U.S. patent application number 10/703887 was filed with the patent office on 2004-05-13 for pharmaceutical compositions of a thiazolidinedione derivative and their use as antidiabetics.
This patent application is currently assigned to SmithKline Beecham pIc. Invention is credited to Blackler, Paul David James, Giles, Robert Gordon, Sasse, Michael John.
Application Number | 20040092555 10/703887 |
Document ID | / |
Family ID | 26315460 |
Filed Date | 2004-05-13 |
United States Patent
Application |
20040092555 |
Kind Code |
A1 |
Blackler, Paul David James ;
et al. |
May 13, 2004 |
Pharmaceutical compositions of a thiazolidinedione derivative and
their use as antidiabetics
Abstract
A polymorphic form of
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]t-
hiazolidine-2,4-dione, maleic acid salt (the "Polymorph")
characterised in that it: (i) provides an infra red spectrum
containing peaks at 1360, 1326, 1241, 714 and 669 cm.sup.-1; and/or
(ii) provides a Raman spectrum containing peaks at 1581, 768, 670,
271 and 226 cm.sup.-1; and/or (iii) provides a solid-state nuclear
magnetic resonance spectrum containing peaks at chemical shifts
substantially as set out in Table I; and/or (iv) provides an X-ray
powder diffraction (XRPD) pattern containing peaks substantially as
set out in Table II; a process for preparing such a compound, a
pharmaceutical composition containing such a compound and the use
of such a compound in medicine.
Inventors: |
Blackler, Paul David James;
(Cadiz, ES) ; Giles, Robert Gordon; (Tonbridge,
GB) ; Sasse, Michael John; (Tonbridge, GB) |
Correspondence
Address: |
GLAXOSMITHKLINE
Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham pIc
|
Family ID: |
26315460 |
Appl. No.: |
10/703887 |
Filed: |
November 7, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10703887 |
Nov 7, 2003 |
|
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10030323 |
May 15, 2002 |
|
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|
10030323 |
May 15, 2002 |
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PCT/GB00/01514 |
Apr 19, 2000 |
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Current U.S.
Class: |
514/342 ;
546/269.7 |
Current CPC
Class: |
A61P 13/12 20180101;
A61P 9/00 20180101; A61P 9/12 20180101; A61P 3/00 20180101; A61P
13/00 20180101; A61P 9/10 20180101; C07D 417/12 20130101; A61P 3/10
20180101; A61P 3/04 20180101 |
Class at
Publication: |
514/342 ;
546/269.7 |
International
Class: |
A61K 031/4439; C07D
417/02 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 23, 1999 |
GB |
9909472.4 |
May 25, 1999 |
GB |
9912197.2 |
Claims
1. A polymorphic form of
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzy-
l]thiazolidine-2,4-dione, maleic acid salt (the "Polymorph")
characterised in that it: (i) provides an infra red spectrum
containing peaks at 1360, 1326, 1241, 714 and 669 cm.sup.-1; and/or
(ii) provides a Raman spectrum containing peaks at 1581, 768, 670,
271 and 226 cm.sup.-1; and/or (iii) provides a solid-state nuclear
magnetic resonance spectrum containing peaks at chemical shifts
substantially as set out in Table I; and/or (iv) provides an X-ray
powder diffraction (XRPD) pattern containing peaks substantially as
set out in Table II.
2. A Polymorph according to claim 1, which provides an infra red
spectrum substantially in accordance with FIG. I.
3. A Polymorph according to claim 1 or claim 2, which provides a
Raman spectrum substantially in accordance with FIG. II.
4. A Polymorph according to any on of claims 1 to 3, which provides
a solid-state nuclear magnetic resonance spectrum substantially in
accordance with FIG. III.
5. A Polymorph according to any one of claims 1 to 4, which
provides an X-ray powder diffraction (XRPD) pattern substantially
in accordance with FIG. IV.
6. A Polymorph according to any one of claims 1 to 5, in isolated
form.
