Crystal structures of mirtazapine molecular salts

Article abstract of DOI:10.1039/c0ce00746c

A few molecular salts of the anti-depressant drug R/S-Mirtazapine with organic carboxylic acids, its HCl salt, and Mirtazapine hemihydrate were crystallized and characterized by X-ray diffraction, IR and Raman spectroscopy, and thermal analysis. Whereas Mirtazapine base sublimed above ambient conditions its molecular salts do not show any sublimation even at elevated temperatures. Crystal structure analysis showed that proton transfer in the hemiadipate salt occurs contrary to the ΔpK_a rule. A strong ionic two-point synthon of N⁺-H...O^- and C-H...O^- hydrogen bonds is a recurring motif in Mirtazapinium carboxylate crystal structures.

Full text of DOI:10.1039/c0ce00746c

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PAPER
Crystal structures of mirtazapine molecular salts†
*
Bipul Sarma, Ranjit Thakuria, Naba K. Nath and Ashwini Nangia
Received 20th October 2010, Accepted 5th January 2011
DOI: 10.1039/c0ce00746c
A few molecular salts of the anti-depressant drug R/S-Mirtazapine with organic carboxylic acids, its
HCl salt, and Mirtazapine hemihydrate were crystallized and characterized by X-ray diffraction, IR
and Raman spectroscopy, and thermal analysis. Whereas Mirtazapine base sublimed above ambient
conditions its molecular salts do not show any sublimation even at elevated temperatures. Crystal
structure analysis showed that proton transfer in the hemiadipate salt occurs contrary to the DpKa rule.
A strong ionic two-point synthon of N+–H/Oꢀ and C–H/Oꢀ hydrogen bonds is a recurring motif in
Mirtazapinium carboxylate crystal structures.
Introduction
Mirtazapine has the chemical name (ꢁ)-1,2,3,4,10,14b-hexa-
hydro-2-methylpyrazino[2,1-a]pyrido[2,3-c]benzazepine
and
empirical formula C17H19N3 (Fig. 1). The molecule has a tetra-
cyclic skeleton belonging to the piperazino-azepine group of
compounds. This drug is used in the treatment of depression and
anxiety, and as an anxiolytic, hypnotic, antiemetic, appetite
stimulant and antihistamine.1 Mirtazapine is marketed as an
R/S-racemate (at the carbon marked *) even as S-(+)-mirtaza-
pine is under development for the treatment of insomnia.
Mirtazapine is the most popular anti-depressant among the top
12 SNRI and SSRI drugs according to a very recent survey.2
Mirtazapine is a white to creamy-white crystalline powder and
a class I drug according to the Biopharmaceutics Classification
System3 with Do (min) and Do (max) values3b of 0.059 and 0.180,
respectively, and half-life of 20–40 h.4 Racemic Mirtazapine is
supplied for oral administration as scored film-coated tablets
containing 15 or 30 mg of mirtazapine base, and unscored film-
coated tablets containing 45 mg of the drug. Each tablet also
contains corn starch, hydroxypropyl cellulose, magnesium stea-
rate, colloidal silicon dioxide, lactose, and other inactive ingre-
dients.5
Fig. 1 Molecular structure of (a) Mirtazapine and (b) Mianserin. The
asymmetric carbon atom is marked with *.
at the histamine (H1) receptor but it is not an inhibitor of
cytochrome P-450 isoenzymes.6
The N-methyl basic site of the piperazine group has a pKa of
7.1. The ‘‘rule of 3’’7 predicts that Mirtazapine will form salts
with organic acids having pKa < 4. A major stability problem of
the drug is that it sublimes at ambient temperature and this poses
problems for tablet formulation. Non-subliming salts of S-Mir-
tazapine, namely maleate, fumarate, and hydrobromide, and the
crystal structure of Mirtazapine hemihydrate are published in the
patent literature.8 We report X-ray crystal structures of
Mirtazapine is believed to act as an antagonist at the alpha 2-
adrenergic presynaptic receptor site. This results in an enhance-
ment of noradrenergic and serotonergic activity. Mirtazapine
shows little activity at serotonergic and muscarinic receptor sites.
