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SEMINAR ON
DRUG EXCIPIENT COMPATIBILTY STUDY
(As a part of preformulation study)
1
INTRODUCTION
2
• INCOMPATIBILITY-Definition-3 Types
• OBJECTIVE OF THE STUDY-Why to screen excipients?
1.need to minimize no of model formulations2.provide rational basis for selecting excipients3.Formulation stability studies are time consuming.
-Goal of the study( Identify the excipients that)1.are compatible with API2.do not have impact on the stability of API
-Importance1.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 substances3. High oxygen and nitrogen atmospheres.4. Effect of stress testing conditions.
3
STEPS IN COMPATIBILITY STUDY
There are THREE steps to consider.
1. Sample preparation
2. Storage
3. Method of analysis
4
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…..
5
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.
6
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.
7
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
8
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 100 c / min) on DSC apparatus.
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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
12
Trace 5 (Physical mixture of Ofloxacin & Starch) shows an
early onset at 268.370C. But no other changes in
thermogram.
DSC RESULT-- COMPATIBLE
13
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
14
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
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. (Ref: C.A. vol:146, No:25,
June18,2007,507180t)
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.
17
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
OF DTA
(interaction)
SHELF
LIFE
INFERENCE
F1 (Avicel) + 3 ½ month Least suitable
F2 (Spray dried
lactose)
–– 1 yr and 3
month
Ideal
F3 (Emcompress) + 8 month Not recommended
F4 (A-tab) + 9 ½ month Not recommended
(Ref:I.J.P.E.,Jan:2000,153)
20
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.
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 2amine and by storage at elevated temp. Two new absorption maxima were observed at 340 nm & 295 nm resply.
• A + L = A–L A–HMF
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.
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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)
When interaction is
repulsive,a sharper
peak is obtained at a
shorter retention
time
When no net
interaction between
the immobilized
drug,Rt=dead volume
of column.
When attractive
interactions,it will
have longer retention
time& wider peak
FIGURE-1 FIGURE-2 FIGURE-3
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
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• 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.
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• 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
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)
30
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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.
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 Stearate4.Polysorbate-205.Polysorbate-856.PEG-40 hydrogenated castor oil7.PEG-35 castor oil
(Ref: J.Ph.Sci.,vol:93,Nov:2004,2755)
32
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Known Incompatibilities
Functional group Incompatibility Type of reaction
Primary amine Mono & Di-saccharidesAmine-Aldehyde &
Amine-Acetal
Ester,
LactoneBasic component
Ester base hydrolysis, Ring
opening,
Aldehyde Amine, CarbohydrateAldehyde-Amine, Schiff base
Or Glycosylamine formation
Carboxyl Base Salt formation
Alcohol OxygenOxidation to Aldehyde
& Ketones
Sulfhydryl Oxygen Dimerization
Phenol Metal Complexation
Gelatin- Capsule Shell Cationic Surfactant Denaturation
34
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
35
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:-
36
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)
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
39
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)
40
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 bare Al.
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-oxidantsAscorbic 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
PreservativesPhenolic 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.
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
43
Sr
.
N
o.
DRUG EXCIPIENTINTERACTION
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
COSOLVENTS
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.
OIL
S A
ND
LIP
IDS
44
DRUG EXCIPIENTINTERACTION
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.
SURFACTANTS & CHELATING AGENTS
Dexamathasone,
Estradiol,
Iterleukin-2 &
Proteins and
Peptides
Modified
cyclodextrins,
Solubilize and stabilize drugs without
apparent compatibility problems.
45
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
JPS 2002, Vol. 91, No. 9-12, page 2283-2296.
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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