Transcript Drug stability - Physical Pharmacy Laboratory

SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
“Drug Stability”
Introduction

The chemical breakdown of drugs
Body



Kinetics of chemical decomposition in solution
Factors influencing drug stability
Stability testing and calculation of shelf-life
Conclusion

Review & Summarize
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
“Drug Stability”
Introduction

The chemical breakdown of drugs
Body



Kinetics of chemical decomposition in solution
Factors influencing drug stability
Stability testing and calculation of shelf-life
Conclusion

Review & Summarize
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

The chemical breakdown of drugs are categorized
 Hydrolysis
 Oxidation
 Isomerization
 Photochemical decomposition
 Polymerization
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

What is hydrolysis?!
 Hydrolysis is a chemical reaction during which molecules of
water (H2O) are split into hydrogen cations (H+) and
hydroxide anions (OH−) in the process of a chemical
mechanism *
 It is the type of reaction that is used to break down certain
polymers, especially those made by step-growth
polymerization
* Compendium of Chemical Terminology, 2nd ed. (1997).
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Drugs that contain these functional groups are
susceptible to hydrolysis
 Imide
 Lactam
 Lactone
 Ester
 Amide
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Hydrolysis can be catalyzed by H+ ions or OH- ions
 Examples of hydrolysis
*
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Controlling drug hydrolysis in solution
 Optimization of formulation
▪ Determine the pH of maximum stability from kinetic experiments at
a range of pH values
▪ Alteration of the dielectric constants by the addition of nonaqeous
solvents
▪ Ex) Alcohol, glycerin or propylene glycol
▪ Suppress degradation by reducing solubility using additives
▪ Ex) Citrates, dextrose, sorbitol , gluconate
▪ Adding a compound that forms a complex with the drug can
increase stability
▪ Ex) Addition of caffeine into solution of benzocaine, procaine and
tetracaine
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Controlling drug hydrolysis in solution
 Modification of chemical structure of drug
▪ The control of drug stability by modifying chemical structure using
appropriate substituent
▪ Hammett linear free energy relationship
log k  log k0  
k : The rate constants for the reaction of the substituted compounds
k0 : The rate constants for the reaction of the unsubstituted compounds
σ : Hammett substituted constant
ρ : Reaction constant
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

What is oxidation?!
 Oxidation is the loss of electrons or an increase in oxidation
state by a molecule, atom, or ion.

Oxidation process
 Initiation
▪ X• + RH → R• + XH
 Propagation
▪ R• + O2 → ROO•
▪ ROO• + RH → ROOH +R•
 Termination
▪ ROO • + ROO • → stable product
▪ ROO • + R • → stable product
▪ R • + R • → stable product
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Drugs susceptible to oxidation
 Steroids and sterols
 Polyunsaturated fatty acids
 Simvastatin
 Polyene Antibiotics
▪ Amphotericin B
 Phenothiazines
*
 Econazole nitrate and miconazole nitrate
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Stabilization against oxidation
 Replace Oxygen in pharmaceutical containers with
nitrogen or carbon dioxide
 Avoid contact with heavy-metal ions which catalyze
oxidation
 Storage at reduced temperatures
 Use of Antioxidant
▪ Interrupt the propagation by interaction with the free radical
▪ More oxidized than the drug
▪ Protect drug from oxidation
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Stabilization against oxidation
 Antioxidant examples
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

What is isomerization?
 Isomerization is the process by which one molecule is
transformed into another molecule which has exactly the
same atoms, but the atoms are rearranged *
 In pharmaceutical aspect, isomerization is the process of
conversion of a drug into its optical or geometric isomers,
which are often of lower therapeutic activity

Examples




Racemization
Epimerization
Base catalyzed isomerization
cis-trans isomerization
* Compendium of Chemical Terminology, 2nd ed. (1997)
Fast track Physical Pharmacy (2008), Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Racemization
 Loss of activity of solutions of adrenaline at low pH

