Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Stability studies

4,846 views

Published on

Stability studies

Published in: Health & Medicine

Stability studies

  1. 1. STABILITY STUDIES ……… A measure of how a pharmaceutical product maintains its quality attributes over time Dr. Gajanan S. Sanap M.Pharm.,Ph.D Department of Pharmaceutics Ideal College of Pharmacy and Research Kalyan 421- 306
  2. 2. STABILITY – The capacity of a drug or product to remain within established specifications of identity , quality, purity in a specific period of time. OR The capacity or the capability of a particular formulation in a specific container to remain with in particular chemical , microbiological , therapeutically , and toxicological specifications. OR USP defines stability of pharmaceutical product as , “extent to which a product retains with in specified limits and throughout its period of storage and use ( i.e. shelf life).
  3. 3. Stability testing is used to:  Provide evidence as to how the quality of the drug product varies with time.  Establish shelf life for the drug product.  Determine recommended storage conditions.  Determine container closure system suitability. Why Stability studies are necessary ?  Chemical degradation of the product leads to lowering of the concentration of the drug in the dosage form.  Toxic products may be formed , due to chemical degradation of the active ingredient. Advantages of Stability studies  Assurance to the patient Economic considerations Legal requirement
  4. 4.  OBJECTIVES 1. To determine maximum expiration date/ shelf life. 2. To provide better storage condition. 3. To determine the packaging components. 4. To gather information during preformulation stage to produce a stable product.
  5. 5. Study Storage condition Minimum time period covered by data at submission Long Term (Ambient) 25º C ± 2º C 60%RH ± 5% 12 months Intermediate (controlled) 30º C ± 2º C 60%RH ± 5% 6 months Accelerated 40º C ± 2º C 75%RH ± 5% 6 months
  6. 6. Kinetics Kinetics Motion or movement Velocity, rate or rate of change Kinetics deals with the study of the rate at which processes occur and mechanism of chemical reactions
  7. 7. It involves the study of rate of change and the way in which this rate is influenced by the concentration of reactants, products, and other chemical species that may be present, and by factors such as solvents, pressure, and temperature. Kinetics applies to: Stability Incompatibility, Dissolution, Absorption, Distribution Drug action at molecular level Elimination processes
  8. 8. WHY DO WE STUDY ABOUT KINETICS? It gives an in light into the mechanism of changes involved Allows a prediction of the degree of change that will occur after a given time has elapsed.
  9. 9. DRUG STABILITY • The resistance of the drug to the various chemical, physical, and microbiological reactions that may change the original properties of the preparations during transport, storage and use. • Quantitatively it is expressed as shelf life. Shelf life  is the time during which the medicinal product is predicted to remain fit for its intended use under specified conditions of storage.  It is the time from manufacture or preparation until the original potency or content of the active ingredient has been reduced by 10% [t10 or t90] which is the limit of chemical degradation
  10. 10. WHY DO WE STUDY ABOUT DRUG STABILITY? Safety of the patient [toxic products or less potent product] Legal requirements with identity, strength, purity and quality To prevent economic repercussions.
  11. 11. RATES AND ORDERS OF REACTIONS RATES • the speed or velocity of a reaction with which a reactant or reactants undergoes a change. • It is determined by the change in the concentration of the reactants or products as a function of time. • The rate may be determined by the slowest or rate determining step. kc n Rate dt dc 
  12. 12. ORDERS OF REACTIONS the number of concentrations that determine rate. the way in which the concentration of the reactant influences the rate. Law of mass action  The rate of a reaction is proportional to the molar concentrations of the reactants each raised to power equal to the number of molecules undergoing reaction. a A + b B Product Rate α [A]a .[B]b Rate = K [A]a .[B]b Order of reaction = sum of exponents Order of A = a and B = b Then Overall order = a + b
  13. 13. Example: The reaction of acetic anhydride with ethyl alcohol to form ethyl acetate and water (CH3 CO)2 + 2 C2H5OH 2 CH3 CO2 C2H5 + H2O Rate = K [(CH3 CO)2 O] . [C2H5OH]2 Order for (CH3 CO)2 O is 1st order Order for [C2H5OH]2 is 2nd order Overall order of reaction is 3rd Order
  14. 14. ZERO ORDER REACTIONS rate is constant and is independent of the concentration of any of the reactants. A constant rate of drug release from a dosage form is highly desirable. Equation for zero order:
  15. 15. Equation for zero order: a [A] k Product (P) Rate = - dc/dt = K [c]0 - dc/dt = k dc = - k dt co = Initial concentration ct = Concentration at time t   t t c c kdtdc t 00 C – C0 = -kt
  16. 16. Units of the rate constant K c = co – Kt K = co – c /t K = Concentration / time = mole / liter . second = M. sec-1 C t
  17. 17. Determination of t1/2 Let c = co /2 and t1/2 = t substitute in equation; c = co – k t Note: Rate constant (k) and t1/2 depend on co Determination of t0.9 Let c = 0.9 co and t= t0.9 substitute in equation; c = co –k t t1/2 = co / 2K t90% = t0.9 = 0.1 co / k
  18. 18. Examples • Drug X degrades by a zero-order process with a rate constant of 0.05 mg ml1 year−1 at room temperature. If a 1% weight/volume (w/v) solution is prepared and stored at room temperature: 1. What concentration will remain after 18 months? 2. What is the half-life of the drug?
