PHAR1822 NOTES (THEORY)

Transcription

1 PHAR1822 NOTES (THEORY) Liquids & Solutions 1 Definitions - Solution = mixture of >2 components that form a single phase which is homogenous down to the molecular level (e.g. NaCl and water) - Phase = part of a system separated by >1 boundaries (interfaces), which can be separated physically (e.g. filtration, centrifuge) - Homogenous = same composition throughout (all liquids + semi-solid dosage forms) - Solvent = largest proportion of the system determines the PHASE of solution (e.g. ethanol, water) - Solute = dispersed throughout the solvent as molecules or ions - 50/50 mix = no solvent (no larger component) in the system - Dissolution = transfer of molecules or ions from the solid state into solution - Solubility = limit to which a solute can be dissolved in a solvent under set of conditions (temperature, presence of other solutes) - DISSOLUTION and SOLUBILITY of a drug ARE NOT related o Drug can be dissolved quickly BUT can be poorly soluble o Drug can dissolve slowly BUT be highly soluble - Miscibility = combo of 2 solvents that mix completely to form a homogenous solution AT ALL CONCENTRATIONS o Ethanol + water = will mix completely regardless of proportion o BUT water will mix with some solvents when solvent is at a small conc. BUT can split into 2 phases at other temps - Gas solute + liquid solvent = carbonated water (soft drink) - Liquid solute + liquid solvent = alcohol in water (liquid in liquid) o Alcohol in water (need a small percentage of alcohol) o OR 90% alcohol + 10% water = alcohol is SOLVENT + water is SOLUTE - Solid solute + liquid solvent = table salt in water Solubility - Solubility is determined at 20 C + relates to amount of solvent in ml/g ( parts ) that is required to dissolve 1 gram of drug o E.g. 1 gram of NaCl = dissolved in 1 gram of water = VERY soluble o E.g. 5 gram of NaCl = dissolved in 1 gram of water = FREELY soluble - Very soluble = LESS THAN 1 PART - Freely soluble = 1-10 parts - Soluble = parts - Practically insoluble = >10,000 parts

2 Water Solubility - LIKE DISSOLVES LIKE - Polar molecules dissolve in polar solvents - Non-polar molecules dissolve in non-polar solvents - Water = solvent used in pharmaceutical formulations (major component of body) - Water solubility = determined by forming HYDROGEN BONDS + ion-dipole bonds - 2 lone pairs of H 2 O point out into space = tetrahedral shape o BIG molecule pulls electron density from bonds closer to OXYGEN o Electrons not shared evenly = dipole moment (small delta neg. on oxygen) - Water has the HIGHEST HEAT CAPACITY due to HYDROGEN BONDING - Water H-bonds with itself = any OTHER molecule that can form similar bonds with water is liked and dissolved o To dissolve in water = need to break water molecules = has to act like water + have something so water can H-bond to it - Any part of DRUG MOLECULE that has NH, OH, C=O = H-BONDS - More functional groups = more hydrogen bonding = more soluble Ion-Dipole Bonds - STRONGER than H-BONDS - REAL positive charge on Na + = bond between oxygen and sodium is MUCH stronger than a water-water bond - Salt form of drugs are MORE water soluble than the neutral form of drugs because they form MORE STRONGER hydrogen bonds with water Salt Forms - SALT FORM of drugs are MORE SOLUBLE than NEUTRAL FORM - BETTER DISSOLUTION RATE + ABSORPTION RATE + FASTER ACTION - BUT samples can be HYDROSCOPIC (draws in moisture from air) o Storage + transport problems = absorbs water from air = LESS drug in solution - Can change ph of solution = IMPORTANT FOR INJECTION + ORAL solutions - Reactions with packaging = glass susceptible to BASIC solutions - Different salts of a drug work differently to each other = causes SLOWER reactions - Salts interact with each other to precipitate out of solution = BAD for injections Common Salt Forms of Drugs - CHLORIDE + SODIUM = MOST USED FORMS o Cheap o Main component of bloodstream (biocompatible) o Highest charge density = SMALL ion = forms H-bonds better + drug MORE SOLUBLE o Sodium salt = more water soluble of drug than potassium

