Chloral Hydrate Polymorphs and Cocrystal Revisited: Solving Two Pharmaceutical Cold Cases

Article abstract of DOI:10.1021/acs.cgd.6b00032

Chloral hydrate has the distinction of perhaps being the first reported example of a pharmaceutical compound to exhibit polymorphism (1877) and the first use of a pharmaceutical cocrystal in a drug product (Beta-Chlor, 1960s). Nevertheless, chloral hydrate represents a microcosm of contemporary issues in solid-state chemistry and its importance to pharmaceutical science. Ironically, the single crystal structures of the β-form of chloral hydrate and its pharmaceutical cocrystal with betaine have not yet been reported. In this contribution, the single crystal structures and physical properties of these crystal forms are reported for the first time. The previously termed "high temperature" β-form of chloral hydrate was obtained by melting the α-form of chloral hydrate and crystallizing from the melt. The α-form of chloral hydrate is comprised of diol-diol homodimers that further assemble into a sheet of six-membered rings. The β-form is sustained by head-to-tail OH?O hydrogen bonds that form a sheet built from two types of three- and five-membered rings. The diol-diol interactions that sustain these polymorphs are placed in context through a Cambridge Structural Database analysis. The chloral hydrate-betaine cocrystal (CHOBTN) was obtained by slow cooling from water, exhibits higher thermal stability than the chloral hydrate polymorphs, and is sustained by a previously known 2-point diol-carboxylate supramolecular heterosynthon that could be of general utility.

Full text of DOI:10.1021/acs.cgd.6b00032

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Article
Chloral Hydrate Polymorphs and Cocrystal
Revisited: Solving Two Pharmaceutical Cold Cases
Daniel O'Nolan, Miranda Perry, and Michael J. Zaworotko
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b00032 • Publication Date (Web): 29 Feb 2016
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Chloral Hydrate Polymorphs and Cocrystal Revisited: Solving Two
Pharmaceutical Cold Cases
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Daniel O’ Nolan, Miranda L. Perry, and Michael J. Zaworotko
Department of Chemical and Environmental Sciences and Materials and Surface Science Institute, University of
Limerick, Limerick, Ireland
ABSTRACT: Chloral hydrate has the distinction of perhaps being the first reported example of a pharmaceutical com-
pound to exhibit polymorphism (1877) and the first use of a pharmaceutical cocrystal in a drug product (Beta-Chlor®,
1960’s). Nevertheless, chloral hydrate represents a microcosm of contemporary issues in solid-state chemistry and its im-
portance to pharmaceutical science. Ironically, the single crystal structures of the β-form of chloral hydrate and its phar-
maceutical cocrystal with betaine have not yet been reported. In this contribution, the single crystal structures and physi-
cal properties of these crystal forms are reported for the first time. The previously termed “high temperature” β-form of
chloral hydrate was obtained by melting the α-form of chloral hydrate and crystallizing from the melt. The α-form of
chloral hydrate is comprised of diol-diol homodimers that further assemble into a sheet of 6-membered rings. The β-form
is sustained by head-to-tail OH…O hydrogen bonds that form a sheet built from two types of 3- and 5- membered rings.
The diol-diol interactions that sustain these polymorphs are placed in context through a CSD analysis. The chloral hy-
drate–betaine cocrystal (CHOBTN) was obtained by slow cooling from water, exhibits higher thermal stability than the
chloral hydrate polymorphs, and is sustained by a previously known 2-point diol-carboxylate supramolecular heterosyn-
thon that could be of general utility.