The drug has potent sedative effects due to antagonistic actions
School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road,
Gachibowli, Central University PO, Hyderabad, 500 046, India. E-mail:
ashwini.nangia@gmail.com
† Electronic supplementary information (ESI) available: FT-IR and
Raman spectra, DSC and TGA plots, and HSM images. CCDC
reference numbers 797387–797393, 806223. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ce00746c
Scheme 1 Piperazino-azepine sub-structure for CSD search gave only
four crystal structures of drugs listed in Fig. 1.
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rac-Mirtazapine salts with hydrochloric acid, maleic acid,
malonic acid, adipic acid, salicylic acid, fumaric acid and hemi-
hydrate of the free base to understand the hydrogen bonding,
molecular packing and hydration state. A Cambridge Structural
Database search (CSD version 5.31)9 using piperazino-azepine
sub-structure (Scheme 1) resulted in only 7 hits, among which
there are only two CNS drugs, Mianserin and Mirtazapine
containing the search moiety. Both these drugs have high solu-
bility (0.2 mg mLꢀ1 for Mianserin, 1 mg mLꢀ1 for Mirtazapine)
even though they do not contain hydrogen bond donor groups. A
guest free form of Mianserin (CSD Refcode BUCVAW) and its
HCl and HBr salts (Refcodes HIJDEJ and MIANSB) are
reported.10 There is only one salt crystal structure of Mirtaza-
pinium saccharinate hydrate (Refcode YANNAD) reported by
Desiraju11 in the published literature. We therefore carried out
a structural analysis of Mirtazapine salts to fill a gap in the
available crystallographic data and also to understand the salt
crystal
structures
for
their
enhanced
stabilities.
Results and discussion
Mirtazapine hemihydrate
Crystallization of Mirtazapine from EtOH produced block-
shaped crystals of Mirtazapine hemihydrate after confirmation
by X-ray diffraction (space group P21/c). Water H atoms could
not be located in the difference electron density map. There are
no strong hydrogen bond donor groups on the Mirtazapine
molecule, and the water acts as a bridge to connect the drug
molecules. However, the difficulty in locating water H positions
makes the structure not as informative for hydrogen bonding
analysis. Water is located in channels down the b-axis (Fig. 2).
The isotropic displacement for the water O atom is large
2
ꢀ
(0.133(2) A ) for a heavy atom in an otherwise good quality
X-ray crystal structure. The difference electron density map gave
ꢀ
two sites for O1 separated by 1.75 A. Since the van der Waals
ꢀ
ꢀ
radius of O is 1.52 A, another O atom at 1.75 A distance is
physically unreasonable. The two O1 sites across the inversion
center were assigned occupancy of 0.50 each. Thus a single unit
cell contains 4 Mirtazapine and 2 water molecules to give
a hemihydrate stoichiometry. The R-factor is lower when the O1
site occupancy is 0.5 compared to 1.0. It is difficult to estimate
Fig. 2 Water molecules reside in channels along [010] in the crystal
structure of Mirtazapine hemihydrate (hydrogen atoms are removed for
clarity).
Table 1 Crystallographic parameters
Mirtazapinium
diHCl
trihydrate
Mirtazapinium
Mirtazapinium hydrogenfumarate Mirtazapinium Mirtazapinium Mirtazapinium
Mirtazapine Mirtazapine
hemihydrate hemihydrate
hydrogenmalonate (0.5 O s.o.f.) (0.529(9) O)
hydrogenmaleate monohydrate
hemiadipate
C20H24N3O2
338.42
salicylate
C24H25N3O3
403.47
Chemical C17H27Cl2N3O3 C21H23N3O4
formula
C21H25N3O5
399.44
C20H23N3O4
369.41
C17H20N3O0.5 C17H20N3O0.5
Formula
weight
Crystal
system
Space
392.32
381.42
274.36
274.36
Monoclinic
P21/c
Orthorhombic
P212121
Monoclinic
C2/c
Monoclinic
P21/c
Monoclinic
P21/c
Triclinic
Monoclinic
P21/c
Monoclinic
P21/c
ꢁ
P1
group
T (K)
ꢀ
298
298
298
100
298
298
298
298
a (A)
ꢀ
8.539(3)
13.703(4)
17.468(5)
90
103.311(5)
90
8.930(3)
9.877(3)
22.497(6)
90
90
90
25.244(4)
18.525(3)
8.9052(13)
90
102.753(3)
90
10.631(9)
9.315(8)
18.052(15)
90
103.771(13)
90
13.941(8)
15.599(9)
9.412(5)
90
99.499(11)
90
10.3222(16)
10.7865(17)
10.8589(17)
111.053(2)
115.931(2)
99.711(2)
2
935.2(3)
1.312
0.093
9.801(3)
17.308(5)
9.009(2)
90
106.000(4)
90
9.801(3)
17.308(5)
9.009(2)
90
106.000(4)
90
b (A)
ꢀ
c (A)
a (ꢂ)
b (ꢂ)
g (ꢂ)
Z
4
1989.1(10)
4
8
4
4
4
4
3
ꢀ
V (A )
1984.4(10)
1.277
0.090
20643
4061.9(10)
1.306
0.094
1736(3)
1.295
0.085
2019(2)
1.328
0.089
20342
1469.0(7)
1.241
0.077
1469.0(7)
1.241
0.077
Dc (g cmꢀ3) 1.310
m (mmꢀ1
Reflns.