Epimerization
 In acidic conditions, carbon atom 4 undergo epimerization
to 4-epi-tetracycline, which is toxic and its content in
medicines restricted to not more than 3%.
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Base catalyzed isomerization
Biologically
inactive
*

Cis-trans isomerization
Decreased activity
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

What is photochemical decomposition?!
 Photochemical decomposition is a chemical reaction in
which a chemical compound is broken down by photons
produced by light.
 There are possibilities of loss of potency of drug, changes
in the appearance of the product
▪ Ex) coloration, precipitation etc
 Phenothiazine tranquilizers, hydrocortisone, prednisolone,
riboflavin, ascorbic acid, and folic acid degrade when
exposed to light.
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Photoreactivity groups
 Carbonyl, nitro aromatic and N-oxide functions, aryl
halides, alkenes, polyenes and sulfides

Examples
*
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Photochemical decomposition may occur not only
during storage, but also during use of the product

Stabilization against photochemical decomposition
 The use of coloured glass containers and storage in the
dark
▪ Amber glass excludes light of wavelength <470 nm and so affords
considerable protection of compounds sensitive to ultraviolet light
 Coating tablets with a polymer film containing ultraviolet
absorbers
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

What is polymerization?!
 Polymerization is the prcoess by which two or more
identical drug molecules combine together to form a
complex molecule

Examples
 The hydrate of formaldehyde
▪ polymerize in aqueous solutions to form paraformaldehyde which
appears white deposit in the solution
▪ Polymerization may be prevented by adding to the solution 10-15%
of methanol
*Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Examples
 Dimers of aminopenicillins form higher polymers which is
highly antigenic to animals
 Increase possibilities of polymerization with the increase in
the basicity of the side-chain group
▪ Cyclascillin<<Ampicillin<Epicillin<Amoxycillin
*
*Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
“Drug Stability”
Introduction

The chemical breakdown of drugs
Body



Kinetics of chemical decomposition in solution
Factors influencing drug stability
Stability testing and calculation of shelf-life
Conclusion

Review & Summarize
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Rate
 The rate of a chemical reaction is proportional to the
product of the molar concentration of the reactants each
raised to a power usually equal to the number of
molecules, a and b, of the substances A and B, respectively,
undergoing reaction
Products
Rate
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Molecularity
 Molecularity is the number of molecules, atoms, or ions
reacting in an elementary process
 Examples
▪ Unimolecular process
▪ Bimolecular process

Specific rate constant
 The constant, k, appearing in the rate law associated with a
single-step reaction
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Zero-order reactions
 The decomposition proceeds at a constant rate and is
independent of the concentrations of any of the reactants

dA
 k [A]
dt
0
0
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Half –life ( t½ or t0.5 ) and Shelf-life(t0.9 )
 The Half-life is the time taken for half of the reactant to
decompose
 The shelf-life is the time required for 10% of the material
to disappear (which is the time require for remaining
material is 90%)
 For example, in zero-order reaction, the half-life and shelf
life can be derived
0.5 A0= A0-kt0.5
0.9 A0= A0-kt0.9
0.5 A0
t0.5 =
k
0.1 A0
t0.9 =
k
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Apparent zero-order reactions
 “Apparent”or “pseudo” –order describes a situation where
one of the reactants is present in large excess or does not
effect the overall reaction and can be held constant
 Examples (suspensions)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

First-order reactions
 A first-order reaction depends on the concentration of only
one reactant (a unimolecular reaction)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

