An ester derivative of the drug gabapentin: PH dependent crystal stability

Article abstract of DOI:10.1016/j.molstruc.2010.03.067

Gabapentin solutions with different pHs were prepared and slow crystallization was allowed to occur. Different crystalline forms were obtained at pHs up to 7, whereas alkaline media (pH 9) gave rise to an amorphous product. A new crystal structure of an ethyl ester derivative, obtained at pH 2 under Fischer esterification conditions, is described herein. Esterification blocked the supramolecular interactions typically observed through the carboxyl group of gabapentin, which resulted in a dramatic change in the solid-state structure. As it is known, this change could have a marked influence on the physiological absorption characteristics of the drug, which supports the search for ester-based gabapentin prodrugs as a means of improving the limited bioavailability of the drug.

Full text of DOI:10.1016/j.molstruc.2010.03.067

Journal of Molecular Structure 973 (2010) 173–179
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
An ester derivative of the drug gabapentin: pH dependent crystal stability
Vânia André , M. Matilde Marques , M.F. Minas da Piedade a,b, M. Teresa Duarte a,
a
a
*
a
Centro de Química Estrutural, Departamento de Engenharia Química e Biológica, Instituto Superior Técnico, Av. Rovisco Pais 1, 1049-001 Lisbon, Portugal
Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Gabapentin solutions with different pHs were prepared and slow crystallization was allowed to occur.
Different crystalline forms were obtained at pHs up to 7, whereas alkaline media (pH 9) gave rise to
an amorphous product. A new crystal structure of an ethyl ester derivative, obtained at pH 2 under
Fischer esterification conditions, is described herein. Esterification blocked the supramolecular interac-
tions typically observed through the carboxyl group of gabapentin, which resulted in a dramatic change
in the solid-state structure. As it is known, this change could have a marked influence on the physiolog-
ical absorption characteristics of the drug, which supports the search for ester-based gabapentin
prodrugs as a means of improving the limited bioavailability of the drug.
Received 18 February 2010
Received in revised form 18 March 2010
Accepted 29 March 2010
Available online 2 April 2010
Keywords:
Gabapentin
Crystal engineering
Prodrug
Ó 2010 Elsevier B.V. All rights reserved.
Hydrogen bonding
pH dependence
1
. Introduction
The search for new crystal forms has become one of the major
Gabapentin itself is highly soluble but has limited and variable
bioavailability, probably due to its dependence on a low-capacity
amino-acid transporter expressed in a limited region of the upper
small intestine. Moreover, gabapentin absorption saturates at clin-
ical doses, which results in dose-dependent pharmacokinetics and
considerable interpatient variability. Therefore, the development
of prodrugs of this API, with better absorption properties and capa-
ble of releasing the parent drug via enzymatic hydrolysis, has re-
cently been receiving much attention [20,32,34].
In the pursuit of new crystal forms of gabapentin, a pH-depen-
dence study of this API was undertaken, not only to check for its
stability but mainly to look for new derivatives with potential ther-
apeutic applications. Having the same functional groups as an ami-
noacid, gabapentin is especially dependent on the pH of the
environment. For that reason, simple changes in the acidity condi-
tions may lead to different final products and the elucidation of
these differences was the goal of the present study. At low pH a
new ester derivative involving the breaking and forming of cova-
lent bonds was disclosed, and in milder conditions hydrogen bonds
breaking and forming are responsible for the formation of the
known chloride hemihydrate form. A comparison study between
both forms is discussed herein. None of these forms are stable at
high temperatures and structural transformations are detected
by XRPD.
issues in modern solid-state chemistry, materials chemistry and
pharmaceutical science. When these new crystal forms involve ac-
tive pharmaceutical ingredients (API) the potential for new discov-
eries, innovation and market protections, as well as intellectual
property issues, can be of the most importance leading to a tre-
mendous evolution in studies on multicomponent crystal forms
in the last several years [1–19].
Gabapentin is a structural analog of
c-aminobutyric acid
(
GABA) with demonstrated therapeutic use in epilepsy, neuro-
pathic pain, restless legs syndrome, anxiety disorders, hot flashes
and numerous other indications. The drug is currently marketed
as an adjunct therapy for partial seizures in adults with epilepsy
and for management of postherpetic neuralgia [20].
