Analysis of supramolecular interactions in alendroniate alkali metal salts: synthesis, structure, and properties of novel sodium alendronate polymorph

Article abstract of DOI:10.1007/s11224-018-1140-2

A new polymorph of anhydrous sodium alendronate, C₄H₁₂NO₇P₂Na, has been synthesized and characterized by single crystal X-ray diffraction as well as infrared spectroscopy and thermal analysis. The title compound crystallizes in the monoclinic P2₁/c space group. Asymmetric unit consists of one alendronic anion and one sodium cation. An interplay of classical strong O-H^…O, N-H^…O and non-classical weak C-H^…O hydrogen bonds creates 3D framework in the crystal. Contrary to previously reported sodium alendronate salts, in which Na⁺ cation is surrounded by six-coordinated sphere, in compound (1), the Na⁺ cation is five-coordinated in a distorted trigonal-bipyramidal geometry. In order to provide a detailed investigation of the molecular arrangement in view of intermolecular interactions, the title compound was compared with alendronic acid and other known alkali metal alendronate salts, retrieved from the Cambridge Crystal Structure Database. The intercontacts were qualitatively and quantitatively compared using Hirshfeld surface analysis. It highlights that strong O^…H/H^…O and subtle H^…H contacts play an influential role in the total surface area. The Me^+…H/H^…Me⁺ and Me^+…O/O^…Me⁺ contacts are meaningful as well. These evidently simple systems show a diverse complexity. Moreover, the powder X-ray diffraction, DSC, thermogravimetry/derivative thermogravimetry, and FT-IR results are also reported.

Full text of DOI:10.1007/s11224-018-1140-2

Structural Chemistry
https://doi.org/10.1007/s11224-018-1140-2
ORIGINAL RESEARCH
Analysis of supramolecular interactions in alendroniate alkali metal
salts: synthesis, structure, and properties of novel sodium alendronate
polymorph
Waldemar Maniukiewicz1 & Joanna Bojarska1 & Lesław Sieroń1
Received: 12 April 2018 /Accepted: 29 May 2018
#
The Author(s) 2018
Abstract
A new polymorph of anhydrous sodium alendronate, C4H12NO7P2Na, has been synthesized and characterized by single crystal
X-ray diffraction as well as infrared spectroscopy and thermal analysis. The title compound crystallizes in the monoclinic P21/c
space group. Asymmetric unit consists of one alendronic anion and one sodium cation. An interplay of classical strong O-H…O,
N-H…O and non-classical weak C-H…O hydrogen bonds creates 3D framework in the crystal. Contrary to previously reported
sodium alendronate salts, in which Na+ cation is surrounded by six-coordinated sphere, in compound (1), the Na+ cation is five-
coordinated in a distorted trigonal-bipyramidal geometry. In order to provide a detailed investigation of the molecular arrange-
ment in view of intermolecular interactions, the title compound was compared with alendronic acid and other known alkali metal
alendronate salts, retrieved from the Cambridge Crystal Structure Database. The intercontacts were qualitatively and quantita-
tively compared using Hirshfeld surface analysis. It highlights that strong O…H/H…O and subtle H…H contacts play an influ-
ential role in the total surface area. The Me+…H/H…Me+ and Me+…O/O…Me+ contacts are meaningful as well. These evidently
simple systems show a diverse complexity. Moreover, the powder X-ray diffraction, DSC, thermogravimetry/derivative
thermogravimetry, and FT-IR results are also reported.
.
.
.
.
Keywords Bisphosphonates Alendronic acid Polymorphism Crystal engineering Hirshfeld surface analysis
Introduction
new insight into their use in medicinal applications [5, 6],
since metal complexation of a bioactive ligand may result in
an improvement of the ligand’s pharmacological properties.
Also, these compounds show interesting magnetic, photo-
chromic, and electrocatalytic properties [7–9]. Alendronic ac-
id (see Scheme 1), chemically known as 4-amino-1-
hydroxybutylidene-1,1-bisphosphonic acid, is a member of a
second-generation bisphosphonate class of active pharmaceu-
tical ingredients, in which the P-C-P bridge replaces the P-O-P
group of naturally occurring pyrophosphate. This feature al-
lows the bisphosphonates to interact quite freely with the min-
eral phase of bone tissue [10, 11].
Human bone system-related diseases may remarkably deteri-
orate the quality of life. Very popular remedies in the treatment
of these diseases are pharmaceuticals from bisphosphonates
family, which can act as selective inhibitors of osteoclastic
bone resorption. Currently, they are used in the clinical treat-
ment of a variety of bone disorders such as osteoporosis,
Paget’s disease, and hypocalcemia [1], and are of some in-
creasing importance in bone cancer therapy [2–4]. Last, works
on metal coordination alendronate compounds have led to
The alendronic acid offers also various opportunities for
crystal engineering due to a number of accessible protonation
points and a carbon chain with a terminal amino group, that
allows the creation of strong P-O…H and N-H…O hydrogen
bonds. In order to provide a detailed systematical analysis of
the molecular arrangement for this class of compounds, a new
crystalline polymorphic form of anhydrous sodium
alendronate (1) synthesized in our laboratory was compared
with other known alendronate alkali metal salts. In-depth
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s11224-018-1140-2) contains supplementary
material, which is available to authorized users.
* Waldemar Maniukiewicz
waldemar.maniukiewicz@p.lodz.pl
1
Institute of General and Ecological Chemistry, Lodz University of
Technology, Żeromskiego 116, 90-924 Łódź, Poland

