CSJM University Kanpur

University Institute of Pharmacy

Drug Excipient
Interaction
Presented by-
Diptee Gupta
M.Pharm (Pharmaceutics) 1

1st Semester ( 2019-20)

 CONTENT

1. Introduction
2. Drug-excipient interaction
3. Importance of these studies
4. Mechanism of drug-excipient interaction
5. Analytical techniques used to detect drug excipient
interaction

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 INTRODUCTION

Pharmaceutical
Excipients- Role of Excipients-

An excipient is a  Provide bulk to the

pharmacologically inactive formulation
substance formulated  Protect, support or
alongside the API of a enhance the stability of
medicine to impart specific formulation.
qualities to them.  Improve bioavailability of
drug

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 DRUG EXCIPIENT
INTERACTION

 Drug substances are usually in intimate contact with excipient.

Although these are pharmacologically inert, they can undergo
chemical and physical interaction with drug substance under
favourable condition. These interactions can lead to instability
resulting in the formulation of new entities.

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 IMPORATNCE OF THESE STUDIES

 To find out how compatible an excipient is with API

 Maximizes the stability of a dosage form.

 Do not have impact on stability of API

 Determine the list of excipient that can be used in final dosage form.

 Helps to avoid surprise problem during formulation process

 These studies are the part of preformulation study and this study
data is essential for IND submission.

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 MECHANISM OF DRUG
EXCIPIENT INTERACTION

 They can be classified as-

Physical interaction

Chemical interaction

Biopharmaceutical interaction

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 1. PHYSICAL
INTERACTION

These are very common in dosage form and also difficult to detect.
These involve change in –
 Dosage uniformity, color, odor, dissolution, stability or sedimentation
rate etc.
 These interactions can either be beneficial or detrimental to the product
performance.
Eg. of some these interactions are as follows –

Contd….
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 Interaction Beneficial effect example Detrimental effect
example
1.Complexation Cyclodextrin • Tetracycline
• Formulation of chlorpromazine
with tween 80 and SLS
2. Adsorption Formulation of Indomethacin (NSAID) using Formulation of Cetyl Pyridinium
kaolin as adsorbent chloride tablets using magnesium
stearate as a lubricant
3.Solid dispersion Formulation of Piroxicam, Norfloxacin, Interaction between Povidone and
Nifedipine and Ibuprofen using PEG of stearic acid in a capsule
different grades

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 2.CHEMICAL INTERACTION

Chemical interaction involves chemical reaction between drugs and

excipients or drugs and impurities/ residues present in the excipients to
form different molecules. Chemical interactions are almost detrimental to
the product because they produce degradation products. They are as
follows-
1.Chemical interactions between drug and excipients- Eg are as follows-
• Maillard reaction- eg chlorpheniramine and dextrose interaction

Primary amines
Which finally break into
+ reducing Form imine
amadori compounds
sugar

Contd….

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 • Release of diclofenac sodium from matrix tablet was inhibited by polymer
chitosan at low pH, due to formation of ionic complex between diclofenac
sodium and ionized cationic polymer
• Sodium alginate dissolve in water to form large negatively charged anions,
co-formulation in aqueous systems with drugs such as neomycin and
polymixin (positively charged) result in precipitation.
2. Interaction of drug with excipient residues/ impurities-
Excipients are not exquisitely pure. They have some residues which
affect the drug action.
Impurities found in common excipients-

Contd….
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 Excipient Residue

Povidone, Polysorbates Peroxides

Magnesium stearate Antioxidants
Lactose Aldehydes, reducing sugars
Benzyl alcohol Benzaldehyde

 Sterilization by autoclaving of parenteral preparations containing dextrose can

cause isomerization of dextrose in fructose and formation of aldehyde which
react with primary amino group to cause color change.
 Peroxide residues in povidone responsible for the enhanced formation of the N-
oxide degradation product of the oestrogen receptor modulator, Raloxifene.

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 3. BIOPHARMACEUTICAL
INTERACTION

These are the interactions which are observed after administration of

medicine. These interactions occur in the form of-
.
 The interaction is between  The interactions have
the medicine (drug the tendency to
substance and excipients) influence the rate of
and the body fluids absorption of the drug.

