1CHEMICAL STABILITY CHEMICAL STABILITY OF DRUGSOF DRUGSTOMMY JULIANTOTOMMY JULIANTO

FACULTY OF PHARMACYFACULTY OF PHARMACYUNIVERSITI TEKNOLOGI MARAUNIVERSITI TEKNOLOGI MARA

CHEMICAL STABILITY OF DRUGSCHEMICAL STABILITY OF DRUGSMany drugs are susceptible to some form of Many drugs are susceptible to some form of

chemical decomposition in their dosage chemical decomposition in their dosage forms.forms.

Solid and liquid dosage formSolid and liquid dosage forml f d tl f d t loss of drugs potency loss of drugs potency

changes in the physical appearance changes in the physical appearance-- discoloration (photochemical discoloration (photochemical

decomposition)decomposition)Classes of drugs susceptible to decompositionClasses of drugs susceptible to decompositionPrecautions to minimize the loss of potencyPrecautions to minimize the loss of potency

Determine a time interval of drugs to be Determine a time interval of drugs to be remain in sufficient potency after remain in sufficient potency after manufactured, especially for unstable drugs.manufactured, especially for unstable drugs.Concentration should be not less than 95 % Concentration should be not less than 95 % after preparedafter preparedafter prepared.after prepared.To predict the shelf life of drugs, we need to To predict the shelf life of drugs, we need to understand the kinetics of drugs understand the kinetics of drugs decomposition process.decomposition process.How reactions can be classified into various How reactions can be classified into various order.order.

Calculate the rate constant in certain Calculate the rate constant in certain environment conditions.environment conditions.Stress conditions: temperature and Stress conditions: temperature and humidity.humidity.Accelerated drugs breakdown (save time).Accelerated drugs breakdown (save time).cce e ated d ugs b ea do (sa e t e)cce e ated d ugs b ea do (sa e t e)Result will determine the conditions of Result will determine the conditions of storage.storage.Stability can be improve by formulation/ Stability can be improve by formulation/ packaging modification.packaging modification.

Chemical decomposition of Chemical decomposition of drugsdrugs

Type of the main decomposition process.Type of the main decomposition process.Conditions of drugs in both liquid and solid Conditions of drugs in both liquid and solid formulations can loss their potency.formulations can loss their potency.T b t h i lT b t h i lTo be aware to some chemical groups To be aware to some chemical groups which when present in drug molecules can which when present in drug molecules can cause stability problem.cause stability problem.How to minimize the chemical breakdown.How to minimize the chemical breakdown.

Type Drug degradation can be occur in Type Drug degradation can be occur in formulations:formulations:

-- HydrolysisHydrolysis-- OxidationOxidation-- IsomerisationIsomerisation-- Photochemical decompositionPhotochemical decomposition-- polymerisation polymerisation

2HydrolysisHydrolysisDrugs are susceptible to this type of Drugs are susceptible to this type of degradation:degradation: Derivate of carboxylic acidDerivate of carboxylic acid Contains functional groupsContains functional groups

Ester, amide, Ester, amide, lactonelactone, , lactamlactam, , imideimide and and carbamatecarbamate..E tE t A til li iliA til li ili idid h ti ih ti i th lth l Ester; e.g. Ester; e.g. AcetilsalisilicAcetilsalisilic acid, acid, physostigminephysostigmine, methyl , methyl dopatedopate, , tetracainetetracaine and procaine.and procaine. a bimolecular reaction involving a bimolecular reaction involving acylacyl--oxygen oxygen cleavage.cleavage.

Amide; e.g. Amide; e.g. chinchocainechinchocaine, , chloramphenicolchloramphenicol, , ergometrinergometrin etc.etc. cleavage the amide linkage cleavage the amide linkage

LactamLactam; ; nitrazepamnitrazepam and and chlordiazopoxidechlordiazopoxide, penicillin, , penicillin, etc.etc.

Examples of chemical Examples of chemical groups susceptible to groups susceptible to hydrolysis. :hydrolysis. :

water plays a dominant role in hydrolysiswater plays a dominant role in hydrolysis as a solvent vector between to reacting as a solvent vector between to reacting solutes in solution.solutes in solution.Hydrophilic reactions involve nucleophilic Hydrophilic reactions involve nucleophilic attack of labile bonds;attack of labile bonds;

l t t id i id b tl t t id i id b te.g.: lactam>ester>amide>imide, by water e.g.: lactam>ester>amide>imide, by water on the drug in solution, and first order.on the drug in solution, and first order.If the attack is by a solvent other than If the attack is by a solvent other than water it is known as water it is known as solvolysissolvolysis..

