FIELD OF THE INVENTION
The field of the invention relates to anhydrous acamprosate calcium and process of its preparation thereof,
BACKGROUND OF THE INVENTION
Acamprosate calcium of formula I, is an important drug used for treating alcohol dependence and is chemically known as 3-(acetylamino)-l-propanesulfonic acid calcium salt (2:1).
(Formula Removed)
Acamprosate has neuromuscular and vasculo-metabolic properties and is thought to stabilize the chemical balance in the brain that would otherwise be disrupted by alcoholism, possibly by blocking glutaminergic N-methyl-1)-aspartate receptors, while gamma-aminobutyric acid type A receptors are activated.
Acamprosate calcium is first disclosed in US patent 4,355,043 and is prepared by treating 3-aminopropane-l-sulfonic acid of formula II,
(Formula Removed)
with calcium hydroxide and acetic acid in water followed by addition of acetic anhydride to obtain crude acamprosate calcium which is further purified in water to get acamprosate calcium. In the example, acamprosate calcium is hydrous in nature
having moisture content of 3.6%. The preparation of 3-aminopropane-l-sulfonic acid of formula II is disclosed in US patent 4,657,704 by the action of aqueous solution of sodium sulfite with 3-chloropropylamine hydrochloride in water
In view of the pharmaceutical value of acomprosate calcium, it has been of prime importance to obtain it with excellent purit. It has also been important to be able to synthesize it by means of a process that can readily be converted to the industrial scale, especially in a form that allows rapid filtration and drying. Finally, that form had to be perfectly reproducible, easily formulated and sufficiently stable to allow its storage for long periods without special requirement for temperature, light or oxygen level.
The US patent 4,355,043 however does not specify the conditions for obtaining acamprosate calcium in a form that exhibits these characteristics in a reproducible manner. Acamprosate calcium is a hydrous solid which is often not ideal for pharmaceutical formulation. There is no reference available wherein anhydrous acamprosate calcium is prepared.
Accordingly, there exists the need for an efficient synthesis of acamprosate calcium which is amenable to scale-up, provides highly pure product.
The Applicant has now found that a particular salt of acamprosate, the calcium, can be obtained in a crystalline form that is well defined and that exhibits valuable characteristics of stability and processability.
SUMMARY OF THE INVENTION
Accordingly, more specifically, the present invention relates to anhydrous acamprosate calcium.
The present invention also provides a process for preparing the anhydrous acamprosate calcium, comprising the steps of:
a) halogenating 3-aminopropanol in halogenated hydrocarbon which in situ is
converted into 3-aminopropanesulphonic acid using aqueous sodium sulfite
solution,
b) purifying crude 3-aminopropanesulphonic acid by treating it with C1-C4
straight or branched chain alcoholic solvents or aqueous mixtures of C1-C4
straight or branched chain alcoholic solvents to obtain purified 3-
aminopropanesulphonic acid,
c) reacting the resulting 3-aminopropanesulphonic acid with a source of calcium
ion and in the presence of acetic anhydride in water to get acamprosate
calcium,
d) treating acamprosate calcium with C1-C4 straight or branched chain alcoholic
solvents or aqueous mixtures of C1-C4 straight or branched chain alcoholic
solvents to obtain anhydrous acamprosate calcium.
In another embodiment, the present invention provides a process for preparing anhydrous acamprosate calcium by treating 3-aminopropanesulphonic acid with a source of calcium ion in the presence of acetic anhydride in water to get acamprosate calcium and treating acamprosate calcium with C1-C4 straight or branched chain alcoholic solvents or aqueous mixtures of C1-C4 straight or branched chain alcoholic solvents to obtain anhydrous acamprosate calcium.
In yet another embodiment, the present invention provides a process for preparing anhydrous acamprosate calcium by treating acamprosate calcium with C1-C4 straight or branched chain alcoholic solvents or aqueous mixtures of C1-C4 straight or branched chain alcoholic solvents, removing alcoholic solvents by known methods to get anhydrous acamprosate calcium.
