Drug Excipient Interaction Studies

Modern Pharmaceutics
Dr. Kailas Mali
Professor in Pharmaceutics,
Adarsh College of Pharmacy, Vita
Drug Excipient Interactions

1. Importance of Drug-Excipient compatibility studies
2. Goals of Drug-Excipient compatibility studies
3. Mechanism of Drug-Excipient(s) interactions
4. Analytical Methods for Drug – Excipient Incompatibility
1. Thermal Techniques
2. Spectroscopic Techniques
3. Chromatographic Techniques
Contents

● Excipients can initiate, propagate or
participate in chemical or physical
interactions with an active substance,
possibly leading to compromised quality
or performance of the medication.
● Study of drug-excipient compatibility is
an important phase in the pre-
formulation stage of drug development.
● The potential interactions between drugs
and excipients have effects on the
chemical, physical, bioavailability and
stability of the dosage form.
Importance of Drug-Excipient compatibility
studies
● It maximizes the stability of a dosage
form.
● It bridges drug discovery and
development.
● It is essential in investigational new drug
(IND) submission.
● It helps to avoid surprise problems during
formulation processes.
Introduction

Goals of Drug-Excipient compatibility
studies
● To find out how compatible an excipient
is with API or candidate drug molecules.
● To find out the excipient that stabilizes
an unstable API.
● To assign a relative risk level to each
excipient.
● To design and develop selective and
stability indicating analytical methods to
determine their impurities.
Types of Drug-Excipient(s) interactions
● Intentional (desirable) interactions
● Unintentional (undesirable) interactions
Mechanism of Drug-Excipient(s)
interactions
● Physical drug-excipient interactions
● Chemical drug-excipient interactions
● Physiological/Biopharmaceutical drug-
excipient interactions
Introduction

● Quite common but are very difficult to
detect.
● Interact without undergoing changes
involving breaking or formation of new
bonds.
● The components retain their chemical
structure but undergo changes which
alter their physical properties.
● Physical interactions may result in
changes in dosage uniformity, colour,
odour, flow properties, solubility,
sedimentation rate, dissolution rate etc.
● Incompatibilities are assessed by
physically observing the test samples.
● Physical interactions can be either
beneficial or detrimental to the product
performance depending on its
application.
Physical drug-excipient interactions

● Improves bioavailability of sparingly
water-soluble drugs: using complexing
agents (e.g., complexation of
cyclodextrin with ursodeoxycholic acid)
increases the rate and extent of drug
dissolution.
● Increases surface area of drugs available
for dissolution: Adsorption of drugs on
excipient surface can increase the
surface area of the drug available for
dissolution (e.g., formulation of
indomethacin using kaolin as adsorbent).
● Improves dissolution rate and
bioavailability of hydrophobic
drugs: Physical interactions of drugs with
excipient improve the dissolution rate
and bioavailability of hydrophobic
drugs.(e.g., solid dispersions of
piroxicam, norfloxacin, nifedipine and
ibuprofen using polyethylene glycol of
different molecular weights).
Benefits of Physical drug-excipient interactions

● Decreases dissolution and absorption
rates of drug substances due to the
formation of insoluble complexes (e.g.,
tetracycline forms an insoluble
complex with calcium carbonate;
Formulation of chlorpromazine with
polysorbate 80 and SLS decreased
membrane permeability of the drug).
● Slow dissolution of drugs: due to Ion
interactions. (e.g., solid dispersion of
povidone and stearic acid in a capsule
showed slow dissolution of the drugs.
● Reduces bioavailability of drugs
available for dissolution: Adsorption of
drugs on excipient surface can also
lead to reduced bioavailability. (e.g., the
marked reduction in the antibacterial
activity of containing cetyl pyridinium
chloride is due to the adsorption on the
surface of magnesium stearate in
tablets).
Detrimental effects of physical drug-excipient
interactions

Complexation
● Drug-polymer, Cyclodextrins
Adsorption
● Activated charcoal, chitosan, cellulose
acetate, minerals
Solid dispersions
● PVP, HPMC, PVA, Soluplus, HPC, CMC,
PEG, etc
Physical drug-excipient interactions

