Indian Patents. 219367:A PROCESS FOR THE PREPARATION OF A NON-HYDRATED FORM II POLYMORPH OF GABAPENTIN AND THE PREPARATION OF THE FORM I POLYMORPH OF GABAPENTIN FROM SAID FORM II POLYMORPH.

Title of Invention	A PROCESS FOR THE PREPARATION OF A NON-HYDRATED FORM II POLYMORPH OF GABAPENTIN AND THE PREPARATION OF THE FORM I POLYMORPH OF GABAPENTIN FROM SAID FORM II POLYMORPH.
Abstract	The non-hydrated gabapentin polymorph is prepared by drying an aqueous solution of gabapentin by spray drying or turbo-drying and it is used for the preparation of pharmaceutical grade gabapentin by subjecting the polymorph to crystallisation from solvents.

Full Text	"A PROCESS FOR THE PREPARATION OF A NON-HYDRATED FORM II POLYMORPH OF GABAPENTIN AND THE PREPARATION OF THE FORM I POLYMORPH OF GABAPENTIN FROM SAID FORM II POLYMORPH DESCRIPTION Field of the invention The present invention relates to a process for the preparation of a non-hydrated Form II polymorph of gabapentin and the preparation of the Form I polymorph of gabapentin from said Form II polymorph. Prior art reference Gabapentin is a synthetic amino acid related to ?-aminobutyric acid (GABA) responding to the chemical name of 1-(aminomethyl) cyclohexane acetic acid (The Merck Index, Ed. XII) and the following formula The said compound has a therapeutical activity for convulsive type cerebral disorders, such as epilepsy, hypokinesia, including fainting, and other brain trauma and, in general, it is deemed to produce an improvement of the cerebral functions. Gabapentin and several processes for the preparation thereof are described in Spanish patent ES-A-443 723, corresponding to US-A-4 024 175, Example 1 of which describes the preparation of the free amino acid from the hydrochloride thereof, by treatment of an aqueous solution thereof with a basic ion exchanger, evaporation of the solvent and subsequent crystallisation from ethanol/ether. The thus obtained product corresponds to a non-hydrated crystalline form coinciding with the one shown by the commercial pharmaceutical Neurontin® which is the pharmaceutical standard for gabapentin. On the other hand, EP-B-0 340 677 and the Spanish part thereof, ES-T3-2 061 774, disclose a new hydrated form of gabapentin characterised by its X-ray diffraction data and the process for the preparation thereof, as well as a process for preparing the non-hydrated crystalline form requiring the prior preparation of the said hydrated form. Said process consists of the following successive steps: a) passinganaqueousgabapentinhydrochloridesolution through a basic ion exchange column. b) concentrating the eluate to form a suspension. c) cooling and adding alcohol to the above suspension. d) cooling and centrifuging the thus prepared suspension. e) drying the product obtained, which is the hydrated form of gabapentin. f) dissolving the above pure hydrated form in methanol. g) diluting and cooling the thus prepared solution until a suspension is obtained. h)centrifuging the suspension and drying the product, which is the non-hydrated form of gabapentin. The above described process is obviously complicated from the, industrial point of view, since it requires several steps and the isolation of an intermediate in pure form, the hydrated form, prior to a final crystallisation. All of this leads to an excessive occupation of the industrial plant and losses in the yield of the desired product. There is, therefore, a need to develop alternative processes for the preparation of non-hydrated pharmaceutical grade gabapentin allowing the industrial preparation of the product to be simplified, with a consequent reduction of the production costs. Summary of the Invention It is an object of the present invention to provide an non-hydrated gabapentin polymorph allowing pharmaceutical grade gabapentin to be prepared in an industrially improved way over the prior art. It is also an object of the invention to provide a process for the preparation of said polymorph and a process for the preparation of pharmaceutical grade gabapentin from said polymorph. Brief Description of the Drawings Figure 1 is an IR spectrum of the non-hydrated gabapentin polymorph of the invention, using KBr tablet. Figure 2 is an X-ray diffraction diagram of said polymorph, with a diffraction angle coverage ranging from 4° to 