The document discusses drug excipient compatibility studies, emphasizing their importance in pre-formulation testing to ensure the stability and effectiveness of proposed dosage forms. It outlines the goals of these studies, the mechanisms of drug-excipient interactions, and various methods for assessing compatibility, such as thermal analysis and chromatography. The document also details specific excipient interactions and their effects on drug formulations, highlighting the need for comprehensive preformulation profiles to guide formulation development.

1. DRUG EXCIPIENTS
COMPATABILITY STUDIES
BY:
Kinjan Mehta

2. Introduction
• Compatibility study is the most important part of any
pre-formulation testing of proposed dosage form, and it
is necessary that it should be carried out before the
development of first formulation of proposed dosage
form with a new drug or new formulation of existing
API.
• This is required due to the following reasons:
• • Formulation stability studies are time consuming and
expensive
• • Need to minimize the number of model formulations
• • Provide rational basis for selecting excipients used in
model formulations

3. Importance of Drug Excipient
Compatibility Study:
• Stability of the dosage form can be maximized.
• It helps to avoid the surprise problems.
• It bridges the Drug discovery and Drug
development.
• Drug excipient compatibility study data is
essential for IND (investigational new drug)
submission

4. Goal of drug-excipients compatibility
study:
• 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 assign a relative risk level to each excipients
within a functional
• 5.To design and develop selective and stability-indicating
analytical methods to determine the
impurities, wherein the
• dosage strength difference is very large.

5. Mechanism of drug-excipients(s)
interaction:
• Drug-excipient(s) interaction occurs more
frequently than excipient-excipient interaction.
Drug-excipients can be classified as:
PHYSICAL CHEMICAL BIOPHARMA
CEUTICAL
1.Solid
dispersion
2.Complexation
3.adsorption
By chemical
interaction with the
excipent and API
through chemical
degradation pathway.

6. Designs of traditional excipient
compatibility experiments:
• Attributes of API Preformulation Profiles:
• Prior to the initiation of any solid-state excipient
compatibility testing of a potential drug candidate, it is
best to generate a preformulation profile of the API.
• This profile should include pHsolubility profiles, pH-stability
profiles, pKa determination, and generation of
log P information, as well as knowledge about
degradation products formed in the solution state under
acidic, basic, oxidative, and oxidative/free radical stress
conditions.

7. Relevant solid-state parameters of the
API:
• Thermal and thermal/humidity stability
• Hygroscopicity
• Thermal calorimetric behaviour
• Single crystal or crystal packing information
• Particle-size distribution and surface area
• Crystal habit and/or amorphous content
• Hot-stage polarized light microscopy data
• Photostability
• Effects of mechanical aggravation

8. Attributes of Excipients:
• Information about excipients is critical in the initial planning
and interpretation of the excipient compatibility results.
• The two key parameters of excipients that are important to
the compatibility formulator are:
• 1.The ability of the excipients to absorb water at variable
humidity and
• 2.The PH of the excipient will impart in the solid-state
• Other key solid-state experimental information useful to
gather on the excipients includes:
• Known incompatibilities of excipients
• Known stabilization effects of excipients
• Reactive impurities in excipients
• Mechanical properties of the excipients

9. Known incompatabilities with functional group.
Functional group Incompatibility Type of reaction
Primary amine Mono & Di-saccharides
Amine-Aldehyde &
Amine-Acetal
Ester,
Lactone
Basic component
Ester base hydrolysis, Ring
opening,
Aldehyde Amine, Carbohydrate
Aldehyde-Amine, Schiff base
Or Glycosylamine formation
Carboxyl Base Salt formation
Alcohol Oxygen
Oxidation to Aldehyde
& Ketones
Sulfhydryl Oxygen Dimerization
Phenol Metal Complexation
Gelatin- Capsule Shell Cationic Surfactant Denaturation

10. Excipient Incompatibility Type of reaction
Parabens Non ionic surfactants
(Polysorbate 80)
Micellization (Reduced
antimicrobial activity)
Plastic Containers Absorption of Parabens
Phenylmercuric
Nitrate
Anionic Emulsifying
agents, Suspending Agents,
Talc, Na-metabisulfite, Na-thiosulfate
Anti-microbial activity
Reduced
Halides Incompatible (forms less
soluble halogen compds)
PEG Penicillin & Bacitracin Anti-bacterial activity reduced
Phenol, Tannic acid &
Salicylic acid
Softening & Liquifaction
Sulphonamide & Dithranol Discoloration
Film coating Migration of PEG from tablet
film coating, leading to
interaction with core

