U.S. patent application number 11/928791 was filed with the patent office on 2008-08-07 for process of preparation of olanzapine form i.
Invention is credited to Hiren V. Patel, Mahendra R. Patel, Pramod B. Patel, Anup K. Ray.
Application Number | 20080188465 11/928791 |
Document ID | / |
Family ID | 29709737 |
Filed Date | 2008-08-07 |
United States Patent
Application |
20080188465 |
Kind Code |
A1 |
Patel; Hiren V. ; et
al. |
August 7, 2008 |
Process of Preparation of Olanzapine Form I
Abstract
A process for the preparation of polymorph Form I of
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2.3-b][1,5]benzodiazepine,
or olanzapine.
Inventors: |
Patel; Hiren V.; (Fords,
NJ) ; Ray; Anup K.; (Staten Island, NY) ;
Patel; Pramod B.; (Bordentown, NJ) ; Patel; Mahendra
R.; (East Brunswick, NJ) |
Correspondence
Address: |
SANDOZ INC
506 CARNEFIE CENTER
PRINCETON
NJ
08540
US
|
Family ID: |
29709737 |
Appl. No.: |
11/928791 |
Filed: |
October 30, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10449643 |
May 30, 2003 |
7297789 |
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11928791 |
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10160958 |
May 31, 2002 |
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10449643 |
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Current U.S.
Class: |
514/220 ;
540/557 |
Current CPC
Class: |
C07D 495/04 20130101;
A61P 25/18 20180101; A61P 25/00 20180101; A61P 25/22 20180101 |
Class at
Publication: |
514/220 ;
540/557 |
International
Class: |
A61K 31/551 20060101
A61K031/551; C07D 243/06 20060101 C07D243/06; A61P 25/18 20060101
A61P025/18; A61P 25/22 20060101 A61P025/22 |
Claims
1-17. (canceled)
18. Olanzapine Form I having a polymorphic purity of at least 98%,
having an X-ray diffraction pattern characterized by the following
interplanar spacing values (d) and relative intensities (I/I.sub.0)
TABLE-US-00004 d value I/I.sub.o value 9.9463 100.0 8.5579 15.18
6.8862 14.73 4.8333 68.37 4.7255 21.88 4.533 17.83 4.2346 18.88
4.855 17.29 3.7489 10.64 3.6983 14.65.
19. Olanzapine Form I of claim 18 having a polymorphic purity of at
least 99%.
20. Olanzapine Form I of claim 18 substantially free of olanzapine
Form II.
21. A pharmaceutical composition comprising a compound of claim 18
and a pharmaceutically acceptable diluent or carrier therefor.
22. A method of treating a person suffering from or being,
susceptible to psychosis, acute mania, or mild anxiety states which
comprises administering to said person an effective amount of a
compound of claim 18.
Description
BACKGROUND OF THE INVENTION
[0001] The compound
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine
is named olanzapine according to the U.S.A.N. It is known as an
anti-psychotic agent. Form I of
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine,
having m.p. 195.degree. C., is used in pharmaceutical formulations.
A process to prepare olanzapine is disclosed in U.S. Pat. No.
5.229,382, which is incorporated herein by reference. The last step
of the reaction disclosed in the patent comprises mixing
4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine and
4-methylpiperazine and refluxing in a suitable organic solvent to
yield the desired Form I. It has been found that olanzapine
prepared according to the process of the '382 patent is
contaminated with olanzapine Form II as an impurity. Accordingly
there is a need for a process to prepare olanzapine Form I free of
the Form II impurity.
SUMMARY OF THE INVENTION
[0002] The present invention provides a process to prepare
olanzapine Form I free from impurity with Form II. The present
invention provides an improvement to the process of the prior art.
This improvement is in the purification and separation of
olanzapine Form I from the reaction mixture by the application of a
different pH in its solution state with different organic solvents.
This technique yields very stable pure anhydrous polymorphic Form I
which is free of other polymorphs and solvating agents such as
water and organic solvents. Form I olanzapine prepared by the
process of the present invention also has satisfactory color and
thermal stability for use in a pharmaceutical solid dosage form.