50° in 0.02° steps. Detailed Description The present inventors have discovered that by drying an aqueous solution of gabapentin using spray-drying or turbo-drying techniques, a new non-hydrated gabapentin polymorph is obtained and which has been named Form II by the inventors. The IR spectrum, on KBr tablet, is shown in Figure 1 and the X-ray diffraction diagram with a diffraction angle coverage ranging from 4° to 50° in 0.02° steps is shown in Figure 2. Table 1 gives numerically the spacing "d" in A and the relative intensity I (%) of the said X-ray diffraction diagram, for the peaks having a relative intensity equal or superior to 5. In turn, for comparative purposes, the X-ray diffraction diagram corresponding to the pharmaceutical grade gabapentin standard, which the present inventors have named Form 1, obtained under the same conditions, gives the results listed in Table 2. Having regard to the IR spectrum, the most significant bands of the new Form II polymorph, in comparison with the Form I polymorph, may be said to be those occurring at 1576, 1522, 985 and 637 cm-1. The present inventors have also found that when the new Form II polymorph is crystallised out of conventional solvents, there is surprisingly obtained pharmaceutical grade non-hydrated gabapentin, i.e. the Form I polymorph is obtained with a high degree of purity and a high yield. Thus, pharmaceutical grade Form gabapentin may be obtained on an industrial scale without it being necessary previously to prepare a pure hydrated form thereof, by a process, also an object of the invention, consisting essentially of crystallising the non-hydrated gabapentin Form II polymorph in a conventional solvent or mixture of solvents. The aqueous gabapentin starting solution for preparing the Form II polymorph may be prepared by the method described in any of the aforementioned documents ES-A-443 723 and EP-B-0 340 677. The concentration of the solution may range from 2% to 11% by weight, although concentrations ranging from 5% to 7% by weight are to be preferred. The gabapentin solution is not dried by conventional evaporation of the solvent, but by spray-drying or turbo-drying techniques, in equipment well known to the man of the art. The air inlet temperature to the spray drier or turbo-drier may range from 100° C to 200° C, preferably from 105° C to 110° C and the exit temperature may range from 60° C to 120° C, preferably from 75° C to 85° C. As previously mentioned, the Form II polymorph is converted to the Form I polymorph by conventional crystallisation methods by using also conventional solvents, although the short chain alcohols and/or mixtures of these alcohols with water are preferred. The presence of small amounts of water in the crystallisation process allows smaller volumes to be used, with the consequent saving, and provides pharmaceutical grade gabapentin (Form I) of a high degree of purity. Methanol, ethanol and isopropanol may be cited among the most preferred alcohols. The following Examples are provided for the purpose of giving the man of the art a sufficiently clear and complete explanation of the present invention, but must not be deemed to be limitations on the essential aspects of the object of the invention, such as those indicated in the foregoing paragraphs hereof. Examples Example 1 Following the method described in Example 1 of EP-B-0 340 677, 1.5 L of an aqueous solution of gabapentin containing 73.8 g/L was obtained. Said solution was dried using a type A/S spray-drier, supplied by NIRO, under the following conditions: flowrate 5.80 L/h, air input temperature 106-109° C and exit temperature 77-78° C. 101.8 g of non- hydrated gabapentin, Form II, were obtained in the form of a white powder having a melting point of 164-5° C, a specific gravity of 0.502 g/mL and a chromatographic purity (HPLC) of 99.3%. The gabapentin obtained showed a solid state (KBr) infra red spectrum and an X-ray diffract/on spectrum in powder conforming to those given in Figures 1 and 2 and in Table 1. An aliquot (10.2 g) of the Form II gabapentin obtained was dissolved in a mixture of 89 mL of methanol and 1 mL of water at a temperature of 60°-65° C. The resulting solution was cooled to 20° C and the appearance of a white precipitate was observed. 