Gabapentin exists as a zwitterion in three anhydrous polymor-
phic forms [21–23]: forms II, III and IV, with II being the most
stable and IV the least stable. Furthermore, two monohydrate
[
24–26], two polymorphic chloride hemihydrate [27,28] and a
hemisulfate hemihydrate (isomorphous of a gabapentin hydro-
chloride hemihydrate form [27]) forms [29] have also been re-
ported. Coordination complexes of this API with Cu and Zn [30]
as well as multicomponent crystal forms (cocrystals and salts)
involving gabapentin with different carboxylic acids were recently
disclosed [23,31–33].
2
. Results and discussion
Following our expectations, gabapentin is pH-sensitive, forming
*
Corresponding author. Tel.: +351 218419282.
E-mail address: teresa.duarte@ist.utl.pt (M.T. Duarte).
both conventional covalent bonds, which gave rise to the ethyl es-
0
022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.03.067

1
74
V. André et al. / Journal of Molecular Structure 973 (2010) 173–179
ter and undergoing supramolecular bonding, forming the chloride
hemihydrate, in our experimental conditions (Scheme 1). An amor-
phous product is obtained whenever basic conditions are
employed.
Not unexpectedly, the ester, 1, is only obtained at low pH (pH
2
), concomitantly with the chloride hemihydrate, 2. The powder
diffraction pattern of the bulk mixture of 1 and 2 (Fig. 1) reveals
that the chloride hemihydrate is present in a higher proportion
than the ester. Under the experimental conditions, gabapentin is
expected to undergo Fischer esterification (Scheme 2) with a low
yield, consistent with this acid-catalyzed equilibrium reaction.
All the other acidic experimental conditions led to the forma-
tion of pure crystalline 2 (pH 3 and 3.5) (Fig. 2), avoiding all the
covalent bond breaking and forming. At even milder pH (pH 5–
7
), different polymorphic forms of gabapentin (Fig. 3) were isolated
depending on the cooling rate of the solutions: the slowest cooling
rate always yielded form III while faster coolings constantly re-
sulted in form II. Both proved to be stable for at least 1 month in
laboratory conditions. At higher pH values, only amorphous prod-
uct was obtained.
The molecular and crystal structures of both 1 and 2 will next
be discussed and compared here, as they were both obtained con-
comitantly. We have also performed thermal studies on this mix-
ture and they will be illustrated and discussed.
10
20
2- θ (º)
30
Fig. 1. Theoretical powder diffraction patterns obtained from single-crystal data of
(top) and 2 (bottom), at 150 K, are represented for identification of the phases.
1
Experimental powder diffraction pattern (middle) obtained from the bulk, corre-
sponding to the mixture of gabapentin ethyl ester (1) and gabapentin chloride
hemi-hydrate (2) at room temperature. The main peaks that allow the identification
of 1 in the bulk are highlighted in grey.
2
.1. Molecular and crystal structures
This section presents a detailed analysis of the molecular and
crystal structure of the ester derivative from gabapentin (see
Fig. 4), followed by a comparative description of the chloride hemi-
hydrate form obtained concomitantly and a general discussion on
conformation details. The most recent disclosed polymorph of
the chloride hemihydrates is not discussed herein as its presence
is not detected in any of our samples. Detailed geometric parame-
ters of the hydrogen bonds are given in Table 1.
The location in the electron density map and the perfect refine-
ment of three hydrogen atoms around the N atoms in the crystal
structure of 1 demonstrated that the ester derivative is protonated
ꢀ
in the amine moiety and Cl acts as a counterion. The C–O dis-
tances in the ester moiety (1.343 Å and 1.203 Å) clearly indicate
the existence of single and double bonds.
At the supramolecular level, all the hydrogen bonds established
in this structure involve the Cl anions and there are no direct inter-
actions between the ester ammonium cations. In a view along b,
Scheme 2. Generic mechanism of the Fischer esterification.
the gabapentin ester aligns in two anti-parallel chains connected
ꢀ
through the anion by two hydrogen bonds: N
1
–H02ꢁ ꢁ ꢁCl and N
1
–
the ammonium group are aligned along the faces of this cube
(Fig. 5b). This motif is repeated along a and b, giving rise to a
cage-like 3-dimensional array. We should stress that this crystal
packing does not involve any oxygen atom, thus deactivating the
acceptor ability of both the carbonyl and the ether functions, pre-
sumably due to steric constraints.
ꢀ
H
03ꢁ ꢁ ꢁCl , the molecules being equally oriented (Fig. 5a). The
ꢀ
remaining N
1
–H01ꢁ ꢁ ꢁCl bonding is used to connect this 2D pattern
with similar ones in parallel planes along b, thus forming a layered
structure of ester cations along a.
