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Drug Excipient Compatibility Testing Protocols and Charaterization: A Review

Article in Asian Journal of Chemical Sciences · October 2019

DOI: 10.9734/ajocs/2019/v6i319000

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 Asian Journal of Chemical Sciences

6(3): 1-22, 2019; Article [Link].51941

ISSN: 2456-7795

Drug Excipient Compatibility Testing Protocols and

Charaterization: A Review
Krishna R. Gupta1*, Anita R. Pounikar1 and Milind J. Umekar1
1
Department of Pharmaceutical Chemistry, Smt. Kishoritai Bhoyar College of Pharmacy,
New Kamptee, Nagpur, India.

Authors’ contributions

This work was carried out in collaboration among all authors. Author KRG wrote the final draft of the
manuscript. Author ARP wrote the first draft of the paper. Author MJU managed the literature
searches. All authors read and approved the final manuscript.

Article Information

DOI: 10.9734/AJOCS/2019/v6i319000
Editor(s):
(1) Dr. Fahmida Khan, National Institute of Technology, Raipur, Chhattisgarh, India.
Reviewers:
(1) Debarshi Kar Mahapatra, Dadasaheb Balpande College of Pharmacy, India.
(2) Buchi N. Nalluri, KVSR Siddhartha College of Pharmaceutical Sciences, India.
Complete Peer review History: [Link]

Received 28 July 2019

Accepted 04 October 2019
Review Article
Published 22 October 2019

ABSTRACT
Drug molecule contains various reactive functional groups which are susceptible to react with
another reactive functional groups which might be excipients, excipient or drugs impurities formed
during manufacturing or storage. The objective of the current review article is to provide a
comprehensive review of excipients-drug compatibility study, their degradation product
characterization with different analytical methods and further impact of methodologies in
pharmaceutical industry for potential stability assessment. The incompatibility of drug excipient was
very common due to the reactive functional groups in drugs and excipients. These leads to
formation of drug related impurities as well as excipient impurities reaction with active
Pharmaceutical Ingredients. Sometimes these impurities found to be mutagenic and genotaxic to
human beings. Identification of drug degradation in presence of excipient impurities requires
extensive knowledge and adequate analytical characterization data. Systematic literature review
and understanding about the drug-excipient chemistry in formulation process is important criteria to
select compatible excipient and formulate ideal formulation. The analytical characterization data
gives idea about degradation pathway. This paper discusses drug-excipient interactions,
compatibility and characterization by different analytical methods with case studies and provides an
overview of different excipients compatibility in formulation.

_____________________________________________________________________________________________________

*Corresponding author: E-mail: krg1903@[Link], krishnargupta@[Link];

 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

Keywords: Different excipients; reactive functional groups; degradation products; characterization.

1. INTRODUCTION the final dosage form to prevent further

incompatability. The common pharmaceutical
Different dosage forms like tablets, capsules, oral excipients and their potentially reactive impurities
liquids, injectable products, implants, eye are listed in Table 2.
products, nasal products, inhalers, topical
creams and gels, transdermal patches and Many formulations undergo reactions such as
suppositories etc, contains different types of hydrolysis, isomerization, dehydration, oxidation,
excipients. To make it acceptable and compatible photodegradation, elimination, cyclization and
various pharmaceutical excipients are added in specific interactions with formulation excipients
pharmaceutical dosage form for their direct and their impurities observed in pharmaceuticals.
therapeutic action, manufacturing process, to Interaction and incompatabilities of the excipients
protect, support or enhance stability, for with functional groups and different types of
bioavailability or patient compliance. The reaction are listed in Table 3. The environmental
common excipients used in tablets are listed in factors such as temperature, pH and moisture in
Table 1 [1]. solids, relative humidity of the environment,
presence of catalysts, light, oxygen etc, and acts
Drug degradation catalyzed by excipients like a catalyst to initiation of drug excipients
impurity reaction with reactive functional groups reaction. Moisture increases the micro-
of organic active pharmaceutical ingredient. environmental pH in the dosage form leads to
Functionality, compatibility between the drug and acid–base catalysis reaction of drug excipients
excipients are the most important criteria for the and source of impurities results in drug
selection of pharmaceutical excipients and their degradation [2].
concentrations in formulation. Because of an
incompatibility between drug and excipient in the 1.1 Isothermal Stress Testing
formulation affect the various pharmaceutical
properties like changes in physical, chemical, In isothermal stress testing, drug excipient
microbiological or therapeutic properties of the blends in the presence of moisture (20%)
dosage form. Various analytical methods exposed to constant temperature for specific
incorporated mainly to estimate the potential period of time. The total no. of drug
incompatibility of the drug, degradation excipient blends were planned as per statistical
pathways, impurities and their concentration in design.