  19. 19. Answer 1. C0 = 1% w/v = 10 mg/ml; t =18 months = 1.5 year; k0 = 0.05 mg ml−1 year−1 C = C0 – k0t = 10 – (0.05 × 1.5) = 9.93 mg/ml 2. t1/2 = 0.5C0/k0 = (0.5 × 10)/0.05 = 100 years
  20. 20. FIRST ORDER REACTION The most common pharmaceutical reactions e.g; drug absorption & drug degradation The reaction rate of change is proportional to drug concentration.
  21. 21. - dc/dt = kc1 = kc - dc/c = kdt    t t t c dtk c dc 00 ktcc o lnln 303.2 loglog 0 kt cc 
  22. 22. C = co e –kt Difficult to determine slope lnc = lnco – kt Slope = c1 – c2 / t1 – t2 Slope = -k lnco Log co Log c = log co – kt / 2.303 Slope = c1 – c2 / t1 – t2 Slope = -k / 2.303 Or use semi log paper C Lnc Logc t t t
  23. 23. Determination of t1/2 Let t = t1/2 and C = C0 /2 substitute in ln C = ln C0 – Kt t1/2 = ln 2/ K = 0.693 / K K units = 0.693 / t1/2 = time-1 Determination of t0.9 Let t = t0.9 c = 0.9 Co substitute in ln c = ln co – Kt t0.9 = 0.105 / K and K = 0.105/ t0.9 t1/2 = 0.693 / K t0.9 = 0.105 / K
  24. 24. Examples 1 Ten (10) ml aqueous solutions of drug A (10% w/v) and drug B (25% w/v) are stored in two identical test tubes under identical storage conditions at 37°C for 3 months. If both drugs degrade by first-order, which drug will retain the highest percentage of initial concentration? (a) Drug A (b) Drug B (c) They will be the same. 2. The concentration of drug X in aqueous solution drops by 10% per month when stored at room temperature. If the degradation occurs by first order, what concentration will remain if a 5 mg/ml solution of the drug is stored under the same conditions for 3 months?
  25. 25. 3. A 5 gm/100 ml solution of drug X is stored in a closed test tube at 25°C. If the rate of degradation of the drug is 0.05 day−1, calculate the time required for the initial concentration to drop to (a) 50% (half-life) and (b) 90% (shelf-life) of its initial value. 4. A 5 gm/100 ml solution of drug X is stored in a closed test tube at 25°C. If the rate of degradation of the drug is 0.05 day−1, calculate the time for the drug concentration to degrade to 2.5 mg/ml.
  26. 26. PSEUDO ORDER REACTIONS • For some reactions, the rate of the reaction may be independent of the concentration of one or more of the reacting species over a wide range of reactions. • These may occur under the following conditions: One or more of the reactants enters into the rate equation in great excess compared to others; One of the reactant is catalyst; One or more of the reactants is constantly replenished during the course of reaction
  27. 27. SECOND ORDER REACTION Rate depends on the product of two concentration terms. When you have two components reacting with each other or one component reacting with itself. Example: 2HI = H2 + I2 , here the reaction is not simply a matter of an HI molecule falling apart, but relies on the collision of two HI molecules. The rate of reaction from the law of mass action is given by: Rate = dc/dt = k[HI][HI] = k[HI]2
  28. 28. dc/dt = -kc2 dc/c2 = -kdt    t t c c dtk c dc 0 2 0 kt cc  0 11 2nd Order reaction
  29. 29. 2nd order graph Units of K: 1/C = 1/Co + Kt K = (1/C - 1/Co) / t K = M-1. sec -1 i.e, K is dependent on initial drug concentration. Derive equation for t1/2 and shelf life Half life: t1/2 = 1 / KCo Shelf life: t0.9 = 0.11 / KCo
  30. 30. DETERMINATION OF ORDER AND RATE CONSTANTS 1. Substitution method [data plotting method] • Data accumulated in experimental kinetic study may be substituted in the integrated form of the equation that describes the various reaction orders and observing which plot is a straight line. • Accordingly, plot of: Concentration against time …….. zero order reaction [if straight line] ln concentration against time ……. First order reaction [if straight line] 1/concentration against time …….. second order reaction [if straight line].
