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Doi:10.1016/j.cplett.2004.03.117
Chemical Physics Letters 390 (2004) 20–24
Using terahertz pulsed spectroscopy to study crystallinity
Clare J. Strachan a, Thomas Rades a, David A. Newnham b, Keith C. Gordon c,
a School of Pharmacy, University of Otago, P.O. Box 913, Dunedin 9001, New Zealand
b TeraView Limited, 302/304 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK
c Department of Chemistry, University of Otago, P.O. Box 56, Dunedin, New Zealand
d Cavendish Laboratory, University of Cambridge, Madingley Road, Cambridge CB3 0HE, UK
Received 27 February 2004; in final form 25 March 2004
The application of terahertz pulsed spectroscopy to polymorphic, liquid crystalline and amorphous forms of pharmaceutical
compounds has been investigated. The different polymorphic forms of carbamazepine and enalapril maleate exhibit distinct tera-hertz absorbance spectra. In contrast to crystalline indomethacin and fenoprofen calcium, amorphous indomethacin and liquidcrystalline fenoprofen calcium show no absorption modes, which is likely to be due to a lack of order. These findings suggest that themodes observed are due to crystalline phonon and possibly hydrogen-bonding vibrations. The large spectral differences betweendifferent forms of the compounds studied is evidence that terahertz pulsed spectroscopy is well-suited to distinguishing crystallinitydifferences in pharmaceutical compounds. Ó 2004 Elsevier B.V. All rights reserved.
both situations variation in drug crystallinity must beinvestigated and monitored.
Polymorphism and crystallinity changes are enduring
Terahertz radiation ($0.1–3 THz, corresponding to
issues in the pharmaceutical industry. Eight out of the
3.3–100 cmÀ1) can induce low frequency bond vibra-
ten most commonly prescribed drugs in the United
tions, crystalline phonon vibrations, hydrogen-bonding
States in 2001 are known to exhibit polymorphism or
stretches, torsion vibrations and in gases molecular ro-
hydrate formation. Crystallinity variations in a phar-
tations [6]. Detection of these modes is likely to yield
maceutical substance may exhibit physicochemical dif-
rich information when characterising materials. How-
ferences that impact at therapeutic, manufacturing,
ever, until recently experimental difficulties, especially
commercial and legal levels [1–3]. While polymorphism
with regard to sources and detectors, inhibited the use of
is usually undesired, a metastable polymorphic form or
the terahertz regime to investigate material properties.
an amorphous form of a drug may sometimes be used
Recent advances are now allowing terahertz technology
advantageously, for example to increase solubility of a
to be applied to many fields such as the semiconductor,
poorly soluble compound or to improve flow properties,
medical, defence and space industries [7,8]. In particular
important in tablet or capsule manufacturing [4,5]. In
terahertz pulsed spectroscopy (TPS), which producesbroadband pulses on the femtosecond time scale, showsseveral application advantages. Its coherent natureprovides high sensitivity with room temperature sources
and detectors over a relatively broad frequency range.
Corresponding author. Fax: +44-0-1223-435382.
TPS measurements allow both the absorption coefficient
[email protected] (P.F. Taday).
and refractive index of a material to be calculated, and
0009-2614/$ - see front matter Ó 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.cplett.2004.03.117
C.J. Strachan et al. / Chemical Physics Letters 390 (2004) 20–24
time-resolved studies on the sub-picosecond time scale
pharmaceutical compounds, demonstrating the tech-
potentially allow insight into dynamic systems [7,8]. In
nique’s applicably to a broad range of solid-state forms
addition the low energy of terahertz radiation minimises
TPS has been applied to biologically active com-
pounds, e.g. to illustrate low frequency vibrational
modes of amino acids, proteins and DNA [9–11], and todifferentiate isomeric configurations of retinal chromo-
phores [12]. Benzoic acid and some monosubstitutedderivatives, including salicylic acid and acetylsalicylic
Carbamazepine (5H-dibenz[b, f]azepine-5-carboxam-
acid (aspirin) have also been differentiated using TPS
ide, purity >99%) and enalapril maleate (N-N-[(S)-
1-ethoxycarbonyl-3-phenyl-propyl]-L-alanyl-L-proline
The ability of TPS to probe lattice and hydrogen-
hydrogen maleate, purity >99%) were obtained from
bonding vibrations [6] makes it an ideal technique to
Salutas Pharma GmbH (Barleben, Germany). Feno-
investigate pharmaceutical polymorphism and crystal-
profen calcium dihydrate (calcium methyl-3-phenoxy-
linity. TPS has been used to probe such vibrations in
polycrystalline and amorphous saccharides [14]. In a
Chemical Manufacturing Corp. (New Jersey, USA).
recent study by Taday et al. [15], two polymorphs of
Indomethacin (1-[19]-5-methoxy-2-methylindole-3-ace-
ranitidine hydrochloride were shown to give distinct
tic acid) was purchased from Sigma Chemical Co. (St.
terahertz spectra, with only one peak at the same fre-
Louis, MO, USA). Polyethylene (PE) powder (Inducos
quency between 0 and 3 THz. To our knowledge, no
13/1, particle size <80 lm) was obtained from Induchem
other studies using TPS to investigate pharmaceutical
crystallinity and polymorphism have been published.
