OLANZAPINE DIHYDRATE D
This invention relates to the crystalline
dihydrate D of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-
thieno[2,3-b][1,5]benzodiazepine (referred to herein as
"olanzapine"). The invention more specifically relates to a
novel crystalline form which is particularly useful for
preparing an aqueous olanzapine formulation.
The stable crystalline Dihydrate D is particularly
important for the commercial development of new formulations
of the pharmaceutically active olanzapine. Olanzapine is
useful for treating psychotic patients. Often an aqueous
formulation or a formulation that is prepared using aqueous
mixing is desired. Applicants have discovered that Form II
olanzapine is the most stable anhydrous form of olanzapine,
providing a stable anhydrous formulation with
pharmaceutically desired characteristics. However, a stable
dihydrate was desired to provide pharmaceutically elegant
aqueous formulations.
A novel dihydrate crystal form of olanzapine has
now been synthesized and characterized which possesses
distinct advantages over the previously known forms, that is
the material produced using the methods described in U.S.
Patent No. 5,299,382 (hereinafter referred to as "the x382
patent"), when aqueous formulations or a stable aqueous
intermediate is desired. This novel dihydrate crystal form
is clearly distinguishable therefrom by x-ray powder
diffractometry. U.S. Patent No. 5,229,382 is hereby
incorporated by reference in its entirety.
Applicants have discovered that Dihydrate D
olanzapine is essential to assure a pharmaceutically
elegant, aqueous formulation. Applicants have found that
olanzapine forms a Dihydrate B; however, this form appears
to be quite unstable compared to Dihydrate D. Dihydrate D
requires controlled conditions to prepare the substantially
pure Dihydrate D material; however, once prepared, the
Dihydrate D is surprisingly robust and stable. Therefore,
Dihydrate D olanzapine is most desired and appears to be
essential for use in preparing consistently stable
commercial pharmaceutically elegant aqueous olanzapine
formulations as well as for pharmaceutically elegant
formulations prepared using extensive aqueous mixing.
The presently claimed invention provides the
stable crystalline Dihydrate D olanzapine polymorph (hereinl
referred to as "Dihydrate D") having a typical x-ray powder
diffraction pattern as represented by the following
interplanar spacings (d) as set forth in Table 1:
The x-ray powder diffraction patterns set forth
herein were obtained with a copper k of wavelength = 1.541
A. The interplanar spacings in the column marked "d" are
reported in Angstroms. The detector was a Kevex silicon
lithium solid state detector.
The present invention further provides an aqueous
formulation comprising Dihydrate D as an active ingredient
with one or more carriers or diluents therefor.
Applicants have discovered that 2-methyl-4-(4-
methyl-1-piperazinyl)-lOH-thieno[2,3-b][1,5]benzodiazepine,
which is a compound of Formula (I):
exists as two different dihydrate forms which are
distinguishable by x-ray powder diffractometry. The less
stable, and therefore less desired dihydrate has been
designated as Dihydrate B. Applicants have discovered that
a stable dihydrate is necessary for the preparation of a
consistently stable pharmaceutically elegant aqueous
formulation. Both dihydrate forms are clearly
distinguishable from the polymorph taught in the '382
patent.
The polymorph obtainable by the process taught in
the x382 patent is an anhydrate form which is not as stable
as desired and not well suited for pharmaceutical
formulations. The anhydrate obtainable by the process of
the x382 patent will be designated as Form I and has a
typical x-ray powder diffraction pattern substantially as
follows, obtained using a Siemens D5000 x-ray powder
diffractometer, wherein d represents the interplanar
spacing:
A typical example of an x-ray diffraction pattern
for Form I is as follows, wherein d represents the
interplanar spacing and I/I; represents the typical relative
intensities:
The x-ray powder diffraction patters herein were
obtained with a copper Ka of wavelength X = 1.541A. The
interplanar spacings in the column marked "d" are in
Angstroms. The typical relative intensities are in the
column marked "I/I-/'.
A typical example of an x-ray diffraction pattern
for the anhydrous Form II polymorph (see EP 733,635) is as
follows wherein d represents the interplanar spacing and
I/Ii represents the typical relative intensities:
As used herein "substantially pure" refers to
Dihydrate D associated with less than about 20% Dihydrate B,
preferably less than about 5% Dihydrate B and may preferably
be less than about 2% Dihydrate B. Further, "substantially
pure" Dihydrate D will contain less than about 0.5% related
substances, wherein "related substances" refers to undesired
chemical impurities or residual organic solvent.
Advantageously, the novel polymorph of the
invention will be free from chemical solvates, for instance
existing as the substantially pure Dihydrate D.
Pharmaceutical formulations containing Dihydrate D
should contain less than about 20% Dihydrate B, more
preferably less than about 10% Dihydrate B polymorph.