The process of the present invention is environmentally friendly
and can be applied in large scale, e.g. on the kg level, for
commercial manufacturing of olanzapine Form I.
DETAILED DESCRIPTION OF THE DRAWINGS
[0003] FIG. 1 is the FT-IR spectrum of olanzapine Form I prepared
according to the present invention.
[0004] FIG. 2 is the FT-IR spectrum of Form I olanzapine prepared
according to the present invention and olanzapine Form II
standard.
DETAILED DESCRIPTION OF THE INVENTION
[0005] The present invention is directed to a process for producing
olanzapine Form I, which comprises reacting N-methylpiperazine and
a compound of formula I:
##STR00001##
in which Q is a radical capable of being split off.
[0006] The radical Q can, for example, be an amino group or a mono-
or dialkyl-substituted amino group (each alkyl substituent
containing 1 to 4 carbon atoms), hydroxyl, thiol, or an alkoxy,
alkylthio, or alkylsulphonyl group containing 1 to 4 carbon atoms,
such as methoxy or methylthio, or a halogen, such as chlorine.
Preferably, Q is amino (--NH.sub.2), hydroxyl, or thiol, amino
being preferred. The amidine of formula I, where Q is --NH.sub.2,
can be in a salt form, for example a salt of a mineral acid such as
the hydrochloride.
[0007] The reaction is carried out in the presence of an aprotic
high boiling solvent, preferably anhydrous dimethyl sulfoxide, at a
temperature of 50.degree. C. to 200.degree. C., or 90.degree. C. to
130.degree. C., or from 115.degree. C. to 120.degree. C., or around
110.degree. C. The aprotic solvent, preferably anhydrous, may be
dimethyl sulfoxide, dimethyformamide, or mixtures of either of
these with toluene. The resulting olanzapine is purified in an
acidic medium followed by extraction with organic solvents. The
acidic medium for the purification step can be prepared with an
organic acid, preferably 40-60% acetic acid. The resulting mixture
is then basified (pH 7.5-9.0) under cold conditions, 0.degree. C.
to 10.degree. C., preferably to a pH of 7.5-8.5, using an inorganic
base such as sodium hydroxide, potassium hydroxide or lithium
hydroxide. Sodium hydroxide is the preferred agent. More preferably
30-60% aqueous sodium hydroxide is used. After the desired pH is
obtained, the mixture is subject to extraction using a low boiling
organic solvent such as diethylether, dichloromethane,
dichloroethane, chloroform, ethyl acetate, or other low polar
ketonic solvents. Preferably, the solvent is dichloromethane.
[0008] After extraction with a low boiling organic solvent, a high
boiling basic solvent is then added to the aqueous phase comprising
olanzapine. A critical step lies in the use of a basic solvent to
purify and separate out olanzapine Form I. "Basic solvent" as used
herein refers to the solvent state that results from the
combination of an inorganic base and a high boiling solvent.
Examples of high boiling solvents include toluene, methyl ethyl
ketone, and acetonitrile. Toluene is most preferred. In a preferred
embodiment, the basic solvent comprises toluene and alcoholic
sodium hydroxide. Examples of alcohols include methanol, ethanol,
and isopropanol, with methanol being most preferred. The most
preferred basic solvent is toluene and methanolic sodium
hydroxide.
[0009] In one embodiment of the present invention, prior to
extraction, the solution is made basic to a pH of about 7.5-9.0
using aqueous sodium hydroxide. With the solution in this basic
state, extraction is done with dichloromethane. Each extraction
step produces an aqueous phase and a dichloromethane phase. After
washings and extraction, the residual dichloromethane is completely
removed by rotary evaporation since it can cause conversion to
olanzapine Form II. After removal of the dichloromethane, a high
boiling solvent, such as toluene, and a basic solvent such as
methanolic NaOH are added. To increase yield, pure olanzapine Form
I can be crystallized from the basic solvent state by seeding.
Crystallization is preferably accomplished at 0.degree. C. to
30.degree. C. The prior art method used toluene as solvent.
However, toluene alone also results in some Form II contamination.
By the addition of toluene in a basic state only polymorph Form I
is obtained.
