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DOI: 10.1039/C8FD00072G

Copley et al. 4 noted how the distinctive nature of the disorder in eniluracil accounted for different structures
being acquired from powder X-ray diffraction (PXRD) data recorded from different samples. In retrospect
single crystal X-ray refinements of publishable quality may have been interpreted as polymorphism rather
than disorder (eniluracil features interchangeable hydrogen bonded motifs). Here the computed crystal
energy landscape was used as an additional form of analysis, and considered to be a valuable complement
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to X-ray diffraction and solid-state NMR when trying to understand and characterise disorder in organic

Faraday Discussions Accepted Manuscript

solid state systems.

In this current contribution we address this theme of disorder further using loratadine as a case study, with
its molecular structure seen in Figure 1. At the outset of this work the only available crystal structure was
that of Form I (BEQGIN; with the structure determined at ambient temperature) 5 which was identified as
exhibiting disorder. Here we describe the crystallisation and crystal structure of a second polymorph, Form
II and report the use of the GRACE programme for in silico polymorphism assessment of loratadine and
incorporation of disorder into the computations.

2 MATERIALS AND METHODS

Loratadine freebase (Form I) was purchased from ABCR (1kg batch AB261650); 98% purity, toluene;
Sigma Aldrich reagent grade ≥99%, tert-butyl methyl ether (TBME); Fluka 99%.

2.1 PREPARATION OF FORM I

Loratadine freebase Form I crystallises from a variety of organic single and mixed solvent systems. Single
crystals were prepared and analysed from acetonitrile, cumene, ethyl acetate, nitromethane, toluene and
toluene/tert-butyl methyl ether.

2.2 PREPARATION OF FORM II

Form II was first recorded based on its PXRD pattern, in a patent by Dibenedetto and Gala (of Schering
Corporation). 6 No other references in the open literature could be found to either its preparation or
characterisation. The patent states “we have discovered specific solvents and experimental conditions
which produce a distinctly different polymorph, Form II, of loratadine”. They described a complex process
in which, briefly, loratadine was dissolved in hot toluene with crystallisation taking place upon addition of
an antisolvent, TBME at -3 to -10 °C. After stirring for about 1-6 hours at this temperature, the resulting
crystals were of Form II.

Unfortunately this written description omitted many essential details with no targeted concentrations,
volumes, solvent compositions or cooling rates being given. Eventually, with advice from Robert Wenslow
of Crystal Pharmatech, isolation of Form II was successfully achieved. 7 Briefly, 480 mg of loratadine Form

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DOI: 10.1039/C8FD00072G

I and 0.8 mL of toluene were loaded into a 5 mL glass vial, stirred magnetically at 50 °C for 90 minutes to
produce a clear solution. This solution was cooled to 30 °C, 1 mL TBME was added and the solution filtered
through a Nylon membrane (pore size of 0.45 μm) into a clean vial. This clear solution was heated, 2 K/min
to 50 °C, held at 50 °C for 16 hours, then cooled at 1 K/min to 4 °C, held at 4 °C for 60 minutes, whereupon
Form II crystallised. The product was filtered under vacuum and dried at 40 °C for 3 hours and 50 °C for 1
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hour. Using this method Form II was successfully prepared at 0.5 g scale. While this recipe is successful

Faraday Discussions Accepted Manuscript

as a consistent methodology for preparing Form II it seemed essential to gain some scientific insight into
the crystallisation processes occurring throughout the procedure. This was achieved by scaling the process
up to ~ 100 g scale and observing the physical changes taking place.

This revealed that during cooling of the mixed loratadine/toluene/TBME solution to 4°C, an amount of
colourless liquid could be seen to condense and cascade down the crystallisation vessel walls into the
cooling solution of loratadine. Assuming this to be TBME, it could offer a form of self-induced antisolvent
crystallisation in combination with the cooling crystallisation. An independent experiment, in which TBME
levels were measured chromatographically, confirmed that the 16 hour, 50 °C hold period allows two
important processes to occur: firstly the loss of TBME results in an increase of the solution concentration
and secondly the TBME in the head space condenses on cooling and enters the solution. It is this process
which effectively provides a solvent drown out in addition to the cooling crystallisation process.

2.3 DSC MEASUREMENTS

Differential Scanning Calorimetry (DSC) data were recorded in order to measure the melting and
recrystallisation enthalpy of the loratadine freebase polymorphs.