Carbamazepine (CBZ), enalapril maleate (EM), in-
domethacin (IM) and fenoprofen calcium (FC) (Fig. 1)are pharmaceutical examples that collectively exist in
CBZ was supplied as form III (P -monoclinic), and
polymorphic, liquid crystalline and amorphous states.
this form was used without further purification. Form I
CBZ is known to exist in four [16] and EM in two an-
(triclinic) was obtained by heating form III to 170 °C for
hydrous crystalline forms [17,18]. IM can be produced in
2 h, as described by Lefebvre et al. [22] and McMahon et
both a crystalline and amorphous form [19,20], and FC
al. [23]. EM designated as form II was used as received.
may form a crystalline dihydrate or a supercooled
Form I of EM was prepared by crystallisation from
thermotropic liquid crystalline state [21]. This Letter
ethyl acetate in the presence of methanol (3.5% w/w) as
extends the work of Taday et al. [15] by investigating the
described by Ip et al. [24]. Crystalline FC dihydrate was
ability of TPS to differentiate crystalline, amorphous
used as received. The supercooled thermotropic liquid
and supercooled liquid crystalline forms of these four
crystalline form of FC was prepared by heating the
Fig. 1. Molecular structures of: (a) carbamazepine; (b) enalapril maleate; (c) indomethacin; (d) fenoprofen calcium.
C.J. Strachan et al. / Chemical Physics Letters 390 (2004) 20–24
crystalline powder in beakers open to air in a preheatedoven for 45 min at 125 °C to remove the water of
crystallization [25]. The samples were then brought backto room temperature over silica gel. Crystalline IM
(c-form) was used as received. Amorphous IM wasproduced by melting the crystalline form at 165 °C,
followed by quench cooling in liquid nitrogen and sub-
sequent warming back to room temperature in a dessi-
cator over silica gel [20]. All samples were gently ground
using a pestle and mortar to reduce particle size as much
as possible and therefore minimize Mie scattering, and
their solid-state form was confirmed by X-ray powderdiffraction. Samples were stored at 4 °C over silica gel.
Sample tablets were prepared by mixing the phar-
maceutical solid powder with PE powder (EM 25% w/w;
CBZ 50% w/w or FC and IM 75% w/w in PE) with apestle and mortar using geometric dilution. PE is a
Fig. 2. Absorbance spectra of CBZ form III (solid line) and form I
tablet binder and diluent with negligible absorption in
the terahertz regime. Circular tablets (300 mg, 13 mmdiameter) were formed with a hydraulic press using1 ton compression (Specac Ltd., UK). Samples were also
compressed into tablets using 2 and 5 ton compres-sion, with no spectral changes observed for any of the
compounds. Samples were prepared and measured intriplicate.
All measurements were made using a TPITM spectra
1000 transmission spectrometer (TeraView Limited,
Cambridge, UK). Samples were measured at an instru-ment resolution of 2–3 cmÀ1 over the range from 2 to 75
cmÀ1. Data was acquired and processed using OPUSTM
Fig. 3. Absorbance spectra of EM form I (solid line) and form II
Figs. 2–5 show the terahertz absorption spectra for
the different solid-state forms of CBZ, EM, IM, and FC
respectively. It is evident from the figures that differencesin the solid-state forms for all four compounds give rise
to marked differences in the terahertz absorption spectrabetween 2 and 75 cmÀ1.
Comparison of the spectra of CBZ forms III and I
(Fig. 2) show peaks that are polymorph-distinct. Thespectrum of form III exhibits major peaks at 41, 60 and
68 cmÀ1, and a smaller peak at 47 cmÀ1 while the form I
spectrum has prominent peaks at 31, 44, 52 and 70
cmÀ1, with a low intensity peak at 23 cmÀ1. The mid-infrared (IR) and Raman spectra of forms III and I aresimilar. Polymorph sensitive absorptions however, can
be observed at 1390 and 1680 cmÀ1 in the IR spectra
[16]. Computational studies have shown that these
modes are associated with the CONH2 moiety. Both
Fig. 4. Absorbance spectra of IM crystalline (solid line) and amor-
forms exhibit dimer formation with hydrogen-bonding
C.J. Strachan et al. / Chemical Physics Letters 390 (2004) 20–24
It is interesting to note the increasing absorbance for
amorphous indomethacin with increasing frequency.