Hydrolysis catalyzed by hydrogen ions Hydrolysis catalyzed by hydrogen ions (acid) or hydroxyl ions (base).(acid) or hydroxyl ions (base).Acid Acid base catalysis.base catalysis. can be prevent by adjusting pH atcan be prevent by adjusting pH at can be prevent by adjusting pH at can be prevent by adjusting pH at

maximum stability kinetic of drugs.maximum stability kinetic of drugs. alteration of dielectric constant by the alteration of dielectric constant by the

addition of nonaddition of non--aqueous solvent; glicerin, aqueous solvent; glicerin, alcohol, PG etc.alcohol, PG etc.

reduce the solubility of drugs by the reduce the solubility of drugs by the addition of additives such as, addition of additives such as, sorbitolsorbitol, , citrates, dextrose etc.citrates, dextrose etc.

addition of caffeine to aqueous solution addition of caffeine to aqueous solution of of benzocainebenzocaine, procaine and , procaine and amethocaineamethocaineto decrease betato decrease beta--catalysedcatalysed hydrolysis.hydrolysis.

by by solubilisationsolubilisation of a drug by of a drug by surfactants.surfactants.

by modifying chemical structure of drugs by modifying chemical structure of drugs without reduce therapeutic efficiency.without reduce therapeutic efficiency.

3A number of conditions catalyse the A number of conditions catalyse the breakdown:breakdown: The presence of OHThe presence of OH-- The presence of HThe presence of H33OO--The presence of divalent metal ionsThe presence of divalent metal ions I i h d l i (P t l i ) i i k thI i h d l i (P t l i ) i i k th Ionic hydrolysis (Protolysis) is quicker than Ionic hydrolysis (Protolysis) is quicker than

molecularmolecular HeatHeat LightLight Solution polarity and ionic strengthSolution polarity and ionic strength High drug concentrationsHigh drug concentrations

OxidationOxidationOxidation is the next common pathway for Oxidation is the next common pathway for drug breakdown and the process usually drug breakdown and the process usually control by the environment.control by the environment.E.g. light, trace metal, oxygen and oxidizing E.g. light, trace metal, oxygen and oxidizing agent.agent.there are little attention on oxidationthere are little attention on oxidationsimultaneoussimultaneous hydrolitic and oxidative hydrolitic and oxidative degradation also can occurdegradation also can occur

The oxidation process has usually been The oxidation process has usually been eliminated by storage under anaerobic eliminated by storage under anaerobic conditions without an investigation of the conditions without an investigation of the oxidation mechanism.oxidation mechanism.Actually oxidation is one of the major Actually oxidation is one of the major cause of drug instability.cause of drug instability. PhenolicPhenolic compounds; morphine and compounds; morphine and

phenyleprinephenyleprine. . CatecholaminesCatecholamines; dopamine and adrenaline.; dopamine and adrenaline. Steroid, antibiotic, vitamins, oils and fats.Steroid, antibiotic, vitamins, oils and fats.

Oxidation involves the removal of an Oxidation involves the removal of an electropositive atom, radical or electron, or the electropositive atom, radical or electron, or the addition of an electronegative atom or radical.addition of an electronegative atom or radical.AutooxidationAutooxidation; ; unanalysedunanalysed reaction. reaction. Oxidation chain reactions is quite slow under the Oxidation chain reactions is quite slow under the influence of oxygen molecular.influence of oxygen molecular.Chain reaction; initiation, propagation and Chain reaction; initiation, propagation and terminationterminationtermination.termination.Initiation can be via free radicals formed from Initiation can be via free radicals formed from organics compounds by the action of light, heat organics compounds by the action of light, heat or transition metals.or transition metals.Propagation of the reaction involves the Propagation of the reaction involves the combination of molecular oxygen with the free combination of molecular oxygen with the free radical Rradical R-- to form radical ROOto form radical ROO--..

