Identification, synthesis, characterization and quality control strategy of new process-related impurities in fosphenytoin sodium

Article abstract of DOI:10.14233/ajchem.2020.22669

Fosphenytoin sodium is a water dissolvable phenytoin prodrug that is directed intravenously to convey phenytoin, conceivably more securely than intravenous phenytoin. It is most ordinarily utilized in the intense treatment of convulsive status epileptics. The examination of the procedure-related contaminants will not help exclusively to advance the process parameters yet additionally to create sensible analytical methods and set the quality standard for a quality control system in pharmaceutical manufacturing. During the production of fosphenytoin sodium, all the process-related impurities are controlled in every stage and three degradation impurities are managed in the final API as per USP monograph. Besides, five unknown and one known contaminants were detected by HPLC method. All these impurities were identified, synthesized, isolated and characterized by IR, 1D-NMR (¹H, ¹³C, DEPT) and HRMS spectral techniques. The mechanism of the formed impurities is examined for the first time. Quality control procedures to manage these impurities were developed to acquire the mass medication of ICH grade quality.

Full text of DOI:10.14233/ajchem.2020.22669

Asian Journal of Chemistry; Vol. 32, No. 8 (2020), 1881-1885
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2020.22669
Identification, Synthesis, Characterization and Quality Control
Strategy of New Process-Related Impurities in Fosphenytoin Sodium
2
SATHIYANARAYANAN SINGARAM1,2,*, VENKATESAN CHIDAMBARAM SUBRAMANIAN ,
1
2
SENTHAMARAIKANNAN KABILAN and DANDU BHASKARA SURESH RAJU
1Department of Chemistry, Faculty of Science, Annamalai University, Annamalai Nagar-608002, India
2Gland Pharma Ltd., Research and Development, D.P. Pally, Hyderabad-500043, India
*Corresponding author: E-mail: ssnkmk1970@gmail.com
Received: 11 February 2020;
Accepted: 14 April 2020;
Published online: 27 July 2020;
AJC-19962
Fosphenytoin sodium is a water dissolvable phenytoin prodrug that is directed intravenously to convey phenytoin, conceivably more
securely than intravenous phenytoin. It is most ordinarily utilized in the intense treatment of convulsive status epileptics. The examination
of the procedure-related contaminants will not help exclusively to advance the process parameters yet additionally to create sensible
analytical methods and set the quality standard for a quality control system in pharmaceutical manufacturing. During the production of
fosphenytoin sodium, all the process-related impurities are controlled in every stage and three degradation impurities are managed in the
final API as per USP monograph. Besides, five unknown and one known contaminants were detected by HPLC method. All these
impurities were identified, synthesized, isolated and characterized by IR, 1D-NMR (1H, 13C, DEPT) and HRMS spectral techniques. The
mechanism of the formed impurities is examined for the first time. Quality control procedures to manage these impurities were developed
to acquire the mass medication of ICH grade quality.
Keywords: Fosphenytoin sodium, Process related impurities.
Fig. 1. In addition to the known impurities, five other unknown
impurities are recognized on HPLC. All these obscure impur-
ities in fosphenytoin sodium must be distinguished and portrayed
by ICH rules [7-9]. As far as we could know, these obscure
impurities have not been accounted for beforehand. When these
mixes have been distinguished, it is critical to develop the syn-
thetic and detection methods for them.
INTRODUCTION
Status epileptics is a solitary epileptic seizure enduring
over five minutes or at least two seizures inside five minutes
without the individual coming back to ordinary between them
[1]. Fosphenytoin sodium is broadly utilized in the treatment
of status epileptics and has been affirmed worldwide under
the brand name Cerebyx. The safety of a medication isn't just
reliant on the toxicological properties of the mass medication
itself; the contaminants in the mass medication also play a
significant role. Consequently, the presence of these undesir-
able contaminations, even in limited quantities, may impact
the viability and safety of pharmaceutical drugs. Therefore,
the identification, measurement and control of impurities in
the medication substance and the drug product are basic strides
in tranquillize improvement and administrative appraisal.