Struct Chem
stirred for ca 3 h. The white crystalline precipitate was washed
with hot water and dried at room temperature (yield 1.96 g,
79%), m.p. 257–260 °C. Anal. Calcd for C4H12NO7P2Na (%):
C 19.27, H 4.82, N 5.62. Found (%): C 19.43, H 4.76, N 5.52.
X-ray data collection and refinement
Colorless prismatic crystals (see Fig. S1 in Supporting
Information) were grown from water solution by slow evapo-
ration at room temperature. Crystallographic data of (1) were
recorded on the Bruker SMART APEXII CCD diffractometer
with MonoCap capillary at 100 K using Cu-Kα radiation.
Data collection, cell refinement, data reduction, and absorp-
tion correction were carried out with the SMART and
SAINTPLUS [24]. The structure was solved by direct
methods using SHELXS97 [25] and all of the non-hydrogen
atoms were refined anisotropically by full-matrix least-
squares technique on F2 using SHELXL-97 [25]. All hydro-
gen atoms were located using difference Fourier techniques
and refined with isotropic temperature factors. Molecular
graphics were prepared by using Mercury program [26].
Additional details of the data collection and refinement are
listed in Table 1. Selected bond lengths and dihedral angles
are shown in Table S1 in Supplementary Materials.
Scheme 1 Chemical structure of alendronic acid
search of literature and the Cambridge Crystal Structure
Database (CSD Version 5.38, May 2017 release) [12] revealed
the following salts with alkali cations such as the following:
sodium, represented by CSD reference codes—UTOKAQ
[13], PUQHAM, TEHWOS01 [14], TEHWOS [15]; lithi-
um—EJEZUP [16]; potassium—PUQFOY, PUQFUE,
PUQHEQ [14]; rubidium—PUQGAL, PUQGAL01,
PUQGOZ, PUQHIU, PUQHOA [14]; and cesium—
PUQGIT, PUQGUF, PUQHUG, PUQJAO [14]. Besides,
alendronic acid crystal structures signed by CSD reference
codes GOWZEX [17] and KOJGUL [18] were included into
the analysis. So far, there were reports that the title compound
exists in dehydrated [14, 15] and trihydrate [14] forms.
Interestingly, in a new polymorph, the Na+ is five-
coordinated in contrast to the other sodium salts, in which
the cation is surrounded by six-coordinated sphere.
Noteworthy, there is a high variability of coordination spheres
in all analyzed crystals. Furthermore, the HS study [19–23]
was employed to gain insight into intermolecular interactions
responsible for crystal packing. Additional features for new
anhydrous sodium alendronate polymorph were revealed by
powder X-ray diffraction (PXRD), differential scanning calo-
rim etry ( DSC), t herm ogravim etry/derivati ve
thermogravimetry (TG/DTG), and Fourier transform infrared
spectroscopy (FT-IR).
Table 1 Crystallographic data of the title compound (1)
Empirical formula
C4H12NO7P2Na
Formula weight [g/mol]
Temperature [K]
271.08
105(2)
Wavelength [Å]
1.54178
Monoclinic
P21/c
Crystal system
Space group
Unit cell dimensions [Å, o]
a = 6.8200(3),
b = 10.1557(5),
c = 14.6577(7),
β = 98.448(1)
Volume [Å3]
1004.20(8)
Z
4
Density (calculated) [mg/m3]
Absorption coefficient [mm−1
F(000)
1.793
]
4.608
560
Theta range for data collection [o]
5.318–66.997
1790
Experimental
Independent reflections
Synthesis
Data/restraints/parameters
Goodness-of-fit on F2
1794/0/140
1.133
All chemicals were commercially purchased from Sigma
Aldrich and used without further purification. Sodium carbon-
ate, Na2CO3 (1.06 g, 10 mmol), and alendronic acid (2.49 g,
10 mmol) were added to water (100 mL), and after the evolu-
tion of CO2 ceased, the reaction mixture was heated and
Final R indices (all data)
Largest hole and peak (eÅ−3
R1 = 0.0471, wR2 = 0.1203
− 0.81 and 0.75
)
R1 = Σ‖Fo ∣ − ∣ Fc‖/Σ ∣ Fo ∣ , wR2 = [Σw(Fo2 − Fc ) /Σw(Fo ) ]
,
2 2
2 2 1/2
2
Weighting scheme: w = 1/[σ2(Fo ) + (xP)2 + yP]; x = 0.0410; y = 0.2322

