Technical Field
The field of the invention relates to processes for the preparation of pure galantamine or
pharmaceutically acceptable salts thereof. More particularly, it relates to the preparation of pure
galantamine hydrobromide. The invention also relates to pharmaceutical compositions that
include the pure galantamine or pharmaceutically acceptable salts thereof and use of said
compositions for treating Alzheimer's disease, dementia, mania, fatigue syndrome, and
schizophrenia.
Background Art
-Galantamine of Formula I is a tertiary amaryllidaceae alkaloid of high
pharmacological activity. Chemically, galantamine is (4aS,6R,8aS)-4a,5,9,10,ll,12-hexahydro-
3-methoxy-ll-methyl-6H-benzofuro[3a,3,2efJ[2]benzazepin-6-ol. Galantamine is indicated for
the treatment of mild to moderate dementia of the Alzheimer's type.
FORMULA I
Galantamine is commercially available in the form of galantamine hydrobromide and is
useful in treatment of Alzheimer's disease, dementia, mania, fatigue syndrome, schizophrenia
and for inhibiting acetyl cholinesterase activity and reported in literature for example, in U.S.
Patent Nos. 4,663,318; 5,312,817; 5,336,675; 5,633,238 and 6,319,919.
Galantamine can be isolated from daffodils (Narcissus pseudonarcissus L.) by the
extraction process which is proved to be quite expensive for pharmaceutical grade material, even
when taking into account large scale production efficiencies.
An alternate source of (-)-galantamine or a pharmaceutically acceptable salt thereof is its
chemical synthesis. Some synthetic routes to galantamine have been reported for example, in J.
Chem. Soc. 1962, 806; Heterocycles 1977, 8, 277; and Chemical Pharmaceutical Bull.
Some processes for the preparation of racemic galantamine have been reported for
example, in J. Heterocyclic Chem., 1988, 25, 1809; J. Org. Chem. 1971, 36, 1295; J. Chemical
Society Perkin Trans. 1, 1972, 1513; J. Heterocyclic. Chem. 1973, 10, 35; Tetrahedron 1989,
45, 3329; and,/. American Chemical Society 1988, 110, 314. However, the racemic galantamine
would still need to be resolved.
Several processes have been reported for the preparation and/or isolation of galantamine
or pharmaceutically acceptable salts thereof for example, in U.S. Patent Nos. 5,877,172;
6,018,043; 6,043,359; 6,087,495; 6,093,815; 6,184,004; 6,346,618; 6,369,238 and 6,407,229.Notwithstanding these advances, the synthetic approach to (-)-galantamine production in
high purity pharmaceutical grade on a commercial scale is still problematic. The formation of
impurities and cost effectiveness coupled with low yields is very common.
Thus, the present invention provides a process which does not result in impure
galantamine or a pharmaceutically acceptable salt thereof; rather pure galantamine having total
impurities less than 1.0% is obtained. The galantamine hydrobromide when made by the process
of the present invention is pure and cost efficient thus making the process amenable
commercial scale use.
Disclosure
Summary of the Invention
In one general aspect there is provided a process for the preparation of pure galantamine
of Formula I, or a pharmaceutically acceptable salt thereof.
H,C
FORMULA I
The process includes reducing racemic narwedine of Formula II,
FORMULA II
with a reducing agent in one or more solvents to get racemic galantamine or a
pharmaceutically acceptable salt thereof, treating the racemic galantamine with a chiral auxiliary
to get (-)-isomer of Formula III,
.CHI
FORMULA III
wherein CHI represent the chiral auxiliary used, and converting the compound of
Formula III to compound of Formula I, or a pharmaceutically acceptable salt thereof.
The reducing agent may be one or more of metal borohydrides wherein the metal may be
lithium, aluminium or sodium. The reducing agent may include one or more of Vitride ®, Lselectride
®, lithium aluminium hydride, and lithium borohydride. The solvent may be one or
more of tetrahydrofuran, 1,4-dioxane, diethyl ether, diisopropyl ether, N-methylpyrrolidine and
N,N-dimethylformamide.
The process may include further drying of the product obtained.
The process may produce the pure galantamine or a pharmaceutically acceptable salt
thereof having purity more than 99% when determined by HPLC. In particular, it may produce
the pure galantamine or a pharmaceutically acceptable salt thereof having purity more than
99.5% by HPLC.