The synthetic route of fosphenytoin sodium is shown in
Fig. 1 [2-6]. The procedure-related impurities and degradation
impurities of fosphenytoin sodium have also been shown in
EXPERIMENTAL
Paraformaldehyde, potassium carbonate, other reagents
and solvents were purchased from Loba Chemie (Mumbai,
India) and sodium dibenzyl phosphate was purchased from
Resin Allids (Gujarat, India). The HPLC grade acetonitrile
(Merck), dodecyl trimethylammonium phosphate (Regis techno-
logies Inc.), tetrabutylammonium bromide, phosphoric acid
and potassium dihydrogen phosphate (KH2PO4)were purchased
from Sigma-Aldrich. Water (Ultrapure) obtained from a Milli-
pore water purification system (Bangalore, India) was used
throughout the studies.
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1882 Singaram et al.
Asian J. Chem.
A)
O
O
O
Thionyl chloride
Ethylacetate
Paraformaldehyde
N
OH
NH
HN
N
Cl
HN
HN
47% Formaldehyde solution
Purified water,
N,N-Dimethylforamamide
n-heptane,purified water
O
O
O
Potassium carbonate
Chloromethyl phenytoin
O
Hydroxymethyl phenytoin
Phenytoin
O
O
O
Sodium dibenzyl phosphate
10% Palladium on carbon
N
O P OBn
OBn
N
O P ONa
ONa
HN
HN
Acetonitrile,purified water
Acetone,MTBE
O
Sodium hydroxide, ethyl acetate
Acetone, purified water
O
Fosphenytoin sodium
Fosphenytoin dibenzyl ester
B)
O
HN
O
O
N
O
O
O
P
O P
O
O
O
O
HN
NH
O
O
N
N
OH
O
O
N
N
N
NH
N
O
O
N
H
O
O
O
OBn
P
Imp-II
O
OBn
Imp-III
Imp-I
O
HN
O
O
HN
O
N
O
O
P
ONa
ONa
N
O
N
O
N
O
O
O
P
ONa
N
O
N
O
O
H
OH
P
Imp-VI
O
OH
Imp-IV
Imp-V
C)
O
O
O
O
OH
O
O
NH
O
P
OBn
NH
O
N
OH
NH2
N
O
O
NH2
N
N
H
O
OH
HN
Cl
OBn
HN
Imp-VIII
HN
Imp-IX
O
O
Imp-XII
Imp-X
Imp-XI
Imp-VII
Fig. 1. (A) Route of synthesis of fosphenytoin sodium; (B) Structures of unknown impurities; (C) Structures of known impurities
HPLC conditions: The HPLC analyses were performed
(TMS) as an internal standard and are referenced using the
central line of the solvent signal CDCl3 (triplet at 77 ppm),
DMSO-d6 (septet at 39.5 ppm). DEPT experiments were also
performed on a similar instrument to assign the correlations.
HRMS: HRMS spectra were recorded utilizing an instru-
ment from Agilent QTOF 6530 model (Agilent Technologies
Inc., CA, USA). The scan of fosphenytoin sodium and process
related impurities in +ESI and –ESI mode were streamlined
and the source parameters are as follows: Gas temp.: 200 ºC;
Gas flow: 9 L/min; nebulizer: 40 psig; sheath gas temp.: 300
ºC; sheath gas flow: 9 L/min and scan portion positive polarity.
The scan source parameters are VCap, 3200; nozzle voltage:
1000V; fragmentor: 175; skimmer1, 65 and octopole RF peak:
750. The operating conditions of all the impurities and the
drug were in +ESI and –ESI mode and recorded in the range
of 110-1200 m/z.
on a Shimadzu LC2010 HPLC instrument utilizing a reverse-
phase symmetry C18, 150 mm × 3.9 mm, and 5 micron particle
size column (Waters Corp, USA). Mobile phaseA was a mixture
of 35%ACN and 65% aqueous KH2PO4, 0.5M dodecyl trimethyl-
ammonium phosphate, pH adjusted to 5.0 by using phosphoric
acid and mobile phase B was a mixture of 50%ACN and 50%
aqueous KH2PO4, 0.5M dodecyl trimethylammonium phosphate,
pH adjusted to 5.0 by using phosphoric acid. The slope program
was set as follows: (time (min)/% B: 0/0, 6/0, 16/100, 60/100,
and 98/0). The column oven temperature was maintained at
25 ºC. The flow rate was kept at 1.0 mL/min and UV detection
was recorded at 214 nm. The data acquisition time was 100 min.
