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Factors influencing drug stability

Factors influencing drug stability. Nahla S Barakat , PhD Professor of Pharmaceutics. C. Microbiological stability: 1. Contamination from microorganisms is a big problem for all formulations containing moisture but

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Factors influencing drug stability

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  1. Factors influencing drug stability Nahla S Barakat, PhD Professor of Pharmaceutics PHR 416

  2. C. Microbiological stability: • 1. Contamination from microorganisms is a big problem for all formulations containing moisture but • it can be a bother in solid dosage forms also if some natural polymers are used because many • natural polymers are fertile sources of microorganisms. • 2. In the type of hygienic manufacture carried out today where “Quality Assurance” is a prerequisite • as per the GMP procedures, there are definite procedures to prevent microbial contamination in all formulations. • • PHR 416

  3. Sources of Microbial Contamination: • 1. Water • 2. Air • 3. Raw materials (gums, starches, pigments), containers and closures • 4. Personnel • 5. Instruments and apparatus PHR 416

  4. Study of the factors that can affect the stability of fast-degrading drugs in pharmaceutical dosage forms is a rational way to develop approaches that will increase the stability of drugs. • In this section, the factors that affect decomposition rates are discussed. PHR 416

  5. Effect of Temperature on Reaction Rates • Experimental observation: Rate of a reaction generally increases with temperature (roughly doubles every 10 ºC) • Arrehenius expression illustrates this for rate constants k = A e-Ea/RT Log k = log A - Ea 2.303 R T Ea is the activation energy (J/mol) and A is the frequency or pre-exponential factor (same units as k) PHR 416

  6. Ea = activation energy • R = 8.314 J/mol·K • T = absolute temperature in Kelvins • A = frequency factor • The Arrhenius equation is based on the collision theory which supposes that particles must collide with both the correct orientation and with sufficient kinetic energy if the reactants are to be converted into products. PHR 416

  7. The activation energy Ea can be determined from the slope of this line: • Ea = slope / R. 2.303 • Values of Ea are usually within the range 50-96 kj/mol • Activation energies are never negative. The line on this plot will have a negative slope, and this will cancel the negative sign in front of R, leaving a positive value for the activation energy • An accurate determination of the activation energy requires at least three runs completed at different reaction temperatures. The temperature intervals should be at least 5°C. PHR 416

  8. The Meaning of “A” and “Ea” A- (frequency of collisions or pre-exponential factor) factor related to the collision frequency of a molecule; represents the limit to how fast two molecules can react (molecules cannot react unless they have enough energy) Ea- (activation energy)even when molecules collide they cannot react unless they possess enough energy; Ea is the minimum energy the reactants must possess in order to react PHR 416

  9. Finding Ea from the ArreheniusEq-n A plot of ln k versus 1/T will yield a straight line with a slope of = -Ea/2.303R PHR 416

  10. "Two-Point" Arrhenius Equation: • The "Two-Point" Equation provides an algebraic method to determine the activation energy for a given reaction from the experimental data found at two different reaction temperatures. • The Arrhenius equation for two temperatures (T1 and T1) • gives two rate constants (k1 and k1): PHR 416

  11. PHR 416

  12. The rate constant k1 of the decomposition of 5 HMF at 120 C is 1.173 h-1 and k2 at 140 C is 4.86 h-1. What is the activation energy Ea in kcal/mole? And the frequency factor A in sec-1 for the breakdown of 5-HMF at the temperature 120 C • Log (4.86/1.173)= Ea x 413-393 2.303x1.9878 413 x 393 0.6173= Ea x 1.232 x 10-4 4.576 1.232 x 10-4 Ea = 2.8248 Ea = 22928.286 cal/mole = 23 K cal/mole PHR 416

  13. Log k= Log A - Ea x 1 2.303x 1.987 T Log 3.258 x 10-4 = log A - 23000 x 1 2.303 x 1.987 393 - 3.487 = log A - 12.789 Log A= 9.30195 A = 2 x 10 9 sec -1 PHR 416

  14. problem • The rate constant for the reaction H2(g)  + I2(g) ---> 2HI(g) • is 5.4 x 10-4 M-1s-1 at 326 oC. At 410 oC the rate constant was found to be 2.8 x 10-2 M-1s-1. Calculate the a) activation energy PHR 416

  15. log(5.4 x 10-4 / 2.8 x 10-2 ) = (-Ea /2.303R ){1/599 K - 1/683} • -3.9484 = - Ea/2.303 R {2.053 x 10-4 } • Ea= (1.923 x 104 ) (8.314 J/K mol) • Ea= 1.60 x 105 J/mol PHR 416

  16. Assignment 6 • The first order rate constant for the hydrolysis of sulfacetamide at 120 C is 9x 10-6 S-1 and the activation energy is 94 kj/mole. Calculate the rate constant at 25  C. • K1 , and the activation energy, Ea PHR 416

