Journal of Chromatographic Science, 2017, 18

doi: 10.1093/chromsci/bmx036
Article

Article

Esterication of Ibuprofen in Soft Gelatin

Capsules FormulationsIdentication,
Synthesis and Liquid Chromatography
Separation of the Degradation Products
Michal Doua1,*, Ludek Meca1, Petr Gibala1, Josef Jirman1,
Marcela Tkadlecov1, Jan Srbek1, Jana alandov1, Eva Kovalckov2,
and Jir Brichc1
1
ZentivaA Sano Company, U Kabelovny 130, 102 37 Prague 10, Czech Republic and 2Saneca Pharmaceuticals,
Nitrianska 100, 920 27 Hlohovec, Slovak Republic
*
Author to whom correspondence should be addressed. Zentiva, k.s. A Sano Company, U Kabelovny 130, 102 37 Prague
10, Czech Republic. Email: michal.dousa@seznam.cz
Received 29 April 2016; Revised 4 January 2017; Editorial Decision 31 March 2017

Abstract
Unknown impurities were identied in ibuprofen (IBU) soft gelatin capsules (SGCs) during long-
term stability testing by a UHPLC method with UV detection and its chemical formula was deter-
mined using high resolution/accurate mass (HRAM) LCMS. Reference standards of the impurities
were subsequently synthesized, isolated by semi-preparative HPLC and characterized using HRAM
LCMS, NMR and IR. Two impurities were formed by esterication of IBU with polyethylene glycol
(PEG), which is used as a ll of the SGCs, and were identied as IBUPEG monoester and IBUPEG
diester. Two other degradants arised from reaction of IBU with sorbitol and sorbitan, which are
components of the shell and serves as plasticizers. Thus, IBU sorbitol monoester (IBUsorbitol) and
IBU sorbitan monoester (IBUsorbitan ester) were identied. An UHPLC method was further opti-
mized in order to separate, selectively detect and quantify the degradation products in IBU SGCs.

Introduction currently in use, namely glycerol, sorbitol/sorbitan mixtures and

Ibuprofen (IBU), 2-(4-isobutylphenyl) propanoic acid, is well-known
non-steroidal anti-inammatory drug (NSAID) that inhibits prosta-
glandin synthesis and has anti-pyretic and non-narcotic analgesic
properties. Recently, the world production of IBU is in the vicinity
of 15,000 tons per year (1). It is widely used orally in tablet, capsule
or soft gelatin capsule (SGC) form (2). Generally, SGC formulation
is gradually being more preferred for increased rate of drug absorp-
tion, improved bioavailability of poorly soluble compounds, due to
the technological reasons and for consumer preference (3). SGCs
consist of a liquid ll enveloped by a one-piece hermetically sealed
elastic outer shell. The formulation of the hydrophilic ll is typically
based on polyethylene glycols (PEGs). The shell of a SGC is com-
posed of gelatin, a plasticizer and water. Only a few plasticizers are
propylene glycol (4).
The chemical stability of an active pharmaceutical ingredient
(API) in pharmaceutical preparations is dependent on the formula-
tion composition, technology and storage environment such as tem-
perature, humidity and light. The potential physical and chemical
interactions between drugs and excipients can affect the chemical
nature, the stability and bioavailability of drugs and, consequently,
their therapeutic efcacy and safety (510). The API can also react
with trace contaminants that the excipients introduce, resulting in
degradation (11). Stability testing provides information about how
the quality of drug product varies with time under the inuence of
various environmental factors and helps to determine recommended
storage conditions and establish retest periods and shelf lives (12).

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2 Doua et al.