Table 1. Common excipients used in tablets

Sr. No. Excipient Function Examples

1 Diluent Provide bulk and enable Sugar compounds e.g. lactose, dextrin,
accurate dosing of potent glucose, sucrose, sorbitol
ingredients Inorganic compounds e.g. silicates,
calcium and magnesium salts, sodium
or potassium chloride
2 Binders, Bind the tablet ingredients Mainly natural or synthetic polymers
compression together giving form and e.g. starches, sugars, sugar alcohols
aids, mechanical strength and cellulose derivatives
granulating
agents
3 Disintegrants Aid dispersion of the tablet in Compounds which swell or dissolve in
the gastrointestinal tract, water e.g. starch, cellulose derivatives
releasing the active and alginates, crospovidone
ingredient and increasing the
surface area for dissolution
4 Glidants Improve the flow of powders Colloidal anhydrous silicon and other
during tablet manufacturing silica Compounds
by reducing friction and

2
 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

Sr. No. Excipient Function Examples

adhesion between particles.
Also used as anti-caking
agents.
5 Lubricants Similar action to glidants, Stearic acid and its salts (e.g.
however, they may slow magnesium stearate)
Disintegration and
dissolution. The properties of
glidants and lubricants differ,
although some compounds,
such as starch and talc, have
both actions
6 Tablet Protect tablet from the Sugar (sucrose) has now been
coatings environment (air, light and replaced by film coating using natural
and films moisture), increase the or synthetic polymers. Polymers that
mechanical strength, mask are insoluble in acid, e.g. cellulose
taste and smell, aid acetate phthalate, are used for enteric
swallowing, assist in product coatings to delay release of the active
Identification. Can be used to ingredient
modify release of the active
ingredient. May contain
flavours and colourings
7 Colouring Improve acceptability to Mainly synthetic dyes and natural
agents patients, aid identification colours. Compounds that are
and prevent counterfeiting. themselves natural pigments of food
Increase stability of may also be used
lightsensitive drugs.

1st phase (Selection of diluent and lubricant): modulated by physico-chemical characterization

The compatibility of drug with diluents and and forced degradation of the drug molecules.
lubricants is tested by storing them in various Design of compatibility studies might involve:-
conditions for a particular time period.
 Use of mixtures of drug with one or more
2nd
phase (Selection of disintegrant and excipients and water is added to
binder): Using diluents- lubricant mixture accelerating drug – excipient interactions.
selected in the first phase, the compatibilityof Also hydrogen peroxide can be added to
other excipient such as binder and disintegrant induce oxidative stress.
nd  Incubation at various elevated
were tested in 2 phase [3].
temperatures, and analyzed for physical
1.2 Protocol for Compatibility Testing and chemical changes in the drug at
predetermined time intervals.
Compatibility studies designed to identify key  Analysis of binary mixtures of drug and
drug–excipient incompatibilities, causes and excipients by thermal methods such as
effects. Compatibility studies started with the differential scanning calorimetry (DSC) and
evaluation of existing information and chemistry isothermal microcalorimetry (IMC), for
of the new molecular entities to identify “soft rapid assessment of potential
spots” in the molecule. Selected excipients incompatibilities.
evaluated for the presence of reactive or 1.3 Experimental Design of Compatibility
unstable functional groups, pKa value and known
Study
reactivities of similar compounds. General
literature, several computational programs or It involves
softwares like e.g., CAMEO R , SPARTAN R ,
EPWIN R and Pharm D 3R etc can be used. To 1. Two - or Multi-component Systems:-
detect the presence and extent of known The binary mixtures include drug and
reactivities, the compatibilitystudy design common pharmaceutical excipients such

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 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

as diluents and in ternary mixtures of drug, ingredients such as colours and flavors,
a diluent and excipients used in lower from solutions and suspensions are
proportions such as disintegrants and prepared with the exclusion of non-critical,
lubricants, that are incubated at quantitatively minor and/or easily
accelerated conditions like pH, interchangeable ingredients. Minimum
Temperature, Humidity, Oxidative number of experimental runs, which can be
conditions or Radiations etc. The variance easily capable of finding the excipients that
is calculated by F-ratio analysis and it cause major incompatibilities.
applied to test whether the normally 3. n-1 design:- n - excipients analyzed by
distributed populations are equal and by n+1 experimental runs design. In this
the calculation of p-value. study, eight experiments included over the
2. The n-1 Design and Mini-formulations: - minimum required to study the effect of
The Plackett–Burman design may applied “pseudo-variables,” to account for random
to Mini-formulations which involved experimental variation.

Fig. 1. Typical modalities of compatibility testing

Background information
and literature review

Binary, ternary mixtures or

mini formulations or n-1
Study design design

Physical mixtures
Compaction
Sample preparation Effect of water
• Incubation in RH chambers
• Addition in sealed container

Incubation at Temperature
stressed conditions Humidity
UV for photostability
Oxidizing agents

Physical (color) changes

Analyses and Thermal changes by DSC
data interpretation Drug degradation by HPLC
Form change by PXRD

Fig. 2. Typical modalities of compatibility study execution. Various stages of the compatibility
testing

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 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

1.4 Impurities Present in the Excipients their own degradation or incompatibilities

with drugs. Table 2 shows various
Various pharmaceutical excipients used in excipients, reactive impurities and known
formulation for different purposes, but due to incompatability.