NMR: Bruker Avance III instrument (Bruker, Karlsruhe,
Germany) was used for recording the NMR spectra at 300
1
MHz for H NMR and 75 MHz for 13C NMR with (CH3)4Si

Vol. 32, No. 8 (2020)
Synthesis and Quality Control Strategy of New Process-Related Impurities in Fosphenytoin Sodium 1883
Synthesis of Imp-I: To a stirred solution of benzyl-((2,5-
dioxo-4,4-diphenylimidazolidine-1-yl)methyl)hydrogen
phosphate (3.5 g, 7.73 mmol) in acetonitrile (175 mL) was added
sodium carbonate (0.115 g, 1.08 mmol), tetrabutylammonium
bromide (0.125 g, 0.38 mmol) followed by chloromethyl
phenytoin (2.63 g, 8.75 mmol). The resulting reaction mixture
was stirred at 80-90 ºC for about 2.5 h. The reaction mixture
was concentrated under reduced pressure at 30-35 ºC to give a
residue, which was purified by column chromatography using
100-200 mesh silica gel using a mixture of methanol (5%) and
dichloromethane (95%) as eluent. The collected pure fractions
were concentrated and the obtained product was dried under
high vacuum at 30-35 ºC for 2 h to give a pure white colour solid
(Scheme-I). Yield: 0.23 g, purity: 94%, 1H NMR (300 MHz,
DMSO-d6) δ ppm: 9.94 (s, 2H), 7.23-7.35 (m, 25H), 5.30-
5.42 (m, 4H), 4.87 (d, 2H); 13C NMR: 172.23, 153.17, 138.97,
128.55, 128.35, 128.29, 127.73, 126.65, 69.26, 68.99, 64.38.
Synthesis of Imp-II: To a stirred solution of impurity I
(350 mg) in ethyl acetate (3 mL) was added 10% Pd/C (0.035
g). The resulting reaction mixture was stirred under H2 pressure
at room temperature for about 1.5 h. After the completion of
the reaction, which was monitored by TLC, the reaction mixture
was filtered through hyflo-bed and washed with ethyl acetate.
The obtained filtrate was concentrated under reduced pressure
at 30-35 ºC for 2 h. The obtained crude compound was purified
by column chromatography using 100-200 mesh silica gel using
a mixture of methanol and dichloromethane as eluent. The colle-
cted pure fractions were concentrated and the obtained product
was dried under high vacuum at 30-35 ºC for 2 h to give a pure
white colour solid (Scheme-I).Yield: 0.22 g; purity: 88%, 1H
NMR (300 MHz, DMSO-d6) δ ppm: 9.85 (bs, 2H), 7.36 (s,
20H), 5.12 (bs, 4H); 13C NMR: 172.62, 154.12, 139.38, 128.52,
128.18, 126.69, 68.99, 62.89.
Synthesis of Imp-III: Impurity X (5.0 g, 9.22 mmol) was
taken in tetrahydrofuran (20 mL) and cooled to 0-5 ºC. Sodium
hydride was then added portion-wise with stirring at the same
temperature. After complete addition, the reaction mixture was
stirred at 0-5 ºC for about 30 min. To this, impurity IX (3.0 g,
10.14 mmol) was added. The resulting reaction mixture was
stirred at 25-30 ºC for about 3 h. The reaction was monitored
by TLC. Upon completion of the reaction, the reaction mixture
was concentrated under vacuum at 30 ºC. The obtained crude
compound was purified by column chromatography using 100-
200 mesh silica gel and the product was eluted at 3% methanol
in dichloromethane. The collected pure fractions were concen-
trated and the product obtained was dried under high vacuum
at 30-35 ºC for 2 h to give a pure white colour solid (Scheme-
II). Yield: 0.3 g; purity: 94%, 1H NMR (400 MHz, CDCl3) δ
ppm: 7.06-7.33 (m, 30H), 5.49 (d, 2H) 5.16 (s, 2H), 4.94-5.04
(m, 4H); 13C NMR: 172.15, 171.78, 154.95, 154.12, 138.62,
135.50, 134.80, 126.47-129.18, 74.93, 69.71, 64.49.
Synthesis of Imp-IV: To a stirred solution of impurity III
(0.35 g, 0.43 mmol) taken in ethyl acetate (6 mL) was added
10% Pd/C (0.035 g). The resulting reaction mixture was stirred
under H2 bladder pressure at room temperature for about 1.5 h.