[0010] In another embodiment of the present invention, the reaction
mixture is extracted using a low boiling point solvent with good
solubility, preferably dichloromethane, prior to basifying, to pH
7.5-9.0 as discussed above.
[0011] Another embodiment of the invention is ultra-pure olanzapine
Form I, i.e., olanzapine Form I substantially free of other
polymorphic forms of olanzapine; in particular, free of olanzapine
Form II. By substantially free is meant 98-100%, preferably at
least 99%, free of other polymorphic forms.
[0012] Another embodiment of the invention is a pharmaceutical
composition comprising ultra-pure olanzapine Form I and a
pharmaceutically acceptable diluent or carrier therefor.
[0013] Another embodiment of the invention is a method of treating
a person in need thereof, e.g. someone suffering from or
susceptible to psychosis, acute mania, or mild anxiety states,
which comprises administering to said person an effective amount of
ultra-pure olanzapine Form I.
[0014] The invention will now be illustrated by the following
examples, which are illustrative and not intended to limit the
scope of the invention.
EXAMPLE 1
Ultra-Pure Olanzapine Form I
##STR00002##
[0016] A three necked flask, fitted with a nitrogen gas inlet and a
water condenser with calcium chloride guard tube, is charged with
4-amino-2-methyl-10H-theino[2,3-b][1,5]benzodiazepine HCl (5.0 g,
0.0188 mol), 1-methylpiperazine (13.0 mL, 0.11 mol. 99.0%, Aldrich
Chemicals, USA) and anhydrous dimethyl sulfoxide (30.0 mL, Aldrich
Chemicals. USA, water<0.1%). The reaction mixture is stirred at
112-115.degree. C. (oil bath temperature 115.degree. C.) for 16
hours under continuous flow of nitrogen to drive away the ammonia
gas generated during the reaction. The reaction is monitored by
HPLC and it is found that within 16 hours 97% product is formed.
The reaction mixture is cooled to room temperature (24-25.degree.
C.) and added dropwise to a mixture of
dichloromethane:water:methanol (190:190:15, 395 mL). After
addition, the reaction mixture is stirred for 30 minutes at room
temperature. The resulting mixture is yellowish hazy with a dark
brown organic layer settled at the bottom of the flask. The dark
brown colored dichloromethane layer is separated from the aqueous
hazy phase.
[0017] After separating the organic layer, the aqueous hazy phase
is again extracted with dichloromethane (1.times.100.0 mL). The
combined dichloromethane phases (total volume 290.0 mL) are
extracted twice with 50% aqueous acetic acid solution (1.times.100
mL. 1.times.75.0 mL). A dark orange color acetic acid layer is
separated. The pH of the acetic acid solution is found to be around
3.0-3.5 when tested by litmus paper. Combined aqueous acetic acid
solution is basified, to pH 7.5-8.5. using 40% aqueous sodium
hydroxide solution under cold conditions (0-10.degree. C.). After
attaining the desired pH of the solution, 200 mL dichloromethane is
added and stirred. The content is transferred to a separating
funnel and is vigorously shaken. The dichloromethane layer is
separated and the aqueous phase is again extracted with
dichloromethane (1.times.75.0 mL). The combined dichloromethane
extracts are washed with cold saturated sodium chloride solution
(1.times.30.0 mL) and dried over anhydrous sodium sulfate. Removal
of solvent on a rotary evaporator with a water bath temperature of
45.degree. C., gives a dark orange brown viscous liquid. To this
viscous liquid, 80-85.0 mL dry toluene is added.
