1. Drug stability Prepared by : Dima Alhashlamoun Doaa Sider Instructor :
Mr. Yaseen Qawasmi

2. Druges in liquid or solid dosage forms susceptible to chemical decomposition which leads to :
physical changes (discoloration)
Chemical changes (loss of potency)

3. To take the precautions to minimise the loss of potency (activity) of drugs in certin enviromental conditions :
Study the kinetics of the decompostion process .
Determine the shelf-life : time taken for the concentration of the drug to be reduced to 95% of it’s value when prepared.

4. Chemical decomposition process
Hydrolysis
Oxidation
Isomerision
Photochemical decomposition
Polymerisation

5. Hydrolysis
The drug is susceptible to this type of degradation if it is a derivative of carboxulic acid or contains functional groups based on this moiety

6. Functional groups can hydrolysis
structure
Example
Imide
Glutethimide
Lactam
Penicillins
Cephalosporins
Lactone
Pilocarpine
Spironolactone
Ester
Aspirin,physostigmine,tetracaine,procaine
Amide
Ergometrine,benzylpenicllin sodium

7. Hydrolysis in water and catalysed by :
Acid catalysis : by hydrogen ion(H+) or other acidic species.
Basic catalysis: by hydroxyl ion(OH-) or other basic species.

8. Hydrolysis of esters
hydrolysis of amide

9. Controlling drug hydrolysis in solution
Optimisation of formulation
Modification of chemical structure of drug

10. Optimisation of formulation
To stabilise a solution of a druge which is susceptible to acid-base catalysed hydrolysis :
Detrmine the pH of maximum stability from kinetic experiments at a range of pH values and to formulate the product at this pH.
Alteration of the dielectric constant by the addition of nonaqueous solvents such as alcohol, glycerin or propylene glycol.

11. 3) Reducing the solubilty of the drug ,by using additives (such as citrates, dextrose, sorbitol and gluconate for pencillin)
(Since only that portion of the drug which is in solution will be hydrolysed, it is possible to suppress degradation by making the drug less soluble)
4)Adding a compound that forms a complex with the drug. The addition of caffeine to aqueous solutions of some druges (procain) decreases the base-catalysed hydrolysis.
5) solubilisation of a drug by surfactants protects against hydrolysis

12. Modification of chemical structure of drug
The modification ( ex: substituention , elemnation)should increase the drug stability without reducing the therapeutic effiency.
Hammett linear free energy relationship Used to measure the effect of substituents on the rates of aromatic side-chain reactions, such as the hydrolysis of esters.

13. Hammett linear free energy relationship
Logk=logk0+σρ
Where:
k : the rate constants for the reaction of the substituted
k0 : the rate constants for the reaction of the unsubstituted
σ : the Hammett substituent constant ( determined by the nature of the substituents and is independent of the reaction)
ρ : the reaction constant. (dependent on the reaction, the conditions of reaction and the nature of the side-chains undergoing reaction).

14. Hammett linear free energy relationship
a plot of log k against the Hammett constant is linear if this relationship is obeyed, with a slope of ρ.

15. 2. Oxidation
oxidation is the next most common pathway for drug breakdown After hydrolysis.
the oxidative process has usually been eliminated by storage under anaerobic conditions without an investigation of the oxidative mechanism.

16. Oxidation process

17. Initiation can be via free radicals formed from organic compounds by the action of light, heat or transition metals such as copper and iron which are present in trace amounts in almost every buffer.
The propagation stage of the reaction involves the combination of molecular oxygen with the free radical R to form a peroxy radical ROO., which then removes H from a molecule of the organic compound to form a hydroperoxide, ROOH, and in so doing creates a new free radical
The reaction proceeds until the free radicals are destroyed by inhibitors or by side-reactions which eventually break the chain.
The rancid odour which is a characteristic of oxidised fats and oils is due to aldehydes, ketones and shortchain fatty acids which are the breakdown products of the hydroperoxides.
Peroxides (ROOR,) and hydroperoxides (ROOH) are photolabile, breaking down to hydroxyl (HO) and or alkoxyl (RO)radicals, which are themselves highly oxidising species.

