Drug excipient Compatibility

Worked by Ayesha (Extended by Suraj C) PPM

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DEFINITIONS:

1. DRUG:

2. EXCIPIENTS:

INTRODUCTION:

An incompatibility may be defined as…..

“An undesirable drug interaction with one or more components of a formulation, resulting in

changes in physical, chemical, microbiological or therapeutic properties of the dosage form.”

An incompatibility in dosage form can result in any of the following changes:

change in colour/appearance;

loss in mechanical properties (e.g., tablet hardness)

changes to dissolution performance;

physical form conversion;

loss through sublimation;

a decrease in potency; and

increase in degradation products.

Excipient compatibility studies are conducted mainly to predict the potential incompatibility of

the drug in the final dosage form.

These studies also provide justification for selection of excipients, and their concentrations in the

formulation as required in regulatory filings.

There fillings has also been an increased regulatory focus on the Critical Quality Attributes

(CQA) of excipients and their control strategy, because of their impact on the drug product

formulation and manufacturing process which enhanced due to increasing QbD trend.

OBJECTIVE

These studies are important in the drug development process, as the knowledge gained from

excipient compatibility studies is used to

Select the dosage form components,

Delineate stability profile of the drug,

Identify degradation products, and

Understand mechanisms of reactions.

If the stability of the drug with the excipients are found to be unsatisfactory, strategies to mitigate

the instability of the drug can be adopted.

IMPORTANCE OF DECS:

Stability of the dosage form can be maximized

It helps to avoid the surprise problems


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Drug discovery can emerge only new chemical entity

DECS data is essential for IND

Determine a list of excipients that can be used in final dosage form

COMPATIBILITY TESTING:

Aspects of compatibility tests are:

Identification of compatible excipient for a formulation

Identification of stable storage conditions for drug in solid or liquid state

Compatibility tests are categorised as:

1. Compatibility test for solid state reactions

o much slower and difficult to interpret

2. Compatibility test for liquid state reactions

o easier to detect

o 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

Typical Modalities of Compatibility Testing

a) Study Execution

b) General Steps and decisions


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General Steps in Compatibility Studies:

1. Experimental Design

2. Sample preparation

3. Storage

3. Sample Analysis & Data Interpretation

I. Experimental Design

o The design of experiments is governed by the potential formulation choices, and

excipient preferences.

o These decisions are made in conjunction with all the other available preformulation data,

API characteristics, and marketing preferences.

o These also determine the types of pharmaceutical excipients that are evaluated.

Ex: compatibility studies for a liquid formulation of an insoluble compound would

differ widely, and include excipients such as surfactants and suspending agents, from the

studies designed for a highly soluble compound.

o Compatibility studies are commonly carried out by accelerated stress testing, and

evaluation of its effect on the binary or multicomponent drug–excipient mixtures.

o Designs:

i. Two- or Multi-component Systems


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Binary mixtures of drug and common pharmaceutical excipients such as

diluents or ternary mixtures of drug, a diluent, and excipients used in lower

proportions such as disintegrants and lubricants.

And are incubated at accelerated conditions of temperature and humidity

for extended periods of time, using drug alone and excipient alone as

controls.

Incompatibilities are physically identified by

Visual observation for color or physical form changes,

Spectroscopic and calorimetric methods, and

Chemically quantified by analytical assays for drug content and

impurities.

ii. n-1 Design & Mini formulations

Compatibility studies are often aimed at solving formulation stability

issues.

In such cases studies are carried out with the exclusion of only one

component in each sub-lot to identify the source of incompatibility.

Often, mini-formulations are prepared with the exclusion of non-critical,

quantitatively minor, and/or easily interchangeable ingredients, e.g., colors

and flavors, from solutions and suspensions.

II. Sample Preparation

a. For solid state reactions:

Sample A: -mixture of drug and excipient

Sample B: -Sample + 5% moisture

Sample C: -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.

b. 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.


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-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.

III. Storage Conditions

o The storage conditions used to examine compatibility can vary widely in term of temp. &

humidity, but a temp. of 50°C for storage of compatibility sample is considered

appropriate.

o Some compounds may require high temp. to make reaction proceed at a rate that can be

measured over a convenient time period.