)
0.347
20269
20808
8744
9393
15057
15057
collected
Observed 3321
reflns.
2889
3300
3127
3228
3686
2143
2143
Total
reflns.
R1(I >
2s(I))
wR2 (all)
3964
3949
3977
3813
3901
2957
2896
2896
0.0499
0.0458
0.0791
0.0784
0.1056
0.0565
0.0652
0.0652
0.1206
0.0888
1.015
0.1917
1.134
0.2147
0.869
0.3023
1.255
0.1223
1.087
0.1574
1.060
0.1554
1.067
Goodness- 1.094
of-fit
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the water content by TGA because sublimation of the drug starts
much below 100 ꢂC in TGA (melting endotherm in DSC at
121 ꢂC). Sublimation begins around 65 ꢂC as seen in HSM. The
thermal behavior of all compounds is discussed later in the paper.
Crystal data and hydrogen bond parameters are listed in Table 1
and 2. In order to assess the correctness of water O atom occu-
pancy assigned as 0.5, a new structure convergence was carried
out in which the O site occupancy was allowed to optimize in the
least squares refinement cycles. The final R-factor indices are
comparable to the above structure and the water site occupancy
factor (s.o.f.) in the freely refined crystal structure is 0.529(9). We
use the hemihydrate stoichiometry in the paper.
and N1 of the pyridine ring. The three water molecules and two
chloride ions make a hydrogen-bonded chain along the a-axis
(Fig. 3). Both the N+–H donors are bonded to Clꢀ ions which are
in turn hydrated through O–H/Clꢀ H bonds.
Mirtazapinium hydrogenfumarate monohydrate
Co-crystallization of Mirtazapine with fumaric acid in methanol
resulted in Mirtazapinium hydrogenfumarate monohydrate
crystal. The asymmetric unit contains one molecule of Mirtaza-
pine, two half fumaric acid molecules, and one water of crys-
tallization. One of the half fumarate ions lies about the inversion
center while the other half fumarate lies about the twofold axis.
The latter half is disordered over two positions and was modeled
using a site occupancy factor of 0.5 each for C21A and C21B.
Hydrogenfumarate anions form an infinite zigzag chain along
the c-axis and Mirtazapinium cations are pendent over the chain
(Fig. 4). Water molecules connect hydrogenfumarate chains,
Mirtazapinium dihydrochloride trihydrate
Mirtazapinium dihydrochloride salt was prepared (see Experi-
mental Section for details†) to give a trihydrate salt, in which
protonation occurred at two basic sites, N3 of the piperazine ring