Struct Chem
Hirshfeld surface analysis
observed in the spectrum, and these are in the typical region
for P−O stretching vibrations [27]. The interpretation of these
P−O stretching vibrations is complicated by the differing co-
ordination modes of each phosphonate group.
The molecular Hirshfeld surfaces partition the crystal space
into non-overlapping molecular volumes and give unique in-
formation about each molecule within a crystal. The size and
shape of Hirshfeld surface characterize the interactions be-
tween atoms in a crystal, and hence reflect different intermo-
lecular interactions [19–23]. The normalized contact distance,
Thermal analysis
The thermal properties of sodium aledronate were studied by
DSC and TG/DTG techniques in air in the range of tempera-
ture from 16 up to 304 °C and at a heating rate of 10 °C min−1,
by using Netzsch TG 209 apparatus in flow of dynamic air
atmosphere υ = 20 mL min−1 in ceramic crucibles. The DSC
curves of anhydrous sodium alendronate (1) are illustrated in
Fig. S4. The TG and DTG results indicated that compound is
stable up to 259 °C.
dnorm, is a ratio including the distances of any surface point to
the nearest nucleus internal to the surface, di, and the nearest
nucleus external to the surface, de, and the van der Waals radii
of the atoms, rvdW, presented by equation.
di−rvi dw de−rvedw
dnorm
¼
þ
rvi dw
rvedw
The dnorm can be negative or positive sum of di and de,
when intercontacts are shorter or longer than the sum of the
vdW radii of atoms, respectively. The three-dimensional HS
surfaces, visualizing existing intercontacts on the electron
density maps and corresponding two-dimensional
FingerPrint (FP) plots, representing quantitative summary in
the percentage of each contact type, were prepared by Crystal
Explorer, ver. 3.1 [20]. Before the calculations, the bond
lengths to H atoms were set to standardized neutron values
(O-H = 0.983 Å, C-H = 1.083 Å).
Results and discussion
The crystal structure and comparison with other
alendronate salts
The crystal structure of (1) was determined by single crystal
X-ray diffraction study. The compound crystallizes in the
space group P21/c (No. 14), belonging to the monoclinic sys-
tem, with one alendronic anion and one sodium cation per
asymmetric unit. A view of the molecular structure with atom
numbering scheme is depicted in Fig. 1.
X-ray powder diffraction
The X-ray powder diffraction data were collected on a
PANalytical X’Pert Pro MPD diffractometer by using CuKα
(λ = 1.54178 Å) radiation. The diffraction patterns were ob-
tained at room temperature with step size of 0.0167° and
counting time 20 s/step over angular range 3°–60° (2θ) using
Bragg-Brentano geometry and a rotating flat-plate sample
holder. The comparisons of diffraction patterns of new poly-
morph (1) and reported earlier anhydrous sodium alendronate
[14] are shown in Fig. S2.
Likewise to previously reported alendronate alkali metal
salts, the structure of (1) has zwitterionic character with a
positively charged ammonium group balanced by one of the
negatively charged phosphonate oxygens. The geometry
around the P atoms is tetrahedral and the P-O bond lengths
are close to 1.50 and 1.55 Å for the P-O (unprotonated) and P-
O (protonated) distances, respectively. The P-C bond dis-
tances 1.834(3) and 1.864(3) Å and P-C-P bond angle of
Fourier transform infrared spectroscopy
The FT-IR spectrum was recorded by using a Thermo-Nicolet
6700 FT-IR spectrometer (Thermo Scientific, USA) with
MCT detector (photoconductive detector HgCdTe) with a
standard sample holder. Transmittance measurement was per-
formed using KBr technique. Pellet was prepared with 5 wt.%
of sodium alendronate and 95 wt.% of KBr. FT-IR spectrum of
(1) was obtained at room temperature in the range of 4000–
650 cm−1. The IR spectrum of the complex (1) displays a
weak broad absorption centered at approximately 3200–
3000 cm−1 attributable to -OH and NH- stretching vibrations
(see Supporting Information Fig. S3). A complex series of
absorption bands between 1250 and 1000 cm−1 is also
Fig. 1 ORTEP plot and atom numbering scheme of (1). The displacement
ellipsoids are shown with 50% probability