The completion of the reaction was monitored by TLC and
the reaction mixture was filtered through hyflo-bed and washed
the bed with ethyl acetate. The filtrate was concentrated under
reduced pressure at 30-35 ºC. The obtained crude compound
was purified by column chromatography using 100-200 mesh
silica gel and the product was eluted at 5% methanol in dichloro-
methane. The collected pure fractions were concentrated and
dried under high vacuum at 30-35 ºC for 2 h to give a pure
white colour solid (Scheme-II). Yield: 0.22 g; purity: 96%,
1H NMR (400 MHz, CDCl3) δ ppm: 7.70 (bs, 1H,), 7.05-7.26
(m, 20H), 5.39 (s, 2H) 4.98 (s, 2H); 13C NMR: 172.16, 155.65,
HO
BnO
O
O
O
O
P
O
O
O
P
N
O
N
O
10% Pd/C, atmp H2
Ethylacetate, Rt, 2 h
NH
O
O
NH
O
N
Na2CO3, TBAB,
O
N
O
HN
OBn
+
HN
Cl
HN
N
HN
N
O
ACN, 80-90 °C, 3 h
O
O
P
OH
O
O
O
Imp-II
Imp-I
Scheme-I: Synthetic route of Imp-I and Imp-II
O
O
10% Pd/C, atmp H2
N
O
O
N
O
O
N
N
+
60% NaH, THF
RT, 3 h
O
HN
N
OBn
Cl
N
N
H
Ethylacetate, RT, 1.5 h
O
O
HN
N
O
OBn
HN
N
O
O
P
OBn
OBn
O
P
O
O
O
Imp-IV
O
OH
P
O
Imp-III
OH
HCOONH4, 10%Pd/C
THF:MeOH, 50°C, 3 h
O
OBn
HN
N
O
P
OH
O
O
Imp-V
Scheme-II: Synthetic route of Imp-III, Imp-IV and Imp-V

1884 Singaram et al.
Asian J. Chem.
200000
100000
0
154.86, 138.43, 134.54, 126.58-129.15, 74.89, 69.59, 64.5,
45.02.
Synthesis of Imp-V: To a stirred solution of FPS stage-
III compound (15.0 g, 27.65 mmol) taken in a mixture of
solvents THF: MeOH (225 mL) was added ammonium formate
(91.74 g, 27.65 mmol) followed by 10% Pd/C (2.25 g). The
resulting reaction mixture was stirred at 50 ºC for about 3 h.
After the completion of the reaction which was monitored by
TLC analysis, the reaction mixture was filtered through a bed
of hyflo, washed with methanol and then concentrated under
vacuum at 30 ºC. The obtained crude compound was purified
by column chromatography using 100-200 mesh silica gel
using a mixture of methanol (5%) and dichloromethane (95%)
as an eluent. The pure fractions were concentrated and dried
under high vacuum at 30-35 ºC for 2 h to give a pure white
color solid compound (Scheme-II).Yield: 6.0 g; purity: 94.0%,
1H NMR (300 MHz, DMSO-d6) δ ppm: 9.77 (bs, 1H), 7.28-
7.36 (m, 15H), 5.07 (d, 2H) 4.63 (d, 2H); 13CNMR: 172.73,
154.29, 139.46, 128.48, 128.14, 127.94, 127.09, 126.95,
126.65, 68.98, 65.97, 62.87.
Synthesis of Imp-VI: Fosphenytoin sodium-containing
about 5% impurityVI was purified by flash column chromato-
graphy using C18 silica gel column with 0.1% TFA containing
water and acetonitrile mixture as a gradient eluent. The pure
fractions collected was concentrated, and the material obtained
was dried under high vacuum at about 30 ºC for 2 h to give an
off white colour solid compound. The compound obtained was
dissolved in 1.5 mL of water; to that 1.5 equivalent of NaOH
solution was added. The solution obtained was precipitated
with acetone, filtered, washed twice with acetone and dried
for 2 h at about 30 ºC to give a pure white colour solid comp-
ound (Scheme-III).Yield: 50 mg; purity: 95%, 1H NMR (400
MHz, D2O): δ ppm: 7.41-7.60 (m, 5H), 5.07 (d, 2H) 2.37-
2.42 (m, 1H), 1.56-1.78 (m, 4H), 0.89-1.30 (m, 6H); 13C NMR:
177.59, 157.78, 136.66, 128.92, 128.46, 125.78, 71.77, 62.85,
44.96, 26.47, 26.18, 25.5.
