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DRUG-EXCIPIENT INTERACTION
 Presented By-
 Hemant Saini
 D50217008
 PDM University
 Faculty of Pharmaceutical Sciences
1
DRUG-EXCIPIENT COMPATIBILITY STUDIES
DRUG-EXCIPIENT COMPATIBILITY STUDIES REPRESENT AN IMPORTANT PHASE IN DRUG
DEVELOPMENT. DRUG SUBSTANCES ARE USUALLY COMBINED WITH EXCIPIENTS WHICH
SERVE DIFFERENT AND SPECIALIZED PURPOSE. ALTHOUGH EXCIPIENTS ARE
PHARMACOLOGICALLY INERT, THEY CAN UNDERGO CHEMICAL REACTIONS AND PHYSICAL
INTERACTIONS WITH DRUG SUBSTANCES UNDER FAVORABLE ENVIRONMENTAL
CONDITIONS. THESE INTERACTIONS CAN LEAD TO INSTABILITY RESULTING IN THE
FORMATION OF NEW ENTITIES WITH DIFFERENT PHYSICOCHEMICAL PROPERTIES AND
PHARMACOLOGICAL EFFECTS.
2
 Contents
 1 Importance of Drug-Excipient compatibility studies
 2 Goals of Drug-Excipient compatibility studies
 3 Mechanism of Drug-Excipient(s) interactions
 3.1 a. Physical drug-excipient interactions
 3.2 b. Chemical drug-excipient interactions
 3.3 c. Physiological/Biopharmaceutical drug-excipient interactions
 4 Analytical Methods for Drug – Excipient Incompatibility
 4.1 1. Thermal Techniques
 4.1.1 a. Differential Scanning Calorimetry (DSC)
 4.1.2 b. Isothermal microcalorimetry
 4.1.3 c. Differential Thermal Analysis
 4.2 2. Spectroscopic Techniques
 4.2.1 a. Vibrational spectroscopy
 4.2.2 b. Flourescence Spectroscopy/ Fluorometry/ Spectrofluorometry
 4.3 3. Chromatographic Techniques
 4.3.1 a. Thin Layer Chromatography (TLC)
 4.3.2 b. High Performance Liquid Chromatography(HPLC)
 5 Conclusion
3
 Importance of Drug-Excipient compatibility studies
 It maximizes the stability of a dosage form.
 It bridges drug discovery and development.
 It is essential investigational new drug submission (IND).
 It helps to avoid surprise problems during formulation processes.
 Goals of Drug-Excipient compatibility studies
 To find out how compatible an excipient is with Active Pharmaceutical
Ingredient (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.
4
 Mechanism of Drug-Excipient(s) interactions
 The mechanisms of drug-excipient(s) interactions are not fully understood
despite the best efforts of several eminent investigators in the field. However,
some of the common ways by which excipients may alter drug stability in a
dosage form include:
 a. Physical drug-excipient interactions
 These types of interactions are quite common, but are very difficult to detect
in dosage forms. Drug substances and excipients interact without undergoing
changes involving breaking or formation of new bonds. The components of
the drug product retain their chemical structure, but undergo changes which
alter their physical properties. Physical interactions may result in changes in
dosage uniformity, color, odor, 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.
5
 Benefits of physical drug-excipient interactions
 Improves bioavailability of sparingly water soluble drugs: The bioavailability
of sparingly water soluble drugs can be enhanced using complexing agents e.g.,
complexation of cyclodextrin with ursodeoxycholic acid increases the rate and
extent of drug dissolution which in turn increases the bioavailability of the drug
substance.
 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. Thus, an increase in bioavailability of drug substance. E.g.,
formulation of indomethacin using kaolin as adsorbent increases its
bioavailability as a result of increased dissolution rate.
 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., improved dissolution rates of
drugs like piroxicam, norfloxacin, nifedipine and ibuprofen were achieved when
these drugs were formulated into solid dispersions using polyethylene glycol of
different molecular weights. 6
 Detrimental (-ve) effects of physical drug-excipient interactions:-
 Decreases dissolution and absorption rates of drug substances due to
formation of insoluble complexes e.g., tetracycline forms an insoluble
complex with calcium carbonate leading to slower dissolution and decreased
absorption in the gastrointestinal tract.