90 mL of isopropanol were added, with subsequent cooling to 0°-5° C and stirring was continued at that temperature for 4 hours. The precipitate was filtered and dried, to give 8.4 g (82%) of Form I gabapentin, with a chromatographic purity (HPLC) of 99.7%. The X-ray diffraction data conform to those given in Table 2. Example 2 When operating in the same way as described in example 1, but with the following variations: gabapentin solution concentration 6% by weight, spray drier flowrate 9 L/h, air input temperature 170°-180° C and air exit temperature 110°-115° C, non-hydrated Form II gabapentin was prepared, with a chromatographic purity (HPLC) of 92.6%, with the solid state (KBr) infra red ray spectrum and powder X-ray diffraction spectrum being in agreement with those given in Figures 1 and 2 and Table 1. Example 3 900 mL of a 6% by weight aqueous solution of gabapentin were evaporated in a Rinajet® turbo-drier, under the following conditions: flowrate 0.45 L/h, air input temperature 120°-130° C and air exit temperature 80°-85° C. Non-hydrated Form II gabapentin was prepared, with a chromatographic purity (HPLC) of 94.6%, with the solid state (KBr) infra red ray spectrum and powder X-ray diffraction spectrum thereof being in agreement with those given in Figures 1 and 2 and Table 1. Example 4 Following the method described in Example 1 of EP-B-0 340 677, 1.5 L of an aqueous solution of gabapentin containing 73.8 g/L was obtained. Said solution was dried using a type A/S spray-drier, supplied by NIRO, under the following conditions: flowrate 7.33 L/h, air input temperature 140-143° C and exit temperature 92-95° C. The product obtained was gabapentin Form II, the infra red spectrum and X-ray diffraction spectrum thereof being in agreement with those given in Figures 1 and 2 and in Table 1. Example 5 10.2 g of the Form II gabapentin obtained in Example 4 were dissolved in a mixture of 94 mL of methanol and 1 mL of water at a temperature of 64° C. The resulting solution was cooled to 20°-25° C and the appearance of a white precipitate was observed. 90 mL of isopropanol were added, with subsequent cooling to 0°-5° C and stirring was continued at that temperature for 4 hours. The precipitate was filtered and dried, to give 7.7 g (75%) of Form I gabapentin, with a chromatographic purity (HPLC) of 99.7%. The X-ray diffraction data conform to those given in Table 2. Example 6 10.1 g of the Form II gabapentin obtained in Example 4 were dissolved in a mixture of 94 mL of ethanol and 1 mL of water at a temperature of 79° C. The resulting solution was cooled to 0°-5° C and stirring was continued at that temperature for 3 hours 15 minutes. The precipitate was filtered and dried, to give 8,3 g (82%) of Form J gabapentin, with a chromatographic purity (HPLC) of 99.3%. The X-ray diffraction data conform to those given in Table 2. WE CLAIM 1. A process for the preparation of a non-hydrated Form II polymorph of gabapentin having substantially the following X-ray diffraction data: wherein an aqueous solution of gabapentin, having a concentration from 2% to 11% by weight, is subjected to spray-drying or turbo drying wherein the air inlet temperature to the spray drier or turbo drier ranges from 100°C to 200°C and the air exit temperature, ranges from 60°C to 120°C. 2. The process as claimed in claim 1, wherein said aqueous gabapentin solution has a concentration from 5% to 7% by weight. 3. The process as claimed in claim 1, wherein the air inlet temperature to the spray drier or turbo drier ranges from 105° C to 110° C and the air exit temperature ranges from 75° C to 85° C. 4. A process for the preparation of the Form I polymorph of gabapentin, wherein the Form II polymorph of gabapentin obtained as claimed in claim 1, is crystallised from a solvent or mixture of solvents. 5. The process as claimed in claim 4, wherein said solvents used are short chain alcohols, such as herein described, and/or mixtures thereof with water. 6. The process as claimed in claim 5, wherein said solvents are selected from the group formed by methanol, ethanol, isopropanol and water. The non-hydrated gabapentin polymorph is prepared by drying an aqueous solution of gabapentin by spray drying or turbo-drying and it is used for the preparation of pharmaceutical grade gabapentin by subjecting the polymorph to crystallisation from solvents.