Also worth noticing is the pattern observed along c, in which
the supramolecular assemblies form a 3-dimensional channel
bearing the N and the Cl ions in the vertices. The hydrogens of
Similarly to what is observed in 1, in 2 gabapentin is also pro-
tonated in the amine moiety. This was ascertained both by the
-
OH
Cl
OH
NH3+
-
Cl
O
O
H
H
.1/2
O
NH2
NH3+
O
O
a
b
c
Scheme 1. Structure of (a) gabapentin, (b) gabapentin ethyl ester chloride, 1 (c) gabapentin chloride hemihydrate, 2.

V. André et al. / Journal of Molecular Structure 973 (2010) 173–179
175
Fig. 4. Molecular diagram of 1, determined at 150 K. Ellipsoids are set at 50%
probability and calculated hydrogen atoms were omitted for clarity. Colour code:
yellow – carbon; green – nitrogen; red – oxygen; magenta – chlorine; light pink –
hydrogens. (For interpretation of the references to colour in this figure legend, the
reader is referred to the web version of this article.)
Table 1
List of hydrogen bonds for 1 and 2.
Structure Sym. Op. D–Hꢁ ꢁ ꢁA
d(D–
H) (Å)
d(Hꢁ ꢁ ꢁA) d(Dꢁ ꢁ ꢁA) (D Hˆ A)
(Å) (Å) (deg)
1
0
20
2
30
40
1
2
/2ꢀx, 3/
ꢀy, z
N
1
H
01ꢁ ꢁ ꢁCl
0.85(3) 2.41(3)
3.243(3) 166(2)
-theta
1
2
x, y, z
N
N
1
H
H
02ꢁ ꢁ ꢁCl
03ꢁ ꢁ ꢁCl
0.93(3) 2.22(3)
0.92(3) 2.24(3)
3.156(3) 177(2)
3.151(3) 168(2)
Fig. 2. Experimental powder diffraction pattern (bottom) obtained from the
synthesis at pH 3.5 and theoretical powder diffraction patterns obtained from
single-crystal data of 2 (top), at 150 K.
1
1
/2ꢀx, y,
1
/2 + z
x, y, z
x, y, z
1ꢀx,
N
1
N
1
N
1
H
H
H
1
ꢁ ꢁ ꢁO3
2
ꢁ ꢁ ꢁOl
2
ꢁ ꢁ ꢁOl
0.90(2) 2.03(2)
0.88(2) 2.05(2)
0.88(2) 2.53(2)
2.915(2) 171(2)
2.760(2) 137(2)
2.883(2) 104(2)
1
ꢀy, ꢀz
x, y, z
N
1
H
3
ꢁ ꢁ ꢁCl
0.87(3) 2.37(2)
0.87(2) 2.14(3)
3.231(2) 171(2)
3.008(2) 177(2)
1
ꢀx,
O
2
H
8
ꢁ ꢁ ꢁC1
1
ꢀy,ꢀz
x, ꢀ1 + y,
O
3
H19ꢁ ꢁ ꢁC1 0.79(2) 2.42(2)
3.183(1) 163(2)
z
The water molecules act as spacers along c connecting the di-
meric motifs, thus obtaining two chains of cations. In these chains
the cyclohexane rings of consecutive gabapentin cations are ro-
tated by 46.9(4)° (Fig. 6b). The chlorine anions besides supporting
+
ꢀ
the dimers using N –Hꢁ ꢁ ꢁCl charge-assisted hydrogen bonds also
play a part when obtaining the anti-parallel chains as they act as
acceptors for the water and the hydroxyl function of the carboxylic
moiety. The role of water is very important in the 3D array ob-
tained as they interact directly with two gabapentin cations related
+
by an inversion centre, acting as hydrogen acceptors (N Hꢁ ꢁ ꢁO). Its
role is further reinforced as they also work as donors for the chlo-
rine anions.
The crystal structure of 1 is distinct from any of the reported
gabapentin forms: both the synthons formed and the type of inter-
actions is different, as the packing of 1 is dominated by charged-as-
+
ꢀ
5
10
15
20
25
30
35
sisted N –Hꢁ ꢁ ꢁCl hydrogen bonds.