Table 2. The common pharmaceutical excipients and their potentially reactive impurities

Sr. Excipient Potentially reactive Examples of known incompatibilities

No. impurities
1 Lactose Glucose, furfuraldehyde, Maillard reactions, Claissen – Schmidt
formic acid, acetic acid and condensation reaction of its impurity, 5
potentially other aldehydes. hydroxylmethyl-2 furfuraldehyde and
catalysis of hydrolysis.
2 Microcrystalline Glucose, formaldehyde, Water sorption resulting in increased
Cellulose nitrates and nitrites hydrolysis, Maillard reaction with
residual glucose, adsorption of basic
drugs, and non-specific incompatibilities
due to hydrogen bonding capability
3 Povidone and Povidone and crospovidone Oxidation attributable to peroxides,
Crospovidone contain significant levels of nucleophilic addition to amino acids and
peroxides. Povidone may peptides, and hydrolysis of sensitive
also contain formic acid and drugs due to moisture
formaldehyde
4 Hydroxypropyl HPC may contain significant Oxidation of sensitive drugs due to
cellulose (HPC) levels of peroxides. residual peroxides
5 Croscarmellose Monochloroacetate, nitriles, Weakly basic drugs can compete with
sodium and nitrates. the sodium counterion, thus getting
Monochloroacetate can adsorbed on the surface of the
react with nucleophiles disintegrant particles. Drug salt form
conversion has also been reported.
6 Sodium starch Monochloroacetate, nitriles, Adsorption of weakly basic drugs and
glycolate and nitrates are potentially their salts due to electrostatic
reactive impurities. [Link] addition, the residual
monochloroacetate may undergo S N 2
nucleophilic reactions.
7 Starch Starch may contain Terminal aldehydes in starch have been
formaldehyde, nitrites and known to react with the hydrazine
nitrates moiety of hydralazine [Link] may
also be involved in moisture-mediated
reactions, may adsorb drugs, and may
react with formaldehyde resulting in
reduced functionality as a disintegrant.
8 Colloidal silicon May contain heavy metal May act as a Lewis acid under
dioxide impurities anhydrous conditions and may adsorb
drugs
9 Magnesium Magnesium oxide is a Magnesium stearate can form hydrates
stearate known reactive impur with water, and exists in four hydration
states—mono-, di- and trihydrates.
MgO impurity is known to react with
ibuprofen. In addition, magnesium
stearate provides a basic pH
environment, and may accelerate
hydrolytic [Link] magnesium
metal may also cause chelation-
induced degradation

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 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

Table 3. Interaction and incompatabilities of the excipients with functional groups and
different types of reaction

Sr. no. Functional group Incompatibilities Type of reaction

1 Primary amine Mono and Amine-aldehyde and amine-
disaccharides acetal
2 Ester, cyclic lactose Basic components Ring opening, ester-base,
hydrolysis
3 Carbonyl, hydroxyl Silanol Silanol Hydrogen bonding
Hydrogen bonding
4 Aldehyde Amine, carbohydrates Aldehyde-amine, Schiff base
or glycosylamine formation
5 Carboxyl Bases Salt formation
6 Alcohol Oxygen Oxidation to aldehydes and
ketones
7 Sulfhydryl Oxygen Dimerization
8 Phenol Metals Complexation
9 Glelatin capsule shell Cationic surfactants Denaturation

Table 4. Analytical techniques used to characterize drug/excipient compatibility

Sr. Investigative Measurement Utility of data

no. technique
1 DSC Energy is absorbed or released by Physicochemical compatibility
a sample as it is heated, cooled, or of drug and Excipients
held at a constant
Temperature
2 TGA Weight changes by a sample as it is Physicochemical compatibility
heated, cooled, or held at a of drug and Excipients
constant temperature
3 Chromatographic Chemical interactions of the sample Excipients, drug product purity;
analysis with the stationary phase and the excipient–drug substance
mobile phase chemical compatibility
4 Microcalorimetry Absorbance or release of heat from Physicochemical compatibility
solution sample of drug and excipients; solution
applications
5 X-ray diffraction Scattering of x-ray radiation by a Polymorph characterization
solid sample
6 Microscopy Magnified appearance of sampl Particle size, morphology
7 LC-MS/MS Chromatographic separation and Impurity, degradation product
fragmentation of molecular species identification

1.5 Interaction and Incompatabilities of 1.6 In Table 4, the Utility of Some

the Excipients with Functional Groups of the Analytical Techniques
[4] Used to Characterize Drug/Excipient
Compatibility are Listed [5]
Different excipients have different chemical
nature, different functional groups and different In this present review article, we discussed about
reactivity towards other functional groups of drug different categories of drugs and commony used
or excipients Table 3. shows interaction and excipient in it’s formulations. Excipients
incompatabilities of the excipients with functional interactions and drug degradation due to
groups and different types of reaction which was Lactose, Magnesium stearate, Polyethylene
observed commonly. glycol, Citric acid, Fumaric acid, Formaldehyde,

6
 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

Starch, Titanium dioxide, Oleic acid and Polyvinyl groups. The sequence of such reaction is
pyrolidone were explained. referred to as the Maillard reaction. The literature
survey reveals the incompatibility of lactose with
2. SACCHARIDES amine-containing APIs. Micheal addition reaction
with primary amine result in formation of 1-4
2.1 Lactose addition products between the drug and the
maleic acid propogated by the free moisture
Lactose disaccharide reducing sugar is the most associated with the starch. Pregelatinized starch
commonly used excipients in various showed Such type of formation of the 1,4-
pharmaceutical oral unit dosage forms but addition reaction which finally leads to the
potentially react with drugs containing amino formation of maillard reaction product [6].