IV. Sample Analysis & Data Interpretation

o Monitoring Drug Degradation

Thermal Methods (DSC, DTA, etc.)

o Monitoring to form changes

PXRD, ssNMR, NIR spectroscopy, etc.

o Data analysis


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Compatibility Studies in Different Dosage Forms

SOLID DOSAGE FORMS:

In case of Tablets, The various excipients used are as follows:

a. Diluents /fillers:

Ex. Lactose, dibasic Ca.phosphate, sucrose, glucose, mannitol, sorbitol

b. Binders :

Ex. PVP, cellulose, MCC, sorbitol, gelatine, PEG

c. Disintegrants:

Ex. PVP, Sodium CMC, sodium CMC, sodium starch glycolate

d. Anti-adherents:

Ex. Magnesium stearate

e. Lubricants:

Ex. Talc, Mg.stearate

f. Glidants:

Ex. Magnesium carbonate

g. Coating Agents

Ex: HPMC, HPMCP, EC

EXCIPIENT EXAMPLE INCOMPATIBILITY REASON

DILUENT

Lactose Primary and secondary

amines

Reducing sugar

Mannitol Omeprazole sodium,

primaquine

Crystallization

Dicalcium

phosphate

dihydrate

temazepam Alkaline nature

BINDERS PVP Haloperidol, ranitidine

Hcl

Peroxides

DISINTEGRANT Starch Strongly oxidising subs Reducing sugar

ANTI-

ADHERENT

Mg.stearate Aspirin Undesirable product is

formed

LUBRICANTS Talc Quaternary ammonium

compds.

GLIDANTS Magnesium

carbonate

Phenobarbital sodium Acids dissolve MgCO3

COATING AGENT INCOMPATIBILITY INTERACTION

HPMC Oxidizing agents

SPLITING OF FILM

HPMCP MCC and calcium CMC

ETHYL

CELLULOSE

Paraffin wax

Microcrystalline wax


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Maillard Reaction:

LIQUID DOSAGE FORMS:

1. PARENTERALS

o The various excipients used in parenteral preparations are

I. Anti-oxidants:

Ex. Ascorbic acid, Na bisulphite, EDTA

II. Preservatives:

Ex. Methyl paraben, propyl paraben

III. Cosolvents:

Ex. Sorbitol, glycerol, PEG

IV. Chelating agents:

Ex. EDTA

V. Tonicity agents:

Ex. sod. Chloride, pot. Chloride, dextrose.

EXCIPIENT EXAMPLE INCOMPATIBILITY REASON

Antioxidant

Ascorbic acid Penicillin G, Phenylephrine

Hcl

Acid unstable

Na. bisulfite Sympathomimetics/ o or p-

hydroxy benzyl alcohol

Sulphonic acid

derivative

Preservatives Phenyl-mercuric acetate Halide ions Less soluble

hydrogen

Co solvents

Polyethylene glycol Aspirin, carbonic acid,

theophylline derivatives

Peroxide impurity

Glycerin Phenols, salicylates, tannin Iron impurity

Chelating agents Edetate salts Zn insulin, thiomersal,

amphotericin

Tonicity agents

Sodium chloride Silver ,lead, mercury salts

Dextrose Strong alkali ,

cyanacobalamine ,warfarin

Brown coloration

and decomposition

,loss of clarity

Amine +Reducing

sugar condensation Water+ketosamine

5(hydroxy methyl)-2

furaldehyde


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2. AEROSOLS

Example: Interaction of propellant-11 with aqueous drug products

o Propellant 11 is trichloromonofluoromethane.

o Interaction of propellant 11 with aqueous drug is as follow

o Therefore, propellant 11 is incompatible with aqueous drug products.

Analytical Techniques for DECS

1. Thermal method of analysis

a) DSC- Differential scanning calorimetry

b) DTA- Differential thermal analysis

2. Accelerated stability studies

3. FT-IR SPECTROSCOPY

4. DRS- Diffuse reflectance spectroscopy

5. Chromatography

a) TLC-Thin layer chromatography

b) SIC -Self interactive chromatography

6. Miscellaneous

a) Fluorescence spectroscopy

b) Vapour pressure osmometry

DSC – DIFFERENTIAL SCANNING CALORIMETRY

DSC is widely used to investigate and predict any physico-chemical interaction between drug and

excipients involving thermal changes.

DSC is the measurement of rate of heat evolved or absorbed by the sample, during a temperature

programme.

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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However, some changes in peak shape and peak height and width are expected because of

possible differences in mixture geometry.