Table 2 Hydrogen bonds and short contacts in crystal structures
ꢀ
ꢀ
Compound
Interaction
H/A (A)
D/A (A)
D–H/A (ꢂ)
Symmetry Code
1–x, 1/2+y, 1/2–z
—
Mirtazapinium diHCl trihydrate
N1+ꢀH1A/Cl2ꢀ
O1–H1B/O2
2.41
2.24
2.35
2.01
2.37
2.07
2.37
2.39
2.72
2.77
2.75
1.84
2.55
2.44
2.57
2.58
2.67
1.30
1.89
2.27
2.55
2.54
2.47
2.55
2.50
2.84
2.60
1.42
2.46
2.53
2.50
2.50
2.69
1.80
1.34
2.79
1.72
1.46
2.47
2.45
2.47
2.68
2.50
3.172(2)
3.027(5)
3.210(3)
2.804(4)
3.162(3)
3.032(2)
3.188(3)
3.197(3)
3.504(3)
3.692(3)
3.703(3)
2.709(3)
3.371(3)
3.279(3)
3.377(3)
3.484(3)
3.587
2.580(5)
2.768(4)
3.043(5)
3.420(6)
3.458(5)
2.794(5)
3.407(9)
3.339(8)
3.487
3.377(4)
2.592(4)
3.312(5)
3.453(4)
3.384(4)
3.402(4)
3.383
2.563(7)
2.521
3.560
2.634(3)
2.468(3)
3.371(3)
3.397(3)
3.344(3)
3.424
144.1
171.1
153.5
170.6
172.7
169.3
170.9
165.6
142.9
159.4
167.9
158.7
142.6
145.8
142.3
165.3
153.7
174.2
157.5
140.6
148.7
158.4
100.6
153.2
150.6
125.4
122.7
175.3
150.0
163.3
155.1
151.5
125.5
142.9
166.3
133.2
169.3
155.7
154.5
167.4
149.6
135.9
175.2
a
O1ꢀH1C/Cl2ꢀ
O2–H2A/O3
1–x, ꢀ1/2+y, 1/2–z
a
—
—
a
O2ꢀH2B/Cl1ꢀ
N3+ꢀH3A/Cl1ꢀ
O3ꢀH3B/Cl2ꢀ
O3ꢀH3C/Cl2ꢀ
C3ꢀH3/Cl1ꢀ
1–x, 1–y, 1–z
x, 1/2–y, 1/2+z
–x, ꢀ1/2+y, 1/2–z
–x, 1/2+y, 1/2–z
1+x, y, z
C13ꢀH13A/Cl1ꢀ
C14ꢀH14B/Cl2ꢀ
N3+ꢀH3A/O2ꢀ
C13–H13A/O4
C17–H17A/O4
C17–H17B/O4
C20ꢀH20/O1ꢀ
bC12–H12/O1ꢀ
O2ꢀH2A/O3ꢀ
N3+ꢀH3A/O3ꢀ
N3+ꢀH3A/O4ꢀ
C13–H13A/O5
C14–H14B/O1
C19–H19/O2
1+x, 3/2–y, 1/2+z
x, 1+y, z
Mirtazapinium hydrogenmaleate
1/2+x, 3/2–y, –z
1/2+x, 3/2–y, –z
—
a
ꢀ1/2+x, 1/2–y, –z
x, 1+y, z
—
a
Mirtazapinium hydrogenfumarate
monohydrate
1/2–x, 1/2–y, 1–z
1/2–x, 1/2–y, 1–z
—
a
1/2–x, 1/2–y, 1–z
–x, –y, 1–zc
1/2–x, 1/2+y, 1/2–z
C21A–H21A/O5
C21B–H21B/O2
bC12ꢀH12/O4ꢀ
N3+ꢀH3A/O1ꢀ
N3+ꢀH3A/O2ꢀ
C2ꢀH2/O1ꢀ
a
—
1/2–x, 1/2–y, 1–z
ꢀ1+x, y, z
Mirtazapinium hemiadipate
ꢀ1+x, y, z
a
—
x, 3/2–y, 1/2+z
ꢀ1+x, y, z
C8–H8/N1
C10ꢀH10/O1ꢀ
C14ꢀH14B/O2ꢀ
bC12ꢀH12/O1ꢀ
O3ꢀH3B/O2ꢀ
N3+ꢀH3A/O1ꢀ
bC12ꢀH12/O2ꢀ
N3+ꢀH3A/O1ꢀ
O4ꢀH4A/O2ꢀ
C13–H13A/O3
C13–H13B/O3
C19–H19B/N1
bC12ꢀH12/O2ꢀ
C1–H1/O1
1–x, 2–y, –z
ꢀ1+x, y, z
a
Mirtazapinium Salicylate
—
—
a
a
—
—
a
Mirtazapinium hydrogenmalonate
c
—
1–x, 1–y, 1–z
x, 1+y, z
–x, 1–y, 1–z
x, y, z
Mirtazapine hemihydrate
3.428(7)
ꢀ1+x, 3/2–y, 1/2+z
a
c
Molecules/ions in the same asymmetric unit. b Ionic C–H/Oꢀ H bond of the R22(8) synthon shown in Fig. 10. Intra molecular H bond.