-
OH OH O OH OH NH Pr

+ Pr-NH2
OH OH OH OH OH OH
H2O
Glucose Schiff base

-
- OH OH NH Pr
- OH OH NH Pr
OH OH NH Pr

OH OH OH
OH OH O
OH OH OH 2,3 - enaminol
Amadori product
1,2 - enaminol
Several steps
H2O OH O
- HO CH2
OH N Pr AGE PRODUCTS

OH OH
-
OH OH OH NH 2 Pr 1
R
OH O
O
O CH3
2
R
-
OH OH O NH2
a-dicarbonyl + NH 2 Pr OH OH OH

1- deoxyosone
COOH
H3C
OH OH O H2O
Several steps
3- deoxyosone Amino acid
1 AGE PRODUCTS
R
H2N N
Further downstream processes
O
2
COOH R
3
Several steps R
CO2
1
1
R
R H2O
R3 O N
NH OH
Strecker aldehyde 2
1 OH
R 2
R3 R
R3 OH R
H2N
OH
2
R

Fig. 3. Simplified scheme of the Maillard reaction

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 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

The mechanism of the Maillard reaction is very 2.2 Baclofen

complicated; however, it is generally divided into
three stages. Maillard reaction between Lactose and Baclofen
were characterized by HPLC, LC-MS/MS and
1) The first stage involves the sugar-amine FT-IR. Mass spectrum shows 4 [Link]
st
condensation and the Amadori 1 impurity is of Baclofen- Lactose
nd
rearrangement. The reaction steps have adduct,Unknown 2 impurity of lactose
been well-defined and no browning occurs condensation reaction result in formation of
at this stage. baclofen–galactose or baclofen–glucose
2) The second stage involves sugar adducts. There are two major impurities in
rd
dehydration and fragmentation, and amino baclofen powder, 3 of them is an oxopentanoic
acid degradation via the Strecker reaction acid derivative: (3R,S)-5-amino-3-(4-
especially at high temperatures. chlorophenyl)-5-oxopentanoic acid and 4th
3) Formation of heterocyclic nitrogen contains a lactam ring and is named (4R,S)-4-(4-
compounds. Browning occurs at this stage. chlorophenyl) [Link] FT-IR data
[7,8]. shows the first step of the Maillard reaction leads

HO HO HO

O OH NH2 OH OH OH
HO HO HO
OH O OH OH N
NH
OO + OO OH OO O
OH OH OH O
OH OH OH OH
OH OH
OH OH

OH OH OH
Cl
Molecular Formula : Molecular Formula : Cl
Molecular Formula : Molecular Formula : Cl
C22H34ClNO13 C22H32ClNO12
C12H22O11 C10H12ClNO2
Nominal Mass value : Nominal Mass value :
Nominal Mass value : 342.3 555.96 537.94
Nominal Mass value
Lactose : 213.66
Condensation product Proposed Unknown - 1
Baclofen

Fig. 4. Formation of 1st unknown impurity from baclofen and lactose Maillard reaction
(Baclofen - lactose adduct)

HO HO
NH2 OH OH OH OH
HO
O
OH NH OH N
OH O OH + OH O O
OH OH OH
OH OH
OH
Cl

Cl Cl
Molecular Formula : Molecular Formula : Molecular Formula : Molecular Formula :
C6H11O6 C10H12ClNO2 C16H24ClNO8 C16H22ClNO7
Nominal Mass value : Nominal Mass value :
Nominal Mass value : Nominal Mass value : 375.8
180.15 393.82
213.66
Proposed Unknown-2
Galactose Condensation Product
Baclofen

nd
Fig. 5. Formation of 2 unknown impurity from galactose and baclofen Maillard reaction
(Galactose- baclofen adduct)

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 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

to the formation of an imine known as a Schiff’s product B and Amadori rearrangement product
base. In the baclofen FTIR spectrum,Adduct labeled as condensation product-A [10].
mixtures showed C=N stretching indicating
convertion of imine into its isomeric enamine 2.4 Fluoxetine
form during the Maillard reaction [9].
Drugs which contains secondary amines also
can undergo the Maillard reaction with lactose
2.3 Doxepin under pharmaceutically relevant conditions.
Fluoxetine was characterized by NMR, GC-
Physicochemical incompatibility of doxepin with MS,HPLC. The fluoxetine undergo Maillard
dextrose was evaluated in solid-state mixtures reaction and formed N-Formylfluoxetine as a
and the compatibility was characterized by using major product. Also GC/MS characterization
different physicochemical methods such as DSC, study reported various characteristic volatile
Fourier transform infrared spectroscopy and products of the Maillard reaction, including
mass spectrometry. The melting endothermic furaldehyde,maltol, and 2,3-dihydro-3,5-
peak of doxepin hydrochloride was disappeared dihydroxy-6-methyl 4H-pyran-4-one [11].
in the doxepin hydrochloride–dextrose binary
mixture and the dissolution of the drug particles 2.5 Memantine
inside the melted excipients and a new peak
appeared due to [Link] spectra of Maillard reaction of Memantine identified
Dextrose–doxepin hydrochloride showd a new by gradient high performance liquid
peak at 1647 cm-1,due to C=N covalent band chromatographic (HPLC) method using charged
indicating incompatibilitydue to Maillard-type aerosol detection (CAD). Reported impurities are
[Link] full-scan positive-ion electrospray memantine-lactose adduct (ML), a memantine-
product ion mass spectra showed that the dimethylamino glycine adduct (DMAG), a
molecular ion of doxepin hydrochloride was a memantine-galactose adduct (MGAL) and a
protonated molecules, formed condensation memantine-glucose adduct (MGLU) [12].
O

