively measured: units of concentration - mole fraction - molarity: number of moles of solute dissolved in one litre of solution - molality: number of moles of solute dissolved in kg of solvent - weight conc: mass of solute per 100 ml of solution or mass of solute per 100g of solution - parts per million 18. how is solubility qualitatively measured: descriptions of solubility - very soluble - soluble - slightly soluble - insoluble 19. Explain "like dissolves like" (polar): - polar solvents dissolve polar solutes why? - polar solvents contain bonds between atoms with different electronegativities - polar solvents, therefore, have strong dipole moments and will dissolve ionic solutes and polar substances 20. how is water polar: - water made of one electronegative oxygen atoms and two hydrogen atoms connecting via covalent bonds - the high electronegativity of oxygen compared to that of hydrogen means that the electrons within these bonds are unequally shared inducing partial charged giving 2 / 10 water its polarity - oxygen is negatively charged and hydrogen is positively charged 21. why is water a good polar solvent: - because it is able to form hydrogen bonds with neighbouring water molecules (or solutes capable of hydrogen bonding) - a hydrogen bond forms between the hydrogen of one water molecule and the lone pair of electrons on the oxygen atom of a neighbouring water molecule 22. explain the structure of a water molecule: - each hydrogen is bound to a central oxygen by a pair of electrons (covalent bond) - 4 outer electrons are left unbonded and arrange themselves as far from each other as possible to minimise repulsion - the two nonbonding pairs remain closer to the oxygen as they exert greater repulsion against the covalent bonding pairs pushing the hydrogen together - results in tetrahedral structure with bond angle of 104.5 degrees 23. why is ice less dense than water: Ice crystallizes with an open structure, and the gaps that form between the water molecules in ice increase its volume. 24. why does water have a high boiling point: - despite its small molecular weight, water has an incredibly big boiling point. - This is because water requires more energy to break its hydrogen bonds before it can then begin to boil 25. explain the surface tension of water: - water molecules are attracted to each other and form hydrogen bonds (cohesion) - the water molecules within the bulk of the liquid experience attractions to neighbouring molecules in all directions, the attractions average out to zero so there is no net force on the molecule. - the water molecules and the surface experience sideways and downward forces so it can form tight bonds causing it to be able to support a pressure from above. - the difference between the forces experienced by a molecule at the surface and one in the bulk liquid gives rise to the liquid's surface tension 26. water is transient. what does this mean: - its ever changing and contains highly ordered regions, disordered areas and multiple cavities and holes where solutes can enter 27. Explain "like dissolves like" (non-polar): non-polar solvents dissolve nonpolar solutes - non-polar solvents contain bonds between atoms with similar electronegativities and have low dielectric constants, meaning they are unable to break ionic or covalent bonds - therefore, polar solutes will not dissolve - however oils and fats will dissolve rapidly in non-polar solvents 3 / 10 28. polar: - polar: two different atoms (minimum) with a difference in electronegativity of 0.5 or greater (up to 1.6). results in partially negative charge in the more electronegative atom and partially positive charge in the less electronegative atom - in order for a molecule to be polar there has to be a dipole moment: a separation of the charge around the molecule into a more positive area and negative area - polar: has asymmetry in both electronegativity and geometry 29. non-polar: - two different atoms (minimum) with a electronegativity of less than 0.4 30. what does increasing the temperature of a system do to the solubility: - it increases the solubility of solids - increasing kinetic energy, causes solute dispersion to increase, which exposes the solute to fresh solvent faster - dissolution represents a change in physical state (solid to liquid) which requires energy to break the bonds present in the bulk solid 31. what does increasing the pressure for solid and liquid systems do to the solubility: - has no notable effect on solubility - for gases dissolved in liquid, increasing the pressure increases their solubility as they can form supersaturated solutions (like fizzy drinks) 32. explain how melting point is related to solubility: - compounds with high melting points usually show poor water solubility and vice versa 33. explain the link between the molecular shape and symmetry of a compound with its solubility: - symmetrical, flat molecules pack tightly together with stronger intermolecular forces resulting in higher melting points and lower aqueous solubility than unsymmetrical molecules 34. explain the link between molecular weight of a compound and its solubility: - increasing molecular weight results in a decrease in water solubility - this is because increasing weight equaes to increased non-polar nature - drugs with molecular weights more than 500 are likely to show reduced solubility 35. explain the link between a compounds hydrogen bonding ability and its solubility: - the addition of group able to hydrogen bond increases the solubility since it can form hydrogen bonds with polar solvents 36. explain the link between polar functional groups and its solubility: - having polar functional groups increases the water solubility - acid and bases exist in charged forms and they are much more soluble than their uncharged equivalents 37. explain the link between non-polar functional groups and its solubility: nonpolar functional groups will decrease aqueous solubility as they increase the hydrophobic character of the solute as they disrupt hydrogen bonding with water 4 / 10 38. why is pH for drugs important with regards to their soluility: - pH determines the proportion of an ionisable drug that is