[0018] The toluene containing crude olanzapine is transferred into
a dry 250 mL single necked round bottom flask. Methanolic sodium
hydroxide solution (0.32 g sodium hydroxide dissolved in 3.0-4.0 mL
methanol by sonication) is added and the mixture is heated in an
oil bath at 60.degree. C. for 2 hours. After the stipulated time,
20-25% of the total volume of solvent is evaporated on a rotary
evaporator with a 55-60.degree. C. water bath, to ensure the
complete removal of dichloromethane and trace amounts of water,
resulting in a final volume of between 55-60 mL. The hot solution
is removed from the water bath and cooled in an ice bath with
stirring. Within 2-3 minutes, the solution is quickly seeded with
previously prepared ultra pure olanzapine Form I, as determined by
X-Ray and IR, with stirring. Stirring is continued for 40-45
minutes. The yellowish solid obtained in the solution is filtered
off, washed with 1.5-2.0 mL dichloromethane and dried on a vacuum
pump for 50-60 minutes to give 4.85 g (82.4% yield) of olanzapine
Form I. The solid obtained is crushed to a fine powder and air
dried to remove traces of dichloromethane. Karl Fisher analysis
indicates 5000-8000 ppm water content. The material is dried in an
oven at 65.degree. C. for 1.5-2.0 hours and analyzed for water
(670-860 ppm water). The weight of the title product is 4.80 g (82%
yield), HPLC purity=99.83%, polymorphic purity is 100% as no
detectable polymorph II is observed by X-ray and IR, as shown in
Example 3.
[0019] The HPLC conditions are as follows: Column:
SymmetryC.sub.18. 4.6.times.250 mm [0020] .lamda..sub.max: 254 nm
[0021] Flowrate: 1.0 mL/min. [0022] Run Time: 70 minutes
[0023] The buffer comprises 5.4 g potassium phosphate: 0.5 g
heptanesulfonic acid sodium salt and 0.5 g 1-octanesulfonic acid
sodium salt dissolved in 500 mL DI water and adjusted the pH to 2.6
using conc. phosphoric acid. The mobile phase was 500 mL buffer/300
mL acetonitrile/200 mL methanol. The final pH of the mobile phase
is about 3.6. The concentration of the standard is 100 .mu.g/mL:
the injection volume is 15 .mu.l: and RT=4.6-4.7 min.
EXAMPLE 2
Recrystallization
[0024] From the dried yellowish solid prepared according to Example
1, 2.0 g (0.0064 mol) is transferred into a single necked round
bottom flask provided with a magnetic stirrer. To the solid, 40.0
mL dry toluene and methanolic sodium hydroxide solution (0.052 g
sodium hydroxide pellets dissolved in 2.0 mL methanol by
sonication) are added. To this mixture 3.5-4.0 mL dichloromethane
is added.
[0025] The mixture is heated for 5-10 minutes in an oil-bath at
60-65.degree. C. until a clear solution is obtained. After heating,
the solution is transferred into an ice bath and seeded with
previously prepared ultra-pure olanzapine Form I. The solution is
stirred for 30-35 minutes at 0-10.degree. C. The yellowish solid
obtained is filtered on vacuum pump and washed with 2.0-2.5 mL
dichloromethane. The solid is dried on a vacuum pump for 40-45
minutes. The solid obtained is crushed into a fine powder and air
dried to remove traces of dichloromethane. The air dried material
is further dried in the oven at 65.degree. C. for 1.5-2.0 hours and
analyzed for water content. Karl Fisher study shows 670-860 ppm
water content. The weight of olanzapine Form I is 1.93 g (95.0%
crystallization yield) of 99.96% HPLC purity.
EXAMPLE 3
X-Ray Powder Diffractometry Study
[0026] Olanzapine Form I prepared according to Example 1 is
analyzed by X-ray, IR, and DSC and found to conform to a
commercially available reference standard olanzapine Form I. DSC of
the olanzapine Form I prepared according to the present invention
shows an endotherm peak at 195.degree. C.
[0027] The X-ray powder diffractometry (XRD) study of olanzapine
Form I and Form II is done in the following manner. The polymorph
powder is filled into an aluminum holder and exposed to CuK.alpha.
radiation (40 kV.times.30 mA) in a wide range X-ray powder
diffractometer (Model D5005, Siemens). The instrument is operated
in the step-scan mode, in increments of 0.02.degree. 2.theta.. The
angular range is 5 to 50.degree. 2.theta. and counts are
accumulated for 1 second at each step. A typical x-ray diffraction
pattern for Form I is as follows, wherein d represents the
interplanar spacing and I/I.sub.0 represents the typical relative
intensities. In the following tables (olanzapine Form I and Form
II) only those peaks are listed whose relative intensity I/I.sub.0
is equal or greater than 10%.