First-order reactions
 Examples
Conversion to log scale
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Second-order reactions
 A second-order reaction depends on the concentrations of
one second-order reactant, or two first-order reactants
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Third-order reactions
 Third-order reactions are only rarely encountered in drug
stability studies involving, as they do, the simultaneous
collision of three reactant molecules.
 Example
▪ Rate of ampicillin breakdown by simultaneous hydrolysis and
polymerization
ka : pH-dependent apparent rate constant for hydrolysis
kb : uncatalyzed polymerization rate constant
kc :general acid–base-catalyzed polymerization rate constant
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Determining the order of a reaction
 To determine the amount of drug decomposed after
various intervals and to substitute the data into the
integrated equations for zero-, first- and second-order
 An alternative method of determining the order of
reaction to avoid misleading results of if a fractional order
of reaction applies
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Determining the order of a reaction
 Examples
Changing the data log scale
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Reversible reaction
 A reversible reaction is a chemical reaction that results in
an equilibrium mixture of reactants and products
*
* MARTIN’s Physical Pharmacy and Pharmaceutical Sciences 6th edition
Patrck J. Sinko
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Parallel reactions
 The decomposition of many drugs involves two or more
pathways, the preferred route of reaction being dependent
on reaction condition
 In other cases decomposition may occur simultaneously by
two different processes
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Parallel reactions
 Examples
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Consecutive reaction
 The simple consecutive reaction is that described by a
sequence where each step is a nonreversible first-order
reaction
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Consecutive reaction
 Examples
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
“Drug Stability”
Introduction

The chemical breakdown of drugs
Body



Kinetics of chemical decomposition in solution
Factors influencing drug stability
Stability testing and calculation of shelf-life
Conclusion

Review & Summarize
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Factors influencing drug stability
Liquid dosage form
Solid dosage form
• pH
• Moisture
• Temperature
• Excipients
• Solvent effect
• Temperature
• Oxygen
• Light and Oxygen
• Light
• Surfactant
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

pH
 pH is the most important parameter which affects the
hydrolysis rate of drugs in liquid formulations
 The Influence of pH on degradation rate
▪ Different pH-rate profile obtained using different buffer
▪ Specific acid-base catalysis
catalytic effect of hydrogen and hydroxyl ions
▪ General acid-base catalysis
accelerating effect of the component of
the buffer system
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

pH
 Examples
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

pH
kobs : experimentally determined hydrolytic rate constant
k0 : uncatalyzed or solvent-catalyzed rate constant
kH+ ,kOH- : specific acid and base catalysis rate constants
kHX , kX- : general acid and base catalysis rate constants respectively [HX]
and [X-]
[HX] , [X ] : concentrations of protonated and unprotonated forms of the
buffer.
0
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

pH
 Examples
▪ Stable over a wide pH range
except low and high pH range
▪ Removing the effect of buffer
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

pH
 Examples
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Temperature
 Increase in temperature usually causes a very pronounced
increase in the hydrolysis rate of drugs in solution
 Arrehnius equation
▪ The effect of temperature on decomposition
▪
▪
▪
▪
Ea is the activationb energy
A is the frquency factor
R is the gas constant
T is the temperature in kelvins
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Temperature
 Examples
*
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Ion strength
 The ionic strength of a solution is a measure of the concent
ration of ions in that solution
 Bronsted-Bjerrum equation
▪ The equation describes the influence of electrolyte on the rate
constant
ZA ,ZB : charge numbers of the two interacting ions
A : constant for a given solvent and temperature
µ : ionic strength
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Ion strength
 Examples
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Solvent effects
 Solvent effects is the group of effects that a solvent has on
chemical reactivity
▪ The equation describes the effect of the dielectric constant, ε, on
the rate of hydrolysis
K : constant for a particular reaction at a given temperature
zA , zB : charge numbers of the two interacting ions
kε=0 : rate constant in a theoretical solvent of infinite dielectric
constant
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Solvent effects
 Examples
*
* Fast track - Physical Pharmacy
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Oxygen
 Molecular oxygen is involved in many oxidation shemes
 Particular drug is likely to be affected by oxidative
breakdown
 Stabilization
▪ Replacing the oxygen in the storage containers with nitrogen or
carbon oxide
▪ Avoiding contact with heavy metal ions
▪ Adding antioxidants
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Light
 Exposure to ultraviolet light is the most usual cause of
photodegradation
 Photolabile drugs are usually stored in containers which
exclude ultraviolet light
 Stabilization
▪ Amber glass is particularly effective
▪ It excludes light of wavelength of less than about 470 nm
▪ Storing photolabile drugs in the dark
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Surfactants
 The presence of surfactants in micellar form has a
modifying effect on the hydrolysis of drugs
k obs , km, kf : observed, micellar and aqueous rate constants
fm, fw : fractions of drug associated with micelles and aqueous phase
 Ionic nature of surfactant have important influence of
decomposition rate
▪ Anionic micelle have stabilization effect to base-catalyzed hydrolysis
 Self-association on stability
▪ Ex) benzylpenicillin- stable 2.5 times micellar >>monomer
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Moisture
 Water-soluble drugs present in a
solid dosage form
▪ Dissolve in any moisutre which has
adsorbed on the solid surface
▪ Influenced by many of the factors as
for liquid dosage forms
 Minimize access of moisture
during manufacture and storage
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Excipients
 Excipients with particularly high water contents
▪ Affect stability by increasing the water content of the formulation
 Chemical interactions between the excipients
▪ Lead to a decrease of stability
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Excipients
 Examples
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Temperature
 The effect of temperature change on the stability of solid
dosage forms can be complicated for many possible
reasons
▪ The drug or one of excipients may melt or change its polymorphic
form as temperature is increased
▪ The drug or one of excipients may contain loosely bound water
which is lost at high temperatures
 Arrhenius equation
▪ Predict stability
▪ Calculate Ea
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Temperature
 Examples
*
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Light and Oxygen
 Same way as liquid dosage form
▪ Replacing the oxygen
▪ Adding antioxidants
▪ Amber glass
 Storing under dry condition
▪ Water contains dissolved oxygen and so the presence of moisture
on the surface of solid preparations may increase the oxidation of
susceptible drugs
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
“Drug Stability”
Introduction