● Interaction through chemical degradation
pathway to produce an unstable
chemical entity.
● Generally, chemical interactions have a
deleterious effect on the formulation
hence; such kind of interactions must be
avoided.
● Chemical interactions can be in the form
of hydrolysis, oxidation, racemization,
polymerization, Maillard reactions,
photolysis etc.,
Some examples of chemical drug-excipient
interactions include
● Inhibition of diclofenac sodium release
from matrix tablet by polymer chitosan at
low pH. This occurs possibly via
formation of ionic complex between
diclofenac sodium and ionized cationic
polymer.
● Oxidation of diethylstilbestrol to the
peroxide and conjugated quinone
degradation products by Silicon dioxide
which acts as a catalyst.
Chemical drug-excipient interactions

Hydrolysis
● The most susceptible drugs are those
containing carbonyl groups like esters,
amides lactones, etc. with a good leaving
group.
● The reaction involves the addition of
water molecules and splitting the parent
drug into two parts.
● The presence of excipients may promote
the reaction either directly or by altering
the aqueous environment or affecting
other parameters such as pH, ionic
strength, or dielectric constant.
● Influence of water availability on
hydrolysis rates in aspirin compacts
containing dibasic calcium phosphate
dihydrate degrade approximately 10
times faster than formulations containing
lactose and two-fold faster than
formulations containing microcrystalline
cellulose.

Oxidation
● Reaction that increases the content of
more electronegative atoms in a
molecule. Electronegative heteroatoms
are generally oxygen or halogens.
● It can be catalyzed by oxygen, heavy
metal ions, and light, leading to free
radical formation (induction).
● Free radicals react with oxygen to form
peroxy radicals which in turn interact with
the oxidizable compound (propagation).
● Aldehydes, alcohols, alkaloids, and
unsaturated fats are of most susceptible
to oxidation.
● Excipients can be a source of oxidants
and metals.
● Excipients can also be involved in
generating mobile oxidative species such
as peroxyl radicals, superoxide, and
hydroxyl radicals.
● Many excipients contain impurities like
peroxides, aldehydes, organic acids,
reducing sugars.
● Raloxifene hydrochloride under went
oxidation to the N-oxide derivative in the
presence of povidone and crospovidone
due to peroxide impurities.

Maillard reaction
● Form colored pigments from sugars and
amines.
● Primary amines in the formulation with
carbonyl compounds, basically reducing
sugars, undergo Maillard reaction.
● Metoprolol + Lactose
Isomerisation
● Isomerization involves the conversion of
a chemical into its optical or geometric
isomer.
● Isomers may have different
pharmacological or toxicological
properties.
● For example, the activity of Levo (L) form
of adrenaline is 15-20 times greaterthan
for the Dextro (D) form.

Polymerization reaction
● Occur as a result of intermolecular
reactions lead to dimeric and higher
molecular weight species.
● Concentrated solutions of ampicillin,
aminopenicillin, progressively form dimer,
trimer, and ultimately polymeric
degradation products.
● Some organoleptic agents also may
undergo polymerization degradation.
● An example is the natural color Betalains
which is susceptible to color fading or
browning due to subsequent
polymerization

● Interactions that occur after the drug
product has been administered to the
patient.
● Differ from physical interactions in the
following aspects-
● The interaction is between the medicine
(drug substance and excipients) and the
body fluids.
● The interactions have the tendency to
influence the rate of absorption of the
drug.
● Physiological interactions can be
detrimental to the patient.
● Increasing gastric pH by antacids
affecting enteric coat integrity.
● Interaction of tetracycline with calcium
ions forming unabsorbable complex.
● Increasing GI motility by sorbitol and
glycols which affect drug transit time and
absorption.
Physiological drug-excipient interactions

● The key to the early assessment of
instability in formulations is the
availability of analytical methods to
detect low levels of degradation
products, generally < 2%.
1. Thermal Techniques
a. Differential Scanning Calorimetry (DSC)
b. Isothermal microcalorimetry
c. Differential Thermal Analysis (DTA)
2. Spectroscopic Techniques
a. Vibrational spectroscopy
b. Flourescence Spectroscopy/ Fluorometry/
Spectrofluorometry
3. Chromatographic Techniques
a. Thin Layer Chromatography (TLC)
b. High Performance Liquid Chromatography
(HPLC)
Analytical Methods of Detection

● Comprise a group of techniques in which
the physicochemical properties of drug
substances are measured as a function
of temperature.
● The test samples are subjected to a
controlled temperature over a given
period of time.
● Plays a vital role in drug-excipient
compatibility studies and has been
frequently used for quick identification of
physicochemical interaction between
drugs and excipients.
Differential Scanning Calorimetry
● In this technique, the DSC curves of pure
samples are compared to that obtained
from 50% mixture of the drug and
excipient (usually 5mg of the drug in a
ratio of 1:1 with the excipient).
● It is assumed that the thermal properties
(melting point, change in enthalpy, etc.)
of blends are the sum of the individual
components if the components are
compatible with each other.
Thermal Techniques