BRIEF DESCRTPTTON OF THE DRAWINGS
Fig 1: X-ray powder diffraction pattern of anhydrous acamprosate calcium Fig 2: Infra- red spectrum of anhydrous acamprosate calcium Fig 3: DSC of anhydrous acamprosate calcium Fig 4: TGA of anhydrous acamprosate calcium
DETAILED DESCRIPTION OF THE INVENTION
The instant invention relates to anhydrous acamprosate calcium and process of preparation thereof. Preparation of anhydrous acamprosate calcium opens a new path for obtaining acamprosate calcium in high purity.
Further, anhydrous compounds are easier to handle and may allow for more convenient means of manufacturing, packaging, transporting, and administrating.
Anhydrous acamprosate calcium of formula I, can be prepared by treating hydrous acamprosate calcium with C1-C4 straight or branched chain alcoholic solvents or with aqueous C1-C4 straight or branched chain alcoholic solvents. C1-C4 straight or branched chain alcoholic solvents can be selected from methanol. ethanol, isopropanol or mixtures thereof.
The process is reproducible and consistent such that it can be applied in the large scale manufacture of anhydrous acamprosate calcium. During the process the slurry/ solution in organic solvent reduces the amounts of water used during crystallization, thus yielding a significant economical and ecological advantage. It is advantageous to charcolize the acamprosate calcium in polar protic solvent such as water to improve colour.
Generally hydrous acamprosate calcium is prepared by the treatment of a source of calcium ion with sulphonic acid of formula II. Sulphonic acid of formula II is prepared directly from 3-aminopropanol without isolating 3-chloropropyl amine. Particularly it is prepared by the reaction of 3-aminopropanol with thionyl chloride in halogenated hydrocarbon at temperature of 0-40°C. The halogenated hydrocarbon can be selected from methylene dichloride, ethylene dichloridc, carbon tctrachloridc. chloroform or mixtures thereof and preferably methylene dichloridc is used. 3-aminopropanol is refluxed with thionyl chloride in methylene dichloride and the completion of reaction is monitored by TLC, and when 3-aminopropanol is absent, the reaction is stopped. After completion of reaction the solvent is removed and the resulting solid residue is treated with aqueous sodium sulphite solution. The sulphonic acid preparation is conducted at reflux temperature and usually it takes 1 -10 hours for completion of reaction. Thereafter, the separation of compound of formula II from liquid reaction mixture may be carried out by any method known in art. For example, water is removed by distillation and then hydrochloric acid is added to dissolve 3-aminopropanesulphonic acid, followed by removal of resulting
inorganic salt through filtration.
The resulting filtrate is concentrated under vacuum to get 3-aminopropanesulphonic acid of formula II. which is further purified using C1-C4 straight or branched chain alcohols, C1-C4 straight or branched chain alcohols with water.
The resulting 3-aminopropanesulphonic acid of formula II is then dissolved in water and treated with a source of calcium ion in water and then added to acetic anhydride and temperature is maintained at 25-40°C till completion of the reaction. The completion of reaction can be monitored by high performance liquid chromatography or thin layer chromatography. The resulting mixture is concentrated to dryncss and is treated with water to remove excess of acetic anhydride. The source of calcium ion can be selected from calcium acetate, calcium hydroxide, calcium chloride, calcium carbonate and the like.
The resulting acamprosate calcium optionally dried or wet is treated with C1-C4 straight or branched chain alcoholic solvents or with aqueous C1-C4 straight or branched chain alcoholic solvents to obtain anhydrous acamprosate calcium. C1-C4 straight or branched chain alcoholic solvents can be selected from methanol, ethanol, isopropanol or mixtures thereof.
In another embodiment, the present invention provides a process for preparing highly pure anhydrous acamprosate calcium by dissolving acamprosate calcium in C1-C4 straight or branched chain alcohols or in aqueous C1-C4 straight or branched chain alcohols, removing solvent by known methods to get anhydrous acamprosate calcium. C1-C4 straight or branched chain alcohols can be selected from methanol. ethanol, isopropanol or mixtures thereof.
In yet another embodiment, the present invention provides a method of preparing anhydrous acamprosate calcium comprising slurrying/dissolving a starting acamprosate calcium in a solvent selected from the group consisting of: C1-C4 alcohols, C3-C8 ketones, tetrahydrofuran, acetonitrile, butyl-acetate, dimethyl form amide (DMF). a mixture of tetrahydrofuran (THF) and isopropyl alcohol, water, diethyl ether (DEE) and acetone; heating the slurry; and isolating anhydrous acamprosate calcium from the slurry/solution.