pose. However, as safer and more effective sedatives were
discovered and developed, chloral hydrate fell out of fa-
vor. Nevertheless, chloral hydrate remained on the mar-
INTRODUCTION
McCrone’s seminal work1 described how polymorphs can
sometimes impact physicochemical properties of rele-
vance to drug delivery. Regulatory requirements for drug
substances to be subject to crystal form screening for the
existence of polymorphs, solvates and hydrates were sub-
sequently introduced in 19872a and remain a key step in
the early stages of drug development.2b,c The relevance of
polymorphism to the pharmaceutical industry is a con-
temporary subject of interest since predicting the exist-
ence of polymorphs before they are made remains a scien-
tific challenge3 and there could be intellectual property
opportunities that accompany the discovery of new crys-
tal forms.4 In this context, the subject of pharmaceutical
cocrystals has risen to prominence in recent years since it
has become apparent that pharmaceutical cocrystals can
offer much greater changes in physicochemical properties
than can occur in polymorphs, solvates and hydrates.5
Benzamide,6 a polymorphic molecular compound that is
still being explored in the 21st century,7,8 was first report-
ed to be polymorphic in 1832 by Liebig and Wöhler. The
same year, Liebig also synthesized chloral hydrate (2,2,2-
trichloroethane-1,1-diol): “by passing dry chlorine gas over
hot alcohol until no more HCl was produced”.9 Chloral
hydrate quickly found utility as a sedative/hypnotic and
was widely used throughout the 19th century for this pur-
ket as an “unapproved drug” after the US congress passed
the Federal Food, Drug, and Cosmetic act of 1938.10
Groth, in 1872, reported studies concerning crystal forms
of chloral hydrate,11 however, having received crystals
from a local factory, may not have observed polymor-
phism. Berthelot (1877) noticed oddities in the latent heat
of fusion in chloral hydrate,12 suggesting that it may have
something to do with the plasticity of the re-solidified
compound. However, it was Pope (1899) who recognized
Berthelot’s findings as polymorphism.13 He obtained two
crystal forms through recrystallization experiments and
polarized micrographs were taken. However, the β-form
was found to be too unstable to be studied with a goni-
ometer. X-ray crystallography was subsequently used to
study the α-form by Ogawa14 and neutron diffraction
studies were later reported by Levy.15 The unit cell param-
eters reported from these experiments disagree with
measurements by Pope, Dufet,16 and Des Cloizeaux.17
Chloral hydrate (CHO) has also been used as a coformer
in a 1:1 pharmaceutical cocrystal with betaine (N, N, N-
trimethylglycine, BTN), CHOBTN. CHOBTN could repre-
sent the first use of a pharmaceutical cocrystal as a drug
substance in a pharmaceutical product, Beta-Chlor®.
Petrow et al. were issued US patent 3,028,240 in 1962. This
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patent details the preparation of CHOBTN and how it Table 1 Crystallographic parameters for the α and β,
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exhibits the same medicinal properties as chloral hydrate
but with less antagonistic effects and a higher melting
point.18 CHOBTN was later marketed by Mead Johnson in
1963 and to our knowledge represents the first pharma-
ceutical cocrystal to be marketed in the US.19
forms of chloral hydrate and its betaine cocrystal,
CHOBTN
α
β
CHOBTN
Formula
M
C2H3Cl3O2
165.40
C2H3Cl3O2
165.40
C7H14Cl3NO4
282.55
In this contribution, the single crystal structures of the
polymorphs of chloral hydrate and CHOBTN are reported
for the first time and we also address the physical proper-
ties of these crystal forms and their implications for crys-
tal engineering of diol compounds.