  31. 31. 2.Half-life method • This method is based on the relationship between the initial concentration of the reactant, the half life, and the reaction order. • For zero-order reactions, t1/2 increases with increasing concentration, whereas for first-order reactions, t1/2 does not change with change in concentration
  32. 32. DEGRADATIVE PATHWAYS Degradation of active drug leads to lowering of quantity of the therapeutic agent in the dosage form.  It may not be extensive , a toxic product formation may take place due to decomposition instability of drug product can lead to a decrease in its bioavailability . Changes in physical appearance of given dosage form may take place. Degradation may increase or may decrease the potency of drug. Sometimes active drug may retain its potency , but excipients like – antimicrobial , preservatives , solubilizers , emulsifying or suspending agent may degrade , lead to compromising the integrity of drug product. EXAMPLE :  Drugs like 5-fluorouracil , carbamazipine , digioxin and theophylline have narrow therapeutic indices these needs to be carefully treated in patient so that plasma levels are neither too high as to be toxic nor too low as to be ineffective  The antimicrobial chloroquine can produce toxic reactions that are attribute to the photochemical degradation of the substance.
  33. 33. DEGRADATION MAY BE OF TWO TYPES  PHYSICAL DEGRADATION  CHEMICAL DEGRADATION 1. OXIDATION 2. DECARBOXYLATION 3. PHOTOLYSIS 4. RACEMIZATION 5. HYDROLYSIS  PHYSICAL DEGRADATION The physical stability properties includes appearance, palatability ,uniformity ,dissolution and suspend ability are retained . Maintained throughout the shelf life of the drug. It includes following : Loss of water loss of volatile oil Water Absorbance Polymorphism Color change
  34. 34. Physical degradation includes following : LOSS OF VOLATILE CONTENT: Volatile compounds used such as Alcohol ether , camphor oils , etc . Try to escape from the formulation leads to degradation of formulation. Example : nitroglycerine from drugs evaporate. LOSS OF WATER : Water loss from liquid preparation (o/w emulsion) leads to changes in stability .It causes crystallization of drug product .which may lead to increase in potency , and decrease in weight. Example : water evaporates from Na2SO4 .BORAX.  WATER ABSORBANCE : pharmaceutical formulations which are hygroscopic in nature absorb the water from its external environment leads to degradation . Example : gelatin capsule , deliquescent salts like –Cacl3 , Potassium citrate. POLYMORPHISM: A stable crystal form is effected (it may loosen) leads to the formation of polymorph and cause instability in formulation. This may lead to alteration in solubility , dissolution of drug COLOR CHANGE: Loss or development of color may occur . (due to change in PH , use of reducing agent , exposure to light )
  35. 35. Physical Stability Physical stability implies that:  The formulation is totally unchanged throughout its shelf life and has not suffered any changes by way of appearance, organoleptic properties, hardness, brittleness, particle size etc.  It is significant as it affects: 1.pharmaceutical elegance 2.drug content uniformity 3.drug release rate.
  36. 36. Physical Stability Formulation Likely physical instability problems Effects Oral solutions 1- Loss of flavor 2- Change in taste 3- Presence of off flavors due to interaction with plastic bottle 4- Loss of dye 5- Precipitation 6- discoloration Change in smell or feel or taste
  37. 37. Formulation Likely physical instability problems Effects Parenteral solutions 1. Discoloration due to photo chemical reaction or oxidation 2. Presence of precipitate due to interaction with container or stopper 3. Presence of “whiskers” 4. Clouds due to: (i) Chemical changes (ii) The original preparation of a supersaturated solution Change in appearance and in bio-availability
  38. 38. Physical stability Formulation Likely physical instability problems Effects Suspensions 1- settling 2- caking 3- crystal growth 1-Loss of drug content uniformity in different doses from the bottle 2- loss of elegance.
  39. 39. Physical stability Formulation Likely physical instability problems Effects Emulsions 1- Creaming 2- coalescence 1- Loss of drug content uniformity in different doses from the bottle 2- loss of elegance
  40. 40. Physical stability
  41. 41. Physical stability Formulation Likely physical instability problems Effects Semisolids (Ointments and suppositories) 1. Changes in: a) Particle size b) Consistency 2. Caking or coalescence 3. Bleeding 1-Loss of drug content uniformity 2- loss of elegance 3-change in drug release rate.
  42. 42. Physical stability Formulation Likely physical instability problems Effects Tablets Change in: a) Disintegration time b) Dissolution profile c) Hardness d) Appearance (soft and ugly or become very hard) Change in drug release
  43. 43. CHEMICAL DEGRADATION Chemical degradation of a dosage form occurs through several pathways like –hydrolysis , oxidation , decarboxylation , photolysis , racemization. which may lead to lowering of therapeutic agent in the dosage form, formation of toxic product , decreased bioavailability etc. 1. HYDROLYSIS  Most important in systems containing water such as emulsion , suspension , solutions , etc.  Also for drugs which are affected by moisture (water vapor) from atmosphere.  It is usually catalysed by hydrogen ion(acid) or hydroxyl ion(base).  In this active drug is decomposed with solvent.  Usually solvent is water some time reaction may involve pharmaceutical co solvents such as ethyl alcohol or poly ethylene glycol  Main classes of drugs that undergo hydrolysis are the ESTERS ,AMIDE ,ALKALI, ACID.