18. Drugs susceptible to oxidation
Steroid and sterols: are subject to oxidative degradation through the possession of carbon–carbon double bonds (alkene moieties) to which peroxyl radicals can readily add.
polyunsaturated fatty acids.

19. From druges :
1) cholesterol-lowering agent simvastatin : contain conjugated double bonds, addition of peroxyl radicals may lead to the formation of polymeric peroxides, cleavage of which produces epoxides which may further degrade into aldehydes or ketones.

20. simvastatin

21. 2) Polyene antibiotics, such as amphotericinB which contains seven conjugated double bonds (heptaene moiety), are subject to attack by peroxyl radicals, leading to aggregation and loss of activity. 3) The oxidation of phenothiazines to the sulfoxide involves two single-electron transfer reactions involving a radical cation intermediate The sulfoxide is subsequently formed by reaction of the cation with water.

23. 4) ether group in drugs such as econazole nitrate and miconazole nitrate is susceptible to oxidation. The process involves removal of hydrogen from the C–H bonds in the α- position to the oxygen to produce radicals, which further degrade to α-hydroperoxides and eventually to aldehydes, ketones, alcohols and carboxylic acids.

24. Stabilisation against oxidation
1) The oxygen in pharmaceutical containers should be replaced with nitrogen or carbon dioxide.
contact of the drug with heavy-metal ions such as iron, cobalt or nickel, which catalyse oxidation, should be avoided.
storage should be at reduced temperatures.
Using antioxidants.

25. antioxidants
The propagation of the chain reaction may be prevented or delayed by adding low concentrations of antioxidants that act as inhibitors. interrupt the propagation by interaction with the free radical.
The antioxidant free radical so formed is not sufficiently reactive to maintain the chain reaction and is eventually annihilated.
Reducing agents such as sodium metabisulfite may also be added to formulations to prevent oxidation. These compounds are more readily oxidised than the drug and so protect them.

26. Oxidation is catalysed by unprotonated amines such as aminophylline, and hence amixture of susceptible drugs with such compounds should be avoided.

27. Structures of some common antioxidants

28. Isomerisation
Isomerisation : is the process of conversion of the drug into its optical or geometric isomers .
various isomers of a drug are frequently of different activity, such a conversion may be regarded as a form of degradation, often resulting in a serious loss of therapeutic activity.

29. Racemisation of adrenaline at low pH

30. Isomerisation of vitamin A (Cis–trans isomerisation )

31. Photochemical decomposition
Photodecomposition occur :
during storage
during use of the product. As sunlight is able to penetrate the skin to a sufficient depth to cause photodegradation of drugs circulating in the surface capillaries or in the eyes of patients receiving the drug.

32. Primary photochemical reaction occurs when
1. the wavelength of the incident light is within the wavelength range of absorption of the drug (usually within the ultraviolet range, unless the drug is coloured), so that the drug molecule itself absorbs radiation and degrades.
2. with drugs that do not directly absorb the incident radiation, as a consequence of absorption of radiation by excipients in the formulation (photosensitisers) which transfer the absorbed energy to the drug, causing it to degrade.

33. The effect of ultraviolet light on chlorpromazine (CLP).

34. V Polymer produced by the ultraviolet irradiation of chlorpromazine under anaerobic conditions

35. Stabilisation against photochemical decomposition
the use of coloured glass containers
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 has been suggested as an additional method for protection from light. In this respect, a film coating of vinyl acetate containing oxybenzone as an ultraviolet absorber has been shown to be effective in minimising the discoloration and photolytic degradation of sulfasomidine tablets.

36. Polymerisation
Polymerisation is the process by which two or more identical drug molecules combine together to form a complex molecule.

37. Dimerisation and hydrolysis of ampicillin.

38. Kinetics of chemical decomposition in solution
Before we can predict the shelf-life of a dosage form it is essential to determine the kinetics of the breakdown of the drug under carefully controlled conditions.

39. Classifying reactions: the order of reaction
Reactions are classified according to the order of reaction: number of reacting species whose concentration determines the rate at which the reaction occurs.
We will concentrate mainly on:
zero-order reactions, in which the breakdown rate is independent of the concentration of any of the reactants.
first-order reactions, in which the reaction rate is determined by one concentration term.
Second order reactions, in which the rate is determined by the concentrations of two reacting species.