The amount of the solvent should be sufficient to form a slurry/solution with the acamprosate calcium. Preferably, the ratio of starting acamprosate calcium to solvent is about 5 to about 25ml of 15% aqueous methanol per gram of acamprosate calcium. More preferably, the ratio of starting acamprosate calcium to solvent is about 8 to about 10 ml per gram of acamprosate calcium. Preferably, the slurry/solution is heated to a temperature of about 50 to about 90°C. More preferably, the slurry/solution is heated to a temperature of about 50 to about 60°C. Preferably, prior to the isolation step the slurry/solution is maintained at the temperature for at least 15-60 minutes, preferably from about 1 hour to about 2 hours. The anhydrous acamprosate calcium can be isolated by any method known in the art. For example, the anhydrous acamprosate calcium can be separated by filtering the slimy or concentrating the solution. The isolating method can further comprise washing and drying the anhydrous acamprosate calcium. Preferably, the anhydrous acamprosate calcium is dried at a temperature of about 60°C to about 100°C. more preferably, at a temperature of about 80°C to about 95°C under reduced pressure. The resulting anhydrous acamprosate calcium is highly pure having an assay of 100.3% by potentiometric analysis and moisture content is less than 0.5% w/w and preferably less than 0.2% w/w by and thermogravimetric analysis (TGA).
As disclosed therein, anhydrous acamprosate calcium has distinct physical properties and may be characterized e.g. by a typical X-ray powder diffraction pattern, infrared spectrum, differential scanning calorimetric (DSC) curve and thermogravimctric analysis (TGA). Each of these characteristics on its own is sufficient to unambiguously define and identify the new polymorphs but they also may be combined with each other. The present invention relates to anhydrous acamprosate calcium characterized by X-ray powder diffraction pattern with peaks at about 11.73, 17.49, 21.63, 24.04, 24.24 and 25.27 + 0.2 degrees two-theta and is further characterized by X-ray powder diffraction pattern with peaks at 9.36, 17.69. 18.70. 22.82, 24.32, and 27.54 degrees two-theta ± 0.2 degrees two-theta.
A characteristic powder X-ray diffraction pattern of anhydrous acamprosate calcium salt is shown in Figure 1 and some characteristic peaks are listed in Table 1.
Table 1
(Table Removed)
Accordingly, in a preferred embodiment, the present invention relates to anhydrous
acamprosate calcium characterized by an X-ray powder diffraction pattern
substantially in accordance with Table 1 and Figure 1.

Anhydrous acamprosate calcium may be also characterized by a typical infrared spectrum as shown in Figure 2. Accordingly, in a further preferred embodiment, the present invention relates to anhydrous acamprosate calcium characterized by an infrared spectrum substantially in accordance with Figure 2. The characteristic bands are present at 3310, 2979, 2935, 1657, 1576, 1370, 1298, 1063, 945 and 789 cm'1.
In addition, anhydrous acamprosate calcium displays a typical DSC curve at a heating rate of 10°C/min from 80-250°C and 5°C/min. from 250-3 50°C/minute. Typical thermogram of anhydrous acamprosate calcium is shown in Figure 3. It can be seen that the DSC curve of anhydrous acamprosate calcium shows two specific endothermic peaks with onset temperatures of about 250°C and 350°C.
Accordingly, in a further preferred embodiment, the present invention relates anhydrous acamprosate calcium which displays differential scanning calorimetric thermogram having two endothermic peaks with onset temperatures of about 250°C and 350°C at a heating rate of 10°C/min from 80-250°C and 5°C/min from 250-350°C/min.
Accordingly, in a further preferred embodiment, the present invention relates anhydrous acamprosate calcium which displays thermogravimetric analysis (TGA) substantially in accordance with Figure 4 that illustrates no loss of water.
X-ray diffraction of acamprosate calcium is measured on a PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacings and relative intensities. One of the ordinary skills in the art understands that experimental differences may arise due to differences in instrumentation, sample preparation or other factors.
All infrared measurements are made on Perkin Elmer Spectrum 100 spectrometer using KBr pellets having the characteristic absorption bands expressed in reciprocal
centimeter. DSC was conducted using a mettler toledo DSC 823e a sample weight of about 4-5 mg.
