Chemical Kinetics-DR. ASM PDF

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Chemical KineticsChemical KineticsDrug stability: Reaction kinetics: zero, pseudo-zero, first & second order(complex reaction: reversible, parallel and side reactions), units of basic rate constants, determination of reaction order. Physical and chemical factors influencing the chemical degr...

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Chemical Kinetics Drug stability: Reaction kinetics: zero, pseudo-zero, first & second order(complex reaction: reversible, parallel and side reactions), units of basic rate constants, determination of reaction order. Physical and chemical factors influencing the chemical degradation of pharmaceutical product: temperature, solvent, ionic strength, dielectric constant, specific & general acid base catalysis, Simple numerical problems. Stabilization of medicinal agents against common reactions like hydrolysis & oxidation. Photolytic degradation and its prevention. Accelerated stability testing in expiration dating of pharmaceutical dosage forms. Dr. Atishkumar S. Mundada Associate Professor

Introduction: • The branch of Physical chemistry which deals with the rate of reactions is called Chemical Kinetics. • The study of Chemical Kinetics includes : (1) The rate of the reactions and rate laws. (2) The factors as temperature, pressure, concentration and catalyst, that influence the rate of a reaction. (3) The mechanism or the sequence of steps by which a reaction occurs. • A mechanism describes in detail exactly what takes place at each stage of an overall transformation. A complete mechanism must also account for all reactants used, the function of a catalyst, stereochemistry, all products formed and the amount of each. 2

Fundamentals of chemical kinetics: • Reaction rates: Speed of any event is measured by the change that occurs in any interval of time. • The speed of a reaction (reaction rate) is expressed as the change in concentration of a reactant or product over a certain amount of time. • Units are usually Mole/sec (M/s). • Rates are affected by several factors: • The concentrations of the reactants • The temperature at which a reaction occurs • The presence of a catalyst • The surface area of solid/ liquid reactants/ catalysts

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• Rate Law: The empirical differential rate equation (or simply the rate law) is determined experimentally and is defined as the expression for the rate of reaction in terms of concentrations of chemical species as indicated by Equation • Rate = k[reactant 1]m[reactant 2]n .... • where k is the rate constant (or rate coefficient) and the exponents (m) and (n) are determined experimentally and can be a whole number (positive or negative) or, in complex reactions, fractions. • The reaction rate equation (RRE) contains concentration terms for all species that interact up to and including the rate-limiting step. 18 March 2020

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• Order of Reaction: The order of reaction (or order of the rate law) is the sum of the exponents in the rate law, that is, the sum of the partial orders with respect to individual reagents, for example, (m+n) of rate law Equation. • However, Zuman and Patel stressed that: “with more complex reactions the overall kinetic order loses its meaning, since the reaction rates are not simple functions of concentration. • In such cases, systematically planned experiments enabling the verification of the complete RRE are necessary”. 18 March 2020

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• Molecularity: Molecularity is the number of colliding molecular entities that are involved in a single reaction step. • While the order of a reaction is derived experimentally, the molecularity is a theoretical concept and can only be applied to elementary reactions. • In elementary reactions, the reaction order, the molecularity, and the stoichiometric coefficient are numerically the same but represent different concepts. • Thus, a reaction involving one molecular entity is called unimolecular, whereas a bimolecular reaction involves two molecular entities. • A reaction involving three molecular entities is called termolecular or trimolecular; these reactions are rare because of the improbability of three molecular entities colliding simultaneously. 6

• Rate Constant: The rate constant, k, is the proportionality constant that relates the reaction rate to the concentration (or activity or pressure, for example) of the reacting substances, as shown in rate law equation. • Consider a first-order reaction of a reagent (1.0 mol L−1) whose k=0.01 s−1. This means that each second, 0.01 mol L−1 of the reactant, is transformed into products. • The value of k for two reactions of different orders (e.g., first, second) cannot be compared directly because their units are different. For second order reaction it is Ltr Mol s−17

