UNIT- V DRUG STABILITY Points to be covered in this topic REACTION KINETICS DETERMINATION OF ORDER DRUG STABILITY STABILIZATION OF MEDICINAL AGENTS AGAINST COMMON REACTIONS LIKE HYDROLYSIS AND OXIDATION ACCELERATED STABILITY TESTING IN EXPIRATION DATING OF PHARMACEUTICAL DOSAGE FORMSReaction kinetics is also known as chemical kinetics. It includes the study of the speed or rate of chemical processes that occur during chemical reactions. Many properties such as the order of a chemical reaction, the rate of reaction or the concentration of the components can be easily calculated | from the study of chemical kinetics. Rate of reaction is the speed at which chemical reaction takes place and it is measured by change in concentration (dc) with respect to time (dt). | It is expressed as Rate of reaction =+ < * Chemical kinetics provide the basis to predict drug stability. * The extent of inactivation of drug due to various environmental | adverse conditions can be understood from the drug stability studies. * Normally, the drug is expected to release from the solid dosage forms and immediately go into molecular solution. | * It involves the study of the transport of the drugs from the site of application to blood, from blood to tissue spaces and other body parts | and finally its removal from the body. | “> DRUG ACTION * The interactions of drugs with biomembranes or receptors are being interpreted using kinetic models. * Such models provide information regarding the quantitative differences in the drug action of different drugs of the same therapeutic category.r ZERO ORDER REACTION * When rate is independent of the reactant concentration, then itis called zero order reaction. * Suppose A>B Rate = k [A]* As this is zero order reaction, x = 0 | Therefore rate = k | da Rate = “ae + Equate both above equations so dA “aenk * Where a = change in concentration with respect to time negative (-) sign indicates decrease in concentration k is specificrate constant for zero order. Derivation * The rate of a zero order reaction is expressed by a =k * Or-dA=kdt * On integrate the equation Concentration [A] t=0 time (t) Plot of Concentration vs time° HALELIFE (12) | It is the time required to reduce initial concentration of the reactant to | become half of its value during the progress of the reaction. * Initial concentration = Ay * Final concentration = Ao, || * By putting these values in eq. K ty2 = Ag- Aoy2 Kty/2 = Aoy2 ty2 = Aoyax * According to this equation, half life is directly proportional to the initial concentration of reactant. “SHELF LIFE * It isthe time required for reactant concentration to decrease to 90% of the initial concentration. At=0.9A0 * By putting these values in eq. t,, = oOo 0.9 k according to pseudo zero order rate. * In suspension drug in solution decompose more of it from the suspended particles goes into the solution so that the concentration in * Many drugs in certain dosage form such as suspension, decompose solution remain constant. | * Once all suspended particles is goes into the solution, the system | converts into first order reaction. * In this situation the rate equation can be written as ATA fa dt* Where + [A] is concentration of undecomposed drug at time t * ktis first order rate constant * When [A] is maintained constant then rate equation changes to - “4, k, x constant = kO * The term constantis the solubility of drug. » EIRST ORDER REACTION * Areaction is to be considered as first order reaction when rate of reaction depends on the first power of concentration of single reactant. * let us consider A> products Rate = k [A]* Rate = “4 * Equate both above eet we get kay = “4 kat=-79 * Integrating the above equation f “dA = kat =- A AO =k j[t]=- 2 [log. Al = kt =[log, A, -log A, | => kt =- optAs we know og x" =nlog x : Ay So, kt = log} : A t =kt =2.303log,, or oF e= 2580p Ae t A t * This equation is integrated rate law equation in exponential form, the equation becomes * For first order equation, when we plot concentration againsttime,a curve is obtained Concentration [A] —oe The curve shows that concentration decrease exponentially with time. If log concentration is plotted against time, the straight line with slop hae F equal to - z30a 8 obtained. 