● An absence, a significant shift in the
melting of the components or
appearance of a new exo/endothermic
peak and/or variation in the
corresponding enthalpies of reaction in
the physical mixture indicates
incompatibility.
● However, slight changes in peak shape
height and width are expected due to
possible differences in the mixture
geometry.
●
Thermal Techniques

Advantages of Differential Scanning
Calorimetry
● Requires short time of analysis
● Low sample consumption
● Provides useful indications of any
potential incompatibility
Limitations of Differential Scanning
Calorimetry
● Conclusions based on DSC results alone
may be misleading and have to be
interpreted carefully.
● DSC cannot be used if thermal changes
are very small. Therefore, it should
always be supported by some non-
thermal methods like TLC or FT-IR or
XRPD.
● DSC cannot detect the incompatibilities
which might occur after long-term
storage.
Thermal Techniques

Isothermal microcalorimetry
● Extremely sensitive and invaluable tool to
determine incompatibilities.
● It measures minute amounts of heat
emitted or absorbed by a sample in a
variety of processes.
● Is used to characterize pharmaceutical
solid to obtain heats of solution, heats of
crystallization, heats of reaction, heats of
dilution and heats of adsorption – since
nearly all physicochemical processes are
accompanied by a heat exchange within
their surroundings.
● In a typical drug-excipient compatibility
study, a solution, suspension, or solid
mixture of drug substance and excipient
is placed in the calorimeter and the
thermal activity (heat gained or evolved)
at a constant temperature is monitored.
● The thermal activity observed is
assumed to be proportional to the rate of
chemical and/or physical processes
taking place in the sample.
● The thermal activity of the test sample is
compared to the “non-interaction” curve
constructed from the control.
Thermal Techniques

● If an experimentally significant difference
is observed, the excipient is considered
to be potentially incompatible with the
drug substance.
Advantages of Isothermal microcalorimetry
● Samples are not heated, and so the
changes are observed as it might
typically occur at ambient conditions.
● It is sensitive to small changes in heat
gained or evolved, thus small samples, or
slow processes, may be investigated.
● It gives meaningful results without
requirement of multiple sample
preparations
● Does not require long storage times, thus
saving valuable time and effort during the
formulation process.
Limitations of Isothermal microcalorimetry
● Isothermal microcalorimetry is not
discriminatory. The exact nature of the
transition must be known in order to
interpret the data.
Thermal Techniques

Differential Thermal Analysis
● An analytical technique in which the
changes in temperature between a test
sample and an inert reference under
controlled and identical conditions is
used to identify and quantitatively
analyze the chemical composition of a
substance.
● When the test sample and inert reference
are heated to a sufficient temperature,
the thermal changes in the test sample
which lead to the absorption or emission
of heat can be detected relative to the
inert reference (control).
● The differences in temperature are then
plotted against time, or against
temperature.
● Drug-excipient interactions can be
identified by comparing DTA curves
obtained from the test sample with those
of inert reference.
● Incompatibilities are indicated by the
appearance of one or more new DTA
peaks or the disappearance of one or
more DTA peaks corresponding to those
of the components of the test sample.
Thermal Techniques

Advantages of Differential Thermal
Analysis
● DTA technique yield data that are
considerably more fundamental in
nature.
● Enthalpy change (under a DTA peak) is
not affected by the heat capacity of the
sample.
Limitations Differential Thermal Analysis
● DTA is usually performed on powders
and for this reason, the resulting data
may not be representative of bulk
samples, where transformations may be
controlled by the buildup of strain energy.
● The rate of heat evolution may be high
enough to saturate the response
capability of the measuring system. This
limitation may be overcome by diluting
the test sample with inert material.
● Problems are encountered in transferring
heat uniformly away from the specimen
at temperature range of 200 to 500◦C.
This problem may be solved by using flat
disc-like thermocouples to ensure
optimum thermal contact with the now
flat bottomed sample container.
Thermal Techniques

● Include all techniques which probe
certain features of a given sample by
measuring the amount of radiation
emitted or absorbed by molecular or
atomic species of interest.
● Uses electromagnetic radiation to
interact with matter and thus investigate
certain features of a sample as a
function of wavelength (λ).
● Because these methods of analysis use a
common set of optical devices for
collimating and focusing the radiation,
they often are identified as optical
spectroscopies.
● Most frequently used methods are
vibrational spectroscopy, diffuse
reflectance spectroscopy, fluorescence
spectroscopy, FT-IR spectroscopy etc.
● Each operates over different, limited
frequency ranges within the broad EM
spectrum, depending on the processes
and degree of the energy changes.
Spectroscopic Techniques