7. A Polymorph according to any one of claims 1 to 6, in pure
form.
8. A Polymorph according to any one of claims 1 to 7, in
crystalline form.
9. A process for preparing a Polymorph according to claim 1,
characterised in that: (a) a slurry of
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benz-
yl]thiazolidine-2,4-dione, maleic acid salt (hereinafter also
referred to as "Compound (I)" or the "Original Polymorph") in
aqueous ethanol containing up to about 2.5% w/v water, is heated
for an extended period of time; after which time the Polymorph is
recovered from the denatured ethanol; or (b) Compound (I) is
admixed with denatured ethanol, heated to an elevated temperature,
over an extended period of time, after which time the Polymorph is
recovered from the solvent; or (c) Compound (I) in denatured
ethanol containing up to 2.5% w/v water at 55.degree. C. is seeded
with the Polymorph then cooled to a temperature in the range of
from 20.degree. C. to 25.degree. C. to provide the Polymorph; the
Polymorph is then recovered from the solvent.
10. A pharmaceutical composition comprising an effective, non-toxic
amount of a Polymorph according to claim 1 and a pharmaceutically
acceptable carrier therefor.
11. A Polymorph according to claim 1, for use as an active
therapeutic substance.
12. A Polymorph according to claim 1, for use in the treatment
and/or prophylaxis of diabetes mellitus, conditions associated with
diabetes mellitus and certain complications thereof.
13. The use of Polymorph for the manufacture of a medicament for
the treatment and/or prophylaxis of diabetes mellitus, conditions
associated with diabetes mellitus and certain complications
thereof.
14. 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
Polymorph to a human or non-human mammal in need thereof.
Description
[0001] 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.
[0002] 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)et-
hoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt (hereinafter
also referred to as "Compound (I)").
[0003] International Patent Applications, Publication Numbers
WO99/31093, WO99/31094 and WO99/31095 each disclose distinct
hydrates of Compound (I).
[0004] It has now been discovered that Compound (I) exists in a
novel polymorphic form which is particularly suitable for bulk
preparation and handling. The novel form can be prepared by an
efficient, economic and reproducible process particularly suited to
large-scale preparation.
[0005] The novel polymorphic form (`the Polymorph`) 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 polymorphic
form of
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione-
, maleic acid salt characterised in that it:
[0007] (i) provides an infra red spectrum containing peaks at 1360,
1326, 1241, 714 and 669 cm.sup.-1; and/or
[0008] (ii) provides a Raman spectrum containing peaks at 1581,
768, 670, 271 and 226 cm.sup.-1; and/or
[0009] (iii) provides a solid-state nuclear magnetic resonance
spectrum containing peaks at chemical shifts substantially as set
out in Table I; and/or
[0010] (iv) provides an X-ray powder diffraction (XRPD) pattern
containing peaks substantially as set out in Table II.
[0011] In one favoured aspect, the Polymorph provides an infrared
spectrum substantially in accordance with FIG. I.
[0012] In one favoured aspect, the Polymorph provides a Raman
spectrum substantially in accordance with FIG. II.
[0013] In one favoured aspect, the Polymorph provides a solid-state
nuclear magnetic resonance spectrum substantially in accordance
with FIG. III.
[0014] In one favoured aspect, the Polymorph provides an X-ray
powder diffraction (XRPD) pattern substantially in accordance with
FIG. IV.
[0015] The present invention encompasses the Polymorph isolated in
pure form or when admixed with other materials, for example the
known forms of Compound I or any other material.
[0016] Thus in one aspect there is provided the Polymorph in
isolated form.
[0017] In a further aspect there is provided the Polymorph in pure
form.
[0018] In yet a further aspect there is provided the Polymorph in
crystalline form.