Olanzapine has useful central nervous system
activity. This activity has been demonstrated using well-
established procedures, for example, as described in the
x382 patent. Dihydrate D provided by the present invention
appears to have the same profile of receptor activity and
has the same therapeutic uses as olanzapine described in the
,382 patent. Therefore, Dihydrate D is useful for the
treatment of schizophrenia, schizophreniform disorders,
psychosis, mild anxiety states, and functional bowel
disorders.
Dihydrate D is effective over a wide dosage range,
the actual dose administered being dependent on the
condition being treated. For example, in the treatment of
adult humans, dosages of from about 0.25 to 50 mg,
preferably from 1 to 30 mg, and most preferably 1 to 25 mg
per day may be used. A once a day dosage is normally
sufficient, although divided doses may be administered. For
treatment of central nervous system disorders, a dose range
of from 1 to 30 mg, preferably 2.5 to 20 mg per day is
suitable.
A typical example of an x-ray diffraction pattern
for Dihydrate D is as follows, wherein d represents the
interplanar spacing and I/I: represents the typical relative
intensities:
The x-ray powder diffraction patterns herein were
obtained with a copper Ka of wavelength A. = 1.541A. The
interplanar spacings in the column marked "d" are in
Angstroms. The typical relative intensities are in the
column marked "I/Ii".
The typical example of an x-ray diffraction
pattern for the less stable Dihydrate B polymorph is as
follows, wherein d represents the interplanar spacing and
I/In represents the typical relative intensities:
A typical example of an x-ray diffraction pattern
for the anhydrous Form II polymorph is as follows, wherein d
represents the interplanar spacing and I/I] represents the
typical relative intensities:
As used herein, the term "mammal" shall refer to
the Mammalia class of higher vertebrates. The term "mammal"
includes, but is net limited to, a human. The term
"treating" as used herein includes prophylaxis of the named
condition or amelioration or elimination of the condition
once it has been established.
The compounds and processes of the present
invention are useful for preparing compounds having
beneficial, central nervous system activity. Certain
compounds and conditions within the scope of this invention
are preferred. The following conditions, invention
embodiments, and compound characteristics listed in tabular
form may be independently combined to produce a variety of
preferred compounds and process conditions. The following
list cf embodiments of this invention is not intended to
limit the scope of this invention in any way.
Some preferred characteristics of this invention
include the following:
A) A compound which is the Dihydrate D polymorph
of 7-methyl-4- (4-methyl-l-piperazinyl)-10H-
thieno[2,3-b][1,5]benzodiazepine (Dihydrate D
polymorph) ;
B} A compound which is the substantially pure
Dihydrate D polymorph;
C) An aqueous suspension formulation containing
Dihydrate D;
D) A tablet formulation containing substantially
pure Dihydrate D which is packaged in a blister
packaged under humid conditions;
E) A consistently stable pharmaceuticaliy elegant
aqueous formulation containing substantially
pure Dihydrate D;
F) Substantially pure Dihydrate D is formulated in
a unit dosage form;
G) Substantially pure Dihydrate D is formulated
for rapid dissolution;
H) Substantially pure Dihydrate D is used for
treating a condition selected from the group
consisting of a psychosis, schizophrenia, a
schizophreniform disorder, mild anxiety, and
acute mania;
I) An aqueous suspension formulation containing
Dihydrate D as an active ingredient wherein
such formulation is suitable for injection.
J) A tablet formulation containing substantially
pure Dihydrate D which is package in an air
resistant package.
Depending on the method of administration, the
compositions for the treatment of central nervous system
conditions may be formulated as tablets, capsules, gel or
suspension for transdermal delivery, suspensions or elixirs
for oral use or suppositories. If such formulation is a
tablet or capsule, then such formulation is most preferably
packaged under humid conditions and sealed in an air
impermeable sachet or blister pack. Preferably, the
compositions are formulated in a unit dosage form, each
dosage containing from 0.25 to 100 mg, more usually 1 to 30
mg, of the active ingredient. When a sustained release
formulation is desired, the unit dosage form may contain
from 0.25 to 200 mg of the active ingredient. A preferred
formulation of the invention is an aqueous suspension
comprising 0.25 to 75 mg or 1 to 30 mg of active ingredient
together with a pharmaceutically acceptable carrier
therefor.
The starting materials for the present invention
can be prepared by a variety of procedures well known to
those of ordinary skill in the art. The material to be
employed as starting materials in the process of this
invention can be prepared by the general procedure taught by
Chakrabarti in U.S. Patent No. 5,229,382 ('382), herein
incorporated by reference in its entirety.
