mode of drug degradation of drugs

MODE OF DRUG DEGRADATION

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PREPARED BY :- DHRUV BHAVSARMPHARM P’CEUTICS

ANAND PHARMACY COLLEGE, ANAND

INTRODUCTION

• Food is spoiled by three varieties of decomposition; physical, chemical and microbiological.

• “more processing- less stable”; “more contact with water – less stable”.

• All this is true for drugs also.• Pure drugs, solids, liquids, or gases are usually more

stable than their formulations. • When they are formulated into medicines

decomposition happens faster because of the presence of excipients, and moisture and because of processing.

2ANAND PHARMACY COLLEGE,

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TYPES OF DRUG DEGRADATION

1. CHEMICAL DEGRADATION○ HYDROLYSIS

ESTER AMIDES BARBITURATES, HYDANOINS & IMIDES SCHIFF BASE AND OTHER REACTION INVOLVING

CARBON NITROGEN BOND CLEAVAGE○ DEHYDRATION○ ISOMERIZATION & RACEMIZATION○ DECARBOXYLATION & ELIMINATION○ OXIDATION○ PHOTODEGRADATION


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• Drug-Excipient and Drug-Drug Interactions Reactions of Bisulfite, an Antioxidant Reaction of Amines with Reducing Sugars Transesterification Reactions

2. PHYSICL DEGRADATION• CRYSTALIZATION OF AMORPHOUS DRUGS• TRANSITION IN CRYSTALINE STATE• FORMATION & GROWTH OF CRYSTAL• VAPOUR PHASE TRANFER INCLUDING

SUBLIMATION• MOISTURE ADSORPTION

3. MICROBIAL DEGRADATION


HYDROLYSIS• Drugs with functional groups such as esters, amides,

lactones or lactams may be susceptible to hydrolytic degradation.

• It is probably the most commonly encountered mode of drug degradation because of the prevalence of such groups in medicinal agents and the ubiquitous nature of water.

• Water can also act as a vehicle for interactions or facilitate microbial growth.


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ESTER HYDROLYSIS• The degradation rate depends on the substituents

R1 and R2, in that electron-withdrawing groups enhance hydrolysis whereas electron-donating groups inhibit hydrolysis

• Another way of viewing this reaction is by considering leaving-group ability.

• Bulky groups on either R1 or R2 decrease the decomposition rate..


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• EXAMPLES• Cocaine has two ester bonds that hydrolyze to produce

benzoylecgonine or ecgonine methyl ester

.

• Lactones, or cyclic esters pilocarpine, dalvastatin and warfarin undergoes hydrolysis due to ring opening.


AMIDES HYDROLYSIS• Amide bonds are commonly found in drug

molecules. Amide bonds are less susceptible to hydrolysis than ester bonds because the carbonyl carbon of the amide bond is less electrophilic (the carbon-to-nitrogen bond has considerable double bond character)

• The leaving group, an amine, is a poorer leaving group


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• EXAMPLES• Acetaminophen, chloramphenicol,lincomycin,

indomethacin and sulfacetamide, all of which are known to produce an amine and an acid through hydrolysis of their amide bonds.

• β-Lactam antibiotics such as penicillins and cephalosporins, which are cyclic amides or lactams, undergo rapid ring opening due to hydrolysis.


BARBITURATES, HYDANTOINS & IMIDES

• Barbiturates, hydantoins, and imides contain functional groups related to amides but tend to be more reactive.

• Barbituric acids such as barbital, phenobarbital and amobarbital, undergo ring-opening hydrolysis.

• Decomposition products formed from these drug substances are susceptible to further decomposition reactions such as decarboxylation.


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• SCHIFF BASE AND OTHER REACTION INVOLVING CARBON NITROGEN BOND CLEAVAGE

• Benzodiazepines such as diazepam,oxazepam, and nitrazepam undergo ring opening due to reversible hydrolysis of the amide and azomethine bonds

• Benzodiazepinoxazoles(oxazole-condensed benzodiazepines) such as oxazolam,flutazolam, haloxazolam, and cloxazolam are not Schiff bases but undergo ring opening due to hydrolysis.


