2 Aspects of compatibility tests are: Identification of compatible excipients for a formulation. Identification of stable storage conditions 2 Types: Solid state reactions: much slower and difficult to interpret. Liquid state reactions: easier to detect According 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.

1. DRUG EXCIPIENT
COMPATIBILTY STUDY
BY
NADIKATLAANUSHA
M.Pharm

2. CONTENTS
 COMPATIBILITY TESTS
1. Sample preparation
2. Storage
3. Method of analysis
 ANALYTICAL TECHNIQUES USED TO DETECT DRUG-EXCIPIENT
COMPATIBILITY
• DSC- differential scanning calorimetry
• Differential thermal analysis(DTA)
• Accelareted stability study
• Diffuse reflectance spectroscopy
• Self interactive chromatography
• TLC and HPTLC
• HPLC and fluorescent measurement
• Vapor pressure osmometry & equilibrium dialysis
 DRUG EXCIPIENT COMPATIBILTY STUDY IN SOLID DOSAGE FORMS
 DRUG EXCIPIENT COMPATIBILTY IN AEROSOLS
 DRUG EXCIPIENT COMPATIBILTY IN PARENTERAL PRODUCTS
ANUSHA NADIKATLA

3. COMPATIBILITY TESTS
2 Aspects of compatibility tests are:
• Identification of compatible excipients for a formulation.
• Identification of stable storage conditions
2 Types:
• Solid state reactions: much slower and difficult to interpret.
• Liquid state reactions: easier to detect
According 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. ANUSHA NADIKATLA

4. Steps in compatibility study:There are 3 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.
ANUSHA NADIKATLA

5. Sample preparation for liquid state reactions:
• Place the drug in the solution of additives.
• Both flint and amber vials are used.
• This will provide information about
Susceptibility to oxidation.
Susceptibility to light exposure.
Susceptibility to heavy metals.
• 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 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.
ANUSHA NADIKATLA

6. ANALYTICAL TECHNIQUES USED TO DETECT DRUG-
EXCIPIENT COMPATIBILITY
• 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 ANUSHA NADIKATLA

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

8. ANUSHA NADIKATLA

9. EXAMPLE: DSC IN OFLOXACIN TABLETS
Trace 1 of figure 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.
ANUSHA NADIKATLA

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

11. 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.
ANUSHA NADIKATLA

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

13. DSC RESULT COMPATIBLE
ANUSHA NADIKATLA

14. DSC STUDY IN ASCORBIC ACID FORMULATION
Excipients: Sod. Crosscarmellose, MCC, Lactose
• Thermal 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 for Ascorbic acid is lowered of
about 50C for MCC & 100C for Na-crosscarmellose & Lactose.
• Such facts must be considered for storage planning of tablets.
LIMITATIONS OF DSC:
• Thermal changes are very small, DSC can’t be used.
• DSC can not detect the incompatibilities which occur after long term
storage.
• Eg. MCC / ASPIRIN…
• Not applicable if test material exhibits properties that make data
interpretation difficult.
ADVANTAGES: Fast, Reliable and very less sample required.
ANUSHA NADIKATLA

15. DIFFERENTIAL THERMALANALYSIS(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.
ANUSHA NADIKATLA

16. DTA( DRUG:ENALAPRIL MALEATE)
ANUSHA NADIKATLA

17. 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.
ANUSHA NADIKATLA

18. 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 respectively.
• A + L = A–L  A–HMF
ANUSHA NADIKATLA

19. 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.
ANUSHA NADIKATLA

20. 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)
ANUSHA NADIKATLA

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

22. • 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.
ANUSHA NADIKATLA

23. HPLC AND FLUORESCENT MEASUREMENT
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
ANUSHA NADIKATLA

24. VAPOR PRESSURE OSMOMETRY & 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 caused
by variation of particle no. ANUSHA NADIKATLA

25. 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.
INCOMPATIBLE IMPURITIES
• DCP: IRON may be present in DCP as impurities. It is incompatible
with MECLIZINE HCl . (Fe NMT 0.04%).
• 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.
ANUSHA NADIKATLA

26. • P- Glycoprotin inhibitor excipients Sometimes, p-Glycoprotein is
membrane associated transport protein. It is an efflux pump lies in
tissue membranes.
• Some excipients have p-Glycoprotein efflux-pump inhibiting
properties.
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
ANUSHA NADIKATLA

27. Known Incompatibilities
ANUSHA NADIKATLA

28. ANUSHA NADIKATLA

29. DRUG EXCIPIENT COMPATIBILTY STUDY IN SOLID
DOSAGE FORMS
Example 1:- Millard reaction:- is a non-enzymatic bimolecular browning
reaction between reducing sugar and an amine.(Anhydrous lactose: no
Millard reaction)
Mechanism:-
ANUSHA NADIKATLA

30. Example2:-Effect of Excipients on Hydrate formation in wet masses
containing Theophylline
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.
ANUSHA NADIKATLA

31. Diluents 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.
• 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.
ANUSHA NADIKATLA

32. DRUG EXCIPIENT COMPATIBILTY STUDY IN
AEROSOLS
• Example 1:- Interaction of propellent-11 with aqueous drug products.
• Propellent 11 is trichloromonofluoromethane.
• HCl corrodes the Al-container.
ANUSHA NADIKATLA

33. 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.
ANUSHA NADIKATLA

34. 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.
• 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.
ANUSHA NADIKATLA

35. 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.
ANUSHA NADIKATLA

36. 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.
COSOLVENTS
• Sorbitol: Increase the degradation rate of Penicillin in Neutral and Aqueous
solutions.
• Glycerol: Increase the mobility of freeze-dried formulation leading to
peptide deamidation.
ANUSHA NADIKATLA

37. OILS AND LIPIDS
ANUSHA NADIKATLA

38. SURFACTANTS & CHELATING AGENTS
ANUSHA NADIKATLA

39. BUFFERS,ANTIMICROBIALS &
ANTIOXIDENTS
ANUSHA NADIKATLA

40. REFERENCES
1.Chadha R, Bhandari S, Drug–excipient compatibility
screening—Role of thermo analytical and spectroscopic
techniques. Journal Pharm and Biomedical Analysis 2014;
87:82-97.
2. Jinnawar KS, Gupta KR. Drug excipient compatibility study
using thermal and non-thermal methods of analysis. Int J Chem
tech Applications 2, (2), 23-49.
3. Sinko PJ. Physical chemical and Biopharmaceutical principle
in the pharmaceutical sciences. Martin’s physical pharmacy and
pharmaceutical sciences (Lippincott), 5thEdition, 352.
4. Pawar A, Gaud RS, Dosageform Design. Modern Dispensing
Pharmacy 2004; 02:77-80. 5. Beringer P, Gupta PK, Felton L.
Stability of pharmaceutical products. Remingon: The Science
and practice of Pharmacy 2005; 01:1029-30.
ANUSHA NADIKATLA

41. ANUSHA NADIKATLA