The Dihydrate D is prepared by extensive stirring
of technical olanzapine, which may be prepared as described
by Preparation 1, under aqueous conditions. The term
"aqueous conditions" refers to an aqueous solvent which may
be either water or a solvent mixture comprising water and an
organic solvent which is sufficiently water miscible to
allow the required stoichiometric quantity of water to be
present in the solvent mixture. If a solvent mixture is
utilized, then the organic solvent must be removed, leaving
behind the water, and/or replaced with water. The term
"extensive stirring" shall be from about one (1) hour to
about six (6) days; however, the artisan will appreciate
that the time will vary with the reaction conditions such as
temperature, pressure, and solvent. It maybe preferred to
stir for at least about four (4) hours. It is preferred
that the aqueous conditions include an aqueous solvent.
However, it is to be noted that to form polymorph D, rather
than other dihydrate polymorphs, more extensive stirring
and/or agitation is required, preferably is excess of 12
hours, more preferably in excess of 24 hours. Further, a
wetting agent may be added to the aqueous mixture to speed
up the formation of the stable Dihydrate D.
Dihydrate D may be air dried or dried using other
standard techniques which are sufficiently mild to avoid
desolvation of the Dihydrate D.
The completion of the reaction may be monitored
using x-ray powder diffraction and other such methods
familiar to the skilled artisan. Several such techniques
are described below.
Compound characterization methods include, for
example, x-ray powder pattern analysis, thermogravimetric
analysis (TGA), differential scanning calorimetery (DSC),
titrametric analysis for water, and H:-NMR analysis for
solvent content.
Accordingly, pharmaceutical compositions
comprising Dihydrate D, as active ingredient associated with
a pharmaceutically acceptable carrier may be prepared. In
making the compositions of the invention conventional
techniques for the preparation of pharmaceutical
compositions can be used. For example, the active
ingredient can usually be mixed with a carrier, or diluted
by a carrier, or enclosed within a carrier which may be in
the form of a capsule, sachet, paper or other container.
When the carrier serves as a diluent, it may be solid, semi-
solid or liquid material which acts as a vehicle, excipient
or medium for the active ingredient. The active ingredient
can be absorbed in a granular solid container, for example,
in a sachet. Some examples of suitable carriers are
lactose, dextrose, sucrose, sorbitol, mannitol, starches,
gum acacia, calcium phosphate, alginates, tragacanth,
gelatin, syrup, methyl cellulose, methyl- and propyl-
hydroxy-benzoate, talc, magnesium stearate or mineral oil.
The compositions of the invention may, if desired, be
formulated so as to provide quick, sustained or delayed
release of the active ingredient after administration to the
patient. For example, one such quick release formulation is
described in US. Patent Nos. 4,305,502 and 4,371,516, hereby
incorporated by reference.
It is typically preferred that such formulation
includes a pharmaceutically acceptable flavoring agent or
combinations of such agents, including natural and synthetic
flavoring agents such as ASPARTANE® and flavor enhancing
agents, such as the commercial product VELTOL® (Pfizer);
preservatives such as methyl paraben, propyl paraben and
combinations thereof are further preferred.
Another preferred embodiment of this invention is
the formulation methods described in U.S. Patent No.
4,758,598, herein incorporated by reference in its entirety.
A particularly preferred method for treating a
subject suffering from or susceptible to a psychotic
condition comprises administering an aqueous oral suspension
formulation comprising Dihydrate D olanzapine and
pharmaceutically acceptable carriers and/or excipients.
The following examples are provided for purposes
of illustration and are not to be construed as limiting the
scope of the claimed invention.
In a suitable three neck flask the following was
added:
Dimethylsulfoxide (analytical): 6 volumes
Intermediate 1 : 75 g
N-Methylpiperazine (reagent) : 6 equivalents
Intermediate 1 can be prepared using methods know to the
skilled artisan. For example, the preparation of the
Intermediate 1 is taught in the '382 patent.
A sub-surface nitrogen sparge line was added to remove the
ammonia formed during the reaction. The reaction was heated
to 120°C and maintained at that temperature throughout the
duration of the reaction. The reactions were followed by
HPLC until < 5% of the intermediate 1 was left unreacted.
After the reaction was complete, the mixture was allowed to
cool slowly to 20°C (about 2 hours). The reaction mixture
was then transferred to an appropriate three neck round
bottom flask and water bath. To this solution with
agitation was added 10 volumes reagent grade methanol and
the reaction was stirred at 20°C for 30 minutes. Three
volumes of water were added slowly over about 30 minutes.
The reaction slurry was cooled to zero to 5°C and stirred
for 30 nunutes. The product was filtered and the wet cake
was washed with chilled methanol. The wet cake was dried in
vacuo at 45°C overnight. The product was identified as
technical olanzapine.
