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Journal of Chromatographic Science, 2017, 18

doi: 10.1093/chromsci/bmx036


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
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:
Received 29 April 2016; Revised 4 January 2017; Editorial Decision 31 March 2017

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

The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: 1
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 3

Figure 3. Preparation of IBUPEG esters (A), IBUsorbitol (B) and IBUsorbitan (C).

was acetonitrile. The gradient program was set as follows: time/% Jose, USA) coupled to an HPLC HTS PAL system (CTC Analytics,
of solvent B: 0/10, 2.0/10, 17/80, 20/80, 20.5/10 with an equilibra- Switzerland). LC separation was performed on a Kinetex C18, 150
tion time of 2 min. The column was thermostated at a temperature 4.6 mm2, 5 m (Phenomenex, Torrance, USA) column using 1.0 ml/min
of 35C. Method II: The solvent A was 0.1% ortho-phosphoric acid ow rate. The gradient elution employed solutions A and B as mobile
and solvent B was acetonitrile. The gradient program was set as fol- phase components. The solvent A was 0.1% formic acid, while sol-
lows: time/% of solvent B: 0/5, 60/90, 61/5 with an equilibration vent B was acetonitrile. The gradient program was set as follows:
time of 2 min. The column was thermostated at a temperature of time/% of solvent B: 0/43, 17/43, 25/100, 30/100, with an equilibra-
45C. Method III: The solvent A was water and solvent B was meth- tion time of 7 min. For an ionization of the analytes an APCI ion
anol. The gradient program was set as follows: time/% of solvent B: source was operated in the positive ion mode (desolvation tempera-
0/0, 70/85, 90/85, 91/0 with an equilibration time of 4 min. The col- ture 400C, capillary temperature 300C, discharge current 4 A and
umn was thermostated at a temperature of 65C. tube lens voltage 40 V).

LCMS instrumentation and methods Semi-preparative instrumentation and methods

High resolution/accurate mass (HRAM) MS experiments were per- Preparative HPLC separation and fraction collection was carried
formed on a LTQ XL Orbitrap Mass Spectrometer (Thermo, San out on a Waters Auto purication system (System uidics organizer,
Table I. NMR Assignments for IBU Esters

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

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 portions. After all CDI had been added, the solution was stirred for
Polysorb 80 (85/70/00) was concentrated in rotary evaporator under 10 min and then slowly added to the solution of polysorb in DMSO.
reduced pressure at 50C to obtain colorless honey, in which 6.6% Resulting clear slightly yellow solution was stirred for 60 h. This
of water was found using Karl Fischer titration method. This con- mixture was puried using semi-preparative HPLC. Collected frac-
centrated polysorb was used for synthesis. A 8.94 g of preconcen- tions containing desired product were evaporated at 40C under
trated polysorb 80 was dissolved in 5 ml warm DMSO, and then reduced pressure. Resulting oil was dried in vacuum of oil pump.
4.58 g (28 mmol) carbonyldiimidazole (CDI) was added to the Yield was 0.4 g of IBUsorbitan ester.
warm solution in portions. Mixture was foaming due to evolution Methods of preparation of IBUPEG, IBUsorbitol and IBUsor-
of carbon dioxide. To the separately prepared solution of 5.16 g bitan esters were not further optimized due to preparation of analyt-
(25 mmol) IBU in 3 ml DMSO was added 4.05 g (25 mmol) CDI in ical standards only.
Esterication of Ibuprofen in Soft Gelatin Capsules FormulationsIdentication, Synthesis and Liquid 7

The characterization of reference standards modied by changing the organic solvent (methanol), gradient prole
In order to prepare in-house standards of IBUPEG monoester, and increasing the temperature to achieve baseline resolution of the
IBUsorbitol ester and IBUsorbitan ester, the structures of prepared individual oligomers. UHPLC methods were used for the chemical
impurities were conrmed and characterized by NMR, MS and IR characterization of IBUPEG monoesters (Method III) and IBUPEG
analysis (Tables IIII). The assignment of NMR signals was per- diesters (Method II). The separation of the corresponding IBUPEG
formed by means of 1H, 13C and 2D (COSY, HSQC and HMBC) esters is shown in Figure 4, including the evaluation of percentage of
spectra. NMR data unambiguously conrmed the proposed struc- individual oligomers in IBUPEG esters by internal normalization.
tures of IBU esters. According to the intensities of the NMR signals, The Method II was successfully applied for determination of related
average number n of PEG units in IBUPEG monoester was 13. substances in pharmaceutical SGCs formulations.
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 The characterization of reference standards
sorbit-6-yl 2-(4-isobutylphenyl)propionate. Each NMR 1H and 13C The obtained MS data for prepared standards were in agreement
NMR signal of IBUsorbitan was formed by one major, one with the data measured in IBU SGCs pharmaceutical formulation
medium and 12 minor peak due to mixture of four isomers, mainly (Fig. 5). UHPLC peak equivalency between synthesized in-house
1,4-anhydrosorbit-6-yl 2-(4-isobutylphenyl)propionate and 3,6- standards and impurities eluting in stability and forced degradation
anhydrosorbit-1-yl 2-(4-isobutylphenyl)propionate. Further stereo- samples was also conrmed (data not shown).
chemical investigation of the formed monoesters was not subject of Finally, esters were quantitatively characterized for pharmaceuti-
this study. 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
Identication of unknown degradation products balance. The potency was 97.0% for IBUPEG monoester, 95.3%
The routine UPLC method was then optimized to reach separation for IBUsorbitol and 90.9% for IBUsorbitan. The response correc-
of IBUPEG oligomers. Previously, the resolution between PEG oli- tion factor was also determined in respect to IBU API for UHPLC
gomers using LC methods was achieved at elevated temperature UV method at 220 nm, namely 3.7 for IBUPEG monoester, 1.9 for
using gradient elution (30). The routine UHPLC method was IBUsorbitol and 1.9 for IBUsorbitan.

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).
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.
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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:
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control by electrochromatography; Farmaco (Societa Chimica Italiana:
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