SEMINAR ON

DRUG EXCIPIENT COMPATIBILTY STUDY

(As a part of preformulation study)

INTRODUCTION

INCOMPATIBILITY
-Definition
-3 Types
OBJECTIVE OF THE STUDY
-Why to screen excipients?
1.need to minimize no of model formulations
2.provide rational basis for selecting excipients
3.Formulation stability studies are time consuming.
-Goal of the study( Identify the excipients that)
1.are compatible with API
2.do not have impact on the stability of API
-Importance
1.Stabity of formulation can be maximised.
2.Helps to avoid surprise problems.
3.Essential for IND submission.
4.Bridges drug discovery and drug development

COMPATIBILITY TESTS

2 Aspects of compatibility tests are:

1. Identification of compatible excipients for a formulation.
2. Identification of stable storage conditions
2 Types:
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.

STEPS IN COMPATIBILITY STUDY

There are THREE steps to consider.
1. Sample preparation
2. Storage
3. Method of analysis

SAMPLE PREPARATION

FOR SOLID STATE REACTIONS:

SampleA: -mixture of drug and excipient
SampleB: -SampleA+ 5% moisture
SampleC: -Drug itself without excipients

All the samples of drug-excipient blends are kept for 1-3 weeks at specified
storage conditions.

o
o
o

Then sample is physically observed .

It is then assayed by TLC or HPLC or DSC.
Whenever feasible, the degradation product are identified by MASS
SPECTROSCOPY, NMR or other relevant analytical techniques.

To determine Solid state stability profile of a new compound.

To test the Surface Oxidation..

SAMPLE PREPARATION
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.

STORAGE CONDITION
The storage conditions used to examine compatibility can very
widely in term of temp. & humidity, but a temp. of 50c 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.

ANALYTICAL TECHNIQUES USED TO DETECT

DRUS-EXCIPIENT COMPATIBILITY
1.
2.
3.
4.
5.

6.

Thermal methods of analysis

DSC- Differential Scanning Calorimetry
DTA- Differential Thermal Analysis
Accelerated Stability Study
FT-IR Spectroscopy
DRS-Diffuse Reflectance Spectroscopy
Chromatography
SIC-Self Interactive Chromatography
TLC-Thin Layer Chromatography
HPLC-High Pressure Liquid Chromatography
Miscellaneous
Radiolabelled Techniques
Vapour Pressure Osmometry
Flourescence Spectroscopy

DSC- DIFFERENTIAL SCANNING

CALORIMETRY
o DSC is widely used to investigate and predict any physicochemical interaction between drug and excipients involving
thermal changes..
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.

10

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
11

Trace 5 (Physical mixture of Ofloxacin & Starch) shows an

early onset at 268.370C. But no other changes in
thermogram.
DSC RESULT-- COMPATIBLE
12

Trace 7 (Physical mixture of Ofloxacin & PVP) shows no change in

position of endothermic peak for PVP but there is increase in peak
area and size & shape of peak for Ofloxacin is also decreased.
DSC RESULT-- INCOMPATIBLE
13

Trace 9 (Physical mixture of Ofloxacin & Talc) shows

combine features of each component but there are
evident changes in onset.
DSC RESULT-- COMPATIBLE
14

15

DSC STUDY IN ASCORBIC ACID

FORMULATION
o Excipients: Sod. Crosscarmellose, MCC, Lactose
o Thermal stability was performed on ascorbic acid std.
samples, binary mix. of ascorbic acid & excipients,
under N2 & air atmospheres.
o IR & X-Ray Diffractometry: No chemical interaction
However thermal stability of pceutical formulations are
different.
o Temp. of beginning of thermal dregradation for
Ascorbic acid is lowered of about 50C for MCC &
100C for Na-crosscarmellose & Lactose.
o Such facts must be considered for storage planning of
tablets.
(Ref: C.A. vol:146, No:25,
June18,2007,507180t)

16

LIMITATIONS OF DSC
o If thermal changes are very small, DSC cant be used.
o DSC can not detect the incompatibilities which occur
after long term storage.
Eg. MCC / ASPIRIN
o Not applicable if test material exhibits properties that
make data interpretation difficult.
o ADVANTAGES:
-Fast
-Reliable and very less sample required.