• Rate-Controlling Step: A rate-controlling (ratedetermining or rate-limiting) step is the slowest step of a chemical reaction that determines the rate of the overall reaction. • In a simplified model, it can be compared to the neck of a funnel. The rate at which water flows through a funnel is limited/determined roughly by the width of the neck of the funnel and not by the rate at which the water is poured into the funnel. • For any multistep reaction, the RLS is taken as the “most sensitive” step, or the step, which, if perturbed, causes the largest change in overall rate. 18 March 2020

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• Reaction Half-Life (t1/2): The half-life (or half-time, t1/2) of a reaction is the time required for the concentration of a given reactant to reach a value that is the arithmetic mean of its initial and final, or equilibrium, values. • For a reactant that is entirely consumed, it is the time required for the reactant concentration to fall to one-half of its initial value. • This term is used to convey a qualitative idea of the timescale for the reaction. • It has a quantitative relationship to the rate constant in simple cases. For example, an irreversible first-order reaction is practically complete after five t1/2, corresponding to 96.9% reactant transformation. 18 March 2020

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• The half-life of a reaction has an exact quantitative meaning only in the following cases: • (i) for a first-order reaction, where the half-life of the reactant may be called the half-life of the reaction; • (ii) for a reaction involving more than one reactant, with their concentrations in their stoichiometric ratios. In this case, the half-life of each reactant is the same and may be called the half-life of the reaction. • If the concentrations of reactants are not in their stoichiometric ratios, the half-lives for the different reactants are not the same and use of the term half-life of the reaction is not warranted. 18 March 2020

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Types of Reactions: • Chemical reactions may be classed into two types : (a) Elementary reactions (b) Complex reactions • An elementary reaction is a simple reaction which occurs in a single step. • A complex reaction is that which occurs in two or more steps. • Namely reversible, consecutive, and parallel reactions. • The simplest case of consecutive reactions is: A→B→C • Compounds that undergo reaction via two or more pathways simultaneously are referred to as parallel or competitive. 18 March 2020

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Zero order reaction: • A reactant whose concentration does not affect the reaction rate is not included in the rate law. In effect, the concentration of such a reactant has the power 0. • Thus [A]0 = 1. • A zero order reaction is one whose rate is independent of concentration. For example, the rate law for the reaction • NO2 + CO ⎯⎯→ NO + CO2 at 200°C is rate = k [NO2]2 • Here the rate does not depend on [CO], so this is not included in the rate law and the power of [CO] is understood to be zero. • The reaction is zeroth order with respect to CO. The reaction is second order with respect to [NO2]. The overall reaction order is 2 + 0 = 2. 18 March 2020

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Pseudo– Pseudo–order reactions: • A reaction in which one of the reactants is present in a large excess shows an order different from the actual order. The experimental order which is not the actual one is referred to as the pseudo order. • Let us consider a reaction A + B ⎯⎯→ products • in which the reactant B is present in a large excess. Since it is an elementary reaction, its rate law can be written as rate = k [A] [B] • As B is present in large excess, its concentration remains practically constant in the course of reaction. Thus the rate law can be written as rate = k′ [A] • where the new rate constant k′ = k [B]. • Thus the actual order of the reaction is second-order but in practice it will be first-order. Therefore, the reaction is said to have a pseudo-first order. 13

First order reactions: • Let us consider a first order reaction A→ products • Suppose that at the beginning of the reaction (t = 0), the concentration of A is a moles litre–1. If after time t, x moles of A have changed, the conc. of A is (a – x). • We know that for a first order reaction, the rate of reaction, dx/dt, is directly proportional to the concentration of the reactant. • The value of k can be found by substituting the values of a and (a – x) determined experimentally at time interval t during the course of the reaction. • Examples of First order Reactions: (1) Decomposition of N2O5 in CCl4 solution (2) Decomposition of H2O2 in aqueous solution. (3) Hydrolysis of an Ester 14

Second order reactions: • Let us take a second order reaction of the type 2A → products • Suppose the initial concentration of A is a moles litre–1. If after time t, x moles of A have reacted, the concentration of A is (a – x). • We know that for such a second order reaction, rate of reaction is proportional to the square of the concentration of the reactant. • Examples of Second order Reaction • Hydrolysis of an Ester by NaOH. 18 March 2020