Several HPLC methods for IBU determination and its related com- Experimental
pounds and impurities in pharmaceutical preparations have been
described in the literature. The most common technique for IBU
Reagents and chemicals
quantication is RP-HPLC using an octadecylsilane column as sta- Acetonitrile HPLC gradient grade (J.T. Baker, USA), methanol (J.T.
tionary phase and UV detection (1316). Capillary electrochromato- Baker, USA) and water puried by Milli-Q system (Millipore, USA)
graphy using RP-18 packed capillary was used for simultaneous were used for preparation of samples, reference solutions and
separation of IBU and its impurities (Ph. Eur. impurity A, B, C, E) as mobile phases. All other chemicals (ortho-phosphoric acid, formic
well (17, 18). acid, dichlormethane, dicyclohexylcarbodiimide and 4-dimethylami-
Although degradation chemistry of IBU API and IBU in tablet nopyridine) were of analytical grade or pure grade quality (Sigma-
formulations was well described (1822), only limited data related Aldrich, Czech Republic). The standard of IBU (in-house standard,
to stability of IBU in SGCs formulation has been reported (23). purity 99.8%) was prepared in Zentiva (Czech Republic). PEG 600
Forced degradation of IBU was observed in tablets containing PEG (range of average molecular weight: 570630, dynamic viscosity at
and polysorbate 80. Unfortunately, the structures of IBU degrada- 20C of 50% solution: 18 mPa s, hydroxyl value: 188 mg KOH/g)
tion products were not determined. Moreover, only accelerated deg- was obtained from Clariant Produkte (Germany). Polysorb 85 con-
radation but not long-term stability data were reported (24). tained 43% of D-sorbitol and 27% of 1,4-sorbitan and was obtained
Decrease of esterication reaction between IBU and PEG was from Roquette (France). The shell of in-house prepared SGCs com-
described when PEG in combination with polyvinylpyrrolidone was posed of gelatin, partially dehydrated sorbitol liquid, carmine red
used as a SGCs ll (25). Formation of IBUPEG ester and its hydro- and puried water in mass ratio 44:22:0.05:34. The ll of the SGCs
lysis was described in EMEA withdrawal assessment report for com- composed of IBU, PEG 600, potassium hydroxide 85% and water
bination product IBU/diphenhydramine hydrochloride (26). Besides in mass ratio 58:29:8:5.
that, IBUPEG esters were prepared and their potential as a drug
prolonged release system was investigated. However, these studies
HPLC instrumentation and methods
were aimed solely to preparation of new IBU polymeric prodrugs
All chromatographic experiments were carried out on an Acquity
and studying of the IBU degradation was not the concern (27, 28).
UPLC system with a photodiode array detector (Waters, USA). The
Further, the various types of poly(ethylene glycol) (PEG)IBU conju-
system control, data acquisition and processing was accomplished
gates by the nucleophilic substitution of bromo-terminated PEG
by the Empower software (Waters, USA). Chromatographic separa-
with IBU-Cs salt were synthesized (29).
tions were performed on an Acquity BEH C18 column (100
This article describes identication of degradation products
2.1 mm2, 1.7 m; Waters, Czech Republic). The mobile phase was
which were found in IBU SGCs pharmaceutical preparations
pumped at 0.5 ml/min, the injection volume was 1 l and analytes
using UHPLC method with UV detection. The impurities were
were monitored at a wavelength of 220 nm. The gradient elution
synthesized, puried by semi-preparative HPLC and character-
employed solutions A and B as mobile phase components. Method
ized using HRAM LCMS, NMR and IR analysis. All character-
I: The solvent A was 0.1% ortho-phosphoric acid, while solvent B
ized degradants are esters formed by drug-excipient interactions.
Two degradants were formed by esterication of IBU with ll of
the SGCs and were identied as IBUPEG monoester and IBU
PEG diester. Two other impurities arised from reaction of IBU
with content of the shell and to best of our knowledge has not
been reported yet. These unknown degradants were determined
as IBU sorbitol monoester (IBUsorbitol) and IBU sorbitan mono-
ester (IBUsorbitan).