HO O
O H
HO + HO
OH O H
+
O OH OH
O
NH
OH + HO OH
N
HO OH HO
H
OH H3C N OH
CH3
Molecular Formula : Molecular Formula : Molecular Formula : C23H27NO6
Molecular Formula : C23H27NO7
C6H12O6 C19H21NO Average Mass : 413.4636 Da
Average Mass : 429.463 Da
Average Mass : 180.1559 Average Mass : 279.3761
Da Condensation product -B
Da Condensation product-A

Fig. 6. Proposed structures for Maillard reaction of doxepin hydrochloride with dextrose

HO

CF 3
OH
CF 3 HO CF 3
OH
Lactose O O
O O N Heat
O OH
O H3C N CH3
OH
NH CH3 HCl
H
O
OH
Amadori Rearrangement product N-formylfluoxetine
Fluoxetine Hydrochloride

Fig. 7. Maillard reaction of lactose and fluoxetine HCl

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 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

Β- Lactose
HO

O OH
NH2
HO
OH
+ O O
OH
CH3 OH OH
H3C

OH
Memantine Galactose Glucose
HO

O + H2O - H2O
HO
OH
HN
OH O O

OH OH

H3C
CH3
OH

Glycosylamine
HO H H
HO OH
HO H H OH
HO
OH HO
OH
H OH O NH
HO HO H NH
O
O NH
OH O O

OH CH3
H3C
H3C CH3
H3C
Memantine-Galactose
OH OH Memantine-Glucose adduct
Adduct (MGAL)
MGLU product
HN
Amadori Rearrangement product
(ARP) O
Memantine-Lactose adduct(ML)

H3C CH3

Memantine-Dimethylamino
Glycine Adduct (DMAG)

Fig. 8. Schematic diagram showing Maillard reaction between lactose and memantine

2.6 Sitagliptin MS/TOF and NMR, further evaluated using in

silico drug designs, in-silico toxicity and ADMET
Formation of the imine bond with sitagliptin found properties, whereas interaction products were
in the presence of lactose (the Maillard reaction) analysed using TOPKAT and ADMETTM
at high temperature and high humidity and it is software and compared to the drug [14].
characterized by FTIR and LC-MS. In LC-MS
characterization other various degradation 2.8 Nebivolol
products were found [13].
Nebivolol (NEB)–lactose adduct formed in
2.7 Abacavir unbuffered solution, buffered alkaline solutions
and dry physical mixture and Maillard adduct
Two newer interaction products (ALm 1 and ALm characterized by FTIR, HPLC and LC-MS. Due
2) generated due to reaction between Abacavir to adduct formation of the NEB–lactose adduct
and lactose which was characterized by results in highly significant loss in the bradycardic
hyphenated analytical techniques like LC- effect of NEB [15].

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 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

CF 3
CF 3 HO
F N
F N O OH N
N N
N HO N
N OH
O O HN O
NH2 O OH
F + OH
F
OH F
F
HO
Sitagliptin OH
O
Lactose OH
HO

O O
OH HO

OH
Unknown impurity
HO

Fig. 9. The Maillard reaction between the NH2 group of sitagliptin and lactose

HO
HN N
HO HN N

HO OH N N
HO O HO OH N N
OH
OH N
N
HO NH
HO O NH
O
O
H3C
H3C
ALm 2
ALm 1

Fig. 10. Abacavir and lactose interaction products ALm1 and ALm2

F
F

HO
HO OH HO
OH O
OH HO OH
OH O
OH O OH
O OH
O OH
OH
O H
OH HO
H HO + OH
HO N
HO + OH
N
H OH
OH H
O
H
O
F
F
Molecular Formula =
Molecular Formula =
C36H50F2NO15+
C36H52FNO16+
Average Mass =774.77 Da
Average Mass =792.79Da
Proposed structure for adduct
Condensation product

Fig. 11. Proposed Maillard reaction condensation products of NEB and lactose

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 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

O OH

O OH
HN
O
H3C
H3C N
O CH3
O

O O CH3 Hydrolysis product - Moexiprilate

M=470;ES+ m/z = 471; ES- m/z=469
-28
O OH CH3
HN
O
H3C O O
H3C N O
O CH3 O
H3C N
O
H3C N
Moexipril -18 O CH3
M =498;ES+ m/z = 499; ES- m/z=497
O
Cyclization product- Diketopiperazine
derivative of Moexipril
M=480;ES+ m/z = 481

