Diffusion Diffusion describes the spread of particles through random motion from regions of higher concentration to regions of lower concentration
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.
DiffusionWays that a solute or a solvent can traverse a physical 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 fibrous membrane strands (fig. 11-1c)- cellulose membrane(filtration process);with interwining nature of the fibers and the tortuous channels.
Passive Diffusion Diffusion is the net movement of material from an area of high concentration to an area with lower concentration. The difference of concentration between the two areas is often termed as the concentration gradient, and diffusion will continue until this gradient has been eliminated.
Passive Diffusion Facilitated diffusionalso called carrier- mediated diffusion, is the movement of molecules across the cell membrane via special transport proteins that are embedded within the cellular membrane. Not energy-dependent.
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.
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.
Drug Absorption and Elimination Transcellular permeationpathway for chemicals to be absorbed into and through the skin is transcellular, or cell-to- cell. Diffusion occuring through the lipoidal bilayer of cells.
Drug Absorption and Elimination Paracellular Diffusion occurs through spaces between adjacent cells.
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.
Diffusion Microfiltration – employs membranes of slightly larger pore size, 100 nm to several um, removes bacteria from IV injections, foods and drinking water.
Diffusion Dialysis is the separation process based on unequal rates of passage of solutes and solvent through microporous membranes. Hemodialysis is used to rid of the blood of metabolic waste products(small molecules) while preserving the high- molecular weight components of the blood.
Fick’s Law of Diffusion Diffusion is described by Fick’s laws. Fick’s first law relates the diffusion flux, J , to the steepness of the concentration gradient where D is the diffusion coefficient, C is the concentration, and x is distance. the units of J are moles cm−2 s−1
Fick’s Law of Diffusion Fick’s Second LawChange in the conc with time at a definite loction. where ∆C/∆t, concentration of diffusant in the volume element changes with time and ∆J/∆x, the flux or amount diffusing changes with distance
Fick’s Law of Diffusion Fick’s 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.
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.
Biological Diffusion Percutaneous absorptionInvolves: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
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 passage through 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 partition coefficient so that the drug is soluble in the vehicle and yet have the great affinity for the skin barrier into which it penetratesc. Components of the vehicle should influence the permeability of the stratum corneum.
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
Pressure in PharmaceuticalSystems Jet injectorsA jet injector is a type of syringe that uses pressure instead of a needle to penetrate the epidermis. Pressure driven jets that produce a high velocity jet(>100m/sec) that pebetrates the skin. INSULIN JET INJECTOR
Temperature in PharmaceuticalSystemsLyophilization The process of freeze drying can achieve product stability, and improved shelf-lifeFrozen aqueous solution containing the drug and an inner matrix building substance.
Electrical potential inPharmaceutical Systems Fentanyl iontophoretic transdermal system Used to enhance transdermal delivery of drugs by applying a small current through a reservoir that contains ionozed drugs.
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.
Temperature potential inPharmaceutical Systems Microwave-assisted extraction - elevated temperature accelerates the mass transfer of target compounds from the matrix.
Drug ReleaseThe process by which a drug leaves a drug product and is subjected to absorption, distribution , metabolism, and excretion (ADME)Described in several ways; Immediate-release Modified-release Delayed-release Extended-release Controlled-release Pulsatile release
DissolutionDISSOLUTION Is the process by which a solid solute with relatively low solubility enters 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 possessing low solubility. Slowest of the various stages involved in the release of drug from its dosage form and passage into systemic circulationDISSOLUTION RATE The rate at which solid (tablet, capsule, and granule) dissolves in a solvent is described by the NOYES AND WHITNEY EQUATION ―The HIXSON-CROWELL CUBE ROOT LAW‖ describes the dissolution rate of drug powder consisting of uniformly sized particles.
DissolutionThe dissolution rate is the time required for a drug substance to dissolve 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 dosage forms including oral capsules, tablets and suspensions and intramuscular suspensions.Methods for increasing dissolution rates: Decrease particle size. This increases the available surface area to the dissolving fluid. [Note: In rare cases, agglomeration of the particles may occur leading to decreased dissolution rates.] Increase solubility in the diffusion layer. The ionized form of the drug (salt of the weak acid or salt of the weak base) will have greater solubility in the diffusion layer than the unionized weak acid or weak base. (e.g. penicillin V potassium will dissolve faster than penicillin V itself). Alter pH of dissolution medium (e.g. buffered aspirin). Increase agitation of dissolution medium (e.g. effervescent, buffered aspirin)
DissolutionNoyes-Whitney Equation where,δC/δt = 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
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 25°C 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
DissolutionFACTORS AFFECTING DRUG DISSOLUTION1. PHYSICOCHEMICAL PROPERTIES OF THE ACTIVE INGREDIENT Ionized VS Unionized Forms – dissolution rate increases with ionization, absorption of drug is more efficient when the drug is in the unionized state Particle size Crystalline state Drug complexes
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
Drug ReleasePhysico-Chemical Factors In Designing a Controlled or Sustained-Release Formulationa. Drug concentrationb. Aqueous solubilityc. Molecular sized. Crystal forme. Protein bindingf. pKa
Drug ReleaseCONTROLLED-RELEASE MECHANISMSThere are three primary mechanisms by which active agents can be released from a delivery system: diffusion, degradation, and swelling followed by diffusion.Any or all of these mechanisms may occur in a given release system. Diffusion occurs when a drug or other active agent passes through the polymer that forms the controlled-release device.
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.
Drug Release Solid drug, dilute solution, or highly concentrated drug solution within a polymer matrix—is 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 diffusion Drug delivery from typical rate of the active agent reservoir devices: (a) can be kept fairly stable implantable or oral throughout the lifetime of systems, and (b) transdermal the delivery system. systems.
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.
Polymer-based drugrelease mechanisms.Scheme showingseveral mechanisms fortemporally controlledpolymer-based drugrelease systems.(a) Delayed dissolution mediated 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