3 Salting Out - Used to PURIFY PROTEINS - TOO MUCH SALT in sol. = water molecules bind to protein OR salt (can t do both) - Need to PRECIPITATE PROTEIN OUT of solution b/c it doesn t H-bond to water - Salting out = precipitation of peptides, proteins from solution at HIGH salt conc. - WATER SOLUBLE PROTEINS have hydrophobic cores + hydrophilic surfaces - Proteins = water soluble because they form hydrogen bonds with water molecules - BUT salt conc. high = water molecules bind to SALT INSTEAD of protein (not enough free water available) - Results in the precipitation of the LESS SOLUBLE SOLUTE = i.e. protein molecules - Implications for pharmacy = some drugs are based on proteins + peptides o Take care when preparing samples for administration to NOT precipitate drugs Salts & Hydrogen Bonding - Drug dissolution = not simply forming single H-bonds between polar groups - There is a NETWORK OF WATER MOLECULES involved - Na + moves through solution with water molecules H-bound = pulls water molecules - WATER hydrogen bonds with itself SO Na + pulls all molecules with it Van De Waals Radius & Hydrodynamic Radius - Van de waals radius = hard actual radius (amount of space it takes up) o Imaginary radius of drug molecule o It is the PHYSICAL SPACE the drug (and only this) takes up - Hydrodynamic radius = affects how drugs move through solution o Imaginary radius of a drug + any bound particles that travel through the solution WITH the drug Brownian Motion - Random movement of particles suspended in a liquid or gas caused by collisions with molecules of the surrounding medium - Rate of drug movement through solution is related to its SIZE - BIG molecule = pushes water molecules out of the way = water pushes back (net result: DOESN T move) - SMALL MOLECULE = moves around gaps much quicker

4 Stokes-Einstein Equation - Rate of drug diffusion through solution (or other barriers) depends on hydrodynamic radius + VISCOSITY of the solvent - Diffusion coefficient = area a drug molecule covers in a certain amount of time -!(!!!!! ) =!"!!"# o n = solvent viscosity (1.2 x 10-3 PaS for water) o r = hydrodynamic radius (metres) Examples: What happens to the rate of a drug s diffusion when we: - Increase the temperature = particles move FASTER - Change from water to oil = viscosity is THICKER, rate is SLOWER - Change from neutral drug to salt form = diffusion SLOWER o Salt form has a REAL neg/pos charge = binds to water molecules BETTER o Drags MORE water molecules through solution = RADIUS INCREASES - Change solvent from water to ethanol for a very soluble drug = 2 competing forces: o WONT hydrogen bond to ethanol = drags less things through = radius smaller o VISCOSITY = ethanol is MORE viscous = harder for drug to push molecules - Make a nanoparticle formulation of the drug = rate is SLOWER o Typical drug molecule = <1nanometre SMALLER than a nanoparticle o Nanoparticles are BIGGER than single drug molecules Liquids & Solutions 2 Vapour Pressure - ANY liquid has a VAPOUR OF GAS molecules ABOVE the liquid - VAPOUR PRESSURE = pressure of the vapour above the liquid when liquid + vapour are at equilibrium - Amount of vapour above liquid depends on IMF b/w molecules (how well they stick together) - Strong IMF = less inclined to evaporate into air (hard to turn water from liquid to gas! high head capacity) - Ease of evaporation + amount of gas above the liquid DEPENDS ON IMF - MORE bonding b/w molecules = LESS vapour forms = LOWER vapour pressure - After TIME liquid molecules turn into gas (MORE TIME = MORE GAS molecules) - LOW vapour pressure = BOILS at a HIGHER temperature (energy put INTO system to turn liquid molecules to gas molecules) o Vapour pressure depends on vapour ALREADY in the AIR o SMALL vapour = smaller VAPOUR PRESSURE (e.g. water) - HIGH vapour pressure = BOILS at a LOWER temperature o MORE VAPOUR = HIGHER vapour pressure o E.g. ethanol (pungent smell) = evaporates EASILY o Can BURN the VAPOUR NOT the liquid