Fig. 12. The proposed scheme for degradation of moexipril hydrochloride in the presence of
magnesium stearate (RH 76.4% and T = 318K)

O OH
CH3
N
NH
O O
HO

Hydrolysis product Enalaprilate

CH3
M=348;ES+ m/z = 349; ES- m/z=347

O O
CH3 CH3
N
NH O O
CH3
O O
HO O
N
Enalapril
N
M=376;ES+ m/z = 377 ; ES- O
m/z=375

Cylization product-Diketopiperazine
derivative of Enalaprilate
M=358;ES+ m/z = 359; ES- m/z=357

Fig. 13. The proposed scheme for degradation of enalapril maleate in the presence of
magnesium stearate (RH 76.4% and T = 318K)

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 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

O
OH O
O OH
O
NH
N NH
H Hydrolysis N
H H
H3C H
N H3C
O O O N
HO O O
CH3
HCl CH3
H3C
Imidapril Hydrochloride Hydrolysis product of Imidapril

Fig. 14. The proposed scheme for degradation of imidapril hydrochloride in the presence of
magnesium stearate (RH 76.4% and T = 318K)

NH2
NH2

O OH
O OH
Cyclization
O
N N
NH H2 O
N
O O
O
HO

Lisinopril
Cyclization product -
M=405;ES+ m/z = 406; ; ES-
Diketopiperazine derivative of
m/z=404 Lisinopril
M=387;ES+ m/z = 388; ES- m/z=386

Fig. 15. The proposed scheme for degradation of lisinopril in the presence of magnesium
stearate (RH 76.4% and T = 318K)

3. MAGNESIUM STEARATE Magnesium stearate and drugs undergo

hydrolysis and cyclization to give various drug
Magnesium stearate is the salt of a complex degradation products [17].
mixture of fatty acids, with the main component
as stearate and palmitate. It has multiple 4. PEG
crystalline forms and an amorphous form [16].
Various researchers reported magnesium In many literature authors revealed that
incompatibilitywith drug. polyoxyethylene linkages containing substances
such as polysorbate surfactants, poloxamers,
3.1 Moexipril Hydrochloride (Moxl), and PEGs undergo auto-oxidation, resulting in
Imidapril Hydrochloride (Imd), the formation of hydroperoxides and peroxide-
Enalapril Maleate, (Ena) and Lisinopril free radicals. Steps in Auto-oxidation reaction of
(Lis) in Solid State with Magnesium PEG
Stearate
 Catalyzed by metal- and/or light-induced
Incompatibilitybetween moexipril hydrochloride decomposition of polyoxyethylene
(MOXL), imidapril hydrochloride (IMD), enalapril chains.
maleate, (ENA) and lisinopril (LIS) in solid state  Chain eaction propogation by consumption
with magnesium stearate noticed when of oxygen and formation of hydroperoxides

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 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

 Reaction termination by the decomposition oxidation of PEG. Oxidation of cetirizine produce

of hydroperoxides and/or collision among as cetirizine N-oxide as degradation product [19].
free radicals.
Cetirizine and PEG undergo esterification due to
Peroxides and other oxidizing species such as free carboxylic group and formation of
peroxide and hydroxyl radicals, in formulations Cetirizine PEG Esters, and Di-Cetirizine PEG
containing low levels of residual peroxides, can Esters [20].
thus lead to fast degradation of the active drug
resulting in significantly compromised therapeutic 4.2 Indomethacine
activity [18].
The esterification of Indomethacine with PEG
4.1 Cetrizine leads to formation of esterified products such as
PEG esters of indomethacin and di-indomethacin
Oxidative degradation of cetirizine occurs in PEG esters. The reported two hydrolysis
polyethylene glycol. The reaction between the products [5-methoxy-2-methyl-1H-indol-3-yl]
drug and the reactive peroxide intermediates acetic acid and 4-chloro-benzoic acid as well as
such as peroxyl radicals formed through their PEG ester was also reported [20].

H –
HO O HO

OH OH
H
OH
O
O O O –
O O
+ O O
N N N N
+
N N
+ H2O

Cl Cl
Cl

Fig. 16. Proposed mechanism for the oxidation of cetirizine to form N-oxide
O
OH
Cl O OH
Cl O N O
N O
N n
N
H3C OH
+ H2O
+ O
n

PEG

Cetrizine PEG esters

Cetrizine, Mexact= 388.16 Da

O
N
O
Cl O
N
N O
O Cl

N
O

Di-Cetrizine PEG esters

Fig. 17. Structure of cetirizine, PEG, cetirizine PEG esters and di-cetirizine PEG esters

14
 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

Cl
H3CO
H3CO

O N
O
O
O
N O

O Di-Indomethacine PEG esters

Cl

Cl
CH3
Cl
O

H3CO
O N
H OH O
+ O + H2O
HO N HO O CH3
O
CH3 n
O
PEG
Indomethacine ,Mexact = 357.08 Indomethacine PEG esters
Da

+ H2O
CH3

O
CH4

O NH
HO
O CH3

PEG (5-Methoxy- 2- methyl

1H- indol- 3- yl- acetate )