2
-theta / deg
In 2, the presence of the intramolecular hydrogen bond and the
2
2
formation of the R ð4Þ synthon resemble what is observed in poly-
Fig. 3. Experimental powder diffraction patterns obtained from the synthesis at pH
–7 and theoretical powder diffraction patterns obtained from single-crystal data of
gabapentin forms II and III, at 150 K.
morphic form IV of gabapentin, the only polymorph that shows an
intramolecular interaction. The charged-assisted N–Hꢁ ꢁ ꢁO interac-
tions present in 2 are also the only type of interactions observed
in the three polymorphic forms of gabapentin.
5
location of the hydrogen atoms in the amine and carboxylic moie-
ties and by the C–O distances (1.325 Å and 1.210 Å). In the gaba-
Gabapentin shows a clear predisposition to form chains not
only in both forms detailed above but also in the three known
polymorphic forms [QIMKIG01, QIMKIG02 and QIMKIG03] [21–
23] (Fig. 7).
+
pentin cations, an intramolecular hydrogen-bond (N –Hꢁ ꢁ ꢁO) is
established between the ammonium and the carboxylic moieties
(
Fig. 6a).
The three known polymorphic forms of gabapentin are confor-
mational polymorphs. Trying to rationalize the conformation of the
structures presented here we compared their solid-state conforma-
tion with the above mentioned polymorphic forms. For this com-
parison, the conformation and substituent positioning are
defined relatively to the cyclohexane backbone.
In 2, gabapentin cations interact directly with each other
through N–Hꢁ ꢁ ꢁO hydrogen bonds thus forming a dimer based in
2
2
R ð4Þ synthon, also involving the intramolecular bond. These di-
mers are reinforced by intermolecular interactions with the chlo-
rine anions (Fig. 6a).

1
76
V. André et al. / Journal of Molecular Structure 973 (2010) 173–179
Fig. 5. Intermolecular interactions in the gabapentin ethyl ester structure (a) view along b of the anti-parallel chains connected through the Cl anions; (b) detailed view of the
supramolecular channel motif; (c) cage-like array seen along c.
In both 1 and 2 the ring adopts a chair conformation (mean
h = 4.7(2)°) [35], in resemblance with what is observed in the
known polymorphic forms of gabapentin. In the new crystal forms
reported herein, the aminomethyl group is in an equatorial
position, and the carboxethyl group in the axial position. This rel-
ative positioning of the substituent groups is similar to the one ob-
served in gabapentin form IV; in the other two polymorphic forms
the relative positions are reversed (see Fig. 8).
The thermogram of the mixture 1 and 2 (Fig. 9) showed two
consecutive endothermic peaks, the first at approximately 110 °C
and the second around 126 °C. Comparing with the thermogram
obtained with the pure hemihydrate form, the peak at higher tem-
perature corresponds to the melting of the latter; the lower tem-
perature peak is due to melting of the new ester form.
The smaller contribution from the ester observed in the thermo-
gram is a consequence of its low percentage in the bulk material, as
already mentioned.
The irregular baseline in the DSC plot led us to perform powder
diffraction studies for the bulk mixture of 1 and 2 at different tem-
peratures (Fig. 10). This study reveals some structural changes at
3
. Thermal studies
In an attempt to further characterize the concomitantly crystal-
6
0 °C and major changes at 100 °C. Changes were investigated,
lized 1 and 2, thermal studies were performed and are discussed
here.
but no conclusions were reached about which new structure(s)
2
2
Fig. 6. (a) Dimeric motif showing the R ð4Þ synthon, using intra and intermolecular hydrogen bonds, represented in blue, and reinforced by interactions with the anions; (b)
chains of gabapentin cations held together by chloride anions and water molecules, the O atom residing on an inversion centre. (For interpretation of the references to colour
in this figure legend, the reader is referred to the web version of this article.)

V. André et al. / Journal of Molecular Structure 973 (2010) 173–179
177
Fig. 7. Chain motifs of gabapentin forms: (a) II, (b) III and (c) IV.
4.1.1. Crystallization of gabapentin at pH 2
A solution of gabapentin form II (0.1436 g, 0.839 mmol) in a
blend of ethanol (4 mL) and water (0.1 mL) was heated at boiling
temperature for 5 min. The final pH of this solution was about 7
and a few drops of HCl 37% were added until the solution reached
pH2.
