U.S. patent application number 11/743684 was filed with the patent office on 2007-08-30 for 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt, hydrate as pharmaceutical.
This patent application is currently assigned to SmithKline Beecham plc. Invention is credited to Paul David James BLACKLER, David C. Lee, Michael John Sasse.
Application Number | 20070203200 11/743684 |
Document ID | / |
Family ID | 26312781 |
Filed Date | 2007-08-30 |
United States Patent
Application |
20070203200 |
Kind Code |
A1 |
Sasse; Michael John ; et
al. |
August 30, 2007 |
5-[4-[2-(N-METHYL-N-(2-PYRIDYL)AMINO)ETHOXY]BENZYL]THIAZOLIDINE-2,4-DIONE,
MALEIC ACID SALT, HYDRATE AS PHARMACEUTICAL
Abstract
A hydrate of
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione-
, maleic acid salt, characterised in that it: (i) comprises water
in the range of from 0.4 to 2.5% w/w; and (ii) provides an infra
red spectrum containing peaks at 1749, 1703, 1645, 1623, 1365 and
736 cm.sup.-1; and/or (iii) provides an X-ray powder diffraction
(XRPD) pattern substantially as set out in FIG. II and/or (iv)
provides a Raman spectrum containing peaks at 3106, 3069, 3002,
2961, 1750, 1718, 1684, 1385, 1335, 1229, 1078, 917, 428 and 349
cm.sup.-1 and/or (iv) provides a solid-state nuclear magnetic
resonance spectrum containing chemical shifts substantially as set
out in Table I; a process for the preparation of such a compound, a
pharmaceutical composition containing such a compound and the use
of such a compound or composition in medicine.
Inventors: |
Sasse; Michael John;
(Tunbridge Wells, GB) ; BLACKLER; Paul David James;
(Tonbridge, GB) ; Lee; David C.; (Linton,
GB) |
Correspondence
Address: |
GLAXOSMITHKLINE;Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham plc
|
Family ID: |
26312781 |
Appl. No.: |
11/743684 |
Filed: |
May 3, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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|
10849591 |
May 20, 2004 |
7230109 |
|
|
11743684 |
May 3, 2007 |
|
|
|
10321055 |
Dec 17, 2002 |
|
|
|
10849591 |
May 20, 2004 |
|
|
|
10082879 |
Feb 26, 2002 |
|
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10321055 |
Dec 17, 2002 |
|
|
|
09581826 |
Jun 16, 2000 |
|
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PCT/EP98/08155 |
Dec 14, 1998 |
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10082879 |
Feb 26, 2002 |
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Current U.S.
Class: |
514/342 |
Current CPC
Class: |
C07D 417/12 20130101;
A61K 31/44 20130101 |
Class at
Publication: |
514/342 |
International
Class: |
A61K 31/44 20060101
A61K031/44 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 16, 1997 |
GB |
GB9726566.4 |
Claims
1. A method for the treatment of Type II diabetes in a human or
non-human mammal in need thereof, said method comprising
administering to said human or non-human mammal an effective amount
of a crystalline
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione-
, maleic acid salt, hydrate wherein said hydrate contains water in
the range of from 1.5 to 2.5% w/w and provides at least one of: (i)
an infra red spectrum containing peaks at 1749, 1703, 1645, 1623,
1365 and 736 cm.sup.-1; (ii) an X-ray powder diffraction pattern
substantially as set out in Table I; (iii) a Raman spectrum
containing peaks at 3106, 3069, 3002, 2961, 1750, 1718, 1684, 1385,
1335, 1229, 1078, 917, 428 and 349 cm.sup.-1; and (iv) a
solid-state .sup.13C nuclear magnetic resonance spectrum containing
chemical shifts substantially at 35.7, 37.9, 50.3, 57.0, 65.6,
109.3, 112.9, 112.9, 119.7, 129.1, 133.2, 134.0, 136.1, 136.8,
143.0, 153.2, 157.4, 168.6, 171.7, 173.6, and 176.6 ppm.