40. 1) zero-order reactions
- Dx/dy=K0
- This type of reaction,can often occur
in suspensions of poorly soluble
drugs.In these systems the suspended
drug slowly dissolves as the drug
decomposes and so a constant drug
concentration in solution is maintained.
Ex : hydrolysis of acetyl
salicylic acid

41. 2) first-order reactions
Dx/dy=K1[A]=K1(a-x)
Ex : hydrolysis of homatropine

42. pseudo first-order reaction: occurs when one of the reactants is in such a large excess that any change in its concentration is negligible compared with changes in the concentration the other reactants.
Such reactions are often met in stability studies of drugs that hydrolyse in solution,the water being in such excess that changes in its concentration are negligible and hence the rate of reaction is dependent solely on the drug concentration.

43. Second order reactions
Dx/dy=K1[A][B] Dx/dy=K1[A] [B]=K1(a-x)(b-x)

44. Complex reactions
There are many examples of drugs in which decomposition occurs simultaneously by two or more pathways, or involves a sequence of decomposition steps or a reversible reaction.
Complex reaction:
Reversible reactions
Parallel reactions
Consecutive reactions

45. Reversible reactions
the kinetics of a reversible reaction involves two rate constants :
Kf: describe the rate of the forward reaction
kr: describe the rate of the reverse reaction
For the simplest example in which both of these reactions are first-order ex: epimerisation of tetracycline

46. Parallel reactions
The decomposition of many drugs involves two or more pathways, the preferred route of reaction being dependent on reaction condition.
Ex: Nitrazepam decomposes in two pseudo first-order parallel reactions giving different breakdown products in solution and in the solid state.
Decomposition of nitrazepam tablets in the presence of moisture will occur by both routes, the ratio of the two products being dependent on the amount of water present.
In other cases decomposition may occur simultaneously by two different processes, as in the simultaneous hydrolysis and epimerisation of pilocarpine .

47. Consecutive reactions
where each step is a nonreversible first-order reaction. The hydrolysis of chlordiazepoxide follows a first-order decomposition

48. Solid dosage forms: kinetics of chemical decomposition
Solids that decompose to give a solid and a gas.
Solids that decompose to give a liquid and a gas.

49. Solids that decompose to give a solid and a gas
Ex : p-aminosalicylic acid, which decomposes to a solid (p- aminophenol) and a gas (carbon dioxide)
The decomposition curves which result from such a reaction show either:
(a) an initial rapid decomposition followed by a more gradual decomposition rate.
The shape produced called topochemical (contracting geometry).
The model used in the treatment is that of a cylinder or sphere.
it is assumed that the radius of the intact chemical substance decreases linearly with time.

51. For the contracting cylinder model, the mole fraction x decomposed at time t is given by
(1 –x)1/2 = 1 – (K/r0)t
Example of this type decompostion of aspirin at elevated tempreture.
For the contracting sphere model
(1-x)1/3 = 1- (k/r0)t
- A similarity between these and the first-order rate equations, this similarity might account for the fact that many decompositions in solid dosage forms appear to follow first-order kinetics.

52. Solids that decompose to give a liquid and a gas
An example of a solid in this category is p- aminobenzoic acid, which decomposes into aniline and carbon dioxide.
Decomposition causes a layer of liquid to form around the solid which dissolves the solid.
The decomposition curves show an initial lag period which corresponds to the establishment of the liquid layer.
Beyond this region, the plot represents the first-order decomposition of the solid in solution in its liquid decomposition products.
There are thus two rate constants, that for the initial decomposition of the solid itself, and that for the decomposition of the solid in solution.

53. Factors influencing drug stability
For Liquid dosage forms: PH
Temperture
Ionic strength
Solvent effect
Oxygen
Light
Surfactant

54. PH
Studying the influence of pH on degradation rate: - a pH rate profile : the hydrolysis rate of the drug in a series of solutions buffered to the required pH is measured and the hydrolytic rate constant is then plotted as a function of pH. - this will almost certainly be influenced by the buffers used to It is probable that a different pH rate profile would be obtained using a different buffer.

