Field of the Invention
The present invention relates to processes for the preparation of anhydrous form of
benfotiamine.
Background of the Invention
Benfotiamine, chemically is S-[2-[[(4-amino-2-methyl-5-pyrimidinyl)methyl]formyl
amino]-1-[2-(phosphonooxy)ethyl]-1-propenyl]ester, represented by Formula I.
N
N
NH2
H3C
N
H O
CH3
S O
O
P
OH
HO
O
Formula I
Benfotiamine is a synthetic S-acyl derivative of thiamine (Vitamin B1) indicated for the
treatment of painful diabetic neuropathy in adults only.
U.S. Patent No. 3,064,000 discloses benfotiamine and its process. Benfotiamine
obtained as per the process disclosed in this patent has melting point about 165C. The
inventors of the present invention reproduced the process and have observed that benfotiamine
obtained is highly hygroscopic and water contents reaches to a value of about 8%.
Japanese Patent No. 37-16042B discloses crystalline forms; crystalline form α having
melting point about 165C; crystalline form β having melting point about 150C and crystalline
form δ having melting point about 195C of benfotiamine. Japanese Patent No. 37-16042B
further discloses that crystalline forms α and β of benfotiamine are hydrated forms whereas
crystalline form δ is without crystal of water.
Japanese Patent No. 37-11040B discloses a preparation of crystalline form δ of
benfotiamine which involves treating benfotiamine with 30% ethanol.
3
Ito et al, “ Research on Vitamins B1 Phosphate ester (no. 6), The crystalline form and
formation of S-Benzoylthiamine O-Monophosphate”, Takamine Kenkyusho Nenpo, 14, 64-66
(1962) discloses crystallization processes wherein α-form is crystallized below 20°C, γ-form
between 20°C to 40°C, and δ-form above 40°C. It further discloses that α-form changes to γform between 30°C to 45°C and to δ-form between 50°C to 100°C in the solid state.
U.S. Patent No. 9,718,846 discloses five crystalline forms of benfotiamine A, B, C, D
and E. U.S. Patent No. ‘846 allegedly discloses that the crystalline form A is free of crystal
water, crystalline form B contains one crystal water, crystalline form C is a solvate, crystalline
form D has half of one crystal water, and crystalline form E has one crystal water.
There is a need in the art to develop an improved process for the preparation of
anhydrous form of benfotiamine.
Summary of the Invention
The present invention relates to processes for the preparation of anhydrous form of
benfotiamine which remains stable in terms of purity, as well as polymorphic form consistency,
and does not absorb moisture over time.
Detailed Description of the Invention
The term “about,” as used herein, refers to any value which lies within the range defined
by a number up to ±10% of the value.
The term “ambient temperature,” as used herein, refers to a temperature in the range of
about 25°C to about 35°C.
The term “reaction mixture”, as used herein, refers to suspension, solution, emulsion,
or precipitate.
The term “contacting”, as used herein refers to dissolving, slurring, stirring, heating,
suspending, or combinations thereof.
The term “anhydrous”, as used herein, refers to a crystalline form that does not have
water bound in the crystal lattice. However the crystal may contain trace amount of water or
other solvents not bound in the crystal lattice. Hydrates and anhydrates may show different
physical properties like stability, dissolution rate and bioavailability as known for polymorphs.
4
The term “base,” as used herein, refers to hydroxides, carbonates, and bicarbonates of
alkali and alkaline earth metals; ammonia; alkyl amines; pyridine; hydrazine; and the like.
Examples of hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals
include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate,
potassium carbonate, sodium bicarbonate, and potassium bicarbonate. Examples of alkyl
amines include diethyl amine, triethylamine, and methyl diethyl amine. Preferably, the base
used is sodium hydroxide.
The term “acid,” as used herein, refers to dilute solution of a strong acid, preferably
dilute hydrochloric acid, dilute sulfuric acid, and dilute nitric acid. Preferably, the acid used is
dilute hydrochloric acid.
The term “seed crystal,” as used herein, refers to a small piece of single
crystal/polycrystal material, which is used for addition to a crystallization system for the
purpose of initiating or enhancing nucleation or acting as a substrate for further crystallization.
