PREPARATION DE GABAPENTINE

PREPARATION OF GABAPENTIN

Abrégé français

L'invention concerne un procédé permettant de convertir du chlorhydrate de gabapentine essentiellement exempt de sels inorganiques en gabapentine de forme (II). Ce procédé comprend les étapes consistant; 1) à obtenir du chlorhydrate de gabapentine essentiellement exempt de sels inorganiques; 2) à mélanger une solution dudit chlorhydrate de gabapentine avec un amine supplémentaire dans un premier solvant, afin d'obtenir un précipité renfermant de la gabapentine; puis 3) à récupérer la gabapentine de forme II à partir dudit précipité. La gabapentine précipitée constitue une nouvelle forme polymorphe de gabapentine, qui possède une structure cristalline caractérisée par de nouvelles crêtes dans le diagramme de diffraction des rayons X de la poudre et dans le spectre infrarouge à transformée de Fourier. Cette nouvelle forme de gabapentine est ici désignée par la gabapentine de forme III. L'étape de récupération peut par exemple comprendre un ou deux autres procédés, qui consistent à mettre en suspension la gabapentine de forme II dans du méthanol, puis à filtrer cette suspension pour obtenir de la gabapentine de forme II, ou à rendre la gabapentine de forme III soluble dans le méthanol en la faisant bouillir à reflux avant de la faire refroidir pour obtenir la gabapentine de forme II par cristallisation.

Abrégé anglais

There is disclosed a method of converting gabapenting hydrochloride
substantially free of inorganic salts to gabapenting form II. The method
comprises the steps of: (1) obtaining gabapentin hydrochloride that is
substantially free of inorganic salts; (2) mixing a solution of the
gabapenting hydrochloride with an additional amine in a first solvent so as to
obtain a precipitate comprising gabapenting; and then (3) recovering
gabapentin form II from the precipitate. The precipitated gabapentin is a
novel polymorphic form of gabapentin possessing a crystalline structure
characterized by novel sets of peaks in the powder X-ray diffraction pattern
and in the FTIR spectra. This newly disclosed polymorph of gabapentin is
characterized herein as gabapentin form III. The recovery step may comprise,
for example, one of two alternative methods, slurrying the gabapentin form II
in methanol, and then filtering the suspension to obtain gabapentin form II,
or solubilizing the gabapentin form III in methanol with heating by reflux,
and then cooling the solution to obtain gabapentin form II by crystallization.

Revendications

What Is Claimed Is:
1. A method of converting gabapentin hydrochloride to
gabapentin form II comprising:
(1) dissolving gabapentin hydrochloride in a first
solvent in which gabapentin is relatively insoluble; and
(2) adding an additional amine to the gabapentin
hydrochloride solution so as to obtain a precipitate
comprising gabapentin.
2. The method of claim 1, further comprising the step of
recovering gabapentin form II from said precipitate.
3. The method of claim 2, the recovering step comprising
slurrying or crystallizing said precipitate in methanol.
4. The method of claim 3, wherein said first solvent is
selected from the group consisting of ethyl acetate,
dimethylcarbonate, ethanol, butanol, t-butanol, n-butanol,
methanol, acetonitrile, toluene, isopropylacetate,
isopropanol, methylethylketone, acetone,
ethyleneglycolmonomethylether, methylene chloride, chloroform,
benzylalcohol or dimethylacetamide.
5. The method of claim 1 wherein said additional amine is
selected from the group consisting of triethylamine,
tributylamine, tripropylamine, trihexylamine, diethylamine,
ethanolamine and benzylamine.
6. The method of claim 5 wherein said additional amine is
tributylamine.
7. The method of claim 1 wherein said first solvent is
selected from the group consisting of ethyl acetate,
dimethylcarbonate, ethanol, butanol, t-butanol, n-butanol,
methanol, acetonitrile, toluene, isopropylacetate,
13