56. • Acidic and alkaline pH influence the rate of decomposition of most drugs. • Many drugs are stable between pH 4 and 8. • Weekly acidic and basic drugs show good solubility when they are ionized and they also decompose faster when they are ionized. Reactions catalyzed by pH are monitored by measuring degradation rates against pH, keeping temperature, ionic strength and solvent concentration constant. Some buffers such as acetate, citrate, lactate, phosphate and ascorbate buffers are utilized to prevent drastic change in pH.

57. So if the pH of a drug solution has to be adjusted to improve solubility and the resultant pH leads to instability then a way out of this tricky problem is to introduce a water miscible solvent into the product. It will increase stability by:
- reducing the extreme pH required to achieve solubility
enhancing solubility
reducing the water activity by reducing the polarity of the solvent. For example, 20% propylene glycol is placed in chlordiazepoxide injection for this purpose

58. Temperture
Increase in temperature usually causes a very pronounced increase in the hydrolysis rate of drugs in solution.
Such studies are usually carried out at high temperatures, say 60 or 80°C, because the hydrolysis rate is greater at these temperatures and can therefore be measured more easily.

59. The equation which describes the effect of temperature on decomposition, and which shows us how to calculate the rate of break down at room temperature from measurements at much higher temperatures, is the Arrhenius equation.
When it is clear from stability determinations that a drug is particularly unstable at room temperature, then of course it will need to be labelled with instructions to store in a cool place.
This is the case, for example, with injections of penicillin, insulin, oxytocin and vasopressin.

60. Ionic strength
electrolytes add to drug solutions to control their tonicity, but we must pay attention to any effect they may have on stability.
The equation which describes the influence of electrolyte on the rate constant is the Brønsted–Bjerrum equation:
Logk= logk0+2AZAZBЛ1/2
In this equation:
- zA and zB are the charge numbers of the two interacting ions
- A is a constant for a given solvent and temperature.
- μ is the ionic strength of the solution.

61. Solvent effects
K is a constant for a given system at a given temperature.
We can see that a plot of log k as a function of the reciprocal of the dielectric constant, ε, of the solvent should be linear with a gradient of magnitude KzAzB
and an intercept equal to the logarithm of the rate constant in a theoretical solvent of infinite dielectric constant.

62. If the charges on the drug ion and the interacting species are the same, then we can see that the gradient of the line will be negative. In this case, if we replace the water with a solvent of lower dielectric constant then we will achieve the desired effect of reducing the reaction rate.
If the drug ion and the interacting ion are of opposite signs, however, then the slope will be positive and the choice of a nonpolar solvent will only result in an increase of decomposition.

63. Oxygen
Since molecular oxygen is involved in many oxidation schemes, we could use oxygen as a challenge to find out whether a particular drug is likely to be affected by oxidative breakdown.
We would do this by storing solutions of the drug in ampoules purged with oxygen and then comparing their rate of breakdown with similar solutions stored under nitrogen.
Formulations that are shown to be susceptible to oxidation can be stabilized by replacing the oxygen in the storage containers with nitrogen or carbon dioxide, by avoiding contact with heavy metal ions, and by adding antioxidants

64. Light
Photolabile drugs are usually stored in containers which exclude ultraviolet light, since exposure to light in this wavelength range is the most usual cause of photodegradation
Amber glass is particularly effective in this respect because it excludes light of wavelength of less than about 470 nm.
As an added precaution, it is always advisable to store photolabile drugs in the dark.

65. Surfactants kobs = kmfm + kwfw
kobs, km and kw are the observed, micellar and aqueous rate constants, respectively, and fm and fw are the fractions of drug associated with the micelles and aqueous phase, respectively.
The value of km is dependent on the location of the drug within the micelle.

66. A solubilisate may be incorporated into the micelle in a variety of locations.
Nonpolar compounds are thought to be solubilised within the lipophilic core and, as such, are likely to be more effectively removed from the attacking species than those compounds that are located close to the micellar surface.

67. Where the drug is located near to the micellar surface, and therefore still susceptible to attack, the ionic nature of the surfactant is an important influence on decomposition rate.
For base-catalysed hydrolysis, solubilisation into anionic micelles affords an effective stabilisation due to repulsion of OH- by the micelles.
Conversely, solubilisation into cationic micelles might be expected to cause an enhanced base-catalysed hydrolysis.
Many drugs associate to form micelles in aqueous solution and several studies have been reported of the effect of this self- association on stability.