H removes from organic compound to H removes from organic compound to form a hydro peroxide, ROOH.form a hydro peroxide, ROOH.And the process continue by producing And the process continue by producing new free radical.new free radical.The reaction proceeds until the free The reaction proceeds until the free radicals destroyed by inhibitors or by sideradicals destroyed by inhibitors or by sideradicals destroyed by inhibitors or by side radicals destroyed by inhibitors or by side reactions which eventually break the chainreactions which eventually break the chainThe rancid odour that is a characteristic of The rancid odour that is a characteristic of oxidised fats and oils due to aldehydes, oxidised fats and oils due to aldehydes, ketone and shortketone and short--chain fatty acid which chain fatty acid which are the breakdown products of the are the breakdown products of the hydroperoxides.hydroperoxides.

Autooxidation

4Another type of oxidation involves the reversible loss Another type of oxidation involves the reversible loss of electrons without the addition of oxygen.of electrons without the addition of oxygen. morphine; the morphine; the undissociatedundissociated and the and the protonatedprotonatedforms of morphine, M, are both forms of morphine, M, are both oxidisedoxidised by by atmospheric oxygen to give a free radical peroxide atmospheric oxygen to give a free radical peroxide and a and a semiquinonesemiquinone, SQ., SQ.> free radical > free radical quinonequinone, Q., Q.Q undergo coupling with M to give theQ undergo coupling with M to give the dimerdimer ofofQ undergo coupling with M to give the Q undergo coupling with M to give the dimerdimer of of pseudomorphinepseudomorphine, PM, resulted in elimination of a , PM, resulted in elimination of a hydrogen free radical HFR.hydrogen free radical HFR.HFR react with HFR to form hydrogen peroxide HP.HFR react with HFR to form hydrogen peroxide HP.HP can react with morphine to form HP can react with morphine to form morphinrmorphinr NN--oxide, MNO, oroxide, MNO, ormay decompose to produce a free radical oxygen may decompose to produce a free radical oxygen which can also react with morphine base to give the which can also react with morphine base to give the NN--oxide.oxide.

Stabilisation of drugs against Stabilisation of drugs against oxidationoxidation

Various precautions during manufacture and Various precautions during manufacture and storage.storage.Oxygen in the containers should be replace with Oxygen in the containers should be replace with nitrogen or carbon dioxide.nitrogen or carbon dioxide.ggContact of drugs with heavy metals should be Contact of drugs with heavy metals should be avoided.avoided.Storage should be at reduced temperatures.Storage should be at reduced temperatures.Difficult to remove all oxygen from a containers, and Difficult to remove all oxygen from a containers, and even traces of oxygen are sufficient to initiate the even traces of oxygen are sufficient to initiate the oxidation chain.oxidation chain.

By the addition of compound that can act as By the addition of compound that can act as inhibitors which can delay or prevent the inhibitors which can delay or prevent the chain reaction of oxidation process of drugs chain reaction of oxidation process of drugs is the best solution; antioxidants. is the best solution; antioxidants. Tocopherols, ascorbic acid, gallic acid, etcTocopherols, ascorbic acid, gallic acid, etcSodium methabisulphite also can act asSodium methabisulphite also can act asSodium methabisulphite also can act as Sodium methabisulphite also can act as antioxidant.antioxidant.These compound readily oxidised than the These compound readily oxidised than the drugs and so protect it from oxidation.drugs and so protect it from oxidation.Oxidation is catalysed by unprotones Oxidation is catalysed by unprotones amines; aminophylline, avoid to admixture amines; aminophylline, avoid to admixture with easily oxidise drugs.with easily oxidise drugs.

5Isomerisation

Process of conversion of a drug into its Process of conversion of a drug into its optical or geometric isomers.optical or geometric isomers.May regarded as a form of drug degradation.May regarded as a form of drug degradation.Often resulting in a serious loss ofOften resulting in a serious loss ofOften resulting in a serious loss of Often resulting in a serious loss of therapeutic activity.therapeutic activity.Adrenaline in solution form at low pH has Adrenaline in solution form at low pH has been attributed to been attributed to raceminationracemination that lead to that lead to loss of activity. Conversion of the loss of activity. Conversion of the therapeutically active form, from laevotherapeutically active form, from laevo--rotary rotary form into its less active isomer.form into its less active isomer.

In acidic conditions the tetracycline In acidic conditions the tetracycline undergo epimerisation at carbon 4 to form undergo epimerisation at carbon 4 to form an equilibrium mixture of tetracycline and an equilibrium mixture of tetracycline and the epimer, 4 epithe epimer, 4 epi--tetracycline. tetracycline.