Struct Chem
Table 2 Hydrogen bond
geometry of the title compound
D-H…A
D-H (Å)
H…A (Å)
D…A (Å)
D-H…A (°)
Symmetry code
N1-H1…O7
N1-H2…O1
N1-H2…O5
O2-H2O… O5*
N1-H3…O6
O4-H40…O1
O7-H70…N1
C1-H4…O4
C1-H5…O3
0.91
0.91
0.91
1.16
0.91
1.07
0.84
0.99
0.99
2.44
2.52
1.97
1.31
1.95
1.43
2.50
2.48
2.56
3.329(4)
3.088(4)
2.824(4)
2.469(3)
2.833(4)
2.496(3)
3.329(4)
3.437(4)
3.176(4)
166
121
155
176
164
175
170
162
121
1 + x, y, z
1 + x, 3/2−y, ½ + z
1 + x, 3/2−y, ½ + z
−x, −1/2 + y, ½-z
1−x, 2−y, 1−z
1 + x, y, z
−1 + x, y, z
x, 3/2−y, ½ + z
1 + x, y, z
*Intramolecular hydrogen bond
112.2(2)° are in a good agreement with the corresponding
values found in analogue compounds. It seems particularly
interesting to analyze the change of coordination sphere
around the central atom. As has already been reported, these
systems demonstrate diverse complexity, which increases
with the central cation radius. Lithium alendronate salts re-
vealed four-coordinate tetrahedral Li+ cation [16]; sodium
salts, six-coordinate octahedral Na+ [13–15]; potassium salts,
seven-coordinated K+ [14]; and rubidium, 6/7/8-coordinated
Rb+ [14]; while cesium, 7/8/9-coordinated Cs+ [14].
Surprisingly, Na+ cation in (1) is surrounded by a five-
coordinated sphere through three of the hydroxyl (-OH) and
two oxygen atoms of the phosphonate (P=O) groups. The Na-
O distances vary from 2665(3) to 2913(3) Å forming distorted
Fig. 2 A partial packing diagram for sodium alendronate (1). Intermolecular hydrogen bonds are indicated by dotted lines

Struct Chem
trigonal-bipyramidal geometry around Na+ cation. These ob-
served distances are longer than those described in the litera-
ture [15], in which the Na-O distances change between 2.228
and 2.580 Å. Another interesting feature found for (1) con-
cerns Kitaigorodsky’s Packing Index, so-called KPI index
[28], estimated in Platon program [29]. It gives a percent of
filled space of 82.2% and therefore there is no accessible space
in the network for solvents. It is the largest value among all
known sodium alendronate salts, presenting the most close-
packed structure. Crystal data, including KPI factor (for sodi-
um alendronate salts), of analyzed alendronate structures re-
trieved from the CSD are summarized in Table S2.
Furthermore, the title structure has been carefully examined
along with other related alendronates due to identified trends
in 3D molecular arrangements and H-bond interaction pat-
terns. The packing of the molecules in (1) is dominated by
strong classical O-H…O, N-H…O and weak non-classical C-
H…O hydrogen bonds. Two P-OH, three P=O, and three hy-
existing H-bond interactions leads to creating the distinctive
three-dimensional H-bonding array. The geometric parame-
ters characterizing H-bonds are listed in Table 2.
The lengths of intermolecular H-bonds range from
2.469(3) to 3.437(4) Å, while the angles change from 121°
to 176°. The four stronger (D…A distances < 2.9 Å) and five
weaker (D…A > 2.9 Å) hydrogen bonds of the type O-H…O,
N-H…O, O-H…N, and C-H…O are observed. The profound
comparative investigation revealed enormous variety of H-
bond synthons. Alendronate anions are connected into dimers
in a head-to-tail manner. According to Etter and Bernstein’s
graph set theory [30, 31], the R1 (6) rings in (1) created by O4-
1
H40…O1 bonds generate corrugated polymeric 1D chain of
corner-sharing NaO5 polyhedra elongated along crystallo-
graphic a axis. Additionally, R2 (16) and R2 (20) motifs
2
2
formed through N1-H3…O6 and N1-H2…O1, respectively,
linking polymeric chains into 2D sheet. The crystal packing
drawing with intermolecular hydrogen bonds in the unit cell is
showed in Fig. 2. The 3D molecular self-assemblies of
alendronate salts are distinguishable. The structures revealed
one-dimensional and two-dimensional pseudo-coordination
+
drogen atoms of NH3 group are involved in intermolecular
hydrogen bonding. Only one intramolecular H-bond exists
utilizing the P-O-H…O=P groups. The cooperativity of all
Fig. 3 Hirshfeld surfaces mapped with dnorm (in the middle) and fingerprint plots resolved into O···H/H···O, H···H, Na+···H/H···Na+, O···O, and Na+···O/
O···Na+ contacts, showing the percentages of contacts contributing to the total Hirshfeld surface area of molecule (1)