In another general aspect there is provided a pure galantamine of Formula I or apharmaceutically acceptable salt thereof having a purity of more than 99% w/w as determinedby HPLC method. In particular, the purity of galantamine or a pharmaceutically acceptable salt
thereof is more than 99.5% w/w as determined by HPLC method.
In another general aspect there is provided Form I of galantamine hydrobromide.
The Form I of galantamine hydrobromide may have the X-ray diffraction pattern of
Figure 1, infrared spectrum of Figure 2, and differential scanning calorimetry thermogram of
Figure 3.
In another general aspect there is provided a process for preparing Form I galantamine
hydrobromide. The process includes treating galantamine or a pharmaceutically acceptable salt
thereof with an aqueous alkali to get galantamine base; extracting the galantamine free base in
one or more solvents to get a solution containing galantamine free base; concentrating the
solution to get a residue; dissolving the residue in a second solvent to get a solution; treating the
solution of galantamine base with ethanolic aqueous hydrobromic acid; and isolating the
galantamine hydrobromide Form I from the reaction mixture thereof.
The process may include further drying of the product obtained.
In another general aspect there is provided a pharmaceutical composition that includes a
therapeutically effective amount of the Form I of galantamine hydrobromide; and one or more
pharmaceutically acceptable carriers, excipients or diluents.
In another general aspect there is provided a method of inhibiting acetyl cholinesterase
enzyme in a warm-blooded animal, the method comprising providing a pharmaceutical
composition to the warm-blooded animal that includes the Form I of galantamine hydrobromide.
The details of one or more embodiments of the inventions are set forth in the description
below. Other features, objects and advantages of the inventions will be apparent from the
description and claims.
Detailed Description of the Invention
The inventors have developed a synthetic process for the preparation of pure
galantamine, or a pharmaceutically acceptable salt thereof, by reducing racemic narwedine of
with a reducing agent in one or more solvents to get racemic galantamine or a
pharmaceutically acceptable salt thereof, treating the racemic galantamine with a chiral auxiliary
FORMULA III
wherein CHI represents the chiral auxiliary used, and converting the compound of
Formula III to compound of Formula I, or a pharmaceutically acceptable salt thereof.
The compound of Formula I may be further or additionally purified to get the pure
galantamine of Formula I, or a pharmaceutically acceptable salt thereof.
In general, the reducing agent used in reduction of keto group to hydroxyl functionality
and the solvents used in such processes are known to a person of ordinary skills in the art
through several literature references. In particular, the reducing agent may be one or more of
metal borohydrides wherein the metal may be lithium, aluminium or sodium. The reducing agent
may include one or more of Vitride ®, L-selectride®, lithium aluminium hydride, and lithium
borohydride. The solvent may be one or more of tetrahydrofuran, 1,4-dioxane, diethyl ether,
diisopropyl ether, N-methylpyrrolidine and N,N-dimethylformamide.
In general, the reduction may be carried out at a temperature of from about -70 °C to
about 10°C. In particular, it may be carried out at a temperature from about -20 °C to about 0°C.
The racemic narwedine of Formula II may be added in lots to a pre-cooled solution of reducing
agent in an organic solvent.
After completion of reduction, the temperature of the reaction mass may be raised to
about 20°C and the excess reducing agent as well as side products formed can be quenched by
addition of ethanol. The resultant mass after filtration gives compound of Formula I as a racemic
mixture which can be isolated by converting to a salt such as hydrobromide by treating with
hydrobromic acid. The solid salt can be filtered from the reaction mass and dried suitably.
The racemic product or its salt obtained can be dissolved in a suitable organic solvent,
water or mixtures thereof. If a salt is used then it can be first converted to a free base by treating
with a dilute alkali solution. The suitable organic solvent can be one or more of water-miscible
or immiscible solvents, including, for example, ethyl acetate, methyl formate, methyl acetate, nbutyl
acetate, tetrahydrofuran, methanol, ethanol, isopropanol, n-butanol, dichloromethane,
chloroform, carbon tetrachloride, acetone, methyl isobutyl ketone, ethyl methyl ketone,
diisobutyl ketone and acetonirile. Mixtures of all of these solvents are also contemplated.The separated base may be extracted in a water immiscible organic solvent, including,
for example, ethyl acetate, methyl formate, methyl acetate, n-butyl acetate, dichloromethane,
chloroform and carbon tetrachloride. The organic extract can be concentrated and the residue
obtained can be re-dissolved in an alcoholic solvent. A suitable alcohol includes one or more of
methanol, ethanol, isopropanol, n-butanol and n-propanol. To this solution, a chiral auxiliary
may be added and the resultant mass can be stirred for a sufficient time at lower temperature to
induce crystallization of the desired (-)-isomer of galantamine as its salt of chiral auxiliary of
Formula III. The precipitated product can be filtered, washed with cold alcoholic organic solvent
and recrystallized if required to get desired purity. Any chiral auxiliary known to a person
skilled in the art can be used. In particular, di-4-toluoyl-D-tartaric acid can be used as a chiral
auxiliary.