5 5 & & z The equation can be written as 2.303 a log — | a-x | k= Where * ais initial concentration and equals to Ay * Xis decrease in concentration with time * a-xisthe concentration remained at time t and equals to A, * The unit of k for first order reaction is time? i.e. sec}, minutes, — hours? HALF LIFE ° Ar=Aoj2 * As we know rate equation for first order reaction is kt =2.303log * t By putting value of At into above equation , we get kt =2.303log Ao wn A tkt, 2 = 2.303 log2 0.693 tpt This equation shows that in first order reaction the half life is independent of the initial concentration SHELF LIFE + A,=0.9A0 + By putting these values in we get 2.303 A t,, =——— log —_ ~ «kk 509A, t. = 2303), 10 0 BG 0.105 t,. =—— k SECOND ORDER REACTION * Second order reaction is defined as a reaction in which the rate depends on the concentration terms of two reactants each raised to the power one. * The following reaction is considered A+B - products * The rate equation can be written as Gear BY * Where [A] and [B] are the concentration of A and B, respectively, and K, is the specific rate constant for second order. * In other words, the rate of reaction is first order with respect to B. * So the overall order of this reaction is second order.v Derivation * As per the definition, the rate equation for second order in * let a and b be the initial concentrations of A and B, respectively, and x be the concentration of each species reacting in time t, substituting these terms in equation gives Eo iky (@-X) (D-X) arse dt : Now consider a case where a = b (both A and B have the same concentration). Then the above equation changes to equation ax z=” K(a-X)2 weereeeeeeeed Integration equation 3 employing the conditions x = 0 att = 0 and x =x | att =tgives x 1 -1(a-x) |, 1 1 (a-x) (a-0) a-atx_ a(a-x) -1=k,[t], =k,(t-0) k,t x — a(a-x) OrEquation is the integral equation for second order reaction, where a = b. If x/a (a-x) is plotted against time, t(on x axis), a straight line with a positive slope is obtained. Intercept will not be zero This graph permits the estimation of k). Since a is defined as the initial concentration of the reactant which is | normally a constant , a plot of x/(a - x) vs. time also gives a straight line | with a positive slope. | The slope is equal to k,/a. The units for k, are concentration time. When the concentration of reactants is expressed as moles/liter, then k, has units liter/mol. time (min). When a ¢ b the integral equation is _ 2.303 b(a-x) 2" t(a-b) a(b—x) When log [ {b(a - x)}/{a(b - x)}] is plotted against t, a straight line with a positive slope can be obtained. (@-b) The slope is equal to k,— spa 40 0 10 20 30 40 50 60 Time (min)«> HALF LIFE © It is the time required to reduce the concentration of the reactant to half of its initial concentration. * As per the definition (a-x) =a/2;t=t,.;x=a/2 ee x — 1 a/2 “at (a-x) at,,"a/2 Kk, _ 1 Z at, 2 1 K= oe * It isthe time required for the concentration of the reactant toreduce to 90 % ofits initial concentration. * The calculating shelf life, equation can be used , when a = b _ Oat 90% ak, 7» GRAPHIC METHOD * In this method data is collected by conducting experiment and graph is plotted. The plot of data in form of graph is used to determine order of reaction. A straight line between concentration against time indicates zero order reaction while a straight line between log concentration against time shows first order reaction. If relation between 1/concentration against time is linear, then reaction is considered to be second order.SUBSTITUTION METHOD In this method data is collected by conducting experiment. | The data is substituted in the integral equations of zero, first and second order reaction to getk values. The equation which gives a fairly constant value of k indicates order of | reaction. ORDER OF RATE EQUATION REACTION Zero First Second ** HALF LIFE METHODS * By calculating value of k by above methods, t,,. value can be estimated for each time period in kinetic study. ORDER OF te REACTION Zero tin =A, /2k First tip =0. 693/k Second - t,,. =1/ak| In case of zero order reaction, half life is directly proportional to — initial concentration of reactants while in case of first order | reactions, half life is independent on initial concentration of | reactants. | For second order, half life is inversely proportional to initial concentration of reactants. But in general | 1 ty, ao Where n is the order of reaction When two reactions are conducted with different initial concentration , a1 and a2, respectively, then ty2 (1) a 1/ay"* 2 (2) a1/a™ Divide both equations we get tye (1) _1/ay"* On applying log and by simplified the equation, we get _logtyya(1)/tya(2) , 4 log(a,/a, ) By plotting a graph between ‘a’ vs '‘t' for two different initial concentrations. The half life can be calculated from the graph by taking reading of 4 a; anda, By substituting the value of half life and initial concentration (a, and a2) in above equation, we can determine the order of reaction.JG STABILITY