Kinetics and drug stability.pptx..........

Integrative pharmaceutical

1. U-6: Kinetics and Drug S tability

2. Chapter Outline Introduction Rate and order of reactions Chemical and physical degradation Factors affecting stability of drugs Stability study Prediction of shelf life BY: FM 2

3. Intr o ducti o n Kinetics : Is study of the rate at which processes or changes occur. The changes may be chemical such as decomposition of a drug, radiochemical decay physical such as transfer across a boundary, such as the intestinal lining or skin BY: FM 3

4. Cont,… Importance of studying kinetics To determine half life To determine shelf life ( t 0.9 ) Selection of proper storage condition Selection of proper container for dispensing To determine incompatibilities Dissolution determinations To study ADME Processes in pharmacokinetics BY: FM 4

5. Cont,… Stability : Is the capacity of a drug product to remain within specifications established to ensure its identity, strength, quality, and purity Stability study: Is the study of the extent to which the properties of a drug substance or drug product remain within specified limits at certain temperature and humidity The properties may be physical, chemical, microbiological , or performance properties such as disintegration and dissolution . BY: FM 5

6. Cont,… Importance of Stability Extensive chemical degradation result in a substantial loss of quantity of therapeutic agent in the dosage form Degradation products may result in adverse events or be unsafe Instability may cause Undesired change in performance, i.e. dissolution/bioavailability Substantial changes in physical appearance of the dosage form causing product failures. BY: FM 6

7. Rate and Order of Reactions A rate is a change in some amount of drug per unit of time Importance of the Rate P rocess Enables drug producer to demonstrate that drug product remain stable for reasonable length of time during storage Assists pharmacist to know drug potential instability Ensures physician , pharmacist & patient that the prescribed drug reaches site of action in sufficient concentration BY: FM 7

8. Rate& OR... Fields of Rate P rocess: Stability and incompatibility : Rate process can lead to inactivation of the drug through decomposition or conversion into inactive or toxic form Dissolution : Main concern is the rapidity with which a solid dosage form is changed to molecular solution Pharmacokinetics : Concerns with the rate of drug absorption, metabolism and excretion Drug action at molecular level : Generation of a response by a drug is a rate process BY: FM 8

9. Rate & OR... Rate process provides a rational approach to stabilization of drug products and prediction of shelf- life and optimum storage conditions . Example : Thiamine HCl is most stable at pH 2-3 and is unstable at pH above 6. If this is combined with a buffered vehicle of say pH 8 or 9 the vitamin is rapidly inactivated Knowing rate at which a drug deteriorates when exposed to various hydrogen ion concentrations allows one to choose a vehicle that will retard or prevent the degradation BY: FM 9

10. Rate & OR... In general, reaction kinetics is the study of rate of chemical change and the way in which this rate is influenced by: concentration of reactants & products other chemical species which may be present, such factors as solvent, pressure & temperature Ionic strength BY: FM 10

11. Rate & OR... Reaction kinetics : is the study of rate of chemical change and the way in which this rate is influenced by conditions of concentration of reactants and products, solvent, ionic strength and temperature Reaction Rate : is the velocity with which a reactant or reactants undergo chemical change Mathematical description of the rate of change of drug concentration with respect to time BY: FM 11

12. Rate & OR... The rate, velocity or speed of a reaction is given by the expression dc / dt , where dc is increase or decrease of concentration over a time interval dt Rate, velocity or speed of reaction is given by: R[V] =  dc/dt This expression gives the increase (+) or decrease (-) in concentration (C ) within a given time intervals (dt) BY: FM 12

13. Order of Reactions Order of Reaction : to the way in which the concentration of the reactant (s) influence the rate of a chemical rxn . The two most common order of reaction associated with pharmaceuticals include: Zero-order reactions First order reactions BY: FM 13

14. OR... Zero Order Rxn: the rate of rxn is independent of the concentration of the reactants and constant with respect to time. First-order rxn the rate of rxn is directly proportional to the concentration reactant remaining with respect to time. BY: FM 14

15. Assignment BY: FM 15

16. Cont,… Drug substances and expients have diverse molecular structures susceptible to many degradation pathways. C hemical degradation pathways H ydrolysis, dehydration, isomerization, oxidation , decarboxylation, elimination and photodegradation Physical change Vaporization, crystallization of amorphous drugs , transitions in crystalline states , and moisture adsorption BY: FM 16

17. Chemical Degradation of Drugs Hydrolysis ( solvolysis) interaction of drug molecules with water molecule to yield breakdown product . Most important In system containing water such as emulsion, suspensions, solutions For drug which are affected by trace of moisture in the form of water by vapour from the atmosphere. BY: FM 17