Thermal weight change measurements were made on a Mettler toledo TGA/SDTA 851e thermogravimetric analyzer. Sample of 6-7mg was placed in an aluminum pan and placed in the device. The data was collected from about 25°C to about 300°C at a rate of 10°C/min.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the analysis of acamprosate calcium and methods for preparing the anhydrous acamprosate calcium of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES
Example 1
Preparation of homotaurine (3-aminopropanesulphonic acid)
To a cooled solution of 3-aminopropanol (l00g) in methylene dichloride (l.0L). thionyl chloride (190g) was added. After complete addition, the temperature of reaction mixture was raised to reflux temperature and stirred for 4 hrs. After completion of the reaction (3-aminopropanol was absent in TLC), methylene dichloride was distilled off completely. To the resulting solid material, a solution of sodium sulphite (220g) in demineralized water (880ml) was added at 40-45°C and refluxed for 6hrs. Thereafter, water was distilled off completely and the residue was dissolved in concentrated hydrochloric acid (400ml). The resulting mixture was filtered to remove sodium chloride and washed with conc, hydrochloric acid (400ml)
and the filtrate was concentrated at 70-90°C to get crude 3-aminopropanesulphonic acid.
Demineralized water (160ml) and methanol (800ml) was added to the crude 3-aminopropanesulphonic acid and stirred for 1hr at 5-10°C. The reaction mass was filtered and washed with methanol (200ml). The wet cake of 3-aminopropanesulphonic acid was charcolized in demineralizcd water (650ml) at 55-60°C thereafter charcoal was filtered off through hyflo bed and the resulting filtrate was concentrated to dryness at 70-90°C.
Demineralized water (160ml) was added to the concentrated residue and the mixture was stirred at 70-90°C till clarity, then reaction mixture was cooled and methanol (800ml) was added. The reaction mixture was further cooled to 5-10°C, stirred for 1hr. The solid, thus obtained, was filtered, washed with methanol (200ml) and dried to get 140g of pure 3-aminopropanesulphonic acid having purity 99.04% area by HPLC
Example 2
Preparation of anhydrous acamprosate calcium
To a solution of 3-aminopropanesulphonic acid (142g) in demineralized water (426ml), a solution of calcium acetate (99.4g) in demineralized water (355ml) was added and the reaction mass was stirred at 35-40°C. The resulting reaction mixture was added to acetic anhydride (1.54kg) slowly at 25-30°C and further stirred for 3hrs. After completion of the reaction, water was distilled off and the resulting residue is dissolved in demineralized water (355ml x 2) and recovered under vacuum at 70-90°C to remove excess acetic anhydride.
Purification
The residue was further taken in demineralized water (170.4ml) at 70-90°C, and after cooling to 50-60°C, methanol was added (1.70L) and stirred for 1-2 hrs at same
temperature. Thereafter the reaction mixture was cooled to ambient temperature. The solid, thus obtained, was filtered and washed with methanol (210ml) to get acamprosate calcium. The wet cake of acamprosate calcium was charcolized in demineralized water (682ml) at 45-50°C thereafter charcoal was filtered off through hyflo bed and the resulting filtrate was concentrated to dryncss at 70-90°C. Demineralized water (142ml) was added to the residue and the mixture was heated to 70-90°C till clear solution. The solution was cooled to 50-60°C and methanol (1.70L) was added and the reaction mixture was further cooled to 20-25°C. The product obtained was filtered, washed with methanol (2.13ml) and dried at 95-l()0°C to obtain 123g of anhydrous acamprosate calcium having an assay 100.1% w/w by potentiometric analysis on dried basis.
Example 3
Preparation of homotaurine (3-aminopropanesulphonic acid)
To a cooled solution of 3-aminopropanol (25g) in methylene dichloride (250ml), thionyl chloride (47.5g) was added. The temperature of reaction mixture was raised and reaction mass was refluxed for 4 hrs. After completion of the reaction (3-aminopropanol absent in TLC), methylene dichloride was distilled off completely. To the resulting solid material, a solution of sodium sulfite (55g) in demineralized water (220ml) was added slowly at 40-45°C and refluxed for further 6hrs. After completion of the reaction, water was distilled off completely and the residue was dissolved in concentrated hydrochloric acid (100ml). The resulting mixture was filtered to remove sodium chloride and washed with concentrated hydrochloric acid (100ml) and the filtrate was concentrated at 70-90°C to get crude 3-aminopropanesulphonic acid. The crude 3-aminopropanesulphonic acid is further purified with demineralized water (40ml) and methanol (200ml) to get the pure 3-aminopropanesulphonic acid having purity 98.72% area by HPLC.