Vibrational Spectroscopy
● Using this method, information on the
molecular structure and environment of
organic compounds are generated by
measuring the vibrations of chemical
bonds that result from exposure to
electromagnetic energy at various
frequencies. These vibrations are
commonly studied by infrared and
Raman spectroscopies.
● IR & Raman Spectroscopy are
complementary to each other.
● The spectra obtained are indicative of the
nature of chemical bonds present in the
test sample, and when pieced together
can be used to identify the chemical
structure or composition of a given
sample.
Spectroscopy Range Measures
IR 4000 – 400
cm-1
Dipole moment
(direct absorption)
RAMAN 4000 – 10
cm-1
(practical)
Polarizability
(inelastic
scattering)

IR Spectroscopy Raman Spectroscopy
IR spectra result from light absorption by vibrating
molecules
Raman spectra result from scattering of light by vibrating
molecules
IR activity results from changing dipole moment Raman activity results from change of polarizability of a x
IR spectroscopy the range is limited to IR
frequencies
A monochromatic light beam of high intensity laser can be
used in UV, visible or IR regions in Raman measurements
Absorption signal is measured in the same direction
as the incident beam.
Scattered light is observed at right angles to the direction
of the incident beam
IR technique requires solid sample preparation using
KBr or permit direct observation of liquids, films and
gels.
Non-destructive. The sample can be measured directly in
glass container or in case of pharmaceuticals samples
can be measured in original sachets.
Less intense light source Highly intense focused laser source. Small samples
possible.
Less costly method More costly method

Advantages of vibrational spectroscopy
● Sensitive and can be used for process
monitoring.
● Requires short time of analysis
● Nondestructive method of analysis with
the exception of some UV-Vis
applications
● Requires minimal or no sampling
preparation (Raman spectroscopy)
● Provides complex fingerprint which is
unique to the compound under
investigation (IR & Raman spectroscopy).
Limitations of vibrational spectroscopy
● Presence of overlapping peaks in the
spectra may hinder the analysis.
● Solvent may interfere if samples are run
in solution (Raman spectroscopy)
● Rarely used as a quantitative technique
because of relative difficulty in sample
preparation and complexity of spectra (IR
spectroscopy).

Flourescence Spectroscopy/ Fluorometry/
Spectrofluorometry
● Analyzes fluorescence properties of
samples to provide information regarding
their concentration and molecular
environments.
● Uses a beam of light, usually UV/visible
radiation, to excite the electrons in molecules
of certain compounds particularly those with
chromophore and rigid structure, causing them
to emit the radiation at a longer wavelength.
The radiation emitted (emission spectrum)
and/or the radiation absorbed by the sample
(excitation spectrum) can then be measured
and compared with the control.
Uses of Fluorescence Spectroscopy
● Determining the stability of peptide drugs
in solution
● Carrying out limit test where the
impurities are fluorescent or can simply
be rendered fluorescent.
● Determination of fluorescent drugs in low
dose formulations containing non-
fluorescent excipients.
● Studying the binding of drugs to
components in complex formulations
and measuring small amount of drugs
and for studying drug-protein binding in
bioanalysis.

Advantages of Fluorescence Spectroscopy
● It is highly sensitive, specific and easy to
carry out.
● Samples are analyzed at low cost as
compared to other analytical techniques.
● It is a selective detection method, thus, it
can be used to quantify a strongly
fluorescent compound in the presence of
a larger amount of non-fluorescent
materials.
● Can be used to monitor changes in
complex molecules e.g., proteins which
are increasingly used as drugs.
Limitations of Fluorescence Spectroscopy
● The technique only applies to a limited
number of molecules as there are
relatively small numbers of compounds
that have characteristic fluorescence.
● The technique is subject to interferences
by UV absorbing species and heavy ions
in solution.
● Fluorescence is affected by temperature.