5 Example Water & Ethanol in 50/50 mixture - Ethanol = HIGH vapour pressure = MANY molecules in AIR - Water = LOW vapour pressure = FEW molecules in AIR - Number of molecules in air = NOT necessarily related of molecules in solution o ONLY relates to how easily it transforms from liquid to gaseous state o 50/50 solution = DOES NT mean 50/50 mixture of ethanol/water in air above Raoult s Law - P TOTAL = X A P A + X B P B + - P TOTAL = total pressure from all molecules in gas/vapour phase (everything in system) - X A = mole fraction of gas A (MUST be LESS THAN 1) - P A = vapour pressure of gas A - Mole fractions when added together MUST equal 1 - X-axis = mole fraction (ACROSS = increase number of moles) - Y-axis = vapour pressure (HEIGHT = increase in vapour pressure) - Ethanol = HIGH vapour pressure = solution is 100% ethanol, LOTS of vapour BUT o REDUCING the amount of ethanol = vapour pressure decreases o NO ethanol = NO liquid = NO gas above = NO vapour pressure o LOTS OF ETHANOL = lots of vapour pressure - Mixture ethanol WITH WATER: o Increase amount of water = partial pressure of water molecules increases o WATER has a lower vapour pressure = will never be at the same extent o NO WATER = NO vapour pressure o LOTS OF WATER = higher vapour pressure - TOTAL pressure in system = adding components together (black line) o TOTAL pressure is initially high = dependent on total amount of ethanol o END total pressure = system dependent on water because ethanol is no longer present

6 Ideal vs. Non-Ideal - TOTAL pressure of solution DEPENDS on mixture - EFFECT OF 2 POLAR MOLECULES on vapour pressure = interacts with each other o NaCl dissolves in water to form ION-DIPOLE bonds o Interaction creates a STRONG BOND o TO push into vapour phase = need to BREAK the bond = requires energy o OVERALL DECREASE IN PARTIAL + TOTAL PRESSURE of the system - H-bonds between 2 different types of molecules (which act to keep them in the liquid phase) = LOWER vapour pressure for both gases o Partial pressure of ethanol (ideal straight line) in a polar-polar system follows a CURVED LINE o Partial pressure of ethanol will be LOWER than what it normally would be because its binding to the water molecules and can t evaporate o SAME for water = partial pressure decreases = it binds to other polar molecule o TOTAL PRESSURE in system = decreases even further o ADD NaCl to water = BOILING TEMP INCREASES = LESS gas molecules o To move from LIQUID to GAS phase = need to ADD energy to break bonds o ADDING A POLAR MOLECULE TO WATER = INCREASES BP " E.g. water + NH 3 = both polar = reduce pressures overall - EFFECT OF 1 POLAR + 1 NON-POLAR MOLECULE in liquid = DON T interact = EASIER to go into gas phase o MORE GAS than normal o Water molecules MORE present in GAS phase = partial pressure INCREASE o MORE ethanol + water in AIR = TOTAL PRESSURE of system INCREASE o LOWER BP = more gas in air = VERY easy to go from liquid to gas state " E.g. H 2 O + ethanol (ethanol not as polar as it could be) " WATER + ETHANOL = BP decreases - 2 molecules repel = both try to escape each other = MORE molecules in gas phase

7 - EFFECT OF 2 NON-POLAR MOLECULES in liquid = WEAK hydrophobic forces - Molecules do not stick together strongly = BUT also NO REPULSIVE FORCE - 2 non-polar molecules = IDEAL = partial pressures remain exactly the same - IDEAL = no effect on the partial pressures of gases/vapours o E.g. hydrophobic substances + not miscible with water Freezing Point Depression - 2 POLAR solutions added together = BP INCREASES - FREEZING POINT (temperature at which it freezes) = DECREASES - Dissolution of POLAR solute (drug) in solvent (water) = DROP in solvent freezing pt - FREEZING POINT DEPRESSION = this is why sea water doesn t freeze in poles o SALT LOWERS the freezing point of the water (more salt = lower freezing pt) - SIZE of the freezing point depression = based on solvent + amount of solute (no. of molecules NOT no. of moles) Pharmacy Relevance - Polar molecule + water = lowers freezing point of water - BLOODSTREAM = has water, salt (NaCl), sugar (glucose), phosphates, protein (polar on outside allowing it to dissolve) o These substances LOWER the freezing point of BLOOD o BLOOD freezes at C - ANY SOLUTION injected into blood that DOES NOT have the same freezing point depression as saline = KILLS the patient o SAME applies for eye drop solutions = eyes swell, burst

