Transcript SEMINAR ON DRUG EXCIPIENT COMPATIBILTY STUDY (As a …

SEMINAR ON
DRUG EXCIPIENT COMPATIBILTY STUDY
(As a part of preformulation study)
1
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
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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 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
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…..
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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.
2.
3.
4.
5.
6.
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
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DSC- DIFFERENTIAL SCANNING
CALORIMETRY
o DSC is widely used to investigate and predict any physicochemical 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
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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
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 Nacrosscarmellose & Lactose.
oSuch 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 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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DTA( DRUG:ENALAPRIL MALEATE)
FORMULATION RESULT
OF DTA
SHELF
LIFE
INFERENCE
(interaction)
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
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(Ref:I.J.P.E.,Jan:2000,153)
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.
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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
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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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 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.
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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
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
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
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Excipient
Parabens
Phenylmercuric
Nitrate
PEG
Incompatibility
Type of reaction
Non ionic surfactants
(Polysorbate 80)
Micellization (Reduced
antimicrobial activity)
Plastic Containers
Absorption of Parabens
Anionic Emulsifying agents,
Suspending Agents, Talc, Nametabisulfite, Na-thiosulfate
Anti-microbial activity
Reduced
Halides
Incompatible (forms less soluble
halogen compds)
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
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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.
(Ref: J. Ph.Sci.,VOL:95,May:2006,1060)
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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.
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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 
sulphide Linkage in Insulin structure.
Break-down of Bi-
-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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COSOLVENTS
Sr
.
N
o.
DRUG
Nicotinamide &
dimethylisosorbide
2.
Paclitaxel,
Diazepam,
Propaniddid and
Alfaxalone
OILS AND LIPIDS
1.
EXCIPIENT
INTERACTION
OBSERVED
Propylene-glycol
Hemolysis (in vivo effect)
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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SURFACTANTS & CHELATING AGENTS
INTERACTION
OBSERVED
DRUG
EXCIPIENT
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 peroxideforming surfactants.
Dexamathasone,
Estradiol,
Iterleukin-2 &
Proteins and
Peptides
Modified
cyclodextrins,
Solubilize and stabilize drugs without
apparent compatibility problems.
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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
human interferon
gamma
Benzyl alcohol
Benzyl alcohol caused the aggregation of
the protein
Cisplatin
Sodium
metabisulfite
Sodium metabisulfite inactivates cisplatin
JPS 2002, Vol. 91, No. 9-12, page 2283-2296.
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REFERENCES
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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
46