The chiral auxiliary salt of Formula III can be converted to a free base of Formula I by
treating it with a dilute alkali solution, including, for example, ammonia. In general, the free
base of Formula I can be isolated from the reaction mass by extractive work-up. Alternatively,
the solution of free base can be treated with a pharmaceutically acceptable acid and
pharmaceutically acceptable salt of galantamine can be prepared.
The salt or the free base can be further or additionally recrystallized to get the pure
galantamine of Formula I, or a pharmaceutically acceptable salt thereof.
The pure galantamine or a pharmaceutically acceptable salt thereof has a purity of more
than 99% w/w as determined by HPLC method. More particularly, the purity of galantamine or a
pharmaceutically acceptable salt thereof is more than 99.5% w/w as determined by HPLC
method.
The pure galantamine or a pharmaceutically acceptable salt thereof has an individual
known impurity less than 0.2% w/w with total impurities less than 1% w/w when determined by
HPLC method. More particularly, the galantamine has an individual impurity less than 0.1%
w/w with total impurities less than 0.5%.The commonly encountered impurities in galantamine are N-desmethyl galantamine of
Formula IV, chloromethyl quaternary salt of Formula V, dihydrogalantamine of Formula VI,
epigalantamine of Formula VII, narwedine of Formula II, dehydrogalantamine of Formula VIII
and bromogalantamine of Formula IX.
.OH
H,C
NH
FORMULA IV
H,C
H3C
FORMULA V
H,C
FORMULA VI
OH
FORMULA VII
H,C
FORMULA II
H,C'
FORMULA IX
H,C
FORMULA VIII
In one aspect, the pure galantamine or a pharmaceutically acceptable salt thereof has a
dehydrogalantamine impurity of Formula VIII less than 0.2% w/w. Dehydrogalantamine is a
known impurity but once formed it is very difficult to remove the impurity from the final
product. Although this is a metabolite of galantamine, its activity and toxicity is not fully
established.
The inventors have found a novel polymorphic Form I of galantamine hydrobromide.
The Form I is characterized by its X-ray powder diffraction pattern as shown in Figure 1,
infrared spectrum as shown in Figure 2, and differential scanning calorimetry thermogram as
shown in Figure 3.
In general, the Form I galantamine hydrobromide may be characterized by X-ray
diffraction peaks at about 12.66, 13.46,17.40, 20.56, 23.12, 26.58 and 27.82 ± 0.2 degrees twotheta.
It may be further characterized by X-ray diffraction peaks at about 13.16, 24.06, 24.76,
27.28, 28.20, 29.10, 29.40, 30.50, and 31.62 ± 0.2 degrees two-theta.
The Form I galantamine hydrobromide may also be characterized by DSC melting
exotherm at 280°C with a melting range of about 275 °C to 283°C.
The inventors also have developed a process for the preparation of Form I of galantaminehydrobromide, by treating galantamine or a pharmaceutically acceptable salt thereof with an
aqueous alkali to get galantamine base; extracting the galantamine free base in one or more
solvents to get a solution containing galantamine free base; concentrating the solution to get a
residue; dissolving the residue in a second solvent to get a solution; treating the solution of
galantamine base with ethanolic aqueous hydrobromic acid; and isolating galantamine
hydrobromide Form I from the reaction mixture thereof.
