The document discusses drug-excipient interactions, which are critical as they can affect the stability and performance of pharmaceutical formulations. It highlights the importance of understanding the mechanisms of these interactions, which can be physical, chemical, or biopharmaceutical, to ensure the efficacy of drugs. Various analytical techniques, such as differential scanning calorimetry and chromatography, are outlined for detecting these interactions during preformulation studies.

1. 1
Presented by-
Diptee Gupta
M.Pharm (Pharmaceutics)
1st Semester ( 2019-20)
CSJM University Kanpur
University Institute of Pharmacy
Drug Excipient
Interaction

2. 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
2
CONTENT

3. An excipient is a
pharmacologically inactive
substance formulated
alongside the API of a
medicine to impart specific
qualities to them.
3
Role of Excipients-
 Provide bulk to the
formulation
 Protect, support or
enhance the stability of
formulation.
 Improve bioavailability of
drug
INTRODUCTION
Pharmaceutical
Excipients-

4.  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.
4
DRUG EXCIPIENT
INTERACTION

5. 5
 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.
IMPORATNCE OF THESE STUDIES

6. 6
MECHANISM OF DRUG
EXCIPIENT INTERACTION
 They can be classified as-
Physical interaction
Chemical interaction
Biopharmaceutical interaction

7. 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 –
7
1. PHYSICAL
INTERACTION
Contd….

8. 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
kaolin as adsorbent
Formulation of Cetyl Pyridinium
chloride tablets using magnesium
stearate as a lubricant
3.Solid dispersion Formulation of Piroxicam, Norfloxacin,
Nifedipine and Ibuprofen using PEG of
different grades
Interaction between Povidone and
stearic acid in a capsule
8

9. 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
9
2.CHEMICAL INTERACTION
Primary amines
+ reducing
sugar
Form imine
Which finally break into
amadori compounds
Contd….

10. • 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.
10
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….

11.  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.
11
Excipient Residue
Povidone, Polysorbates Peroxides
Magnesium stearate Antioxidants
Lactose Aldehydes, reducing sugars
Benzyl alcohol Benzaldehyde

12. These are the interactions which are observed after administration of
medicine. These interactions occur in the form of-
.
12
 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.
Various eg. of these interactions are as follows-
3. BIOPHARMACEUTICAL
INTERACTION
Contd….

13. 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.
13

14. 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.
14

15. 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
15
ANALYTICAL TECHNIQUES USED TO DETECT
DRUG-EXCIPIENT INTERACTION-

16.  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.
16
DSC- DIFFERENTIAL SCANNING
CALORIMETRY

17. Interaction detected by DSC -
17
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

18.  This technique is useful in the investigation
of solid-state interactions and detection of
eutectics.
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.
18
DTA- DIFFERENTIAL THERMAL
ANALYSIS
• Thermogram (DTA curve)
of a mixture show
appearance or disappearance
of one or more peaks
corresponding to those of
the components.
If any
interaction
occur-
• The thermogram of
mixtures show same
patterns corresponding to
those of the individual
components
If no
interaction
occur-

19. 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.
19
SIC-SELF INTERACTIVE
CHROMATOGRAPHY

20. 20
Figure (a) Figure (b) Figure (c)

21. 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.
21
TLC & HPTLC

22. • 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
22
REFERENCES

23. 23