  44. 44. Cont…  ESTER HYDROLYSIS involve acyl – acid cleavage.  Example of drugs: aspirin ,atropine , physostigmine , procaine..  R .COOR (ester) + H2O  RCOOH (acid) + HOR(alcohol)  AMIDE HYDROLYSIS is more stable than ester , susceptible to specific and general acid base hydrolysis. It involves cleavage of amide linkage to give an amine instead of alcohol as in case of esters.  Example of drugs : chloramphenicol , barbiturates .  RCONHR(amide) + H2 O  RCOOH + NH2 R(AMINE)
  45. 45. Some functional groups subject to Hydrolysis Drug type Examples Esters Aspirin, alkaloids Dexmethasne sodium phosphate Nitroglycerin Lactones Pilocarpine Spironolactone Amides Chloramphenicol Imides Glutethimide Malonic ureas Barbiturates
  46. 46. PROTECTION AGAINST OXIDATION  Avoiding contact with moisture at time of manufacture.  Packaging in suitable moisture resistant packs such as strip packs and storage in controlled humidity and temperature.  In liquid dosage form since , hydrolysis is acid or base catalyzed , an optimum PH for max stability should be selected and the formulation should be stabilized at this PH by inclusion of proper buffering agents.  Hydrolysis of certain drugs such as benzocaine and procaine can be decreased by the addition of specific complexing agent like caffeine to the drug solutions .  Hydrolysis susceptible drugs such as penicillin and derivatives can be prevented by formulating them in the dry powder form for reconstitution or dispersible tablets instead of a liquid dosage form such as solutions or suspensions.
  47. 47. 2. OXIDATION  Oxidation is controlled by environment i.e, light ,trace elements , oxygen and oxidizing agent .  Occurs when exposed to atmospheric oxygen.  Either the addition of oxygen or removal of hydrogen .  Oxidation is the loss of electrons while reduction is the gain of electrons. AUTOXIDATION  The reaction between the compounds and molecular oxygen is required for initiating the chain reaction is called autoxidation .  Free radicals produced during initial reaction are highly reactive and further catalyze the reaction produced additional free radicals and causing a chain reaction.
  48. 48.  Heavy metals such as copper , iron , cobalt , and nickel have been known to catalyze the oxidative degradation .Heat and light further influence the kinetics of oxidative degradation processes. STEPS INVOLVED OXIDATION REACTION  INITIATION : Formation of free radicals is taken place . R--H  R’ + [H’}  PROPOGATION : here the free radical is regenerated and react with more oxygen . R’ + O2  R’—O2 R’O2 + RH  ROOH + R’  HYDROPEROXIDE DECOMPOSITION ROOH  RO’ + OH’  TERMINATION : free radicals react with each other resulting in inactive products. R’--O2 + X  Inactive product RO2 + RO2  Inactive product EXAMPLE OF DRUGS DECOMPOSED BY OXIDATION PATHWAYS Archis oil , clove oil , ethyl oleate ,Heparin , Ascorbic acid , Morphine ,Vitamin A , Vitamin B12 , etc.
  49. 49. PROTECTION AGAINST OXIDATION USE OF ANTIOXIDANTS : antioxidants are Mainly of 3 types : 1. The first group probably inhibits the oxidation by reacting with free radicals. Example – tocopheral , butylated hydroxyl anisole (BHA) , butylated hydroxyl toluene's (BHT). Concentration 0.001 – 0.1%. 2. The second group comprising the reducing agents , have a lower redox potential than the drug or other substance that they should protect and are therefore more readily oxidized. Example –ascorbic acid and iso ascorbic acid , potassium or sodium salts of metabisulfite. 3. The third group, little antioxidant effect themselelf but enhance the action of true antioxidant .example Example -- Citric acid , tartaric acid , disodium edetate and lecithin . USE OF CHELATING AGENT when heavy metals catalyze oxidation . Example -- EDTA , citric acid , tartaric acid form complexes.