Example : Ofloxacin

Experimental excipients: Lactose, Starch, PVP, Talc

How to detect

interaction by DSC

Appearance of new peak

Elimination of endothermic

peak

Area of peak/enthalpy

Melting point/peak temperature

Change in peak shape

Onset of a peak

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LIMITATIONS OF DSC:

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

DSC can not detect the incompatibilities which occur after long term storage.

E.g. MCC / ASPIRIN

Not applicable if test material exhibits properties that make data interpretation difficult.

ADVANTAGES:

o Fast

o Reliable and very less sample required.

DTA – DIFFERENTIAL THERMAL ANALYSIS

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.


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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.

ACCELERATED STABILITY STUDIES

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.

Ex: Experimental drug: Enalapril maleate

Experimental excipients: (Directly compressible diluents):

1. Avicel

2. Spray dried lactose

3. Emcompress

4. A-tab

NOTE: In all the formulations excipients other than directly compressible vehicle are kept same.

Formulation DTA Shelf life Inference

F1(AVICEL) + 3½ months Least stable

F2(SPRAY DRIED

LACTOSE)

_ 1 year and 3 months Ideal

F3(EMCOMPRESS) + 8 months Not recommended

F4(A-TAB) + 9½ months Not recommended


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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.

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.

FTIR

In FTIR technology, the presence of a peak at a specific wave number indicates the presence of a

specific chemical bond.

If specific interactions took place between the materials, the most obvious and significant

difference would be the appearance of new peaks or a shift of existing peaks.

It is used to study the interaction occurring between drug and excipient by matching the peaks of

spectra.

The absence of any significant change in the IR spectral pattern of drug & polymer physical

mixture indicated the absence of any interaction between the drug and the excipient.

Ex: Moxifloxacin

Experimental Excipients: PLGA

The IR-spectra of the physical mixture of both drug and polymer exhibited all the characteristics

peaks as shown.


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Therefore, it shows compatibility of drug with the polymer.

All the spectra acquired were scanned between 400 and 4000 cm-1 at a resolution of 4 cm-1.

TLC & 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.


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The material is identified by its Rf value.

The position of the material on the plate is indicated by spraying the plate with certain reagents or

exposing the plate to UV radiation.

If there is no interaction between drug & excipient, the mixture will produce two spots.

The Rf value of which are identical with those of individual drug & excipient.

If there is interaction, the complex formed will produce a spot.

The Rf value of which is different from those of the individual components.

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.

INCOMPATIBLE IMPURITIES

Chemical impurity profiles

Chemical impurity profiles of the excipient can be very important in influencing the long term

chemical stability performance of the formulated drug product.

E.g..

(1)DCP – Sometimes, IRON may be present in DCP as impurities. & it is incompatible with

MECLIZINE HCl (Fe NMT 0.04%).

(2)Hydroperoxides (HPO) - Evaluation of Hydroperoxides ( HPO) in common

pharmaceutical excipients:

POVIDONE

PEG 400

HPC

POLYSORBATE 80

Contains substantial conc. of

HPOs with significant batch to

batch OR manufacturer to

manufacture variations


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o While MCC, Lactose, High mol. Wt. PEG contains less amt. of HPOs.

o In solid dosage forms, PVP is commonly used as a bonder for wet granulation & often

used at very low conc.

o However, the total HPO content is high enough in PVP to promote significant

degradation when formulating oxidatively sensitive drugs.

o 5% of PVP was shown to be responsible for N-oxide formation of Raloxifen HCl, due

to high HPO content.

o So for these excipients, active monitoring and control of HPOs by the supplier may be

necessary.

(3)Iron (Fe) - Gelatin is also containing IRON as impurities

o Dark spots may occur in the shell due to the migration of water soluble iron sensitive

ingredients from fill material into the shell.

REFERENCES

Qui Y. et.al; Developing Solid Oral Dosage Forms; Elsevier Academic Press, 125-143, 2011.

Leon Lachman & Liberman; Pharmaceutical Dosage forms 2010.

Hand book of Pharmaceutical Excipients, 2011.

Modern Pharmaceutics by Banker & Rhodes, 4th edition, 2002.

I.J.P.E., Vol 1, 2002

J.Ph.Sci, Vol 97, 106-110; 2007.

Health & Medicine

Drug excipient Compatibility