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Fig. 3 (a) N+–H/Clꢀ hydrogen bond connecting Mirtazapinium and chloride ion. (b) Hydrogen bonding motifs of water molecules and chloride ions
along [100].
although the detailed hydrogen binding is not possible to analyze
because water H atoms could not be located in the X-ray struc-
ture. The N+–H donor of Mirtazapinium is bonded to fumarate
Oꢀ as shown below.
Surprisingly, the crystal structure is in chiral non-centrosym-
metric space group P212121 for this racemic salt, a phenomenon
that occurs in no more than 10% structures.12 Mirtazapinium
hydrogenmaleate units are arranged along the [100] direction
(Fig. 6).
Mirtazapinium hydrogenmalonate
Crystallization of Mirtazapine with malonic acid in methanol
gave a 1 : 1 salt (Fig. 5) in which one proton of malonic acid is
transferred to N3 of the piperazine ring (N+–H/Oꢀ). The Mir-
tazapinium hydrogen malonate units are connected by C–H/O
interactions (not shown in Figure but listed in Table 2).
Mirtazapinium hemiadipate
In the case of Mirtazapinium hemiadipate salt the proton resides
partially betweenthe acidicandbasic groups. Thereishalfmolecule
of adipate ion, which lies about the inversion center, for one
Mirtazapinium cation. Drug molecule layers are connected via
adipate through N+–H/Oꢀ hydrogenbonds (Fig. 7). Incontrastto
previoussaltswhereinonly oneH atom ofdiacidistransferred, here
a dianion is bonded to two cationic drug molecules.
Mirtazapinium hydrogenmaleate
Co-crystallization of Mirtazapine and maleic acid from methanol
resulted in a 1 : 1 salt, similar to the previous example.
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Fig. 4 (a) A chain of water molecules along [001] connects fumarate ions. (b) N+–H/Oꢀ hydrogen bond connecting Mirtazapinium to hydro-
genfumarate ion. (c) Overall packing showing the hydrogen bond pattern forming layers of Mirtazapinium and hydrogenfumarate ion and water
channel connecting the anions.
Mirtazapinium salicylate
The crystal structure of Mirtazapinium salicylate is unsurprising
with the ionic units close packed in the monoclinic P21/c space
group (Fig. 8).
Thermal, spectral and powder diffraction analysis of salts
X-ray powder diffraction of all the salts (Fig. 9) was recorded to
confirm the polymorphic purity of the bulk material. The
experimental XRPD pattern matched with the calculated lines
from the crystal structure in all cases except for Mirtazapinium
diHCl trihydrate. The Rietveld refinement parameters are given
in Table S1 (ESI†).
All the salts showed satisfactory IR and Raman spectra in the
solid state (Table S2 and Figure S1 in ESI†).
Fig. 5 Piperazine–acid N+–H/Oꢀ hydrogen bond in Mirtazapinium
hydrogen malonate structure.
DSC and TGA plots are given in the Supplementary
Information† (Figure S2). The TGA of Mirtazapine hemihydrate
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Fig. 6 (a) N+–H/Oꢀ ionic hydrogen bond connecting Mirtazapinium and maleate ions and (b) molecular packing along the [100] axis.
Fig. 7 (a) One adipate anion connects two Mirtazapinium cations through N+–H/Oꢀ hydrogen bond and (b) the overall molecular packing.
ꢂ
shows a gradual weight loss starting at about 50 C. The subli-
ꢂ
structure. It is possible that part of the water escapes from the
channel structure to give the lower water content in TGA. The
loss of one water stoichiometry could have happened at the time
of powdering the sample for XRPD and moreover the experi-
mental XRD lines do not match with the calculated pattern for
the trihydrate salt. The available data are not consistent for
Mirtazapinium dihydrochoride trihydrate and a detailed analysis
is pending. For Mirtazapinium hydrogenfumarate monohydrate
salt the observed weight loss of 4.04% corresponds to one water
molecule stoichiometry (calc. 4.52%).
mation of Mirtazapine base starts at 65 C as seen under a hot
stage microscope (see Figure S3 for HSM images, ESI†) and the
sudden drop in TGA curve at 120 ꢂC corresponds to the melting
point of Mirtazapine based on the DSC endotherm at Tpeak
121 ꢂC.
¼
In case of Mirtazapinium dihydrochoride trihydrate salt the
weight loss of 8.97% corresponds to the loss of two water
molecules based on theoretical weight (calc. 9.18%). Mirtazapi-
nium dihydrochoride is a trihydrate according to the crystal
Fig. 8 (a) N+–H/Oꢀ ionic hydrogen bond connecting Mirtazapinium and salicylate ions and (b) the zigzag layer packing in the structure.