  17. Assignment 7 For the reaction A + B  C, the rate constant at 215 oC is 5.0 x 10-3 S-1 and the rate constant at 452o C is 1.2 x 10-1 S-1. a) What is the activation energy in kJ/mol? b) What is the rate constant at 100o C. a) 39.4 kJ/mol b) 2.50 x 10-4 s-1 PHR 416

  18. Assignment 8 The initial concentration of active principle in an aqueous preparation was 5.0 x 10-3 g cm-3. After 20 months the concentration was shown by analysis to be 4.2 x 10-3 g cm-3. The drug is known to be ineffective after it has decomposed to 70% of its original concentration. Assuming that decomposition follows first order kinetics, calculate the expiry date of the drug preparation. Log A = log A0 - k t 2.303 k = 8.719 × 10−3 month−1 t = 40.9 months PHR 416

  19. Theoretical Models for Chemical Kinetics Such models explain what reaction rates, k, depend on • 1. Collision Theory - In order for two molecules to react, old chemical bonds have to be broken. That requires energy! Collision theory considers that such energy is provided by kinetic energies of molecules upon their collisions. • Collision theory can qualitatively explain: • 1) why the reaction rate, k, increases with increasing temperature and 2) why only 1 of 10 10 collisions results in reaction PHR 416

  20. Collision Theory Considers Distribution of Kinetic Energies of Molecules - If the minimum energy required for a reaction to occur (activation energy) is indicated by the arrow in the figure, then the fraction of molecules possessing this energy will be greater at T2 than at T1 • Units of activation energy is cal/mole or Kcal/mole. PHR 416

  21. The speed of many reactions increases about two to three times with each 10 rise in temperature. As a reaction proceeds from reactants to products. The system must pass through a state whose energy is greater than that of the initial reactants. This barrier is what prevents the reactants from immediately becoming products. • The activation energy, Ea is a measure of this barrier PHR 416

  22. Transition State Theory An unobserved, activated complex is proposed to exist as a transition state between reactants and products • The activated complex is short-lived because it is highly reactive (may break apart to form products or revert to reactants) Example: N2O(g) + NO(g) → N2(g) + NO2(g) PHR 416

  23. The rate of the reaction is dependent on the concentration of the activated complex. • The enthalpy change for the reaction is the difference in the activation energies of the forward and reverse reaction PHR 416

  24. Log k = log A – Ea/2.303RT In some cases the t1/2 is used instead of k as follow: For 1st order reaction t 1/2 = 0.693/k Log t1/2 = log (0.693/k) Log t1/2 = log 0.693 – log k Log t1/2 = log 0.693 – (log A – Ea/2.303R T) Log t1/2 = log 0.693 – log A + Ea/2.303R T Log t1/2 = constant + Ea/2.303 R T PHR 416

  25. Log t 1/2 = constant + Ea / 2.303RT PHR 416

  26. Different temperature scale Freezer What storage conditions?:between -10 to -20 degCrefrigerator What storage conditions?:between 2 and 8 degCcold What storage conditions?:not exceeding 8degCcool What storage conditions?:between 8 and 15 degC room temperature What storage conditions?:between 15 and 30 degCwarm What storage conditions?:between 30 and 40 degC excessive heat What storage conditions?:above 40 degC PHR 416

  27. Effect of pH • pH is perhaps the most important parameter which affects the hydrolysis rate of drugs in liquid formulations; it is certainly the one which has been most widely examined. • It is probable that a different pH–rate profile would be obtained using a different buffer. • When drugs are formulated in solution, it is essential to construct a pH versus rate profile so that the optimum pH for stability can be located. PHR 416

  28. Effect of buffer concentration on the hydrolytic rate constant for ciclosidomine at 60°C as a function of pH. Log rate–pH profile for the degradation of codeine sulfate in buffer-free solutions at 60°C. PHR 416

  29. Solvent • It may be necessary to incorporate water-miscible solvent to solubilizate the drug. • Drugs susceptible to hydrolysis may be formulated in non-aqueous solutions, such as ethanol, glycerol or propylene glycol. Diazepam and phenobarbitone injections are examples of such drugs. • The protective effect of such solvent mixtures is mainly due to change of the polarity (dielectric constant) of solvent system. • The effect of dielectric constant of a solvent system on stability of drugs is dependent on the charges of the two reacting ions. • The hydrolysis of barbiturate occurs 6.7 – fold faster than in 50% ethanol and 2.6 – fold faster in water than in 50% glycerol. PHR 416

  30. If both the drug and the attacking ion are similarly charged, as in hydroxyl ion catalyzed hydrolysis of anionic drugs or hydrogen ion catalyzed hydrolysis of cationic drugs, lowering the dielectric constant of solvent system will decrease the decomposition rate resulting in stabilization of the system. • If the charges are of opposite sign, as in general or specific base-catalyzed hydrolysis of protonated drugs, stabilization will not be achieved by lowering the dielectric constant of the solvent PHR 416

  31. For neutral reactants which produce a highly polar transition activated complex, lowering the dielectric constant will decrease the decomposition rate (stabilization). • Example: Interaction of triethylamine with ethyl iodide (both are neutral) will produce charged quaternary ammonium salt. Lowering the dielectric constant will decrease the reaction rate. • For neutral reactants that produce neutral product, change of dielectric constant will not affect the reaction rate. PHR 416