Example 4
Preparation of anhydrous acamprosate calcium
To a solution of 3-aminopropanesulphonic acid (10g) in demineralized water (30ml). a solution of calcium acetate (7g) in demineralized water (25ml) was added and the reaction mass was stirred at 35-40°C. The resulting reaction mixture was added to acetic anhydride (108.4g) slowly at 25-30°C and further stirred for 3hrs. After completion of the reaction, water was distilled off and the resulting residue is dissolved in demineralized water (25ml x 2) and recovered under vacuum at 70-90°C to remove excess acetic anhydride.
Purification
The residue was further taken in demineralized water (12ml) at 70-90°C, and after cooling to 50-60°C, methanol was added (120ml) and stirred for 1-2 hrs at same temperature. Thereafter the reaction mixture was cooled to ambient temperature. The solid, thus obtained, was filtered and washed with methanol (15ml) to get acamprosate calcium. The wet cake of acamprosate calcium was charcolized in demineralized water (48ml) at 45-50°C thereafter charcoal was filtered off through hyflo bed and the resulting filtrate was concentrated to dryness at 70-90°C.Demineralized water (10ml) was added to the residue and the mixture was heated to 70-80°C till clear solution. The solution was cooled to 50-60°C and methanol (120ml) was added and the reaction mixture was further cooled to 20-25°C. The product obtained was filtered, washed with methanol (15ml) and dried at 95-100°C to obtain l0g of anhydrous acamprosate calcium having an assay 99.6% w/w by potentiometric analysis on dried basis.

WE CLAIM
1. A process for the preparation of anhydrous acamprosate calcium which
comprises:
a) halogenating 3-aminopropanol in halogenated hydrocarbon which is
converted in situ to 3-aminopropanesulphonic acid using aqueous sodium
sulfite solution,
b) purifying crude 3-aminopropanesulphonic acid by treating it with C1-C4
straight or branched chain alcoholic solvents or aqueous mixtures of C1-C4
straight or branched chain alcoholic solvents to obtain purified 3-
aminopropanesulphonic acid,
c) reacting the resulting 3-aminopropanesulphonic acid with a source of calcium
ion and in the presence of acetic anhydride in water to get acamprosate
calcium.
d) treating acamprosate calcium with C1-C4 straight or branched chain alcoholic
solvents or aqueous mixtures of C1-C4 straight or branched chain alcoholic
solvents to obtain anhydrous acamprosate calcium.

2. The process according to claim 1, halogenated hydrocarbon used in step a) is
selected from methylene dichloride, ethylene dichloride, carbontetrachloride.
chloroform or mixtures thereof.
3. The process according to claim 1, C1-C4 straight or branched chain alcoholic
solvents is selected from ethanol, methanol, isopropanol or mixtures thereof.
4. The process according to claim 1, source of calcium ion used in step c) is selected
from calcium acetate, calcium hydroxide, calcium chloride and calcium carbonate
and the like.
5. Anhydrous acamprosate calcium.
6. Anhydrous acamprosate calcium having moisture content of NMT 0.5% w/w and
XRD characteristic peaks at 11.73, 17.49, 21.63, 24.04, 24.24 and 25.27 + 0.2
degrees two-theta as shown in Fig. 1.
7. A process for the preparation of anhydrous acamprosate calcium which comprises:

a) treating acamprosate calcium with C1-C4 straight or branched chain alcoholic
solvents or aqueous mixtures of C1-C4 straight or branched chain alcoholic
solvents,
b) removing alcoholic solvents by known methods to get anhydrous acamprosate
calcium.
8. The process according to claim 7, C1-C4 straight or branched chain alcoholic
solvents is selected from ethanol, methanol, isopropanol or mixtures thereof.
9. The process according to claim 7, wherein solvent is removed by filtration.
10. The process according to claim 7, wherein solvent is removed by vacuum drying
or evaporation.