A first aspect of the present invention provides a process for the preparation of
anhydrous form of benfotiamine comprising
a) contacting crude benfotiamine with purified water;
b) adding appropriate base to obtain a reaction mixture;
c) adding appropriate acid to the reaction mixture of step b);
d) heating the reaction mixture of step c);
e) optionally seeding the reaction mixture of step d) with seed crystal of anhydrous
form of benfotiamine;
f) adding further appropriate acid to the reaction mixture of step e); and
g) isolating and drying to obtain the anhydrous form of benfotiamine.
Crude benfotiamine used for the preparation of anhydrous form may be prepared by any
method provided in the art, for example, the method as disclosed in U.S. Patent No. 3,064,000.
The seed crystal of anhydrous form of benfotiamine is prepared by method as disclosed
in our co-pending application.
5
In step a), the crude benfotiamine is treated with purified water at ambient temperature
to obtain a reaction mixture. In an embodiment, the reaction mixture of step a) is cooled to
about 15°C.
In an embodiment, the base in step b) is selected from lithium hydroxide, sodium
hydroxide, potassium hydroxide or calcium hydroxide.
In step b), the base is added to the reaction mixture of step a). In an embodiment, the
base is added at a temperature of about 15°C. In another embodiment, the base is added until
the pH is about 6.8 to about 7.8. In yet another embodiment, the base is added until the pH is
about 7.0 to about 7.6. In yet another embodiment, the base is added until the pH is about 7.1
to about 7.5.
In step c), the acid is added to the reaction mixture of step b). In an embodiment, the
acid is added at a temperature of about 15°C. In another embodiment, the acid is added to the
reaction mixture of step b) until the pH about 6.0 to about 6.9. In another embodiment, the acid
is added until the pH is about 6.2 to about 6.8. In yet another embodiment, the acid is added
until pH is about 6.4 to about 6.7.
In step d), the reaction mixture of step c) is then heated to about 35°C to about 50°C. In
an embodiment, the reaction mixture of step c) is heated to about 38°C to about 48°C. In
another embodiment, the reaction mixture of step c) is heated to about 40°C to about 45°C.
The reaction mixture of step d) is further treated with dilute acid until the pH is about
5.0 to about 5.8. In an embodiment, the reaction mixture of step d) is treated with dilute acid
until the pH is about 5.2 to about 5.6. In another embodiment, the reaction mixture of step d)
is treated with dilute acid until the pH is about 5.4 to about 5.5.
In step e), the seed crystal of anhydrous benfotiamine is optionally added to the reaction
mixture of step d). The reaction mixture of step e) is stirred for about 5 minutes to about 30
minutes. In an embodiment, the reaction mixture of step e) is stirred for about 10 minutes to
about 20 minutes. In another embodiment, the reaction mixture of step e) is stirred for about
10 minutes to about 15 minutes.
In step f), the reaction mixture of step e) is further treated with dilute hydrochloric acid
until the pH is about 3.5 to about 4.8. In an embodiment, the reaction mixture of step e) is
6
treated with dilute hydrochloric acid until the pH is about 3.7 to about 4.4. In another
embodiment, the reaction mixture of step e) is treated with dilute hydrochloric acid until the pH
is about 3.9 to about 4.0.
In step g), anhydrous form of benfotiamine may be isolated by filtration, decantation,
extraction, distillation, evaporation, chromatography, precipitation, concentration,
crystallization, centrifugation, and recrystallization. Anhydrous form of benfotiamine may be
dried using conventional techniques, for example, drying, drying under vacuum, spray drying,
suck drying, air drying, or agitated thin film drying.
A second aspect of the present invention provides a process for the preparation of
anhydrous form of benfotiamine comprising
a) contacting crude benfotiamine with purified water;
b) adding appropriate base to obtain a reaction mixture;
c) cooling the reaction mixture of step b);
d) adding appropriate acid to the reaction mixture of step c);
e) optionally seeding the reaction mixture of step d) with seed crystal of anhydrous
form of benfotiamine;
f) adding further appropriate acid to the reaction mixture of step e); and
g) isolating and drying to obtain the anhydrous form of benfotiamine.