Yield: 76.7%; Potency: 98.1%
Example 1
Dihydrate D
A 100 g sample of technical grade olanzapine (see
Preparation 1) was suspended in water (500 mL). The mixture
was stirred at about 25°C for about 5 days. The product was
isolated using vacuum filtration. The product was
identified as Dihydrate D olanzapine using x-ray powder
analysis. Yield: 100 g. TGA mass loss was 10.2%.
Example 2
A sample of gelatin powder (1 g) is admixed with
maltodextran (2 g), gelatin A (0.5 g); sucrose (2 g) and
ASPARTANE© (1 g). Distilled water is added to the mixture
to about 100 mL total volume. The mixture is stirred and
heated to about 60°C. The mixture should be heated until it
appears to be a clear solution. The mixture is cooled to
about 37°C. Blister molds are prepared by rinsing with a
solution of lecithein (about 10';:) in about 190 proof grain
alcohol. The molds so prepared are dried at room
temperature. An aliquot of the cooled mixture is added to
each compartment of the mold. The mold containing the
mixture is cooled to a temperature of about -10°C or lower
for about 40 minutes. The mold containing the mixture is
removed from the < -10°C environment and about 20 mg of
anhydrous olanzapine is added to the surface of each tablet
within the mold. The mold should remain protected from
thawing. The mold containing the mixture and olanzapine is
again cooled to about -10°C for about 40 minutes.
The mold is removed from the cooled about -10°C
environment and an additional aliquot of the gelatin based
mixture (to which no olanzapine has been added) is added to
the surface of each compartment of the mold prepared as
described supra. The mold is again cooled to about -10°C
for about 40 minutes.
The tablets are removed from the mold to a mesh
plastic bag. The bag and its contents are hermetically
sealed in a container of anhydrous ethyl alcohol and
maintained at a temperature of -20°C. The tablets are
maintained in the hermetically sealed bag until the tablets
are completely dehydrated. The dehydration continues until
no odor or other evidence of alcohol can be detected on the
tablets. The formulation is studied using x-ray powder
diffraction techniques to assure that substantially pure
Dihydrate D is present.
The medicament is passed through a No. 45 mesh
U.S. sieve and mixed with the sodium carboxymethylcellulose
and syrup to form a smooth paste. The benzoic acid
solution, flavor and color is diluted with some of the water
and added to the past with stirring. Sufficient water is
then added to produce the required volume.
The medicament is passed through a No. 45 mesh
U.S. sieve and mixed with the sodium carboxymethylcellulose
and syrup to form a smooth paste. The benzoic acid
solution, flavor and color is diluted with some of the water
and added to the paste with stirring. Sufficient water is
then added to produce the required volume.
C3raims~
1. Dihydrate D olanzapine polymorph having a
typical x-ray powder diffraction pattern as represented by
the following interplanar spacings (d) as set forth in Table
1:
2. A Dihydrate D polymorph as claimed in Claim 1
further characterized by substantially the following x-ray
powder diffraction pattern wherein d represents the
interplanar spacing and I/It represents the typical relative
intensities:
3. Dihydrate D of Claim 1 wherein the Dihydrate
D is substantially pure.
4. Dihydrate D of Claim 2 wherein the Dihydrate
D is substantially pure.
5. Dihydrate D of Claim 2 wherein "substantially
pure" refers to less than2% Dihydrate B wherein Dihydrate B
has a typical x-ray powder diffraction pattern as
represented by the following interplanar spacings (d) as set
forth in Table 2:
6. Bihydrate D of Claim 1 wherein_Dihydrate D is
a stable crystalline pharmaceuticaily polymorph.
7. Dihydrate D of Claim 2 wherein dihydrate D is
a stable crystalline pharmaceuticaily 'polync'rph.
8. A pharmaceutical formulation comprising as an
active ingredient a compound of Claim 1 associated with one
or more pharmaceuticaily acceptable carriers, diluents, or
excipients therefor.
9. A pharmaceutical formulation comprising as an
active ingredient a compound of Claim 2 associated with one
or more pharmaceutically acceptable carriers, diluents, or
excipients therefor.
10. A formulation of Claim 8 wherein the
formulation is an aqueous suspension.
11. A formulation of Claim 8 wherein the
formulation is a tablet.
12. A pharmaceutical formulation comprising as an
active ingredient a compound of Claim 3 associated with on
or more pharmaceutically acceptable carriers, diluents, or
excipients therefor.
13. A formulation of Claim 12 wherein the
formulation is an aqueous suspension.
14. A method for treating a psychotic condition
in a mammal comprising administering an effective amount of
a compound of Claim 1.
15. A method for treating a condition selected
from the group consisting of a/ixiety, schizophrenia,
schizophreniform disorder, a/functional bowel disorder, and
psychosis in a mammal comprising administering an effective
amount of a compound of Claim 1.

The present invention provides the novel Dihydrate
D 2-methyl-thieno-benzodiazepine and a formulation therefor.