charged - when the pH increases above the pKa of an acid, the acid is deprotonated and becomes negatively charged and can form hydrogen bonds with water, increasing the solubility - when the pH decreases below the pKa of an acid, the majority of the acid will be in its free uncharged state and its solubility in water is low 39. what is intrinsic solubility: - the solubility of the free (unionised) solute - buffers can be used to maintain the free acid/base 40. how can you alter the aqueous solubility of a compound (functional grousp): - by attaching differing functional groups - polar functional groups increase solubility 41. how can you measure logP (shake flask method): - a volume of octanol and water is left to equilibrate - a third substance is added and shaken mechanically for >1hrour and left to settle - the conc of the substance in one solvent is found using UV spectroscopy - the amount of substance added and the volume of the solvents are known - if the conc of solute in one phase is known (using UV) the solute conc in the other solvent can be calculated: (moles in oct + moles in aqueous = total moles of drug added) 42. why is octanol used for the shake flask method: - because the structure of octanol resembles the approximate amphiphilic (having both hydrophilic and hydrophobic parts) form of a phospholipid - therefore, octanol is used to represent the phospholipid bilayer of a cell membrane and, as such, logP can indicate whether or not a substance may pass through a cell membrane and enter a cell 43. logP and the development of pharmaceuticals: - due to the importance of logP, it is often one of the first physicochemical properties considered during drug development - it is too slow to use experimental approaches to determine logP therefore computational tools are used - estimation program interface (EPI) suite uses knowledge of structural contributions to solubility (logP) to derive a predicted logP value known as the logKow 44. how can we predict water solubility using computational tools: - we know the contributions that certain structural features have on solubility - the tools can break down a molecule into its components groups and combine these contributions together to generate a prediction - most widely used tool: estimation program interface (EPI) suite 5 / 10 45. why do we exploit solubility differences: - differences in solubility can be exploited in the extraction of acidic and basic drugs from natural sources - e.g. morphine from opium poppy plants - morphine is poorly water soluble is very soluble in acid - acid extraction from the plant concentrated up the active molecules in the aqueous solvent. the unwanted plant material can be filtered away from the solution 46. what are colligative properties: properties depend upon the ratio of solute molecules present in a solution, compared to the number of solvent molecules - molality is used to represent concentration (number of moles of solute dissolved in one kg of solvent molkg-1) - molality is independent of water 47. what is the difference between molarity and molality: - molarity is the moles of solute in litres of solution and the molality is the moles of solute in a kg of solvent - molarity: litres of solution mean the solute and solvent are combined. dissolve solute in a bit of water and then make it up to 1 litre - molality: is the solvent by itself. dissolve solute in an already weighed 1kg of water 48. why is molality used instead of molarity: - is easier to make a molality solution than a molarity solution - molarity you have to weight mass of solute and then and enough solvent to reach 1000ml, but for molality you just have to add the weighed solute into 1kg of solvent - also molality stays constant over a wide range of temp and pressure: - decreasing the temp of a molar solution will cause the water to contract so you will have less than 1l (increasing the molarity) and increasing the temp of solution will cause the water to expand so you will have more than 1l (decreasing the molarity) - for molality: even though water can contract and expand, it will still weight the same, therefore the molality of a solution wouldn't change 49. explain the colligative property of lowering vapour pressure: - adding a non-volatile (a substance that does not easily vaporize) solute reduces the vapour pressure of the solution 50. explain the colligative property of elevation of boiling point and depression of freezing point: - the addition of a solute stabilises the solvent in the liquid phase meaning it has less tendency to move to the gas or solid phase - these effects are proportional to the reduction in vapour pressure - the size of the difference in temperature for boiling point or freezing point = Kmb where (for boiling point elevation) k is the ebullioscopic constant of the solvent (for depression of freezing point) K is the cryoscopic constant of the solvent. mb is the molality of the solution 51. explain the colligative property of osmotic effect: - osmosis: net movement of solvent molecules through a partially permeable membrane driven by the difference 6 / 10 in solute concs on the two sides - if solute is added to water on one side of the membrane, water will flow towards that solution - osmotic pressure is the pressure needed to stop the movement of water 52. what is tonicity: - the osmotic pressure gradient of two solutions separated by a semipermeable membrane - if a cell is placed in distilled water (hypotonic), water will enter the cell since water is less concentrated within the interior of the cell than outside of it. this will cause the cell to swell and possibly burst - if a cell is placed in a solution with a very high solute conc (hypertonic), the cell will shrink and loose water - isotonic solution: A solution that has the same salt concentration as cells and blood - to stop movement of water a solution must be isotonic with the body - tonicity of blood = 275-295mOsmol kg-1 - therefore, the tonicity of any liquid preparation coming into contact with the body must be equivalent to that of blood 53. what are hydrophobic compounds: - compounds that are not soluble in water and are only soluble in non-polar