Figure 1. Long-term stability of IBU SGCs in climatic chamber at 25C and

60% relative humidity. Content of impurities IBUPEG monoester (circles),
IBUsorbitol (squares) and IBUsorbitan (triangles) as average from three
batches is depicted. Content of IBUPEG diester was bellow reporting thresh- Figure 2. Structures of IBUPEG monoester (A), IBUPEG diester (B), IBU
old and therefore was not monitored during stability testing. sorbitol (C) and IBUsorbitan (D).
Esterication of Ibuprofen in Soft Gelatin Capsules FormulationsIdentication, Synthesis and Liquid
Figure 3. Preparation of IBUPEG esters (A), IBUsorbitol (B) and IBUsorbitan (C).
was acetonitrile. The gradient program was set as follows: time/%
of solvent B: 0/10, 2.0/10, 17/80, 20/80, 20.5/10 with an equilibra-
tion time of 2 min. The column was thermostated at a temperature
of 35C. Method II: The solvent A was 0.1% ortho-phosphoric acid
and solvent B was acetonitrile. The gradient program was set as fol-
lows: time/% of solvent B: 0/5, 60/90, 61/5 with an equilibration
time of 2 min. The column was thermostated at a temperature of
45C. Method III: The solvent A was water and solvent B was meth-
anol. The gradient program was set as follows: time/% of solvent B:
0/0, 70/85, 90/85, 91/0 with an equilibration time of 4 min. The col-
umn was thermostated at a temperature of 65C.
LCMS instrumentation and methods
High resolution/accurate mass (HRAM) MS experiments were per-
formed on a LTQ XL Orbitrap Mass Spectrometer (Thermo, San
3
Jose, USA) coupled to an HPLC HTS PAL system (CTC Analytics,
Switzerland). LC separation was performed on a Kinetex C18, 150
4.6 mm2, 5 m (Phenomenex, Torrance, USA) column using 1.0 ml/min
ow rate. The gradient elution employed solutions A and B as mobile
phase components. The solvent A was 0.1% formic acid, while sol-
vent B was acetonitrile. The gradient program was set as follows:
time/% of solvent B: 0/43, 17/43, 25/100, 30/100, with an equilibra-
tion time of 7 min. For an ionization of the analytes an APCI ion
source was operated in the positive ion mode (desolvation tempera-
ture 400C, capillary temperature 300C, discharge current 4 A and
tube lens voltage 40 V).
Semi-preparative instrumentation and methods
Preparative HPLC separation and fraction collection was carried
out on a Waters Auto purication system (System uidics organizer,
Table I. NMR Assignments for IBU Esters

4
Position (C) (H) Mult. Integ. H J(H,H) Position (C) (H) Mult. Integ. H J(H,H) (C) (H) Mult. Integ. H J(H,H)

IBUPEG monoester IBUsorbitol IBUsorbitan

1=2 22.3 0.86 d 6 6.7 1 139.7 139.7
3 30.1 1.81 Nonet 1 ~7 2=6 129.0 7.10 d 2 8.0 129.0 7.10 d 2 8.0
4 44.91 2.41 d 2 7.3 3=5 127.1 7.20 Overlap 2 127.1 7.20 d 2 8.0
5 140.4 4 138.0 137.9
6 129.2 7.05 d 2 8.2 7 44.2 2.41 d 2 7.1 44.2 2.41 d 2 7.2
7 127.1 7.18 d 2 8.2 8 29.6 1.80 Nonet 1 6.6 29.6 1.80 Nonet 1 6.8
8 137.5 9 = 12 22.2 0.85 d 6 6.6 22.2 0.85 d 6 6.6
9 44.87 3.69 Overlap 1 10 44.2 3.74 Overlap 1 44.2 3.75 q 1 7.1
10 18.5 1.46 d 3 7.2 11 18.7 1.38 Overlap 3 18.8 1.39 d 3 7.1
11 174.6 13 174.1 174.0
12, 13 72.54 3.58 Overlap Approx. total 16 67.1 3.84.3 4 dd (overlap) Approx. 2 67.4 4.31 m 1
70.4968.94 3.513.64 intensity 52 66.9
66.3
63.78 4.19 66.2 3.85 m 1
61.56 3.69
14 Not observed 17,19,21, 23 6874 (13 signals) 3.33.8 Overlap Overlap 80.4 3.66 dt 1 8.3, 2.9
76.3 3.95 Overlap 1
75.4 3.91 Overlap 1
65.9 3.83 Overlap 1
18,20,22,24,26 4.35.0 Broad signals Overlap
18,22,24 5.04 br.s
4.90
4.83
25 63.4 3.33.6 Overlap Overlap 73.5 3.89 m 1
62.4 3.44 m 1

Note: in ppm, J in Hz. Reference for IBUPEG monoester 1H and 13C was CDCl3 signal. Reference for IBUsorbitol and IBUsorbitan was DMSO signal: 1H (DMSO) = 2.5 ppm and 13C (DMSO) = 39.50 ppm.