2. A method for the treatment of Type II diabetes in a human or
non-human mammal in need thereof, said method comprising
administering to said human or non-human mammal an effective amount
of a crystalline
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione-
, maleic acid salt, hydrate, wherein said hydrate contains water in
the range of from 1.5 to 2.5% w/w and provides an X-ray powder
diffraction pattern substantially in accordance with FIG. 2.
3. A method for the treatment of Type II diabetes in a human or
non-human mammal in need thereof, said method comprising
administering to said human or non-human mammal an effective amount
of a crystalline
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione-
, maleic acid salt, hydrate, wherein said hydrate contains water in
the range of from 1.5 to 2.5% w/w and provides a Raman spectrum
substantially in accordance with FIG. 3.
4. A method for the treatment of Type II diabetes in a human or
non-human mammal in need thereof, said method comprising
administering to said human or non-human mammal an effective amount
of a crystalline
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione-
, maleic acid salt, hydrate, wherein said hydrate contains water in
the range of from 1.5 to 2.5% w/w and provides a solid state
nuclear magnetic resonance spectrum substantially in accordance
with FIG. 4.
5. The method according to claim 1, wherein said hydrate contains
water in the range of from 1.5 to 2.0% w/w.
6. The method according to claim 2, wherein said hydrate contains
water in the range of from 1.5 to 2.0% w/w.
7. The method according to claim 3, wherein said hydrate contains
water in the range of from 1.5 to 2.0% w/w.
8. The method according to claim 4, wherein said hydrate contains
water in the range of from 1.5 to 2.0% w/w.
Description
[0001] This application is a divisional of application Ser. No.
10/849,591, filed May 20, 2004, which is a continuation of
application Ser. No. 10/321,055, filed Dec. 17, 2002, which is a
continuation of application Ser. No. 10/082,879, filed Feb. 26,
2002, which is a continuation of application Ser. No. 09/581,826,
filed Jun. 16, 2000, which is a 371 of International Application
No. PCT/EP98/08155, filed Dec. 14, 1998.
[0002] This invention relates to a novel pharmaceutical, to a
process for the preparation of the pharmaceutical and to the use of
the pharmaceutical in medicine.
[0003] International Patent Application, Publication Number
WO94/05659 discloses certain thiazolidinedione derivatives having
hypoglycaemic and hypolipidaemic activity including
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione-
, maleic acid salt (hereinafter also referred to as "Compound
(I)").
[0004] Compound (I) is disclosed solely as an anhydrous form. It
has now been discovered that Compound (I) exists in a novel form
which is particularly suitable for bulk preparation and handling.
This can be prepared by an efficient, economic and reproducible
process particularly suited to large scale preparation.
[0005] The novel form also has useful pharmaceutical properties and
in particular it is indicated to be useful for the treatment and/or
prophylaxis of diabetes mellitus, conditions associated with
diabetes mellitus and certain complications thereof.
[0006] Accordingly, the present invention provides a novel form of
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione-
, maleic acid salt (the "Hydrate") characterised in that the
Hydrate:
(i) comprises water in the range of from 0.4 to 2.5% w/w; and
(ii) provides an infra red spectrum containing peaks at 1749, 1703,
1645, 1623, 1365 and 736 cm.sup.-1; and/or
(iii) provides an X-ray powder diffraction (XRPD) pattern
substantially as set out in Table I and /or
(iv) provides a Raman spectrum containing peaks at 3106, 3069,
3002, 2961, 1750, 1718, 1684, 1385, 1335, 1229, 1078, 917, 428 and
349 cm.sup.-1 and/or
(iv) provides a solid-state nuclear magnetic resonance spectrum
containing chemical shifts substantially as set out in Table
II.
[0007] Suitably the Hydrate contains water in the range of from 0.5
to 2% w/w, such as from 1.5 to 2.0% w/w or from 1.85 to 2.0% w/w,
for example 1.85, 1.86, 1.87 or 1.88% w/w.