Fig. 18. Structure of indomethacin, PEG and PEG esters of indomethacin and di-indomethacin
PEG esters. In addition, the structures of the two hydrolysis products [5-methoxy-2-methyl-1H
indol-3-yl] acetic acid and 4-chloro-benzoic acid as well as their PEG ester reaction products
are presented
5. CITRIC ACID SWAXS patterns and also by characteristic
peaks in the Raman fingerprint region-Raman
In various formulations Citric acid used for pH spectra [22].
[Link] release rates and absorption were
different at different pH level [14]. But some 6. FUMARIC ACID
times it also react with drug components [21].
In some formulations Fumaric acid used to
5.1 Carvedilol and Codeine Phosphate improve stability and moisture sensitivity
via the dry granulation. It was observed that
Esterification of Carvedilol (CAR) and Codeine slow dissolution kinetics of fumaric acid
Phosphate (COP) with citric acid (CA) alter drug prolongs an acidic microenvironment around
biological action. Due to mechano-activation the API granules and excipients leading
means co-milling of API and Citric acid causes to increased dissolution and increased
faster reaction than in physical powder mixtures absorption [23]. But due to fumaric acid, some
kept at accelerated storage conditions. It is drug excipient incompatibility found in
characterized by thermal behavior in DSC, their formulations.

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 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

NH NH
O
NH
OH

H3C H3C
O O
H3C + H3C CH3 O O
O O O O
NH NH
O
NH O O
O O O
OH HO OH
O
O O OH
HO OH
OH
HO O
Fig. 19. Esterification reactions of carvedilol with citric acid

N CH3
N CH3
H2 H
O
N CH3 H2 H
OH
H

+ H3C CH3
H3C
O
O O O
H3C H
O O O O
O HO HO
H3C
O O OH HO
OH O
O HO
OH
H3C
O

Fig. 20. Esterification reactions of codein phosphate and citric acid

CF 3
CF 3
F N
F N O N
N N
N
N
N
+ HO
OH
NH O
NH2 O O F
F O
F
F HO
OH
Sitagliptin Fumaric acid
O

Michael addition product

Fig. 21. Interactions between the NH2 group of sitagliptin and the double bond of fumaric acid
(The Michael addition)

6.1 Sitagliptin cross Povidon, packaging components.

Formaldehyde reacts with amine functional group
Degradation of sitagliptin in fumaric acid occurs of drugs to form N-formyl adducts (hemiaminals)
at highly stressed condition. The amino group of that can further react to form dimer [24].
sitagliptin and double bond of fumaric acid
undergo Michael addition reaction to form
7.1 Amlodipine
unknown sitagliptin-lactose adduct. It is
characterized by LC-MS,FTIR [13].
New unknown impurity were observed during the
7. FORMALDEHYDE accelerated stability analysis in the
multicomponent tablets of amlodipine besylate.
Formaldehyde and other aldehydes are known This formed impurity characterized by UHPLC-
impurities in several excipients such as Starch, MS and NMR [Link] reported
degradation product of lactose, Povidon and degradation product of amlodipine besylate as

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 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

H3C H3C
H H H
+
O Cl N O O Cl
N O

O O

HN O HN O
CH3 CH3

CH3 O CH3 O

Chemical Formula :- C21H25ClN2O5

Chemical structure :-
Exact Mass :-421.15
C21H26CIN2O5 Unknown impurity : 3-ethyl 5-methyl
Exact Mass:- 421.1525 4-(2-chlorophenyl)-6-methyl-2-(morpholin-2-yl)-1,4-dihydropyri
dine-3,5-dicarboxylate

Fig. 22. The proposed unknown impurities of amlodipine

3-ethyl 5-methyl 4-(2-chlorophenyl)-6-methyl-2- starch in a gelatin capsule dosage form. It
(morpholin-2-yl)-1,4-dihydropyridine-3,5- undergoes Micheal addition to form 1-4 addition
dicarboxylate [25]. product in the presence of pregelatinized
starch while a Maillard reaction product was
8. STARCH formed [6].

Chemically, starches are polysaccharides, 9. TITANIUM DIOXIDE

contains monosaccharides or sugar (glucose)
molecules linked together with α-d-(1-4) and/or Titanium dioxide specimens like Wackherr TiO2,
α-d-(1-6) linkages. Starch has been used as prepared TiO2 and Aeroxide P25 toward the
excipient in many novel drug delivery systems photocatalytic synthesis widely used in
which acts as disintegrants, fillers or binders. pharmaceuticales. TiO2 Wackherr has low cost
Due to its partial cold water solubility, performs than other therefore more useful when high
dual functions of both a disintegrant and a binder photocatalyst loading is required at high
and in capsule filling processes, Starch and Star substrate concentration. But periodically it
Cap Co-Processed Starch Excipients used as causes incompatibilitywith drugs [27].
binders. As a result of its partial cold water
solubility, starch functions exceptionally well in 9.1 Metoprolol
tablet manufacture by wet granulation
applications and performs dual functions of both The comparision between photocatalytic activity
a disintegrant and a binder. In capsule filling of TiO2 Wackherr and TiO2 Degussa P25 under
processes, Starch function as effective binders UV irradiation. Under UV, the process involving
[26]. TiO2 Wackherr significantly showed faster
photocatalytic activity than direct photolysis. The
8.1 Seproxetine Transformation with Degussa P25 it is due to the
higher radiation scattering by Degussa P25
Seproxetine maleate hemihydrate salt, a compared to TiO2 Wackherr ensures that the
selective serotonin re-uptake inhibitor, showed former photocatalyst is less efficient in using
incompatibilitybetween primary amine containing radiation. Fourteen intermediates were identified
active metabolite of fluoxetinen with lactose and by LC–MS/MS (ESI+).
NH2
HN R
NH N N
R
N N
N
+ RCHO N N
Starch N N

