2. Definition:
It can be defined as an investigation of physical and chemical
properties of a drug substance alone and or when combined with
excipients in order to develop safe, effective and stable dosage form.
Objectives:
• To establish the physio-chemical parameters of a new drug entity.
• To determine its kinetics and stability.
• To establish its compatibility with common excipients.
• It generates useful information to the formulator to design an
optimum drug delivery system.
3. CONCEPT
• Prior to the development of these major
dosage forms, it is essential that certain
fundamental, physical and chemical properties
of drug molecule and other properties of drug
powder are determined. This information
decides many of the subsequent events and
approaches in formulation development.
5. Hygroscopicity
Asorance spectrum
UV , IR
Solubility
Partition co efficient
Polymorphism potential
PHYSIO MECHANICAL PROPERTIES
bulk and tapped density
Compressibility
IN VITRO AVAILIBILITY PROPERTIES
Dissolution of drug crystals, drug pellet
OTHERS - PPB, Kinetics study
7. DRUG EXCIPIENT INTERACTIONS
• Excipients play an important role in formulating a dosage form.
• Excipients are ingredients which along with active pharmaceutical
ingredients makeup the dosage forms.
• Excipients act as protective agents ,bulking agents and can also be
used to improve bioavailability of drug.
• Excipients as like other active pharmaceutical ingredients need to
be stabilized and standardized.
EXCIPIENT:
An excipient is a substance formulated alongside the active
ingredient of a medication ,included for the purpose of long term
stabilization,bulking up solid formulations that contain potent active
ingredients in small amounts.
8. Excipients used as carriers for active ingredients are
• Binders
• Disintegrants
• Fillers(diluents)
• Lubricants
• Glidants
• Compression aids
• Colors
• sweeteners
• Preservatives
• Flavors
• Film formers/coatings
• Surfactants
• Anti adherents
• Antioxidants
• Humectants
9. Drug excipient interaction:
In pharmaceutical dosage forms the active pharmaceutical
ingredients are in intimate contact with the excipient which are greater
quantity excipient and drugs may have certain incompatibility which
lead to drug excipient interaction.
Types of drug excipient interactions:
Physical interactions
Chemical interactions
Biopharmaceutical interactions
Excipient- excipient interactions
10. Physical interactions:
• Physical interactions alter the rate of disssolution, dosage
uniformity,etc.,
• They are quite common but are difficult to detect.
• A physical interaction doesn‘t involve any chemical changes.
• Physical interactions are frequently used in the manufacturing of
dosage forms, for example, to modify drug dissolution.
• Many of such interactions can be categorized as noncovalent. These
may include vanderWaals attractions (or dispersion forces),
hydrogen bonding, and electrostatic interactions(also called ionic
bonding). All of these interactions involve an electrical chargedue to
temporary dipoles or ion formation.
11. Interactions
Complexation:
• Usually binds reversibly with drugs to form complex.
• Insoluble complexes are formed which lead to slower dissolution.
• Decreased adsorption of drug.
Beneficial effect examples:
• Cyclodextrin is often used to improve bioavailability of poorly
water soluble drugs.
• This increases bioavailability and increases rate.
Detrimental effect examples:
tetracycline formed insoluble complex with calcium carbonate
leading to slower dissolution and decreased absorption.
12. Chemical interactions:
• Active pharmaceutical ingredients and excipients react with each
other to form unstable compounds.
Oxidation and the role of excipients:
• Oxidation is broadly defined as loss of electrons in a system, but it
can be restated as an increase in oxygen or a decrease in hydrogen
content.
• Oxidation always occurs in tandem with reduction;the so called
REDOX reaction couple.
• It can be defined as the loss of electron positive atom, radical or
electron, or the addition of an electronegativite moiety.
• Oxidation reaction can be catalysed by heavy metals, light, leading
to free radical formation. Free radical then react with oxygen to
form peroxy radicals.
13. Biopharmaceutical interactions:
These are the interactions which are observed after administration of
medicine.
These interactions occur in the form of:
The interaction is between the medicine (drug substance and
excipients) and the body fluids.
The interaction have the tendency to influence the rate of absorption
of drug.
14. Various e.g. of these interactions are as :
remature breakdown of enteric coat-
Enteric coating polymers e.g, cellulose acetate phthalate and
hydroxyl propyl cellulose acetate phthalate,
Dissolve prematurely in the stomach in the presence of
antacids or drugs.
cause increase in the pH of the stomach
cause premature release of API in stomach itself,which
results in degradation of drug in stomach.
e.g.,side effects like gastric bleeding as in the case of NSAIDs.
