Organic salts of pharmaceutical impurity p-aminophenol

Article abstract of DOI:10.3390/molecules25081910

The presence of impurities can drastically affect the efficacy and safety of pharmaceutical entities. p-Aminophenol (PAP) is one of the main impurities of paracetamol (PA) that can potentially show toxic effects such as maternal toxicity and nephrotoxicity. The removal of PAP from PA is challenging and difficult to achieve through regular crystallization approaches. In this regard, we report four new salts of PAP with salicylic acid (SA), oxalic acid (OX), l-tartaric acid (TA), and (1S)-(+)-10-camphorsulfonic acid (CSA). All the PAP salts were analyzed using single-crystal X-ray diffraction, powder X-ray diffraction, infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. The presence of minute amounts of PAP in paracetamol solids gives a dark color to the product that was difficult to remove through crystallization. In our study, we found that the addition of small quantities of the aforementioned acids helps to remove PAP from PA during the filtration and washings. This shows that salt formation could be used to efficiently remove challenging impurities.

Full text of DOI:10.3390/molecules25081910

molecules
Article
Organic Salts of Pharmaceutical Impurity
p-Aminophenol
U. B. Rao Khandavilli 1,2,
and Patrick J. Frawley 1
*
, Leila Keshavarz 1, Eliška Skorˇepová 3,4 , René R. E. Steendam 1
1
Synthesis and Solid State Pharmaceutical Centre (SSPC), Bernal Institute, University of Limerick, Limerick,
Ireland; Leila.Keshavarz@ul.ie (L.K.); renesteendam@gmail.com (R.R.E.S.); Patrick.Frawley@ul.ie (P.J.F.)
PSC Biotech Limited, Blanchardstown, Dublin 15, Ireland
Department of Chemical Engineering, University of Chemistry and Technology Prague, Technická 3,
16628 Prague 6, Czech Republic; skorepova@fzu.cz
2
3
4
Institute of Physics ASCR, Na Slovance 2, 182 21 Praha 8, Czech Republic
Correspondence: 113220305@umail.ucc.ie; Tel.: +353-61-202178
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 12 March 2020; Accepted: 18 April 2020; Published: 21 April 2020
Abstract: The presence of impurities can drastically affect the efficacy and safety of pharmaceutical
entities. p-Aminophenol (PAP) is one of the main impurities of paracetamol (PA) that can potentially
show toxic effects such as maternal toxicity and nephrotoxicity. The removal of PAP from PA is
challenging and difficult to achieve through regular crystallization approaches. In this regard, we
report four new salts of PAP with salicylic acid (SA), oxalic acid (OX), l-tartaric acid (TA), and
(1S)-(+)-10-camphorsulfonic acid (CSA). All the PAP salts were analyzed using single-crystal X-ray
diffraction, powder X-ray diffraction, infrared spectroscopy, differential scanning calorimetry, and
thermogravimetric analysis. The presence of minute amounts of PAP in paracetamol solids gives
a dark color to the product that was difficult to remove through crystallization. In our study, we
found that the addition of small quantities of the aforementioned acids helps to remove PAP from PA
during the filtration and washings. This shows that salt formation could be used to efficiently remove
challenging impurities.
Keywords: paracetamol; 4-aminophenol or p-aminophenol; salt; impurity removal; particle size
1. Introduction
From a pharmaceutical point of view, unwanted substances existing in the final formulation
are regarded as impurities or pollutants, and these impurities, even in minute quantities, sometimes
compromise the stability and safety of the drug substance [
Harmonization (ICH) has given guidelines in order to control the presence of impurities in the final
active pharmaceutical ingredient (API) [ ]. It is not always possible to remove or control the impurities
during the synthesis of APIs, so companies usually try to minimize their presence after completion of
the synthetic pathway [ ]. However, it is not straightforward to eliminate the range of structurally
1,2]. The International Conference on
3
4
related impurities from the final product; therefore, impurity management becomes an expensive
process. Hence, pharmaceutical companies dedicate their research in order to find new cost-effective
methodologies to remove or avoid impurities from the final product [5].
4-Aminophenol or p-aminophenol (PAP) is one of the major impurities in paracetamol (PA) and
mesalazine (MZ), which originates from the synthesis and/or as a primary hydrolytic degradation
product from storage conditions and that is difficult to remove [
such as nephrotoxicity and teratogenic toxicity and can cause methemoglobinemia even at the lower
concentrations [ 12]. PAP degrades under certain pH conditions, which can cause a dark coloration
6,7]. PAP can show adverse effects
8–
Molecules 2020, 25, 1910; doi:10.3390/molecules25081910
www.mdpi.com/journal/molecules