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Fig. 9 Overlay of the calculated X-ray crystal structure (red) and experimental XRPD pattern (black) of the bulk material.
Interestingly, contrary to the ready sublimation of Mirtaza-
pine base hemihydrate, the salt forms of Mirtazapine prepared in
our study did not show any evidence of sublimation in TGA and/
or HSM, thus justifying the need to analyze the crystal structures
of salts to understand the improvement in the stability of
Mirtazapine after salt formation.
The oft-quoted DpKa rule states that if the pKa difference
between the base (conjugate acid of) and acid is > 3, then salt
formation will result.13 This is found to be the case based on
calculated values and our experimental results (Table 3). The
pKa of only the N-methyl piperazinyl site of Mirtazapine is
reported but the value of the pyridyl N moiety pKa is not
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Table 3 pKa values of Mirtazapine16 and acidsa used in this study
Molecule
pKa value
Product complex
OpKa value
Mirtazapine
HCl
7.1, 7.0b
ꢀ7
Mirtazapinium HCl
14.1
4.07
4.27
5.18
2.67, 1.69
4.13
Fumaric acid
Malonic acid
Maleic acid
Adipic acid
Salicylic acid
3.03, 4.44
2.83, 5.69
1.92, 6.27
4.43, 5.41
2.97
Mirtazapinium hydrogenfumarate
Mirtazapinium hydrogenmalonate
Mirtazapinium hydrogenmaleate
Mirtazapinium hemiadipate
Mirtazapinium salicylate
a
b
D. R. Lide, CRC Handbook of Chemistry & Physics, 86th Ed., Taylor & Francis. Ch. 8: pp. 42–51; www.wikipedia.org. Pyridine basicity was
estimated from a closely related compound (ref. 14a).
known. The latter value was estimated from the reported pKa
Conclusions
for the closely related compound ortho-N,N-dimethylamino
pyridine, whose N atom has pKa of 7.0.14a SPARC pKa calcu-
lator14b gave the pKa values of N-methyl piperazinyl and pyridyl
Salt formation is the first-choice method to improve the physical
stability and solubility of drug substances. A few non-subliming
salts of Mirtazapine along with the hemihydrate of the parent
N basic sites of Mirtazapine as 6.62 and 6.13 respectively.7b,14b
drug were crystallized. The proton transfer in these crystal
The only exception to the DpKa rule is Mirtazapinium hemi-
structures is consistent with the DpKa rule except in the hemi-
adipate for which DpKa < 3 but it is a salt structure, which is
adipate salt for which the difference < 3. All salts were fully
explained next.
characterized by diffraction, spectroscopic and thermal methods.
Except the dihydrochloride and fumarate salts, all other Mirta-
zapine salts are non-hygroscopic in nature. Whereas the free base
undergoes sublimation at slightly above ambient temperature,
Ionic two–point synthon
the maleate, salicylate and fumarate salts do not sublime even at
We observed in all Mirtazapinium carboxylate salts an ionic
elevated temperatures. Long term stability studies and the
unexplained behavior of Mirtazapinium dihydrochloride trihy-
drate in TGA and XRPD are being studied in our laboratory.
Crystallographic information on the piperazino-azepine class of
drugs is scarce to make definitive structure-property conclusions
which should be possible in the near future as new crystal data
are deposited.
two-point synthon R2 (8) between the carboxylate anion
2
acceptor and the protonated N+–H site and the activated C–H
of the asymmetric carbon atom. This C–H donor is both
benzylic and a to the tertiary amine, being sandwiched between
these functional groups, and hence is activated as a carbon
acid.15 In the adipate salt, two protons are transferred to two
molecules of Mirtazapine even though OpKa < 3. A reason for
proton transfer over and above the acidity-basicity differences
in the present system is the formation of strong N+–H/Oꢀ and
C–H/Oꢀ two-point synthon (Fig. 10) compared to the neural
motif, N/H–O and C–H/O. This special situation is appli-
cable to five carboxylate structures which contain the above
Experimental section
Preparation of salts
50 mg (0.2 mmol) of Mirtazapine and stoichiometric amount of
the carboxylic acid were mixed in a mortar-pestle, 4–5 drops of
methanol was added, the material was manually ground for
15 min, and then dissolved in 10 mL methanol and left for slow
evaporation at room temperature. The resulting solid was
analyzed by X-ray diffraction and vibrational spectroscopy.