[0008] In one favoured aspect, the Hydrate provides an infra red
spectrum substantially as set out in accordance with FIG. I.
[0009] In one favoured aspect, the Hydrate provides an X-ray powder
diffraction (XRPD) pattern substantially in accordance with FIG.
II.
[0010] In a further favoured aspect, the Hydrate provides a Raman
spectrum substantially as set out in accordance with FIG. III.
[0011] In yet a further favoured aspect, the Hydrate provides a
solid-state nuclear magnetic resonance spectrum substantially in
accordance with FIG. IV.
[0012] The present invention encompasses the Hydrate isolated in
pure form or when admixed with other materials, for example the
known anhydrous form of Compound I, the above mentioned reversibly
rehydratable forms or any other material.
[0013] Thus in one aspect there is provided the Hydrate in isolated
form.
[0014] In a further aspect there is provided the Hydrate in pure
form.
[0015] In yet a further aspect there is provided the Hydrate in
crystalline form.
[0016] The invention also provides a process for preparing the
Hydrate, characterised in that
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione-
, maleic acid salt is crystallised from ethanol, suitably denatured
ethanol, containing 15 to 25% by volume of water, for example 17.5%
by volume.
[0017] Other aqueous solvents may also be used in the said
crystallisation of the Hydrate, for example methanol, acetonitrile
or ethyl acetate or mixtures thereof. The precise amount of water
used in each of the alternative solvents will depend upon the
particular solvent chosen, for example approximately 3% by volume
in acetonitrile or ethyl acetate. Methanol has also been shown to
provide the hydrate when the crystallisation is conducted open to
the atmosphere. Water can also be used as the crystallization
solvent.
[0018] Compound I is prepared according to known procedures, such
as those disclosed in WO94/05659. The disclosures of WO94/05659 are
incorporated herein by reference.
[0019] When used herein the term `prophylaxis of conditions
associated with diabetes mellitus` includes the treatment of
conditions such as insulin resistance, impaired glucose tolerance,
hyperinsulinaemia and gestational diabetes.
[0020] Diabetes mellitus preferably means Type II diabetes
mellitus.
[0021] Conditions associated with diabetes include hyperglycaemia
and insulin resistance, especially acquired insulin resistance and
obesity. Further conditions associated with diabetes include
hypertension, cardiovascular disease, especially atherosclerosis,
certain eating disorders, in particular the regulation of appetite
and food intake in subjects suffering from disorders associated
with under-eating ,such as anorexia nervosa, and disorders
associated with over-eating, such as obesity and anorexia bulimia.
Additional conditions associated with diabetes include polycystic
ovarian syndrome and steroid induced insulin resistance.
[0022] The complications of conditions associated with diabetes
mellitus encompassed herein includes renal disease, especially
renal disease associated with the development of Type II diabetes
including diabetic nephropathy, glomerulonephritis, glomerular
sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end
stage renal disease.
[0023] As mentioned above the compound of the invention has useful
therapeutic properties: The present invention accordingly the
Hydrate for use as an active therapeutic substance.
[0024] More particularly, the present invention provides the
Hydrate for use in the treatment and/or prophylaxis of diabetes
mellitus, conditions associated with diabetes mellitus and certain
complications thereof.
[0025] The Hydrate may be administered per se or, preferably, as a
pharmaceutical composition also comprising a pharmaceutically
acceptable carrier. The formulation of the Hydrate and dosages
thereof are generally as disclosed for Compound (I) in
International Patent Application, Publication Number
WO94/05659.
[0026] Accordingly, the present invention also provides a
pharmaceutical composition comprising the Hydrate and a
pharmaceutically acceptable carrier therefor.
[0027] The Hydrate is normally administered in unit dosage
form.
[0028] The active compound may be administered by any suitable
route but usually by the oral or parenteral routes. For such use,
the compound will normally be employed in the form of a
pharmaceutical composition in association with a pharmaceutical
carrier, diluent and/or excipient, although the exact form of the
composition will naturally depend on the mode of
administration.