DEHYDRATION○Sugars such as glucose and lactose are known to

undergo dehydration to form 5-(hydroxymethyl)furural.

○Erythromycin is susceptible to acidcatalyzed dehydration.

○ prostaglandins E1 and E2 undergo dehydration followed by isomerization.

○Batanopride undergoes an intramolecular ring-closure reaction in the acidic pH range due to dehydration whereas streptovitacin A exhibits two successive acid-catalyzed dehydration reactions,.


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ISOMERIZATION ○ isomerisation is the process by which one molecule is

transformed into another molecule which has exactly the same atoms, but the atoms are rearranged e.g. A-B-C → B-A-C

○Pilocarpine undergoes epimerization by base catalysis. ○Tetracyclines such as rolitetracycline and ergotamine

exhibit epimerization by acid catalysis. ○Etoposide converts reversibly to picroetoposide, a cis-

lactone, and then hydrolyzes to cis-hydroxy acid in the alkaline pH region.


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RACEMIZATION

• Racemization refers to partial conversion of one enantiomer into another.

• Epinephrine is oxidized and undergoes racemization under strongly acidic conditions.


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DECARBOXYLATION

• Drug substances having a carboxylic acid group are sometimes susceptible to decarboxylation,

• 4-Aminosalicylic acid is a good example.• Foscarnet also undergoes decarboxylation under

strongly acidic conditions,


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ELIMINATION

• In elimination reaction reaction some groups of the substance is eliminated.

• Trimelamol eliminates its hydroxymethyl groups and forms formaldehyde.

• Levothyroxine eliminates iodine.


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OXIDATION• Oxidation mechanisms for drug substances depend

on the chemical structure of the drug and the presence of reactive oxygen species or other oxidants.

• Catechols such as methyldopa and epinephrine are readily oxidized to quinones.


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PHOTODEGRADATION• Photodegradation is the process by which light-

sensitive drugs or excipient molecules are chemically degraded by light, room light or sunlight.

The variation of degradation depends on the wavelength of light, shorter wavelengths because more damage than longer wavelengths.

Before a photodegradation reaction can occur, the energy from light radiation must be absorbed by the molecules.

Photodegradation of the chloroquine and primaquine gives the various product through different pathways.


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Two way in which photodegradation can occur are: the light energy absorbed must be sufficient to achieve the activation energy or the light energy absorbed by molecules is passed on to other molecules which allow degradation to take place.

• Representative photodegradation routes for drug substances include dehydrogenation of nifedipine, dehydrogenation accompanied by transmutation of a nitro group in nimodipine observed.

• Representative photodegradation routes for drug substances include dehydrogenation of nifedipine, dehydrogenation accompanied by transmutation of a nitro group in nimodipine observed.


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DRUG-EXCIPIENT & DRUG-DRUG INTERACTION

• drugs are rarely formulated as just the drug substance itself.

• Often, additives or excipients are present in the formulation.

• Quite often, reactions can occur between the drug and one or more additives. Similarly, two drugs might be formulated in the same product and react with each other.


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REACTION OF BISULPHITE, AN ANTIOXIDANT

• epinephrine, a catecholamine, undergoes displacement of its hydroxy group by bisulfite.

• Dexamethasone 21-phosphate, an α/β-unsaturated ketone, is known to undergo addition by bisulfite.


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REACTION OF AMINES WITH REDUCING SUGARS

• Reducing sugars readily react with primary amines, including those of amino acids, through the Maillard reaction.

• Drug substances with primary or secondary amine groups undergo this addition/rearrangement reaction, also called the .browning. reaction because of the resulting discoloration


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• Examples are the reaction of amphetamine,isoniazid dextroamphetamine sulfate and norphenylephrine with sugars such as lactose and the degradation products of sugars, such as 5-(hydroxymethyl)furfural.

• Sulpyrine forms ann addition product with glucose


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TRANSESTERIFICATION REACTION

• In the presence of drug substances with hydroxy groups, aspirin undergoes a reversible transacylation reaction to form salicylic acid, while acetylating the drug substance. For example, codeine and sulfadiazine are acetylated by aspirin Similar acetylation reactions with aspirin have been reported for acetaminophen and the excipient polyethylene glycol.


