Lecture 3
PREFORMULATION
Stability And Compatibility
studies
Learning objective
At the end of this session students should able
to
• Understand the importance of stability and
compatibility studies in preformulation
• Describe the stability and compatibility
studies
• Explain the methods to find out instability and
incompatibility of drug and formulations
Outline Of Principal Areas Of
Preformulation Research
Principal areas
Stability analysis
Physico-chemical
properties Solution stability
Bulk
Solubility analysis Solid state
Organoleptic characterization
Crystallinity and stability
properties Ionization constant pka
Particle size polymorphism Bulk stability
PH solubility profile
and shape Hygroscopicity Compatibility
Common ion effect
Purity Particle size
characterization Thermal effects
Surface
Bulk density Partition co-efficient
area
solubilization
Powder flow
Dissolution
properties
STABILITY
According to pharmacopoeia a product is stable means it
should be within limits of monograph specification like its
identity, strength, quality, purity etc.
The purpose of stability testing is to ensure that the drug
shows perfect quality throughout its shelf life.
In designing dosage form, it is necessary to know the inherent
stability of the drug substance, to give an idea of what
excipients to use, as well as how best put them together with
the drug, so that no toxic substance are formed.
The preformulation studies are usually the first quantitative
assessment of chemical stability of a new drug.
The objective of this study is to identify, help, avoid and control the
situations where the stability of the active ingredient may not be
compromised.
These studies are conducted under conditions typical for the
handling, formulation, storage, and administration of a drug
candidate.
A drug product must satisfy stability in terms of chemical, toxic,
therapeutic and physical characteristics.
Samples of the chemical are usually subjected to various conditions
of light, heat and moisture in the presence and absence of oxygen.
The chemicals is placed in sealed vials with and without moisture
and stored at various elevated temperatures.
During the development of the drug substance into the dosage
form, the stability should be carried out under following
categories:
Solution phase
Solid-state of the drug alone
with the expected excipients
. The most common factors, which cause instabilities are Heat,
Humidity, light, oxygen, etc.
Solution phase stability
Solution phase stability:
Chemical instability of the drug product is
more in solution dosage form than that of
solid dosage form due to increased contact
area between the ingredients.
In this solution phase stability, studies include
assurance of the drug substances about its
stability when it is exposed to G.I.T fluids.
Solid phase stability
Solid phase stability: Solid state reactions in
general are slow due to very less contact area
between the reacting molecules.
The stability study should be designed to
identify the factors which cause degradation
of the drug product
Stability under high humidity:
In presence of moisture drug substance under goes
hydrolysis and react with other excipients.
Controlled humidity conditions are maintained using lab
desiccators.
The manufacturing, packing of the humidity sensitive
drug’s are to be carried out under controlled humidity
conditions. Eg: Hard gelatin capsule filling process.
Photolytic stability:
Many drug substance fade or darken on
exposure to light.
But it leads to an aesthetic problem which can be
readily controlled by using amber glass or
opaque container or incorporating the dye in the
product to mask the discoloration. Eg :
Nitroglycerin tablets USP.
Stability to Hydrolysis:
The most likely causes of drug stability is
hydrolysis. Water plays a very important role.
Drugs, which are susceptible to hydrolysis are:
Penicillins, Cephalosporins, Aspirin,
Chloramphenicol etc.
Stability to oxidation: The sensitivity of the new drug
entity to atmospheric oxygen to be evaluated to
decide whether the final product should be packed
under inert atmosphere or not.
If it is sensitivity to the oxygen then the addition of
antioxidant should be considered. The drugs, which
are prone to oxidation, are Morphine, Adrenaline,
Steroids, Antibiotics, fats and oils.
The oxidation can be prevented by addition of anti-
oxidants like Sodium sulfite, Ascorbic acid and
Vitamin – E etc.
Accelerated stability study and Arrhenius theory
It is possible conduct experiments at elevated
temperature and obtain rate constant from the
Arrhenius plot.
The elevated temperature commonly used are 400C,
500C, and 600C along with ambient humidity.