Full Text

"A PROCESS FOR THE PREPARATION OF A NON-HYDRATED FORM II
POLYMORPH OF GABAPENTIN AND THE PREPARATION OF THE FORM I
POLYMORPH OF GABAPENTIN FROM SAID FORM II POLYMORPH
DESCRIPTION
Field of the invention
The present invention relates to a process for the preparation of a
non-hydrated Form II polymorph of gabapentin and the preparation of the
Form I polymorph of gabapentin from said Form II polymorph.
Prior art reference
Gabapentin is a synthetic amino acid related to ?-aminobutyric acid
(GABA) responding to the chemical name of 1-(aminomethyl) cyclohexane
acetic acid (The Merck Index, Ed. XII) and the following formula

The said compound has a therapeutical activity for convulsive type
cerebral disorders, such as epilepsy, hypokinesia, including fainting, and
other brain trauma and, in general, it is deemed to produce an
improvement of the cerebral functions.
Gabapentin and several processes for the preparation thereof are
described in Spanish patent ES-A-443 723, corresponding to US-A-4 024
175, Example 1 of which describes the preparation of the free amino acid
from the hydrochloride thereof, by treatment of an aqueous solution thereof
with a basic ion exchanger, evaporation of the solvent and subsequent
crystallisation from ethanol/ether.
The thus obtained product corresponds to a non-hydrated
crystalline form coinciding with the one shown by the commercial
pharmaceutical Neurontin® which is the pharmaceutical standard for
gabapentin.
On the other hand, EP-B-0 340 677 and the Spanish part thereof,
ES-T3-2 061 774, disclose a new hydrated form of gabapentin
characterised by its X-ray diffraction data and the process for the
preparation thereof, as well as a process for preparing the non-hydrated
crystalline form requiring the prior preparation of the said hydrated form.
Said process consists of the following successive steps:
a) passinganaqueousgabapentinhydrochloridesolution
through a basic ion exchange column.
b) concentrating the eluate to form a suspension.
c) cooling and adding alcohol to the above suspension.
d) cooling and centrifuging the thus prepared suspension.
e) drying the product obtained, which is the hydrated form of
gabapentin.
f) dissolving the above pure hydrated form in methanol.
g) diluting and cooling the thus prepared solution until a
suspension is obtained.
h)centrifuging the suspension and drying the product, which is
the non-hydrated form of gabapentin.
The above described process is obviously complicated from the,
industrial point of view, since it requires several steps and the isolation of
an intermediate in pure form, the hydrated form, prior to a final
crystallisation. All of this leads to an excessive occupation of the industrial
plant and losses in the yield of the desired product.
There is, therefore, a need to develop alternative processes for the
preparation of non-hydrated pharmaceutical grade gabapentin allowing the
industrial preparation of the product to be simplified, with a consequent
reduction of the production costs.
Summary of the Invention
It is an object of the present invention to provide an non-hydrated
gabapentin polymorph allowing pharmaceutical grade gabapentin to be
prepared in an industrially improved way over the prior art.
It is also an object of the invention to provide a process for the
preparation of said polymorph and a process for the preparation of
pharmaceutical grade gabapentin from said polymorph.
Brief Description of the Drawings
Figure 1 is an IR spectrum of the non-hydrated gabapentin
polymorph of the invention, using KBr tablet.
Figure 2 is an X-ray diffraction diagram of said polymorph, with a
diffraction angle coverage ranging from 4° to 50° in 0.02° steps.
Detailed Description
The present inventors have discovered that by drying an aqueous
solution of gabapentin using spray-drying or turbo-drying techniques, a new
non-hydrated gabapentin polymorph is obtained and which has been
named Form II by the inventors. The IR spectrum, on KBr tablet, is shown
in Figure 1 and the X-ray diffraction diagram with a diffraction angle
coverage ranging from 4° to 50° in 0.02° steps is shown in Figure 2.
Table 1 gives numerically the spacing "d" in A and the relative
intensity I (%) of the said X-ray diffraction diagram, for the peaks having a
relative intensity equal or superior to 5.
In turn, for comparative purposes, the X-ray diffraction diagram
corresponding to the pharmaceutical grade gabapentin standard, which the
present inventors have named Form 1, obtained under the same conditions,
gives the results listed in Table 2.
Having regard to the IR spectrum, the most significant bands of the
new Form II polymorph, in comparison with the Form I polymorph, may be
said to be those occurring at 1576, 1522, 985 and 637 cm-1.
The present inventors have also found that when the new Form II
polymorph is crystallised out of conventional solvents, there is surprisingly
obtained pharmaceutical grade non-hydrated gabapentin, i.e. the Form I
polymorph is obtained with a high degree of purity and a high yield.
Thus, pharmaceutical grade Form gabapentin may be obtained on
an industrial scale without it being necessary previously to prepare a pure
hydrated form thereof, by a process, also an object of the invention,
consisting essentially of crystallising the non-hydrated gabapentin Form II
polymorph in a conventional solvent or mixture of solvents.
The aqueous gabapentin starting solution for preparing the Form II