● It is an analytical technique frequently
used for separating sample mixture into
its individual components. This
technique is based on selective
adsorption of the components on a
stationary phase (usually a solid or liquid
with high surface area).
● As the solute mixture passes over the
stationary phase, the components are
adsorbed and released at the surface at
varying rates depending on differential
affinities of individual components
towards stationary and mobile phase.
● Compared to other available analytical
techniques used in drug-excipient
compatibility studies, chromatography is
known for its characteristics of high
resolution and detection power, making it
suitable for detecting multiple
components in a complex mixture with
high accuracy, precision, specificity, and
sensitivity.
● Various chromatographic methods of
analysis have been used in drug-excipient
compatibility studies.
Chromatographic Techniques

Thin Layer Chromatography
● Carried out on glass, plastic or metal
plates coated on one side with a thin
layer of adsorbent (stationary phase) and
is usually made of silica, alumina,
polyamide, cellulose or ion exchange
resin.
● Test samples (i.e., drug – excipient
mixture) and the controls (individual drug
and excipients) are prepared and spotted
on the same baseline at the end of the
plate (the origin). The plate is then placed
upright in a closed chamber containing
mixtures of organic solvents which serve
as the mobile phase. The analyte moves
up the plate, under the influence of the
mobile phase which moves through the
stationary phase by capillary action
(development).

● The distance moved by the analyte is
dependent on its relative affinity for the
stationary and the mobile phase.
Incompatibilities are indicated by the
formation of a spot with Rf value
(retardation factor) different from that of
the controls after the plate has been
developed with solvent.
● An excipient on the other hand is
considered to be potentially compatible
with the drug substance if the spots
produced have identical Rf value with
those of the controls.
● Because some samples undergo
negligible thermal changes which might
be difficult to detect by thermal methods
of analysis, TLC is widely used in drug-
excipient compatibility study as a
confirmative test of compatibility after
performing DSC.

Advantages of Thin Layer Chromatography
● The technique is robust and cheap
● The compound formed as a result of
incompatibilities between the drug and
the excipient can be detected if a suitable
detection reagent is used.
● Unlike GC and HPLC in which some
components of a mixture may elute from
the chromatographic system, there is no
risk of losing any component of the
mixture in TLC since all component of a
mixture can be seen in the
chromatographic system.
● Batch chromatography can be used to
analyze many samples at a time, thus
increasing the speed of analysis.
Limitations of Thin Layer Chromatography
● This technique is not suitable for volatile
substances.
● Sensitivity in often limited.
● Requires more operators skill for optimal
use than HPLC

High Performance Liquid Chromatography
● Quantitative estimation of test samples
that have been subjected to isothermal
stress testing (IST) is possible.
● Based on mechanisms of adsorption,
partition and ion exchange, depending on
the nature of the stationary phase.
● In HPLC, a liquid mobile phase is pumped
under high pressure through the
stationary phase. A small volume of the
test sample is loaded onto the head
stainless-steel column via a loop valve.
● Separation of a sample mixture occurs
according to the relative lengths of time
spent by its components in the stationary
phase (Rt). Column effluent can be
monitored with a variety of flow-through
device/detector that measures the
amount of the separated components.
● HPLC results that show a percentage
loss similar to the control (drug
considered individually) indicate no
interaction between drug and the
excipients and vice versa.

Advantages of HPLC
● Suitable for separating nonvolatile or
thermally sensitive molecules such as
amino acids, steroids etc.
● Has broad applicability, that is, it can be
used for both organic and inorganic
samples.
● Can be very sensitive and accurate.
● Provides better precision relative to the
changes being investigated.
● Can be readily automated.
● Less risk of sample degradation since
heating is not required in the process.
Limitations of HPLC
● Takes considerable time and resources
● Solvents used cannot be recycled.
● There is still need for reliable and
inexpensive detectors which can monitor
compounds that lack chromophores.

● Drug-excipient compatibility study is a
necessary pre-requisite to the development of
drug products that are safe and stable for use.
● Proper selection and assessment of possible
incompatibilities between the drug and
excipients during preformulatiion studies is of
paramount importance to accomplish the
target product profile and critical quality
attributes.
● To avoid stability problems during drug
development and post-commercialization,
there is need for proper assessment of
possible incompatibilities between the drug
and excipients using appropriate analytical
techniques.
● These analytical techniques are needed not
only to generate useful information with
regards to which excipient is compatible
with a drug substance, but also for
troubleshooting unexpected problems
which might arise during formulation
processes.
● Drug-excipient interactions may take a long
time to be manifested in conventional
stability testing programs, and are not
always predicted by stress and pre-
formulation studies.
Drug-excipient Interactions

Thank you
Professor in Pharmaceutics,
Adarsh College of Pharmacy, Vita, Sangli
415311
drkailasmali4u@gmail.com
+91 955 252 7353

Drug Excipient Interaction Studies

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