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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
SAMPLE PREPARATION
All the samples of drug-excipient blends are kept for 1-3 weeks at specified
storage conditions.
o
o
o
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.
6.
10
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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.
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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.
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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
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(Ref:I.J.P.E.,Jan:2000,153)
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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 = AL AHMF
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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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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
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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.
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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
PEG 400
HPC
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(Ref: J.Ph.Sci.,vol:93,Nov:2004,2755)
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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
Carboxyl
Base
Salt formation
Alcohol
Oxygen
Oxidation to Aldehyde
& Ketones
Sulfhydryl
Oxygen
Dimerization
Phenol
Metal
Complexation
Cationic Surfactant
Denaturation
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Excipient
Parabens
Phenylmercuric
Nitrate
PEG
Incompatibility
Type of reaction
Micellization (Reduced
antimicrobial activity)
Plastic Containers
Absorption of Parabens
Anti-microbial activity
Reduced
Halides
Discoloration
Film coating
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Example2:-
36
(Ref- J.Ph.Sci,vol:92,Jan:2003,516)
August10,2009 ,
131557w)
37
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
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Preservatives
Phenolic Preservatives
-Lente- Insulin + Phenolic preservative
Bi-sulphide Linkage in Insulin structure.
Break-down of
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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COSOLVENTS
Sr
.
N
o.
DRUG
Nicotinamide &
1. dimethylisosorbide
Paclitaxel,
Diazepam,
Propaniddid and
Alfaxalone
2.
EXCIPIENT
INTERACTION
OBSERVED
Propylene-glycol
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.
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DRUG
EXCIPIENT
Proteins
Tween 80 and
other
nonionic
polyether
surfactants
Protein
formulations
Thiols such as
cystiene,
glutawthion
e asnd
thioglycerol
Modified
cyclodextrins,
Dexamathasone,
Estradiol,
Iterleukin-2 &
Proteins and
Peptides
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EXCIPIENT
INTERACTION
N-nitrosourea
Tris buffer
5-flurouracil
Tris buffer
Chlorpromazine
Meta-cresol
Incompatible
Recombinant
human interferon
gamma
Benzyl alcohol
Cisplatin
Sodium
metabisulfite
REFERENCES
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