solvents - water fearing hydrophobicity and water solubility are inversely related (increasing water solubility decreases hydrophobicity) 54. what factors affect hydrophobicity: - molecular weight: increasing will increase the non-polar character of a compound, increasing its hydrophobic nature - polarity: addition of polar functional groups increases water solubility, therefore decreasing hydrophobicity - pH: free (unionised) forms of drugs are less water soluble, they show a greater solubility in non-polar solvents. - hydrogen bonding ability: compounds that are able to form hydrogen bonds with water are usually highly water soluble, therefore increasing hydrogen bond ability decreases hydrophobicity 55. explain miscibility: - due to difference in hydrophilic/hydrophobic nature of liquids, not all liquids are miscible with one another and not capable of forming a homogenous solution - when two liquids are immiscible they form distinct layers with the most dense of the liquids falling to the bottom (mixing oil and water: oil stays at top water falls to bottom) 56. explain partitioning: - taking advantage of immiscible mixtures to asses the hydrophilic/hydrophobic nature of a third substance - add third substance to an oil, water system 7 / 10 - it will distribute throughout the two layers (partitioning) - if the substance is hydrophobic it will concentrate within the oil phase and if it is hydrophilic it will concentrate in the aqueous phase [all substances are soluble in polar and nonpolar solvents to some degree] [a substance can distribute equally between two phases if it possesses equal hydrophilic and hydrophobic character] 57. how can the partitioning of a substance between two phases be measured: - by the partition coefficient P - this is the ratio of conc of a substance between the two immiscible phases P = [nonpolar phase]/[polar phase] - sometimes referred to as K (or Kow when an octanol:water system is used) - the logarithm of the coefficient is taken giving logP - when the nonpolar phase is preferred: p>1 & logp>0 - when the polar phase is preferred p<1 & logp<0 58. how can we use the partitioning characteristics of compounds to benefit us: - can be used to extract a specific substance from a solution using knowledge of which phase it has greater affinity towards 59. what is the effect of pH on partitioning: - charged compounds are a lot more soluble in polar solvents than the uncharged equivalents - the measure of charge depends on the pH 60. explain weakly acidic drugs and pH: - for weak acidic drugs (pKa 3.0) - gastric fluid has pH of 1-2 therefore majority of drugs is unionised - intestinal fluid has pH of 7-8 therefore majority of drug is ionised - therefore the drug is more likely to be absorbed in the stomach 61. explain weakly basic drugs and pH: - for weak basic drugs (pKa 5.0) - gastric fluid has pH of 1-2 therefore majority of drug is protonated - intestinal fluid has pH of 7-8 therefore majority of drug is deprotonated - therefore the drug is more likely to be absorbed in the small intestine 62. what can you do when the solute of interest (drug) is likely to be ionised under certain conditions: - adjust the pH to prevent ionisation or - calculate the partitioning of ionised species by redefining P as the apparent partition coefficient (Papp or more commonly known as D) - D(Papp) = P x Funionised 63. what is funionised: - fraction of the total amount of drug unionised at that specific pH - calculation = 1/(10+/-^(pH-pKa) + 1) - for acidic drugs + is used 8 / 10 - for basic drugs - is used (look at study pack pic for better representation of equation) 64. pKa values of common drugs: acidic: - aspirin: 3.5 - paracetamol: 9.5 basic: - diazepam: 3.3 - diphenhydramine: 9.0 amphoteric: - morphine: 8.0(amine), 9.9(phenol) - adrenaline: 8.7(amine), 10.2, 12.0(phenol) 65. why is partitioning (logP) important: - provides insight into a drugs bioavailability when it enters the body - body is a two phase system made up of aqueous and non-polar components - if a drug is too hydrophilic, it will show excellent water solubility but it will not be able to cross biological membranes (since membranes have hydrophobic heads) - if a drugs is too hydrophobic, it would be poorly water soluble and would enter, but not leave cell membranes - hydrophobicity plays big role in determining a drugs ADME profile - hydrophobic characteristics are important for drugs in terms of receptor binding also 66. what is a drugs ADME profile: abbreviation in pharmacokinetics and pharmacology for "absorption, distribution, metabolism, and excretion", and describes the disposition of a pharmaceutical compound within an organism 67. bioavailability of a drug: The ability of a drug or other substance to be absorbed and used by the body 68. how can drugs pass into the blood stream: - for drugs to pass into the blood stream they must pass through membrane of intestinal epithelium: it must be hydrophobic enough to partition into the lipid bilayer but not so hydrophobic that it is unable to partition back out again - therefore a drug must posses both hydrophilic and hydrophobic character and fall within a specific logP range 69. give a summary of the changes to solubility with changes to the solute/solvent (solubility increase): generally, aqueous solubility increases with: - decreasing melting point - increasing temp - decreasing molecular weight 9 / 10 - increasing polarity - increasing H-bonding 70. give a summary of the changes to solubility with changes to the solute/solvent (hydrophobicity increase): - generally hydrophobicity increases with: - increasing melting point - decreasing temp - increasing molecular weight - decreasing polarity - decreasing H bonding 71. Lipinski's Rule of Five: - lipinski rules state that problems with absorption can be prevented if two of these four rules are avoided - an increasing number of rule violations indicate that an absorption-related problem is likely - rule of 5 used to indicate the drug-likeness of a compound rules: - molecular weight: less than 500 - partition coefficient: less than 5 - number of H-bond donors: less than 5 - number of H-bond acceptors: less than 10 10 / 10