Drug stability is the ability of a pharmaceutical product to retain its chemical, physical, microbiological and biopharmaceutical Properties | within the specified limits throughout the shelf life. » PHYSICAL DEGRADATION OF DRUG | % LOSS OF VOLATILE COMPONENTS Volatile components such as alcohol, ether , iodine volatile oils camphor menthol etc. Escape from the formulation. E.G. Nitroglycerine from drugs evaporates. Preventive measures : keeping the product in well closed container | and storing in a cool place. Loss of water from o/w emulsions thus its stability changes. Water evaporates causing the crystalline growth. This will result into increase in potency and decrease in weight. This tendency depends on temperature and humidity of surrounding environment. ABSORPTION OF HO | Hygroscopic drugs absorb the water from external atmosphere | causing the physical degradation. Depends on temperature and humidity of surrounding material. Eg. glycerine suppositories may become opaque CRYSTAL GROWTH In solutions after super saturation crystal growth occurs. Reason may be the fall in temperature and a consequent decrease in solubility of solute. E.g. injection of calcium glucconate. In suspension crystals settle down and caking occurs and suspension becomes unstable.> POLYMORPHIC CHANGES * In polymorphic changes crystal forms are changed. v * With every 10°C rise in temperature, the rate of reaction also rises two * The effect of temperature on rate of reaction is explained by Arrhenius * Svante Arrhenius developed a mathematical relationship between k * Astable crystal form loosens. * This may cause alteration in solubility and possibly crystalline growth in aqueous suspensions. * Colour change are of two types 1. Loss of colour 2. Development of colour + Loss of colour is due to pH change and presence of reducing agent. * Development of colour is due to exposure to light. * High temperature accelerate oxidation, reduction and hydrolysis reaction which lead to drug degradation. or three times. equation. and Ea K= Ae t*/RT Where * Kisspecific rate constant * Avis frequency factor or Arrhenius factor ¢ Eaisactivation energy * Tis kelvin temperature * Risuniversal gas constant“> SOLVENT * The nature of the solvent can also affect the rate of decomposition of drugs. * The relation between reaction rate constant and solubility of reactant and products is given by Log k = log kO + 575 (AS, - AS, - AS*) vy Where K = observed reaction rate constant Ko= rate constant in infinitely dilute solution V = molar volume of solute AS,, AS, and AS* = difference in solubility parameter of solvent and reactant ‘a’ reactant ‘b’ and activated complex respectively. * The effect of ionic strength on rate of decomposition of drug is explained by the following equation: log k = log KO + 1,02 Z, Zg Vt vy Where * ZA and ZBare the charges on reactant A and B respectively. * Isthe ionic strength * Kisrate constant of degradation * Koisrate constantat infinite dilution in which pt = 0 * The dielectric constant is used to measure polarity of the solvent. * Dielectric constant shows significant effect on the rate of reaction. * The effect of the dielectric constant on the rate constant of an ionic reaction, extrapolated to infinite dilution where the ionic strength effect is zero is determined by the following equation NzAzBe' 1 Ink=Inke=o0- eev v Where + ke = isthe rate constant in a medium of infinite dielectric constant * Kis observed rate constant in medium of dielectric constant é * Nis Avogadro’s number * ZA and ZB are the charges on the two ions, e is the unit of electric charge , r* is the distance between ions in the activated complex * eis dielectric constant of the solution. * The rate ofa reaction is also influenced by the presence of a catalyst. * Acatalyst is a substance that either increase or decrease the rate of a reaction but itself remain unchanged chemically. * The catalyst only makes the reaction faster, it does not affect the yield of product. A catalyst that reduces the rate of reaction is called | Negative catalyst. | Specific acid base catalysis * The number of drugs decomposed on the addition of acids or bases. * When the rate law for an accelerated decomposition reaction contains | a term involving the concentration of the hydrogen ion or the concentration of the hydroxyl ion, the reaction is called specific acid | base catalysis. General acid base catalysis * Buffers are used to maintain pH of the solution. * Buffer salts (i.e acetates, phosphates, borates etc shows catalytic effects on drug degradation rate in solution. * The reaction is said to be general acid catalysis if catalytic component is acidic while reaction is said to be general base catalysis if catalytic component is basic.