[0029] Compositions are prepared by admixture and are suitably
adapted for oral, parenteral or topical administration, and as such
may be in the form of tablets, capsules, oral liquid preparations,
powders, granules, lozenges, pastilles, reconstitutable powders,
injectable and infusable solutions or suspensions, suppositories
and transdermal devices. Orally administrable compositions are
preferred, in particular shaped oral compositions, since they are
more convenient for general use.
[0030] Tablets and capsules for oral administration are usually
presented in a unit dose, and contain conventional excipients such
as binding agents, fillers, diluents, tabletting agents,
lubricants, disintegrants, colourants, flavourings, and wetting
agents. The tablets may be coated according to well known methods
in the art.
[0031] Suitable fillers for use include cellulose, mannitol,
lactose and other similar agents. Suitable disintegrants include
starch, polyvinylpyrrolidone and starch derivatives such as sodium
starch glycollate. Suitable lubricants include, for example,
magnesium stearate. Suitable pharmaceutically acceptable wetting
agents include sodium lauryl sulphate.
[0032] Solid oral compositions may be prepared by conventional
methods of blending, filling, tabletting or the like. Repeated
blending operations may be used to distribute the active agent
throughout those compositions employing large quantities of
fillers. Such operations are, of course, conventional in the
art.
[0033] Oral liquid preparations may be in the form of, for example,
aqueous or oily suspensions, solutions, emulsions, syrups, or
elixirs, or may be presented as a dry product for reconstitution
with water or other suitable vehicle before use. Such liquid
preparations may contain conventional additives such as suspending
agents, for example sorbitol, syrup, methyl cellulose, gelatin,
hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate
gel or hydrogenated edible fats, emulsifying agents, for example
lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles
(which may include edible oils), for example, almond oil,
fractionated coconut oil, oily esters such as esters of glycerine,
propylene glycol, or ethyl alcohol; preservatives, for example
methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired
conventional flavouring or colouring agents.
[0034] For parenteral administration, fluid unit dose forms are
prepared containing a compound of the present invention and a
sterile vehicle. The compound, depending on the vehicle and the
concentration, can be either suspended or dissolved. Parenteral
solutions are normally prepared by dissolving the active compound
in a vehicle and filter sterilising before filling into a suitable
vial or ampoule and sealing. Advantageously, adjuvants such as a
local anaesthetic, preservatives and buffering agents are also
dissolved in the vehicle. To enhance the stability, the composition
can be frozen after filling into the vial and the water removed
under vacuum.
[0035] Parenteral suspensions are prepared in substantially the
same manner except that the active compound is suspended in the
vehicle instead of being dissolved and sterilised by exposure to
ethylene oxide before suspending in the sterile vehicle.
Advantageously, a surfactant or wetting agent is included in the
composition to facilitate uniform distribution of the active
compound.
[0036] In addition such compositions may contain further active
agents such as anti-hypertensive agents and diuretics.
[0037] As is common practice, the compositions will usually be
accompanied by written or printed directions for use in the medical
treatment concerned.
[0038] As used herein the term `pharmaceutically acceptable`
embraces compounds, compositions and ingredients for both human and
veterinary use: for example the term `pharmaceutically acceptable
salt` embraces a veterinarily acceptable salt.
[0039] The present invention further provides a method for the
treatment and/or prophylaxis of diabetes mellitus, conditions
associated with diabetes mellitus and certain complications
thereof, in a human or non-human mammal which comprises
administering an effective, non-toxic, amount of the Hydrate to a
human or non-human mammal in need thereof.
[0040] Conveniently, the active ingredient may be administered as a
pharmaceutical composition hereinbefore defined, and this forms a
particular aspect of the present invention.
[0041] In the treatment and/or prophylaxis of diabetes mellitus,
conditions associated with diabetes mellitus and certain
complications thereof the Hydrate may be taken in doses, such as
those described above.