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BASIC KINETIC PRINCIPLE

• The simplest concept of chemical and physical reaction is the case of a drug D reacting to form a product P. This process is described by the following scheme

• The extent to which D rearranges to P will depend on the free-energy differences between

• D and P. If P is of much lower free energy than D, then the reaction is better defined by


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• Most drugs degrade by reactions that involve a so-called bimolecular reaction in which drug D collides with a reactant A to produce one or more products. This is illustrated in its simplest form by the following equation:

• the rate of loss of D,-d[D]/dt, is said to be proportional to the activity


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• When the proportionality constant is included, the following equation is obtained:

• where k is the proportionality constant, usually referred to as the rate constant. If k is large,the reaction is fast; if k is small, the reaction is slow. In this case, the reaction rate (-d[D]/d t )is said to be frrst-order in D and first-order in A.


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If A is present in excess of D, that is, [A] >> [D], then even though some of A is consumed during the reaction, effectively only D is lost. Under these circumstances

where kobs is said to be the observed rate constant, a pseudo-first-order constant. In most studies of the stability of pharmaceuticals, especially in aqueous solution, the kinetics can often be simplified to pseudo-fist-order conditions


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Kinetic Models to Describe Drug Degradation

• The generalized rate expression for drug degradation is represented by the rate equation.

• When a drug substance, D, degrades via a certain mechanism in which reactants A, B, . . . participate, the degradation rate generally depends on the concentrations of the various reactants A, B, . . . and D according to , assuming that all the reactants are involved directly or indirectly in the rate-controlling step.


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Simple Pseudo-First-Order Reaction

The differential rate equation for a pseudo-first-order reaction is

The integrated form of this equation is where [D]0 is the initial concentration of the drug. From these equations, the degradation rate is seen to be proportional to drug concentration.

Most drug degradation kinetics in solutions like syrup and elixir conform to apparent or pseudo-first-order kinetics


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PSEDO ZERO ORDER REACTION

• The rate equations for pseudo-zero-order kinetics are

• In this case, the drug degradation rate is independent of drug concentration.

• A specific example of pseudo-zero-order kinetics can be seen with drug degradation in suspensions


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• Time course of degradation of aspirin in suspension (pH 3.0), showing apparent zero-order behavior and a dependency on temperature but no dependency on particle size. Particle size: , 60 mesh; O, 100 mesh.


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PSEUDO FIRST ORDER REVERSIBLE REACTION

• When drug D converts to product P according to reversible pseudo-first-order reactions, the rate is described by following equation

• Hydrolysis of triazolam and racemization of oxazepam conform to this kinetic model,


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• Time course of formation of triazolam from its hydrolysis product (pH 2.30, 37°C).


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• Time course of racemization of oxazepam


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Pseudo second and pseudo first order reversible reaction

• When drug D reacts reversibly with A to form P according to a pseudo-second-orderm reaction, the rate expression for the loss of D is given by

• Interaction of Isoniazid with reducing sugar follow this type of model


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• Time course of reaction of isoniazid with various reducing sugars under second-order reaction conditions (pH 1.8, 37°C). , Galactose; X, lactose; O, glucose; Δ, maltose. 39


Pseudo First and pseudo second order reversible reaction

• Equation represents the rate of reversible conversion of drug D to products P1 and P2. When [P1]0 = [P2]0 = 0 at t = 0, Eq. can be integrated to give Eq.

• The loss of hydrochlorothiazide follows this model


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Pseudo first order consecutive reaction

Equations and represent the case when drug D converts to P1, which is subsequently converted to P2 according to consecutive pseudo-fist-order reactions

A good example of consecutive reactions is the degradation of carmethizole (NSC-602668), an experimental cytotoxic agent

The hydrolysis of hydrocortisone hemisuccinate fit this mathematical model even though their degradation pathways are more complex.


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• Time course of hydrolysis of hydrocortisone hemisuccinate 42


Pseudo-FirstOrder Reversible and Parallel Reactions

When both P1 and P2 are capable of being converted back to D, Eqs. and adequately describe the kinetics.