The solution was left to crystallize at room temperature, by
slow evaporation of the solvents. After 4 days, two different
types of colourless crystals could be identified under the micro-
scope: thick needles (gabapentin ethyl ester [ethyl (1-(amino-
methyl)cyclohexyl)acetate], 1) and plate-like (gabapentin
chloride hemihydrate, 2). Both these forms grew concomitantly
in the bulk, as proven by XRPD.
Fig. 8. Molecular structures of 1 (magenta), 2 (black) and gabapentin polymorphic
forms II (blue), III (orange) and IV (green). (For interpretation of the references to
colour in this figure legend, the reader is referred to the web version of this article.)
4
.1.2. Crystallization of gabapentin at pH 3 and 3.5
Two solutions of gabapentin form II (0.5854 g, 3.419 mmol and
.5855 g, 3.419 mmol) in a blend of ethanol (3 mL) and water
1
1
0
0
.5
.0
.5
.0
0
(2 mL) were prepared and heated at boiling temperature for
0 min. The pH of these solutions was approximately 7. Drops of
3
HCl 37% were added to both solutions until pH 3 was reached in
one and pH 3.5 in the other. The solutions were left to crystallize
at room temperature, by slow evaporation of the solvents. After
1
day, crystals of gabapentin chloride hemihydrate, 2, formed in
50
75
100
125
150
both preparations.
Temperature (°C)
Fig. 9. Thermogram obtained from the mixture of 1 and 2 (bottom), at a heating
rate of 5 °C/min, in closed aluminium capsule, with sample of 7.6 mg.
global = 101.315 J/g) compared with a thermogram of pure 2 (top) obtained in
similar conditions ( global = 98.758 J/g).
4.1.3. Crystallization of gabapentin at pH 5–7
a
a
Several crystallizations of gabapentin were performed in the pH
range from 5 to 7, using water and ethanol as solvents and condi-
tions similar to those described in the other experiments reported
herein. These experiments always yielded gabapentin polymorphic
form II. Within this pH range, and maintaining similar experimen-
tal conditions but cooling the solution more slowly by using man-
ual cooling steps of 0.5 °C/min in the hot-plate, form III could also
be isolated.
(DH
D
H
was(were) being formed. These transformations are not immedi-
ately reversible, as the diffractogram collected after cooling to
room temperature is similar to the diffractogram collected at
1
00 °C. Nonetheless, we observed that the form produced at high
temperature is not stable and is converted into 2 after a few
months on the shelf.
One hypothesis for the explanation of the appearance of this
new form would be the transformation of both 1 and 2 into gaba-
pentin–lactam [23], but this was discarded by comparing the
experimental diffractogram obtained after heating and the theoret-
ical diffractogram of the known form of the lactam [refcode AWU-
WOE] [27] (Fig. 10).
4.1.4. Crystallization of gabapentin at pH 9
Gabapentin form II (0.3670 g, 2.1430 mmol) was dissolved in
2.5 mL of ethanol and heated at boiling temperature for 30 min.
After heating, the solution was filtered for removal of the undis-
solved material. The pH of this solution was 7 and a few drops of
NaOH solution (0.5 M) were added until pH 9 was reached. The
solution was left to crystallize at room temperature, by slow evap-
oration of the solvents. After 2 days an amorphous material was
observed.
4
. Experimental
4.1. Synthesis
4.2. Crystal structure determination
All reagents were acquired from Sigma and used as received. pH
measurements were performed using a pH electrode Hanna HI
025. All the solid products were analysed by XRPD.
Single-crystal X-ray structures were determined for 1 and 2.
Both crystal structures were determined at 150 K on a Bruker
AXS-KAPPA APEX II diffractometer with graphite-monochromated
9

1
78
V. André et al. / Journal of Molecular Structure 973 (2010) 173–179
Due to the
sample holder
2
0°C heating
6
1
0°C heating
00°C heating
5
10
15
20
25
30
35
2
-theta / deg
2
0°C cooling
5
10
15
20
25
30
35
2
- θ (º)
Fig. 10. Powder diffraction patterns obtained from a mixture of a 1 and 2, at different temperatures (right) and comparison of the final product obtained after heating (top
left) with gabapentin–lactam (middle left) and the transformation into 2 after a few months on the shelf (bottom left).
radiation (Mo K
a
, k = 0.71069 Å). The X-ray generator was oper-
chromator, operating at 40 kV and 30 mA. Data were acquired in
the range 5° < 2h < 38°, using a 0.016 step size and 1.5 s/step.