17

DIFFERENTIAL THERMAL
ANALYSIS(DTA)
Thermal Analysis is useful in the investigation of solidstate 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.
18

DTA( DRUG:ENALAPRIL MALEATE)

FORMULATION RESULT
OF DTA

SHELF
LIFE

INFERENCE

(interaction)
F1 (Avicel)

3 month

Least suitable

F2 (Spray dried
lactose)

1 yr and 3
month

Ideal

F3 (Emcompress)

8 month

Not recommended

F4 (A-tab)

9 month

Not recommended
19

(Ref:I.J.P.E.,Jan:2000,153)

ACCELARETED STABILITY STUDY

o Different formulations
of the same drug are
prepared.
o Samples are kept at
40C / 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.

20

DIFFUSE REFLECTANCE
SPECTROSCOPY
Principle: Penetration of a portion of incident radiation flux
into the interior of the solid sample, return of some portion of
radiation to the surface of sample following partial absorption
and multiple scattering at boundary of individual sample
particles.
Detects the decomposed products, along with physical and
chemical adsorption of excipients on to A.P.I. and vice versa.
Example: Ethanol mediated interaction between
dextroamphatamine sulphate and spray dried lactose in solid
solid mixture:
Discoloration of powdered mixture was accelerated by 2
amine and by storage at elevated temp. Two new absorption
maxima were observed at 340 nm & 295 nm resply.
A + L = AL AHMF

21

DIFFUSE REFLECTANCE
SPECTROSCOPY
A shift in the diffuse reflectance spectrum of the drug due to
the presence of the excipient indicates physical adsorption.
whereas the appearance of a new peak indicates
chemisorption or formation of a degradation product.
DRS is more useful than HPLC assay to detect surface
discoloration due to oxidation or reaction with excipients.

22

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.

23

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)

FIGURE-1

When interaction is
repulsive,a sharper
peak is obtained at a
shorter retention
time

FIGURE-2

When no net
interaction between
the immobilized
drug,Rt=dead volume
of column.

FIGURE-3

When attractive
interactions,it will
have longer retention
time& wider peak
24

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.

25

TLC AND HPTLC

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.

26

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
27

VAPOR PRESSURE OSMOMETRY & EQUILIBRIUM DIALYSIS

Principle: samples of solutions and pure solvent are introduced into a temperaturecontrolled enclosure, which is saturated with solvent vapor.Since the vapor pressure of
solution is lower than that of solvent, solvent vapor condenses on solution sample causing
its temperature to rise. The temperature rise is predicted by Clausis Clapcyron equation.

Characteristics:
Either liquid or solid sample and must be soluble in organic solvent or in water
Sample must not undego association in solution.
Sample size is approx. 3 gms for multiple analysis.
Measures a no. of avg. mole. Wt. of about 10,000 Daltons.
This method measures interactions, & records the interaction caused by variation of
particle no.
28

 RADIO LABELLED TECHNIQUES:

It is important when the API is having radio
activity.
Method is carried out by using either 3H or 13C.
Highly sensitive method but the cost of carrying out
the method & the availability of well established
other techniques & methods, this method is
generally not preferred.

29

INCOMPATIBLE IMPURITIES
o Chemical impurity profiles -Very important in influencing the long term
chemical stability.
Eg:(1) Evaluation of Hydroperoxides ( HPO) in common pharmaceutical
excipients.
POVIDONE

Contains substantial conc.

PEG 400
HPC

of HPOs with significant

batch to batch or mfger
POLYSORBATE 80
to mfger variations.
o While MCC, Lactose, High M.wt PEG, Polyxamer contains less amt. of
HPOs.
o 5% PVP responsible for N-oxide formation of Raloxifen HCl, due to high
HPO content.
(Ref: J.Ph.Sci,vol:97,Jan:2007,106)

30

(2) DCP Sometimes, IRON may be present in

DCP as
impurities. It is incompatible with
MECLIZINE HCl . (Fe NMT 0.04%)
(3)Gelatin is also containing IRON as
impurities, Dark spots may occur in the shell
due to the migration of water soluble iron
sensitive ingredients from fill material into the
shell.
31

P- Glycoprotin inhibitor excipients

o p-Glycoprotein is membrane associated transport protein. It is an
efflux pump lies in tissue membranes.
o Some excipients have p-Glycoprotein efflux-pump inhibiting
properties.
o EXAMPLES:-

1.PEG-32 lauric glycerides.

