The document discusses drug-excipient compatibility studies, which are important to understand interactions between active pharmaceutical ingredients and excipients. There are three main types of incompatibility - physical, chemical, and therapeutic. Compatibility studies help identify incompatible excipients, ensure excipients do not impact drug stability, and can help stabilize unstable drugs. Methods to study compatibility include thermal techniques like DSC, spectroscopic techniques, microscopy, and chromatography. The goal is to avoid issues with drug stability and efficacy during storage and use.

1. DRUG-EXCIPIENT
COMPATIBILITY
STUDIES
BY: VAISHNAVI PANDYA
M PHARM SEM:1
LJ INSTITUTE OF PHARMACY
LJ UNIVERSITY

2. CONTENT
 Introduction
 Excipients
 Importance of drug excipient compatibility studies
 Goal of DECS
 Incompatibility general aspects
 Types of incompatibility
 Mechanism of drug excipient interaction
 Methods of estimation of drug excipient compatibility
 Predictive softwares
 Summary

3. INTRODUCTION
 Drug-excipient studies is the first step for dosage form development.
 The integral part of preformulation stage is a complete understanding of physiochemical
interactions of API and is necessary for consistent efficacy ,safety and stability of product.
 The physical and chemical interactions between drugs and excipients affect the therapeutic
properties of dosage form .
 Careful selection of excipients is required if you want a effective formulation of dosage form that
make administration easier , improve bioavailability, patient compliance, promote release.

4. Excipients
 “Pharmaceutical excipients are substance other than
pharmacologically active drug or prodrug in finished dosage form
as to impart specific qualities to them.”
Role of excipient
1. Protect, support or enhance stability of the Formulation.
2. Bulk up the formulation in case of potent drug for assisting in formulation of an accurate
dosage form.
3. Improve patient acceptance.
4. Help improve bioavailability of active drug.
5. Enhance overall safety and effectiveness of the formulation during its storage and use.

5. Excipient

6. IMPORTANCE OF DRUG EXCIPIENT
COMPATIBILITY STUDIES
 Stability of dosage form can be maximized.
 It helps to avoid the surprise problem .
 Drug discovery can emerge only new chemical entity
 DECS data is essential for IND (investigational new drug )submission. Now
,USFDA has made it compulsory to submit DECS data for any coming
formulation before its approval.
 Determine a list of excipients that can be used in final dosage form.
 To reduce associated side effect of drug due to DECS in dosage form.
 To overcome problems associated with incorporation of multiple
excipients.

7. GOAL OF DECS
1. To find out the excipients that are incompatible with the API.
2. To find out that excipients do not have any impact on the stability of the
API.
3. To find out the excipients that can stabilize the unstable API .
4. To design and develop selective and stability indicating analytical
methods to determine the impurities wherein the dosage strength
difference is very large.

8. INCOMPATABILITY- GENERAL
ASPECTS
 Inactivation of drug through either decomposition or loss of drug by its
conversion to a less favorable physical or chemical form.
 It affects safety, therapeutic efficacy, appearance or Elegance.
 When we mix two or more API and / or excipient with each other & if
they are antagonistic & affect adversely the safety, therapeutic efficacy,
appearance or elegance then they are said to be incompatible.

9. TYPES OF INCOMPATIBILITY
 There are three types of incompatibility studies :
1. Physical incompatibility :
It involves the change in the physical form of the formulation which involves color changes, liquefaction,
phase separation or immiscibility.
2. Chemical incompatibility :
It involves undesirable change in formulation which is due to formation of new chemical comp. with
undesirable activity or our formulation undergoes hydrolysis, oxidation, reduction, precipitation,
decarboxylation, racemization.
3. Therapeutic incompatibility :
It is type of in vivo compatibility. It involves change in therapeutic response of the formulation which is
undesirable to patient as well as physician.

10. Mechanism of drug excipient
interaction
 Exact mechanism of drug excipients interaction is not clear.
 However, there are several well documented mechanisms in the literature.
 Drug excipients interaction occurs more frequently than excipient-
excipient interaction. Drug-excipients interaction can either be beneficial
or detrimental, which can be simply classified as
1. Physical interactions
2. Chemical interactions
3. Biopharmaceutical interactions

11. 1. PHYSICAL INTERACTION

12. 2. CHEMICAL INTERACTION
 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 usually avoided.
 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.

13. Methods of estimation of drug excipient
compatibility
 Formulation scientists have explored various thermal and nonthermal
analytical techniques for early prediction of suitable excipients for the
dosage forms to minimize or mitigate the untoward reactions (stability
issues) which arise from drug– excipient incompatibility.
 Frequently used analytical techniques for prospective compatibility
screening studies include :
 Thermal Techniques:
1. Differential scanning calorimetry (DSC)
2. Isothermal microcalorimetry
3. Hot stage microscopy (HSM)

14. Methods of estimation of drug
excipient compatibility
 Spectroscopic techniques
1. Vibrational spectroscopy
2. Powder X-ray diffraction (PXRD).
3. Solid state nuclear magnetic resonance spectroscopy (ss NMR)
 Microscopic technique
1. Scanning electron microscopy (SEM)
 Chromatographic technique
1. High performance liquid chromatography

15.  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.
 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 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. 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.

16. Continue……
 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.

17.  SPECTROSCOPIC TECHNIQUES
 Spectroscopic analytical methods include all techniques which probe certain
features of a given sample by measuring the amount of radiation emitted or
emitted or absorbed by the molecular or atomic species of interest.
 This method of analysis uses electromagnetic radiation to interact with
matter and thus investigate certain features of a samples as a function of
wavelength
 Vibrational Spectroscopy
• 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.

18. 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.
This Photo by Unknown Author is licensed under CC BY-SA

19.  Chromatographic technique
 High performance liquid chromatography
 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 the 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.

20. HPLC
 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.
This Photo by Unknown Author is licensed under CC BY

21. Predictive softwares (in-silico
prediction)
I. CAMEO (Computer-Assisted Mechanistic Evaluation of Organic reactions):
Historical degradation predictions involved the use of for modeling and predicting organic
chemical reactivity, software developed by William L. Jorgensen. This software was
discontinued, since predictions often over looked secondary or ternary degradants, and its
major downfall was the inability to program the software with new chemistry reactions.
II. DELPHI (Degradation Expert Leading to Pharmaceutical Insight):It was another
historical expert system, capable of predicting reaction products under given conditions. In
contrast to CAMEO, DELPHI was specifically designed to predict reactivity and degradation of
molecules and preceded beyond a primary reactive degradant to subsequent degradants of
degradants. Even though described in the literature, DELPHI is a proprietary software system at
Pfizer that has been discontinued due to its inflexibility.
III. Zeneth: This in silico software released in 2010 is the only commercially available program
designed to predict degradation pathways of pharmaceutical compounds. advantages of
Zeneth are, total recall and the absence of bias. A further major benefit is the steady
accumulation of knowledge about degradation chemistry in an accessible form.

22. SUMMARY
 Drug-excipient interactions/incompatibilities are major concerns in
formulation development.
 Selection of the proper excipient during preformulation studies is of
prime importance.
 Drug-excipient interactions may take a long time to be manifested in
conventional stability testing programmes, and are not always predicted
by stress and pre-formulation studies.
 It is possible to reduce the probability of such undesirable and costly
scenarios by allying knowledge of the propensity of a drug to undergo
degradation reactions with awareness of excipient reactivity and of the
residues that they may contain.

23. SUMMARY
 In short, knowledge of drug–excipient interactions is a necessary
prerequisite to the development of dosage forms that are stable and of
good quality.

24. THANK YOU FOR
YOUR ATTENTION