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Biopharmaceutic factors in dosage form design and theories of dissolution

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Biopharmaceutic factors in dosage form design and theories of dissolution

  1. 1. Biopharmaceutic factors in Dosage Form Design and Theories of Dissolution By: Dr. (Mrs)Suvarna Phadatare Associate Professor NCRD’s Sterling Institute of Pharmacy, Nerul, Navi mumbai
  2. 2. Biopharmaceutic factors in Dosage Form Design OR Factors influencing GI absorption of a Drug A. PHARMACEUTICAL FACTORS a. Physicochem props of drug substance Drug Soly &Dissoln rate, Pcle size and Surface area Polymorphism, Hydrates/ solvates Salt form, Drug stability Stereochemical nature of drug Lipophilicity, pKa of drug –pH partition theory b. Pharmacotechnical factors – DT, Manufacturing variables, Excipients,Nature and type of D.F., Storage and aging S.P. Phadtare, SIP, Navi Mumbai.
  3. 3. Factors influencing GI absorption of a Drug B. PATIENT RELATED FACTORS (8) Age ,gastric emptying time, pH, Disease states, GI contents, Presystemic metabolism S.P. Phadtare, SIP, Navi Mumbai.
  4. 4. A. PHARMACEUTICAL FACTORS Physicochem props of drug substance 1. Drug solubility and Dissolution rate Rate Determining Steps 1. Rate of dissolution (RDS - ______drugs) * drug product drug substance in solutn 2. membrane transport (permeatn across bio. Membrane) (RDS- __________drugs) *  drug substance in the system * simplified mechanistic view of bioavailability S.P. Phadtare, SIP, Navi Mumbai.
  5. 5. Physicochem props Drug solubility and Dissolution rate Correlation between Therap. Doses and desired solubilty DOSE (mg/kg) DESIRED SOLUBILITY VALUES (mg/ml) FOR DRUGS WITH High permeability Medium permeability Low permeability 0.1 1 5 21 1 10 52 207 10 100 520 2100 S.P. Phadtare, SIP, Navi Mumbai.
  6. 6. Physicochem props Drug solubility and Dissolution rate Concept of Max. Absorbable Dose (MAD): MAD = Ka SGI VGI tr Where, Ka = intrinsic absorptn rate const SGI = Soly of drug in GI fluid VGI = Volume of GI fluid tr = Residence of drug in GI Key parameters that have limiting effect on drug absorption 1. Solubility of drug in the GIT. 2. Intrinsic absorption rate constant specific to drug in solution. Eg. - 2 drugs,same Ka, one with greater SGI - ??_MAD In General, if projected clinical dose << MAD, then D. Absorptn as limitng factor . If dose >> MAD, then S.P. Phadtare, SIP, Navi Mumbai.
  7. 7. Biopharmaceutics Classification System (BCS) for drugs SOLUBLT Y PERMBLTY BCS Class & eg. Absorpn Pattern RDS in Absorptn High High I (Diltiazam, Propranolol) Well absobed as no limitn Gastric emptying Low High II ( Nifedipine, Glibenclamide) Variable Dissolution High Low III (Insulin, Atenolol) Variable Permeabilty Low Low IV (Taxol, Azathioprine) Poorly absorbed Case by case (both limtns) S.P. Phadtare, SIP, Navi Mumbai.
  8. 8. Biopharmaceutics Classification System (BCS) for drugs High solubility  the highest single dose is completely soluble in 250 ml or less of aqueous solution at pH 1 - 6.8 (37 °C)  generate a pH-solubility profile High permeability ♦ EU guidance: “Linear and complete absorption reduces the possibility of an IR dosage form influencing the bioavailability” ♦ FDA guidance: absolute BA >90 % ♦ WHO guidance: at least 85 % absorption in humans S.P. Phadtare, SIP, Navi Mumbai.
  9. 9. Physico chemical factors affecting GI absorption of a Drug Definition-  Dissolution is a process in which a solid substance solubilizes in a given solvent i.e. mass transfer from the solid surface to the liquid phase.  Abs / Intrinsic Solubility: Max amt of solute dissolved in a given solvent under std conditions of temp, pressure and pH.  Rate of dissolution is the amount of drug substance that goes in solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition. S.P. Phadtare, SIP, Navi Mumbai.
  10. 10. Theories of Drug Dissolution I. Diffusion layer model/Film Theory II. Danckwert’s model/Penetration or surface renewal Theory III. Interfacial barrier model/Double barrier or Limited solvation theory. S.P. Phadtare, SIP, Navi Mumbai.
  11. 11. I. Diffusion layer model/Film Theory :- * It involves two steps :- a. Solution of the solid to form stagnant film or diffusive layer which is saturated with the drug b. Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; slower so this is r.d.s in drug dissolution. S.P. Phadtare, SIP, Navi Mumbai.
  12. 12. S.P. Phadtare, SIP, Navi Mumbai.
  13. 13. * The rate of dissolution is given by Noyes and Whitney:  dc = k (Cs- Cb)  dt dc/dt= dissolution rate of the drug K= dissolution rate constant Cs= concentration of drug in stagnant layer Cb= concentration of drug in the bulk of the solution at time t S.P. Phadtare, SIP, Navi Mumbai.
  14. 14. Modified Noyes-Whitney’s Equation -  dC   dt  Where,  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. DAKw/o (Cs – Cb ) Vh S.P. Phadtare, SIP, Navi Mumbai.
  15. 15.  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. S.P. Phadtare, SIP, Navi Mumbai.
  16. 16.  Under sink conditions, if the volume and surface area of the solid are kept constant, then dC  dt  This represents that the dissolution rate is constant under sink conditions and follows zero order kinetics. K S.P. Phadtare, SIP, Navi Mumbai.