 Reduces bioavailability of drugs available for dissolution: Adsorption of
drugs on excipient surface can also lead to reduced bioavailability as the drug
is not available for dissolution. E.g., the marked reduction in the antibacterial
activity of cetyl pyridinium chloride cations in tablets containing cetyl
pyridinium chloride is due to the adsorption of cetyl pyridinium chloride on the
surface of magnesium stearate which acts as a lubricant.
 Slow dissolution of drugs: Ion interactions can result in slow dissolution of
drugs. E.g., solid dispersion product formed due to interaction between
povidone and stearic acid in a capsule showed slow dissolution of the
drugs.
7
 b. Chemical drug-excipient interactions
 This involves the interaction of drug substance and excipient through chemical
degradation pathway. The formulation undergoes a chemical reaction in which the
constituent atoms are rearranged via bond breakage and bond formation to produce
an unstable chemical entity. Generally, chemical interactions have a deleterious effect
on the formulation hence; such kind of interactions must be avoided.
 Hydrolysis Drugs ( Methyl DOPA and Penicillin) with functional groups such as
esters, amides,lactones or lactams may be susceptible to hydrolytic degradation.
 Oxidation Oxidative degradation is second only to hydrolysis as a mode of
decomposition. Oxidation involves removal of an electropositive atom, radical or
electron or, conversely, addition of an electronegative moiety. Oxidation reactions can
be catalyzed by oxygen, heavy metal ions and light, leading to free radical formation.
Free radicals react with oxygen to form peroxy radicals which in turn react with
oxidizable compound to generate additional free radicals to fuel further reactions.
Aldehydes, alcohols, phenols, alkaloids and unsaturated fats and oils are all
susceptible to oxidation.
 Isomerization involves 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 greater than for the dextro
(D) form.
 Photolysis Reactions such as oxidation-reduction, ring alteration and polymerization
can be catalyzed or accelerated by exposure to sunlight or artificial light. Energy
absorption is greater at lower wavelengths. Exposure to light leads to discoloration
even when chemical transformation is modest or even undetectable. e.g; Riboflavin,
Folic Acid, Nifidipine.
 Polymerization Intermolecular reactions can lead to dimeric and higher molecular
weight species. Concentrated solutions of Ampicillin, an amino-pencillin,
progressively form dimer, trimer and ultimately polymeric degradation products.
8
 C. Physiological/Biopharmaceutical drug-excipient interactions
 By this we mean interactions that occur after the drug product has been administered
to the patient. These interactions are similar to physical interactions but differs in the
sense that 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.
 All excipients interact in a physiological sense when they are administered as part of a
dosage form. They are included in a formulation specifically because they interact with
the physiological fluids and function in certain ways e.g., disintegrants in immediate
release tablets and capsule formulations. On the other hand, physiological interactions
can be detrimental to the patient. Examples of such interactions include
 Premature 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 that cause increase in the pH
of the stomach. This results in premature release of active pharmaceutical ingredient
in stomach itself, which results in degradation of drug in stomach e.g., pro-drugs or
side effects like gastric bleeding as in the case of NSAIDs.
 Interactions due to adjunct therapy– A classic biopharmaceutical incompatibility is
the interaction between tetracycline antibiotics and antacids containing aluminium,
calcium, magnesium, bismuth and zinc ions. The tetracycline antibiotics chelates with
these metallic ions to form complexes which only are not poorly absorbed, but also
have reduced antibacterial effects.
9
 Increase in gastrointestinal motility – Certain excipients such as sorbitol
and xylitol have the tendency to increase gastrointestinal motility, thus
reducing the available time for absorption of drugs like metoprolol. The effect
is very much dependent on the amount of the excipient administered at one
time. Polyethylene glycol 400 has also been reported to influence on the
absorption of ranitidine.
 Analytical Methods for Drug – Excipient Incompatibility
 The key to the early assessment of instability in formulations is the availability
of analytical methods to detect low levels of degradation products, generally
less than 2%. Below are some of the analytical methods which are used in
drug-excipient compatibility studies.