18. Cont,… If the drug is derivative of carboxylic acid or contain functional groups based on this moiety, for example, esters, amides, imides and lactam functional groups are among those prone to hydrolysis. BY: FM 18

19. Cont,… Protection Against H ydrolysis Hydrolysis may be prevented by: A voiding their contact with moisture at the time of manufacture, Formulating susceptible drugs in the form of dry powder for reconstitution Storage in controlled humidity and temperature. Incorporating a suitable desiccant in the packs Selecting an optimum pH for maximum stability and the formulation. BY: FM 19

20. Chemical degradation,… Oxidation In pharmaceutical dosage forms, oxidation is usually mediated through reaction with atmospheric oxygen under ambient conditions. Autoxidation is the most common of oxidative degradation that occur in many of the pharmaceutical preparation. Only small amount of oxygen is required for initiating the rxn I nvolves multiple pathways: initiation, propagation and termination . BY: FM 20

21. Cont,… Many oxidation reactions are catalyzed by acids and bases . Heavy metals like copper, iron, cobalt and nickel catalase the oxidation rxn. Heat and light further influence the kinetics of oxidative degradation process. An increase in temperature leads to an acceleration in the rate of oxidation. BY: FM 21

22. Cont,… Protection Against O xidation Use of Antioxidants Replacing oxygen in pharmaceutical containers with nitrogen or carbon dioxide. Storage at reduced temperatures Oxidation of fats and oils may be retarded by hydrogenation If oxidation is catalyzed by hydrogen or hydroxyl ion, the pH of optimum stability must be ensured BY: FM 22

23. Chemical degradation,… Photodegradation Sunlight or room light may cause substantial degradation of drug molecules. The energy from light radiation must be absorbed by the molecules to cause a photolytic reaction . Photolysis reactions often are associated with oxidation. E.g. phenothiazines, hydrocortisone, prednisolone, riboflavin, nifedipine, colchicine and chlorpromazine BY: FM 23

24. Cont,.. Protection Against Photolysis U se of coloured glass containers (amber glass). Storage in the dark place. Packaging in cartons (physical barrier to light ). Opaque shells for capsules. Coating tablets with a polymer film containing ultraviolet absorbers. BY: FM 24

25. Chemical degradation,… Polymerisation Is the process by which two or more identical drug molecules combine together to form a complex molecule . P olymerisation process occurs during the storage of concentrated aqueous solutions of aminopenicillins, such as ampicillin sodium. The reactive β- lactam bond of the ampicillin molecule is opened by reaction with the side-chain of a second ampicillin molecule and a dimer is formed . The process can continue to form higher polymers . BY: FM 25

26. Cont,… BY: FM 26

27. Chemical degradation,… Dehydration The elimination of a water molecule from structure of the cpd . In covalent (chemical) dehydration process , there is the formation of a double bond that can then participate in electronic resonance with neighboring functional groups. In physical dehydration processes water removal does not create new bonds but often changes the crystalline structure of the drug . BY: FM 27

28. Chemical degradation,… Isomerization The process of conversion of a drug in to its optical or geometric isomers. May be regarded as a form of degradation resulting in serious loss of therapeutic activity. Examples of isomerization of drug substance: Trans- cis isomerization of amphotericin B and vitamin A Pilocarpine undergoes epimerization by base catalysis, tetracyclines and ergotamine exhibit epimerization by acid catalysis . BY: FM 28

29. Cont,… BY: FM 29

30. Chemical degradation,… Elimination Drug substances having a carboxylic acid group are sometimes susceptible to decarboxylation E.g . 4-Aminosalicylic acid under strongly acidic conditions Other elimination reactions have been reported for various drug substances E.g . levothyroxine eliminates iodine BY: FM 30

31. Physical Degradation of the Drugs Vaporization Some drugs and excipients possess sufficiently high vapor pressures at room temperature that their volatilization constitutes a major route of drug loss . Flavors, solvents and cosolvents may be lost from the formulation. E.g. Nitroglycerin Reduction of vapor pressure can be achieved through dispersion of the volatile drug in macromolecules that can provide physicochemical interactions BY: FM 31

32. Physical degradation,… Adsorption (Sorption) Drug-plastic interaction is a major potential problem when intravenous solutions are stored in bags or infused via administration sets that are made from polyvinyl chloride. Up to 50% drug loss can occur after nitroglycerin is stored in PVC infusion bags for 7 days at room temperature. A diverse array of drugs, including diazepam, insulin, isosorbide dinitrate, and others, has shown substantial adsorption to PVC . BY: FM 32