[0019] The invention also provides a process for preparing the
Polymorph, characterised in that a slurry of Compound (I) in
aqueous ethanol containing up to about 2.5% w/v water, preferably
aqueous denatured ethanol containing up to about 2.5% w/v water,
for example 2.5% w/v water, is heated, suitably to a temperature in
the range of from 35.degree. C. and 60.degree. C., such as
40.degree. C. to 50.degree. C., for example to 45.degree. C., for
an extended period of time, for example 65 hours, after which time
the Polymorph is recovered from the denatured ethanol. Optionally,
the reaction mixture is seeded with the Polymorph.
[0020] In a further process of the invention, Compound (I) is
admixed with denatured ethanol, heated to an elevated temperature,
preferably a temperature in the range of from 35.degree. C. and
60.degree. C., such as 40.degree. C. to 50.degree. C., for example
from 45.degree. to 47.degree. C., over an extended period of time,
for example 65 hours, after which time the Polymorph is recovered
from the solvent. Optionally, the reaction mixture is seeded with
Polymorph.
[0021] In a further process a solution of Compound (I) in denatured
ethanol containing up to 2.5% w/v water, for example 0.8 to 2.5%
w/v water, at 55.degree. C. is seeded with the Polymorph then
cooled to a temperature in the range of from 20.degree. C. to
25.degree. C. to provide the Polymorph. The Polymorph is then
recovered from the denatured ethanol.
[0022] The solution of Compound (I) in the denatured ethanol is
conveniently prepared by dissolving Compound (I) in the required
amount of denatured ethanol at an elevated temperature, for example
60.degree. C. In our hands this latter process is also effectively
carried out using Compound (I) containing up to 25% w/w of the
hydrate disclosed in WO99/31093 mentioned above
[0023] Conveniently the Polymorph is recovered from the reaction
solvent, such as denatured ethanol, by filtration and subsequent
drying, preferably at an elevated temperature, for example
45.degree. C.
[0024] In a further aspect the present invention also provides a
process for preparing Compound (I) (also for convenience referred
to as the "Original Polymorph") from the Polymorph of the
invention, which process comprises first preparing a solution of
the Polymorph in a mixture (100:1 v/v) of absolute ethanol and
methanol, at an elevated temperature, suitably in the range of from
60.degree. C. to 75.degree. C. for example at 68.degree. C., and
then allowing the solution to cool to ambient temperature, for
example 20-25.degree. C., thereby allowing the Original Polymorph
to crystallise.
[0025] In a preferred form of the said process to prepare the
Original Polymorph, the solution of the Polymorph in the absolute
ethanol/methanol mixture is filtered, usually once complete
dissolution of the Polymorph is attained and the resulting solution
is reheated to an elevated temperature, for example to 65.degree.
C., which solution is then allowed to cool to ambient temperature,
for example 20 to 25.degree. C.
[0026] In the above mentioned processes for preparing the Original
Polymorph the solution may be seeded with the Original Polymorph
but this is not essential.
[0027] 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.
[0028] For the avoidance of doubt the term "Compound (I)" as used
herein refers to the form of
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]-
thiazolidine-2,4-dione, maleic acid salt as disclosed an
characterised in International Patent Application, Publication
Number WO94/05659. When used herein "denatured ethanol" means
ethanol containing small amounts of methanol, usually up to 5% v/v
of methanol, such as from 0.9% v/v to 5% v/v of methanol, for
example ethanol containing 4% v/v of methanol.
[0029] 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.
[0030] Diabetes mellitus preferably means Type II diabetes
mellitus.
[0031] Conditions associated with diabetes include hyperglycaemia
and 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.
[0032] 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.
[0033] As mentioned above the compound of the invention has useful
therapeutic properties: The present invention accordingly the
Polymorph for use as an active therapeutic substance.
[0034] More particularly, the present invention provides the
Polymorph for use in the treatment and/or prophylaxis of diabetes
mellitus, conditions associated with diabetes mellitus and certain
complications thereof.