8 Liquids & Solids 3 How Drugs Dissolve - Solubility depends on H-BONDS with water AND chemical structure - Medicines must be dissolved in solution=but always begin with solid particles of drug - Solid drug particle made up of individual drug molecules - Blue squares = drug molecule part of a larger drug particle - Yellow = solution that drug will be dissolved in - Solid particle + solution = drug molecules come off one by one into solution - When particle comes off = empty space is filled by the solution of the solvent - Over time, more particles dissolve into solution = some move a short or long distance - Area close to the particle where there is a high concentration of drug = diffusion layer - Further away from diffusion layer = concentration of drug decreases - NOT a one way process = once a drug molecule comes off, doesn t have to stay in solution = CAN GO BACK onto the drug (happens with SATURATED drug in sol.) o E.g. NaCl dissolved in water = keep adding salt until no more dissolved o Some salt dissolves into solution OR salt in solution goes back into solid form - Particles that dissolve in solution = only SURFACE of the solid form o ONLY molecules in contact with the solution can dissolve - ONLY drug molecules at the surface of the solid form can dissociate + dissolve Physical Factors that affect Solubility - Particle SIZE = small particles have LARGER surface area RATIO = more molecules in contact with water o SMALLER PARTICLES = FASTER + BETTER DISSOLUTION o Smaller particles = higher surface to weight ratio o E.g. nanoparticle formulations will dissolve faster - Dispersibility of solid particles = stick together OR separate with water molecules in between o How well drugs separate from each other = MORE SURFACE AREA o How well drugs disperse in solution determines how fast + well they dissolve o IF particles hydrophobic = particles stick together = reducing overall surface o PARTICLES that SEPARATE from each other to have water in between them = DISSOLVE FASTER

9 - Porosity of particles = holes IN structure = water accesses inner parts of particles o Channels through particle to the core = water travels to dissolve the particle o Formulations for fast/slow drug release: " Tablet breaks apart quickly in stomach to release drug quickly = porous " Tablet breaks down slowly over time = NOT porous - Whether the mixtures are crystalline, amorphous or a mixture of both Amorphous vs. Crystalline - Molecule interact with itself via polar-polar OR nonpolar-nonpolar interactions - BEST type of material for pharmaceutical preparations = AMORPHOUS - AMORPHOUS= NO organised structure = MOST SOLUBLE form for solid particles - CRYSTALLINE = molecules ONLY interact via nonpolar regions (no polar contact) o STACKED configuration - SECOND CRYSTAL TYPE = same drug, same type of stacking interactions BUT only hydrophobic interactions OR WEAK polar interactions between polar regions o SAME molecule BUT stacking configuration changes the crystal type o STACKING can change SOLUBILITY

10 What Solid State is Best? - Drug dissolution means BONDS b/w molecules have to be BROKEN to go into sol. o Bonds between drug molecules in solid state need to break before dissolving - BREAKING BONDS REQUIRES ENERGY - FEWER BONDS = easier to pull apart to go into solution o Amorphous = RANDOM structure + not many bonds holding molecule together = HIGH Gibbs free energy o Crystalline = both polar + non-polar interactions holding molecule together (need to break these bonds so drug can go into solution) o Compounds LOW Gibbs Free Energy dissolve the worst (in a stable state) o Compounds opt for lowest energy state = amorphous material TRANSFORMS into crystalline AFTER TIME - Solid state with FEW bonds to break is MOST SOLUBLE = high Gibbs Free energy dissolves most readily - Amorphous drugs are almost always MORE SOLUBLE than crystalline drugs - Want to manufacture amorphous type drugs = BUT crystalline drugs can be soluble - Over time amorphous drugs CAN become crystalline AND crystalline drugs CAN change to another form o Expiry date = drug is degrading OR changing from amorphous to crystalline o Drug needs to be in the RIGHT FORM AND be the right chemical - POLYMORPHISM = more than 1 crystalline state for a drug Examples of Polymorphism - Paracetamol = exists in 3 different crystal polymorphs o 2 MOST COMMON = stable polymorph I + metastable polymorph II o Metastable polymorph II dissolves FASTER in water + used in tablets o METAstable = reverts to polymorph I = LESS stable + worse dissolution - Glibenclamide (diabetes) = forms irregular + asymmetrically structured crystals when cooled quickly o BUT cooled quickly after MELTING = forms an amorphous solid - Memantine (Alzheimers) = simple small organic drug produced as amorphous powder OR in different crystal polymorphs Serious, Problematic Real World Example - Ritonavir = used for treatment of HIV marketed since Sold in oral solution + semi-solid dosage form (liquid filled capsules) o Plastic outercoating with liquid centre = drug is dissolved in liquid centre o NEEDS to be dissolved to ACT = solid form of the drug takes longer to dissolve + incorrect concentration in bloodstream - Has TWO crystal forms = NEW POLYMORPH of drug was LESS soluble o During storage = crystals formed INSIDE the capsules o Crystallisation = didn t dissolve at correct rate = ineffective dose of drug