Mirtazapinium diHCl trihydrate salt was prepared by dis-
solving 50 mg (0.2 mmol) of Mirtazapine in acetonitrile. A
diluted solution of HCl in acetonitrile was prepared by adding
2 drops of HCl in 10 ml of acetonitrile and slowly adding the
diluted HCl solution to the base solution till hydrochloride salt
precipitated out. The solid was filtered, dried and kept for crys-
tallization in methanol for X-ray diffraction quality material.
R2 (8) motif of C–H/O distance 2.67, 2.84, 2.69, 2.79 and
2
2
2
ꢀ
2.68 A (interaction labeled b in Table 2). This cyclic R (8)
synthon is not just a one off motif because an single charged
hydrogen bond is also possible, but not observed in these
structures. As mentioned in the Introduction, there is a paucity
of structural data on the piperazino-azepine ring system in the
CSD, and more crystal structures are needed to understand the
structural significance of this newly identified synthon in
Mirtazapine salts.
X-ray crystallography
X-Ray reflections for all compounds were collected at 298 K
(Mirtazapinium hemiadipate data collected at 100 K) on Bruker
SMART APEX CCD equipped with a graphite monochromator
ꢀ
and Mo-Ka fine-focus sealed tube (l ¼ 0.71073 A). Data inte-
Fig. 10 Possible carboxylic acid–piperazine hydrogen bonding motif for
Mirtazapine base and carboxylic acid. The stronger ionic two-point
synthon is observed.
gration was done using SAINT.17 Intensities for absorption were
corrected using SADABS.18 Structure solution and refinement
This journal is ª The Royal Society of Chemistry 2011
CrystEngComm, 2011, 13, 3232–3240 | 3239

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were carried out using Bruker SHELXTL.19 The hydrogen atoms
were refined isotropically and the heavy atoms were refined
anisotropically. N–H and O–H hydrogens were located from
difference electron density maps and C–H hydrogens were fixed
using HFIX command in SHELX-TL. In case of Mirtazapinium
fumarate monohydrate, the methylene C of one of the fumarate
molecule is disordered over two positions and modeled using
FVAR command with s.o.f. of 0.53 and 0.47. For the Mirtaza-
pine hemihydrates the oxygen atom of the water molecule has
s.o.f. of 0.5 and is situated near the inversion center. Crystallo-
graphic data are summarized in Table 1. Crystallographic. cif
files (CCDC Nos. 797387–797393, 806223) are available at http://
www.ccdc.cam.ac.uk/data_request/cif.
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.
Vibrational spectroscopy
Nicolet 6700 FT-IR spectrometer with an NXR FT-Raman
module was used to record IR and Raman spectra. IR spectra
were recorded on samples dispersed in KBr pellets. Raman
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DSC was performed on Mettler Toledo DSC 822e module.
Samples were placed in crimped but vented aluminium sample
pans. The typical sample size is 3–4 mg, and the temperature
range is 30–300 C at heating rate of 5 C minꢀ1. Samples were
ꢂ
ꢂ
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14 (a) A. F. Pozharskii, V. V. Kuzmenko, V. A. Azimov and
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,
SPARC is
sparc.chem.uga.edu/sparc.
a
program for
p
Ka calculation, http://
and the N2 flow is 50 mL minꢀ1
.
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Acknowledgements
We thank the DST (SR/S1/RFOC-01/2007 and SR/S1/OC-67/
2006) and CSIR (01(2079)/06/EMR-II) for research funding.
DST (IRPHA) and UGC (PURSE grant) for providing instru-
mentation and infrastructure facilities. B.S. thanks the CSIR,
and R.T. and N.K.N. thank the UGC for fellowship.
17 SAINT-Plus, version 6.45, Bruker AXS Inc., Madison, WI, 2003.
18 G. M. Sheldrick, SADABS, Program for Empirical Absorption
€
Correction of Area Detector Data, University of Gottingen,
Germany, 1997.
19 (a) SMART (Version 5.625) and SHELX-TL (Version 6.12), Bruker
AXS Inc., Madison, WI, 2000; (b) G. M. Sheldrick, SHELXS-97 and
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This journal is ª The Royal Society of Chemistry 2011