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Mode of drug degradation of drugs
1. MODE OF DRUG
DEGRADATION
PREPARED BY :- DHRUV BHAVSAR
MPHARM P’CEUTICS
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2. 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. ANAND PHARMACY COLLEGE,
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3. 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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4. • Drug-Excipient and Drug-Drug
Interactions
Reactions of Bisulfite, an Antioxidant
Reaction of Amines with Reducing
Sugars
Transesterification Reactions
1. PHYSICL DEGRADATION
• CRYSTALIZATION OF AMORPHOUS DRUGS
• TRANSITION IN CRYSTALINE STATE
• FORMATION & GROWTH OF CRYSTAL
• VAPOUR PHASE TRANFER INCLUDING
SUBLIMATION
• MOISTURE ADSORPTION
2. MICROBIAL DEGRADATION
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5. 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
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or facilitate microbial growth.
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6. 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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7. • 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.
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8. 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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9. • 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.
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10. 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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11. • 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.
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12. 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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13. 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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14. 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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15. 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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16. 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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17. 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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18. 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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19. 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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21. 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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22. 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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23. 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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24. • 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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25. 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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27. 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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28. • 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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29. • 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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30. 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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31. 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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32. 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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33. 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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34. • 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. ANAND PHARMACY COLLEGE,
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35. 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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36. • Time course of formation of triazolam from its
hydrolysis product (pH 2.30, 37°C).
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37. • Time course of racemization of oxazepam
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38. 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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39. • 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.
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40. 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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41. 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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42. • Time course of hydrolysis of
hydrocortisone hemisuccinate
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43. 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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44. • Time course of degradation of pilocarpine
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45. 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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46. • 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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47. • Time courses of epimerization and
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48. • Time course of hydrolysis of
chlorothiazide
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49. 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.
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50. • Time course of degradation of ampicillin
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51. 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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52. • The degradation of carbenicillin in the
presence of human serum albumin1 follows
this Model
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53. 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
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54. • 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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55. 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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56. • Cianidanol exhibits polymorphic transitions between seven
different crystalline forms, depending on temperature and
humidity
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57. 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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58. • 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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59. 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. PHARMACY COLLEGE,
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60. 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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61. • 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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62. 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 62
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63. 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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64. 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 Spectroscopy
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65. 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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66. 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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67. • 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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68. 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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69. • 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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70. 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 PHARMACY COLLEGE,Packaging
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the Use of
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71. 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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72. 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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73. 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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74. • 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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75. 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
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76. • 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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77. 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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78. 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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79. • 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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