Doua et al.
Esterication of Ibuprofen in Soft Gelatin Capsules FormulationsIdentication, Synthesis and Liquid 5

Table II. MS Accurate Mass Elemental Composition of IBU Esters

Impurity Measured Theoretical Mass error Molecular formula [M + H]+ Fragments/adducts Fragments/adducts formulas
mass (m/z) mass (m/z) (ppm) mass (m/z)

IBUPEG monoester 515.3224 515.3215 1.75 C27H47O9, n = 7 532.3490 C27H50O9N, [M + NH4]+

779.4812 779.4787 3.21 C39H71O15, n = 13 796.5080 C39H74O15N, [M + NH4]+
1175.7157 1175.7147 0.85 C57H107O24, n = 22 1192.7434 C57H110O24N, [M + NH4]+
IBUPEG diester 703.4432 703.4416 2.27 C40H63O10, n = 7 720.4691 C40H66O10N, [M + NH4]+
967.5987 967.5989 0.21 C52H87O16, n = 13 984.6274 C52H90O16, [M + NH4]+
1363.8367 1363.8348 1.39 C70H123O25, n = 22
IBUsorbitol 371.2068 371.2064 1.08 C19H31O7 388.2334 C19H34O7N, [M + NH4]+
353.1962 C19H29O6, [M-H2O + H]+
335.1857 C19H27O5, [M-2H2O + H]+
IBUsorbitan 353.1962 353.1959 0.85 C19H29O6 370.2227 C19H32O6N, [M + NH4]+
335.1856 C19H27O5, [M H2O + H]+
161.1325 C12H17, [IBUHCO2]+

Table III. FT-IR Spectral Data for IBU Esters

Impurity IR

IBUPEG monoester (OH) 3500, (CH) 2953, 2867, (C = O) 1732, (C = C) 1512, 1456, (COC) 1201, (CO) 1095
IBUsorbitol (OH) 3360, (CH) 2951, 2867, (C = O) 1702, (C = C) 1512, 1462, (COC) 1213, (CO) 1089, 1024
IBUsorbitan (OH) 3402, (CH) 2952, 2918, 2865, (C = O) 1723, 1700, (C = C) 1512, 1464, (COC) 1168, (CO) 1064, 1043

All frequencies are in per cm.