11 Ritonavir Polymorphism - FORM I = plate-like crystal o Solubility 90 mg/ml o Soluble in solution for capsules o Therapeutic doses dissolved well under the point of saturation o Oral solution can be stored in the fridge = RELATIVELY stable - FORM II = needle-like crystals o Solubility 19 mg/ml o SAME dose of crystal = 400 times past maximum solubility o 400% supersaturated = crystallisation in capsules o Oral solution CAN T be stored in fridge = crystallises in fridge o VERY stable = doesn t convert to Form I - Discoveries: o Add Form I to a solution of Form II = no change in solubility o Add Form II to a solution of Form I = solubility rapidly decreases o Needle-like crystals = act as a nucleation site to pull drugs out of solution + crystallise into Form II from Form I - Features of Form I (soluble form): o Each drug molecule forms 8 hydrogen bonds to other drug molecules o Alcohol forms only one hydrogen bond to the thiazole group = bond is WEAK o For a drug molecule to dissolve = need to break bonds to get it into solution o Weak hydrogen bonds = good = can be broken + get into solution = SOLUBLE - Features of Form II: o Also held together by 8 hydrogen bonds o Alcohol group forms 2 hydrogen bonds BUT not to the thiazole group o No weak thiazole-alcohol hydrogen bond o 2 hydrogen bonds act simultaneously to make each other stronger = super strong Methods of Solid Drug Production - Slower to form something = bigger, better quality crystal - Spray drying = amorphous material from drying very quickly o Sprayed into air as a fine mist = water/solvent evaporates quickly o Compound doesn t have time to form bonds with itself = amorphous material - Dry solid state drugs = made by taking solution of drug + removing the solvent - Freeze drying = from solid to gas state o Drug in a liquid + freeze rapidly in liquid nitrogen o Vacuum created = water transforms from solid to gas state instantly o Water is CONDENSED to FREEZE o LATER water is sucked out = left with amorphous material - Precipitation = drug dissolved in solution + anti-solvent added (drug is not soluble in) o Changing the interactions between solvent + particles = slightly hydrophobic o E.g. Drug highly soluble in water = can add acetone to precipitate out - Evaporation = sample in solution is heated! evaporates

12 Hydrates & Solvates - To produce solid drug particles = need to remove solvent - As solvent is removed = some SOLVENT is trapped in SOLID drug particles o Water soluble drugs form H-bonds (bound to water) BUT sometimes water molecules remain bound to drug when DISSOLVED - Solid drugs with water/solvent molecules inside = solvates OR hydrates (water only) - For SOLID drug particle to go into solution = need to BREAK BONDS o Need to break bonds between drug particles o Hydrogen bound to water molecules - Solvents/hydrates LESS soluble (dissolve slower) than anhydrous (no water) solid particles = drugs are already bonded to solvent/water molecules in the particles o No benefit to them dissolving to form bonds with the solvent - Erythromycin (antibiotic) = produced in 3 different ways o For every drug molecule = 2 water molecules in solid particle o Anhydrate = no water in the solid particle (10% in 30 minutes) o Dihydrate = more water = dissolve much faster (100% in 30 minutes) o BUT water can evaporate OUT of the sample over time o Dihyrate over time can degrade down to anhydrate form (not as effective) Reaction Kinetics Chemical Kinetics determines: - How fast a drug is metabolised + excreted - How long radioisotopes emit radiation within the body - Shelf-life of drugs based on rate of degradation - How long to wait to administer the next drug after one dose has been administered - Drug release from controlled or modified release formulations and patches