The chemical breakdown of drugs
Body



Kinetics of chemical decomposition in solution
Factors influencing drug stability
Stability testing and calculation of shelf-life
Conclusion

Review & Summarize
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

What is stability testing? *
 Testing program designed to assess the stability characteristics
of drug products.
 The results of such stability testing shall be used in determining
appropriate storage conditions and expiration dates.
 The written program shall be followed and shall include
1)
2)
3)
4)
5)
Sample size and test intervals
Storage conditions for samples retained for testing
Reliable, meaningful, and specific test methods
Testing of the drug product in the same container-closure system as
that in which the drug product is marketed
Testing of drug products for reconstitution at the time of dispensing
(as directed in the labeling) as well as after they are reconstituted
*21 Code of Federal Regulations 211.166
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

*
The purpose of stability testing
 To provide evidence on how the quality of a drug
substance or drug product varies with time under the
influence of a variety of environmental factors
 To establish a retest period for the drug substance or a
shelf life for the drug product and recommended storage
conditions
*

Formal stability studies
 Long-term and accelerated (and intermediate) studies
undertaken on primary and/or commitment batches
 To establish or confirm the retest period of a drug
substance or the shelf life of a drug product
*Guidance for Industry, Q1A(R2) Stability Testing of New Drug Substances and Products,ICH,
November 2003
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Long-term testing
*
 Stability studies under the recommended storage
condition for the retest period or shelf life proposed (or
approved) for labeling

Intermediate testing
*
 Studies conducted at 30°C/65% RH and designed to
moderately increase the rate of chemical degradation or
physical changes for a drug substance or drug product
intended to be stored long-term at 25°C
*Guidance for Industry, Q1A(R2) Stability Testing of New Drug Substances and Products,ICH,
November 2003
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Accelerated testing
*
 Studies designed to increase the rate of chemical
degradation or physical change of a drug substance or drug
product by using exaggerated storage conditions as part of
the formal stability studies
 To assess longer term chemical effects at non accelerated
conditions
 To evaluate the effect of short-term excursions outside the
label storage conditions
 Results from accelerated testing studies are not always
predictive of physical changes
*Guidance for Industry, Q1A(R2) Stability Testing of New Drug Substances and Products,ICH,
November 2003
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