The samples stored at high temperature should be
examined for physical and chemical changes by
comparing with the control sample (stored at 50C or
room temperature).
If no change is seen after 30 days at 600C the stability
is excellent.
Incompatibility
Definition of incompatibilities:: Incompatibility is an
undesirable reaction that occurs between the drug and the
excipients, container or another drug, which will affect the
Physical, chemical and therapeutic quality of the product
or dosage form.
May occur during preparation, storage and administration.
Determined by the use of
o Infra Red Spectroscopy (IR),
o Differential Scanning Calorimetry (DSC)
optimization technique used for a best possible
formulation to minimize the interactions.
Eg of interactions: Drug-drug, drug –excipient, excipient-
excipient, drug packaging.
Physical incompatibilities: Immiscibility, insolubility,
liquefaction.
Chemical incompatibilities: Oxidation-reduction, acid-
base, hydrolysis, complexation or combination reactions.
Therapeutic incompatibilities: when two drugs given in
one formulation, there is more chances for drug-drug
interactions.
It is very difficult to investigate all the interactions and
formulate the dosage form, free from all the
interactions.
Compatibility studies
The excipients are added to the different dosage forms like Tablets,
Capsules, and parenterals depending on requirement of particular
formulation.
As a definition, these excipients are considered as non-reactive in
outlook. However, it may not be true for all excipients in different
formulation.
Hence in developing any formulation while selecting the excipients
the formulator should see how it is compatible with the other
ingredients.
Generally the formulator has wide choice in any group of
excipients, if one additive does not fit if can be substituted for
other.
Flow diagram to identify excipient
compatibility with drug
No
Drug interaction
Excepient
IR Or
50%Mixture of recommended
DSC
Drug &
excepient Interaction
Excepient
HPLC
Or TLC
Alternative excepient Yes Drug No
suggested breakdown
Compatibility
Drug & Excipient Interactions
Drug and excipients studies are designed to determine a list of
excipients that can be used routinely in the final dosage forms.
Lactose, sucrose, calcium sulfate, di-calcium phosphate, starch and
magnesium stearate are some of the substances routinely tested in
combinations.
Some basic observations with the drug substance and or its salt
form can sometimes dictate what excipients can be used.
For eg. One would not consider using sucrose or lactose if the
drug substance being considered is a primary amine.
Thus system has the potential for interaction to form a colored
compound readily detected by a color change.
Sometimes problems arise because of the interactions with
additives such as preservatives, stabilizers, dyes and possibly
flavors.
Preservatives: Each time a liquid or semisolid pharmaceutical
dosage is prepared it is necessary to include a preservative in the
formulation.
e.g. of some commonly used preservatives are sodium benzoate,
sorbic acid and propyl and methyl parabens.
Antioxidants: Sodium bisulfite and ascorbic acid are two
antioxidants that are widely used in pharmaceutical systems.
Sodium bisulfate yields a colorless water-soluble salt when it is
oxidized. It is also a very reactive ion.
Ascorbic acid on the other hand is relatively nonreactive.
However, when mixed with compound having a primary amine
nucleus there is a tendency for interaction to form a highly
colored schiff base.
One must be aware of this possibility when selecting a suitable
antioxidant.
Suspending agents: Carboxy methyl cellulose, carrageenan
form complexes possibly with many medicinal agents
including procaine, chlorpromazine, benadryl, quinine, etc.
When this problem is suspected it is important to conduct
appropriate tests to ensure that an interaction does not
take place in the system being evaluated.
Dyes: Dyes are chemical in nature and contain reactive sites
capable of causing incompatibilities.
Techniques used in the detection of drug excipient
compatibility:
Diffuse reflectance techniques
Thin layer chromatography
Thermal analysis
REFERENCES
• Lachman, L, Leiberman, HA and Kanig, JL,
1999. The Theory and Practice of Industrial
Pharmacy, Lea and Febiger, Philadelphia.
• Aulton, ME, 2001. Pharmaceutics: The Science
of Dosage form Design, 2nd, Churchill
Livingstone, Edinburgh.
• Pharmaceutical dosage forms and drug
delivery system by Ansel.
THANK YOU