* The principles that generally govern hydrolysis reactions may be listed as follows Drugs with ester an amide groups react with one molecule of water | and undergo hydrolysis. Ester groups break faster than amide groups. Drug are either weak acids or bases. Therefore, these may be available as ionic forms or neutral molecules. Hydrolysis reaction between ionic species proceeds faster than with neutral molecules Hydrolysis reactions are catalyzed by H* and (OH): ions. Hydroxyl ions catalyse hydrolysis by about 100 to 1000 times more actively than hydrogen ions. These principles help in rationalizing the design of formulations from stability point of view. A few drugs which decompose by hydrolytic pathway are given below : Esters Amides Aspirin Chloramphenicol Procaine Ampicillin Atropine _Cephalosporins, barbituric acid 7 OXIDATION * Oxidation involves the removal of electrons from a molecule. * The reaction between the compounds and molecular oxygen is called | auto-oxidation. * The general principles that govern an oxidation reaction may be listed as follows * The presence of atmospheric oxygen (also air) promotes the rate of oxidation.* Since oxidation frequently involves free radicals, chain reactions occur. * The presence of trace metals also accelerate the rate of oxidation. * Organic peroxides promote the chain initiation and propagate the | oxidation reaction. * Drugs are either weak acids or bases. Therefore these may be available as ionic forms or neutral molecules. Oxidation reaction between ionic species proceeds faster than with neutral molecules. * Oxidation reactions are catalyzed by H* and OH’ ions. Hydroxyl ions | catalyze oxidation faster than hydrogen ions. Alkaline solutions are known to react with atmospheric oxygen and form oxides. * Drugs which decompose by oxidation pathways are given below. Arachis oil vitamin A Ethyl Oleate riboflavin Clove oil vitamin B12 Cinnamon oil ascorbic acid Promethazine morphine Epinephrine prednisolone » ACCELERATED STABILITY TESTING * Stability is defined as the time during which the drug product regions the same properties existing at the time of manufacture. + Accelerated stability test is designed to test stability and set self life as formulations under normal as recommended storage condition. * The study is carried out under accelerated condition at temperature moisture and light. * The product which are to be stored 25°C and 45% Rh should be stored | | at 40°C and 60% Rh | * Similarly test is carried out for product to be stored cool and cold temperature.¢ Temperature :- Increase in temperature increase degradation. ¢ Humidity :- High humidity results in hydrolysis | * Light :- Artificial light can be used accelerate the effect of sun light. > SELF LIFE | It is defined as the time required for the concentration of the reactant to reduce 90% of its original/initial concentration. The various steps for self life are as follows Each portion is stored at different temperature such as 40°C , 50 °C, 60°C, 70°C. Samples from each portion are withdrawal at various interval of time. The order of reaction is determine by plotting concentration verses | } time graph. The slope of line give the rate constant ‘k’ for degradation at each | temperature. 70° 60° 50° 40° 30°From Arrhenious equations, the rate constant ‘k’ for degradation at room temperature (25°C) is determined | K = Ae#a/FT The values of k at 25°C is substituted in appropriate rate equation and | estimate for self life of the product is obtained. | 2.303 (£} log) — a c 1/T k= Many pharmaceutical compounds including ascorbic acid, cyanocobalamine, riboflavin, folic acid, hydrocortisone, prednisolone etc. undergo degradation when it exposure to light. Exposure to light. Exposure to light may produce oxidation and reduction, ring arrangement, malification and polymerization. Example- f + Cyanocobalamine Light H Hydroxocobalamine + Ca- Darken Oxidation Biologically inactive product * Photochemical reaction may be accompanied by thermal reaction. * The thermal reaction once induced by light may continue after the light | source has been withdrawn. |“PREVENTION It can be reduced by using amber coloured glass container. By using black plastic it can also be reduced. By storing product in dark place or by packing in cartoons also act as varrier to light. Coating of tablet with polymer film containing ultraviolet absorbes also protect from light. Ordinary containers can be wrapped with black paper also provide protection against light.