2,545 binary gradient module, 2,767 sample manager, 515 HPLC
pump, MS and 2,487 dual-wavelength absorbance detector; Waters,
USA). The ow rate of 20 ml/min was employed throughout the
preparation. The injection volume was 900 l. In order to monitor
UV signal from the semi-preparative column, the efuent was
splitted in the ratio 1:1,000 into the methanol ow from 515 HPLC
pump, which was directed to MS and UV detector. A semi-
preparative XBridge Prep C18 OBD column (100 19 mm2, 5 m;
Waters, USA) was used for preparative purposes.
Method IV was used for isolation of IBUPEG monoester:
The fraction collection was triggered by setting a minimal inten-
sity threshold (MIT = 3,500 V for UV detection) of the UV sig-
nal at 265 nm. The mobile phase consisted of 0.025% aqueous
solution of ammonium hydroxide (solvent A) and acetonitrile
(solvent B). The separation was performed using gradient elution
based on following program: time/% of solvent B: 0/50, 2.0/50,
4.4/80, 4.6/100, 6.5/100, 7.0/50 with a re-equilibration time of
1.0 min. Method V was used for preparation of IBUsorbitol and
IBUsorbitan: The fraction collection was triggered by setting a
minimal intensity threshold (MIT = 15,000 V for UV detection)
of the UV signal at 265 nm. The mobile phase consisted of 0.1%
aqueous solution of formic acid (solvent A) and acetonitrile (sol-
vent B). The separation was performed using gradient elution
based on following program: time/% of solvent B: 0/35, 0.5/35,
7.5/42, 7.7/100, 8.7/100, 8.9/35 with a re-equilibration time of
1.1 min.
NMR instrumentation and methods
Nuclear magnetic resonance (NMR) spectra were obtained using a
Bruker Avance 500 (Bruker Biospin, Germany) at 500.13 MHz
(1H) and 125.78 MHz (13C) with Prodigy probe in CDCl3 at
298 K.
Results
Identication of unknown degradation products
Unknown degradation products were detected during the long-term
stability testing of the IBU SGCs formulation in climatic chamber at
25C and 60% relative humidity (Fig. 1). Gradient UHPLC method
(Method I) was used showing relative retention time (RRT) 0.78,
0.86, 1.05, 1.521.63 in respect to IBU. The similar impurities pro-
le was observed for IBU SGCs developed by Zentiva and obtained
from original manufacturer (data not shown).
Subsequently, HRAM LCMS measurement was performed in
order to investigate chemical structure of the unknown degradants.
HPLC peak corresponding to impurity RRT 1.05 was identied
as ester of IBU and PEG (IBUPEG monoester). PEG is used as a ll
of the SGCs and the ratio of IBU with PEG in the formulation is
2:1. The polymeric compound consisted of a varying number of
repeating ethoxy units between terminal hydroxyl group and IBU
group (Fig. 2A). The isotopic pattern was represented by typical
polymeric envelope with distance corresponding to ethylenglycol
monomer unit (44, C2H4O). Molecular formula was identied as
C2n+13H4n+18On+2 and monoisotopic mass was ranging from
514.3142 (for n = 7) to 1,174.7074 (for n = 22). The range of
molecular weight was in agreement with specication of PEG 600,
which was used in the formulation.
Moreover, degradation product RRT 1.521.63 was identied
as conjugate of two IBU molecules connected by PEG via ester
bonds (IBUPEG diester, Fig. 2B). Molecular formula was deter-
mined as C2n+26H4n+34On+3 and monoisotopic mass was ranging
from 702.4343 (for n = 7) to 1,362.8275 (for n = 22). The isotopic
pattern was again represented by typical polymeric envelope.
Two other degradants arised from reaction of IBU with sorbi-
tol and sorbitan, which are components of the shell and serves as
plasticizers. Impurity RRT 0.78 was identied as IBU sorbitol
6 Doua et al.

monoester (IBUsorbitol, Fig. 2C) with molecular formula

C19H30O7 and molecular weight 370. The proposed structure for
impurity RRT 0.86 was IBU sorbitan monoester (IBUsorbitan,
Fig. 2D) with molecular formula C19H28O6 and molecular weight
352.

Synthesis and purication of identied impurities

Preparation of IBUPEG esters
IBUPEG diester was prepared by procedure from Ref. (27). IBU
PEG monoester was prepared by modication of procedure (27), in
which ratio of reactants was changed to the excess of PEG and only
one equivalent of dicyclohexylcarbodiimide (DCC) was used
(Fig. 3). 1.7 g of IBU (8 mmol), 1.7 g of DCC (8 mmol) and 0.16 g of
4-dimethylaminopyridine (DMAP) were dissolved in 50 ml of di-
chloromethane. Solution of 9.6 g of PEG in 50 ml of dichloro-
methane was added to the mixture. Mixture was stirred under
laboratory temperature for 15 h. Then solid dicyclohexyl urea was
ltered off. Clear solution was evaporated to the viscous semicrys-
talline matter. The residuum was diluted by 10 ml of acetone and
cooled to 18C. Obtained solid was ltered off and liquid portion
was concentrated under vacuum of 1mbar and 40C. Remaining
9.5 g was mixture of semisolid IBU, PEG and IBUPEG esters. The
product was dissolved in acetonitrile to concentration 50 mg/ml and
subsequently puried by semi-preparative HPLC. The collection
parameters of the semi-preparative HPLC method were optimized
with respect to high concentration of IBUPEG esters in the solution
of crude sample. The solution of crude sample was injected onto the
semi-preparative column and the fractions of IBUPEG esters were
repeatedly collected and combined. The combined fractions were
evaporated under vacuum at 40C to obtain pure liquid oily stan-
dard. Yield was 2.6 g of IBUPEG monoester.