The design of the formal stability studies for the
drug product at least 3 batches
*
*Guidance for Industry, Q1A(R2) Stability Testing of New Drug Substances and Products,ICH,
November 2003
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Testing frequency
 For long-term study, every 3 months over the first year,
every 6 months over the second year, and annually
thereafter through the proposed shelf life.
 At the accelerated storage condition, a minimum of three
time points, including the initial and final time points (e.g.,
0, 3, and 6 months), from a 6-month study is
recommended.
*Guidance for Industry, Q1A(R2) Stability Testing of New Drug Substances and Products,ICH,
November 2003
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

In general, significant change for a drug product is
defined as one or more of the following (as appropriate
for the dosage form)
 5 percent change in assay from its initial value
 Any degradation product’s exceeding its acceptance criterion
 Failure to meet the acceptance criteria for appearance, physical
attributes, and functionality test
▪ Ex) color, phase separation, resuspendibility, caking, hardness, dose
delivery per actuation
 Failure to meet the acceptance criterion for pH
 Failure to meet the acceptance criteria for dissolution for 12
dosage units
*Guidance for Industry, Q1A(R2) Stability Testing of New Drug Substances and Products,ICH,
November 2003
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Stress testing
 Stress testing to elucidate the intrinsic stability of the drug
substance is part of the development strategy and is
normally carried out under more severe conditions than
those used for accelarated testing
 The testing typically includes the effects of temperature,
humidity where appropriate, oxidation, and photolysis on
the drug substance
▪ Temperature – in 10°C increments above that for accelerated testing
▪ Humidity – 75% realative humidity or greater
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Accelerated testing based on the chemical kinetics
(by Garrett and Carper)

*
Accelerated breakdown of a drug in aqueous
solution at elevated temperature
* MARTIN’s Physical Pharmacy and Pharmaceutical Sciences 6th edition
Patrck J. Sinko
*
Arrhenius plot for predicting drug stability at room
temperature
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

*
Fractional life-period Method
(by Free and Blythe and Amirijahe et al )
Fig. 1. A log plot of t90 (i.e., time to 90% potency) on the
vertical axis against reciprocal temperature (both Kelvin
and centigrade scales are shown) on the horizontal axis
* Fig. 2. Time in days required for durg potency to fall to 90%
of original value. These times, designated t90, are then
plotted on a log scale in Fig. 1
* MARTIN’s Physical Pharmacy and Pharmaceutical Sciences 6th edition
Patrck J. Sinko
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Nonisothermal kinetics (by Rogers)
 Enable decomposition rate to be determined from a single
experiment
 Involve raising the temperature of the product with
predetermined temperature-time program
T0 : initial temperature
a : reciprocal heating rate constant
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Shelf-life
 Shelf-life is the time period during which a drug product is
expected to remain within the approved specification for
use, provided that it is stored under the conditions defined
on the container label
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Calculation of Shelf-life
 Examples
▪ The equations which we can use for 10%
loss of activity are obtained by substituting
t 0.5 to t 0.9
▪ Extrapolations to 25℃ could predict the *
Shelf-life of the drug
* MARTIN’s Physical Pharmacy and Pharmaceutical Sciences 6th edition
Patrck J. Sinko
Fig. 1. A log plot of t90 (i.e., time to 90% potency) on the
vertical axis against reciprocal temperature (both Kelvin
and centigrade scales are shown) on the horizontal axis
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
“Drug Stability”
Introduction

The chemical breakdown of drugs
Body



Kinetics of chemical decomposition in solution
Factors influencing drug stability
Stability testing and calculation of shelf-life
Conclusion