Molecules 2020, 25, 1910
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to the product. In recent years, biological treatments have gained attention due to their capability to
remove the impurities efficiently and cost effectively [13]. However, amino phenols can damage the
microorganisms due to their toxicity that would limit the usage of biological treatments to remove
amino phenolic impurities [14]. Drug regulatory agencies such as the Food and Drug Administration
(FDA) and European Medicines Agency (EMEA) have restricted PAP impurity levels to 50 ppm (0.005%
w/w) in a drug substance due to its high toxicology profile [15–17].
Salts and cocrystals are some of the well-known techniques to improve the physicochemical properties
of pharmaceutical and bioactive compounds and can be used in the purification of APIs [18–27]. Larger
pKa variations between the components (usually ∆pKa > 3.0) can lead to the formation of salts, and
salts often show greater solubilities than the single individual components [6,28,29]. Based on this
knowledge, we prepared four organic salts of PAP in an attempt to efficiently remove this impurity
from PA.
Removal of PAP from PA through crystallization is challenging and cannot be achieved by regular
cooling crystallization, to the best of the knowledge of the authors. This may be due to the similar
physical–chemical properties of the impurity with respect to the API. To increase the physical–chemical
differences between the impurity and API in an attempt to remove PAP from PA, four new salts of PAP
with oxalic acid (OX), salicylic acid (SA), l-tartaric acid (TA), and (1S)-(+)-10-camphorsulfonic acid
(CSA) have been synthesized (Figure 1). All the salts have been analyzed using infrared spectroscopy
(IR), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric
analysis (TGA), and single-crystal X-ray diffraction (SCXRD). Furthermore, we have attempted to
understand the behavior of the product with and without traces of these salt formers during the
crystallization process of paracetamol (PA) in the given solvent system and temperature conditions.
Figure 1. List of compounds used in this study: (
a) paracetamol (PA), (
b) p-aminophenol (PAP),
(
c
) oxalic acid (OX), ( ) l-tartaric acid (TA), ( ) salicylic acid (SA), and (f
d
e
) camphorsulfonic acid (CSA).

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2. Results and Discussion
2.1. X-ray Crystallography
Single-crystal data for all the four salts were collected (please see Table 1 for parameters) at
room temperature using a three-circle Bruker D8 Quest diffractometer with a sealed tube Mo anode,
Kα radiation = 0.71073 Å.
Table 1. Crystallographic parameters.
PAP+CSA−·H2O
PAP+SA−
PAP+OX−
PAP+TA−
Compound
Formula
MW, g/mol
Crystal system
Space group, Z
a, Å
C13H13NO4
247.25
triclinic
P 1, 2
6.798(7)
8.596(1)
10.256(1)
93.756(4)
99.530(4)
94.663(4)
587.2(6)
1.398
C7H8NO3
154.14
monoclinic
P 21/n, 4
6.6471(5)
17.357(7)
6.768(5)
90
117.233(5)
90
694.2(3)
1.475
C16H25NO7S
359.43
monoclinic
C2, 4
42.654(2)
7.4090(3)
11.765(5)
90
97.2740(1)
90
3575.7(3)
1.335
C10H14NO7
259.21
monoclinic
P 21, 2
7.206(6)
8.043(7)
10.53 (7)
90
98.361(8)
90
603.9(1)
1.426
b, Å
c, Å
α, ◦
β, ◦
γ, ◦
V, Å3
Dc gcm−3
µ, mm−1
2θ range, ◦
T, K
0.105
3.0–26.38
299
0.117
3.56–26.36
282
0.212
2.79–26.39
304
0.123
2.86–26.85
299
Total ref.
Unique ref.
Obs. ref., I > 2σ(I)
# Parameters
R1 [I > 2σ(I)]
wR2
14,425
2398
2046
7997
1414
1042
117
0.0450
0.1003
0.9748
23,035
7278
5649
9330
2480
2347
191
0.0727
0.1601
0.9779
178
464
0.0393
0.0967
0.9792
0.0474
0.1021
0.9847
S
2.2. Crystal Structure Analysis
The solved crystal structures of PAP salts have been compared with respect to the conformation
(see Figure S26 in Supplementary Materials) and crystal packing of the PAP cation (Figure 2). The cation
of PAP has a rigid aromatic core with hydroxyl and ammonium groups. The conformations of PAP in
all of the newly described salts differ only in the relative positions of the hydrogen atoms on these
groups evidenced by the different rotation about the C–O and C–N bonds.
The proton transfer has been in all salts confirmed by the electron density maps (for example, see
Figure S27 in Supplementary Materials) that clearly show that there are three maxima around the PAP
nitrogen atom corresponding to the ammonium group.