  17. 17. Dissolution rate under non-sink and sink conditions. Time Dissolution rate under non- sink and sink conditions. zero order dissolution under sink condition Conc of dissolved drug S.P. Phadtare, SIP, Navi Mumbai.
  18. 18.  Hixon-Crowell’s cubic root law of dissolution takes into account the particle size decrease and change in surface area, W0 1/3 – W1/3 = Kt Where, W0=original mass of the drug W=mass of drug remaining to dissolve at time t Kt=dissolution rate constant. S.P. Phadtare, SIP, Navi Mumbai.
  19. 19. 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 solid-liquid interface, absorb the solute by diffusion and carry it into the bulk of solution.  These packets get continuously replaced by new ones and expose to new solid surface each time, thus the theory is called as surface renewal theory. S.P. Phadtare, SIP, Navi Mumbai.
  20. 20. S.P. Phadtare, SIP, Navi Mumbai.
  21. 21.  The Danckwert’s model is expressed by equation Where, m = mass of solid dissolved Gamma (γ) = rate of surface renewal dC dt = V dm dt = A (Cs-Cb). γ D S.P. Phadtare, SIP, Navi Mumbai.
  22. 22. III. Interfacial barrier model/Double barrier or Limited solvation theory  It is based on solvation mecha- intermediate concn exists at interface and is a function of soly, not diffusion (not mass transport).  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. S.P. Phadtare, SIP, Navi Mumbai.
  23. 23. Factors affecting Drug Dissolution : A.Factors relating to physico-chemical properties of drug. Pcle size and Surface area Polymorphism, Hydrates/ solvates Salt form, Drug stability Stereochemical nature of drug Lipophilicity, pKa of drug –pH partition theory B. Dosage form related Factors- DT, Mfg variables,Excipients,Nature and type of D.F., Storage and aging. S.P. Phadtare, SIP, Navi Mumbai.
  24. 24. A.Factors affecting Dissoln : relating to physico-chemical properties of drug. 1.* Solubility:Solubility plays important role in controlling dissolution from dosage form. All factors –affect drug solubility. Noyes-Whitney equation: it shows that aqueous solubility of drug which determines its dissolution rate. Empirical relation for prediction of dissoln rate from solubility : Disoln rate R= dC/dt = 2.24 Cs Drug should have a min aq solubty of 1% to avoid bioavalblty problems. S.P. Phadtare, SIP, Navi Mumbai.
  25. 25. 2. Pcle size and Surface area of the drug –  Particle size and surface area are inversely related to each other. Two types of surface area – Absolute surface area which is the total surface area of any particle. Effective surface area which is the area of solid surface exposed to the dissolution medium. Modified Noyes whitney eqn Disoln rate directly proportnl to A S.P. Phadtare, SIP, Navi Mumbai.
  26. 26.  Effective surface area is directly related to the dissolution rate.  Greater the effective surface area, more intimate the contact between the solid surface and the aqueous solvent, increased interaction with solvent and faster the dissolution.   in SA by  pcle size- Micronizn to < 0.1 for poorly water sol drugs eg. griseofulvin, chloramphenicol, tetracycline salts S.P. Phadtare, SIP, Navi Mumbai.
  27. 27. 3.Polymorphism and amorphism –  When a substance exists in more than one crystalline form, the different forms are designated as polymorphs and the phenomenon as Polymorphism.  Stable polymorphs has lower energy state, higher M.P. and least aqueous solubility.  Metastable polymorphs has higher energy state, lower M.P. and higher aqueous solubility S.P. Phadtare, SIP, Navi Mumbai.
  28. 28.  Amorphous form of drug which has no internal crystal structure represents higher energy state and greater aqueous solubility than crystalline forms.  E.g.- amorphous form of novobiocin is 10 times more soluble than the crystalline form.  Thus, the order for dissolution of different solid forms of drug is – amorphous > metastable > stable S.P. Phadtare, SIP, Navi Mumbai.
  29. 29. 4.Hydrates/solvates –  The stoichiometric type of adducts where the solvent molecules are incorporated in the crystal lattice of the solid are called as the solvates.When the solvent in association with the drug is water, the solvate is known as hydrate.  Anhydrous form- greater aq solubility...? eg anhyd theophylline (vs monohyd) & ampicillin(vs trihydrate)  The organic (non aq)solvates have greater aqueous solubility than the nonsolvates.  E.g. – chloroform solvates of griseofulvin is more water soluble than their nonsolvated forms S.P. Phadtare, SIP, Navi Mumbai.
  30. 30. 5.Salt form of the drug-  Dissolution rate of weak acids and weak bases can be enhance by converting them into their salt form.  With weakly acidic drugs, a strong base salt is prepared eg. sodium and potassium salts of barbiturates and sulfonamides.  With weakly basic drugs, a strong acid salt is prepared like the hydrochloride or sulfate salts of alkaloidal drugs. S.P. Phadtare, SIP, Navi Mumbai.
  31. 31. Factors affecting Dissolution : Pharmaceutical excipients –  Vehicle  Diluents  Lubricants  Binders  Surfactants  colorants S.P. Phadtare, SIP, Navi Mumbai.
  32. 32. Factors affecting Dissolution : Manufacturing processes - Method of granulation – Wet granulation Direct compression Agglomerative phase of communication (APOC) S.P. Phadtare, SIP, Navi Mumbai.

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