T (K)
273(2)
301(2)
298(2)
9
Crystal Sys-
tem
Monoclinic Monoclinic
Monoclinic
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Spacegroup
a (Å)
P 21/c
10.5714(10)
5.9647(6)
9.6727(8)
111.226(2)
568.54(9)
4, 1
P 21/n
10.0216(16)
5.9870(9)
39.612(6)
92.446(4)
2374.5(6)
16, 4
P21/c
9.2451(9)
11.5444(11)
11.5227(10)
91.390(2)
1229.4(2)
4, 1
EXPERIMENTAL
Synthesis. Chloral hydrate was purchased from Sigma
Aldrich and used without further purification. Single crys-
tals of the α–form were obtained by slow evaporation of
the as-received chloral hydrate (331 mg, 2.oo mmol) in
acetone (220 μl) from an open vial under ambient condi-
tions. After six weeks, colorless prismatic crystals were
obtained and harvested. Single crystals of the β–form
(992 mg, 6.00 mmol) were obtained by recrystallization of
the melted α–form via heating to 60 °C and cooling to
room temperature. A powder X-ray diffraction (PXRD)
study indicated that the α–form of chloral hydrate con-
verts to the β–form after the first melt. Repeating this
process three times afforded needles of the β–form. PXRD
further revealed that the β–form reverts to the α–form
over a period of seven days. CHOBTN was obtained by
dissolving as-received chloral hydrate (32.0 mg, 0.193
mmol) and betaine (22.6 mg, 0.193 mmol) in 200 μl deion-
ized H2O. This solution was placed on a watch glass and
b (Å)
c (Å)
β (°)
Volume (Å3)
Z, Zʹ
μ, mm-1
Reflections
1.494
1.431
0.739
7341
30976
20272
Unique Re-
flections
1305
3426
2080
Rint
0.0382
0.0378
0.1362
0.0852
0.0227
0.0403
Final R1
[I>2σ(I)]
Final wR(F2)
[I>2σ(I)]
R1 (all data)
wR(F2)
0.1123
0.1470
0.1096
o
heated to 60 C. Square plates were observed to form up-
0.0539
0.1246
0.1280
0.1570
0.0440
0.1146
on cooling to room temperature. Microcrystalline pow-
ders of CHOBTN were obtained by solvent-drop grinding
at room temperature using the same quantities as above.
(all data)
GooF
0.925
1.150
1.188
Single Crystal X-ray Diffraction (SXRD). The crystallo-
graphic and structural parameters for the polymorphs of
chloral hydrate and CHOBTN are presented in Table 1.
Reflection data for the α– and β–form of chloral hydrate
and CHOBTN were collected on a Bruker D8 Quest single
crystal X-ray diffractometer with sealed tube MoKα
source (λ = 0.71073) and TRIUMPH mirror. Absorption
corrections were carried out using the multi-scan method
in SADABS. XPREP in APEX3 was used for spacegroup
determination. The structures were solved in the APEX3
program using intrinsic methods in SHELXT and refined
against all Fo using SHELXL in the program SHELXLE. All
non-hydrogen atoms were refined anisotropically. Hydro-
gen atoms in the α-form of chloral hydrate and CHOBTN
were refined with torsion angles derived from a difference
Fourier synthesis and refined as a rigid group. Hydrogen
atoms in the β–form were refined using a riding model.
Due to the difficulty in obtaining the β-form, a small
poorly diffracting crystal was used for data collection.
Further to this, due to the β-form existing at higher tem-
peratures, data collection was carried out at room tem-
perature. Ultimately, these restrictions, as well as the in-
stability of the β-form which decomposed during data
collection, led to the mediocre quality of crystal data. See
ESI for further details.
Powder X-ray Diffraction (PXRD). Diffraction studies
of microcrystalline samples were performed in Bragg-
Brentano geometry on a Panalytical Empyrean diffrac-
tometer (40 kV, 40 mA, CuKα1,2 (λ = 1.5418 Å). A scan
speed of 0.5 s/step (6°/min) with a step size of 0.05° in 2θ
was used at room temperature.
Differential Scanning Calorimetry (DSC). Thermal
analysis was conducted using a TA Q2000 heat flux DSC.
Microcrystalline samples of chloral hydrate were hermeti-
cally sealed in aluminum pans and a ramp rate of 20
°C/min between -20 °C and 120 °C was applied under a N2
atmosphere. Measured heat flow was compared with that
of an empty aluminum pan.
Survey of the Cambridge Structural Database (CSD).
Conquest v5.37 with the November 2015 update was used
to survey organic geminal and vicinal diols. Filters were as
follows: 3D coordinates determined; no ions; R ≤ 0.075.
The intermolecular distance between –OH groups was 2.7
± 0.3 Å and entries were analyzed using Mercury 3.7.