Degradation of pilocarpine in the neutral pH region appears to conform to this model


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• Time course of degradation of pilocarpine44


Pseudo-First-Order Reversible, Parallel and Consecutive Reactions

• When the P1 is in equilibrium with D After Integration the Equation becomes


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• Isomerization and hydrolysis of chlorphenesin carbamate under strongly alkaline pH condition and epimerization and hydrolysis of carumonam and moxalactam all appear to conform to this model.

• Hydrolysis of chlorothiazide, under alkaline pH conditions, is explained by this model when k3 is set to zero


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• Time courses of epimerization and hydrolysis of cazumonam 47


• Time course of hydrolysis of chlorothiazide 48


Pseudo-First- and Pseudo-Second-Order Parallel Reactions

• When a reaction pathway involves toth pseudo-fist and pseudo-second-order pathways, and the following equation adequately describe the kinetics

• Degradation of Ampicillian follow this Pathway.49


• Time course of degradation of ampicillin50


Equilibriam pseudo first order parallel reaction

• This case obtains when a drug, D, forms a complex (DA) with A, which is defined by the equilibrium constant, K, and both D and DA are capable of undergoing independent pseudo-first-order reactions.

• When the concentration of A is significantly higher than that of D, the kinetics can be described by Eq


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• The degradation of carbenicillin in the presence of human serum albumin1 follows this Model


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Crystallization of Amorphous Drugs

• Attempts are often made to formulate poorly water-soluble drugs in their amorphous state. This is because the solubility of amorphous materials is generally higher than that of the same substances in their crystalline state.

• However, because of the lower free energy of the crystalline state, amorphous substances tend to change to their more thermodynamically stable crystalline state with time.

• Amorphous nifedipine, coprecipitated with polyvinylpyrrolidone, undergoes partial crystallization during storage under high-humidity conditiods. This change resulted in altered dissolution and solubility behavior, 53


• Oxyphenbutazone, which can exist in an amorphous state and three different crystalline states (anhydrous, monohydrate, and hemihydrate), exhibits crystallization and polymorphic transitions during storage depending on humidity, as illustrated in Scheme.


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Transitions in Crystalline States Polymorphs are different crystalline forms of the same drug.

Because these forms have different free energy or chemical potentials, depending on temperature conditions, transitions between polymorphs occur.

Polymorphic transitions during storage may alter critical properties of drugs because the solubility and dissolution rate of drug substances generally vary with changes in their crystalline form. From a storage perspective, temperature and humidity affect polymorphic transitions.

Transitions between anhydrous and hydrated forms have been reported for many drug substances such as raclopride, theophylline, nitrofurantoin, sulfaguanidine, and phenobarbital.


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• Cianidanol exhibits polymorphic transitions between seven different crystalline forms, depending on temperature and humidity


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Formation and Growth of Crystals Molecules in a crystal, and the crystals themselves, should

not be considered static. Crystals can grow or decrease in size provided that there is a

medium across which the molecules can travel. This could be a liquid phase or a gaseous phase into which the molecules can sublime. For example, drug substances and excipients in solid dosage forms, such as tablets and granules, may recrystallize or sublime onto the surface of the dosage form during storage. So-called .whisker. Crystallization was observed in tablets of ethenzamide and caffeine anhydride.

This crystallization was enhanced in porous tablets and at higher temperatures


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• Whisker formation in ethenzamide tablets conformed to apparent zero-order kinetics, and the rate constant followed Arrhenius behavior in the temperature range 20.65°C.

• Particles of a valproate-synthetic aluminum silicate mixture formed whiskers comprised of valproic acid and sodium valproate (1:1) on their surface.

• Carbamazepine tablets containing stearic acid formed column-shaped crystals on the tablet surface during storage at high temperature


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Vapor-Phase Transfers Including Sublimation

• Pharmaceuticals containing components that sublime easily may undergo changes in drug content owing to the sublimation of the drug substances or excipients.

• In the case of nitroglycerin, which is a liquid with a significant vapor pressure, sublingual tablets exhibited significant variations in drug content during storage owing to intertablet migration through the vapor phase, This transfer was inhibited by adding water-soluble, nonvolatile fixing agents such as polyethylene glycol.