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Figure 2. The crystal structures of the salts. Left–asymmetric unit with the thermal ellipsoids.
Middle–molecular packing (anion highlighted). Right–details of H-bonding.
2.2.1. PAP+OX− Salt (2:1)
The PAP+OX− salt crystallizes in the monoclinic crystallographic system with the space group
P 21/n. In the asymmetric unit, there is one cation of PAP and half of an oxalate anion (it lies in a special
position on an inversion center). On average, there are four molecules of PAP and two molecules of
OX in the unit cell.
In this structure, the molecules are arranged in hydrophobic and hydrophilic layers.
The hydrophilic layers consist of the aromatic cores of PAP, which are arranged in face-to-face
offset π–π stacking. The hydrophilic layers consist of the oxalate anions and the hydroxyl and
ammonium groups of PAP, which all interact via H-bonding. In the H-bonding network, the oxalate
anion acts as an acceptor for both the hydroxyl and ammonium groups of PAP.
2.2.2. PAP+TA− Salt (1:1)
The PAP+TA− salt crystallizes in the monoclinic crystallographic system with the space group
P 21. In the asymmetric unit, there is one cation of PAP and one hydroxytartrate anion. There are two
molecules of PAP and two molecules of TA in the unit cell.

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In this structure, the molecules are also arranged into hydrophobic and hydrophilic layers.
The hydrophilic layers consist of the aromatic cores of PAP, which are arranged in face-to-face zig-zag
π–π stacking. The hydrophilic layers consist of the tartrate anions and the hydroxyl and ammonium
groups of PAP, which all interact via H-bonding. In the H-bonding network, the tartrate anion acts as
acceptors for both the hydroxyl and ammonium groups of PAP. Each tartrate anion forms H-bonds
with five PAP molecules and also with four other tartrates.
2.2.3. PAP+SA− Salt (1:1)
The PAP+SA− salt crystallizes in the triclinic crystallographic system with the space group P
1.
In the asymmetric unit, there is one cation of PAP and one salicylate anion. There are two molecules of
PAP and two molecules of TA in the unit cell. In this structure, the molecules are arranged into layers,
where molecules interact both by H-bonding and by aromatic face-to-face interactions of pairs of PAP
cations and edge-to-face between SA and PAP. The layers are then connected to each other by aromatic
interactions between the neighboring SA anions. In the H-bonding network, all three ammonium
hydrogens of PAP form a charge-assisted H-bond with the carboxylate groups of the salicylate anions.
The salicylate carboxyl also accepts H-bonds from the hydroxyl groups of both PAP and salicylate,
as the latter bond is intramolecular.
2.2.4. PAP+CSA−·H2O Salt (1:1:1)
The PAP+CSA− H2O− salt crystallizes in the monoclinic crystallographic system with the space
·
group C 2. In the asymmetric unit, there are two cations of PAP, two camphor sulfonate anions, and
two water molecules. Identical to those in the other salt structures, in this structure, the molecules are
arranged into hydrophobic and hydrophilic layers, but here, the layers are more complex. The sulfonate
groups of CSA form an H-bonded network with the water molecules and the ammonium and hydroxyl
groups of PAP (layer ‘H’). There is an aromatic layer of the PAP benzene cores arranged into the
herringbone pattern (layer ‘AR’) [6,29]. The aliphatic cycles of CSA form the last layer, ‘AL.’ In the
crystal structure, the layers alternate in the . . . H-AR-H-AL-H-AR-H-AL-H . . . pattern.
2.3. Crystallization Experiments
2.3.1. Crystallization of Paracetamol in the Absence of PAP
In benchmark experiment 1, which was carried out in the absence of PAP, colorless crystals of PA
were obtained as shown in Figure 3. PXRD and IR of this sample matched with the commercial sample,
and these crystals were used to compare to the crystals obtained from experiments 2, 3, 4, 5, and 6.
Figure 3. Paracetamol batch crystallized in the absence of the PAP impurity.