15. Excipient- excipient interactions:
• This type of interaction occurs between two or more excipient in a
drug molecule.
• Ex:in proper addition of electrolyte such as calcium or magnesium
ion in suspension containing NaCMC which will cause formation
of calcium or magnesium CMC.
• The suspending agent will be destroyed and cannot perform it’s
function.
17. DSC-Differntial Scanning Calorimetry
DSC is widely used technique to predict any interaction
involving thermal changes.
METHOD:
• The preformulation screening of drug–excipient interaction requires
(1:1) Drug:excipient ratio, to maximise the likehood of observing an
interaction.
• Mixture should be examined under N2 to eliminate oxidative and
pyrrolytic effects at heating rate (2,5 or 100c/min) on DSC
apparatus.
Interaction detected:
• Elimination of endothermic peak.
• Any new peak appeared.
• Change in melting point/ peak temperature.
18. DTA-Differential Thermal Analysis
• This technique is useful for identifying and quantitatively
analyzing the chemical composition of substances by observing the
thermal behaviour of a sample as it is heated.
• In this change in temperature between test sample and reference
material is measured under controlled and identical condition.
• This differential temperature is plotted against time or temperature.
• Interaction can be identified by comparing DTA curve obtained from
the test sample with those of reference material.
If any interaction occur-thermogram (DTA curve) of a mixture show
appearance or disappearance of one or more peaks corresponding to
those of the components.
If no interaction occur- the thermogram of mixtures show same
patterns corresponding to those of the individual components.
19. TLC AND HPTLC
TLC is generally use as confirmative test of compatibility after
performing DSC because if sample undergo negligible thermal
changes,it will difficult by thermal method.
Method-stationary phase consist of powder(silica, alumina,
polyamide, cellulose,etc.) adhered onto glass, plastic or metal plate.
Solution of drug,excipient and drug : excipient mixture are prepared
and spotted on the same baseline at the end of the plate.
The plate is then placed upright in a closed chamber containing the
solvent which constitutes the mobile phase.
Any change in chromatograph such as appearance of a new spot or a
change in Rf values of component is indicative of an interaction.
20. RADIO LABELLED TECHNIQUES
It is important when the API is having radio-activity.
Method is carried out by using either 3H or 13C.
Highly sensitive method but the cost of carrying out the method and
bioavailability of well established other techniques and methods
,this method is generally not preferred.
21. KINETICS OF STABILITY
Drug stability means the ability of the pharmaceutical dosage
form to maintain the physical,chemical, therapeutic and microbial
properties during the time of storage and usage by the patient.
Stability is defined as the capacity of drug substance to remain
within the established specification to maintain its identity,
strength, quality and purity throughout the retest or expiration
during period.
Chemical kinetics is the study of rate of chemical changes taking
place during the chemical reaction.
It determines stability of drug/ half life of the drug which is
defined as time necessary for a drug to decay to its half life or
50% conc.
22. Rate and order of reaction
The velocity with which a reaction or a process occurs is called as
its rate,
concentration of drugs which influences the rate of reaction or
process is called as the order of reaction or order of process.
Consider the following chemical reaction
Drug A Drug B
The rate of forward reaction is expressed as:
-dA/dt
-ve sign =concentration of drugs A decreases with time.
As the reaction proceeds,the concentration of the drugs B increases
and the rate of reaction can also be expressed as :
dB/dt
23. Experimentally the rate of reaction is determined by measuring the
decrease in concentration if drug A with time.
If c is the concentration of drug A , the rate of decrease in c of drug
A as it is changed to B can be described by expression as function of
time t.
dC/dt=-kc
Where,
k=rate constant
n=order of reaction
if,
n=0 (zero order process)
n=1 ( first order process)
24. • The three commonly encountered rate process:
zero order reaction
first order reaction
mixed order reaction
Zero order kinetics:
• It is also called as constant rate process.
• The reaction is said to be zero-order reaction, if the rate of reaction
is independent of the concentration i.e.the rate of reaction cannot be
increased further by increasing the concentration of reactants.
dc/dt = -KoCo =-Ko equation….1
Where
KO=zero-order rate constant ( in mg/min )
Rearrangement of eqn 1 yields:
dc=-Kodt equation…….2
25. Integration of equation 2 gives:
C-Co = -kot
where,
Co=concentration of drug at t=0, and
C = concentration of drug yet to undergo reaction at time t.