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How to determine the order of a reaction: • There are at least four different methods to determine the order of a reaction. • (1) Using integrated rate equations: The rate equation which yields a constant value of k corresponds to the correct order of the reaction. • This method of ascertaining the order of a reaction is essentially a method of hit-and-trial but was the first to be employed. It is still used extensively to find the order of simple reactions. • (2) Graphical method: we can determine the reaction order by seeing whether a graph of the data fits one of the integrated rate equations. 18 March 2020

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• (3) Using half-life period: Two separate experiments are performed by taking different initial concentrations of a reactant. • The progress of the reaction in each case is recorded by analysis. When the initial concentration is reduced to onehalf, the time is noted. Let the initial concentrations in the two experiments be [A1] and [A2], while times for completion of half change are t1 and t2 respectively. • Calculation of order of reaction. We know that half-life period for a first order reaction is independent of the initial concentration, [A]. • We also know : half-life ∝ 1/[A] for 2nd order reaction • half-life ∝ 1/ [A]2 for 3rd order reaction 18 March 2020

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• (4) The Differential method: This method was suggested by van’t Hoff and, therefore, it is also called van’t Hoff’s differential method. • According to it, the rate of a reaction of the nth order is proportional to the nth power of concentration. • (5) Ostwald’s Isolation method: • This method is employed in determining the order of complicated reactions by ‘isolating’ one of the reactants so far as its influence on the rate of reaction is concerned. • Suppose the reaction under consideration is : A + B + C ⎯⎯ → products • The order of the reaction with respect to A, B and C is determined. The order of the reaction is then determined by using any of the methods described earlier. 18

Degradation of pharmaceutical product: • The USP defines the stability of a pharmaceutical product as “extent to which a product retains, with in specified limits, and through out its period of storage and use i.e. its shelf life, the same properties and characteristics that it possessed at the time of its manufacture”. Why stability testing is necessary• Chemical degradation may lead lowering of concentration of drug in dosage form • Toxic product may form due to degradation of active ingredients. Stability is used to determine: • Quality of a drug substance or drug product • Shelf life for the drug product • Recommended storage conditions 18 March 2020

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Degradation Pathways: • Pharmaceutical products tends to deteriorate on storage, even though it is expected to retain acceptable chemical, physical and microbiological stability. • To get desired effect from any pharmaceutical product has to be stable throughout its shelf life. • Drug substances used as pharmaceuticals have diverse molecular structures, therefore, they are susceptible to different kinds of degradation pathways. • Degradation of drugs occur through three principal pathways namely • Chemical Degradation • Physical Degradation • Microbial Degradation. 18 March 2020

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Chemical degradation: • Hydrolysis/Solvolysis: Drugs with the following functional groups:esters, amides, lactones or lactams, Imides, may be susceptible to hydrolysis. • Oxidation: Some functional groups subject to oxidation are phenols, aldehydes, alcohols and unsaturated fats and oils. • In order to reduce degradation by oxidation, nitrogen and carbon dioxide are often used to replace the airspace in pharmaceutical dosage forms. • Polymerization: This is the process by which two or more identical molecules combine together to form a much larger and more complex molecule. The reactants are called monomers and the products are called polymers. • Eg. Aminopenicillin, such as ampicillin sodium in aqueous 21 solution.

• Isomerisation: is the process of conversion of a drug into its optical or geometric isomers. • The isomers are often of different therapeutic activity. • There are two types of isomerization- Optical & Geometric • Optical isomerism divided into Racemization & epimerization. • Racemization is a reversible conversion between optical isomers also known as enantiomers. Eg. Thalidomide. • Epimerization is a irreversible conversion. Eg. Tetracyclines to epitetracycline. • Geometric isomerism: Forms CIS and Trans isomers of the compounds. E.g.vitamin A forms the cis–trans isomers. 18 March 2020

