Drug excipient compatibility

SEMINAR ON
DRUG EXCIPIENT COMPATIBILTY STUDY
(As a part of preformulation study)
PREPARED BY
NISARG PATEL
(M.PHARM-SEM-I)
DEPARTMENT OF PHARMACEUTICS &
PHARMACEUTICAL TECHNOLOGY
SMT.B.N.B SWAMINARAYAN PHARMACY
COLLEGE,SALVAV-VAPI
SMT.BNB SWAMINARAYAN PHARMACY COLLEGE,VAPI 1

INCOMPATIBILITY
DEFINATION - 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.
Types Of Incompatibility
Physical incompatibility:- It involves the change in the physical form of the
formulation which involves color changes, liquefaction, phase separation or
immiscibility.
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.

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.
OBJECTIVES:
Drug: active part of dosages form and it is mainly responsible for therapeutic
value.
Excipient:substances which are included along with drugs being formulated in a
dosage form so as to impart specific qualities to them.
Incompatibility- 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.

COMPATIBILITY TESTS
Aspects of compatibility tests are:
1. Identification of compatible excipients for a formulation.
2. Identification of stable storage conditions
Types:
1. Solid state reactions:
- much slower and difficult to interpret.
2. Liquid state reactions:
- easier to detect
- The 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.
 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:
oPlace the drug in the solution of additives.
oBoth flint and amber vials are used.
oThis will provide information about
-Susceptibility to oxidation.
-Susceptibility to light exposure.
-Susceptibility to heavy metals.
oIn 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
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.

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

DSC- DIFFERENTIAL SCANNING
CALORIMETRY
o DSC is widely used to investigate and predict any
physico-chemical interaction between drug and excipients
involving thermal changes..
oMETHOD
-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.

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

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

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

Trace 9 (Physical mixture of Ofloxacin & Talc) shows
combine features of each component but there are evident
changes in onset.
DSC RESULT-- COMPATIBLE

DSC STUDY IN ASCORBIC ACID
FORMULATION
oExcipients: Sod. Crosscarmellose, MCC, Lactose
oThermal stability was performed on ascorbic acid std.
samples, binary mix. of ascorbic acid & excipients, under N2 &
air atmospheres.
oIR & X-Ray Diffractometry: No chemical interaction
However thermal stability of p’ceutical formulations are
different.
oTemp. of beginning of thermal dregradation for Ascorbic acid
is lowered of about 50C for MCC & 100C for Na-
crosscarmellose & Lactose.
oSuch facts must be considered for storage planning of tablets.

LIMITATIONS OF DSC
oIf thermal changes are very small, DSC can’t be used.
oDSC can not detect the incompatibilities which occur
after long term storage.
Eg. MCC / ASPIRIN…
oNot applicable if test material exhibits properties that
make data interpretation difficult.
oADVANTAGES:
-Fast
-Reliable and very less sample required.

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

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

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.

INCOMPATIBLE IMPURITIES
oChemical impurity profiles -Very important in influencing the long term chemical
stability.
Eg:-
(1) Evaluation of Hydroperoxides ( HPO) in common pharmaceutical excipients.
POVIDONE It all Contains substantial conc.
PEG 400 of HPOs with significant
HPC batch to batch or mfger
POLYSORBATE 80 to mfger variations.
o While MCC, Lactose, High M.wt PEG, Polyxamer contains less amt. of HPOs.
o5% PVP responsible for N-oxide formation of Raloxifen HCl, due to high HPO content.

(2)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.

P- Glycoprotin inhibitor excipients
op-Glycoprotein is membrane associated transport protein. It is an efflux pump lies in
tissue membranes.
oSome 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

Known Incompatibilities
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

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 component

DRUG EXCIPIENT COMPATIBILTY
STUDY IN AEROSOLS
oExample 1:- Interaction of propellent-11 with aqueous drug products.
oPropellent 11 is trichloromonofluoromethane.
oHCl corrodes the Al-container.

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.

oAnhydrous 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.
oFor 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.

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  Break-down of Bi-
sulphide Linkage in Insulin structure.
-Protamine- Insulin + Phenolic preservative tetragonal oblong
crystals which is responsible for prolong action of insulin.

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.

S
r.
N
o.
DRUG EXCIPIENT
INTERACTION
OBSERVED
1.
Nicotinamide &
Dimethylisosorbide
Propylene-
glycol
Hemolysis (in vivo effect)
2.
Paclitaxel,
Diazepam,
Propaniddid and
Alfaxalone
Cremophor EL
(polyoxyl 35
castor oil)
Precipitation of Cremophor EL
COSOLVENT
S
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.
OILSANDLIPIDS

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,
glutawthio
and
thioglycerol
Most effective in stabilizing protein
formulations containing peroxide-
forming surfactants.
SURFACTANTS & CHELATING AGENTS
Dexamathasone,
Estradiol,
Iterleukin-2 &
Proteins and
Peptides
Modified
cyclodextrins,
Solubilize and stabilize drugs without
apparent compatibility problems.

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
BUFFERS,ANTIMICROBIALS & ANTIOXIDENTS

REFERENCES
Pharmaceutical Dosage forms By Leon Lachman & Liberman
Hand book of Pharmaceutical Excipients
Remington’s Pharmaceutical Science,21st edition,2005.
Modern Pharmaceutics by Banker & Rhodes,4th edition,2002.
Theory and Practice of Industrial Pharmacy by Lachman & Lieberman.

o Write a note on Drug Excipient compatibility study
oElaborate the necessity of drug-excipient compatibility study with
examples.Discuss how it is carried out.
oExplain the importance of Drug-excipient compatibility
QUESTION BANK

Drug excipient compatibility

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