26. First order kinetics:
whose rate is directly proportional to the concentration of the drugs
undergoing reaction i.e. greater the concentration , faster the reaction.
First –order process is said to follow linear kinetics
dC /dt = -K C
where
K= first –order rate constant (per hour)
Graph showing linear relationship between rate of reaction and concentration
of drug.
27. Factors affecting rate of reaction
• Temperature
• Light
• Solvent
• Surface area
• Catalysis
• Concentration
• Dielectric constant
28. STABILITY TESTING
Stability:
defined as capability of a particular formulation in a specific
container/ closure system to remain within its physical, chemical,
microbilogical, toxicological, protective and informational
specifications.
• It is the extent to which a product retains, within the specified limits,
throughout its period of storage and use, the same properties and
characteristics possessed at the time of its packaging.
Scope :
• Provide evidence as to how the quality of drug product varies with
time.
• Establish shelf life of drug product.
• Determines recommended storage conditions.
29. Stability testing methods
1. Real time stability testing
2. Accelerated stability testing
3. Retained sample stability testing
4. Cyclic temperature stress testing
30. REAL TIME STABILITY TESTING
• Performed for longer duration of the test period in order to allow
significant product degradation under recommended storage
conditions.
• Depends upon the stability of the product which should be long
enough to indicate clearly that no measurable degradation occurs.
Data collected at to distinguish stability of reference
Appropriate instability from material include the
frequency day to day stability of reagent as
well as consistency
performance
31. ACCELERATED STABILITY TESTING
• A product is stressed at several high temp and the amount of heat
input required to cause product failure is determined.
• This is done to subject the product to a condition that accelerates
degradation.
• This information is then projected to predict shelf life or used to
compare the relative stability of alternative formulations.
Samples subjected Refrigerated Assayed
to stress simultaneously
The concept of accelerated stability testing is based upon Arrhenius
equation,
ln K = lnA + E
` RT
32. RETAINED SAMPLE STABILITY STUDY
• Usual practice for every marketed product for which stability data
are required.
• Only one batch a year are selected.
• If the number of batches marketed exceeds 50, stability samples
from two batches are recommended to be taken.
• Stability testing by evaluation of market samples is a modified
method which involves taking samples already in the market place
and evaluating stability attributes.
33. CYCLIC TEMPERATURE STRESS TESTING
• Is not a routine testing method for marketed products.
• In this method, cyclic temp.stress tests are designed on knowledge
of the product so as to mimic likely conditions in market place
storage.
• The period of cycle mostly considered is 24 hours.
• The min and max. temp for the cyclic stress testing is recommended
to be selected on a product by product basis and considering factors
like recommended storage temp for the product.
• The test should normally have 20 cycles.
34. THEORIES OF DISPERSION
Dispersed system consist of particulate matter, known as the
dispersed phase,distributed throughout a continuous or dispersion
medium.
The dispersed material may range in size from particles of atomic
and molecular dimensions to particles whose size is measured in
millimetres.
35. Solid dispersion system
• Solid despersion is defined as the despersion of
one or more active ingridennts in an inert carrier
or matrix at solid state prepared by melting
solvent or melting solvent method.
• 1. MOLECULAR DIFFUSION- obeys ficks law and
second law of diffusion
• 2. ficks first law relates diffusive flux to
concentration under the assumption of stedy
state.
• J= -D ds/dx
• J=FLUX, D=diffusion, S= concentration
36. • C. Ficks second law predicts how diffusion
causes the concentration to change with time
. It is partial differential equation which in one
dimension reads
dY/dt=D d2y/d2X
t= time in sec
D= diffusion coefficent in dimensions
X= position
37. MECHANICAL DISPERSION
Because of the variation in microscopic velocity
within each flow channel from one channel to
another
spreading is present.
EDDY DIFFUSION;
the mixing process that is due to the random
flucuation of fluid mass or the occurance of eddies
in condition described as turbulent flow , exist in
porous media in slight extent more in large
particles.
38. MIXING DUE TO STRUCTURAT CONTROL
The apparent mixing mechanism due to large
scale structural variations in the granular
material these variation scontrol the direction of
movement of a given fluid partice, hence , if
average concentration is taken along a given
plane parallel or transverse to the direction of
flow a large scale mixing is observed
39. ADSORPTION
A process which differs the others in the amount
of mass transported depends on the
physiochemical interaction of the transported
substance and the solid of the medium. The
existane of an unbalanced force field causes
migration of a liquid- borne contaminat from the
liquid to the solid surface whereas in others it
moves continuously from liquid to solid or vice
versa.