68. Semisolid dosage forms

69. The chemical stability of active ingredients incorporated into ointments or creams is frequently dependent on the nature of the ointment or cream base used in the formulation.
Such dilution is, unfortunately, common practice in cases where the practitioner wishes to reduce the potency of highly active topical preparations, particularly steroids. The pharmaceutical and biopharmaceutical dangers of this procedure have been stressed.
Of particular interest here are the problems of drug stability which can occur through the use of unsuitable diluents.

70. the dilution of betamethasone valerate cream with a cream base having a neutral to alkaline pH. Under such conditions, conversion of the 17-ester to the less-active betamethasone 21-ester can occur.
Similarly, diluents containing oxidising agents could cause chemical degradation of fluocinolone acetate to less-active compounds.

71. Solid dosage forms

72. Moisture
Water-soluble drugs present in a solid dosage form will dissolve in any moisture which has adsorbed on the solid surface. The drug will now be in an aqueous environment and its decomposition could be influenced by many of the factors which affect the liquid dosage forms.
moisture is considered to be one of the most important factors that must be controlled in order to minimise decomposition.

73. The effect of water vapour pressure on the decomposition of aminosalicylic acid.

74. Excipients
Excipients such as starch and povidone have particularly high water contents (povidone contains about 28% equilibrium moisture at 75% relative humidity).
However, whether this high moisture level has an effect on stability depends on how strongly it is bound and whether the moisture can come into contact with the drug.
Magnesium trisilicate causes increased hydrolysis of aspirin in tablet form because, it is thought,of its high water content.

75. Chemical interaction between components in solid dosage forms may lead to increased decomposition.

76. Reactions showing the postulated transacetylation between aspirin and paracetamol and the direct hydrolysis of paracetamol.

77. Development of free salicylic acid in aspirin–paracetamol–codeine and aspirin–phenacetin–codeine tablets at 37°C.

78. Temperature The drug or one of the excipients may, for example,
melt or change its polymorphic form as temperature is increased,
it may contain loosely bound water which is lost at higher temperatures.
the relative humidity will change with temperature and so we must take care to keep this at a constant value.

79. Light and oxygen
the stability problems which arise with drugs which are susceptible to photodecomposition or oxidation.
water contains dissolved oxygen and so the presence of moisture on the surface of solid preparations may increase the oxidation of susceptible drugs; such drugs must, therefore, be stored under dry conditions.

80. 1. Effect of temperature on stability
Stability testing and prediction of shelf-life
1. Effect of temperature on stability
the basic method of accelerating the chemical decomposition by raising the temperature of the preparations.

81. 1. The order of reaction can be determined by plotting stability data at several elevated temperatures according to the equations relating decomposition to time for each of the orders of reaction, until linear plots are obtained. 2. calculate values of rate constant at each temperature from the gradient of these plots 3. plot the logarithm of k against reciprocal temperature according to the Arrhenius equation:

82. The required value of k can be interpolated from this plot at room temperature, and the activation energy Ea can be calculated from the gradient, which is –Ea/ 2.303R. Values of Ea are usually within the range 50–96 kJ mol-1.

83. Example :

84. Expiry date calculation
Once the rate constant is known at the required storage temperature, it is a simple matter to calculate a shelf-life for the product based on an acceptable degree of decomposition.
The equations which we can use for 10% loss of activity are obtained by substituting x=0.1a in the zero- and first-order equations giving

85. where [D]0 is the initial concentration of drug.
t0.9 is usually used as an estimate of shelf-life, other percentage decompositions may be required,
for example when the decomposition products produce discoloration or have undesirable side-effects. The equired equations for these may be derived by substituting in the relevant rate equations.

86. Example :

88. Suspensions
stability testing of suspensions is the changes in the solubility of the suspended drug with increase in temperature.
With suspensions, the concentration of the drug in solution usually remains constant because, as the decomposition reaction proceeds, more of the drug dissolves to keep the solution saturated. this situation usually leads to zero-order release kinetics.

89. Solid state
The main problems arising in stability testing of solid dosage forms are:
(a) that the analytical results tend to have more scatter because tablets and capsules are distinct dosage units rather than the true aliquots encountered with stability studies on drugs in solution.
(b) that these dosage forms are heterogeneous systems often involving a gas phase (air and water vapour), a liquid phase (adsorbed moisture) and the solid phase itself. The compositions of all of these phases can vary during an experiment.