Galantamine or its pharmaceutically acceptable salt may be taken in water and pH of the
reaction mass may be adjusted with an alkali solution to about 8.5 to 9.5. Any alkali can be used
including for example, liquor ammonia. The aqueous layer may be extracted with an organic
solvent. A suitable solvent includes a solvent in which the galantamine free base is soluble and
the solvent is insoluble in water. Some examples of such solvents include chloroform, methylene
chloride, ethyl acetate, ethyl formate, methyl formate, methyl acetate, isopropyl acetate, isobutyl
acetate and n-butyl acetate. The organic extract may be washed with water to remove traces of
inorganic and related organic impurities and the extract may be concentrated. It may be
concentrated by distillation at atmospheric pressure or under reduced pressure. The residue of
galantamine free base may be dissolved in a second organic solvent including for example, CM
straight or branched chain alcohols, polar aprotic solvents, CB-IO ketones, water or mixtures
thereof. A suitable alcohol includes one or more of methanol, ethanol, n-propanol, isopropanol,
n-butanol, isobutanol and t-butanol. Examples of polar aprotic solvents include tetrahydrofuran,
1,4-dioxane, N,N-dimethylformamide, dimethylsulphoxide, acetonitrile and Nmethylpyrrolidone.
Examples of ketones include acetone, ethyl methyl ketone, methyl isobutyl
ketone, diisobutyl ketone, methyl t-butyl ketone. A mixture of second organic solvent with water
in varying proportions can also be used.
The solution obtained may be cooled up to about -15°C to 10°C and treated with
ethanolic aqueous hydrobromic acid solution to attain a pH of about 2 to 4. In particular, the pH
may be adjusted to about 2.5 to 3.0. It may be stirred for about 1 to 10 hours; the product
obtained may be filtered and washed with a second organic solvent.
The product obtained may be further or additionally dried. For example, the product may
be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
The resulting crystalline galantamine hydrobromide may be formulated into ordinary
dosage forms such as, for example, tablets, capsules, pills, solutions, etc. In these cases, the
medicaments can be prepared by conventional methods with conventional pharmaceutical
excipients.
The galantamine hydrobromide can be administered for the treatment of Alzheimer's
disease, dementia, mania, fatigue syndrome, schizophrenia and for inhibiting acetyl
cholinesterase activity in a warm-blooded animal.
For the purpose of this disclosure, a warm-blooded animal is a member of the animal
kingdom possessed of a homeostatic mechanism and includes mammals and birds.
The salt is generally administered as part of a pharmaceutical composition with a
pharmaceutically acceptable carrier, diluent or excipient and optionally other therapeutic
ingredients. The salt may be conventionally formulated into tablets, capsules, suspensions,
dispersions, injectables and other pharmaceutical forms. Any suitable route of administration
may be employed for example, peroral or parenteral.
The present invention is further illustrated by the following examples which are provided
merely to be exemplary of the invention and do not limit the scope of the invention. Certain
modifications and equivalents will be apparent to those skilled in the art and are intended to be
included within the scope of the present invention.
Example 1: Preparation of racemic galantamine hydrobromide
L-Selectride (lithium tri-sec-butylborohydride, l.OM solution in tetrahydrofuran) (396.5
g) was charged under nitrogen atmosphere, followed by tetrahydrofuran (100 ml) at 0-5°C. This
mixture was cooled to -20 to -22°C and narwedine (100 g) was charged in lots over a period of
about 3 hours at -18 to -20°C. Tetrahydrofuran (25 ml) was used to wash the addition vessel
and the reaction mixture was stirred for 30 minutes at -15 to -20°C. It was heated to 20°C and
10
ethanol (400 ml) was added. The reaction mixture was stirred for 30 minutes at 20 - 30°C,
filtered and washed with a mixture of tetrahydrofuran and ethanol (200 ml, 1:1). The filtrate was
cooled to 0 to -5°C and aqueous hydrobromic acid (-48%, 82 ml) was added to adjust the pH to
3.0 to 3.5 at 0 to -5°C. It was stirred for 2 hours at 0 - 5°C. The separated solids were filtered,
washed with cold ethanol (300 ml) and air dried at 50 - 55°C till loss on drying was not more
than 2.5%.
Yield: 116g.