10
 1. Thermal Techniques
 Thermal methods of analysis comprise a group of techniques in which the
physicochemical properties of drug substances are measured as a function of
temperature. In this method, the test samples are subjected to a controlled
temperature over a given period of time. This method of analyses plays a vital
role in drug-excipient compatibility studies and has been frequently used for
quick identification of physicochemical interaction between drugs and
excipients.
 a. Differential Scanning Calorimetry (DSC)
 DSC represents a leading thermal screening technique that has been
increasingly used for excipient compatibility studies for over five decades. 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 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. 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.
11
Advantages of Differential Scanning Calorimetry
Requires of 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.
12
 B. Isothermal microcalorimetry
 This is an extremely sensitive and invaluable tool used to determine drug-excipient
incompatibilities. It measures minute amounts of heat emitted or absorbed by a sample in a
variety of processes. This method of analysis 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 sample. The
thermal activity of the test sample is compared to the “non-interaction” curve constructed
from the control (i.e., thermal activity of drug substance and excipient that were measured
individually).
 If an experimentally significant difference is observed, the excipient is considered to be
potentially incompatible with the drug substance.
13
 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.
14
 C. Differential Thermal Analysis
 Differential Thermal Analysis (DTA) is 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. In the absence of any interaction, the DTA peak of the
test sample show patterns corresponding to those of the individual components.
15
 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 of Differential Thermal Analysis
 Differential Thermal Analysis are 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 flat bottomed sample
container.
16
 2. Spectroscopic Techniques
 Spectroscopic analytical methods 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. This method of analysis 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.
 Some of the most frequently used spectroscopic methods of analysis include vibrational
spectroscopy, diffuse reflectance spectroscopy, fluorescence spectroscopy, FT-IR spectroscopy etc.
and each operate over different, limited frequency ranges within this broad spectrum, depending on
the processes and degree of the energy changes.
 a. 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. While infrared spectroscopy uses the infrared region of the
electromagnetic spectrum (from about 400 cm-1 to 4000 cm-1) to measures the change in dipole
moment, Raman spectroscopy uses inelastic scattering process to measures the change in
polarization of the sample.
 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.Vibrational spectroscopy are not only used to investigate solid state properties of drug
substances and their formulations, but are also used as compatibility study tool as the vibrational
changes serve as probe of potential intermolecular interactions among the components. Thus, drug-
excipient interactions that occur during processing can easily be detected with the aid of these
spectroscopic techniques.
17
 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 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).
18
 b. Flourescence Spectroscopy/ Fluorometry/ Spectrofluorometry
 This is a type of spectroscopic techniques which analyzes fluorescence
properties of samples in order to provide information regarding their
concentration and molecular environments. It involves using 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. Apart from
determining stability of peptide drugs in solution, fluorescence spectroscopy
has also been used in:-
 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 excipient.
 Studying the binding of drugs to components in complex formulations and
measuring small amount of drugs and for studying drug-protein binding in bio-
analysis.
19
 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.
20
 3. Chromatographic Techniques
 Chromatography is an analytical technique frequently used in pharmaceutical research 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, all following the same basic principles
of operation.
 a. Thin Layer Chromatography (TLC)
 TLC is a chromatographic method of analysis carried out on glass, plastic or metal plates
coated on one side with a thin layer of adsorbent. The thin layer of adsorbent serves as the
stationary phase and is usually made of silica, alumina, polyamide, cellulose or ion exchange
resin. In TLC, solutions of the test samples (that is, a mixture of the drug and the excipient)
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 mixture 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. The distance moved by the analyte is dependent on its
relative affinity for the stationary or 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.
21
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 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 gas chromatography and high-performance liquid chromatography 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 high-performance liquid
chromatography.
22
 b. High Performance Liquid Chromatography/ High Pressure Liquid
Chromatography (HPLC)
 HPLC is a chromatographic technique widely used in drug-excipient
compatibility studies by quantitative estimation of test samples that have been
subjected to isothermal stress testing (IST). This method of analysis is based
on mechanisms of adsorption, partition and ion exchange, depending on the
nature of stationary phase used.
 In HPLC, a liquid mobile phase is pumped under high pressure through the
stationary phase (a stainless-steel column packed with tiny particles with a
diameter of 3 to 10 micron). 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. 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.
23
Advantages of High-performance liquid chromatography
 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 High-performance liquid chromatography
 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. 24
 Conclusion
 Drug-excipient compatibility study is a necessary prerequisite 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 preformulation studies is of
paramount importance to accomplish the target product profile and critical quality
attributes.