isopropanol, methylethylketone, acetone,
ethyleneglycolmonomethylether, methylene chloride, chloroform,
benzylalcohol or dimethylacetamide.
8. The method of claim 7 wherein said first solvent is
ethylacetate.
9. The method of claim 1 wherein said first solvent is one in
which the hydrochloride salt of said additional amine is
soluble.
10. The method of claim 1 further comprising pre-treating
said gabapentin hydrochloride to remove inorganic salts, which
pre-treatment comprises (a) dissolving gabapentin
hydrochloride in a second solvent in which inorganic salts are
insoluble, (b) filtering off the inorganic salts, and (c)
recovering gabapentin hydrochloride from said second solvent.
11. The method of claim 10 wherein said second solvent is
selected from the group consisting of methanol, ethanol,
n-propanol, isopropanol, butanol, t-butanol, n-butanol,
ethyleneglycolmonomethylether, benzylalcohol or
dimethylacetamide.
12. The method of claim 11 wherein said second solvent is
isopropanol.
13. The method of claim 1 or 10 wherein the precipitated
gabapentin comprises gabapentin form III.
14. The method of claim 20 wherein the precipitated
gabapentin comprises gabapentin form III, said second solvent
is isopropanol, said first solvent is ethylacetate, and said
additional amine is tributylamine.
19

15. The method of claim 14 wherein said precipitated
gabapentin is slurried or crystallized from methanol to yield
gabapentin form II.
16. Crystalline gabapentin form III characterized by powder
X-ray diffraction peaks at 6.11~0.2, 12.22~0.2, 17.00~0.2,
17.63~0.2, 18.20~0.2, 19.94~0.2, 20.81~0.2, 24.54~0.2,
25.11~0.2, 28.91~0.2, 30.20~0.2, 30.78~0.2, and 32.46~0.2
degrees 2-theta.
17. Crystalline gabapentin form III characterized by powder
X-ray diffraction peaks at 6.11~0.2, 12.22~0.2, 17.00~0.2,
17.63~0.2, 18.20~0.2, 19.94~0.2, 20.81~0.2, 24.54~0.2,
25.11~0.2, 28.91~0.2, 30.20~0.2, 30.78~0.2, and 31.46~0.2
degrees 2-theta, wherein the size of the peaks is in the order
6.11 degrees > 12.22 and 24.54 > 17.00, 17.63, 18.20, 19.94,
20.81, 25.11, 28.91, 30.20, 30.78, and 31.46.
18. Crystalline gabapentin form III characterized by
infra-red absorptions having peaks at 708, 760, 885, 926, 979,
1160, 1180, 1290, 1420, 1460, 1510, 1586, and 1664 cm-1.
19. Crystalline gabapentin form III produceable by a process
comprising the steps of:
(a) dissolving gabapentin hydrochloride in a solvent
selected from the group consisting of ethyl acetate,
dimethylcarbonate, ethanol, butanol, t-butanol, n-butanol,
methanol, acetonitrile, toluene, isopropylacetate,
isopropanol, methylethylketone, acetone,
ethyleneglycolmonomethylether, methylene chloride, chloroform,
benzylalcohol or dimethylacetamide;
(b) adding an additional amine selected from the group
consisting of triethylamine, tributylamine, tripropylamine,
trihexylamine, diethylamine, ethanolamine and benzylamine; and
(c) drying the precipitated gabapentin.
15

Description

CA 02275912 1999-06-21
WO 98128255 - PCT/ITS97123164
PREPARATION OF GABAPENTIN
S FIEZD OF THE INVENTION
This invention relates to a new process for converting
gabapentin hydrochloride salt to gabapentin via a novel
polymorphic form of gabapentin.
BACKGROUND OF THE INVENTION
Gabapentin is 1-(aminomethyl)-1-cyclohexaneacetic acid, having
the chemical structure:
H2NCH2 CH2COOH
Gabapentin is used in the treatment of cerebral diseases such
as epilepsy. The literature describes many ways of preparing
gabapentin from a variety of starting materials. U.S. Patent
4,024,175 describes at least three methods of preparing
gabapentin from cyclohexyl-1,1-diacetic acid. Each of these
methods results in the formation of gabapentin hydrochloride
salt, which may be converted to 1-(aminomethyl)-1-
cyclohexaneacetic acid by treatment with a basic ion exchanger
and then crystallized from a solvent such as ethanol/ether.
U.S. Patent 4,894,476 specifically discloses an improved
method for converting the hydrochloride salt into the free
amino acid. This involves pouring a deionized water solution
of the salt over an ion exchange column, eluting with
deionized water, producing a slurry from the eluate, adding an