  50. 50. 3. PHOTOLYSIS  Exposure to light cause substantial degradation of drug molecule. • When molecules are exposed to electromagnetic radiation they absorb light (photons) at characteristic wavelength which cause increase in energy which can :  Cause decomposition.  Retained or transferred.  Be converted to heat .  Result in light emission at a new wavelength (fluorescence , phosphorescence). • Natural sun light lies in wavelength range (290– 780nm) of which only higher energy (UV) range (290 --320) cause photo degradation of drugs.  `
  51. 51.  Example of phototoxic drugs: Furosemide , acetazolamide , cynocobalamine .  EXAMPLE Sodium nitropruside in aqueous solution (which is administered by IV infusion for management of acute hypertension ).  If protected from light it is stable to at least 1yr.  If exposed to normal room light it has a shelf life of 4 hrs. PROTECTION  Use of amber colored bottles .  Storing the product in dark , packaging in cartons also act as physical barrier to light.  Coating of tablets with polymer films.
  52. 52. Accelerated Stability StudiesAccelerated Stability Studies Stability study to predict the shelf life of the product, by accelerating the rate of decomposition, preferably by increasing the temperature of reaction conditions. With the advancement in branch of kinetics, shelf life of a dosage form can be predicted within months based on accelerated stability reports Preparations are subjected to high stresses during stability testing. Common high stresses include :  Temperature  Humidity  Light
  53. 53. It is defined as the time required for the concentration of the reactant to reduce to 90% of its initial concentration .Represented as t90 and the units of time /conc. t90 = (a-0.9a) = 0.1 a ko ko Where , a = initial concentration . ko = specific rate constant for zero order reaction. (the time from the date of manufacture and packaging of the formulation until its chemical or therapeutic activity is maintained to a predetermined level of labeled potency and , its physical characteristic have not changed appreciably or deleteriously ).
  54. 54. Arrhenius equation It explains the effect of temperature on rate of a reaction. According to Arrhenius, for every 10º rise in temperature, the speed of reaction increases about 2-3 times. k = A e -Ea / RT Arrhenius factor Energy of activation Ideal gas constant Log k = log A – Ea / 2.303 RT Arrhenius factor is the frequency of molecular collisions occuring between the molecules.
  55. 55. Estimation of k value  The reaction is conducted at several temperatures.  Concentration of reactants is determined.  Appropriate graphs are drawn for the kinetic data.  Data is processed for all the orders.  The order of the reaction is identified.  From the slopes of the lines, k values are calculated for all temperatures.
  56. 56. Estimation of energy of activation  A graph can be drawn by taking log k on y-axis and reciprocal temperature (1/T) on x-axis.  A straight line is obtained, the slope of the line is negative and the magnitude is Ea / 2.303 R.  The intercept corresponds to log A  All the constants in the Arrhenius equation can be obtained from the graph. Activation energy is the minimum energy that a molecule should possess so that the molecular collisions produce the product.
  57. 57.  The Preparation is stored at different elevated temperatures, to accelerate the degradation  Samples are withdrawn at different time intervals  The Order of the reaction is determined by plotting the appropriate function of concentration against time and linear relationship is determined  Straight line in a graph permits the estimation of k value from the slope  Similarly graphs are drawn for different elevated temperatures.  K value for each temperature are calculated.  By using Arrhenius relationship, Log k values are plotted against reciprocal of absolute temperature, energy of activation can be calculated. Steps involved in prediction of shelf life
  58. 58.  Extrapolate the straight line to room temperature (k25) or refrigerated temperature and read the log k value on y-axis.  Substitute the k value in the appropriate equation to get the shelf life of the product.
  59. 59. Arrhenius plot for predicting the rate constant at ambient temperature(25ºC).
  60. 60. Stability investigation Organoleptic and physicochemical stability Photostability Chemical stability Dosage form Solid Semisolid Liquid All Solid Semisolid Liquid Storage condition Storage in open container until equilibrium is reached at 25ºC/60%,30ºC/70%, 40ºC/75% 5ºC ≥ - 10ºC 5ºC -40ºC Temperature cycle within 24 hrs 40ºC(content uniformity) 5ºC ≥ -10ºC Xenon lamp 40ºC, 50ºC, 60ºC, 70ºC 30ºC, 40ºC, 50ºC 40ºC, 50ºC, 60ºC, 70ºC Storage period 1-2 weeks 4 weeks 4 weeks 2 weeks 3 months 4 Weeks 4 weeks 48 hrs 3 months 3 months 3 months
  61. 61. LONG TERM STABILITY STUDIES : According to WHO, long term stability testing during and beyond expected shelf life under storage conditions in the intended market. RECOMMENDED CONDITIONS FOR LONG TERM STABILITY ACCELERATED STABILITY STUDIES: In , general the accelerated stability conditions must be at least 15’C above the actual storage temperature and appropriate relative humidity . Substances and drugs products intended to be stored in a refrigerator . the accelerated stability studies should be carried out at 25+/-2’c and 60+/-5% relative humidity. STORAGE CONDITIONS TEMPERATURE (‘C) RELATIVE HUMIDITY% MINIMUM TIME 25’C+/- 2’C 60 +/- 5% 12 MONTHS 30’C +/- 2’C 30+/- 5% 6 MONTHS STORAGE CONDITIONS TEMPERATURE (‘C) RELATIVE HUMIDITY% MINIMUM TIME 40’C +/- 2’C 75 +/-5% 6 MONTHS
  62. 62. Testing Frequency: For Long term testing, during first year sampling should be done every three months, during second year, sampling should be done every six months and after two years, sampling should be done once a year. Accelerated testing should be done atleast six months and it suggests sampling points of 0, 3, 6 months.