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Figure 3. (a) Prismatic crystals of the α-form of chloral hy-
drate; (b) Emergence of β–form needles from the mother
liquor already containing α–form prisms.
hydrate and for measurement of its PXRD pattern. We
observed that the metastable β-form survives for ca. sev-
en days under ambient conditions before full conversion
to the more stable α-form occurs (Figure 1). The crystal
habits and melting points can distinguish between the
two forms of chloral hydrate. DSC, PXRD, and SXRD ex-
periments also indicate that the β-form can be readily
prepared by cooling the melted α-form. The polymorphic
behavior of chloral hydrate is consistent with an enantio-
tropic system. The narrow temperature range within
which these polymorphs exist suggests that the crystal
forms are of similar energy. Pope’s assertion, that the pe-
culiar melting points of chloral hydrate were due to pol-
ymorphism, is therefore validated by our study.
Figure 1. Comparisons of the calculated PXRD patterns of the
α and β polymorphs of chloral hydrate with experimentally
measured PXRD patterns.
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Synthesis and Structural Analysis of Chloral Hydrate
Polymorphs. Single crystals of the α-form were obtained
by slow evaporation from an acetone solution of chloral
hydrate in a scintillation vial. Removal of α–form crystals
and mother liquor from the vial in order to obtain images
of these crystals resulted in fast evaporation of solvent
and crystals of the β-form needles were observed to ap-
pear within minutes (Figure 3). The difference between
crystal habits (i.e. prismatic α-form and needle-like β-
form) that allows for distinction between the polymorphs
is in good agreement with Pope’s study13 and was verified
by measurement of the respective unit cell parameters.
Room temperature slow evaporation of chloral hydrate in
ethanol resulted in the formation of 2,2,2-trichloroethyl
acetate, consistent with the known instability of geminal-
diol compounds (see ESI for crystallographic data).
Figure 2. DSC thermograms of the α–form of chloral hydrate
melting (bottom) and re-crystallizing as the β–form (middle)
and the melt of the β–form (top).
RESULTS & DISCUSSION
Interconversion of Chloral Hydrate Polymorphs.
Pope’s contribution over a century ago gave insight into
how to obtain single crystals of both polymorphs of chlo-
ral hydrate. Experiments varying the temperature, sol-
vent, and crystallization method (slow evaporation, re-
crystallization from the melt, and supersaturated slurries)
were conducted to study the relationship between the
two polymorphs. As-received chloral hydrate was deter-
mined to be the α–form by comparison of experimental
powder X-ray diffractograms with that calculated for the
single crystal structure (Figure 1). Melting and cooling of
the α–form resulted in clusters of colorless needles which
were observed to be brittle and become opaque upon be-
ing stressed by touching with a needle. Repetitive melting
and recrystallizing in an oven (heat to 60 °C, slow cool to
RT, repeat) afforded larger and more stable single crystals
of the β–form and allowed for an SXRD study. DSC exper-
iments conducted on the α–form revealed that onset of
the melt occurred at approximately 56 °C and that, upon
cooling, a recrystallization event occurred at approxi-
mately 20 °C (Figure 2). Reheating this recrystallized
sample resulted in a broad melting event at a lower tem-
perature than before; suggesting that a new, less stable,
phase had been formed. Reproduction of this experiment
on a hotplate enabled isolation of the β-form of chloral
The crystal structure of the α-form of chloral hydrate
packs with four molecules per unit cell in P21/c with Z′ = 1.
Chloral hydrate molecules form hydrogen-bonded ho-
modimers through diol–diol interactions which exhibit an
R2 (8) graph set20 motif with OH···O distances of 2.837(3)
2
Å. The motif and atoms involved in the diol – diol dimers
are reminiscent of the supramolecular heterosynthons21
formed by carboxamides22 which result in exterior H-
bond donors that remain to be satisfied and thereby tend
to afford extended H-bond networks. In the structure of
the α-form, the extra two donors on the periphery of each
dimer form hydrogen bonds to open acceptor sites on
neighboring dimers, thereby forming 4,4 sheets that are
corrugated (Figure 4). A schematic illustration of how
four diol-diol dimers engage to form a larger R4 (16) motif
4
that sustains the 4,4 sheets is given in Figure 5(a). The
larger ring motif appears to be stabilized by bifurcated
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Figure 6. Self-assembly of heat-to-tail hydrogen bonds form-
ing pentagonal and triangular rings in the β-form of chloral
hydrate
Figure 4. Self-assembly of diol-diol homodimers (left) results
in corrugated 4,4 sheets (right) in the α-form of chloral hy-
drate.