Struct Chem
Fig. 4 Relative contributions of various intermolecular contacts to the Hirshfeld surfaces area in analyzed structures
polymeric architectures and in structure (1) has intermediate
character between the anhydrous polymorph determined from
the powder data [13] and hydrated sodium salts [14, 15]. The
associating from 22.2% in (1) to 42.8% in sodium salt
(PUQHAM) [14], providing extra stabilization in addition to
the presence of the abovementioned strong hydrogen bonds.
Besides, Me+…H/H…Me+ (where M+ means alkali metal cat-
ions) contacts seem also important, although we observe here
some differences among the analyzed structures (from 1.8%
for EJEZUP to 11.8% in (1)). At the similar level are Me+…O/
O…Me+ contacts (from 3.8% in PUQHEM to 18.6% in
PUQFOY). Notably, contributions of O…O and Me+…H/
H…Me+ are the greatest in (1) among sodium salts. Relative
percentage contributions of individual interactions to the HS
areas existing in all analyzed compounds are summarized in
Fig. 4 and Table S3.
R2 (20) synthon is observed in all sodium alendronate salts.
2
Notably, among all sodium alendronates, only in the case of
PUQHAM crystal [14], the intramolecular graph set synthons,
described by S1 (6) and S1 (7) motifs, were found.
1
1
Molecular Hirshfeld surface analysis
Herein, Fig. 3 presents the HS together with resolved FP plots
quantifying the percentage contributions of O…H/H…O,
H…H, Na+…H/H…Na+, O…O, Na+…O/O…Na+ contacts in-
volved in crystal packing of (1). The information given in
Table 2 is summarized effectively in the Hirshfeld surfaces
as the circular red areas indicating strong H-bonding interac-
tions, such as O-H…O, N-H…O, and O-H…N, white-colored
areas correspond to regions with weak contacts C-H…O, while
the blue areas are considered to be free of significant intermo-
lecular contacts. The HS diagram was generated using a high
surface resolution. The electron density with the function d-
norm was mapped by using a fixed color scale of 0.5 and − 1.5
for red and blue, respectively. The FP plots were drawn on the
de and di distances, from the HS to the nearest outside-external
and inside-internal atoms, respectively. The de–di pairs are in
intervals of 0.01 Å.
Conclusions
This article reports crystal structure of new anhydrous sodium
alendronate (1) polymorph: a crystallographic study revealing
the different geometry of this new form from those described
in the literature previously. The comparison with other known
alendronate alkali metal salts proved that these simple systems
demonstrate considerable versatile structural complexity.
While it was found that the intermolecular interactions and
packing arrangements appear to be consistent among struc-
tures, this was verified by HS analysis which allowed the
identification in a quantitative way of all interactions in the
alendronate salt crystals. The O…H/H…O, H…H, and Me+
…O(H)/O(H)…Me+ interactions play a major role in all ana-
lyzed self-assemblies. To sum up, discussed observations can
From the 2D FP plot analysis, it was found that the O…H/
H…O bonds are dominant and cover the total HS area in the
range from 41.6% in rubidium salt (PUQHOA) [14] to 70.6%
in alendronic acid (GOWZEX) [17]. On the other hand, subtle
interactions such as H…H are also significant contributors,

Struct Chem
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Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
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creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a link
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