EpiEpi--tetracycline have much lower tetracycline have much lower therapeutic activity than natural isomers.therapeutic activity than natural isomers.The degradation rate is pH dependenceThe degradation rate is pH dependenceThe degradation rate is pH dependence The degradation rate is pH dependence (max. epimerisation at pH 3.2) and the (max. epimerisation at pH 3.2) and the reaction is also catalysed by phosphate reaction is also catalysed by phosphate and citrate ions.and citrate ions.

Pilocarpine undergoes simultaneous base Pilocarpine undergoes simultaneous base catalyzed hydrolysis and epimerization in catalyzed hydrolysis and epimerization in aqueous solution.aqueous solution.

Both the hydrolysis and the Both the hydrolysis and the epimerisationepimerisationreactions followed pseudo firstreactions followed pseudo first--order rate order rate equations.equations.Other drug is cephalosporin ester CE.Other drug is cephalosporin ester CE.CE are used as intermediates in CE are used as intermediates in cephalosporin synthesis and as cephalosporin synthesis and as prodrugsprodrugsfor oral administration of for oral administration of parentralparentral admin.admin.CE undergoes reversible baseCE undergoes reversible base--catalysedcatalysedisomerisationisomerisation..

6CisCis--trans isomerisation may be a cause of loss trans isomerisation may be a cause of loss of potency of a drug if the two geometric isomer of potency of a drug if the two geometric isomer have different therapeutic activities.have different therapeutic activities.Isomerisation of a vitamin A to form cis isomers Isomerisation of a vitamin A to form cis isomers at the 2at the 2-- and 6and 6--position leads to decreased position leads to decreased activity compared with the allactivity compared with the all--trans molecule.trans molecule.

Photochemical decomposition Photochemical decomposition (Photolysis)(Photolysis)Light is often catalised oxidation and hydrolysisLight is often catalised oxidation and hydrolysisWhen molecules are exposed to electromagnetic When molecules are exposed to electromagnetic radiation they absorb light (photons) at radiation they absorb light (photons) at characteristic wavelengths which an increase in characteristic wavelengths which an increase in ggenergy, which can:energy, which can:-- cause decompositioncause decomposition-- be retained or transferredbe retained or transferred-- be converted to heatbe converted to heat-- result in light emission at a new wavelengthresult in light emission at a new wavelength(fluorescence, phosphorescence)(fluorescence, phosphorescence)

Many drugs, including the phenothiazine Many drugs, including the phenothiazine tranquallisers, hydrocortisone, tranquallisers, hydrocortisone, prednisolone, riboflavine, ascorbic acid prednisolone, riboflavine, ascorbic acid and folic acid are light sensitive.and folic acid are light sensitive.Phenothiazine chlopromazine (CLP) isPhenothiazine chlopromazine (CLP) isPhenothiazine chlopromazine (CLP), is Phenothiazine chlopromazine (CLP), is rapidly decomposed under the action of rapidly decomposed under the action of UV light, follow by discolorisation of the UV light, follow by discolorisation of the solutions.solutions.

The lost of an electron to yield the The lost of an electron to yield the semiquinone free radical R.semiquinone free radical R.Degradation yield the phenazathonium ion Degradation yield the phenazathonium ion P, react with water to yield P, react with water to yield chlorpromazine sulphoxide (CPO).chlorpromazine sulphoxide (CPO).CPO is itself photolabile and further CPO is itself photolabile and further decomposition occurs.decomposition occurs.Other products are chlorpromazine NOther products are chlorpromazine N--oxide oxide and hydroxychlorpromazine.and hydroxychlorpromazine.

7Chlorpromazine behaves differently under Chlorpromazine behaves differently under UV irradiation in anaerobic conditions.UV irradiation in anaerobic conditions.A polymerisation has been proposed.A polymerisation has been proposed.The polymer isolated after intracutaneous The polymer isolated after intracutaneous injection of some patient that have receive injection of some patient that have receive injection of some patient that have receive injection of some patient that have receive prolonged chlorpromazine medication.prolonged chlorpromazine medication. bluish bluish--purple discoloration, purple discoloration, may be a result of the HCl liberation may be a result of the HCl liberation during photodecomposition. during photodecomposition.

Drugs can be protected from oxidation by Drugs can be protected from oxidation by the use of coloured glass bottle and the use of coloured glass bottle and storage in the dark.storage in the dark.Amber glass exclude light of wavelength Amber glass exclude light of wavelength higher polymer.