Molecules 2020, 25, 1910
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2.3.2. Crystallization of Paracetamol in the Absence and Presence of PAP
The PAP impurity was introduced during the crystallization of PA in experiment 2, in order
to understand its effect on the PA physicochemical properties. The presence of the PAP impurity
was shown to significantly impact the color and purity of the final PA product. The presence of
decomposed/polymerized PAP gave the dark coloration of the PA final product (as shown in Figure 4).
However, we were unable to detect this impurity with our current analytical methods using UV
and HPLC (see Supplementary Materials). Most likely, the impurities are a complex mix of many
aromatic compounds.
Figure 4. PA batch crystallized in the presence of the PAP impurity.
2.3.3. Crystallization of PA in the Presence of PAP and a Counterion
In experiments 3, 4, 5, and 6, the same quantity of the PAP impurity was introduced to the PA
crystallization batch, and an equimolar quantity of PAP salt former (either OX/CSA/TA/SA) at 80 ◦C
has been introduced. Due to the expected high solubility of the resulting PAP salts, the impurity
solubilized easily and could be easily removed by washing with the mother liquor and additional
washing steps. The colorless PA products were harvested and illustrate that the products contained
significantly less PAP-colored impurities (see Figure 5).
Figure 5. Crystallization experiments:
(d) PA+PAP+SA, and (e) PA+PAP.
(a) PA+PAP+OX, (b) PA+PAP+TA, (c) PA+PAP+CSA,

Molecules 2020, 25, 1910
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HPLC is a widely used method to detect the PAP in the literature and it is not easy to detect the
impurities generated from the PAP [30]. We recorded the HPLC analysis for all the obtained PA samples
and found that there are no traces of PAP in the samples (see Supplementary Materials). He et al.
reported that the degradation of PAP in the presence of O3 generates the intermediate products that
could only be detected by gas chromatography coupled with mass spectrometry (GC/MS) [31]. Our
testing methods (HPLC and UV) can reveal the presence of PAP or any other detectable impurities in
the obtained PA samples from the above experiments. We could not quantify or detect the dark-color
impurity in the obtained PA samples with our available resources now. Visual identification is the only
way to confirm that the product is free of colored impurities in the experiments (see Figures 4 and 5).
However, we are confident that our future collaborative studies will work toward quantifying and
understanding the toxicology profile of this color impurity. SEM and particle size analysis experiments
were also carried out on the PA samples obtained from the above experiments. These results revealed
that the obtained crystals from the experiments involving salt formation have uniform-sized/shaped
crystals and were comparable to the crystals obtained from the initial experiment, which was carried
out under the absence of PAP (see Supplementary Materials).
3. Materials and Methods
3.1. Materials and General Methods
All organic solvents and samples were purchased from Sigma-Aldrich and used without any
further purification. Milli-Q water was used as a solvent for all the experiments.
IR spectra have been collected on a PerkinElmer Spectrum 100 FT-IR Spectrometer fitted with a
PerkinElmer Universal ATR Sampling Accessory.
DSC measurements of all salts were performed on a DSC 214 Polyma, NETZSCH instrument.
Typically, 3–5 mg of sample was accurately weighed into a hermetically sealed aluminum pan and
heated to 300 ◦C with a 10 ◦C·min−1 heating rate, under a nitrogen gas flow of 40 mL·min−1
.
Thermograms of all salts were measured with a Perkin-Elmer TGA 4000 with a heating rate of
10 ◦C
·
min−1 under a nitrogen stream of 20 mL min−1 to detect traces of solvents in the crystalline samples.
·
An EasyMax 102 Advanced Synthesis Workstation (Mettler Toledo) has been used to perform
impurity removal crystallization experiments using the salt formation technique.
PXRD data were collected on an Empyrean diffractometer (PANalytical, Philips) using Cu Kα1,2
radiation (
λ
= 0.1541 nm) at room temperature operated at 40 kV and 40 mA. The samples were scanned
using a step size of 0.02◦ 2 and a scan speed of 0.02◦ 2
/s. Single-crystal
over the range of 4–40◦ 2
θ
θ
θ
data for all the salts were collected at ambient temperature using a three-circle Bruker D8 Quest with a
sealed tube Mo anode, Kα radiation = 0.71073 Å, and a Photon 100 detector.
High-pressure liquid chromatography (HPLC) analysis was performed on all the paracetamol
samples after the EasyMax spiking experiments. An Agilent 1260 Infinity quaternary LC system in
combination with a ZORBAX Eclipse XDB-C18 column (4.6 mm
×
150 mm, 3.5 µm) has been used
to calculate the ratio of paracetamol to p-aminophenol in the solid and liquid samples. The mobile
phase consisted of a 0.01 M sodium phosphate buffer of pH 3 and methanol in a 0.15/0.85 (v/v)
ratio, respectively.
Scanning electron microscopy (SEM) images of all the crystals after the EasyMax experiments
were taken using a JEOL Carryscope. The crystalline samples on the sample holders were coated with
a thin layer of gold before analysis.
3.2. Synthesis of the PAP Salts
Salts were obtained by both solvent-drop grinding and crystallization methods. PAP was mixed
with the corresponding acid in the equimolar ratio except for OX, which was prepared in a 2:1 PAP:OX
ratio. Both solids were mixed in a mortar and ground for 20 min using drops of a 9:1 ratio of methanol
and water solvent mixture. The resulting powder was used for further analysis. Single crystals could