2.Polysorbate-80
3.PEG-50 Stearate
4.Polysorbate-20
5.Polysorbate-85
6.PEG-40 hydrogenated castor oil
7.PEG-35 castor oil

(Ref: J.Ph.Sci.,vol:93,Nov:2004,2755)
32

Known Incompatibilities
Functional group
Primary amine

Incompatibility
Mono & Di-saccharides

Type of reaction
Amine-Aldehyde &
Amine-Acetal
Ester base hydrolysis,
opening,

Ring

Ester,
Lactone

Basic component

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
33

Excipient
Parabens

Phenylmercuric
Nitrate

PEG

Incompatibility

Type of reaction

Non ionic surfactants

(Polysorbate 80)

Micellization (Reduced
antimicrobial activity)

Plastic Containers

Absorption of Parabens

Anionic Emulsifying agents,

Suspending Agents, Talc, Nametabisulfite, Na-thiosulfate

Anti-microbial activity
Reduced

Halides

Incompatible (forms less soluble

halogen compds)

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 component
34

DECS in solid dosage forms

Example 1:o Millard reaction:- is a non-enzymatic bimolecular
browning reaction between reducing sugar and an
amine.(Anhydrous lactose: no Millard reaction)
o Mechanism:-

35

Example2:-

Effect of Excipients on Hydrate formation in

wet masses containing Theophylline
o During wet granulation Theophylline Shows
Pseudopolymorphic changes that may alter its
dissolution rate.In the presence of moisture
Theophylline monohydrate is formed which has slow
dissolution rate.
o Diluents Used:
1.- Lactose monohydrate : Minimum water
absorbing capacity. So not able to prevent but
enhance Hydrate formation of Theophylline.
2.Silicified MCC : Highly water absorbing
capacity.Able to inhibit the formation of
Theophylline monohydrate at low moisture content.

36
(Ref- J.Ph.Sci,vol:92,Jan:2003,516)

SILICIFIED MCC as a multifunctional

pharmaceutical excipient
Multifunctional excipient
Characteristics offered by Prosolv are high compactibilty, high
intrnsic flow, enhanced lubrication efficiency and improved
blending properties.
Provide tremendous advantages through out product life cycle.
MCC is a dry binder- when comes in contact with water ,its
compressibilty is decreased..but that is not the case with
SMCC.
(Ref:CA,Vol:151,No:6,

August10,2009 ,

131557w)

37

DRUG EXCIPIENT COMPATIBILTY

STUDY IN AEROSOLS
o Example 1:- Interaction of propellent-11 with aqueous drug
products.

o Propellent 11 is trichloromonofluoromethane.
o HCl corrodes the Al-container.
38

Example2:
Beclomethasone- Hydroflouroalkane interactions:
BDP is a Steroidal drug used in Asthma

Manipulation of above interaction: BDP particles

coated with amphiphilic macromolecular excipient by
Spray drying.
Therefore, prevention of aggregation
& production of physically stable
suspension with excellent
aerosolisation properties.
(Ref: J. Ph.Sci.,VOL:95,May:2006,1060)
39

o Anhydrous ethanol is corrisive to Al containers.

-Hydrogen produced in the reaction increases the
pressure of the container.So drugs containing polar
solvents tend to be corrosive to bare Al.
o For containers which contain 2%Tin and 98% Lead
-Lead reacts with the fatty acids(for product
cont.soaps) to form Lead salts which cause valve
clogging.