 In order to avoid stability problems encountered 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.
25
S
26

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Drug excipients interaction : Types and techniques

  • 1. DRUG-EXCIPIENT INTERACTION  Presented By-  Hemant Saini  D50217008  PDM University  Faculty of Pharmaceutical Sciences 1
  • 2. DRUG-EXCIPIENT COMPATIBILITY STUDIES DRUG-EXCIPIENT COMPATIBILITY STUDIES REPRESENT AN IMPORTANT PHASE IN DRUG DEVELOPMENT. DRUG SUBSTANCES ARE USUALLY COMBINED WITH EXCIPIENTS WHICH SERVE DIFFERENT AND SPECIALIZED PURPOSE. ALTHOUGH EXCIPIENTS ARE PHARMACOLOGICALLY INERT, THEY CAN UNDERGO CHEMICAL REACTIONS AND PHYSICAL INTERACTIONS WITH DRUG SUBSTANCES UNDER FAVORABLE ENVIRONMENTAL CONDITIONS. THESE INTERACTIONS CAN LEAD TO INSTABILITY RESULTING IN THE FORMATION OF NEW ENTITIES WITH DIFFERENT PHYSICOCHEMICAL PROPERTIES AND PHARMACOLOGICAL EFFECTS. 2
  • 3.  Contents  1 Importance of Drug-Excipient compatibility studies  2 Goals of Drug-Excipient compatibility studies  3 Mechanism of Drug-Excipient(s) interactions  3.1 a. Physical drug-excipient interactions  3.2 b. Chemical drug-excipient interactions  3.3 c. Physiological/Biopharmaceutical drug-excipient interactions  4 Analytical Methods for Drug – Excipient Incompatibility  4.1 1. Thermal Techniques  4.1.1 a. Differential Scanning Calorimetry (DSC)  4.1.2 b. Isothermal microcalorimetry  4.1.3 c. Differential Thermal Analysis  4.2 2. Spectroscopic Techniques  4.2.1 a. Vibrational spectroscopy  4.2.2 b. Flourescence Spectroscopy/ Fluorometry/ Spectrofluorometry  4.3 3. Chromatographic Techniques  4.3.1 a. Thin Layer Chromatography (TLC)  4.3.2 b. High Performance Liquid Chromatography(HPLC)  5 Conclusion 3
  • 4.  Importance of Drug-Excipient compatibility studies  It maximizes the stability of a dosage form.  It bridges drug discovery and development.  It is essential investigational new drug submission (IND).  It helps to avoid surprise problems during formulation processes.  Goals of Drug-Excipient compatibility studies  To find out how compatible an excipient is with Active Pharmaceutical Ingredient (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. 4
  • 5.  Mechanism of Drug-Excipient(s) interactions  The mechanisms of drug-excipient(s) interactions are not fully understood despite the best efforts of several eminent investigators in the field. However, some of the common ways by which excipients may alter drug stability in a dosage form include:  a. Physical drug-excipient interactions  These types of interactions are quite common, but are very difficult to detect in dosage forms. Drug substances and excipients interact without undergoing changes involving breaking or formation of new bonds. The components of the drug product retain their chemical structure, but undergo changes which alter their physical properties. Physical interactions may result in changes in dosage uniformity, color, odor, 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. 5
  • 6.  Benefits of physical drug-excipient interactions  Improves bioavailability of sparingly water soluble drugs: The bioavailability of sparingly water soluble drugs can be enhanced using complexing agents e.g., complexation of cyclodextrin with ursodeoxycholic acid increases the rate and extent of drug dissolution which in turn increases the bioavailability of the drug substance.  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. Thus, an increase in bioavailability of drug substance. E.g., formulation of indomethacin using kaolin as adsorbent increases its bioavailability as a result of increased dissolution rate.  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., improved dissolution rates of drugs like piroxicam, norfloxacin, nifedipine and ibuprofen were achieved when these drugs were formulated into solid dispersions using polyethylene glycol of different molecular weights. 6
  • 7.  Detrimental (-ve) effects of physical drug-excipient interactions:-  Decreases dissolution and absorption rates of drug substances due to formation of insoluble complexes e.g., tetracycline forms an insoluble complex with calcium carbonate leading to slower dissolution and decreased absorption in the gastrointestinal tract.  Reduces bioavailability of drugs available for dissolution: Adsorption of drugs on excipient surface can also lead to reduced bioavailability as the drug is not available for dissolution. E.g., the marked reduction in the antibacterial activity of cetyl pyridinium chloride cations in tablets containing cetyl pyridinium chloride is due to the adsorption of cetyl pyridinium chloride on the surface of magnesium stearate which acts as a lubricant.  Slow dissolution of drugs: Ion interactions can result in slow dissolution of drugs. E.g., solid dispersion product formed due to interaction between povidone and stearic acid in a capsule showed slow dissolution of the drugs. 7