Example 2: Preparation of (-) galantamine tartarate
Racemic galantamine hydrobromide (100 gm) was dissolved in water (3200 ml) and the
solution was filtered through celite bed. The celite bed was washed with water (300 ml) and
washings were combined with the filtrate. The combined aqueous layer was washed with
dichloromethane (300 ml) and the organic layer was discarded. To the aqueous layer,
dichloromethane (1000 ml) was charged and pH of the aqueous layer was adjusted to 8.9 to 9.1
using aqueous ammonia at 0 - 5°C. The aqueous layer was separated and extracted with
dichloromethane (100 ml). The combined organic layers were washed with water (2 x 300 ml)
and the organic layer was concentrated under vacuum at 30 - 35°C. The residue was dissolved
in methanol (200 ml) and cooled to 5 - 10°C. Di-p-toluoyl-D-tartaric acid (105 gm) was
separately dissolved in methanol (300 ml) and cooled to 5 - 10°C. The solution of tartaric acid
was added to the solution of the compound and additional quantity of methanol (250 ml) was
used to wash the flask containing solution of tartaric acid. This mixture was stirred for 30 min at
5 - 10°C and for 24 hours at 0 - 2°C. The solids were filtered and washed with cold methanol
(300 ml). The wet product was crystallized in ethanol (400 ml) by refluxing for 30 minutes
followed by stirring at 0 - 2°C for 3 hours, solid was filtered and washed with cold ethanol (100
ml). Crystallization in ethanol was repeated again. Finally, the product was refluxed with
methanol (400 ml) for 30 minutes, cooled to 15 - 20°C, stirred for 3 hours and filtered. It was
washed with methanol (100 ml) and air dried at 50 - 55°C till loss on drying was not more than
1.0%.
Yield: 57 g.
Example 3: Preparation of crude galantamine hydrobromide
(-) Galantamine tartarate (100 g) was taken in a mixture of dichloromethane (600 ml),
water (400 ml) and pH of the mixture was adjusted to 8.9 to 9.1 using aqueous ammonia at 5 -
10°C. The organic layer was separated and the aqueous layer was extracted with
dichloromethane (600 ml). The combined organic layer was washed with water (2 x 300 ml). A
mixture of ethanol and -48% aqueous hydrobromic acid (1:1, 1 ml) was added to the organic
layer and the mass was concentrated at 30 - 35°C under reduced pressure. The free base so
11
obtained was dissolved in a mixture of ethanol (1260 ml) and water (110 ml) and cooled to 0 to
-5°C. A mixture of ethanol and -48% aqueous hydrobromic acid (1:1, 32 ml) was added at 0 to
-5°C to bring pH to 2.5 - 3.0, and stirred for 3 hours at 0 - 5°C. The separated solids were
filtered and washed with ethanol (200 ml) to afford crude wet galantamine hydrobromide. This
material was used as such for the next step.
Yield: 62 g.
Example 4: Preparation of pure galantamine hydrobromide
Crude wet galantamine hydrobromide (62 g) was taken in water (220 ml) and pH of the
mixture was adjusted to 8.9 to 9.1 using aqueous ammonia at 10 - 15°C. The free base thus
obtained was extracted in ethyl acetate (2 x 750 ml + 375 ml). The combined organic layers
were washed with water (2 x 200 ml) and were concentrated at 45 - 50°C at reduced pressure.
The free base was dissolved in a mixture of ethanol (1150 ml) and water (100 ml) at 40 - 50°C.
The solution was filtered through a micron filter and cooled to 0 to -5°C. Ethanolic aqueous
hydrobromic acid solution (1:1, 30 ml) was added to adjust pH to 2.5 to 3.0 at 0 to -5°C. The
resultant mass was stirred for 3 hours at 0 - 5°C, filtered and washed with ethanol (300 ml). The
solid product was dried under vacuum at 50 - 55°C till loss on drying is not more than 0.2% to
get the pure galantamine hydrobromide having XRD, FTIR and DSC properties as shown in
Figures 1, 2 and 3, respectively.
Yield: 38 g.
Impurity profile:
a) Any single impurity: Less than 0.2% w/w
b) Total impurities: 0.42% w/w
While the present invention has been described in terms of its specific embodiments,
certain modifications and equivalents will be apparent to those skilled in the art and are intended
to be included within the scope of the present invention.
Description of the Drawings
Figure 1 is X-ray powder diffraction pattern of Form I of galantamine hydrobromide.
Figure 2 is an infrared spectrum of Form I of galantamine hydrobromide.
Figure 3 is differential scanning calorimetry thermogram of Form I of galantamine
hydrobromide.