11. INTERACTION WITH CO SOLVENT
Sr.
No. DRUG EXCIPIENT
INTERACTION
OBSERVED
1.
Nicotinamide &
dimethylisosorbid
e
Propylene-glycol Hemolysis (in vivo effect)
2.
Paclitaxel,
Diazepam,
Propaniddid and
Alfaxalone
Cremophor EL
(polyoxyl 35
castor oil)
Precipitation of Cremophor EL
WITH OILS AND LIPIDS
Sr.
No. DRUG EXCIPIENT INTERACTION
1. Lidocaine Unpurified
sesame oil
Degradation of
lodocaine
2.
Calcium chloride,
phenytion sodium,
tetracycline
hydrochloride
Soybean oil Incompatible with
All.

12. SURFACTANTS AND CHELATING AGENTS
DRUG EXCIPIENT
INTERACTION
OBSERVED
Proteins Tween 80 and
other
nonionic
polyether
surfactants
Surfactants undergo oxidation and the
resultant alkyl hydroperoxides
formed contribute to the
degradation of protein.
Protein
formulations
Thiols such as
cystiene,
glutawthion
e asnd
thioglycerol
Most effective in stabilizing protein
formulations containing peroxide-forming
surfactants.
Dexamathasone,
Estradiol,
Iterleukin-2 &
Proteins and
Peptides
Modified
cyclodextrins,
Solubilize and stabilize drugs without
apparent compatibility problems.

13. BUFFERS,ANTIMICROBIALS & ANTIOXIDENTS
Chlorpromazine EXCIPIENT INTERACTION
Recombinant
human
interferon
gamma
Tris buffer Form stable complex with N-nitrosourea
and retard the
degradation of this agent.
Chlorpromazine Tris buffer Tris buffer will degrade 5-flurouracil,
causing the formation of two
degradation products that can cause
serious cardiotoxicities

14. Compatability tests are categorized
are:
1. Solid state reactions:
- much slower and difficult to interpret.
2. Liquid state reactions:
- easier to detect
- Acc. to Stability Guidelines by FDA following conditions
should be evaluated for solutions or suspensions
1. Acidic or alkaline pH.
2. Presence of added substances
3. High oxygen and nitrogen atmospheres.
4. Effect of stress testing conditions.

15. Typical modalities in compatibility
studies:
• A) study execution
• B) general steps and discussion
Compability studies
Proactive/explatory retrospective
Binary and
ternary
mixtures
N-1
formulations
Mini formulations

16. STEPS IN COMPATIBILITY STUDY
There are THREE steps to consider.
1. Sample preparation
2. Storage
3. Method of analysis

17. Background info. And
literature review
Study design
Sample preparation
Incubation at
stressed condition
Analysis and data
interpretation

18. SAMPLE PREPARATION
• FOR SOLID STATE REACTIONS:
SampleA: -mixture of drug and excipient
SampleB: -SampleA+ 5% moisture
SampleC: -Drug itself without excipients
o All the samples of drug-excipient blends are kept for 1-3
weeks at specified storage conditions.
o Then sample is physically observed .
o It is then assayed by TLC or HPLC or DSC.
o Whenever feasible, the degradation product are identified by
MASS SPECTROSCOPY, NMR or other relevant analytical
techniques.
o To determine Solid state stability profile of a new
compound….
o To test the Surface Oxidation…..

19. FOR LIQUID STATE REACTIONS:
o Place the drug in the solution of additives.
o Both flint and amber vials are used.
o This will provide information about
-Susceptibility to oxidation.
-Susceptibility to light exposure.
-Susceptibility to heavy metals.
o In case of oral liquids, compatibility with ethanol,
glycerin ,sucrose, preservatives and buffers are usually
carried out.

20. STORAGE CONDITION
The storage conditions used to examine compatibility
can very widely in term of temp. & humidity, but a
temp. of 50°c for storage of compatibility sample is
considered appropriate.
 Some compounds may require high temp. to make
reaction proceed at a rate that can be measured over a
convenient time period.

21. ANALYTICAL TECHNIQUES USED TO DETECT
DRUS-EXCIPIENT COMPATIBILITY
1. Thermal methods of analysis
▫ DSC- Differential Scanning Calorimetry
▫ DTA- Differential Thermal Analysis
2. Accelerated Stability Study
3. FT-IR Spectroscopy
4. DRS-Diffuse Reflectance Spectroscopy
5. Chromatography
▫ SIC-Self Interactive Chromatography
▫ TLC-Thin Layer Chromatography
▫ HPLC-High Pressure Liquid Chromatography
6. Miscellaneous
▫ Radiolabelled Techniques
▫ Vapour Pressure Osmometry
▫ Flourescence Spectroscopy

22. DSC- DIFFERENTIAL SCANNING
CALORIMETRY
o 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
or 100 c / min) on DSC apparatus.