  • 8.  b. Chemical drug-excipient interactions  This involves the interaction of drug substance and excipient through chemical degradation pathway. The formulation undergoes a chemical reaction in which the constituent atoms are rearranged via bond breakage and bond formation to produce an unstable chemical entity. Generally, chemical interactions have a deleterious effect on the formulation hence; such kind of interactions must be avoided.  Hydrolysis Drugs ( Methyl DOPA and Penicillin) with functional groups such as esters, amides,lactones or lactams may be susceptible to hydrolytic degradation.  Oxidation Oxidative degradation is second only to hydrolysis as a mode of decomposition. Oxidation involves removal of an electropositive atom, radical or electron or, conversely, addition of an electronegative moiety. Oxidation reactions can be catalyzed by oxygen, heavy metal ions and light, leading to free radical formation. Free radicals react with oxygen to form peroxy radicals which in turn react with oxidizable compound to generate additional free radicals to fuel further reactions. Aldehydes, alcohols, phenols, alkaloids and unsaturated fats and oils are all susceptible to oxidation.  Isomerization involves 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 greater than for the dextro (D) form.  Photolysis Reactions such as oxidation-reduction, ring alteration and polymerization can be catalyzed or accelerated by exposure to sunlight or artificial light. Energy absorption is greater at lower wavelengths. Exposure to light leads to discoloration even when chemical transformation is modest or even undetectable. e.g; Riboflavin, Folic Acid, Nifidipine.  Polymerization Intermolecular reactions can lead to dimeric and higher molecular weight species. Concentrated solutions of Ampicillin, an amino-pencillin, progressively form dimer, trimer and ultimately polymeric degradation products. 8
  • 9.  C. Physiological/Biopharmaceutical drug-excipient interactions  By this we mean interactions that occur after the drug product has been administered to the patient. These interactions are similar to physical interactions but differs in the sense that 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.  All excipients interact in a physiological sense when they are administered as part of a dosage form. They are included in a formulation specifically because they interact with the physiological fluids and function in certain ways e.g., disintegrants in immediate release tablets and capsule formulations. On the other hand, physiological interactions can be detrimental to the patient. Examples of such interactions include  Premature 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 that cause increase in the pH of the stomach. This results in premature release of active pharmaceutical ingredient in stomach itself, which results in degradation of drug in stomach e.g., pro-drugs or side effects like gastric bleeding as in the case of NSAIDs.  Interactions due to adjunct therapy– A classic biopharmaceutical incompatibility is the interaction between tetracycline antibiotics and antacids containing aluminium, calcium, magnesium, bismuth and zinc ions. The tetracycline antibiotics chelates with these metallic ions to form complexes which only are not poorly absorbed, but also have reduced antibacterial effects. 9
  • 10.  Increase in gastrointestinal motility – Certain excipients such as sorbitol and xylitol have the tendency to increase gastrointestinal motility, thus reducing the available time for absorption of drugs like metoprolol. The effect is very much dependent on the amount of the excipient administered at one time. Polyethylene glycol 400 has also been reported to influence on the absorption of ranitidine.  Analytical Methods for Drug – Excipient Incompatibility  The key to the early assessment of instability in formulations is the availability of analytical methods to detect low levels of degradation products, generally less than 2%. Below are some of the analytical methods which are used in drug-excipient compatibility studies. 10
  • 11.  1. Thermal Techniques  Thermal methods of analysis comprise a group of techniques in which the physicochemical properties of drug substances are measured as a function of temperature. In this method, the test samples are subjected to a controlled temperature over a given period of time. This method of analyses plays a vital role in drug-excipient compatibility studies and has been frequently used for quick identification of physicochemical interaction between drugs and excipients.  a. Differential Scanning Calorimetry (DSC)  DSC represents a leading thermal screening technique that has been increasingly used for excipient compatibility studies for over five decades. 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 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. 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. 11
  • 12. Advantages of Differential Scanning Calorimetry Requires of 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. 12
  • 13.  B. Isothermal microcalorimetry  This is an extremely sensitive and invaluable tool used to determine drug-excipient incompatibilities. It measures minute amounts of heat emitted or absorbed by a sample in a variety of processes. This method of analysis 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 sample. The thermal activity of the test sample is compared to the “non-interaction” curve constructed from the control (i.e., thermal activity of drug substance and excipient that were measured individually).  If an experimentally significant difference is observed, the excipient is considered to be potentially incompatible with the drug substance. 13