[0042] Similar dosage regimens are suitable for the treatment
and/or prophylaxis of non-human mammals.
[0043] In a further aspect the present invention provides the use
of the Hydrate for the manufacture of a medicament for the
treatment and/or prophylaxis of diabetes mellitus, conditions
associated with diabetes mellitus and certain complications
thereof.
[0044] No adverse toxicological effects are indicated in the above
mentioned treatments for the compounds of the invention.
[0045] The following examples illustrate the invention but do not
limit it in any way.
EXAMPLE 1
Preparation of the Hydrate of
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione-
, maleic acid salt.
[0046]
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,-
4-dione free base (6.0 g) and maleic acid salt (2.1 g, 1.05 molar
equivalents) were heated in methanol (40 ml) to 55.degree. C. and
held at this temperature for 30 minutes during which a solution was
obtained. The solution was filtered, re-heated to 55.degree. C.,
and then cooled to 0-5.degree. C. and stirred for two hours. The
product was filtered, and dried at 52.degree. C. in vacuo for 18
hours to give the title compound (6.7 g, 84%). The water content of
the product was 0.54% w/w.
[0047] The Hydrate of
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione-
, maleic acid salt was also prepared by means of the following
procedures:
EXAMPLE 2
[0048]
5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,-
4-dione (1.5 g, 4.2 mmole) and maleic acid (0.525 g @ 97.6% assay,
4.4 mmole, 1.05 mole equivalents) were heated in methanol (15 ml)
and the temperature was held at 60.degree. C. The resulting
solution was filtered and then cooled to 0.degree. C. with magnetic
stirring at which point a thick suspension was formed. The product,
5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione
maleate, was isolated, washed with methanol and dried, in vacuo, at
52.degree. C. (Yield 1.4 g, 70.5%). Water content of the product
was 2.0%.
EXAMPLE 3
[0049]
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,-
4-dione free base (6.0 g) and maleic acid (2.1 g, 1.05 molar
equivalents) were heated in acetonitrile (60 ml) containing water
(2 ml) to 55.degree. C. and held at this temperature for 30 minutes
during which time a solution was obtained. The solution was
filtered, re-heated to 55.degree. C., and then cooled to
0-5.degree. C. and stirred for two hours. The product was filtered,
and dried at 52.degree. C. in vacuo for 18 hours to give the title
compound (5.7 g, 72%). The water content of the product was 1.86%
w/w.
EXAMPLE 4
[0050] The maleate salt of
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione
anhydrate (3.0 g) was heated to 80.degree. C. in water (200 ml),
then filtered hot and cooled to 20-25.degree. C. with magnetic
stirring. The product was filtered, washed with denatured alcohol
(20 ml) and dried at 50.degree. C. to give the title compound (1.6
g, 53%), water content 1.87%.
EXAMPLE 5
[0051] The maleate salt of
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidione-2,4-dion-
e anhydrate (2.0 g) was heated to 75.degree. C. in ethyl acetate
(100 ml) containing water (3 ml), then filtered hot and cooled with
magnetic stirring to 20-25.degree. C. The product was filtered and
dried at 50.degree. C. to give the title compound (1.43 g, 72%),
water content 1.88%.
EXAMPLE 6
[0052]
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,-
4-dione free base (6.0 g) and maleic acid (2.1 g, 1.05 molar
equivalents) were heated in denatured ethanol (60 ml) containing
water (17.5% by volume) to 60.degree. C. and held at this
temperature for 30 minutes during which a solution was obtained.
The solution was filtered, re-heated to 55.degree. C., and then
cooled to 5-10.degree. C. and stirred for four hours. The product
was filtered, and dried at 52.degree. C. in vacuo for 18 hours to
give the title compound (5.05 g, 62%), water content 1.85%.