  32. So, polar solvents tend to accelerate reactions that form products having higher polarity than the reactants. • If, on the other hand, the products are less polar than the reactants, they are accelerated by solvents of low polarity and retarded by solvents of high polarity . PHR 416

  33. Effect of solubility • Penicillins are unstable in aqueous solution , a successful method of stabilizing penicillin in liquid dosage forms is to prepare insoluble salts and formulate them in suspensions. This will decrease the amount of drug available for hydrolysis PHR 416

  34. 3- Effect of surfactant • The surfactant in micellar form may affect hydrolysis rate of drugs according to the extent of solubilization • Ko = Km ƒm + Kw ƒw ……… • Where : Ko , Km and Kw are the observed, micellar and aqueous rate constants. ƒm and ƒw are the fractions of drug associated with the micelles and aqueous phase respectively. • Km value is dependent on the drug location within the micelle, i.e. non-polar drugs are solubilized within the lipophilic core (more protected), while those located close to micellar surface are less protected. PHR 416

  35. Example: greater solubilization and protection of benzocaine (more lipophilic) against base-catalyzed hydrolysis than homatropine by non-ionic surfactants. • The ionic nature of surfactant is an important factor. For base-catalyzed hydrolysis, solubilization into anionic micelles affords an effective stabilization due to repulsion of OH- by the micelles. • Solubilization has also a protective effect against oxidation. PHR 416

  36. Effect of complexing agents • Aromatic esters can be stabilized in aqueous solution in the presence of xanthines such as caffeine. The half-lives of benzocaine, procaine HCl are increased by 2-5 fold in presence of 2.5% caffeine. • Complexation by derivatives of cyclodextrin PHR 416

  37. Effect of ionic strength of solvent • In a reaction between ions, the reactants A and B have charges ZA and ZB, respectively, and the activated complex (A-----B)* has a charge (ZA + ZB) This reaction can be expressed as: • The rate of this reaction will depends on the ionic strength and the rate equation can be expressed as follow: log k = log k0 + 2AzAzBμ1/2 Where k is specific rate constant. μ is the ionic strength. k0 is the rate constant at infinite dilution of solution where μ = zero. PHR 416

  38. μ is the ionic strength of the solution, • If one of the reactants is neutral (i.e. ZA + ZB =0) and the reaction rate is independent on ionic strength. PHR 416

  39. Effect of light • Photolabile drugs are usually stored in containers which exclude ultraviolet light, since exposure to light in this wavelength range is the most usual cause of hotodegradation Amber glass is particularly effective in this respect because it excludes light of wavelength of less than about 470 nm. • As an added precaution, it is always advisable to store photolabile drugs in the dark. PHR 416

  40. Effect of humidity • Humidity is a major determinant of drug product stability in solid dosage forms. Elevation of relative humidity usually decreases stability, particularly for those drugs highly sensitive to hydrolysis. In addition, increased humidity also can accelerate the aging process PHR 416

  41. Effect of dosage form (semi solid dosage form) • The chemical stability of active ingredients incorporated into ointments or creams is frequently dependent on the nature of the ointment or cream base used in the formulation. • Hydrocortisone in a series of commercially available bases exhibits maximum decomposition in polyethylene glycol base. • Incorporation of drugs into gel structures frequently leads to a change in their stability, such as increased degradation of benzylpenicillin sodium in hydrogels of various natural and semisynthetic polymers. • Diluents containing oxidising agents could cause chemical degradation of fluocinolone acetate to less-active compounds • Little influence of viscosity on the rate of oxidation of ascorbic acid in solutions of gels of Polysorbate 80 has been noted PHR 416

  42. Solid dosage form: Effect of Excipients • One of the main ways in which the excipients of the solid dosage form can affect the degradation of drugs is by increasing the moisture content of the preparation. Excipients such as starch and povidone have particularly high water contents • Magnesium trisilicate causes increased hydrolysis of aspirin in tablet form because, it is thought, of its high water content. • Chemical interaction between components in solid dosage forms may lead to increased decomposition. • Replacement of the phenacetin in compound codeine tablets by paracetamol in NHS formulations in Australia in the 1960s led to an unexpected decreased stability of the tablets PHR 416

  43. The base used in the formulation of suppositories can often affect the rate of decomposition of the active ingredients. Aspirin decomposes in several polyoxyethylene glycols which are often incorporated into suppository bases. • Excipients present in tablet formulations can have an impact on the photostability of the product, the effect arising in many cases from impurities present in the excipients. • For example, free radical reactions involving phenolic impurities in tablet binding agents such as povidone, disintegrants such as crospovidone and viscosity-modifying agents such as alginates can lead to photodegradation. PHR 416

  44. Similarly, coloured products may be formed by the reaction of aldehydes formed during spray-drying or autoclaving of lactose with primary amine groups in the product PHR 416

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