Crude benfotiamine used for the preparation of anhydrous form may be prepared by any
method provided in the art, for example, the method as disclosed in U.S. Patent No. 3,064,000.
The seed crystal of anhydrous form of benfotiamine is prepared by method as disclosed
in our co-pending application.
In step a), the crude benfotiamine is treated with purified water at ambient temperature
to obtain a reaction mixture. In an embodiment, the reaction mixture of step a) is cooled to
about 15°C.
In an embodiment, the base in step b) is selected from lithium hydroxide, sodium
hydroxide, potassium hydroxide or calcium hydroxide.
In an embodiment, the base is added is added to the reaction mixture of step a) at a
temperature of about 15°C. In another embodiment, the base is added until the pH is about 6.8
7
to about 7.8. In yet another embodiment, the base is added until the pH is about 7.0 to about
7.6. In yet another embodiment, the base is added until the pH is about 7.1 to about 7.5.
In step c), the reaction mixture of step b) is cooled to a temperature of about 0°C to
about 10°C. In an embodiment, the reaction of step b) is cooled to a temperature of about 0°C
to about 8°C. In another embodiment, the reaction mixture of step b) is cooled to a temperature
of about 0°C to about 5°C.
In step d), the acid is added to the reaction mixture of step c). In an embodiment, the
acid is added at a temperature of about 15°C. In another embodiment, the acid is added until
the pH about 5.0 to about 6.0. In another embodiment, the acid is added until the pH is about
5.3 to about 5.9. In yet another embodiment, the acid is added until pH is about 5.5 to about
5.7.
In step e), the seed crystal of anhydrous benfotiamine is optionally added to the reaction
mixture of step d). The reaction mixture of step e) is stirred for about 5 minutes to about 30
minutes. In an embodiment, the reaction mixture of step e) is stirred for about 10 minutes to
about 20 minutes. In another embodiment, the reaction mixture of step e) is stirred for about
10 minutes to about 15 minutes.
In step f), the reaction mixture of step e) is further treated with dilute acid until the pH
is about 4.0 to about 4.8. In an embodiment, the reaction mixture of step e) is treated with dilute
acid until the pH is about 4.2 to about 4.6. In another embodiment, the reaction mixture of step
e) is treated with dilute acid until the pH is about 4.3 to about 4.5.
The reaction mixture of step f) is further treated with dilute hydrochloric acid until the
pH is about 3.5 to about 4.4. In an embodiment, the reaction mixture of step f) is treated with
dilute hydrochloric acid until the pH is about 3.7 to about 4.4. In another embodiment, the
reaction mixture of step f) is treated with dilute hydrochloric acid until the pH is about 3.9 to
about 4.0.
In step g), anhydrous form of benfotiamine may be isolated by filtration, decantation,
extraction, distillation, evaporation, chromatography, precipitation, concentration,
crystallization, centrifugation, and recrystallization. Anhydrous form of benfotiamine may be
8
dried using conventional techniques, for example, drying, drying under vacuum, spray drying,
suck drying, air drying, or agitated thin film drying.
While the present invention has been described in terms of its specific aspects and
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.
The following examples are for illustrative purposes only and should not be construed
as limiting the scope of the invention in any way.
EXAMPLES
Example 1: Preparation of anhydrous form of benfotiamine of Formula I
Benfotiamine (100 g) was added to demineralized water (400 mL) at ambient
temperature and flushed with water (50 mL) to obtain a reaction mixture. The reaction mixture
was cooled to 15±2°C and dilute aqueous sodium hydroxide solution (~12 %, ~90 mL) was
added to dissolve the material until pH became 7.1 to 7.3 at 15±2°C to obtain a clear solution.