Preparation of IBUsorbitol ester

A 0.91g of D-sorbitol (5 mmol) was dissolved under mild heating in
5 ml of dimethylsulfoxide (DMSO) to form clear colorless solution.
To this warm solution 1.03 g (5 mmol) of IBU and 0.06 g (0.5 mmol)
of DMAP was added. Subsequently, 1.03 g (5 mmol) of DCC was
added. During addition of DCC white precipitate of dicyclohexyl urea
started to form. The mixture was stirred for 20 h, and then cooled in
liquid nitrogen to solidify it. This solid mixture was placed to lyophili-
zator to reduce DMSO amount. After 4 h the content of DMSO was
reduced to 3 g. Dichloromethane (15 ml) was added to the mixture,
the mixture was cooled down to 5C and the solid was ltered off.
Filtrate was concentrated in vacuum at 50C to receive 4.13 g colorless Figure 4. UHPLC chromatogram of a dosage form after stability storage at
oil. This oil was puried using semi-preparative HPLC. Collected frac- 25C and 60% relative humidity for 18 months using Method I (A).
tions containing desired product were evaporated at 40C under Separation of the IBUPEG monoester using Method III (B) and IBUPEG
diester using Method II. The percentage of individual oligomeric units is de-
reduced pressure. Resulting white waxy solid was dried in vacuum of
picted above each chromatographic peak.
oil pump. Yield was 0.3 g of IBUsorbitol ester.

Preparation of IBUsorbitan ester
Polysorb 80 (85/70/00) was concentrated in rotary evaporator under
reduced pressure at 50C to obtain colorless honey, in which 6.6%
of water was found using Karl Fischer titration method. This con-
centrated polysorb was used for synthesis. A 8.94 g of preconcen-
trated polysorb 80 was dissolved in 5 ml warm DMSO, and then
4.58 g (28 mmol) carbonyldiimidazole (CDI) was added to the
warm solution in portions. Mixture was foaming due to evolution
of carbon dioxide. To the separately prepared solution of 5.16 g
(25 mmol) IBU in 3 ml DMSO was added 4.05 g (25 mmol) CDI in
portions. After all CDI had been added, the solution was stirred for
10 min and then slowly added to the solution of polysorb in DMSO.
Resulting clear slightly yellow solution was stirred for 60 h. This
mixture was puried using semi-preparative HPLC. Collected frac-
tions containing desired product were evaporated at 40C under
reduced pressure. Resulting oil was dried in vacuum of oil pump.
Yield was 0.4 g of IBUsorbitan ester.
Methods of preparation of IBUPEG, IBUsorbitol and IBUsor-
bitan esters were not further optimized due to preparation of analyt-
ical standards only.
Esterication of Ibuprofen in Soft Gelatin Capsules FormulationsIdentication, Synthesis and Liquid
The characterization of reference standards
In order to prepare in-house standards of IBUPEG monoester,
IBUsorbitol ester and IBUsorbitan ester, the structures of prepared
impurities were conrmed and characterized by NMR, MS and IR
analysis (Tables IIII). The assignment of NMR signals was per-
formed by means of 1H, 13C and 2D (COSY, HSQC and HMBC)
spectra. NMR data unambiguously conrmed the proposed struc-
tures of IBU esters. According to the intensities of the NMR signals,
average number n of PEG units in IBUPEG monoester was 13.
Moreover, the elucidation of chemical structure by NMR showed
the IBUsorbitol in-house standard is racemic mixture of four
isomers, mainly sorbit-1-yl 2-(4-isobutylphenyl)propionate and
sorbit-6-yl 2-(4-isobutylphenyl)propionate. Each NMR 1H and 13C
NMR signal of IBUsorbitan was formed by one major, one
medium and 12 minor peak due to mixture of four isomers, mainly
1,4-anhydrosorbit-6-yl 2-(4-isobutylphenyl)propionate and 3,6-
anhydrosorbit-1-yl 2-(4-isobutylphenyl)propionate. Further stereo-
chemical investigation of the formed monoesters was not subject of
this study.
Discussion
Identication of unknown degradation products
The routine UPLC method was then optimized to reach separation
of IBUPEG oligomers. Previously, the resolution between PEG oli-
gomers using LC methods was achieved at elevated temperature
using gradient elution (30). The routine UHPLC method was
Figure 5. Full scan HRAM mass spectra in positive APCI ionization mode of synthesized IBUPEG monoester (A), IBUPEG diester (B, average mass spectrum at
RT ranging from 24.0 to 25.9 min), IBUsorbitol (C) and IBUsorbitan (D).
7
modied by changing the organic solvent (methanol), gradient prole
and increasing the temperature to achieve baseline resolution of the
individual oligomers. UHPLC methods were used for the chemical
characterization of IBUPEG monoesters (Method III) and IBUPEG
diesters (Method II). The separation of the corresponding IBUPEG
esters is shown in Figure 4, including the evaluation of percentage of
individual oligomers in IBUPEG esters by internal normalization.
The Method II was successfully applied for determination of related
substances in pharmaceutical SGCs formulations.
The characterization of reference standards
The obtained MS data for prepared standards were in agreement
with the data measured in IBU SGCs pharmaceutical formulation
(Fig. 5). UHPLC peak equivalency between synthesized in-house
standards and impurities eluting in stability and forced degradation
samples was also conrmed (data not shown).
Finally, esters were quantitatively characterized for pharmaceuti-
cal use and the corresponding in-house reference standards were es-
tablished. The potency of the standards was calculated based on the
values obtained from determination of impurities (organic, inor-
ganic, water and residual solvents) by applying the principle of mass
balance. The potency was 97.0% for IBUPEG monoester, 95.3%
for IBUsorbitol and 90.9% for IBUsorbitan. The response correc-
tion factor was also determined in respect to IBU API for UHPLC
UV method at 220 nm, namely 3.7 for IBUPEG monoester, 1.9 for
IBUsorbitol and 1.9 for IBUsorbitan.
8 Doua et al.