0
25
50
75
100
min
Fig. 2. HPLC chromatogram of Fosphenytoin sodium spiked with unknown
impurities
TABLE-1
CRITICAL INFORMATION ABOUT THE
IMPURITIES OF BULK FOSPHENYTOIN SODIUM
Compound
Fosphenytoin sodium
Impurity I
Impurity II
Impurity III
Impurity IV
Impurity V (known impurity)
Impurity VI
RRT
1.0
m.w.
Nature
406.24
716.67
626.56
806.81
626.56
474.38
369.12
Drug substance
Process related
Process related
Process related
Process related
Process related
Process related
2.52
2.08
5.20
1.85
1.69
1.29
weight is 716.67. In the 1H NMR spectrum, aromatic protons
are clubbed together and appeared peak at 7.23-7.35 ppm.
The benzyl CH2 appeared at 4.87 (2H, doublet). The two -NCH2
groups have appeared at 5.30-5.42 (4H, multiplet). The peak
appeared at 9.94 corresponds to two -NH protons (2H, singlet).
The DEPT-135 NMR spectrum shows five peaks above the plane
and two peaks below the plane confirming that the compound
having 25CH groups (16CH groups are in two different sets
of similar environment, 3CH groups are in one set of similar
environment, 2CH groups are in one set of similar environment
and 4CH groups are in one set of similar environment) and
3CH2 groups (of which 2CH2 groups are in similar environ-
ment) in the molecule.
Characterization of Imp-II: The ESI-MS spectrum of
Imp-II shows a molecular ion peak at m/z 626.16 ([M+H]+) in
positive ion mode, indicating that the molecular weight is
627.16.Aromatic protons appeared at 7.36 (20H, singlet), two
-NCH2 protons have appeared at 5.12 (4H broad singlet), two
-NH protons appeared at 9.85 (2H, broad singlet). The DEPT-
135 NMR spectrum shows three peaks above the plane and one
peak below the plane confirming that the compound is having
20CH groups (16CH groups are in two different sets of similar
environment and 4CH groups are in one set of similar environ-
ment) and 2CH2 groups (both are in the same environment) in
the molecule.
RESULTS AND DISCUSSION
Identification of impurities: A typical analytical HPLC
chromatogram of fosphenytoin sodium along with their spiked
impurities was recorded using the HPLC and shown in Fig. 2.
The structures, relative retention time (RRT), molecular weight
(m.w.) and nature of these impurities are given in Table-1.
Structural elucidation of synthesized impurities
Characterization of Imp-I: The ESI-MS spectrum of
Imp-1 showed a molecular ion peak at m/z 717.21 ([M+H]+)
in positive ion mode, which complies with the Imp-I molecular
O
O
O
HN
ONa
HN
ONa
HN
ONa
O
O
+
O
N
P
N
P
N
P
ONa
ONa
Purification by
Flash column
ONa
O
O
O
O
O
O
Imp VI
Fosphenytoin sodium
Imp-VI
Fosphenytoin sodium containes 6% of Imp VI
Scheme-III: Synthetic route of Imp-VI

Vol. 32, No. 8 (2020)
Synthesis and Quality Control Strategy of New Process-Related Impurities in Fosphenytoin Sodium 1885
Characterization of Imp-III: The ESI-MS spectrum of
Imp-III shows a molecular ion peak at m/z 805.24 ([M-H]−) in
negative ion mode, indicating that the molecular weight is
806.24. In 1H NMR spectrum of impurity III, aromatic protons
appeared to peak at 7.06-7.33 (30H, multiplet). The two benzyl
CH2 appeared at 4.94-5.04 (4H, multiplet). The -NCH2 attached
to phosphate groups appeared at 5.49 (2H, doublet). The -NCH2
appeared at 5.16 (2H, singlet). The DEPT-135 NMR spectrum
shows nine peaks above the plane and three peaks below the
plane confirmed that the compound has 30CH groups that are
in nine different sets of similar environment and 4CH2 groups
(of which 2CH2 groups are in a similar environment) in the
molecule.