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• Dehydration: Is the elimination of a water molecule from the molecular structures. Found in the degradation of prostaglandin E2 and tetracycline. • Decarboxylation: Occurs sometimes in drugs with carboxylic acid groups. It is not a common. • Decarboxylations occur in the following antibiotics: carbenicillin sodium, carbenicillin free acid, ticarcillin sodium, and ticarcillin free acid. • Chemical Incompatibilities: May occur in APIs as well as between API & Excipients. 18 March 2020

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Physical Degradation: • Polymorphism: Polymorphs are different crystal forms of the same compound caused by exposure to changes in temperature, pressure, relative humidity, drying, granulation, milling and compression. • Polymorphs differ in their crystal energy, insolubility, dissolution rate and melting point. The metastable seeks to revert to the most stable form. • Steroids, sulphamides and barbiturates are notorious for their propensity to form polymorphs. • Adsorption: Drug-plastic interaction has been a major challenge when drugs are stored in plastic materials. • This compromises the preservative content and predisposes the drug to microbial degradation. 18 March 2020

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• Temperature: Increase in temperature degrades thermolabiles, it enhances degradation chemically and physically. • Evaporation of water from liquid preparation will cause the drug concentration to change with the possibility of crystallization, if the solubility of the drug in the solvent is exceeded. • Water loss from emulsion will cause it to crack or suspension to cake. • Volatile components such as alcohol, ether, ketones, aldehydes, iodine, volatile oils, camphor and cosolvent of lower molecular weight etc., escape from formulation through vaporization, even at room temperature, leading to drug loss. SNJB's SSDJ College of Pharmacy, Chandwad (Nasik) 25

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• Photodegradation: Degradation of light sensitive drugs or excipients by room or sunlight. • Photodegradation occurs when molecules absorb light wavelength, especially 300–400 nm. UV light causes more damage than red or orange light and shorter wavelengths cause more damage than longer ones. • Photodecomposition involves oxidation mechanism, although others like polymerization or ring opening may occur. Once initiated can progress in the absence of light in a chain reaction. • It occurs during manufacture, storage and during the use of the product. • In susceptible compounds, photodecomposition creates free radical intermediates, which can perpetuate chain reactions. 26

• To avoid photochemical reactions, photolabile formulations are packaged in coloured containers. • Yellowish green glass is best protector against UV radiation; amber colour gives only a little protection from infrared radiation. • The addition of an antioxidant like sodium thiosulfate or sodium metabisulfite hinders the photodegradation of sulfacetamide. • Nifedipine, nicardipine, nitroprusside, chlorthalidone, acetazolamide, retinol, riboflavin, furosemide and phenothiazines are very labile to photo-oxidation. • Photochemical reactions are common in steroids. 18 March 2020

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• pH: Acidic and alkaline pH influence the rate of decomposition of most drugs. • Many drugs are stable between pH 4 and 8. • Weekly acidic and basic drugs show good solubility when they are ionized and they also decompose faster when they are ionized. • So if the pH of a drug solution has to be adjusted to improve solubility and the resultant pH leads to instability then a way out of this tricky problem is to introduce a water-miscible solvent into the product. • It will increase stability by: • suppressing ionization • reducing the extreme pH required to achieve solubility enhancing solubility and • reducing the water activity by reducing the polarity of the solvent. 20% PG is placed in chlordiazepoxide injection.

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• Reactions catalyzed by pH are monitored by measuring degradation rates against pH, keeping temperature, ionic strength and solvent concentration constant. • Some buffers such as acetate, citrate, lactate, phosphate and ascorbate buffers are utilized to prevent drastic change in pH. • Sometimes pH can have a very serious effect on decomposition. As little as 1 pH unit change in pH can cause a change of ten fold in rate constant. • So when we are formulating a drug into a solution we should carefully prepare a pH – decomposition profile and then formulate the solution at a pH which is acceptable physiologically and stability-wise also. 18 March 2020

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• Moisture: • a. Water catalyses chemical reactions as oxidation, hydrolysis and reduction reaction • b. Water promotes microbial growth. • Concentration: rate of drug degradation is constant for the solutions of the same drug with dif...