polymorph may be prepared by the method described in any of the
aforementioned documents ES-A-443 723 and EP-B-0 340 677. The
concentration of the solution may range from 2% to 11% by weight,
although concentrations ranging from 5% to 7% by weight are to be
preferred.
The gabapentin solution is not dried by conventional evaporation of
the solvent, but by spray-drying or turbo-drying techniques, in equipment
well known to the man of the art.
The air inlet temperature to the spray drier or turbo-drier may range
from 100° C to 200° C, preferably from 105° C to 110° C and the exit
temperature may range from 60° C to 120° C, preferably from 75° C to 85°
C.
As previously mentioned, the Form II polymorph is converted to the
Form I polymorph by conventional crystallisation methods by using also
conventional solvents, although the short chain alcohols and/or mixtures of
these alcohols with water are preferred. The presence of small amounts of
water in the crystallisation process allows smaller volumes to be used, with
the consequent saving, and provides pharmaceutical grade gabapentin
(Form I) of a high degree of purity. Methanol, ethanol and isopropanol may
be cited among the most preferred alcohols.
The following Examples are provided for the purpose of giving the
man of the art a sufficiently clear and complete explanation of the present
invention, but must not be deemed to be limitations on the essential
aspects of the object of the invention, such as those indicated in the
foregoing paragraphs hereof.
Examples
Example 1
Following the method described in Example 1 of EP-B-0 340 677,
1.5 L of an aqueous solution of gabapentin containing 73.8 g/L was
obtained. Said solution was dried using a type A/S spray-drier, supplied by
NIRO, under the following conditions: flowrate 5.80 L/h, air input
temperature 106-109° C and exit temperature 77-78° C. 101.8 g of non-
hydrated gabapentin, Form II, were obtained in the form of a white powder
having a melting point of 164-5° C, a specific gravity of 0.502 g/mL and a
chromatographic purity (HPLC) of 99.3%. The gabapentin obtained showed
a solid state (KBr) infra red spectrum and an X-ray diffract/on spectrum in
powder conforming to those given in Figures 1 and 2 and in Table 1.
An aliquot (10.2 g) of the Form II gabapentin obtained was
dissolved in a mixture of 89 mL of methanol and 1 mL of water at a
temperature of 60°-65° C. The resulting solution was cooled to 20° C and
the appearance of a white precipitate was observed. 90 mL of isopropanol
were added, with subsequent cooling to 0°-5° C and stirring was continued
at that temperature for 4 hours. The precipitate was filtered and dried, to
give 8.4 g (82%) of Form I gabapentin, with a chromatographic purity
(HPLC) of 99.7%. The X-ray diffraction data conform to those given in
Table 2.
Example 2
When operating in the same way as described in example 1, but
with the following variations: gabapentin solution concentration 6% by
weight, spray drier flowrate 9 L/h, air input temperature 170°-180° C and air
exit temperature 110°-115° C, non-hydrated Form II gabapentin was
prepared, with a chromatographic purity (HPLC) of 92.6%, with the solid
state (KBr) infra red ray spectrum and powder X-ray diffraction spectrum
being in agreement with those given in Figures 1 and 2 and Table 1.
Example 3
900 mL of a 6% by weight aqueous solution of gabapentin were
evaporated in a Rinajet® turbo-drier, under the following conditions:
flowrate 0.45 L/h, air input temperature 120°-130° C and air exit
temperature 80°-85° C. Non-hydrated Form II gabapentin was prepared,
with a chromatographic purity (HPLC) of 94.6%, with the solid state (KBr)
infra red ray spectrum and powder X-ray diffraction spectrum thereof being
in agreement with those given in Figures 1 and 2 and Table 1.
Example 4
Following the method described in Example 1 of EP-B-0 340 677,
1.5 L of an aqueous solution of gabapentin containing 73.8 g/L was
obtained. Said solution was dried using a type A/S spray-drier, supplied by
NIRO, under the following conditions: flowrate 7.33 L/h, air input
temperature 140-143° C and exit temperature 92-95° C. The product
obtained was gabapentin Form II, the infra red spectrum and X-ray
diffraction spectrum thereof being in agreement with those given in Figures
1 and 2 and in Table 1.
Example 5
10.2 g of the Form II gabapentin obtained in Example 4 were
dissolved in a mixture of 94 mL of methanol and 1 mL of water at a
temperature of 64° C. The resulting solution was cooled to 20°-25° C and
the appearance of a white precipitate was observed. 90 mL of isopropanol
were added, with subsequent cooling to 0°-5° C and stirring was continued
at that temperature for 4 hours. The precipitate was filtered and dried, to
give 7.7 g (75%) of Form I gabapentin, with a chromatographic purity
(HPLC) of 99.7%. The X-ray diffraction data conform to those given in
Table 2.
Example 6
10.1 g of the Form II gabapentin obtained in Example 4 were
dissolved in a mixture of 94 mL of ethanol and 1 mL of water at a
temperature of 79° C. The resulting solution was cooled to 0°-5° C and
stirring was continued at that temperature for 3 hours 15 minutes. The
precipitate was filtered and dried, to give 8,3 g (82%) of Form J gabapentin,
with a chromatographic purity (HPLC) of 99.3%. The X-ray diffraction data
conform to those given in Table 2.
WE CLAIM
1. A process for the preparation of a non-hydrated Form II polymorph of gabapentin
having substantially the following X-ray diffraction data:

wherein an aqueous solution of gabapentin, having a concentration from
2% to 11% by weight, is subjected to spray-drying or turbo drying wherein
the air inlet temperature to the spray drier or turbo drier ranges from 100°C
to 200°C and the air exit temperature, ranges from 60°C to 120°C.
2. The process as claimed in claim 1, wherein said aqueous gabapentin solution has a
concentration from 5% to 7% by weight.
3. The process as claimed in claim 1, wherein the air inlet temperature to the spray
drier or turbo drier ranges from 105° C to 110° C and the air exit temperature
ranges from 75° C to 85° C.
4. A process for the preparation of the Form I polymorph of gabapentin, wherein the
Form II polymorph of gabapentin obtained as claimed in claim 1, is crystallised
from a solvent or mixture of solvents.
5. The process as claimed in claim 4, wherein said solvents used are short chain
alcohols, such as herein described, and/or mixtures thereof with water.
6. The process as claimed in claim 5, wherein said solvents are selected from the
group formed by methanol, ethanol, isopropanol and water.

The non-hydrated gabapentin polymorph is prepared by drying an
aqueous solution of gabapentin by spray drying or turbo-drying and it is
used for the preparation of pharmaceutical grade gabapentin by subjecting
the polymorph to crystallisation from solvents.

Documents:

in-pct-2000-584-kol-granted-abstract.pdf

in-pct-2000-584-kol-granted-assignment.pdf

in-pct-2000-584-kol-granted-claims.pdf

in-pct-2000-584-kol-granted-correspondence.pdf

in-pct-2000-584-kol-granted-description (complete).pdf

in-pct-2000-584-kol-granted-drawings.pdf

in-pct-2000-584-kol-granted-examination report.pdf

in-pct-2000-584-kol-granted-form 1.pdf

in-pct-2000-584-kol-granted-form 18.pdf

in-pct-2000-584-kol-granted-form 3.pdf

in-pct-2000-584-kol-granted-form 5.pdf

in-pct-2000-584-kol-granted-gpa.pdf

in-pct-2000-584-kol-granted-letter patent.pdf

in-pct-2000-584-kol-granted-reply to examination report.pdf

in-pct-2000-584-kol-granted-specification.pdf

in-pct-2000-584-kol-granted-translated copy of priority document.pdf

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Patent Number

219367

Indian Patent Application Number

IN/PCT/2000/584/KOL

PG Journal Number

18/2008

Publication Date

02-May-2008

Grant Date

30-Apr-2008

Date of Filing

04-Dec-2000

Name of Patentee

MEDICHEM S.A.

Applicant Address

FRUCTUOS GELABERT, 6-8, 08970 SANT JOAN DESPI, BARCELONA

Inventors:

#	Inventor's Name	Inventor's Address
1	BOSCH LLADO JORDI	PLAZA MIQUEL COLLI, ALENTORN 2, 17003-GIRONA
2	GARCIA CRUZ RAFAEL	PLACA MERCE RODOREDA 3, E-08470 SANT CELONI
3	MOLINS GRAU ELLAS	JUAN GARCIA NIETO, 14, E-08980 SANT FELIU DE LLOB REGAT
4	ONRUBIA MIGUEL MARIA DEL CARMEN	PASAJE DEL CREDITO 5, E-08002 BARCELONA

PCT International Classification Number

C 07 C 229/28

PCT International Application Number

PCT/ES99/00127

PCT International Filing date

1999-05-10

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	P 9801078	1998-05-25	Spain