CA 02275912 1999-06-21
WO 98128255 - PCT/US97/23164
alcohol to the slurry, centrifuging and drying the slurry to
obtain the free amino acid.
Alternative methods for preparing gabapentin have been
described that do not proceed via the hydrochloride or any
other mineral acid salt. Such methods include those described
in U.S. Patent Nos. 5,132,451, 5,095,148, 5,068,413. Each of
these methods involve a cyanic intermediate which is
hydrogenated under severe conditions to produce the free amino
acid.
These methods are industrially impractical. Those methods
comprising ion exchange columns require the use of large
amounts of ion exchanger for lengthy periods of time to lower
the level of chloride ions to the desired level. The
alternative methods involve further more demanding steps.
Commercially available gabapentin is crystalline and exhibits
an X-ray diffraction pattern with peaks of 2-theta values at
7.8, 13.3, 15.0, 17.0, 20.4, 21.3, 23.1, 23.6, 25.7, 27.0 and
28.2 degrees. Hereinafter, the commercially available
polymorphic form of gabapentin is referred to as polymorph
form "II".
2 5 SUI~iARY OF THE INVENTION
The present invention relates to an improved method for
purifying gabapentin comprising converting gabapentin
hydrochloride salt to gabapentin form II. The present
invention avoids the disadvantages associated with prior art
methods, by adding alternative steps and by proceeding via a
novel polymorphic form of gabapentin.
Accordingly, the present invention relates to a method of
converting gabapentin hydrochloride salt to gabapentin form
II, comprising reacting a solution of gabapentin hydrochloride
2

CA 02275912 1999-06-21
WO 98/28255 - PG"T/L1S97/23164
with an additional amine in a first solvent to produce a novel
polymorphic form as a precipitate, thereafter, converting the
novel polymorphic form to form II by forming a suspension
and/or a solution of the precipitate in methanol, and then
recovering gabapentin form II.
The present invention further relates to a novel polymorphic
form of gabapentin designated as gabapentin form III. The
polymorph may be identified by its unique X-ray diffraction
pattern.
A further aspect of the present invention relates to the novel
polymorphic form of gabapentin that is of use as an
intermediate in the preparation of polymorphic form II.
Further objectives and advantages of the subject invention
will be apparent to those skilled in the art from the detailed
description of the disclosed invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an x-ray diffraction pattern of a sample of
gabapentin hydrate.
Fig. 2 is an x-ray diffraction pattern of gabapentin form II.
Figs. 3a and 3b are x-ray diffraction pattern of gabapentin
form III, possibly containing small amounts of gabapentin form
II and/or gabapentin hydrate.
3o Fig. 4 is an FTIR (Fourier Transform Infra Reds spectrum of
gabapentin hydrate.
. Fig. 5 is an FTIR spectrum of gabapentin form II.
Fig. 6 is an FTIR spectrum of gabapentin form III, possibly
3