  63. 63. Methods Of Accelerated Stability Testing In Dosage forms  Freeze Thaw test  Centrifugal Test  Shaking test  Elevated Temperature test
  64. 64. Accelerated Stability Testing in Emulsions An emulsion is stored at elevated temperature. This decreases viscosity of the continuous phase. If the emulsion withstands this stress it is assumed to be stable at normal conditions of storage. Centrifugation Method: Creaming and flocculation are slow processes. Centrifugation accelerates rate of creaming and flocculation in emulsions. The emulsion is subjected to different centrifugal speeds and separation of phases is observed at different time periods. Bad emulsion separates oil instantly. Good emulsion does not exhibit detectable separation of oil phase until certain time period.
  65. 65. Accelerated tests for Suspensions Cake formation is accelerated by centrifugation. High speed centrifugation is hence not preferred, low speed centrifugation is used to study the physical stability. A Freeze-Thaw cycling technique is one of the stress testing . This cycling treatment promotes particle growth and has primary importance for changes in absolute particle size, particle size distribution and crystal habit.
  66. 66. Accelerated Tests for moisture absorption In this method, products are placed in an environment of high relative humidity and controlled temperature. Their physical and chemical stabilities are assessed. The results will indicate whether the product is susceptible to moisture and also whether the container needs to provide a high degree of protection.
  67. 67. Limitations  Stability predictions based on Arrhenius equation are valid only when the break down depends on temperature.  The energy of activation obtained in the study should be between 10 to 30 kcal/mole.  When degradation is due to Microbial contamination Photochemical reactions  When the product looses its physical integrity at higher temperatures.  When the order changes at elevated temperatures.  In case of disperse systems, when temperature is elevated viscosity is decreased and this may introduce errors in the prediction of stability.
  68. 68.  Describes regarding sampling times ,storage conditions& specific test parameters for each dosage form. The FDA & The expert working group of the ICH of technical requirements for the registration of pharmaceuticals for human use have published guidelines for conducting the actual studies.
  69. 69. ICH Guidelines • Quality Guidelines “Q” (chemical and pharmaceutical QA) • Safety Guidelines “S” (in vitro and in vivo pre-clinical studies) – covering Carcinogenicity Testing, Genotoxicity Testing, Toxicokinetics and Pharmacokinetics ….. etc. • Efficacy Guidelines “E” (clinical studies in human subject) – Covering clinical safety, Dose Response Studies, Good Clinical Practices, Clinical evaluation …. etc. • Multidisciplinary Guidelines “M” – Covering Medical Terminology, Electronic Standards for Transmission of Regulatory Information …… etc. – Important for Stability ! » Guideline M4: The Common Technical Document (CTD)
  70. 70. Stability Testing Q1  Stability Testing in Climatic Zone I and II (Q1A)  Photo stability Testing (Q1B)  Stability Testing for New Dosage Forms (Q1C)  Bracketing and Matrixing Designs (Q1D)  Evaluation of Stability Data (Q1E)  Stability Testing in Climatic Zones III and IV (Q1F) Validation of Analytical Procedures (Q2) Impurities (Q3)  Impurities in New Drug Substances (Q3A)  Impurities in New Drug Products (Q3B) Pharmacopoeial Harmonization (Q4) Biotechnological Products (Q5) Specifications (Q6) ICH – Q – Guidelines
  71. 71. DEFINITIONS Shelf life (expiration dating period, conformance period) Self life is the time period during which a drug product is expected to remain within the approved specification for use, provided that it is stored under the conditions defined on the container label. Re-test period The period of time during which the drug substance is expected to remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored under the defined conditions.
  72. 72. Formal stability studies Long term and accelerated (and intermediate) studies undertaken on primary and/or commitment batches according to a prescribed stability protocol to establish or confirm the re-test period of an API or the shelf life of a FPP. Stress testing – forced degradation (API) Studies undertaken to elucidate the intrinsic stability of the API. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing. Stress testing – forced degradation (FPP) Studies undertaken to assess the effect of severe conditions on the FPP. Such studies include photostability testing (see ICH Q1B) and compatibility testing on APIs with each other in FDCs and API(s) with excipients during formulation development.