Previous experimental work on both PE and lactose
with various particle sizes (data not shown) has dem-
onstrated that as particle size approaches the incident
radiation wavelength, attenuation of the terahertz ra-
diation occurs, as would be expected for Mie scattering.
The average particle size of the crystalline IM sample
was very small (<80 lm). As the amorphous IM was
formed by quench cooling of the melt, with a solid mass
resulting from the process it was necessary to createparticles by grinding this mass with a pestle and mortar.
Care was taken in this process to avoid recrystallisation
of the amorphous drug making it difficult to reduce the
particle size to the same size range as that of the crys-
talline form. It is thus likely that some particles of the
Fig. 5. Absorbance spectra of FC crystalline hydrate (solid line) and
amorphous form of the drug remained sufficiently large
liquid crystalline anhydrate (dashed) 75% in PE.
to induce Mie scattering, causing the absorbance of thesample to increase with wavenumber. However, withlonger wavelengths, larger particle sizes are required for
between the CONH2 groups. Differences in the crystal
Mie scattering than is the case for shorter wavelength
structure associated with this hydrogen-bonding are
techniques, and thus it is likely that TPS can toler-
likely to be responsible for the differences observed in
ate much larger particles before particle size influ-
ences the spectra obtained than for example, near-IR
EM forms I and II also show pronounced spectral
differences (Fig. 3). Form I has peaks which occur at 23,
FC was chosen as a further pharmaceutical example
39 and 69 cmÀ1, with form II exhibiting peaks at 20, 27,
due to its ability to exist in a thermotropic liquid crys-
and 57 cmÀ1. In addition both forms have a common
talline state that can be cooled to room temperature.
mode at approximately 44 cmÀ1. Forms I and II of EM
The liquid crystalline state has previously been identified
exhibit nearly identical mid-IR and Raman spectra. This
as hexagonal [21]. The crystalline hydrate exhibited
has been attributed to very similar crystal packing, hy-
spectral peaks at 17, 27, 52 and approximately 66 cmÀ1.
The liquid crystalline form, however, lacked any distinct
However, differences have been observed between the
peaks in the spectral region studied. Comparison of the
two forms of EM in the far-IR Raman spectra of forms
crystalline and liquid crystalline samples suggests that
I and II between 25 and 100 cmÀ1 [27]. The TPS results
all modes present in the crystalline sample are due to
presented in this Letter suggest that the terahertz regime
long-range order resulting in phonon modes and/or
is better suited than the mid-IR region to differentiate
hydrogen-bonding between the water and FC molecules.
polymorphs when dealing with organic crystals showing
The liquid crystalline form exists as a hexagonal close-
packed thermotropic phase formed by 1.7 nm diameter
IM was studied in both the c-crystalline and amor-
rods [25]. The absence of any terahertz signature in the
phous forms. The crystalline form shows peaks at 41, 50
liquid crystalline form would suggest that either the
and 66 cmÀ1. There are no distinct peaks in the spectrum
1.7 nm order is insufficient to sustain a phonon mode in
of the amorphous form. Diffuse, unstructured absorp-
the spectral region studied or the modes observed in the
tion was observed in the amorphous from. A similar
crystalline form are a consequence of interactions with
observation was made by Walther et al. [14] when
the water molecules in the crystal as no solvent mole-
comparing polycrystalline and amorphous forms of the
cules are present in the thermotropic mesophase.
saccharides glucose, fructose and sucrose. Bertie et al. [28] observed a broad featureless spectrum of amor-phous ice when comparing crystalline and amorphous
forms, however the spectrum only extended down to130 cmÀ1. Such spectra suggest that the observed signals
The pharmaceutical examples investigated in this
with the crystalline IM are due to intermolecular
study show that a variety of different crystalline and
vibration modes of long-range order. If the modes
amorphous forms of organic molecules are readily dif-
present in the crystalline sample were due to intramo-
ferentiated by their terahertz absorption spectra. The
lecular vibrations, one would also expect to see these
absence of distinct modes in the amorphous and liquid
crystalline samples suggests that the absorbances in
C.J. Strachan et al. / Chemical Physics Letters 390 (2004) 20–24
more ordered samples are due to crystalline phonon
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