Review & Summarize
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Hydrolysis
Polymerization
Oxidation
Chemical breakdown
of drugs
Isomerization
Photochemical
decompositon
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Hydrolysis
 Catalyzed by hydrogen ions or hydroxyl ions
Ex) Imide, Lactam, Lactone, Ester, Amide groups
 Optimization
▪ Determine the pH of maximum stability
▪ Alteration of the dielectric constants
▪ Alteration of the solubility
▪ Adding the compound that form complex
with drug
Oxidation
 Removal of an electropositive atom, radical or electron, or the addition of an
electronegative atom or radical
Ex) Steroids and sterols, polyunsaturated fatty acids, phenothiazines etc
 Optimization
▪ replaced with nitrogen or carbon dioxide ▪ Storage should be at reduced temperatures
▪ Avoid heavy-metal ions
▪ Addition of Antioxidant
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Isomerization
 Isomerization is the process of conversion of a drug into its optical or
geometric isomers, which are often of lower therapeutic activity
Ex) Adrenaline(racemization), tetracycline(epimerization), cephalosporins(base-catalyzed
isomerization) and vitamin A(cis-trans isomerization)
Photochemical decomposition
 Degrade when exposed to light
Ex) Phenothiazine tranquilizers, hydrocortisone, prednisolone, riboflavin, ascorbic acid
 Optimization
▪ The use of coloured glass containers and storage in the dark
Polymerization
 Two or more identical drug molecules combine together to form a complex
molecule
Ex) Amino-penicillins such as ampicillin sodium in aqueous solution, formaldehyde
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Zero-order
reactions
First-order
reactions
Second-order
reactions
• The decomposition
proceeds at a constant
rate and is independent
of the concentrations of
any of the reactants
• First-order reaction
depends on the
concentration of only
one reactant
(a unimolecular reaction)
• Second-order reaction
depends on the
concentration of one
second-order reactant,
or two first-order
reactants
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Reversible reaction
 A reversible reaction is a chemical reaction that results in an equilibrium
mixture of reactants and products
Parallel reaction
 The decomposition of many drugs involves two or more pathways, the
preferred route of reaction being dependent on reaction condition
Consecutive reaction
 The simple consecutive reaction is that described by a sequence where
each step is a nonreversible first-order reaction
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Liquid dosage form
Solid dosage form
• pH
• Moisture
• Temperature
• Excipients
• Solvent effect
• Temperature
• Oxygen
• Light and Oxygen
• Light
• Surfactant
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Liquid dosage form
 pH
▪ The most important parameter which affects the hydrolysis rate of drugs
in liquid formulations
▪ The rate of reaction is influenced not only by the catalytic effect of
hydrogen and hydroxyl ions, but also by the components of the buffer
system
 Temperature
▪ Increase in temperature usually causes a very pronounced increase in
the hydrolysis rate of drugs in solution
▪ Arrehnius equation
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Liquid dosage form
 Ion strength
▪ The ionic strength of a solution is a measure of the concentration of ions
in that solution
▪ Bronsted-Bjerrum equation
 Solvent effects
▪ Solvent effects is the group of effects that a solvent has on chemical
reactivity
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Liquid dosage form
 Oxygen
▪ Molecular oxygen is involved in many oxidation shemes
▪ Particular drug is likely to be affected by oxidative breakdown
 Light
▪ Exposure to ultraviolet light is the most usual cause of photodegradation
▪ Photolabile drugs are usually stored in containers which exclude
ultraviolet light
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Solid dosage form
 Moisture
▪ Water-soluble drugs present in a solid dosage form will dissolve in any
moisutre which has adsorbed on the solid surface
 Excipients
▪ high water contents and Chemical interactions
 Temperature
▪ melt or change its polymorphic form
 Light and Oxygen
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Stability testing
 To ensure the quality, safety, and efficacy of drug products up to their
expiration date
Formal stability testing
▪ Long-term/Intermediate/Accelerated stability test
Stress testing
▪ Temperature – in 10°C increments above that for accelerated testing
▪ Humidity – 75% relative humidity or greater
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Shelf-life
 Time period during which a drug product is expected to remain
within the approved specification for use, provided that it is stored
under the conditions defined on the container label
▪ Extrapolations from high temperature
to 25℃ could predict the Shelf-life of *
the drug
Fig. 1. A log plot of t90 (i.e., time to 90% potency) on
the vertical axis against reciprocal temperature (both
Kelvin and centigrade scales are shown) on the
horizontal axis
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실