Various eg. of these interactions are as follows-

Contd….
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a) 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 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.

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b) Increase in gastrointestinal motility-
Many excipients such as sorbitol and xylitol have the tendency to increase
gastrointestinal motility, thus reducing the available time for absorption of drugs like
Metoprolol.
c) Effect on P-glycoprotein efflux transporter-
P-glycoprotein thus interferes in the bioavailability of different anticancer and other
drug substances. Thus, several excipients e.g., Span 20, Tween 20, Tween 80,
Pluronic, Poloxamer etc. are incorporated in the formulations which help in
inhibition of P-glycoprotein to enhance availability of the drug into the cell, to
produce the desired action.

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 ANALYTICAL TECHNIQUES USED TO DETECT
DRUG-EXCIPIENT INTERACTION-
1. Thermal methods-
DSC- Differential Scanning Calorimetry
DTA- Differential Thermal Analysis
Isothermal micro Calorimetry
Hot stage microscopy
2. Spectroscopic techniques-
FT-IR Spectroscopy
Powder X- ray diffraction
Solid state NMR
3. Chromatography - SIC-Self Interactive Chromatography
TLC-Thin Layer Chromatography and HPTLC
HPLC-High Pressure Liquid Chromatography
4. Accelerated stability study
4. Miscellaneous- Radiolabelled Techniques
Fluorescence Spectroscopy
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 DSC- DIFFERENTIAL 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 maximize the
likehood of observing an interaction. -
Mixture should be examined under N2 to
eliminate oxidative and pyrrolytic effects
at heating rate ( 2,5 or10 degree C/min)
on DSC apparatus.

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Interaction detected by DSC -
Elimination of endothermic peak

Any new peak appeared

Change in melting point / peak temperature

Change in peak shape (height and width)

Change in area of peak or enthalpy

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 DTA- DIFFERENTIAL THERMAL
ANALYSIS

 This technique is useful in the investigation

of solid-state interactions and detection of
eutectics.
In this change in temperature between test • Thermogram (DTA curve)
sample and reference material is measured If any of a mixture show
appearance or disappearance
under controlled and identical condition. interaction of one or more peaks
occur-
This differential temperature is plotted corresponding to those of
the components.
against time or temperature.
Interaction can be identified by comparing • The thermogram of
DTA curve obtained from the test sample If no mixtures show same
interaction patterns corresponding to
with those of reference material. occur- those of the individual
components

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 SIC-SELF INTERACTIVE
CHROMATOGRAPHY

SIC is useful for proteinous drug and excipients.

Principle - For different mobile phases (i.e. different excipients) the
injected drug have different interactions (may be repulsive or attractive)
with the stationary phase of drug leads to shift in retention time
Method -It is a modified type of affinity chromatography. Here, drug is
made immobilized as the stationary phase & solution to be tested( excipient
solution) acts as mobile phase.
Measure retention time and compare with non-retained marker.
Eg. INF-Tau(an antiviral drug)- Interactions of it with different types of
buffers were studied by SIC. Here, buffer is used to prevent aggregations.

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Figure (a) Figure (b) Figure (c)

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 TLC & HPTLC

TLC is generally used as confirmative test of compatibility after

performing DSC because if sample undergo negligible thermal changes,
it will difficult to detect 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 & drug: excipient mixture are prepared &
spotted on the same baseline at the end of 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.

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 REFERENCES

• Lachman & Lieberman, The Theory and Practice of Industrial Pharmacy

• N. Fathima, Kajal Ahir, Vandana Patel, Lata Manani, Chirag Patel Drug
excipient interaction and its importance in dosage form development,
Journal of applied Pharmaceutical Science 2011
• Priyanka Patel, Kajal Ahir, Vandana Patel, Lata Manani, Chirag Patel
Drug-Excipient compatibility studies: First step for dosage form
development, The Pharma Innovation Journal 2015
• Bapi Gorain, Hira Choudhury, Manisha Pandey, Thiagarajan
Madheswaran, Prashant Kesharwani and Rakesh K. Tekade Drug–
Excipient Interaction and Incompatibilities 2018

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