The analyses were performed using TA Instruments Discovery DSC. Accurately weighed samples (0.2 - 1
mg) were placed into crimped aluminium pans. A reference was prepared using the same sample pan
without any material added. The DSC thermogram was recorded as follows: the temperature of the
apparatus was equilibrated at 20 °C, and heated to 300 °C at a heating rate of 10 K/min, under a nitrogen
flow of 50 mL/min. The instruments were calibrated for temperature and enthalpy with indium, at least
99.9999% pure. The TA Discovery DSC instrument was controlled by and data collected and processed
using Trios V 4.1.133073.

2.4 CRYSTAL STRUCTURE DETERMINATION

Single crystal X-ray diffraction data were collected at various temperatures (as specified) with a Bruker AXS
SMART 6000 CCD detector on a three-circle platform goniometer with Cu Kα radiation (λ = 1.54178 Å) from
a microsource generator equipped with multilayer mirrors. Data processing and global cell refinement were
performed with Saint. A semi-empirical absorption correction (SADABS) was applied, 8 based on the
intensities of symmetry-related reflections measured at different angular settings. All structures were solved

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conformations, (starting at N19) with a ratio of 0.51:0.49. This result essentially mirrors the previous
determination, BEQGIN 18 performed at 300 K. Figure 1(b) provides a packing diagram viewed down b
showing how the two conformers pack and how the alternate carbamate tail orientations are accommodated
within the structure. These conformers are related by rotation around the torsion C22-O24-C25-C26,
defined below as (Torsion 3) conformer 1 and 2. Structure determinations between 10 and 353 K indicated
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that this disorder could not be frozen-out. This is discussed in more detail later in this section.

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(a) (b)

Figure 1. Molecular and crystal structure of loratadine Form I. (a) Loratadine molecular structure and numbering
scheme, (b) projection down b, conformer 2 is coloured magenta from C22 to C26 in order to highlight the alternative
“tail” orientation adopted by the minority component

Figure 2 shows details of the molecular packing. Molecules are related by translation along the b axis
through utilisation of short C-H···N and C-H···O contacts shown in Figure 2(a). The two weak H-bonds in
this b axis chain are between the piperidine axial proton and the pyridine nitrogen (2.713 Å) in addition to
the carbamate ether oxygen and the methyl proton CH26 of the translated molecule (2.418 Å). Additionally
the pyridine nitrogen (N13) forms an intramolecular weak H-bond to the piperidine N···HC (CH17) (2.397
Å).

The existence of the two conformers in the structure results in different non-bonded interactions involving
the carbamate moiety and as such the dimers in the (010) plane shown in Figure 2(b). Conformer 1 and 2
are overlaid to depict the difference in the relative position of the carbonyl oxygen at 0.490 Å distance. As
a result the position of the carbamate tail in conformer 1 is closer to the translated molecule, thus a shorter
2
contact distance for the R (22) centrosymmetric carbonyl···phenyl dimer results (2.451 compared to 2.767
2

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2
Å) seen in Figure 2(c). Whereas conformer 2 has a shorter contact distance for the R (12)
2
carbonyl···piperidine dimer in the same plane (2.470 compared to 2.773 Å) as seen in Figure 2(d).
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Faraday Discussions Accepted Manuscript

(a)
(b)

(c)
(d)

Figure 2. Packing in loratadine Form I. 2(a) Molecules are related by translation along the b axis through utilisation of
short C-H···N and CH···O contacts, (b) overlay of conformer 1 (green) and 2 (orange) highlighting the deviation of
carbonyl oxygen relative position, (c) conformer 1 short contacts and distances, (d) conformer 2 short contacts and
distances

Figures 2(c) and (d) illustrate that both conformers have the same catemeric head to head
chlorine···alicyclic cycloheptane CH8 and chlorine···aromatic pyridine CH10 interactions within the (010)
plane depicted in Figure 1(b)).

3.1.2 Form II
Loratadine Form II (GWO30, 10 K) also crystallises in the monoclinic space group C2/c. In contrast to the
carbamate tail disorder of Form I in this form it is the cycloheptane CH 2-CH2 bridge (C7-C8-C9) that is
disordered. Conformational flexibility at this ‘head’ is discussed further below. The single crystal structure
was solved by modelling two different conformations in the ratio of 0.53:0.47, shown in Figure 3 and defined
below as (Torsion 1) conformer 1 and 2.

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