  73. 73.  Primary batch (called also exhibit batch) A batch of an API or FPP used in a formal stability study, from which stability data are submitted in a registration application for the purpose of establishing a re-test period or shelf life, respectively. A primary batch of an API should be at least a pilot scale batch. For a FPP, two of the three batches should be at least pilot scale batch, and the third batch a production batch.  Commitment batches Production batches of a drug substance or drug product for which the stability studies are initiated or completed post approval through a commitment made in the registration application.  Pilot (scale) batch A batch of an API or FPP manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch. (For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger.)  Production (scale) batch A batch of an API or FPP manufactured at production scale by using production equipment in a production facility as specified in the application.
  74. 74.  Specification - Release The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug product at the time of its release.  Specification - Shelf life The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of an API throughout its re-test period, or that anFPP should meet throughout its shelf life.  Mass balance The process of adding together the assay value and levels of degradation products to see how closely these add up to 100% of the initial value, with due consideration of the margin of analytical error.
  75. 75. WORLDWIDE ZONES / TEMPERATURE AND HUMIDITY CONDITIONS Zone Mean kinetic temperature Yearly average humidity (%RH) Zone I ( Moderate) 21 ̊C 45 Zone II (Mediterranean) 25 ̊C 60 Zone III (Hot, dry) 30 ̊C 35 Zone IV (Very hot, moist) 30̊ C 70
  76. 76. COUNTRIES AND ZONES Regions Zone I &II Zone III&IV EUROPE All countries AMERICA Argentina, Bolivia, Canada, Mexico, US Brazil, Columbia, Cuba, Jamaica ASIA Afghanistan, China, Iran, Nepal, Turkey, Japan Bahrain , Hong Kong, India, Oman , Pakistan, Srilanka, UAE AFRICA Egypt, Algeria, South Africa, Libya Angola, Benin, Congo, Uganda, Sudan, Somalia, Senegal
  77. 77. Study Storage condition Minimum time period covered by data at submission Long term 25°C ± 2°C / 60% ± 5% r.h or 30°C ± 2°C / 65% ± 5% r.h. 12 months Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months Accelerated 40°C ± 2°C / 75% ± 5% r.h. 6 months STORAGE IN A REFRIGERATOR Study Storage condition Minimum time period covered by data at submission Long term 5°C ± 3°C 12 months Accelerated 25°C ± 2°C / 60% ± 5% r.h. 6 months STORAGE CONDITIONS FOR STABILITY STUDY API/DRUG SUBSTANCES TO BE STOTRED AT AMBIENT TEMPERATURES Study Storage condition Minimum time period covered by data at submission Long term -20°C ± 5°C 12 months STORAGE IN FREEZER
  78. 78. DRUG PRODUCTS - PACKAGED IN SEMI-PERMEABLE CONTAINERS Study Storage condition Minimum time period covered by data at submission Long term 25°C ± 2°C / 40% ± 5% r.h. or 30°C ± 2°C / 35% ± 5% r.h. 12 months Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months Accelerated 30°C ± 2°C / 65% ± 5% r.h. 6 months
  79. 79. The Stability Chambers are designed for an operating range of 4°C to 70°C Temperature only, 5°C to 60°C Temperature with Humidity. These units employ a programmable controller to control the temperature, defrost and humidity settings. The cabinets use an evaporator coil, located on top of the cabinet as the heat-removing source. Through the refrigeration process, heat is captured in the evaporator, transferred to the condensing unit on top of the cabinet, and expelled to the surrounding outside air. It is extremely important to allow a four-inch clearance on the top, rear, and sides of the unit for the refrigeration process to function properly.
  80. 80. STABILITY CABINETS:
  81. 81. STABILITY CABINETS:
  82. 82. Packaging And Stability 1.Glass  Glass is resistant to chemical and physical change and is the most commonly used material. Limitations Overcome 1. Its alkaline surface use of Borosilicate glass 2. Ions may precipitate insoluble crystals from the glass the use of buffers 3- Permits the transmission of light which may accelerate decomposition. Amber coloured glass
  83. 83. Packing and Stability 2.PLASTICS The problems with plastic are:  Migration of the drug through the plastic into the environment.  Transfer of environmental moisture, oxygen, and other elements into the pharmaceutical product.  Leaching of container ingredients into the drug.  Adsorption of the active drug or excipients by the plastic.
  84. 84. Packing and Stability 3.Metals  Various alloys and aluminum tubes may be utilized as containers for emulsions, ointments, creams and pastes.  Limitation: They may cause corrosion and precipitation in the drug product.  Overcome: Coating the tubes with polymers may reduce these tendencies.
  85. 85. Packing and Stability Rubber  Rubber also has the problems of extraction of drug ingredients and leaching of container ingredients.  The pretreatment of rubber vial stoppers and closures with water and steam reduces potential leaching.