CA 02275912 1999-06-21
WO 98128255 - PCT/(1S97/23164
containing small amounts of gabapentin form II and/or
gabapentin hydrate.
DETAILED DESCRIPTION OF THE PREFERRED EI~ODIMENTS
The subject invention will now be described in detail for
specific preferred embodiments of the invention, it being
understood that these embodiments are intended only as
illustrative examples and the invention is not to be limited
thereto.
The method of the present invention comprises:
(1) obtaining gabapentin hydrochloride that is
substantially free of inorganic salts;
(2) mixing a solution of the gabapentin hydrochloride
with an additional amine in a first solvent so as to
obtain a precipitate comprising gabapentin; and then
(3) recovering gabapentin form II from the precipitate.
Preferably, the gabapentin hydrochloride used as a starting
material in the process of the present invention is
substantially free of other inorganic salts such as sodium
chloride and sodium bromide, that is, such impurities are only
present in trace amounts. Alternatively, gabapentin
hydrochloride containing inorganic salts may be used subject
to the addition of a further step for removing the inorganic
salts prior to mixing gabapentin hydrochloride with the
additional amine.
Thus, gabapentin hydrochloride containing inorganic salts may
optionally be pre-treated to remove the inorganic salts by the
steps of (a) dissolution in a solvent in which gabapentin
hydrochloride is soluble, but the inorganic salts are not; (b)
filtration of the inorganic salts and, optionally, (c)
evaporating the solvent to recover gabapentin hydrochloride
substantially free of inorganic salts. Appropriate solvents
4

CA 02275912 1999-06-21
WO 98128255 - PCTIUS97123164
for the optional pre-treatment step include those selected
from the group consisting of methanol, ethanol, n-propanol,
isopropanol, butanol, t-butanol, n-butanol,
ethyleneglycolmonomethylether, benzylalcohol or
dimethylacetamide. Preferably the pre-treatment solvent is
identical to the first solvent. This pre-treatment solvent,
which is identified in Table 1 and in the claims as the
"second solvent", would be used prior to using the "first
solvent", if, in fact, this optional pre-treament step is
included in the process.
The second step of the present invention comprises mixing a
solution of the gabapentin hydrochloride in a solvent that
contains an additional amine. The solvent may be any solvent
in which the hydrochloride salt of the additional amine is
soluble but in which gabapentin form III is insoluble, such
that a precipitate of gabapentin form III is formed. Such
solvents are preferably selected from the group consisting of
ethyl acetate, dimethylcarbonate, ethanol, butanol, t-butanol,
n-butanol, methanol, acetonitrile, toluene, isopropylacetate,
isopropanol, methylethylketone, acetone,
ethyleneglycolmonomethylether, methylene chloride, chloroform,
benzylalcohol or dimethylacetamide. The precipitated
gabapentin, which may be separated by filtration, is
characterized herein as a novel polymorphic form of
gabapentin, possessing a crystalline structure characterized
by peaks in the powder X ray diffraction pattern with 2-theta
values at 6.12, 12.22, 17.00, 18.20, 19.94, 20.81, 24.54, and
25.11 degrees, all ~0.2 degrees. The x-ray diffraction
pattern in the samples obtained appears to show a preferred
orientation in which the peak at 6.11 degrees is larger than
any other peak in the pattern, and the peaks at 12.22 and
24.59 degrees are larger than any of the remaining peaks in
the pattern. This polymorph is referred to herein as
gabapentin form III.
5

CA 02275912 1999-06-21
WO 98128255 - PCTIITS97/23I64
Two representative embodiments of the third step of the
present invention, recovery of gabapentin form II from the
precipitate, are slurrying and crystallization. Slurrying may
be performed by suspending the precipitated gabapentin in
methanol by mixing, stirring, and/or providing continuous
agitation with some mechanical device so as to induce
transformation into the gabapentin form II that is the
commercially available polymorphic form of gabapentin.
Gabapentin form II may then be filtered off and washed.
Alternatively, the precipitated gabapentin may be crystallized
from methanol with heating by reflux until dissolved, cooling,
optionally seeding with gabapentin, followed by further
cooling, and then collecting and drying the crystals of
gabapentin form II. Second and multiple crops may be obtained
from the concentrated mother liqueurs.
Suitable amines for use in the present invention include
triethylamine, tributylamine, tripropylamine, trihexylamine,
diethylamine, ethanolamine and benzylamine. Preferably the
amine is tributylamine.
The form II gabapentin obtained by the methods of the present
invention may be crystallized using processes known in the
art.
Certain specific representative embodiments of the invention
are described in detail below, the materials, apparatus and
process steps being understood as examples that are intended
to be exemplary and illustrative only. In particular, the
invention is not intended to be limited to the methods,
materials, conditions, process parameters, apparatus and the
like specifically recited herein.
EXAMPhES
6