[0053] CHARACTERISING DATA: The following characterising data was
generated for the Hydrate from example 2:
[0054] A Infrared
[0055] The infrared absorption spectrum of a mineral oil dispersion
of the Novel form was obtained using a Nicolet 710 FT-IR
spectrometer at 2 cm.sup.-1 resolution. Data were digitised at 1
cm.sup.-1 intervals. The spectrum obtained is shown in FIG. I. Peak
positions are: 3428, 3139, 3054, 1749, 1703, 1645, 1623, 1584,
1566, 1539, 1510, 1411, 1365, 1333, 1318, 1302, 1275, 1264, 1247,
1238, 1187, 1178, 1166, 1143, 1109, 1098, 1078, 1060, 1039, 1006,
979, 972, 956, 929, 924, 917, 896, 885, 864, 843, 810, 775, 764,
736, 718, 656, 604, 598, 587, 562 and 542 cm-1
[0056] B X-Ray Powder Diffraction (XRPD)
[0057] The XRPD pattern of the Novel form is shown below in FIG. II
and a summary of the XRPD angles and calculated lattice spacing
characteristic of the Novel form is given in Table I.
[0058] A PW 1710 X-ray powder diffractometer (Cu X-ray source) was
used to generate the spectrum using the following acquisition
conditions: TABLE-US-00001 Tube anode: Cu Generator tension: 40 kV
Generator current: 30 mA Start angle: 3.5 .degree.2.theta. End
angle: 35.0 .degree.2.theta. Step size: 0.02 Time per step: 4.550
s
[0059] TABLE-US-00002 TABLE I X-Ray Powder Diffraction Angles and
Calculated Lattice Spacing Characteristic of the Novel form.
Diffraction Angle Lattice Spacing (.degree.2.theta.) (Angstroms)
10.9 8.13 14.5 6.09 15.9 5.56 16.7 5.30 18.4 4.82 19.7 4.50 20.7
4.29 21.9 4.06 22.3 3.98 23.9 3.72 24.7 3.61 25.3 3.52 25.9 3.44
27.4 3.25 28.2 3.16 29.7 3.01 30.4 2.94 33.1 2.70
[0060] C Raman
[0061] A Raman spectrum of the Hydrate was recorded from a sample
held in a glass vial using a Perkin-Elmer 2000R FT-Raman
spectrometer at 4 cm.sup.-1 resolution and is shown in FIG. III.
Data were digitised at 1 cm.sup.-1 intervals. Excitation was
achieved using a Nd:YAG laser (1064 nm) with a power output of 500
mW. Peak positions are as follows: 3106, 3069, 3042, 3002, 2961,
2939, 2914, 2872, 1750, 1718, 1684, 1645, 1612, 1586, 1546, 1468,
1445, 1434, 1410, 1385, 1364, 1335, 1304, 1277, 1263, 1246, 1229,
1208, 1192, 1181, 1150, 1121, 1100, 1078, 1039, 1000, 980, 953,
917, 896, 883, 864, 843, 827, 805, 777, 742, 724, 657, 637, 607,
561, 540, 525, 497, 467, 452, 428, 400, 349, 317, and 297
cm.sup.-1.
[0062] D NMR
[0063] The 90.55 MHz .sup.13C-CP-MAS NMR spectrum for the Hydrate
is shown below in FIG. IV. Chemical shifts are tabulated in Table
II. Data were recorded at ambient temperature and 10 kHz spinning
frequency, with minimal prior grinding of the sample, using a
Bruker AMX360WB spectrometer, with 1.6 ms cross-polarisation and a
repetition time of 15 s. Chemical shfts were referenced to the
carboxylate signal of a glycine test sample at 176.4 ppm relative
to tetramethylsilane and are judged accurate to within +/-0.5 ppm.
Peaks were not assigned. TABLE-US-00003 TABLE II .sup.13C Chemical
Shifts of the Hydrate Chemical Shift (ppm) 35.7 37.9 50.3 57.0 65.6
109.3 112.9 (2 resonances) 119.7 129.1 133.2 134.0 136.1 136.8
143.0 153.2 157.4 168.6 171.7 173.6 176.6
* * * * *