24. EXAMPLE: DSC IN OFLOXACIN TABLETS
Trace 1 of figure 1-4 shows peak at 278.330C. (melting
endothermic peak of Ofloxacin).
Trace 3 (Physical mixture of Ofloxacin & Lactose) shows
absence of peak at 278.330C and slight pre shift in Lactose
peaks.
DSC RESULT-- INCOMPATIBLE

25. Trace 5 (Physical mixture of Ofloxacin & Starch)
shows an early onset at 268.370C. But no other
changes in thermogram.
DSC RESULT-- COMPATIBLE

26. DIFFERENTIAL THERMAL
ANALYSIS(DTA)
Thermal Analysis is useful in the investigation of solid-state
interactions.
 It is also useful in the detection of eutectics.
Thermograms are generated for pure components and
their physical mixtures with other components.
In the absence of any interaction, the thermograms of
mixtures show patterns corresponding to those of the
individual components.
 In the event that interaction occurs, this is indicated in
the thermogram of a mixture by the appearance of one or
more new peaks or the disappearance of one or more
peaks corresponding to those of the components.

27. ACCELARETED STABILITY STUDY
o Different formulations of the same drug
are prepared.
o Samples are kept at 40ºC / 75 % RH.
o Chemical stability is assessed by
analyzing the drug content at regular
interval.
o Amt. of drug degraded is calculated.
o % Drug decomposed VS time(month) is
plotted.

28. SELF INTERACTIVE
CHROMATOGRAPHY
• SIC is useful for proteinous drug and excipients.
• METHOD:-
• SIC is a modified type of affinity chromatography.
• Here,drug is made immobilized as the SP & soln. to be
tested( excipient soln.) acts as MP.
• Measure Rt (Retention time) & compare with non –retained
marker.
• PRINCIPLE:-
• For different mobile phases (i.e. different excipients) the
injected drug have different interactions (may be
repulsive or attractive) with the SP of drug leads to shift
in retention time (Rt)

29. TLC AND HPTLC
o TLC is generally used as confirmative test of
compatibility after performing DSC.
o S.P. consist of powder (Silica, Alumina, Polyamide,
Cellulose & Ion exchange resin) adhered onto glass,
plastic or metal plate.
o Solution of Drug, Excipient & Drug: Excipient
mixture are prepared & spotted on the same baseline
at the end of plate.
o The plate is then placed upright in a closed chamber
containing the solvent which constitutes the M.P.

30. Any change in the chromatograph such as the appearance of a
new spot or a change in the Rf values of the components is
indicative of an interaction.
The technique may be quantitated if deemed necessary. If
significant interaction is noticed at elevated temperatures,
corroborative evidence must be obtained by examining
mixtures stored at lower temperatures for longer durations.
Among the advantages of thin-layer chromatography in this
application are:
Evidence of degradation is unequivocal.
The spots corresponding to degradation products can be
eluted for possible identification.

31. HPLC AND FLUORESCENT
MEASUREMENT
• HPLC (high pressure liquid chromatography)
Characteristics:
-The APIs and model compounds of diversified chemical
structure was studied.
-Elution rate: 7.5 ml/hr at ambient temp.
-Allows the detection and quantification of impurities,
which span a wide range of polarities, including nonpolar
compounds.
• FLUORESCENT MEASUREMENT:
-This technique is restricted to those compounds, which
can generate florescence. As the no. of such compounds
are restricted, this method is used in Analysis and not in
preformulation

32. INCOMPATIBLE IMPURITIES
• Chemical impurity profiles -Very important in
influencing the long term chemical stability.
• Eg. DCP- sometimes iron may be present in DCP as
impurities and it is incompatabile with MECLIZINE
HCL (NMT 0.04%)
• HYDROPEROXIDES (HPO): evaluation of HPO in
ommon pharmaceutical execipients:
• Polydone
• PVC
Contains substantial conc. Of
• Polysorbate 80
HPO with significant bacth
to batch or manufacturer to
• HPC
manufactuer variatians

33. • While MCC, lactose, high mol.wt. PEG contains
less amount of HPOS.
• 5% PVP was shown responsible for n- oxide
formation rafloxicin HCl due to high HPO
content.