1.Ana Marie L. Rubenicia, RPh

2. Diffusion Diffusiondescribes thespread of particlesthrough randommotion fromregions of higherconcentration toregions of lowerconcentration 3. Diffusion Mass transport phenomena includes:1. Release and dissolution of drugs from tablets, powders and granules.2. Lyophilization, ultrafiltration, and other mechanical processes3. Release from ointments and suppository bases4. Passage of water vapor, gases, drugs and dosage form additives through coatings, packaging,films, plastic container walls, seals and caps5. Permeation and distribution of drug molecules in living tissues. 4. DiffusionWays that a solute or a solvent can traverse aphysical or biologic membrane Simple molecular diffusion or permeation (fig.11-1a)- homogenous membrane w/o pores Diffusion through a solvent-filled pores (fig.11-1b)- membrane with straight through pores Movement through and/or between the fibrousmembrane strands (fig. 11-1c)- cellulosemembrane(filtration process);with interwining nature ofthe fibers and the tortuous channels. 5. Passive Diffusion Diffusion is the netmovement of materialfrom an area of highconcentration to an areawith lowerconcentration. Thedifference of concentrationbetween the two areas isoften termed as theconcentration gradient,and diffusion will continueuntil this gradient hasbeen eliminated. 6. Passive Diffusion Facilitateddiffusionalso called carrier-mediated diffusion, isthe movement ofmolecules across the cellmembrane via specialtransport proteins thatare embedded within thecellular membrane. Notenergy-dependent. 7. Passive Diffusion Filtrationis movement of water and solute molecules across the cell membrane .Influenced by hydraulic pressure.Depending on the size of the membrane pores, only solutes of a certain size may pass through it. 8. Passive Diffusion Osmosis the diffusion of water molecules across a selectively permeable membrane. The net movement of water molecules through a partially permeable membrane from a solution of high water potential to an area of low water potential. 9. Drug Absorption and Elimination LIPID BILAYER 10. Drug Absorption and Elimination Transcellularpermeationpathway for chemicals tobe absorbed into andthrough the skin istranscellular, or cell-to-cell. Diffusionoccuring through thelipoidal bilayer ofcells. 11. Drug Absorption and Elimination Paracellular Diffusion occurs through spaces between adjacent cells. 12. Drug Absorption and Elimination 13. Drug Absorption and Elimination 14. Drug ReleaseSTEPS IN DRUGRELEASEINCLUDESDIFFUSION,DISSINTEGRATION,DEAGGREGATIONANDDISSOLUTION. 15. Drug Release 16. Drug Release OSMOTIC DRUG RELEASE SYSTEM 17. Diffusion Ultrafiltration is used to separate colloidal particles and macromolecules by the use of a membrane. Hydraulic pressure is used to force the solvent through the membrane.Used to purify albumin and enzymes. 18. Diffusion Microfiltration employs membranes of slightly larger pore size, 100 nm to several um, removes bacteria from IV injections, foods and drinking water. 19. Diffusion Dialysis is the separationprocess based on unequalrates of passage of solutesand solvent throughmicroporous membranes. Hemodialysis is used torid of the blood ofmetabolic wasteproducts(small molecules)while preserving the high-molecular weightcomponents of the blood. 20. Ficks Law of Diffusion 21. Ficks Law of Diffusion Diffusion is describedby Ficks laws. Ficksfirst law relates thediffusion flux, J , to thesteepness of theconcentration gradient where D is thediffusion coefficient, Cis theconcentration, and x isdistance. the units of J aremoles cm2 s1 22. Ficks Laws of Diffusion 23. Ficks Law of Diffusion Ficks Second LawChange in the concwith time at adefinite loction. whereC/t, concentrationof diffusant in thevolume elementchanges with timeand J/x, the flux oramount diffusingchanges withdistance 24. Ficks Law of Diffusion Ficks second law states that the change in comcentration with time in a particular region is proportional to the change in the concentration gradient at that point in the system. 25. Biological Diffusion GI absorption of drugs- major pathway for drugs absorption the body. Governed by state of ionization of the drug, its solubility and concentration in the intestines, and its membrane permeability. 