The sulfate salt
is the second most common pharmaceutical salt behind the hydrochloride.
Bisulfate salts are quite acidic so the base involved needs to be
acid-stable.
Sulfuric acid is a
diprotic acid. It can form two different stoichiometric salt types: the 1:1
bisulfate salt and the 2:1 sulfate salts in the latter of which two moles of amine are
protonated by the two protons of H2SO4. The pKas
of sulphuric acid are –3 and 1.92 so there are almost five orders of magnitude difference
between the acidity of the first and second hydrogen. Most pharmaceutical salts
are of the 1:1 bisulfate type. Sulfates are most often made by the addition of at least a partially aqueous solution of acid because neat acid is not
soluble in apolar solvents and it has some dehydrating capability which can
lead to by-products when the acid is in excess. Typical organic solvents
used in making sulfates are methanol, ethanol, 1-propanol, 2-propanol, acetone , and mixtures thereof. Acetone, however, is
not recommended because an excess of acid causes the oligomerization of acetone
creating color in the solution.
Kilomentor
anticipates that by providing some examples of pharmaceutical sulfate salt
preparations with some commentary to draw attention to important aspects of the
methods a skilled experimentalist should have no difficulty making others.
US7230016
PREPARATION OF PIOGLITAZONE SULFATE
24.g of sulfuric acid was added slowly, at room
temperature, to 250 ml of methanol followed by addition of 80 g of pioglitazone
base with stirring. The mixture turned into a clear solution. 250 ml of ether
was slowly added followed by 500 ml of heptane. A solid precipitated, and the
suspension was stirred for 3 hours. The solid (98.4 g; yield 96.5%) was
collected by filtering and washed once with ether. The solid had mp: 113.5-116.5° C (recrystallized from methanol).
Comment:
This example illustrates the addition of the base to the organic solution of sulphuric acid in methanol. Although a small amount of methyl hydrogen sulfate might form, this not a problem because MeOSO2OH is a pharmaceutically acceptable counterion. Note also that in the procedure the chemistry provided three opportunities to obtain crystals. Pioglitazone hydrogen sulfate might have precipitated from the methanol solution itself after partial dissolution. The salt might have crystallized when the methanol was diluted 50:50 with diethyl ether. The final opportunity occurred when the solution was diluted 1:1 with heptane and this was successful. Notice that the methanol could not be diluted with heptane directly. Two phases would have resulted. This is an example of a well-designed approach to getting crystalline solid. If crystals still had not formed the solution would have been concentrated.
This example illustrates the addition of the base to the organic solution of sulphuric acid in methanol. Although a small amount of methyl hydrogen sulfate might form, this not a problem because MeOSO2OH is a pharmaceutically acceptable counterion. Note also that in the procedure the chemistry provided three opportunities to obtain crystals. Pioglitazone hydrogen sulfate might have precipitated from the methanol solution itself after partial dissolution. The salt might have crystallized when the methanol was diluted 50:50 with diethyl ether. The final opportunity occurred when the solution was diluted 1:1 with heptane and this was successful. Notice that the methanol could not be diluted with heptane directly. Two phases would have resulted. This is an example of a well-designed approach to getting crystalline solid. If crystals still had not formed the solution would have been concentrated.
WO06040728A1:
Preparation of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3- (2-methyl-quinolin-4-yl)-urea
Preparation of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3- (2-methyl-quinolin-4-yl)-urea
Example 1
1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (1 equivalent) is dissolved in ethanol at a concentration of 25% w/w and the mixture is heated at 50°C. Aqueous sulfuric acid (1M, 1.1 equivalents) is added. Optionally, the crystallization is initiated by a wet seed of Example 1 (0.5%). The suspension is cooled to 0°C with a cooling rate of 15 C°/h and maintained at this temperature at least 1 hour before filtration and washing with aqueous ethanol (50 % W/V). The solid is dried at 30°C under a wet stream of nitrogen (50% RH) to provide the title compound with a purity of 97.7% in a yield of approximately 90%.
Comment:
The example illustrates the addition of the acid to an excess of base. The addition is performed warm. An aqueous sulphuric acid reagent is used and it is added to a water-miscible solvent in this case ethanol. Using seeds of the salt product is optional here. The example prescribes a cooling rate that will lower the temperature to the final filtration temperature over somewhat more than 3 hours. This is followed by a hold time to ensure that all the material that can crystallize has come out before the filtration. The wash solution is a mixture of solvents similar to that from which the solid is crystallized. Often a slightly less polar wash solution is used than the mixture from which the crystals are produced. This gives some assurance that the wash will not redissolve the solid. Although it is not reported the wash solvent is usually cooled to the temperature of the slurry that was filtered originally. On-scale, this is done simply by loading the wash solvent mixture into the crystallizer. Because the solvent is a mixture comprising water, there is no danger of condensing damaging moisture into the wash solution. The example illustrates using a moist gas stream to dry the solid without dehydrating it.