CA 02275912 1999-06-21
WO 98!28255 - PCT/US97123164
1. Prebaration of aabapentin from abapentin hydrochloride
A. Removal of Inorganic Salts
Gabapentin hydrochloride containing inorganic salts (NaCl,
NaBr), which may be prepared, for example, as shown in U.S.
Pat. No. 4,024,175, Example 4, Variant A, was dissolved in 150
ml isopropanol and mixed at 25°C. Active carbon (0.9 g) was
added and the suspension mixed for a further 2 hours. The
inorganic salts were removed by filtering. The filter cake
was washed twice with 15 ml isopropanol and the washings were
added to the gabapentin hydrochloride solution.
B. Precipitation of Gabapentin Base~Formation of Gabapentin Form III
The gabapentin hydrochloride solution of part A was
concentrated to dryness in vacuum while ensuring that the
temperature of the heating bath did not exceed 35°C. 210 ml
ethylacetate and 16.5 ml tributylamine were added and the
solution was mixed for 2 hours at 25°C. The aabanent-in
precipitate was then separated by filtration, the filter cake
being washed with 20 ml ethylacetate and then 20 ml methanol.
The filter cake contained gabapentin form III which when dried
displayed a characteristic X-ray diffraction pattern with 2-
theta values at 6.1, 12.2, 17.0, 17.7, 18.3, 20.0, 20.8, 24.6
and 25.5 degrees.
C. Alternative Methods for Conversion of Precipitated
Gabapentin to Gabapentin Form II
( 1 ? Slurryinq
The still humid filter cake from step 2 was suspended in
52.5 ml methanol for about 14 hours at 25°C. Solid
gabapentin was then separated from the suspension by
filtration. The filter cake was washed with 20 ml
methanol and then dried under vacuum at 35°C. 10.8 g
crystalline gabapentin form II (yield 720) was obtained.
7

CA 02275912 1999-06-21
WO 98128255 - PCTlUS97/23164
(2) Crystallization
The still humid filter cake from step 2 was suspended in
210 ml of methanol and the suspension was heated to
reflux (65°C). If dissolution was incomplete, additional
methanol was added.
After dissolution, the reactor content was cooled to 34°C
at which temperature crystallization was induced by
seeding with pure Form II gabapentin base (0.1 g).
After maintaining the mixture at 34°C for 60 minutes the
reactor content was cooled to 25°C and methanol was
distilled by vacuum distillation. Approximately 160 ml
of methanol was collected. Then the suspension was
cooled to 0-10°C and maintained at this temperature for 2
hours.
The crystalline gabapentin was separated by filtration
from the suspension. The filter cake was washed with 20
ml methanol and then dried under vacuum at 35°C. 10.8 g
of crystalline gabapentin form II (yield 720) was thus
obtained.
Examples 2-20
The method of Example 1 was followed using the slurrying
technique of step C(1) and employing the amines and solvents
shown in Table 1 below. The percent yields are of purified
product except where marked with an asterisk (*), where the
yield was measured at the stage prior to the slurrying in
methanol.
8

CA 02275912 1999-06-21
WO 98/28255 - PCT/US97/23164
Table 1. Summary of the first solvent, second solvent, amine
and yield of examples 2-20.
Example No. First Solvent Second Solvent Amine Yield()
2 IPA IPA TBA 61.5
' 3 Et Ac IPA TBA 74.0
4 Et Ac IPA THA 66.2
5 Et Ac IPA TPA 63.~
6 Et Ac IPA THA 79.6*
7 IPA Ac IPA TBA 64.9
8 ACN IPA TBA 67.8
9 DMC IPA TBA 57.9
10 DMA DMA TBA 65.7
11 BzOH BzOH TBA 43.0*
12 MEK IPA TBA 88.0*
I3 t-BuOH t-BuOH TBA 79.4*
19 Acetone IPA TBA 73.1*
15 Et Ac BuOH TBA 69.8
16 MeOH MeOH TBA 67.4
17 EGMME EGMME TBA 66.8*
I8 IPA IPA TEA 76.2*
19 IPA IPA BzA 56.0*
20 CHzCl2 DMA DEA 8 9 . 4
IPA isopropanol MEK methyl ethyl ketone
ACN acetonitrile EGMME
ethyleneglycol
monomethylether
BzOH benzyl alcohol TBA tributylamine
MeOH methanol BzA benzylamine
CHZCIZ methylene chloride IPA Ac isopropylacetate
THA trihexylamine DMC dimethylcarbonate
TPA tripropylamine (t)-BuOH
(tert)-butanol
Et Ac ethyl acetate TEA triethylamine
9

