PRESENTATION ON KINETICS OF DRUG RELEASEFROM THEORY OF MASS TRANSFER Presented by Vikas Aggarwal M.Pharm (Ist sem) Pharmaceutics 1
Matrix Type Soluble drug Also called as Monolith dissolution controlled system. Controlled dissolution by: 1.Altering porosity of tablet. 2.Decreasing its wettebility. 3.Dissolving at slower rate. First order drug release. Slowly dissolving matrix Drug release determined by dissolution rate of polymer. Examples: Dimetane extencaps, Dimetapp extentabs.
Encapsulation Called as Coating dissolution controlled system. Soluble drug Dissolution rate of coat depends upon stability & thickness of coating. Masks colour,odour,taste,minimising Slowly GI irritation. dissolving or erodible One of the microencapsulation coat method is used. Examples: Ornade spansules, Chlortrimeton Repetabs 3
Diffusion Major process for absorption. No energy required. Drug molecules diffuse from a region of higher concentration to lower concentration until equilibrium is attainded. Directly proportional to the concentration gradient across the membrane. 4
Matrix Diffusion Types Rigid Matrix Diffusion Materials used are insoluble plastics such as PVP & fatty acids. Swellable Matrix Diffusion 1. Also called as Glassy hydrogels.Popular for sustaining the release of highly water soluble drugs. 2. Materials used are hydrophilic gums. Examples : Natural- Guar gum,Tragacanth. Semisynthetic -HPMC,CMC,Xanthum gum. Synthetic -Polyacrilamides.Examples: Glucotrol XL, Procardia XL 5
Matrix system Rate controlling step: Diffusion of dissolved drug in matrix. 6
Higuchi Equation Q = DE/T (2A.E Cs)Cs.t)1/2Where , Q=amt of drug release per unit surface area at time t. D=diffusion coefficient of drug in the release medium. E=porosity of matrix. Cs=solubility of drug in release medium. T=tortuosity of matrix. A=concentration of drug present in matrix per unit volume. 7
Reservoir System Also called as Laminated matrix device. Hollow system containing an inner core surrounded in water insoluble membrane. Polymer can be applied by coating or micro encapsulation. Rate controlling mechanism - partitioning into membrane with subsequent release into surrounding fluid by diffusion. Commonly used polymers - HPC, ethyl cellulose & polyvinyl acetate. Examples: Nico-400, Nitro-Bid 8
Reservoir System Rate controlling steps : Polymeric content in coating, thickness of coating, hardness of microcapsule. 9
Dissolution & Diffusion Controlled Release system Drug encased in a partially soluble membrane. Insoluble membrane Pores are created due to dissolution of parts of membrane. Entry of dissolution fluid It permits entry of aqueous medium into core & drug dissolution. Drug diffusion Diffusion of dissolved drug out of system. Pore created by dissolution of soluble Ex- Ethyl cellulose & PVP mixture fraction of dissolves in water & create pores of membrane insoluble ethyl cellulose membrane. 10
FACTORS INFLUENCING DRUG RELEASE1. Permeation-Depends on crystallinity,nature of polymer,its degree of polymerization,presence of fillers and plasticizers,matrix properties like thickness,porosity,diffusion layer etc.2. Diffusion-diffusion coefficient3. Partition coeffficient-imp. when matrix contains drug dissolved in polymer.4. Solubility-imp when drug is not dissolved in polymer matrix,rather dispersed.5. Pharmaceutical manipulations-porosity,compression pressure,coat thickness,plasticizer conc., polarity of coating materials etc.
This is the one dimensional form of fick’s first law.As long as we are at steady state,solutions to Fick’s first lawprovides a completely adequate description of the diffusionalprocess.When a drop of dye is placed in a beaker of water at constanttemp,the dye tends to diffuse throughout the water,eventuallygiving the solution a uniform colour.Dye molecules can beviewed as being in a state of continual random motion.Assuch,each molecule can move in any direction with equalprobability.The reason that molecules diffuse away from theirsource is that there are more dye molecules at the source than inthe bulk solution.Therefore more molecules can move awayfrom the source than towards the source.
In first case amt. in core changes but conc remains same insideupto a particular time and undergoes dilution so that dCbecomes constt.So when concentrations are changing withtime,as in the case of above experiment,we may know dC/dXat the beginning of experiment,but the mass flow willcontinually be changing the conc. gradient.Therefore it isnecessary to introduce time as a variable.Eqn then becomes- J=[dC/dt]x=D[d²C/dX²] ᵼThis equation is called Fick’s 2nd law of diffusion.Interpretation from the equation-Rate of change in conc. in volume element is proportional toarea of change of conc. gradient in that region of field.Diffusion coefficient(D) is a measure of rate of drug movt.