  86. 86. Physical stability Formulation Likely physical instability problems Effects Capsules Change in: a) Appearance b) Dissolution c) Strength Change in drug release
  87. 87. Types of Stability Studies 1.Long-Term (Real-Time) Stability Testing  Stability evaluation of the physical, chemical, biological and microbiological characteristics of a drug product  duration of the shelf life
  88. 88.  Packaging materials permeable to water vapor result in a falsification of the results for semisolid and liquid dosage forms if varying degrees of weight loss occur that leads to differences in the active ingredient concentration or ion strength.  The use of inert standard packaging materials that are impermeable to water vapor is important precondition for stress tests that are evaluated in terms of reaction kinetics, and on the results on which stability predictions are to be tested.
  89. 89.  Solid dosage forms: 50-mL glass container with twist-off closure polypropylene tube  Semisolid dosage forms: Standard tube, small volumetric flask, Aluminum tube, inert internal lacquering  Liquid dosage forms: 25mL volumetric flask with ground-glass stopper  However, furture investigations for the selection of the final packaging are necessary.
  90. 90.  On the basis of the results of the stress tests for solid dosage forms, the sensitivity to moisture can be determined and suitable packaging materials can be selected.  As a rule, no interactions are to be expected.  If the final packaging material has been selected and samples packed in the final packaging material are available, the investigation of photostability should be performed.  Photostability :The samples with and without container are irradiated with a Xenon lamp for 24 hours.
  91. 91.  Packaging: Aluminum tube internally lacquered, plastic tubes.  Problems: Corrosion , permeation, sorption.  Tests packaging material – dosage form: To test for corrosion ,the filled metal tubes are stored horizontally upright and inverted at 400C, for 3 months and are then investigated.  To test for permeation and sorption the filled plastic tubes are stored for 3 months at 500C, 400C, 300C/70%.  If the final packaging material has been selected, the investigations on the photostability are performed.
  92. 92.  Packaging ampoule, injection vial with rubber stopper, glass bottle or plastic bottle with screw closure.  Problems: leakage.  To test for permeation, and leakage, the finale formulation solution is filled in the container, and for desorption placebo solution is used.  The samples are stored vertically and inverted under 500C, 400C, 300C/70% for up to 12 weeks.  Tested intervals: 0, 1, 2, 3 months.  If the final packaging material has been selected the investigations on the photostability are performed.
  93. 93. TABLET  Stable tablets retain their original size ,shape , weight ,roughness ,colour variation , cracking under normal handling and storage conditions throughout their shelf life. • FRIABILITY TEST : studies revel the physical instability if any in tablet. Maximum weight loss should not be more than 1%. • HARDNESS TEST : shows resistance to crushing. • COLOR STABILITY : by colorimeter , reflectometer with heat , sunlight and intense artificial light.  Uniformity of weight , odor , texture , drug and moisture content , humidity effects are also Studied during a tablet test.
  94. 94. GELATINE CAPSULE Gelatin capsules are found to be stable in dry conditions but they rapidly reach equilibrium with the atmospheric conditions under they are stored. This shows gelatin capsules are largely effected by temperature and humidity and susceptibility to microbial degradation .  soft gelatin capsule have Relative Humidity 20 to 30% at 21 to 24’C.  hard gelatin capsule contain 13 to 16% moisture. Humidity - capsule shell softens and becomes sticky. Dried- capsule shell becomes brittle and crack. Hard gelatin capsule are tested for Brittleness , dissolution , water content and level of microbial contamination.
  95. 95. EMULSIONS Tested for phase separation , PH , viscosity , level of microbial contamination , and distribution of dispersed globules. ORAL SOLUTIONS AND SUSPENSIONS Formation of precipitate , clarity for solutions , PH , viscosity , microbial contamination. Additionally for suspensions , redispersibility , rheological properties ,mean size and distribution of particles should be considered . NASAL SPRAYS : solution and suspensions Clarity (for solution) , level of microbial contamination , PH , particulate matter , unit spray medication , content uniformity , droplet and/or particle size distribution , weight loss , pump delivery. Microscopic evaluation ,(for suspension) , foreign particulate matter and extractable/ leachable from components of the container , closure and pump. TOPICAL , OPTHALMIC AND OTIC PREPRATION Included in this broad category are ointments ,creams , lotions ,paste , gel , solutions ,eye drops and cutaneous sprays.
  96. 96. TOPICAL preparations should be evaluated for clarity , homogeneity , PH , resuspendibility for lotions , consistency , viscosity , particle size distribution ,level of microbial contamination / sterility and weight loss FOR OPTHALMIC OR OTIC PREPRATION Should include the following additional attributes : sterility ,particulate matter ,and extractable. SUPPOSITORIES Softening range , dissolution (at 37’C) PARENTERALS Color , clarity (for solutions) , particulate matter , PH, sterility , pyogen / endotoxins . Stability studies for powders for injection solution ,include color monitoring , reconstitution time and water content ,to be performed at regular intervals .

×