[0035] The Polymorph may be administered per se or, preferably, as
a pharmaceutical composition also comprising a pharmaceutically
acceptable carrier. The formulation of the Polymorph and dosages
thereof are generally as disclosed for Compound (I) in
International Patent Application, Publication Numbers WO94/05659
and WO98/55122.
[0036] Accordingly, the present invention also provides a
pharmaceutical composition comprising the Polymorph and a
pharmaceutically acceptable carrier therefor.
[0037] The Polymorph is normally administered in unit dosage
form.
[0038] 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.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] In addition such compositions may contain further active
agents such as anti-hypertensive agents and diuretics.
[0047] In addition, the Polymorph may be used in combination with
other antidiabetic agents such as insulin secretagogues, for
example sulphonylureas, biguanides, such as metformin, alpha
glucosidase inhibitors, such as acarbose, beta agonists, and
insulin such as those disclosed in WO98/57649, WO98/57634,
WO98/57635 or WO98/57636. The other antidiabetic agents, the
amounts thereof and methods of administration are as described in
the above mentioned publications. The formulation of the Polymorph
and dosages thereof in said combinations are generally as disclosed
for Compound (I) in the above mentioned publications. As is common
practice, the compositions will usually be accompanied by written
or printed directions for use in the medical treatment
concerned.
[0048] 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.
[0049] 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 Polymorph to a
human or non-human mammal in need thereof. Conveniently, the active
ingredient may be administered as a pharmaceutical composition
herein before defined, and this forms a particular aspect of the
present invention.
[0050] In the treatment and/or prophylaxis of diabetes mellitus,
conditions associated with diabetes mellitus and certain
complications thereof the Polymorph may be taken in doses, such as
those described above.
[0051] Similar dosage regimens are suitable for the treatment
and/or prophylaxis of non-human mammals.
[0052] In a further aspect the present invention provides the use
of the Polymorph for the manufacture of a medicament for the
treatment and/or prophylaxis of diabetes mellitus, conditions
associated with diabetes mellitus and certain complications
thereof.
[0053] No adverse toxicological effects are indicated in the above
mentioned treatments for the compounds of the invention.
[0054] The following examples illustrate the invention but do not
limit it in any way.
EXAMPLES
Example 1
[0055] A slurry of Compound (I) (3.0 g, prepared as per WO94/05659
in denatured ethanol (30.5 ml, water content 2.5% w/v) ) was heated
at 45.degree. C. for 65 hours. The product was filtered at
45.degree. C. and dried at 50.degree. C. in vacuo to give the
Polymorph (1.55 g).
Example2
[0056] To a mixture of absolute ethanol (30 ml, water <0.1 %
w/v) and methanol (1.2 ml) was added Compound (I) (2.00 g). The
resulting suspension was heated to 45-7.degree. C. and maintained
at this temperature for 65 h. The solid was isolated at 45.degree.
C. and dried at 50.degree. C. in vacuo to give 0.83 g (41%) of
Polymorph.
Example 3
[0057] Compound (I) (6.0 g, containing approximately 25% w/w of the
hydrate disclosed in WO99/31093) was heated at 60.degree. C. in
denatured ethanol (60 ml, water content 0.8% w/v) until complete
dissolution was obtained. The resultant solution was cooled to
55.degree. C., seeded with the title compound (0.06 g), then cooled
to 20-25.degree. C. The product was filtered, washed with denatured
ethanol (10 ml) and dried at 50.degree. C. in vacuo to give the
Polymorph (4.8 g, 80%).
Example 4
Conversion of the Polymorph to Compound (I) (the Original
Polymorph)
[0058] The Polymorph (4.0 g) was heated to 68.degree. C. in a
mixture of absolute ethanol (40 ml) and methanol (0.4 ml) until
complete dissolution was obtained. The resultant solution was
filtered, re-heated to 65.degree. C., and then cooled to
20-25.degree. C. The product was filtered, washed with absolute
ethanol (8 ml) and dried at 50.degree. C. in vacuo to give Compound
(I) as disclosed in WO94/05659 (3.32 g, 83%).