TABLE-US-00001 FORM I d I/Io 9.9463 100.00 8.5579 15.18 6.8862
14.73 4.8333 68.37 4.7255 21.88 4.533 17.83 4.2346 18.88 4.855
17.29 3.7489 10.64 3.6983 14.65
[0028] A typical example of an X-ray diffraction pattern for Form
II is as follows, wherein d represents the interplanar spacing and
I/I.sub.0 (>10%) represents the typical relative intensities.
Standard polymorph Form II was obtained from Neuland Laboratories,
India.
TABLE-US-00002 FORM II d I/Io 10.2689 100.00 4.4787 14.72 4.2294
23.19 4.141 11.28 3.7206 14.04
EXAMPLE 4
Form I vs Form II
[0029] Identification and polymorphic purity of olanzapine Form I
prepared according to Example 1 has been investigated by FT-IR.
FT-IR can distinguish clearly the presence of either polymorphic
Form I or polymorphic Form II in the mixture. A peak-to-peak
comparison of the FT-IR for both forms clearly show characteristic
regions where one of the forms does not show any peak while the
other form does (Table 1).
[0030] The expanded FT-IR spectrum (FIG. 1, Table 1 in bold) shows
that Form II's peak region at 886 cm.sup.-1 is missing in Form I
and is well separated from the closest peak of Form I at 903
cm.sup.-1. In a standard addition method using FT-IR, a
contamination level of a minimum 2% of Form II in Form I can be
detected and quantified. The expanded FT-IR spectrum (FIG. 2) shows
Form II at a 3% level and a 5% level in Form I. Reference standard
polymorph Form I was obtained from Dr. Reddy's Laboratories and
Form II from Neuland Laboratories. India.
TABLE-US-00003 TABLE 1 FT-IR of Olanzapine Polymorphic Form I and
Form II Form I (.nu., cm.sup.-1) Form II (.nu., cm.sup.-1) 661 --
-- 671 -- 746 758 -- 779, doublet 785, singlet 832 -- -- 886 903 --
-- 941 -- 964 970 -- 1005 -- -- 1009 -- 1102 -- 1259 -- 1330 1344,
singlet 1344, doublet -- 1369 1526 --
EXAMPLE 5
Synthesis of Olanzapine Polymorphic Form I
[0031] A three necked flask, fitted with nitrogen gas inlet and a
water condenser with a calcium chloride guard tube, was charged
with 4-amino-2-methyl-10H-theino[2,3-b][1,5]benzodiazepine HCl (5.0
g, 0.0188 mol. Neuland Laboratories, India), 1-methylpiperazine
(13.0 mL. 0.11 mol. 99.0%, Aldrich Chemicals, USA), and anhydrous
dimethyl sulfoxide (30.0 mL, Aldrich Chemicals, USA,
water<0.1%). The reaction mixture was stirred at 112-115.degree.
C. (oil bath temperature 115.degree. C.) for 16 hours under
continuous flow of nitrogen to drive away the ammonia gas generated
during the reaction. The reaction was monitored by HPLC and it was
found that within 16 hours 97% product was formed. After the
reaction the mixture was cooled to room temperature (24-25.degree.
C.) and added dropwise to a mixture of
dichloromethane:water:methanol (190:190:15, 395 mL). After
addition, the reaction mixture was stirred for 30 minutes at room
temperature. The resulting mixture was yellowish hazy with dark
brown organic layer settled at the bottom of the flask (500 mL).
The dark brown color dichloromethane layer was separated from the
aqueous hazy phase. After separating the organic layer, the aqueous
hazy phase was again extracted with dichloromethane (1.times.100.0
mL). The combined dichloromethane phase (290.0 mL) was extracted
twice with 50% aqueous acetic acid solution (1.times.100 mL.
1.times.75.0 mL). A dark orange color acetic acid layer was
separated. The pH of the acetic acid solution was found to be
around 3.0-3.5 (tested by litmus paper). The combined aqueous
acetic acid solution was basified using 40% aqueous sodium
hydroxide solution under cold condition (0-10.degree. C.) to pH
7.5-8.0. (During the basification step, pH above 8.0 results in the
appearance of solids.) After attaining the desired pH,
dichloromethane was added (200 mL) and the solution was stirred.