  • 14.  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. 14
  • 15.  C. Differential Thermal Analysis  Differential Thermal Analysis (DTA) is 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. In the absence of any interaction, the DTA peak of the test sample show patterns corresponding to those of the individual components. 15
  • 16.  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 of Differential Thermal Analysis  Differential Thermal Analysis are 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 flat bottomed sample container. 16
  • 17.  2. Spectroscopic Techniques  Spectroscopic analytical methods 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. This method of analysis 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.  Some of the most frequently used spectroscopic methods of analysis include vibrational spectroscopy, diffuse reflectance spectroscopy, fluorescence spectroscopy, FT-IR spectroscopy etc. and each operate over different, limited frequency ranges within this broad spectrum, depending on the processes and degree of the energy changes.  a. 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. While infrared spectroscopy uses the infrared region of the electromagnetic spectrum (from about 400 cm-1 to 4000 cm-1) to measures the change in dipole moment, Raman spectroscopy uses inelastic scattering process to measures the change in polarization of the sample.  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.Vibrational spectroscopy are not only used to investigate solid state properties of drug substances and their formulations, but are also used as compatibility study tool as the vibrational changes serve as probe of potential intermolecular interactions among the components. Thus, drug- excipient interactions that occur during processing can easily be detected with the aid of these spectroscopic techniques. 17
  • 18.  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 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). 18
  • 19.  b. Flourescence Spectroscopy/ Fluorometry/ Spectrofluorometry  This is a type of spectroscopic techniques which analyzes fluorescence properties of samples in order to provide information regarding their concentration and molecular environments. It involves using 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. Apart from determining stability of peptide drugs in solution, fluorescence spectroscopy has also been used in:-  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 excipient.  Studying the binding of drugs to components in complex formulations and measuring small amount of drugs and for studying drug-protein binding in bio- analysis. 19
  • 20.  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. 20
  • 21.  3. Chromatographic Techniques  Chromatography is an analytical technique frequently used in pharmaceutical research 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, all following the same basic principles of operation.  a. Thin Layer Chromatography (TLC)  TLC is a chromatographic method of analysis carried out on glass, plastic or metal plates coated on one side with a thin layer of adsorbent. The thin layer of adsorbent serves as the stationary phase and is usually made of silica, alumina, polyamide, cellulose or ion exchange resin. In TLC, solutions of the test samples (that is, a mixture of the drug and the excipient) 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 mixture 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. The distance moved by the analyte is dependent on its relative affinity for the stationary or 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. 21
  • 22. 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 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 gas chromatography and high-performance liquid chromatography 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 high-performance liquid chromatography. 22
  • 23.  b. High Performance Liquid Chromatography/ High Pressure Liquid Chromatography (HPLC)  HPLC is a chromatographic technique widely used in drug-excipient compatibility studies by quantitative estimation of test samples that have been subjected to isothermal stress testing (IST). This method of analysis is based on mechanisms of adsorption, partition and ion exchange, depending on the nature of stationary phase used.  In HPLC, a liquid mobile phase is pumped under high pressure through the stationary phase (a stainless-steel column packed with tiny particles with a diameter of 3 to 10 micron). 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. 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. 23
  • 24. Advantages of High-performance liquid chromatography  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 High-performance liquid chromatography  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. 24
  • 25.  Conclusion  Drug-excipient compatibility study is a necessary prerequisite 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 preformulation studies is of paramount importance to accomplish the target product profile and critical quality attributes.  In order to avoid stability problems encountered 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. 25
  • 26. S 26