33. Physical degradation,… Crystallization of Amorphous Drugs Poorly water-soluble drugs formulated in their amorphous state to improve the solubility. Crystallization of amorphous drug substances may occur during long-term storage and may lead to drastic changes in the release characteristics of the drug and, hence, the absorption. BY: FM 33

34. Physical degradation,… Transitions in Crystalline States Polymorphs are different crystalline forms of the same drug . M ay alter critical properties of drugs because the solubility and dissolution rate of drug substances generally vary with changes in their crystalline form. Temperature and humidity affect polymorphic transitions. Examples:- Nitrofurantoin, Theophylline BY: FM 34

35. Physical degradation,… Physical changes in solution, suspension and emulsion Lose of original test, odor, colour and clarity Change in viscosity, precipitation, caking Creaming, Sedimentation, Flocculation, Coalescence Breaking, Phase inversion Changes in semisolids Change in consistency , bleeding, loss of homogeneity BY: FM 35

36. Stability... Drug products must remain stable. Why ? Because of: Chemical degradation of active agent lowers amount of therapeutic agent Product chemical decomposition process may give rise to potentially toxic agent Instability of a product can lower bioavailability of dosage form, hence reducing therapeutic efficacy of the drug Physical instability due to degradation of such excipients as product stabilizers, solubilizers, emullgent , suspending agents ,etc leads to creaming, mottling , caking, etc which in turn leads to product rejection and Compromisation of product integrity BY: FM 36

37. Factors affecting stability of drugs Temperature High temperature accelerate oxidation, reduction and hydrolysis reactions which lead to drug degradation The speed of many reactions increases about two to three times with each 10 oC rise in temperature. For example, there is pronounced increase in hydrolysis rate of many drugs by increase in temperature. Light Ultraviolet light is the most usual cause of photo degradation. Photolabile drugs are usually stored in containers which exclude ultraviolet light. BY: FM 37

38. Factors... Moisture: Water catalyses chemical reactions such as oxidation, hydrolysis and reduction Water promotes microbial growth, triggering microbial contamination and lead instability. Pharmaceutical dosage forms: solid dosage forms are more stable than liquid dosage forms for presence of water. BY: FM 38

39. Cont,… Formulation factors PH pH is perhaps the most important parameter which affects hydrolysis rate of drugs in liquid formulations It also affects oxidative degradation of some drugs in solution. For example , oxidation of predinsolone Excipients Some excipients absorb moisture. Starch and povidone absorb water when stored at high relative humidity As the result they affect stability of products which contains them BY: FM 39

40. Influence of temperature on reaction rates Reaction rates are expected to be proportional to the number of collision of reactants per unit time The number of collision increases as the temperature increases. The reaction rate is expected to increase with increase in temperature. The effect of temperature on reaction rate is given by the equation, first suggested by Arrhenius. BY: FM 40

41. Cont,… BY: FM 41 is the Boltzmann factor, which represents the fraction of molecules having energies greater than or equal to Ea. Where K is the specific reaction rate constant A is a constant known as the Arrhenius factor Ea is the energy of activation R is the gas constant , 1.987 calories/ deg mole T is the absolute temperature

42. Cont,… A convenient, approximate method which is useful for estimation of decomposition rates at two different temperatures makes use of the ratio of rate constants. BY: FM 42

43. Stabilization of drug products Destabilizing factor Methods to stabilize Examples of labile drugs Temperature Establish suitable storage conditions Hydrolysis Buffering, use nonaqueous solvents such as alcohol, glycerin, or propylene glycol, make powder for reconstitution Drugs containing ester, amide, etc bonds such as penicillin , cephalosporin Photolysis Use amber container Hydrocortisone, folic acid, riboflavin, prednisolone, ascorbic acid 09/08/2024 43 BY FM

44. Destabilizing factor Methods to stabilize Examples of labile drugs Isomerization Establish optimal pH range Adrenaline, pilocarpine, tetracycline, vitamin A, cephalosporin Oxidation Replace O 2 by nitrogen, add antioxidant or chelating agents antibiotics, vitamins, oils, and fats , Phenolic compounds [phenylephrine, morphine ] , steroids, catecholamine [ dopamine & adrenaline] Drug incompatibility Avoid direct contact of incompatible drugs or excipients Phenol and thymol 09/08/2024 44 BY FM

45. Assignment BY: FM 45

46. Stability Studty Stability: The products should retain their properties during storage This should guarantee the efficacy and safety Efficacy: Optimum therapeutic level for specified period of time Safety: Minimum or no side effects BY: FM 46