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Moisture Adsorption Moisture adsorption during storage can also affect the

physical stability of pharmaceuticals, leading to changes in such properties as appearance and dissolution rate.

Adsorption of moisture is governed by the physical properties of the drug substance and excipients. For example, the adsorption of moisture by aspirin crystals was enhanced by adding hydrophilic excipients.

Zografi and co-workers reported that the moisture adsorption rate, W´, for water-soluble substances can be represented by the following equations, based on a heattransport control model


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• RHi and RH0 are relative humidity and critical relative humidity, respectively, and C and F are the conductive coefficient and the radiative coefficient, respectively.

• The above equation described the adsorption of moisture by a sucrose-potassium bromide mixture.


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Microbial degradation Contamination of a product may sometimes cause a lot of

damage and sometimes may not be anything at all. Thus it is dependent on the type of microbe and its level of toxicity it may produce.

If parenterals or opthalmic formulations are contaminated, it may cause serious harm.

Pyrogens which are the metabolic products of bacterial growth are usually lipo-polysaccharides and they represent a particularly hazardous product released by gram negative bacteria. If administered inadvertently to a patient they may cause chills and fever.


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Prevention of microbial spoilage

• A preservative has to be used thus it must have the require oil/water partition coefficient, it must be non-toxic, odourless, stable and compatible with other formulation components while exerting its effects.


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Methods for Detecting Chemical and Physical Degradation

• Critical for good studies involving the analysis of drugs and their degradants is the establishment and validation of so-called .stability indicating methods.

• These methods are.• Thermal Analysis method

– Differential scanning calorimetry (DSC), – differential thermal analysis (DTA), and– differential thermogravimetry (DTG)

• Diffuse Reflectance Spectroscopy64


Thermal analysis Differential scanning calorimetry (DSC), differential

thermal analysis (DTA), and differential thermogravimetry (DTG) are very useful in formulation screening because calorimetric changes and weight changes caused by chemical and physical degradation of pharmaceuticals can be readily detected.

DSC was employed in the preformulation study of a poorly water-soluble drug substance, α -pentyl-3-(2-quinolinylmethoxy) benzenemethanol (REV5901).

Thermal analysis is often capable of easily detecting drug-excipient interactions.


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For example, accelerated degradation of aspirin caused by physical mixture with silica and aluminum was detected by DSC. Interaction of ibuprofen with magnesium oxide was detected from changes in DSC thermograms

DSC can also be employed to investigate the stability of finished dosage forms, as was done, for example, with aminophylline suppository formulation.

The kinetics of degradation can be studied using isothermal calorimetry, that is, calorimetry performed at constant temperature.


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• Recently, sensitive thermal conductivity microcalorimeters useful for detecting even small amounts of degradation at room temperature have become available.

• For example, the slow solid-state degradation of cephalosporins at a rate of approximately 1% per year was successfully measured by microcalorimetry.


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Diffuse Reflectance Spectroscopy• Diffuse reflectance spectroscopy was employed to

detect the solid-state interactions between various drug substances such as oxytetracycline and various excipients such as magnesium trisilicate.

• The DRS spectrum of an isoniazid-magnesium oxide mixture exhibited a decrease in reflectance r∞ with increasing isoniazid content.

• The remission function, calculated by the Kubelka-Munk equation was proportional to isoniazid content.


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• Thus, the solid-state degradation could be followed quantitatively by DRS. A difficulty with technique, especially when performed at short wavelengths, is spectral interference from the degradation products.

• DRS is especially useful for detecting small changes occurring locally on solid surfaces.


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Stabilization of Drug Substances against Chemical Degradation

• Stabilization by Modification of Molecular Structure of Drug Substances

• Stabilization by Complex Formation• Stabilization by the Formation of Inclusion

Complexes with Cyclodextrins• Stabilization by Incorporation into Liposomes,

Micelles, or Emulsions• Addition of Stabilizers Such as Antioxidants and

Stabilization through the Use of Packaging70


Stabilization by Modification of Molecular Structure of Drug Substances

• Drug degradation rates depend on the chemical structure of the drug. Most often, structure modifications are performed to enhance activity or to have a positive impact on the in vivo properties of the drug.

