Physicochemical and biological properties of sustained release formulations


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Physicochemical and biological properties of sustained release formulations

  2. 2.  1.Aqueous solubility. 2.Partition coefficient. 3.Drug stability. 4.Protein binding. 5.Molecular size and diffusivity.
  3. 3.  Itis an important consideration in its biological performance as a SDRF. Aqueous solubility of a drug exerts its control on the absorption process in two ways- 1. By influence on the dissolution rate of a compound which establish the drug concentration in solution and the driving force for tissue permeation. 2. By its effect on the ability of the drug to penetrate tissues which is determined in part by its solubility in the tissue.
  4. 4.  Dissolutionrate is related to aqueous solubility which is given by NOYES-WHITNEY’S EQUATION. dc/dt=KDA.CsWhere-dc/dt=dissolution rate. KD=dissolution rate constant. A= total surface area of drug particle. Cs=aqueous saturation solubility of drug.
  5. 5. Between the time that a drug is administered and thetime it is eliminated from the body.It diffuse through a variety of biological membranesthat act primarily as lipid like barriers.The major criteria in evolution of the ability of a drug to penetrate these lipid membranes is it apparent oil-water partition co-efficeint, defined as- K=Co/CwWhere,Co=equilibrium concentration of all forms of the drug. Cw=equilibrium concentration of all forms of in an aqueous phase.
  6. 6.  In oral dosage forms, loss of drug through acid hydrolysis or metabolism in GIT. A drugin solid state undergoes degradation at much slower rate than drug in suspension/solution. Drugs with low aqueous solubility have low dissolution rate and usually suffer oral bioavailability problems. Aqueous solubility of weak acids and base is governed by pka value and pH of the medium.
  7. 7.  Distributionof drug in to extra space is governed by dissociation of drug from protein. Drug-protein complex acts as reservoir in the vascular space for sustained drug release to extra vascular tissue for drug exhibiting high degree protein binding. Somedrugs shows higher degree protein binding ex- Diazepam shows greater than 95% protein binding
  8. 8.  Ability of drug to diffuse through membrane is called as diffusivity, is a function of molecular size. In most of polymers, its possible to logD empirically to some function of molecular size as – LogD=-Sv log V+Kv=-Sm log M+KmWhere,V=molecular volume M=molecular weight Sv,Sm,Kv,Km are constants value of D is related to size and shapes of drugs.
  9. 9.  1. Absorption 2. Distribution 3. Metabolism 4. Elimination and Biological half-life 5. Side Effects and Safety Considerations
  10. 10.  Rate,extent , and uniformity of absorption are the important factors when considering sustained release. Sincethe rate limiting step in drug delivery from a sustained release is its release from dosage form , rather than absorption,a rapid release is essential if the system is successful
  11. 11.  The distribution of drug in to vascular and extravascular spaces in the body is an important factor in its overall elimination kinetics. This influences the formulations of that drug in to a sustain release, primarily by restricting the magnitude of release rate and dose size.
  12. 12.  Volume of distribution obeys only one compartment model v=dose/Co where-Co –plasma drug concentration Apparent volume of distribution is merely a propotionately constant that relates the drug concentration in blood or plasma to the total amount of drug in the body.
  13. 13. For two compartment models Vss= (1+ k12/k21)V1where k12-rate constant for distribution of drug from central to peripheral compartment k21-peripheral to central Vss-drug concentration in blood or plasma at steady state to the total amount of drug
  14. 14.  If the amount of drug in central compartment p, is the known amount of drug in peripheral compartment T. Hence total amount of drug in body can be calculated by; T/p= k12 (k21-β)Where β=slow disposition rate constant T/p=estimates the relative distribution of drug B/w compartments Vss=estimate extent of distribution in body
  15. 15.  Metabolism is the conversion of a drug to another chemical form and this is considered in the design of sustained release system for the drugs. Factors associated with metabolism 1.ability of the drug to induce or inhibit enzyme synthesis. 2.fluctuating drug blood level and first pass metabolism ex- nitroglycerine
  16. 16.  The rate of elimination of drug is described quantitatively by its biological half life. t1/2= 0.693 v/cls Where v=volume of distribution cls=systemic clearence cls = I.V administered dose AUC where, AUC=area under curve,
  17. 17. Significance of Half life Drug having shorter half life requires frequent dosing, making it desirable to develop SDRS. This will be opposite for drugs with higher half lives. Drug with half life less than 2hrs and those with more than 8hrs should not be used. ex-for drugs with half life less than 2hrs Ampicillin, furosemide, penicillin…etc for drugs with more than 8hrs of half life Diazepam, digitoxin,digoxin …etc
  18. 18.  Minimizing side effect for a particular drug done by controlling its plasma concentration and using less total drug over time course of therapy. To measure margin of safety of drug its therapeutic index is considered. TI= TD50/ED50Where, TD50-median toxic dose ED50-median effective dose
  19. 19. THANK YOU !