Characterization of Imp-IV: The ESI-MS spectrum of
Imp-IV shows a molecular ion peak at m/z 627.15 ([M+H]+)
in positive ion mode indicating that the molecular weight is
626.16. In 1H NMR spectrum of impurity IV, all the aromatic
protons merged and appeared at 7.05-7.26 (20H, multiplet).
The appeared at 5.39 (2H, singlet) corresponds to -NCH2 attac-
hed to the phosphate group. The peak appeared at 4.98 (2H,
singlet) belongs to -NCH2 protons. The DEPT-135 NMR spectrum
shows eight peaks above the plane and two peaks below the
plane confirming that the compound has 20 CH groups that
are in eight different sets of similar environment and 2 CH2 groups
in the molecule.
during synthesis or through a purification procedure to produce
high-quality pharmaceuticals. If we realize the route cause
for the formation of process-related impurities, it is easy to
design a rational process to reduce or avoid the development
of contaminations or by altering the workup procedure to remove
the formed impurities indicated by the idea of quality by design
(QBD). In presentAPI process, six impurities in the final product,
including the four known impurities are identified and
controlled in the finalAPI to be less than 0.10% by HPLC.All
of these impurities are evacuated to accomplish ICH-grade
quality.
Conclusion
Isolation and successful synthesis of these unknown process
related impurities [Imp-I, Imp-II, Imp-III, Imp-IV, Imp-V (known
impurity) and Imp-VI] were possible during the manufacturing
of fosphenytoin sodium from phenytoin. All the impurities are
observed to be less than 0.10% based on HPLC analysis. Six
unknown impurities were identified, synthesized, isolated and
characterized by using IR, NMR and HRMS techniques. The
formation mechanisms of these obscure polluting influences
are also discussed. Improved procedures of impurity control
were created by the physical and chemical properties of these
contaminations. At long last, because of the above studies,
fosphenytoin sodium of ICH-grade quality was effectively
acquired.
Characterization of Imp-V: The ESI-MS spectrum of
Imp-V (known impurity) shows a molecular ion peak at m/z
453.12 ([M+H]+) in positive ion mode, indicating that the mole-
ACKNOWLEDGEMENTS
1
The authors are grateful to Gland Pharma Ltd., Hyderabad,
India for giving the exploration of research facilities to complete
the work and appreciative to Mr. Mahesh Varma, Analytical
R&D, Gland Pharma for the scientific support.
cular weight is 452.11. In H NMR spectrum of impurity V,
the aromatic protons have appeared at δ 7.28-7.36 ppm (15H,
multiplet). Benzyl -CH2 protons appeared at δ 4.63 ppm (2H,
doublet). The peak appeared at δ 5.07 ppm (2H, doublet) corre-
sponds to -NCH2 protons. The peak appeared at δ 9.77 ppm
(1H, broad singlet) belongs to -NH proton. The DEPT-135
NMR spectrum shows six peaks above the plane and two peaks
below the plane confirming that the compound is having 15CH
groups (8CH groups are in two different sets of similar environ-
ment, 5CH groups are in three different sets of the same environ-
ment and the remaining 2CH groups are in similar environ-
ment) and 2CH2 groups in the molecule.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
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Characterization of Imp-VI: The ESI-MS spectrum of
Imp-VI shows a molecular ion peak at m/z 369.12 ([M+H]+)
in positive ion mode, indicating that the molecular weight is
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1
368.11. In H NMR spectrum of impurity VI, the aromatic
protons appeared at δ 7.41-7.60 ppm (5H, multiplet). In cyclo-
hexyl group, C10 proton appeared at δ 2.37-2.42 ppm, the
peak appeared at δ 0.89-1.30 ppm (6H, multiplet) belongs to
C-8H, C-8′H & C-9H protons, and the peak appeared at δ
1.56-1.78 ppm (4H, multiplet) belongs to C-7H, C-7′H. The
peak appeared at δ5.07 ppm (2H, doublet) corresponds to -NCH2
protons. The DEPT-135 NMR spectrum shows four peaks above
the plane and six peaks below the plane, confirming that the
compound is having 6 CH groups and 6 CH2 groups in the mole-
cule.
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International Conference on Harmonization, IFPMA, Geneva (2006).
Control of impurities: One of our primary objectives is
to investigate how these process-related impurities controlled