26. Biological Diffusion PercutaneousabsorptionInvolves:a. Dissolution of the drug in its vehicle.b. Diffusion of the solubilized drug from the vehicle to the surface of the skin.c. Penetration of the drug through the layers of the skin, principally the stratum corneum (most impermeable biological membrane).Stratum Corneum 27. Biological DiffusionPercutaneous absorptionFactors Influencing the Penetration of a Drug Into the Skin:a. Concentration of dissolved drug.b. Partition coefficientc. Diffusion coefficientRate limiting step: either release from vehicle or passagethrough the skin.Guidelines for effective topical dosage forms:a. All the drug should be in a solution in the vehicle.b. The solvent mixtures must maintain a favorable partitioncoefficient so that the drug is soluble in the vehicle and yethave the great affinity for the skin barrier into which itpenetratesc. Components of the vehicle should influence thepermeability of the stratum corneum. 28. Biological Diffusion Buccal Absorption buccal membrane does not have significant aqueous pore pathways. Utilizing an aqueous-in a lipid phase model, the weak acid specie are transported across the aq diffusion layer and only the nonionized species pass across the lipid membrane. ORAL MUCOSAE 29. Pressure in PharmaceuticalSystems Jet injectorsA jet injector is a type ofsyringe that usespressure instead of aneedle to penetrate theepidermis. Pressuredriven jets that producea high velocityjet(>100m/sec) thatpebetrates the skin.INSULIN JET INJECTOR 30. Temperature in PharmaceuticalSystemsLyophilization The process of freezedrying can achieveproduct stability, andimproved shelf-lifeFrozen aqueous solutioncontaining the drug andan inner matrix buildingsubstance. 31. Electrical potential inPharmaceutical Systems Fentanyl iontophoretictransdermal system Used to enhancetransdermal delivery ofdrugs by applying a smallcurrent through areservoir that containsionozed drugs. 32. Electrical potential inPharmaceutical Systems electrophoresis apparatus involves the movemen of charged particles through a liquid under the influence of an applied potential difference. Used as an analytical tool in pharmaceutical science. 33. Temperature potential inPharmaceutical Systems Microwave-assisted extraction - elevated temperature accelerates the mass transfer of target compounds from the matrix. 34. Ana Marie L. Rubenicia, RPh 35. Drug ReleaseThe process by which adrug leaves a drugproduct and is subjectedtoabsorption, distribution, metabolism, andexcretion (ADME)Described in several ways; Immediate-release Modified-release Delayed-release Extended-release Controlled-release Pulsatile release 36. DissolutionDISSOLUTION Is the process by which a solid solute with relatively low solubilityenters into solution in the presence of a solvent. Importance of dissolution A predictor of the in vivo behavior of a drug formulation Important tool to evaluate batch-to-batch uniformity of formulationDISSOLUTION It is the rate-limiting step in the bioabsorption of drugs possessinglow solubility. Slowest of the various stages involved in the release of drug from itsdosage form and passage into systemic circulationDISSOLUTION RATE The rate at which solid (tablet, capsule, and granule) dissolves in asolvent is described by the NOYES AND WHITNEY EQUATION The HIXSON-CROWELL CUBE ROOT LAW describes the dissolutionrate of drug powder consisting of uniformly sized particles. 37. DissolutionThe dissolution rate is the time required for a drug substance todissolve in the fluids at the absorption site. It is often the rate-limiting step in the absorption process . Dissolution is important for the bioavailability of solid dosageforms including oral capsules, tablets and suspensions andintramuscular suspensions.Methods for increasing dissolution rates: Decrease particle size. This increases the available surface areato the dissolving fluid. [Note: In rare cases, agglomeration of theparticles may occur leading to decreased dissolution rates.] Increase solubility in the diffusion layer. The ionized form of thedrug (salt of the weak acid or salt of the weak base) will havegreater solubility in the diffusion layer than the unionized weakacid or weak base. (e.g. penicillin V potassium will dissolvefaster than penicillin V itself). Alter pH of dissolution medium (e.g. buffered aspirin). Increase agitation of