The solution was filtered through filter paper and washed with water (50 mL). Dilute
hydrochloric acid (1:1) was added to the solution until the pH became 6.70 to 6.75 at 15±2°C
and then heated to 40°C to 45°C. Dilute hydrochloric acid was further added until pH became
5.4 to 5.5. The reaction mixture was then seeded with anhydrous benfotiamine (2 g) and stirred
for 10 minutes to 12 minutes for complete precipitation. Dilute hydrochloric acid was further
added until pH became 4.3 to 4.4 at 40°C to 45°C. Dilute hydrochloric acid was continuously
added until pH became 3.9 to 4.0 at 40°C to 45°C to obtain precipitates. The precipitates so
obtained was stirred for 30 minutes and then cooled to 0°C to 5°C. The reaction mass was
further stirred for one hour to obtain a solid. The solid was washed with chilled water (100 mL)
and dried in vacuum tray drier (VTD) at 80°C to 85°C till moisture contents is not more than
(NMT) 0.5%.
Yield: 88.8 g
Melting Point: 190-198°C
Example 2: Preparation of anhydrous form of benfotiamine of Formula I
9
Benfotiamine (50 g) was added to demineralized water (200 mL) at ambient temperature
and flushed with water (50 mL) to obtain a reaction mixture. The reaction mixture was cooled
to 15±2°C and then dilute aqueous sodium hydroxide solution (~12%, ~90 mL) was added to
dissolve the material until pH became 7.0 to 7.5 at 15±2°C to obtain a clear solution. The
solution was filtered through filter paper and washed with water (50 mL). The solution so
obtained was cooled to 0°C to 5°C and then dilute hydrochloric acid (1:1) was added until pH
became 5.5 to 5.8 at 0°C to 5°C. The reaction mixture was seeded with anhydrous benfotiamine
(2 g) and stirred for 10 minutes to 12 minutes for complete precipitation at 0°C to 5°C. Dilute
hydrochloric acid was added to adjust pH became 4.3 to 4.4 and continuously added until pH
became 3.9 to 4.05 to obtain precipitates. The precipitates so obtained was stirred for 60
minutes to obtain a solid. The solid was filtered, washed with chilled water and then dried
under VTD at 80°C to 85°C till moisture contents is NMT 0.5%.
Yield: 44 g
Melting Point: 191-196°C

Claims

1. A process for the preparation of anhydrous form of benfotiamine comprising
a) contacting crude benfotiamine with purified water;
b) adding appropriate base to obtain a reaction mixture;
c) adding appropriate base appropriate acid to the reaction mixture of step b);
d) heating the reaction mixture of step c);
e) optionally seeding the reaction mixture of step d) with seed crystal of anhydrous
form of benfotiamine;
f) adding further appropriate acid to the reaction mixture of step e); and
g) isolating and drying to obtain the anhydrous form of benfotiamine.
2. A process for the preparation of anhydrous form of benfotiamine comprising
a) contacting crude benfotiamine with purified water;
b) adding appropriate base to obtain a reaction mixture;
c) cooling the reaction mixture of step b);
d) adding appropriate acid to the reaction mixture of step c);
e) optionally seeding the reaction mixture of step d) with seed crystal of anhydrous
form of benfotiamine;
f) adding further appropriate acid to the reaction mixture of step e); and
g) isolating and drying to obtain the anhydrous form of benfotiamine.
3. The process according to claim 1 or claim 2, wherein the base is selected from lithium
hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide.
4. The process according to claim 1 or claim 2, wherein the base is added to the reaction
mixture of step a) until the pH is 6.8 to 7.8.
5. The process according to claim 1, wherein the reaction mixture of step c) is heated to
35°C to 50°C.
6. The process according to claim 2, wherein the reaction mixture of step b) is cooled to a
temperature of 0°C to 10°C.
7. The process according to claim 1, wherein the acid is to the reaction mixture of step b)
until the pH is 6.0 to about 6.9.
8. The process according to claim 2, wherein the acid is to the reaction mixture of step c)
until the pH is 5.0 to about 6.0.
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9. The process according to claim 1 or claim 2, wherein the seed crystal of anhydrous form
of benfotiamine is added at an ambient temperature.
10. Anhydrous benfotiamine of Formula I having greater than 99% chromatography purity
obtained according to processes claimed in claims 1 to 9.