Molecules 2020, 25, 1910
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be obtained after dissolving PAP and the corresponding acid in 9 mL of methanol and 1 mL of water
upon slight heating. After 3 days, good-quality crystals of salts were obtained (as shown in Table 2)
through evaporative crystallization for the single-crystal analysis.
Table 2. List of salts and their ratios.
Acid
Product (Ratio in the Bracket)
Oxalic acid (OX)
l-tartaric acid (TA)
p-Salicylic acid (SA)
(1S)-(+)-10-Camphorsulfonic acid (CSA)
PAP+OX− Salt (2:1)
PAP+TA− Salt (1:1)
PAP+SA− Salt (1:1)
PAP+CSA−·H2O Salt hydrate(1:1:1)
3.3. Impurity Spiking Experiments
Initially, 11 g of PA was dissolved in 50 mL of isopropyl alcohol (IPA) and water 20:80 (v/v). In a
second experiment, 400 mg of PAP was added that also dissolved upon addition. The mixture was
heated to 80 ◦C and stirred to get a clear solution using an overhead mixer at 500 rpm. For these two
experiments, stirring continued at this temperature for 2 h. Then, the solution was cooled to 5 ◦C to
induce crystallization and the slurry was filtered under vacuum using Whatman qualitative grade
1 filter paper. The filtered material was washed two times with 20 mL of 20:80 (v/v) water and IPA.
The filtered and dried PA obtained from the above experiments was tested by PXRD, ultraviolet
spectroscopy (UV), HPLC, SEM, and laser diffraction.
4. Conclusions
Four novel salts of PAP were prepared and characterized. In all four salts, the molecules were
arranged into hydrophobic and hydrophilic layers. Salt formation of PAP was used to remove the
coloration of the product from PA through recrystallization of the API. We foresee that this approach
can be used more generally to remove other impurities from other systems, provided that the solubility
of the impurity salt is higher than that of the API. We could only identify the colored impurity visually;
however, we are optimistic that our future studies will progress in the detection and quantification of
this dark-colored impurity and reveal its nature.
Supplementary Materials: The following are available online; IR spectra, PXRD diffractograms, DSC-TGA
thermograms, HPLC chromatograms and crystallographic images. CCDC deposition numbers: 1966147-1966150.
Author Contributions: U.B.R.K. (conceptualization, methodology, validation and writing—original draft
preparation), L.K. (data curation, formal analysis and formal analysis, writing—review and editing), E.S.
(software, visualization and writing—review and editing), R.R.E.S. (validation, data curation, formal analysis and
writing—review and editing) and P.J.F. (supervision, resources, funding acquisition, project administration and
writing—review and editing). All authors have read and agreed to the published version of the manuscript.
Funding: Science Foundation Ireland (SFI) under the grant numbers: 12/RC/2275 and ES acknowledges the
ˇ
support from the Czech Science Foundation (GA CR) project, grant No. 17-23196S, and from the Technology
Agency of the Czech Republic, grant No. TJ02000256.
Acknowledgments: The authors gratefully acknowledge the financial support from the Science Foundation
Ireland (SFI) and Synthesis and Solid State Pharmaceutical Centre (SSPC) and the Bernal Institute facilities at the
University of Limerick
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds PA, PAP, PAP+SA−, PAP+OX−, PAP+CSA− H2O, PAP+TA− are
·
available from the authors.
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