sembly and help to explain the high Z’ value. The first
pentagonal ring is sustained by the hydrogen bonding of
one –OH group from each of five chloral hydrate mole-
cules (Figure 5(b)). The OH···O bond distances within the
first pentagonal ring range between 2.667(8) Å - 2.930(9)
Å.
The second pentagonal ring is an expanded ring because
it results from a different motif formed by both hydroxyl
groups of three geminal diols and a single hydroxyl group
of two other chloral hydrate molecules (Figure 5(c)).
Similar to the first pentagonal ring, this motif is also an
irregular pentagon with intermolecular hydrogen bond
distances ranging from 2.740(9) Å to 2.798(9) Å. The first
triangular ring forms via self-assembly of two diols and a
single hydroxyl group of a third chloral hydrate molecule
(Figure 5(d)). One of the diols uses both donor contacts
in the ring while the other utilizes both acceptor contacts.
The hydroxyl group closes the ring as a triangle. The hy-
drogen bond distances found within this ring range from
2.703(9) Å to 2.798(9) Å. The second triangular ring is
constructed through OH···O interactions between three
diol functional groups (Figure 5(e)). Hydrogen bond dis-
tances range from 2.667(8) Å to 2.930(9) Å. Figure 6 re-
veals how these triangular and pentagonal ring motifs
combine to form sheets which in turn stack with –CCl3
functional groups at the surface. The closest contacts be-
tween the sheets are Cl···Cl interactions23 with distances
of 3.5178(3) Å.
Figure 5. (a) Self-assembly of diol-diol dimers in the α-form
of chloral hydrate result in self-assembly as shown; (b) First
pentagonal ring of the β-form generated from head-to-tail
interactions of five hydroxyl groups; (c) Second pentagonal
ring of the β-form generated by hydrogen bonding between
three geminal diols and two hydroxyl groups; (d) First trian-
gular ring of the β-form sustained by two geminal diols and
one hydroxyl group; (e) Second triangular ring of the β-form
containing three geminal diols (R = -CCl3, non-interacting
hydrogen atoms removed for clarity).
Cl···O interactions with distances of 3.0777(2) and
3.1883(19) Å. Chloral hydrate molecules are arranged in
such a manner that the –CCl3 functional groups are ori-
ented at the surface of each layer. This results in stacking
of the 4,4 sheets with the closest distance between layers
being the result of Cl···Cl interactions23 (3.6406(3) Å).
The First Pharmaceutical Cocrystal to Reach Market?
Chloral Hydrate – Betaine. The subject of pharmaceuti-
cal cocrystals has been thoroughly reviewed in recent
years.24 The history of pharmaceutical cocrystals dates
back to at least the 1930’s with the complexation of APIs
to hydrotropic agents.30 In 1934 Von Heyden AG was
awarded what may be the first patent of a molecular co-
crystal with the potential for pharmaceutical utility.25
However, there is no evidence that these multi-
component materials (barbiturate – pyridine derivative
cocrystals) were ever used as drug substances in drug
The crystal structure of the β-form of chloral hydrate is a
high Z’ structure with 16 molecules per unit cell in P21/n
and Z′ = 4. The crystal packing of the β-form can also be
described as sheets but these sheets are not based upon
self-assembly of diol-diol dimers. Indeed, the diol–diol
dimers seen in the α-form are not even present in the β-
form. Instead, the hydroxyl groups on chloral hydrate
molecules form head-to-tail assemblies that generate
rings. Specifically, two types of pentagonal ring and two
types of triangular ring afford the observed sheet-like as-
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Figure 8. Two carboxylate-diol heterodimers of CHOBTN
form tetramers through Cl···O interactions
Figure 7. Diol-diol homodimers as observed in the α-form of
chloral hydrate (left) and the charge-assisted diol-
carboxylate heterodimers that sustain CHOBTN (right).