90. The first of these problems can be overcome by ensuring uniformity of the dosage form before commencing the stability studies.
The problems arising from the heterogeneity are more difficult to overcome.

91. The main complicating factor is associated with the presence of moisture. moisture can have a significant effect on the kinetics of decomposition and this may produce many experimental problems during stability testing.
For example, what happen with gelatin capsules.

92. To reduce some of these problems , particularly those associated with moisture, during stability testing, the following have been suggested:
the use of tightly sealed containers, except where the effect of packaging is to be investigated
that the amount of water present in the dosage form should be determined, preferably at each storage temperature
that a separate, sealed ampoule should be taken for each assay point and water determination, thus avoiding disturbance of water equilibrium on opening the container.

93. - Light 2. Other environmental factors affecting stability
Photostability testing of drug substances
the sample is irradiated at all absorbing wavelengths using a broad-spectrum light source.
Those drugs or formulations which are shown to be photosensitive are then subjected to more formal photostability testing in which they are challenged with light of wavelength comparable to that to which the formulations are exposed in practical situations.
During their shelf-life it is most likely that the products will be exposed to fluorescent light, direct daylight and daylight filtered through window glass, and the stability testing procedures are designed to cover these possibilities

94. - Oxygen - Moisture content
Exaggeration of the effect of oxygen on stability may be achieved by an increase in the partial pressure of oxygen in the system.
- Moisture content
The stability of solid dosage forms is usually very susceptible to the moisture content of the atmosphere in the container in which they are stored

95. Protocol for stability testing
The stability test protocol should be found on :
Drug substance is a pure material which exerts a pharmacological action
Drug product is a finished end product which may contain one or more drug substances in combination with excipients meant for use by humans and animals 

96. Drug substances
Stability information from accelerated and long-term testing is required to be provided on at least three batches manufactured to a minimum of pilot plant “ one tenth that of the batch ”.
The containers to be used in the long-term evaluation should be the same as, or simulate, the actual packaging used for storage and distribution.

97. The testing should be designed to cover those features susceptible to change during storage and likely to influence quality, safety and/or efficacy, including, as necessary, the physical, chemical and microbiological characteristics.
The length of the studies and the storage conditions should be sufficient to cover storage, shipment and subsequent use.

98. The specifications for the long-term testing are a temperature of 25 ± 2°C and 60±5% relative humidity (RH) for a period of 12 months.
For accelerated testing the temperature is specified as 40 ± 2°C and RH as 75 ± 5% for a period of 6 months. if a ‘significant change’ occurs during this period, additional testing at an intermediate temperature (such as 30±2°C,60% ± 5% RH) should be conducted for drug substances.
‘Significant change’ at 40°C75% RH or 30°C60% RH is defined as failure to meet the specification.
Temperature sensitive drugs that should be stored at a lower temperature, is tested under these conditions

99. The long-term testing is required to be continued for a sufficient period beyond 12 months to cover all appropriate re-test periods.
under the long term conditions this will normally be every 3 months over the first year, every 6 months over the second year and then annually.

100. Drug product
The conditions and time periods for long-term and accelerated storage testing are the same as those outlined above for drug substances but with special considerations arising from the nature of the drug product.
For example , If it is necessary to store the product at a lower temperature because of its heat sensitivity then consideration should be given to any physical or chemical change in the product which might occur at this temperature; for example,
suspensions or emulsions may sediment or cream,
while oils and semi-solid preparations may show an increased viscosity.

101. In the case of drug products, ‘significant change’ at the accelerated condition is definedas ● A 5% potency loss from the initial assay value of a batch ● Any specified degradant exceeding its specification limit ● The product exceeding its pH limits ● Dissolution exceeding the specification limits for 12 capsules or tablets ● Failure to meet specifications for appearance and physical properties, e.g. colour, phase separation, resuspendability, delivery per actuation, caking and hardness

102. If significant change occurs at 40°C75% RH then it is necessary to submit a minimum of 6 months’ data from an ongoing one-year study at 30°C60% RH using the same criteria for ‘significant change’.