Chapter 3 - Pharmaceutical Principles and Drug Dosage Forms (Ch 2 in CPR 8) (Dear Friends, we will study APhA Ch 13 with this chapter because that is also same topic) I .I ntermolecular forces of attraction Atomsvaryinelectronegativity,so,electronsharingbetweenatomswillbeunequal.So,themolecule behaves like a dipole over a covalent bond. Dipole moment (mu) = distance of charge separation X charge Nonpolar molecules: perfect symmetry and dipole moment = zero.Example: carbon tetrachloride. Whenthenegativepoleofadipoleapproachthepositivepoleofanothermolecularattractioncalled dipole-dipole interaction. If similar poles approach molecular repulsion (intermolecular repulsive forces) Types of intermolecular forces of attraction Van der Waals forces (liquids) Induceddipoleinduceddipole(Londondispersionforce):whenatransientdipoleinanonpolar molecule induces another transient dipole in another molecule. Force = 0.5-1 Kcal/mole Dipole-induceddipole(Debyeinductionforce):Atransientdipoleisinducedbyapermanentdipole.Force = 2 Kcal/mole Permanent dipole (Keesom orientation force): 4 Kcal/mole Hydrogen bonds Hydrogen ions are small and have a large electrostatic field, so it approaches highly electronegative atoms (O, F, Cl, N, S) and interact electrostatically to form a hydrogen bond. Force = 5 Kcal/mole. Ion-ion, ion-dipole, ion-induced dipole Forceofpositive-negativeioninteractioninthesolidstate=150Kcal/mole.Covalentandionicforces are much stronger than van der Waals forces. I I .States of matter Gases Molecules move in straight path at high speed until they randomly collide with another molecule, creating pressure.Intermolecular forces ~ zero. Ideal gas law: Pressure (P) x Volume (V) = number of moles (n) X Molar Gas Constant (R) X Temperature (T) Gasesinpharmacy:anesthetics(nitrousoxide,halothane),compressedoxygen,liquefiableaerosol propellants(nitrogen,CO2,hydrocarbons,halohydrocarbons),ethyleneoxideforsterilizationofheat labile objects. Volatile liquids (ether, halothane, methoxyfurane) are used as anesthetics.Amyl nitrite (volatile liquid) is inhaled as a vasodilator in acute angina.Sublimation: a solid is heated directly to the gaseous or vapor state (or vice versa, also called deposition) without passing through the liquid state.Examples: camphor, iodine. Liquids VanderWaalsintermolecularforcesaresufficienttoimposesomeordering.Hydrogenbonding cohesion in liquids. Surface and interfacial tension Moleculesatthesurfaceoftheliquidexperienceanetinwardpullfromtheinteriorandtheytendto contract.This makes liquids assume a spherical shape as it is the volume with minimum surface and least free energy. Surface free energy / surface tension:the work required to the surface area A of the liquid by 1 unit area.Example: SFE for water = 72 mN/m. Interfacial tension:at the surface of two immiscible liquids. Viscosity Viscosity = shear stress / shear rate Non-Newtonian viscosity: exhibit shear dependent or time dependent (apparent) viscosity. Sheardependentviscosity:Shearthickening(dilatancy)asinsuspensionsofsmalldeflocculated particleswithhighsolidcontent.Shearthinning(pseudoplastic):asinpolymersolutions.Plastic (Bingham body): as in flocculated particles in concentrated suspensions that have yield value. Time dependent viscosity:yield value of plastic systems may be time dependent. Thixotropic systems are shear thinning but they do not recover viscosity after shear is removed, i.e., structural recovery is slow comparedtostructuralbreakdown.Itoccursinheterogenoussystemswiththreedimensionalstructural network(gel-soltransformation).Negative(anti)thixotropy:viscositywithshearuptoan equilibrium (sol-gel transformation). Solids High intermolecular forces. Crystalline solids: fixed molecular order, distinct melting point, anisotropic (properties are nto the same in all directions).Amorphous solids: randomly arranged molecules, nondistinct melting point, isotropic (properties are the same in all direction). Polymorphs: substance has more than one crystalline form.Different molecular arrangments / crystalline lattice structure, melting point, solubility, dissolution rate, density, stability.Polymorphs are common in steroids, theobroma oil, cocoa butter. Latent heat of fusion:heat absorbed when 1 g of solid melts.I I I .Physicochemical behavior Homogenous systems Solution: homogenous system in which a solute is molecularly dispersed or dissolved in a solvent. Nonelectrolytes:substancesthatdonotformionsinsolution,e.g.,estradiol,glycerin,urea,sucrose.Solution doesnt conduct electricity. Electrolytes: form ions in solutions.Solution conducts electricity.Can be strong (completely ionized in water; HCl, NaCl) or weak (partially ionized; aspirin, atropine). Colligative properties:Dependonthetotalnumberofionicandnonionicsolutemoleculesinsolution.Theyaredependenton ionization but independent of other chemical properties of the solute. Vaporpressuredepression:(Raoultslaw):partialvaporpressureisequaltotheproductofthemole fraction of the component in solution and the vapor pressure of the pure component. Boiling point elevation and freezing / melting point depression Osmoticpressure:Osmosisistheprocessbywhichsolventmoleculespassthroughsemipermeable membranefromdilutesolutiontoconcentratedsolution.Thatisbecausesolventmoleculeshavelower