40

DRUG EXCIPIENT COMPATIBILTY IN

PARENTERAL PRODUCTS
Anti-oxidants
Ascorbic acid: Incompatible with acid- unstable drugs
Na bisulfite:+ Epinephrine Sulphonic acid dvt.
-Incompatible in Opthalmic solution containing Phenyl mercuric
acetate
Edetate salts: Incompatible with Zn Insulin,
Thiomerosal,
Amphotericin & Hydralazine

Preservatives
Phenolic Preservatives
-Lente- Insulin + Phenolic preservative
Bi-sulphide Linkage in Insulin structure.

Break-down of

-Protamine- Insulin + Phenolic preservative tetragonal oblong

crystals which is responsible for prolong action of insulin.
41

 Surface active agents

Polysorbate 80:
One must concern about the residual peroxide present in Polysorbate.
PS 80
Polyoxyethylene sorbitan ester of Oleic acid
( Unsatd.F.A)
PS 20
Polyoxyethylene sorbitan ester of lauric acid
( Satd.F.A)
So PS 20 is less prone to oxidation than PS 80.

Cosolvants
Sorbitol
Increase the degradation rate of Penicillin in Neutral and Aqueous
solutions.
Glycerol
Increase the mobility of freeze-dried formulation leading to peptide
deamidation.

42

COSOLVENTS
Sr
.
N
o.

DRUG

Nicotinamide &
1. dimethylisosorbide
Paclitaxel,
Diazepam,
Propaniddid and
Alfaxalone

OILS AND LIPIDS

2.

EXCIPIENT

INTERACTION
OBSERVED

Propylene-glycol

Hemolysis (in vivo effect)

Cremophor EL
(polyoxyl 35
castor oil)

Precipitation of Cremophor EL

Sr.
No.

DRUG

EXCIPIENT

INTERACTION

1.

Lidocaine

Unpurified
sesame oil

Degradation of
lodocaine

Soybean oil

2.

Calcium chloride,
phenytion sodium,
tetracycline
hydrochloride

Incompatible with
All.
43

SURFACTANTS & CHELATING AGENTS

INTERACTION
OBSERVED

DRUG

EXCIPIENT

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 peroxideforming surfactants.

Modified
cyclodextrins,

Solubilize and stabilize drugs without

apparent compatibility problems.

Dexamathasone,
Estradiol,
Iterleukin-2 &
Proteins and
Peptides

44

BUFFERS,ANTIMICROBIALS & ANTIOXIDENTS

DRUG

EXCIPIENT

INTERACTION

N-nitrosourea

Tris buffer

Form stable complex with N-nitrosourea

and retard the degradation of this agent.

5-flurouracil

Tris buffer

Tris buffer will degrade 5-flurouracil,

causing the formation of two degradation
products that can cause serious
cardiotoxicities

Chlorpromazine

Meta-cresol

Incompatible

Recombinant
human interferon
gamma

Benzyl alcohol

Benzyl alcohol caused the aggregation of

the protein

Cisplatin

Sodium
metabisulfite

Sodium metabisulfite inactivates cisplatin

JPS 2002, Vol. 91, No. 9-12, page 2283-2296.

45

REFERENCES

Pharmaceutical Dosage forms By Leon Lachman & Liberman

Hand book of Pharmaceutical Excipients
Remingtons Pharmaceutical Science,21st edition,2005.
Modern Pharmaceutics by Banker & Rhodes,4th edition,2002.
Theory and Practice of Industrial Pharmacy by Lachman & Lieberman.
Int. J. Ph.Exci., Vol-1, Jan-2000, 153.
Int. J. Ph.Exci., Nov-2002, 2283
Int. J. Ph.Exci.,jan-march,2003
J. Ph. Sci..,Vol-97, Jan-2007,106
J. Ph. Sci., Vol-95, May-2006, 976.
J. Ph. Sci., Vol-95, May-2006, 1060.
J. Ph. Sci., Vol-95, June-2006, 1342.
J. Ph. Sci., Vol-93, Jan-2004,132
J. Ph. Sci., Vol-93, Nov-2004, 2755.
J. Ph. Sci., Vol-92, May-2003, 516.
JPS 2002, Vol. 91, No. 9-12, page 2283-2296
C.A. vol:146, No:25,June 18 :2007,507180t
C.A. vol:147, No:4, July 23 :2007,79121
CA,Vol:151,No:6, August10,2009 ,131557w

46