FACTORS INFLUENCING DIFFUSIVITY Temperature-Diffusion is a dynamic process.Movt of a molecule in a particular build of matrix will take place based on enthalpy of system.As the temp. is increased,D value increases.At higher temp.,there will be a higher flux rate.As per Arrhenius equation - D=Dᵼe ᵼᵼ/ ¯ ᵼᵼ Or lnD=lnD₀‒Ed⁄RTD₀=temp independent frequency factor i.e. all molecules are at rest at 0⁰KEd=Energy of activation for polymer diffusion Molecular wt.-As molecular weight and mol. Volume related to each other directly,because density is constt.As molecular wt increases,there will be more amt of resistance to movt. D α (1/Mol. Wt)⅓
Factors continued……… to be Radius of particles .Particles are assumed spherical,small and electrically neutral.We can find out the diameter of particles and its diffusivity in any particular media. D=RT/Na(6πƞ)rwhere Na=Avogadro’s no(no. of particles in any particular system)As radius increases ,diffusion decreases.Ƞ=viscosity.As viscosity increases diffusion decreases
4 Drug solubility As diffusion depends on conc gradient, drug solubility inpenetrant becomes important and then drug release becomes dissolutiondependent for sparingly soluble drugs . This can be expressed by Noyes –Whitney eqn dC/dt= K(Cs-C)Where dC/dt = Amt of drug release per unit timeK= dissolution rate constantCs= Saturation solubility in solventC = Conc in solvent at time t. releasingK= DsA/Vlb AmtTherefore Noyes- Whitney Eqn becomesdC/dt= DsA/Vlb (Cs-C) Timewhere Ds=diffusion coeff. in solventV=vol of soln.
DRUG DIFFUSION THROUGH MICROPARTICLESWhen drug diffusion through microparticles/microcapsules is concerned,drug transport involves dissolution of permeating drug in polymer and diffusion across the membrane.J=(DKA.ΔC/lm)ΔC=conc difference on either side of membranelm=membrane thicknessK=partition coefficient of drug towards polymerDK=permeability coefficient(imaginary)DK/lm=permeability when lm is not knownD/lm=permeability constant(actual)In case of nanoparticles of size 100 nm say and coat thickness about 2nm or < 1nm,lm is insignificant,so DK/lm=DK only
Si-Nang and Carler eqn for drug releasefrom microcapsules dC/dt= [DsAK/Vlm] Where A= internal surface area of coating. K= Porosity and tortuosity.Mechanisms/ Mathematical models of drug release1. First order ln Xt = ln Xo+Kt (Release proportional to amount of drug remaining )Systems that follow the model – Water soluble drugs in porus metrix
2 Zero orderFt= Kot (Release independent of drug conc)Eg : Osmotic Systems, Transdermal systems3 Higuchi eqn.Ft= Kн t½Eg :Diffusion matrix formulations4 Khanna et al modified Noyes Whitney eqn. orHixson and Crowell’s cubic root low of dissolution W0⅓-Wt⅓= KaᵼWhere Wo = Original mass of drugWt= mass of drug remaining to dissolve at time t.aᵼ = surface wt fraction at time t
5 Korsmeyer-Peppas eqn. Mᵼ/Mᵼ = KtᵼWhere Mᵼ/Mᵼ fraction mass of drug released at time t.Eg Hydrating sytems, Eroding systems where D is not constant, thereby giving anomalous diffusion .For Non-Fickian or anomalous diffusion m>0.5, which is usually found in swellable systems
APPLICATIONS OF DRUG RELEASE DATA1. Quality control2. Understanding physiochemical aspects of drug delivery system.3. Understanding the release mechanisms.4. Predict behaviour of system in vivo. However there are difficulties in modelling drug release data as there is great diversity in the physical form of microcapsules/microparticles with respect to size,shape,arrangement of core and coat,properties of core like difffusivity,partition coeffficient,properties of coat like porosity,thickness,crystallinity,inertness etc.
REFERENCESBrahmankar D.M., Jaiswal Sunil B.“Biopharmaceutics and Pharmacokinetics ATreatise Pg 408, 409,432.Robinson Joseph R., Lee Vincent H.L.“Controlled drug delivery Fundamentals andApplications Pg 97, 101, 105.Chien Yie W. “Novel Drug Deliverysystems” Pg 45,47,58,62,64,67.