chemicalpotentialinconcentratedsolution.Osmoticpressureisthepressurethatmustbeappliedto solution to prevent the flow of pure solvent.It is defined by the vant Hoff equation. Electrolyte solutions and ionic equilibria Arrhenius dissociation theory: an acid is a substance that liberates H+ (donates protons) in water, a base liberatesOH- (accpetsprotons).LowryBronstedtheory:appliestobothaqueousandnonaqueous systems.Inwater,afreeprotoncombineswithwaterforminghydroniumion(H3O+).Astrongacidin water can behave as a weak acid in a different solvent. Lewis theory: defines acid as a molecule or ion that accepts an electron pair from another atom.A base donates an electron pair to be shared with another atom. pH is the negative logarithm of molar H+ concentration. As pH , H+ concentration exponentially. Ionization:isthecompleteseparationfotheionsinacrystallatticewhenthesaltisdissolved.Dissociation: is the separation of ions in solution when the ions are associated by interionic interactions.For weak electrolytes, dissociation is reversible.According to the law of mass action, concentration of dissociation products results in dissociation.pKa is the dissociation constant of a weak acid. pKb is used for weak bases. Acidsandbasesthatcanacceptordonatemorethanoneprotonwillhavemorethanonedissociation constant. Henderson-Hasselbalch equation:describes the relationship between ionized and nonionized species of aweakelectrolyte(baseisUP).pH=pKawhen[dissociatedspecies]=[nondissociatedspecies],i.e., 50% ionization. SolubilityofaweakelectrolytevariesasafunctionofpH.SolubilityofaweakacidwithpH.Opposite is true for weak bases. Buffer: a mixture of salt with acid or base that resists changes in pH when small quantities of acid or salt are added.Buffer is a combination of weak acid and its conjugate base (salt) (more common), or a weak base and its conjugate acid (salt). Buffercapacity:isthenumberofgramequivalentsinanacidorbasethatchangesthepHof1liter bufferby1unit.MaximumbuffercapacityoccurswhenpH=pKa.Higherconcentrationofbuffer constituents buffer capacity due to the acid or base reserve. Heterogenous (disperse) systems: Suspension: two phas system that is composedof solid material dispersed in a liquid.Particle size is > 0.5 mm. Emulsion:heterogeneoussystemthatconsistsofoneimmiscibleliquiddispersedinanotherasdroplets.Droplets diameter > 0.1 micron.Emulsions are inherently unstable because the droplet tend to coalesce.An emulsifying agent is used to prevent coalescence. In ideal (not real) dispersion, the dispersed particles are uniform in size and do not interact. StokesslawdefinesSedimentationrate.Theratewithparticlesizeandthedifferenceindensity between particles and medium.The rate with medium viscosity. Highparticulate(dispersedphase)concentrationleadstoparticlecollisionandaggregation, coalsecnce, instability. Avoidanceofparticle-particleinteractions:ifparticleshavesimilarelectricalcharge(e.g.fromthe surfactant).Zeta potential (magnitude of the charge) is the difference in electrical potential between the particlechargedsurfaceanddispesionmedium.Whenzetapotentialishigh( attractive forces, which results in deflocculation and stability.Coalescence of droplets in O/W emulsions is by electrostatic repulsion of similarly charged particles. Creaming:isthereversibleseparationofalayerofemulsifiedparticles.Mixingorshakingmaybe sufficient to reconstitute the emulsion. Phase inversion:from o/w to w/o emulsion or vice versa. I V.Chemical kinetics and drug stability Degradation rate depends on concentration, temperature, pH, solvents, additives, light, radiation, catalysts (polyvalent cations), surfactants, buffers, complexing agents. Order of reaction: the way in which the concentration affects rate. Zero order:rate is independent of concentration, e.g., 5 mg/hr, i.e., straight line concentration vs. time. Firstorder:ratedependsonthefirstpowerofconcentration,e.g.,5%/hr.Concentration exponentially with time.Straight line log concentration vs.time.t1/2 = 0.693/k,t90% = 0.104/k.Half life is concentration independent. Temperature: T reaction rate (Arrenius equation). Solvent:maychangepKa,surfacetension,viscosity,reactionrate,etc.Additionalreactionpathways may be created (e.g. aspirin in ethanol). pH: H+ catalysis occurs at pH, OH- catalysis occurs to pH.Rate constant at intermediate pH range is usually lower than at or pH.pH of optimum stability (point of inflection) is measured. Aromaticesters(benzocaine,procaine,tetracaine)t1/2ispresenceofcaffeineduetocomplex formation. Modes of pharmaceutical degradation: Hydrolysis:mostcommon.Occursforesters,amides,lactams.H+andOH-arethemostcommon catalysts.Esters easily hydrolize and should be avoided in liquids.Oxidation:byoxygenintheairorinsolvent.Oxidizablecompoundsshouldbepackedinaninert atmosphere(nitrogenorCO2).Oxidationinvolvesfreeradicalmechanismandchainreaction.Free radicalstakeelectronsfromothercompounds.Antioxidantsreactwithfreeradicalsbyproviding electrons.Antioxidantsinclude:ascorbicacid,tocopherols,sodiumbisulfite,sodiumsulfite,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate. Photolysis: degradation in sunlight or room light.Molecules may absorb the proper wavelenght of light (usually 50%oftotal weight. Content uniformity: USP standards apply if drug