Fig. 23. Reaction of hydralazine with terminal aldehydes of starch residue

17
 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

CF 3

CF 3 O
O
OH Starch H O

H O
+ OH OH
NH
OH
NH2 OH
OH

Seproxetine Maleic acid

CF 3

O
H O
OH
NH
OH

OH

1,4 - Addition product

Fig. 24. Interaction between seproxetine and maleic acid in the presence of starch

OH
O NH CH3

H3C O CH3
O (OH) 3

Unknown A

O NH CH3
H3C
OH
O OH CH3
O NH CH3
H3C NH
OH
H3C CH3
O Unknown B
H3C O
Metoprolol

O
OH
OH
O N CH3

H3C CH3
O
Unknown C

Fig. 25. The photocatalytic degradation products of MET. Note that a was only identified with
TiO2 Wackherr, B and C only with Degussa P25

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 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

Characterization by LC-MS/MS involved 10.1 WR 30090 (Mefloquine and

photocatalytic degradation process like Halofantrine Analog)
 Hydroxylation of the aromatic ring, Incompatibility between novel antimalarial WR
 Shortening of the methoxyl containing 30090 an analog of mefloquine and hal of antrine
lateral chain, were observed when it formulated in a high purity
 Cleavage of, or addition of •OH to, the sample of oleic acid as the vehicle. WR 30090
amine-containing one. [28] showed considerable chemical instability to form
Oleic acid ester of WR [Link] was due to oleic
10. OLEIC ACID acid anhydrate which was prepared by fraction
distillation of oleic acid.
Oleic acid (OA), commonly used as vehicle in The lipid lowering agent, 3-(2,4 diflurophenyl)-1-
many pharmaceuticals. OA added in the heptyl- 1-(neopentylbenzyl)urea (3), also
formulations to increase drug solubility. But formulated with oleic acid. On storage 3 rapidly
during purification by aid of distillation, degraded to a complex mixture with two of the
dehydrated oleic acid formation leads to degradation products identified shown in Fig. 26
incompatibility between drugs and excipient. [29].

(CH 2) 6 (CH 2)6 CH 3

O C 4 H9
HO C 4H 9 N
N Oleic Acid
Cl C 4H 9
Cl C4 H9

Cl
Cl N
N
Cl
Cl Cl
Cl

2
1
Fig. 26. Reaction pathway for the degradation of WR 30090 in an oleic acid vehicle (1), possibly
due to oleic acid anhydride in the purified oleic acid sample

F
O
NH NH
CH3
NH N
F F F
F F
Oleic Acid

3
CH3

CH3
H3C

3- ( 2,4- diflurophenyl)- 1- (4- neopentylbenzyl ) urea

Fig. 27. Some degradation products seen when 3-(2,4-diflurophenyl)-1-heptyl-1
(neopentylbenzyl)urea (3) was formulated with oleic acid (2)

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 Gupta et al.; AJOCS, 6(3): 1-22, 2019; Article [Link].51941

Peroxides from excipients

R ( Povidone ) in formulation
HO O

HO
O O +
N N

O O
HCl HCl

+ ROH
OH OH
HO S HO S

Raloxifen hydrochloride Raloxifen N- Oxide

Fig. 28. Excipient-induced (Povidone and crospovidone) oxidation of a tertiary amine

Raloxifene hydrochlorid [31]

11. PVP excipients in drug formulation. Best excipient,

storage conditions and its prevention of drug
Nitrates, nitrites are common nitrosating excipient interaction establishing the good
impurities that can be found in most excipients at formulation. Advanced analytical development
parts per million (ppm) levels. Sodium starch should ensure any unknown peaks formed during
glycolate, croscarmellose sodium, pre-gelatinized the drug excipient compatibility studies helps to
starch, PVP, cPVP. Many literature revealed that ensure drug compatibility. Thorough monitoring
it also contain peroxides. The drugs containing and prevention of unknown impurities and its
functional groups that can potentially form NOCs origin during drug development process reduces
with PVP, cPVP include dialkyl, alkylaryl, diaryl, the delay in the product filings and USFDA
cyclic secondary amines, N-alkylureas, N- approvals.
alkylcarbamates and N-alkylamides to
synthesize nitrosamines or nitrosamides COMPETING INTERESTS
products. To a much lesser extent, tertiary
amines, cyanamides, guanidines, amidines, Authors have declared that no competing
hydroxylamines, hydrazines, hydrazones and interests exist.
hydrazides may also form NOCs [24].
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