The program PowderCell 2.4 [41] was used for calculation of the
X-ray powder patterns. The correspondence between the bulk
material and the structures obtained by single crystals was verified
by comparing calculated and observed powder diffraction patterns.
ated at 50 kV and 30 mA. All data were corrected for Lorentzian,
polarization and absorption effects using SAINT [36] and SADABS
[
37] programs. SIR97 [38] was used for structure solution and
SHELXL-97 [39] was used for full matrix least-squares refinement
2
on F . All non-hydrogen atoms were refined anisotropically. HNH
atoms were located from a difference Fourier map and their posi-
tional coordinates and isotropical parameters were refined. HCH
atoms were added in calculated positions and refined riding on
their C atoms. MERCURY 2.2 [40] was used for packing diagrams.
Table 2 summarizes the crystallographic data for 1 and 2.
4.4. X-ray powder diffraction analysis at different temperatures
In order to check for structural changes of the bulk mixture of 1
and 2 with temperature, powder diffraction patterns were ac-
quired at different temperatures.
The data were collected in a RIGAKU D300 diffractometer, with
copper radiation and a secondary monochromator, operating at
4
.3. X-ray powder diffraction analysis at room temperature
4
0
0 kV and 30 mA. Data were collected from 2h 5 to 38°, using a
.02 step size and 1 s/step. Different diffractograms were collected
Powder data were collected in a D8 Advance Bruker AXS hꢀ2h
at 20 °C, 60 °C and 100 °C. After the samples returned to room tem-
perature, new diffractograms at 20 °C were collected to evaluate
the reversibility of the transformations occurred.
diffractometer, with a copper radiation and a secondary mono-
Table 2
Summary of crystallographic data for crystal structures 1 and 2.
4.5. DSC measurements
1
2
The thermal behavior of the mixture of 1 and 2 obtained was
Chemical formula
C
11
H
22NO
2
C1
C
18 38 2 5 2
H N O C1
M
r
235.75
150(2)
0.71069
Thick needle,
colourless
0 18 ꢂ 0.10 ꢂ 0.04
Orthorhombic
Pccn
14.632(2)
23.460(3)
7.460(4)
90
2560.8(15)
8
433.4
150(2)
0.71069
Plate, colourless
investigated by measuring the enthalpy change on a Setaram
DSC121 calorimeter. Crystals (7.6 mg) were placed on a closed alu-
minium pan and were analysed from 40 to 200 °C, using an empty
pan as the reference. The heating rate was 5 °C/min and argon gas
was used for purging.
Temperature (K)
Wavelength (Å)
Morphology, colour
Crystal size (mm)
Crystal system
Space group
a (Å)
b (Å)
c (Å)
0.20 ꢂ 0.14 ꢂ 0.02
Monoclinic
C2/c
27.746(7)
6.540(1)
13.173(3)
111.766(1)
2219.9(8)
4
5
. Conclusions
Gabapentin is very sensitive to pH variations in solution, which
b (deg)
V (Å )
Z
may lead to the breaking and forming of either covalent or hydro-
gen bonds allowing the discovery of new crystal forms of this API.
The esterification presented herein induced a dramatic change
in the solid-state characteristics of the gabapentin scaffold, block-
ing the supramolecular interactions associated with the carboxylic
acid moiety, to such an extent that the carboxyethyl group was
even inactive as a hydrogen bond acceptor. The typical charge-as-
sisted N–Hꢁ ꢁ ꢁO hydrogen-bonds observed in the forms of gabapen-
tin are totally replaced by N–Hꢁ ꢁ ꢁCl interactions in the ethyl ether
disclosed herein, once the functional groups have changed and the
formation of the salt is preferred. This alteration resulted in a less
compact packing that could have an effect upon the rate of disso-
3
Calculated density (mg mꢀ3)
1.223
0.282
1.297
0.322
Absorption coefficient
ꢀ
1
(
mm )
h min (deg)
h max (deg)
Reflections collected/unique
2.73
25.34
15,233/2341
0.0962
0.85
3.21
26.44
13,674/2263
0.0634
1.08
>2r(I)
0.0329
0.045
R
int
GoF
Threshold expression
>2r
(I)
R
1
(obsd)
0.0373
0.0744
wR (all)
2

V. André et al. / Journal of Molecular Structure 973 (2010) 173–179
179
lution and membrane permeability of the drug under physiological
conditions. Given the significance of kinetic solubility in drug
absorption phenomena [42], our results substantiate the search
for ester prodrugs of gabapentin as a means of achieving improved
bioavailability.
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[
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