dissolution medium (e.g. effervescent,buffered aspirin) 38. Dissolution 39. DissolutionNoyes-Whitney Equation where,C/t = dissolution rate - D = Diffusion coefficient - S = Surface area of the dissolving particle - h = Thickness of the diffusion layer - V = Volume of the dissolution medium - Cs = Saturation Solubility of the drug in the medium - Ct = Conc. of drug in the medium at time, t 40. DissolutionNoyes-Whitney Equation Problem 1. Calculate the rate of dissolution (dM/dt) of relatively hydrophobic drug particles with a surface area of 2.5 x 103 cm2 and a saturated solubility of 0.35mg/mL at 25C in water. The diffusion coefficient is 1.75 x 10-7 cm2/s, and the thickness of the diffusion layer is 1.25 m. The concentration of drug in bulk solution is 2.1 x 10-4 mg/mL 41. DissolutionFACTORS AFFECTING DRUG DISSOLUTION1. PHYSICOCHEMICAL PROPERTIES OF THEACTIVE INGREDIENT Ionized VS Unionized Forms dissolution rateincreases with ionization, absorption of drug ismore efficient when the drug is in the unionizedstate Particle size Crystalline state Drug complexes 42. Dissolution2. FORMULATION FACTORSa. Solid dosage forms For tablets, dissolution depends on disintegration and deaggregation, which are affected by tablet excipients and compression force. Effect of excipients to dissolution rate Binders increase rate of dissolution of hydrophobic drug particles probably through an enhanced wetting on the surface Diluents increase dissolution rate Lubricants decrease dissolution rateb. Suspensions and emulsions Dissolution of suspensions are affected by settling, aggregation and change in the crystalline structure upon aging Viscosity affects the dissolution rate of suspensions and emulsionsc. Semisolid dosage forms Dissolution depends on the base used 43. Drug ReleasePhysico-Chemical Factors In Designing aControlled or Sustained-ReleaseFormulationa. Drug concentrationb. Aqueous solubilityc. Molecular sized. Crystal forme. Protein bindingf. pKa 44. Drug ReleaseCONTROLLED-RELEASE MECHANISMSThere are three primary mechanisms by which activeagents can be released from a delivery system: diffusion, degradation, and swelling followed by diffusion.Any or all of these mechanisms may occur in a givenrelease system. Diffusion occurs when a drug or otheractive agent passes through the polymer that forms thecontrolled-release device. 45. Drug Release A polymer and active agent have been mixed to form a homogeneous system, also referred to as a matrix system. Diffusion occurs when the drug passes from the polymer matrix into the external environment. As the release continues, its rate normally decreases with this type of system, since the active agent has a progressively longer distance to travel and therefore requires a longer Drug delivery from a typical diffusion time to release.matrix drug delivery system. 46. Drug Release Solid drug, dilute solution, or highly concentrated drug solution within a polymer matrixis surrounded by a film or membrane of a rate- controlling material. The only structure effectively limiting the release of the drug is the polymer layer surrounding the reservoir. Since this polymer coating is essentially uniform and of a nonchanging thickness, the diffusionDrug delivery from typical rate of the active agentreservoir devices: (a) can be kept fairly stable implantable or oral throughout the lifetime ofsystems, and (b) transdermal the delivery system.systems. 47. Drug Release Higuchi (Equation) ModelCalculate Q, the amount in milligrams, of micronized benzocaine released per cm sq of surface area from an aqueous gel after 9000 sec (2.5 hr) in a diffusion cell. Assume that the total concentration,A, is 10.9 mg/mL;the solublity, Cs, is 1.31 ng/mL; Cv = 1.05 mg/mL; the diffusional resistance, R, of a silicone rubber barrier separating the gel from the donor compartment is 8.10 x 103 sec/cm; and the diffusivity , D, of the drug in the gel is 9.14 x 10-6 cm2 / sec. 48. Polymer-based drugrelease mechanisms.Scheme showingseveral mechanisms fortemporally controlledpolymer-based drugrelease systems.(a) Delayed dissolutionmediated by a polymer which dissolves or degrades slowly,(b) Diffusion-controlled release through voids in polymeric devices, and(c) Controlled flow of the drug solution utilising an osmotic potential gradient across a semi- permeable membrane