Antigenic in animal, they are considered to Antigenic in animal, they are considered to play a part in eliciting pencilloylplay a part in eliciting pencilloyl--specific specific allergic reactions to ampicillin in man.allergic reactions to ampicillin in man.Dimerising tedency of ampicillin increases Dimerising tedency of ampicillin increases with the increase in the basicity of the sidewith the increase in the basicity of the side--chain group.chain group.In term of increasing rates;In term of increasing rates;

cyclacillin

8The hydrates of formaldehydeThe hydrates of formaldehydeUnder certain conditions polymerise in Under certain conditions polymerise in aqueous solution to form aqueous solution to form paraformaldehyde, which appears as a paraformaldehyde, which appears as a white deposit in the solution.white deposit in the solution.The polymerisation may be prevented by The polymerisation may be prevented by adding to the solution 10 adding to the solution 10 15 % of 15 % of methanol. methanol.

Trace metal catalysisTrace metal catalysisthe presence of metal can induce some the presence of metal can induce some reaction on drug, such as oxidation.reaction on drug, such as oxidation.Other Drug degradationsOther Drug degradations TemperatureTemperature Influence of pHInfluence of pH

The degradation of most drugs is catalysed The degradation of most drugs is catalysed by extreme pH.by extreme pH.

SolvolysisSolvolysis Chelating agentsChelating agents HygroscopicityHygroscopicity SolidSolid--state stabilitystate stability ORDER OF REACTIONORDER OF REACTION

KINETIC OF CHEMICAL LYSISKINETIC OF CHEMICAL LYSIS

Before we can predict the shelf life of a Before we can predict the shelf life of a dosage form it is essential to determine the dosage form it is essential to determine the kinetics of the breakdown of the drug under kinetics of the breakdown of the drug under carefully controlled conditions. carefully controlled conditions. yy

Kinetics is the study of the rate at which Kinetics is the study of the rate at which processes occur.processes occur.

The changes may be; The changes may be; ChemicalChemical; decomposition of a drug, ; decomposition of a drug,

radiochemical decay)radiochemical decay) PhysicalPhysical; transfer across a boundary, such ; transfer across a boundary, such

as the intestinal lining or skin)as the intestinal lining or skin)Kinetic studyKinetic study are useful in providingare useful in providingKinetic studyKinetic study are useful in providing are useful in providing information that:information that: gives an insight into the mechanisms of the gives an insight into the mechanisms of the

change involvedchange involved allows a prediction of the degree of change allows a prediction of the degree of change

that will occur after a given time has elapsedthat will occur after a given time has elapsed

PrePre--formulation stability assessmentformulation stability assessmentBy investigation the intrinsic stability of the By investigation the intrinsic stability of the

drug it is possible to advise on formulation drug it is possible to advise on formulation approaches and indicate types of excipient, approaches and indicate types of excipient, specific protective additives and packaging specific protective additives and packaging which are likely to maintain the stability of which are likely to maintain the stability of y yy ydrug and product.drug and product.

The assessment use a stress conditions to The assessment use a stress conditions to predict drug stability.predict drug stability.

SolidSolid; Heat, Moisture uptake and Physical ; Heat, Moisture uptake and Physical stress.stress.

Aqueous solutionAqueous solution; pH, Light and Oxidation.; pH, Light and Oxidation.

Stress condition for stability of assessmentStress condition for stability of assessmentSolidSolid-- Heat (Heat (C); 4, 20, 30, 40, 40/75% RH, 50 and 75.C); 4, 20, 30, 40, 40/75% RH, 50 and 75.-- Moisture uptake; 30, 45, 60, 75 and 90% RH at Moisture uptake; 30, 45, 60, 75 and 90% RH at

room temperature.room temperature.-- Physical stress; ball milling.Physical stress; ball milling.Aqueous solutionAqueous solution-- pH; 1, 3, 5, 7, 9 and 11 at RT and 37 pH; 1, 3, 5, 7, 9 and 11 at RT and 37 C. Reflux in 1 C. Reflux in 1

M HCl and 1 M NaOH.M HCl and 1 M NaOH.-- Light; UV (245 and 366 nm) and visible at RTLight; UV (245 and 366 nm) and visible at RT-- Sparging with oxygen at RT; UV.Sparging with oxygen at RT; UV.