CHARACTERISING DATA
[0059] The following characterising data were generated for The
polymorph:
[0060] A Water Content
[0061] This was determined as 0.08% w/w using a Karl Fischer
apparatus.
[0062] B Infrared
[0063] The infrared absorption spectrum of a mineral oil dispersion
of the Polymorph 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 as follows: 2720, 1750, 1703, 1640, 1618, 1610, 1573,
1541, 1529, 1513, 1412, 1400, 1360, 1326, 1309, 1300, 1265, 1241,
1213, 1183, 1162, 1112, 1096, 1080, 1068, 1033, 1014, 989, 972,
933, 902, 866, 843, 832, 812, 774, 741, 734, 729, 669, 660, 636,
613, 605, 577, 558, 540, 527, 515, 508 and 473 cm.sup.-1.
[0064] C Raman
[0065] The Raman spectrum of the Polymorph was recorded through a
glass vial using a Perkin Elmer 2000R spectrometer at 4 cm.sup.-1
resolution and is shown in FIG. II (X-axis shows Intensity, Y-axis
shows Raman shift cm.sup.-1, 1800-200 cm.sup.-1). Excitation was
achieved using a Nd:YAG laser (1064 nm) with a power output of 400
mW. Peak positions are as follows: 1749, 1706, 1683, 1611, 1581,
1546, 1511, 1468, 1445, 1435, 1388, 1361, 1327, 1301, 1269, 1250,
1229, 1210, 1179, 1149, 1103, 1056, 1036, 1024, 1005, 989, 920,
843, 827, 800, 782, 768, 744, 722, 670, 637, 605, 560, 541, 512,
473, 429, 408, 397, 347, 322, 298, 271 and 226 cm.sup.-1.
[0066] D NMR
[0067] The 90.56 MHz .sup.13C CP-MAS NMR spectrum for the Polymorph
is shown in FIG. III. Chemical shifts are tabulated in Table I.
Data were recorded at ambient temperature and 10 kHz spinning
frequency on a Bruker AMX360 spectrometer, with 1.6 ms cross
polarization, and a repetition time of 15 s. Chemical shifts were
externally referenced to the carboxylate signal of a glycine test
sample at 176.4 ppm relative to tetramethylsilane, and are regarded
as accurate to within +/-0.5 ppm. Peaks were not assigned.
1TABLE I .sup.13C Chemical Shifts of the Polymorph. Chemical Shift
(ppm) 42.2 112.3 131.5 146.5 172.4 50.7 113.9 134.1 151.4 177.4
55.9 118.8 138.7 158.7 62.7 129.8 140.5 170.3
[0068] E X-Ray Powder Diffraction (XRPD)
[0069] The XRPD pattern of the Polymorph is shown below in FIG. IV
and a summary of the XRPD angles and calculated lattice spacings
characteristic of the Polymorph is given in Table II.
[0070] A PW1710 X-ray powder diffractometer (Cu X-ray source) was
used to generate the powder pattern using the following acquisition
conditions:
2 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: 0.020.degree. 2.theta. Time per step: 2.3 s
[0071]
3TABLE II X-Ray Powder Diffraction Angles and Calculated Lattice
Spacings Characteristic of the Polymorph. Diffraction Angle Lattice
Spacing (.degree.2.theta.) (Angstroms) 8.9 9.90 12.0 7.35 14.0 6.32
15.4 5.73 15.9 5.55 16.8 5.26 17.4 5.08 18.1 4.89 19.2 4.60 19.6
4.52 20.0 4.44 20.3 4.37 20.8 4.27 21.2 4.18 22.3 3.97 23.7 3.80
24.3 3.75 25.1 3.54 25.8 3.44 26.7 3.33 27.2 3.27 28.7 3.10 29.6
3.01 30.6 2.92 31.6 2.83 32.2 2.78 33.3 2.69
* * * * *