DRUG EXCIPIENT COMPATIBILTY STUDY

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 INTRODUCTION
• 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
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 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
- 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.

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 STEPS IN COMPATIBILITY STUDY

 There are THREE steps to consider.

1. Sample preparation
2. Storage
3. Method of analysis

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 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 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…..
 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.

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 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.

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ANALYTICAL TECHNIQUES USED TO DETECT
DRUS-EXCIPIENT COMPATIBILITY
1. Thermal methods of analysis
– DSC- Differential Scanning Calorimetry
– DTA- Differential ThermalAnalysis
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

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 DSC- DIFFERENTIAL SCANNING
CALORIMETRY
o DSC is widely used to investigate and predict any physico-
chemical 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
10°C/ min) on DSC apparatus.

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10
 EXAMPLE: DSC IN OFLOXACIN TABLETS

Trace 1 of figure 1-4 shows peak at 278.33°C. (melting endothermic peak

of Ofloxacin).
Trace 3 (Physical mixture of Ofloxacin & Lactose) shows absence of peak
at 278.33°C and slight pre shift in Lactose peaks.
DSC RESULT-- INCOMPATIBLE
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Trace 5 (Physical mixture of Ofloxacin & Starch) shows an
early onset at 268.370C. But no other changes in
thermogram.
DSC RESULT-- COMPATIBLE
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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

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Trace 9 (Physical mixture of Ofloxacin & Talc) shows
combine features of each component but there are
evident changes in onset.
DSC RESULT-- COMPATIBLE
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 DSC STUDY IN ASCORBIC ACID
FORMULATION
 Excipients: Sod. Crosscarmellose, MCC, Lactose oThermal
stability was performed on ascorbic acid std. samples, binary
mix. of ascorbic acid & excipients, under N2 & air
atmospheres.
 IR & X-Ray Diffractometry: No chemical interaction
However thermal stability of p’ceutical formulations are
different.
 Temp. of beginning of thermal dregradation forAscorbic
acid is lowered of about 50C for MCC & 100C for Na-
crosscarmellose & Lactose.
 Such facts must be considered for storage planning of
tablets.
 (Ref: C.A. vol:146, No:25, June18,2007,507180t)

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 LIMITATIONS OF DSC

o If thermal changes are very small, DSC can’t 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.

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 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.

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 DTA(DRUG:ENALAPRIL MALEATE)

FORMULATION RESULT SHELF INFERENCE

OF DTA LIFE

(interaction)
F1 (Avicel) + 3 ½ month Least suitable

F2 (Spray dried –– 1 yr and 3 Ideal

lactose) month
F3 (Emcompress) + 8 month Not recommended

F4 (A-tab) + 9 ½ month Not recommended

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(Ref:I.J.P.E.,Jan:2000,153)
 ACCELARETED STABILITY STUDY
• Different formulations of the
same drug are prepared.
• Samples are kept at 40ºC / 75
% RH.
• Chemical stability is assessed
by analyzing the drug content
at regular interval. Amt. of
drug degraded is calculated.
• % Drug decomposed VS
time(month) is plotted.

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 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 = A–L A–HMF

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 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.

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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.

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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 FIGURE-2 FIGURE-3

When interaction is When no net When attractive

repulsive,a sharper interaction between interactions,it will
peak is obtained at a the immobilized have longer retention
shorter retention drug,Rt=dead volume time& wider peak
time of column.
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 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.

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 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.

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 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

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 VAPOR PRESSURE SMOMETRY &
EQUILIBRIUM DIALYSIS
• Principle:‘samples of solutions and pure solvent are introduced
into a temperature-controlled 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
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caused by variation of particle no.
• 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.

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 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 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.
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)

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 (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.

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 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)

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 Known
Incompatibilities

Functional group Incompatibility Type of reaction

Amine-Aldehyde &
Primary amine Mono & Di-saccharides
Amine-Acetal
Ester base hydrolysis, Ring
Ester,
Basic component opening,
Lactone

Aldehyde-Amine, Schiff base

Aldehyde Amine, Carbohydrate
Or Glycosylamine formation
Carboxyl Base Salt formation
Oxidation to Aldehyde
Alcohol Oxygen
& Ketones
Sulfhydryl Oxygen Dimerization
Phenol Metal Complexation
Gelatin- Capsule Shell Cationic Surfactant Denaturation
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 Excipient Incompatibility Type of reaction
Parabens Non ionic surfactants Micellization (Reduced
(Polysorbate 80) antimicrobial activity)
Plastic Containers Absorption of Parabens

Phenylmercuric Anionic Emulsifying agents, Anti-microbial activity

Nitrate Suspending Agents, Talc, Na- Reduced
metabisulfite, Na-thiosulfate
Halides Incompatible (forms less soluble
halogen compds)
PEG Penicillin & Bacitracin Anti-bacterial activity reduced
Phenol, Tannic acid & Softening & Liquifaction
Salicylic acid
Sulphonamide & Dithranol Discoloration
Film coating Migration of PEG from tablet film
coating, leading to interaction with
core component
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 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:-

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Example2:-
Effect of Excipients on Hydrate
formation in wet masses containing
Theophylline
oDuring 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.
oDiluents Used:
1.α- 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.
(Ref- J.Ph.Sci,vol:92,Jan:2003,516) 36
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)

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 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.

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 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.
39 (Ref: J. Ph.Sci.,VOL:95,May:2006,1060)
 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 to bareAl.
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.

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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.

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  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.

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 S
Sr
. INTERACTION
DRUG EXCIPIENT
N OBSERVED
o.
Nicotinamide & Propylene-glycol Hemolysis (in vivo effect)
1.
dimethylisosorbide
Paclitaxel, Cremophor EL Precipitation of Cremophor EL
Diazepam, (polyoxyl 35
2.
Propaniddid and castor oil)
Alfaxalone
OILS AND LIPIDS

Sr.
DRUG EXCIPIENT INTERACTION
No.
1. Lidocaine Unpurified Degradation of
sesame oil lodocaine
Calcium chloride, Soybean oil Incompatible with
phenytion sodium, All.
2.
tetracycline
hydrochloride 43
 AGENTS
INTERACTION
DRUG EXCIPIENT
OBSERVED
Proteins Tween 80 and Surfactants undergo oxidation and the
other resultant alkyl hydroperoxides
nonionic formed contribute to the
polyether degradation of protein.
surfactants
Protein Thiols such as Most effective in stabilizing protein
formulations cystiene, formulations containing peroxide-
glutawthion forming surfactants.
e asnd
thioglycerol
Dexamathasone, Modified Solubilize and stabilize drugs without
Estradiol, cyclodextrins, apparent compatibility problems.
Iterleukin-2 &
Proteins and
Peptides
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 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 Benzyl alcohol Benzyl alcohol caused the aggregation of
human interferon the protein
gamma
Cisplatin Sodium Sodium metabisulfite inactivates cisplatin
metabisulfite

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

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 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.
 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

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