• An example of analog development to effect stabilization is the masking of reactive hydroxyl groups.

• Degradation of erythromycin via 6,9-hemiketal breakdown under acidic pH conditions is inhibited by substituting a methoxy group for the C-6 hydroxyl.

• For example, the acid stability of clarithromycin is 340 times greater than that of erythromycin.


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Stabilization by Complex Formation• Complex formation between drugs and excipients

often leads to stabilization of drugs. The forces involved in complex formation include van der Waals forces, dipole.dipole interactions, hydrogen bonding,and hydrophobic interactions.

• If drug D forms a complex with ligand L, the complex (assuming a 1 : 1 interaction) can be defined by a complexation constant K.


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The term [D.L] represents the concentration of the complex, D.L, [D]. is the concentration of free or uncomplexed drug, and [L]. is the concentration of free ligand.

Kf represents the rate constant for the degradation of the drug in the absence of complexation, and k, is the rate constant for the degradation of the drug in its complexed form. As can be seen, the drug will be stabilized by the presence of L if kc < k.. The degree of stabilization will also depend on the relative amounts of free and complexed drug, which in turn depends on the concentrations of D and L and the magnitude of K. Conversely,


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• if kc > k., complex formation will result in acceleration of the degradation. Differing ligands (L) in a series can affect the degradation rate in two ways: first, by affecting the degree of complexation, as measured by K, and, second, by affecting kc.

• Ampicillin, cephalexin, and bacampicillin are stabilized by complex formation with aldehydes such as benzaldehyde and furfural, although this stabilization involves reversible formation of covalent species.

• Stabilization of esters such as benzocaine (Fig. 120), procaine, and tetracaine by complex formation with caffeine

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Stabilization by the Formation of Inclusion Complexes with Cyclodextrins

• Cyclodextrins are nonreducing cyclic oligosaccharides, consisting of six (α -(CD), seven (β -CD), or eight (γ -CD) dextrose units.

• Cyclodextrins have a .doughnut. shape, with the interior of the molecule being relatively hydrophobic and the exterior being relatively hydrophilic.

• Because of their unique chemical structure, cyclodextrins are capable of forming so-called .inclusion. complexes with many drug molecules.

• The natural cyclodextrins, α − , β −, and γ -CD, have been chemically modified either to effect stronger complexation or to improve their safety


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• α -CD and β -CD cannot be used parenterally because of their nephrotoxicity.

• For example, Hydrolysis of bencyclane fumarate is inhibited by α −, β −, and γ –CD.


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Stabilization by Incorporation into Liposomes, Micelles, or Emulsions

• Entrapment of drug substances in liposomes and micelles can lead to changes in their stability.

• Aspirin can be partially stabilized by incorporation in L- α -dimyristoylphosphatidylcholine (DMPC)-based liposomes.

• Anesthetics such as procaine are also stabilized by incorporation in liposomes.

• Physostigmine salicylate in a phospholipid emulsion is stabilized through interaction with phospholipids at the oil.water interface and through incorporation into the internal phase of the emulsion.


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Addition of Stabilizers Such as Antioxidants and Stabilization through the Use of Packaging the effect of oxygen can be eliminated by the

addition of antioxidants. Oxidation of lovastatin in aqueous solution is inhibited by antioxidants such as α -tocopherol and butylated hydroxyanisole (BHA).

Pharmaceuticals are often stabilized by the utilization of packaging containing an antioxidant.

For example, the photooxidation of cianidanol in the solid state was inhibited by lowering the concentration of oxygen with the use of an oxygen absorbent.

The use of photoprotective films generally eliminates the effect of light.


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• a film coating containing oxybenzone inhibited coloration and photolytic degradation of sulfisomidine tablets.

• Titanium dioxide in a gelatin capsule shell stabilized indomethacin.

• Incorporation of synthetic iron oxides resulted in the stabilization of uncoated tablets of nifedipine and sorivudine against phododegradation.


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mode of drug degradation of drugs

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