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hydrate – betaine heterodimers self-assemble to form a
discrete tetrameric assembly through two identical Cl···O
products. Our review of the literature suggests that the 1:1
cocrystal of chloral hydrate and betaine, CHOBTN, could
be the first use of a pharmaceutical cocrystal as the drug
substance in a drug product, Beta-Chlor®; which first ap-
peared on the US market in 1963. To our knowledge, the
only other examples to date are the active ingredients of
Depakote®,26 Entresto®,27 Cafcit®28 and Lexapro®,29 most of
which are ionic cocrystals.24a
interactions (3.2608(2) Å) which generate a second R2 (8)
2
motif. The next closest Cl···O distance, 3.6437(2) Å, is out-
side the sum of Van der Waals radii. Upon heating above
150 °C under N2, chloral hydrate is released to afford beta-
ine (See ESI for thermogravimetric and crystallographic
analysis). This observation indicates that CHOBTN im-
parts improved thermal stability to chloral hydrate since
o
chloral hydrate is itself only thermally stable to ca. 56 C.
The concepts of crystal engineering31 can be exploited for
the design of new pharmaceutical cocrystals from first
principles.32 Rational design of novel cocrystals requires
an understanding of supramolecular synthons,33 in partic-
ular the propensity of a given functional group to form
specific hydrogen-bonded supramolecular heterosyn-
thons in the presence of competing interactions. Our re-
search group has systematically addressed the hierarchy
of several supramolecular synthons that are of general
relevance to drug molecules.34 Figure 7 illustrates that
there is in effect a competition between diol homodimers,
as observed in the α-form of chloral hydrate, and the diol-
carboxylate supramolecular heterosynthon that sustains
CHOBTN.22 That CHOBTN and the cocrystal between
vitamin C and betaine, ASCBTN,34c exist suggests that the
carboxylate-diol charge-assisted supramolecular hetero-
synthon is favored over diol-diol supramolecular homo-
synthons (Figure 7). The single crystal structure of
CHOBTN revealed that chloral hydrate molecules and
Betaine was isolated in the form of a previously known
hydrate of betaine.35
Survey of the CSD for Geminal/Vicinal Diol – Diol
Interactions. The differences in the diol–diol interac-
tions exhibited by the α and β polymorphs of chloral hy-
drate prompted us to consider what other supramolecular
synthons between diols are feasible and/or known. A CSD
survey of geminal and vicinal diols revealed that OH···O
hydrogen bond distances average 2.7 ± 0.3 Å. When the
hitlist was refined to include only those structures with
diol–diol interactions, there are only seven unique entries
as summarized in Table 2: three geminal diols and four
vicinal diols. That hydroxyl groups can serve as both hy-
drogen bond donor and acceptor sites affords diols a de-
gree of freedom in their mode of packing that is more
promiscuous than that of carboxylic acids and carbox-
amides. Of the vicinal diols, WUXGIF forms dimers that
extend through their extra donor/acceptor sites to gener-
ate a tape, a classic motif seen in amide structures24b (Fig-
ure 9(a)) This motif is repeated in SIJJAX, however, there
are two diols present in SIJJAX, which enables the for-
mation of a sheet. Similar to the interactions displayed in
the α-form of chloral hydrate, catechol (CATCOL) pro-
duces dimers, with each hydroxyl group acting as both a
hydrogen bond donor and a hydrogen bond acceptor.
CATCOL thereby forms a 4,4 network (Figure 9(b)). The
four remaining structures generate what can be best de-
scribed as tubes wherein each diol generates a
betaine zwitterions form R2 (8) heterodimers with the
2
geminal diol of chloral hydrate hydrogen bonding to the
carboxylate moiety of the betaine zwitterion (OH···O dis-
tances of 2.635(3) and 2.648(3) Å, Figure 8). These chloral
Table 2 Summary of CSD Survey
Molecule
Type
Assembly
Ribbon
Synthon
CSD Refcode
SENZIW36
SENZOC36
TUGXAU37
SEFRIE38
WUXGIF39
CATCOL0140
SIJJAX41
Geminal
Diol
R4 (8)
head-to-tail hydrogen bonded ring with one hydroxyl
group and a head-to-tail chain with the other hydroxyl
group. The result is a tubular hydrogen bonded network.
