PRESENTED BY:- GUIDED BY:-TARUN POKHARIYAL Mr. AJAY KUMAR TIWARIM.PHARM.(1st SEM.) LECTURER DEPT. OF pharmaceutics JAIPUR NATIONAL UNIVERSITY JAIPURDATE:-15 NOV.2011
(A). PHARMACEUTICAL FACTORS:- I. PHSICOCHEMICAL PROPERTIES OF DRUG:- 1. DRUG SOLUBILITY AND DISSOLUTION RATE Solid disintegration dissolution Drug in permeation Drug Soliddosag solution at across mem. in druge form absorption the particles site body Maximum absorbable dose (MAD) is used to correlate drug absorption MAD= Ka Sgi Vgi tr Ka= intrinsic absorption rate constant Sgi=solubility of drug in GI fluid Vgi=volume of GI fluid present. tr= residence of drug in GI
BIOPHARMACEUTICS CLASSIFICATION SYSTEM:-CLASS I DRUG:- high solubility and highpermeability eg. diltiazemCLASS II DRUG:-low solubility and high permeability eg.nifedipine.CLASS III DRUG:-high solubility and low permeability eg. Insulin.CLASS IV DRUG:-low solubility and low permeability eg. taxol
THEORIES OF DRUG DISSOLUTION:-DISSOLUTION IS THE MASS TRANSFER FROM SOLIDSURFACE TO THE LIQUID PHASE.Theories:-1.Diffusion layer model/film theory2.danckwerts’s model/penetration theory3.Interfacial barrier model/limited solvation theory
The rate of dissolution is given by Noyes and Whitney: dc = k (Cs- Cb)Where, dtdc/dt= dissolution rate of the drugK= dissolution rate constantCs= concentration of drug in stagnant layerCb= concentration of drug in the bulk of the solution at time t
dC DAKw/o (Cs – Cb ) dt VhWhere,D= diffusion coefficient of drug.A= surface area of dissolving solid.Kw/o= water/oil partition coefficient of drug.V= volume of dissolution medium. h= thickness of stagnant layer.(Cs – Cb )= conc. gradient for diffusion of drug.
This is first order dissolution rate process, for which the driving force is concentration gradient. This is true for in-vitro dissolution which is characterized by non-sink conditions. The in-vivo dissolution is rapid as sink conditions are maintained by absorption of drug in systemic circulation i.e. Cb=0 and rate of dissolution is maximum.
Under sink conditions, if the volume and surface area of the solid are kept constant, then dC K dtThis represents that the dissolution rate isconstant under sink conditions and follows zero zero order dissolutionorder kinetics. under sink condition first order dissolution under non-sink condition Conc. of drug Time
Danckwert’s model/Penetration or surface renewal Theory :- Dankwert takes into account the eddies or packets that are present in the agitated fluid which reach the solidliquid interface, absorb the solute by diffusionand carry it into the bulk of solution.These packets get continuously replaced by newones and expose to new solid surface each time,thus the theory is called as surface renewaltheory.
III. Interfacial barrier model/Double barrier or Limited solvation theory :- The concept of this theory is explained by following equation- G = Ki (Cs - Cb)Where,G = dissolution rate per unit area,Ki = effective interfacial transport constant.
2. PARTICLE SIZE & EFFECTIVE SURFACE AREA OF DRUG:-TWO TYPES OF SURFACE AREA CAN BE DEFINED:-1.ABSOLUTE SURFACE AREA2.EFFECTIVE SURFACE AREA3. POLYMORPHISM:- enantiotropic polymorph:-which can be reversiblychange into another form by altering the temp.orpressure.Monotropic polymorph:-is the one which is unstableat all temp. and pressure.
Internal structure of a compound Crystalline noncrystallinePolymorph( Molecular single adduct molecule) Stocheometricenantiotropic Nonstochiometric complexes complexes Organic monotropic Hydrates solvates
5. drug pka and lipophilicity and gi Ph(PH PARTITION HYPOTHESIS):-This theory states for those drug compound ofmolecular weight greater than 100 which primariliytransported across the biomembrane by passivediffusion.Most drugs are weak electrolyte(weak acid or base)If the pH of either side of membrane is different thanthe compartment whose pH favours greaterionisation of drug will contain greater amount ofdrug and only unionised fraction of drug ifsufficiently lipid soluble can permeate themembrane passively until the conc. Ofunioniseddrug on either side of membrane become equal.
6. DRUG STABILITY:- Degredation of drug into inactive form. Interaction with one or more different components7. STERIOCHEMICAL NATURE OF THE DRUG:-DOSAGE FORM(PHARMACOTECHNICAL)FACTORS:-1) DISINEGRATION TIME:-2) DISSOLUTION TIME:-3) MANUFACTURING VARIABLES:- *excipients and manufacturing process*EXCIPIENTS:-vehicle,diluents(filler),binder and granulating agents, disintegrants,lubricants,surfactants,viscosity imparters,buffers,complexing agents,ColorantsCrystal growth inhibitors.
MANUFACTURING VARIABLES:-*Method of granulation-wet granulation method ismost conventional technique but limited.Most recent method is APOC(agglomerative phase ofcommunition)*Compression force:-*Intensity of packing of capsule contents-4.NATURE AND TYPE OF DOSAGE FORM5.PRODUCT AGE AND STORAGE CONDITION
PATIENT RELATED FACTORS:-1. AGE-2. GASTRIC EMPTYING:-the passage from stomach to small intastine.Gastric emptying is first order process Gastric emptying rate:-is the speed at which the stomach content empty into intestine. Gastric emptying time:-is the time required for gastric content to empty into small intestine. Gastric emptying t1/2 is the time taken for half the stomach content to empty.FACTORS EFFECTING GASTRIC EMPTYING:- VOLUME OF MEAL COMPOSITION OF MEAL PHYSICAL STATE AND VISCOSITY OF MEAL TEMP. OF MEAL
GI pH Electrolyte and osmotic pressure Body posture Emotional state Exercise Disease state Drug3.INTESTINAL TRANSIT:-the passage of drugthrough intestine called as intestinal transit.4.GIT Ph:- it influence absorption in variousways;-
a. Disintegrationb. Dissolutionc. Absorptiond. Stability5.Disease state :-a. GIT diseaseb. Cardiovascular diseasec. Hepatic disease6.BLOOD FLOW TO GIT:-
7.GASTROINTESTINAL CONTENT:-1. Food- drug interaction2. Fluid volume3. Interaction of drug with normal gi contents4. Drug –drug interaction8. PRESYSTEMIC METABOLISM:-The loss of drug through biotransformation by sucheliminating organs during its passage to systemiccirculation is called first pass metabolism.Three types of systems:-1. Luminal enzyme (digestive and bacterial enzyme)2. Gut wall enzyme3. Hepatic enzyme