CA 02275912 1999-06-21
WO 98/28255 . PCT/US97/23164
DMA dimethylacetamide DEA diethylamine
The gabapentin form III was characterized by comparing the x-
ray diffraction pattern and the FTIR absorption spectra of
gabapentin form III with gabapentin form II and gabapentin
hydrate. The x-ray powder diffraction patterns of Figures 1,
2, and 3a were obtained using a Philips x-ray powder
diffractometer with the following parameters:
Goniometer model 1050/70, Cu-tube, Curved graphite
monochromator.
Sample holder: Quartz monocrystal plate
Settings:
X-Ray tube:
KV-90
mA-28
Target-Cu
Divergence slit-1°
Receiving parallel slit-0.2 mm
Scatter slit-1°
Scintillation detector:
Voltage-832
Lower level-33.8%
Window-39.50
Scan parameters:
Scanning speed: 2°/min
Paper speed: 2cm/min
Gain: 32
Calibration: External calibration with silicon fine
powder
Type of radiation: copper Ka.
Figure 3b was obtained using a Siemens B5100 with a presample
(Kal only)monochromator, step scan, Cu radiation, beam slits
0.3, receiving slit 0.05, standard Siemens rotating sample

CA 02275912 1999-06-21
WO 98128255 - PCT/LTS97123164
holder, start/stop/step angles in degrees were 4.0, 35, and
0.04, with a step duration of 15 seconds. Standard Siemens D-
5000 software was used. The diffractometer was calibrated with
KIST large d-spacing standard. No theta-compensating slits
were employed.
The x-ray spectra of gabapentin hydrate, gabapentin form II
and gabapentin form III are shown in Figs. 1-3, respectively.
The main diffraction peaks that characterize each material are
listed in Table 2.
Table 2. X-ray Diffraction peaks of gabapentin hydrate,
gabapentin form II and gabapentin form III.
Hydrate Form II Form III
2-theta ( ) 2-theta ( ) 2-theta ( )
6.1 7.9 6.11
12.2 13.3 12.22
16.0 15.0 17.00
18.3 17.0 17.63
19.1 19.5 18.20
19.8 20.3 19.94
20.7 21.3 20.81
24.5 21.8 24.54
26.4 23.0 25.11
28.9 23.6 28.91
30.7 25.7 30.20
32.3 26.9 30.78
28.2 31.46
The FTIR spectra for gabapentin hydrate, gabapentin form
II and gabapentin form III are shown in Figs. 4-6,
11

CA 02275912 1999-06-21
WO 98/28255 - PCT/US97/23164
respectively. The FTIR peaks are summarized in Table 3.
Table 3. FTIR peaks of gabapentin hydrate,
gabapentin form II and gabapentin form III.
Form I Form II Form III
cm 1 crn-1 crri 1
648 709 708
726 749 760 -_
880 890 8g5
926 922, 928 926
968 976 974
1154 1165 1160
1175 1180
1292 1300 1290
1420 1420
1476 1460
1510
1542 1596 1586
1624 1615 1664
1662
Morpholoqy of the three forms:
1. The hydrate form typically exists as large crystals with
undefined shapes.
2. Form II typically exists as plate shaped crystals.
3. Form III typically exists as small rhomboidal crystals.
The melting point for gabapentin was not determined since
gabapentin decomposes prior to melting.
12