WE CLAIM:
1. A process for the preparation of pure galantamine of Formula I or a pharmaceutically
acceptable salt thereof, having purity more than 99% by HPLC,
FORMULA I
the process comprising:
a) reducing racemic narwedine of Formula II,
FORMULA II
with a reducing agent in one or more solvents to get racemic galantamine or a
pharmaceutically acceptable salt thereof;
b) treating the racemic product of step a) with a chiral auxiliary to get (-)-isomer of
Formula III,
FORMULA III
wherein CHI represent the chiral auxiliary used; and
c) converting the compound of Formula III to compound of Formula I, or a
pharmaceutically acceptable salt thereof.
13
2. The process of claim 1, wherein the reducing agent comprises one or more of metal
borohydrides, wherein the metal is lithium, aluminium or sodium.
3. The process of claim 1, wherein the reducing agent is L-selectride®.
4. The process of claim 1, wherein the solvent comprises one or more of tetrahydrofuran,
1,4-dioxane, diethyl ether, diisopropyl ether, N-methylpyrrolidine, and N,Ndimethylformamide.
5. The process of claim 1, wherein the chiral auxiliary is di-4-toluoyl-D-tartaric acid.
6. The process of claim 1, wherein the compound of Formula III is converted to compound
of Formula I, by treating it with an alkali.
7. The process of claim 1, further comprising purification of compound of Formula I.
8. The process of claim 1, further comprising forming the product obtained into a finished
dosage form.
9. A pharmaceutical composition comprising a therapeutically effective amount of pure
galantamine of Formula I or a pharmaceutically acceptable salt thereof; and one or more
pharmaceutically acceptable carriers, excipients or diluents.
10. A method of inhibiting acetyl cholinesterase enzyme in a warm-blooded animal, the
method comprising providing a dosage form to the warm-blooded animal that includes
pure galantamine of Formula I or a pharmaceutically acceptable salt thereof.
14
11. Pure galantamine or a pharmaceutically acceptable salt thereof having purity more than99% when determined by HPLC.12. Galantamine or a pharmaceutically acceptable salt thereof having less than 0.2% w/w of
dehydrogalantamine of Formula VIII when determined by HPLC.
FORMULA VIII
13. Form I of galantamine hydrobromide, wherein the galantamine hydrobromide has the Xray
diffraction (XRD) pattern of Figure 1.
14. The galantamine hydrobromide of claim 13, wherein the galantamine hydrobromide has
the X-ray diffraction peaks at about 12.66, 13.46, 17.40, 20.56, 23.12, 26.58 and 27.82 ±
0.2 degrees two-theta.
15. The Form I of galantamine hydrobromide having infrared spectrum of Figure 2.
16. The Form I of galantamine hydrobromide having differential scanning calorimetry
thermogram of Figure 3.
17. The galantamine hydrobromide of claim 16, wherein the galantamine hydrobromide has
a melting exotherm at 280°C with a melting range of about 275 °C to about 283°C.
18. A process for the preparation of Form I of galantamine hydrobromide, the process
comprising:
15
a) treating galantamine or a pharmaceutically acceptable salt thereof with an aqueous
alkali to get galantamine base;
b) extracting the galantamine free base in one or more solvents to get a solution
containing galantamine free base;
c) concentrating the solution obtained in step b) to get a residue;
d) dissolving the residue obtained in step c) in a second solvent to get a solution;
e) treating the solution of galantamine base obtained in step d) with ethanolic aqueous
hydrobromic acid; and
f) isolating galantamine hydrobromide Form I from the reaction mixture thereof.
19. The process of claim 18, wherein the alkali is ammonia.
20. The process of claim 18, wherein the solvent comprises one or more of chloroform,
methylene chloride, ethyl acetate, ethyl formate, methyl formate, methyl acetate,
isopropyl acetate, isobutyl acetate and n-butyl acetate.
21. The process of claim 18, wherein the second solvent comprises one or more of 1-.4
straight or branched chain alcohol, polar aprotic solvent, C3-10 ketone, water, or mixtures
thereof.
22. A pharmaceutical composition comprising a therapeutically effective amount of Form I
of galantamine hydrobromide; and one or more pharmaceutically acceptable carriers,
excipients or diluents.
23. A method of inhibiting acetyl cholinesterase enzyme in a warm-blooded animal, the
method comprising providing a dosage form to the warm-blooded animal that includesForm I of galantamine hydrobromide.