SEFRIE exhibits three hydrogen bonded chains that cross-
link to create trimeric assemblies with three molecules
adding one hydroxyl group to a ring. In each of the gemi-
nal diol structures (SENZIW, SENZOC, and TUGXAU),
two catemers are produced which are double cross-linked
to generate tetrameric assemblies (Figure 9(c)). These
4
Ribbon
Tape
R3 (6)
3
R2 (8)
2
Vicinal
Diol
R2 (8)
2
Sheet
R2 (8)
2
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lar synthons that are possible for diols. In principle, gem-
1
2
3
4
5
6
7
inal and vicinal diols are more promiscuous in terms of
possible motifs than carboxylic acids and amides. This
makes diols less predictable but does not impact their
propensity to form cocrystals through supramolecular
heterosynthons. However, further studies are required
concerning the hierarchy of supramolecular synthons in
diols before broader conclusions can be drawn.
8
9
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Supporting Information
Supporting Information is available free of charge via the
Internet at http://pubs.acs.org.
Figure 9. (a) Tapes (b) Sheets and (c) Tubes generated from
OH···O hydrogen bonds found in vicinal and geminal diol
crystal structures. Below are schematic representations of
tapes, sheets, and the conceptual “rolling-up” of tapes/sheets
to form tubes
AUTHOR INFORMATION
Corresponding Author
ring assemblies are also exhibited by carboxylic acids42,
with amides being more prone to forming tapes. Concep-
tually, the tubular networks can be viewed as “rolling-up”
a sheet to generate packing efficiency (Figure 9).
*Email: xtal@ul.ie
Notes
The authors declare no competing financial interests.
While the supramolecular synthons found in the α-form
of chloral hydrate also sustain the structure of CATCOL,
the synthons that hold together the β-form of chloral
hydrate were not found in any existing structures. Indeed,
the unusual packing of the β-form is validated by a survey
of the CSD for any hydroxyl groups that form the same
motif resulting in zero hits.
ACKNOWLEDGMENT
The authors gratefully acknowledge Science Foundation Ire-
land (SFI) Award 13/RP/B2549 for their financial support.
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CONCLUSIONS
Encapsulated within the historical significance of chloral
hydrate polymorphism are contemporary issues in solid-
state chemistry and pharmaceutical science. Berthelot’s
studies into the melting points of chloral hydrate place
knowledge of its polymorphism at nearly 140 years ago.
However, the single crystal structure of the β-form of
chloral hydrate is only now elucidated. This remains a
contemporary issue for several reasons: understanding of
polymorphism is still a scientific challenge; polymor-
phism can play a role in the efficacy of a drug substance
and its ability to be formulated and processed; there are
also intellectual property implications to polymorphism.
Although the structural motifs sustaining the α-form of
chloral hydrate are found in other structures utilizing
diol-diol interactions, the structural motifs of the β-form
have not been found elsewhere in the CSD.
The molecular cocrystal, CHOBTN, which we believe to
be the first example of a pharmaceutical cocrystal to be
used in a marketed drug product in the 1960’s, also repre-
sents a contemporary subject, i.e. the potential utility of
pharmaceutical cocrystals in drug products thanks to im-
proved physicochemical properties. The superior proper-
ties of CHOBTN over chloral hydrate polymorphs are that
CHOBTN exhibits much better thermal stability while
maintaining its efficacy. Indeed, both polymorphs of chlo-
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above 120o C.
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drate and CHOBTN exhibit just some of the supramolecu-
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Chloral hydrate is arguably the earliest-known example of pharmaceutical polymorphism and also the first use of a
pharmaceutical cocrystal in a drug product. The α- and β-form of chloral hydrate as well as the cocrystal have been
obtained and intermolecular interactions characterized by X-ray diffraction.
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