Conclusion formulations against the common cold; Journal of Pharmaceutical and

Biomedical Analysis, (2011); 55: 949956.
New impurities were identied in IBU SGCs formulation. The analyti- 12. International Conference on Harmonization; Stability Testing of New
cal standards of impurities were synthesized, puried and fully char- Drug Substances and Products Q1A(R2), 2003.
acterized by HRAM LCMS, NMR and IR. All identied impurities 13. Gasco-Lopez, A.I., Izquierdo-Hornillos, R., Jimenez, A.; LC method
arised from drug-excipient interaction. IBUPEG monoester and IBU development for ibuprophen and validation in different pharmaceuticals;
PEG diester are formed by esterication of IBU with PEG, the ll of Journal of Pharmaceutical and Biomedical Analysis, (1999); 21:
the SGC. On the other hand, IBUsorbitol and IBUsorbitan esters 143149.
are created by reaction of IBU with plasticizer of SGC shell. 14. Asmus, P.A.; Determination of 2-(4-isobutylphenyl)propionic acid in bulk
drug and compressed tablets by reversed-phase high-performance liquid
The results show that despite many SGCs advantages, SGCs for-
chromatography; Journal of Chromatography, (1985); 331: 169176.
mulations show also some disadvantages. The stability of an API in
15. Haikala, V.E., Heimonen, I.K., Vuorela, H.J.; Determination of ibuprofen
a liquid dosage form and compatibility of the excipients are major in ointments by reversed-phase liquid chromatography; Journal of
challenges. Most of the lls and plasticizers which are currently in Pharmaceutical Sciences, (1991); 80: 456458.
use contain hydroxyl groups, which might bear a risk for API con- 16. Huidobro, A.L., Ruprez, F.J., Barbas, C.; Tandem column for the simul-
taining carboxylic groups due to possibility of esterication. taneous determination of arginine, ibuprofen and related impurities by
Finally, fast and efcient UPLCUV method was developed to liquid chromatography; Journal of Chromatography A, (2006); 1119:
monitor newly described degradation products and might be helpful 238245.
for further formulation development of SGCs IBU products. 17. Quaglia, M.G., Donati, E., Fanali, S., Catarcini, P.; Ibuprofen quality
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