47. Five stabilities of drug that must be considered:: Physical stability Chemical stability Microbiological stability Therapeutic stability Toxicological stability 09/08/2024 BY FM 47

48. Criteria for acceptable level of stability Types of stability Conditions to be maintained through out the shelf life of the drug product Physical Such original physical properties as dissolution, suspendability, uniformity, palatability, and appearance should be retained Chemical Each active ingredient should retain its chemical integrity & labeled potency over limited periods Microbiological The product remain sterile and resistant to microbial growth. Antimicrobial agents present in the product retains its effectiveness over specified period Therapeutic Therapeutic effectiveness should remain unchanged Toxicological No significant increase in level of toxicity 09/08/2024 48 BY FM

49. Stability S tudy The purpose of stability testing is to provide evidence on how the quality of a drug substance (active ingredient) or drug product ( formulation) varies with time under the influence of a variety of environmental factors . Permits the establishment of recommended storage conditions , retest periods , and shelf lives . The testing should cover, as appropriate, the physical, chemical, and microbiological attributes, preservative content and functionality test. BY: FM 49

50. Cont,… Climatic zone According to WHO guideline on stability studies, the world has been divided in to four zones taking in to account the prevalent annual climatic conditions of temperature and humidity. Zone I- temperate (21ºC/45% RH) Zone II – subtropical with possible high humidity (25ºC/60% RH ) Zone III- hot, dry (30ºC/35% RH ) Zone IV Zone IVA: 30ºC/65% RH (hot/ humid) Zone IVB: 30ºC/75% RH (hot/very humid) BY: FM 50

51. Stability testing protocols Stability testing requires the careful design of protocols which must define The temperature and humidity for storage Storage time before sampling The number of batches to be sampled The number of replicates within each batch A suitable light challenge Details of assay C ontainer BY: FM 51

52. Type of stability study Major types of stability testes are: Long term stability test Accelerated stability test and Field stability test BY: FM 52

53. Long term stability (Real time studies) long term studies as stability studies under the recommended storage conditions for the retest period or shelf life proposed or approved for labeling . WHO guideline defines long term testing as the stability testing during and beyond expected shelf life under storage conditions in the intended market. Conducted in the laboratory under controlled stresses similar to those likely to be encountered during storage . BY: FM 53

54. Long term stability,… Minimum of 12 months data For product stored at room temperature : 25 ± 2oC and RH of 60 ± 5 % ( zone I and II) and 30 ± 2 oC and RH 65 ± 5 % (zone III and IV ) . For drug substances and drug products recommended to be stored in a refrigerator : 5± 3 o C. For drug substances and drug product to be stored in a freezer: -20 ± 5 o C BY: FM 54

55. Accelerated stability study Use of exaggerated conditions of temperature, humidity, light & others . Accelerated stability tests are done: To detect the deterioration of the product rapidly, in order to select the best formulation; To predict shelf life; To provide rapid means of quality control . BY: FM 55

56. Accelerated stability,… Accelerated storage condition For drug substance and drug products stored at room temperature: 40± 2 o C with 75 ± 5 % RH (for all zone) For drug substance and drug products intended to be stored in a refrigerator : 25 ± 2 o C and RH of 60 ± 5 % BY: FM 56

57. Prediction of shelf life An expiration date is the time up to which the product will remain stable when stored under recommended storage conditions. Thus , an expiration date is the date beyond which it is predicted that the product may no longer retain fitness for use . Shelf life is the time during which the product, if stored appropriately as per the manufacturer’s instructions, will retain fitness for use (>90% of label claim of potency ). BY: FM 57

58. Cont,… The expiration date is also defined as the date placed on the container/labels of a drug product designating the time during which a batch of the product is expected to remain within the approved shelf life specifications . The shelf life is determined from the data obtained from the long term storage studies . BY: FM 58

59. Expiry date : refers to the date after which drug products can not be used since concentration of drug is lower than therapeutic concentration and some drug products’ degradation are toxic and harmful to patients. NB: Shelf-life should since manufacture date of product Maximum shelf life for such drug products as implants, injectables, tablets, capsules, soluble Powder is 5 years After opening of drug container, expiry date will be shorter due to effects of external factors 09/08/2024 59 BY FM

60. Examples: Eye drops : can be used for one month after opening the droppers Syrups and suspension of antibiotics : can be used for one week if stored in room temperature and for two weeks if stored at 4 C Tablets and capsules remain stable in the package but after removal the expiry date will change Ampoules : must be used immediately Vials which are multidose are stable for 24 hours due to presence of preservatives 09/08/2024 BY FM 60