(In the alternative, the pH may be adjusted after the addition of
dichloromethane in the aqueous acetic acid phase). The content was
transferred to a separating funnel and vigorously shaken. The
dichloromethane layer was separated and the aqueous phase was again
extracted with dichloromethane (1.times.75.0 mL). The combined
dichloromethane extract was washed with cold saturated sodium
chloride solution (1.times.30.0 mL) and dried over anhydrous sodium
sulfate. While drying, the solution with sodium sulfate is shaken
vigorously up and down in order to remove the water efficiently.)
Removal of solvent on rotary evaporator (water bath temperature
45.degree. C.) gave a dark orange brown viscous liquid with 10-15%
total dichloromethane. To this viscous liquid, 80-85.0 mL dry
toluene was added. The toluene containing crude olanzapine was
neatly transferred into a dry 250 mL single necked round bottom
flask and the mixture was heated (oil bath temperature 60.degree.
C.) after the addition of methanolic sodium hydroxide solution
(0.32 g sodium hydroxide dissolved in 3.0-4.0 mL methanol by
sonication). The reaction mixture was heated for 2 hours at
60.degree. C. After the stipulated time, 20-25% of the total volume
of solvent was evaporated on rotary evaporator (water bath
temperature 55-60.degree. C.) to ensure the complete removal of
dichloromethane and trace amounts of water, resulting in a final
volume of the solution between 55-60 mL. The hot solution was
removed from the water bath and kept at room temperature. The
yellowish solid obtained in the solution was filtered off, washed
with a small amount of dichloromethane (1.5-2.0 mL), and dried on a
vacuum pump for 50-60 minutes to give 4.85 g (82.4 % yield) of the
title product. The solid obtained was crushed to a fine powder and
air dried to remove all traces of dichloromethane and toluene. Karl
Fisher analysis indicated 5000-8000 ppm water content. The material
was dried in an oven at 65.degree. C. for 1.5-2.0 hours and
analyzed for water (670-860 ppm water). The weight of the title
product was 4.80 g (82% yield), HPLC purity=99.83%. X-ray, IR, and
DSC conform to the reference standard olanzapine Form I.
EXAMPLE 6
Synthesis of Ultra-Pure Olanzapine Polymorphic Form I
[0032] From the dried yellowish solid prepared according to Example
5, 2.0 g (0.0064 mol) was transferred into a single necked round
bottom flask provided with a magnetic stirrer. To this 40.0 mL dry
toluene and methanolic sodium hydroxide solution (0.052 g sodium
hydroxide pellets dissolved in 2.0 mL methanol by sonication) was
added. To this mixture 3.5-4.0 mL dichlorolmethane was added. The
mixture was heated for 5-10 minutes (oil-bath temperature
60-65.degree. C.) until a clear solution was obtained. After
heating, the solution was placed immediately into an ice-bath
(ice-bath temperature 0-10.degree. C.) and seeded quickly with
previously made pure olanzapine Form I. The solution was stirred
for 30-35 minutes at 0-10.degree. C. temperature. The yellowish
solid obtained was filtered on a vacuum pump and washed with a
small quantity of dichloromethane (2.0-2.5 mL). The solid was dried
on a vacuum pump for 40-45 minutes. The obtained solid was crushed
into fine powder and air dried to remove all traces of
dichloromethane and toluene. The air dried material was dried in
the oven at 65.degree. C. for 1.5-2.0 hours and analyzed for water
content. Karl Fisher study showed 670-860 ppm water content. The
weight of the title product was 1.93 g (95.0% crystallization
yield) of 99.96% HPLC purity.
[0033] X-ray. IR. DSC of the crystallized product conforms to
reference standard olanzapine Form I and equivalent to the results
of the solid obtained in first crystallization (as is). FT-IR shows
apparently 100% polymorphic purity when compared with 2% standard
addition technique of Form II with Form I. [0034] Yield=79%, HPLC
Purity=99.86% [0035] X-ray, IR, DSC exactly matches with the
product of Example 5.
* * * * *