The example illustrates the addition of the acid to an excess of base. The addition is performed warm. An aqueous sulphuric acid reagent is used and it is added to a water-miscible solvent in this case ethanol. Using seeds of the salt product is optional here. The example prescribes a cooling rate that will lower the temperature to the final filtration temperature over somewhat more than 3 hours. This is followed by a hold time to ensure that all the material that can crystallize has come out before the filtration. The wash solution is a mixture of solvents similar to that from which the solid is crystallized. Often a slightly less polar wash solution is used than the mixture from which the crystals are produced. This gives some assurance that the wash will not redissolve the solid. Although it is not reported the wash solvent is usually cooled to the temperature of the slurry that was filtered originally. On-scale, this is done simply by loading the wash solvent mixture into the crystallizer. Because the solvent is a mixture comprising water, there is no danger of condensing damaging moisture into the wash solution. The example illustrates using a moist gas stream to dry the solid without dehydrating it.
Example 2
1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate trihydrate.
To a suspension of
1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea
(21.36 kg) in CH3OH (178 L) is added aqueous H2SO4 (6 L, 9.91%)
during 10 min. The clear solution is filtered and further aqueous H2SO4 (33.8
L, 1.07 M) is added during 45 min. The solution is cooled to -2°C during 1.5 h
and stirred at -5 to -9°C for 1 h. The precipitate is filtered, washed
with cooled CH30H (- 5°C, 54 L) and dried under a stream of nitrogen provide
1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea
sulfate of formula l as an undefined hydrate. A slurry of the salt, so obtained, in H2O (16.2% w/w) is stirred for 3 days at 25°C. Filtration and drying at 30°C
under a wet stream of nitrogen (50% relative humidity) provides the title compound.
Comment:
This example replaces the ethanol with methanol and is very much the same. Here unhydrated gas was used in the drying and there apparently was some dehydration. Stirring a slurry in water for an extended period recreates the hydrate illustrating a method of preparing a pseudopolymorph hydrate. Drying to the trihydrate was successful when the relative humidity was controlled at 50%.
This example replaces the ethanol with methanol and is very much the same. Here unhydrated gas was used in the drying and there apparently was some dehydration. Stirring a slurry in water for an extended period recreates the hydrate illustrating a method of preparing a pseudopolymorph hydrate. Drying to the trihydrate was successful when the relative humidity was controlled at 50%.
Example 5
1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea
sulphate dihydrate
1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea
(1.01 kg, 1 equivalent) is dissolved in ethanol (3.05 kg) under stirring
(200±20 rpm) and the mixture is heated at 50°C. Aqueous sulfuric acid (1 M, 1.1
equivalents) is added during 20 minutes. The crystallization is initiated by a
wet seed of Example 1 (1 %) as described below. The obtained mixture is
maintained at 50°C for about 15 minutes, then it is cooled to 0°C with a
cooling rate of 15°C/h and maintained at this temperature for least 1 hour
before filtration and washing with aqueous ethanol (50 % W/W, 3 kg). The solid
is dried in a conductive agitated dryer at a temperature of 35± 3°C under a wet
stream of nitrogen (45±5% relative humidity), optionally under stirring (max. rpm) in case the
cake humidity is below 25%, to provide the title compound with a purity of
99.8% with a yield of approximately 94%.
The wet seed used in the above procedure is added in
two shots and is prepared by mixing
1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea
sulfate dihydrate (Example 1, 6.5 9) with a saturated solution (13.9 9 for the
first shot, plus 15.6 9 for subsequent rinsing and second shot) of
1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea
sulfate dihydrate (Example 1, 7.0 9) in aqueous ethanol (50 % W/W, 50.0 9) for
about 2 minutes. The first shot of wet seed is prepared at least 5 minutes
before use to ensure that the seed is correctly wetted.
Comment:
Example 5 illustrates that in a process description of crystallization the mixing times, cooling rates and stirring need to be precisely controlled. The need to properly moisten the seed crystals with the solvent is also illustrated. If the seeds’ surface does not wet properly they cannot catalyze crystal growth properly.
Example 5 illustrates that in a process description of crystallization the mixing times, cooling rates and stirring need to be precisely controlled. The need to properly moisten the seed crystals with the solvent is also illustrated. If the seeds’ surface does not wet properly they cannot catalyze crystal growth properly.
US20060194833A1:
Crystalline 1H-imidazo[4,5-b]pyridin-5-amine, 7-[5-[(cyclohexylmethylamino)-methyl]-1H-indol-2-yl]-2-methyl, sulfate (1:1), trihydrate and its pharmaceutical uses
Crystalline 1H-imidazo[4,5-b]pyridin-5-amine, 7-[5-[(cyclohexylmethylamino)-methyl]-1H-indol-2-yl]-2-methyl, sulfate (1:1), trihydrate and its pharmaceutical uses
According to the method, ER807447 is first suspended
in water to form an aqueous suspension. Sulfuric acid is added to the aqueous
suspension to form a solution while keeping the internal temperature of the
solution below 25° C. The solution typically has a yellow color. The solution
may optionally be filtered to remove particulates from the solution. Other
techniques for removing particulates known in the art, centrifuging, etc. may
be used as the filtering step. The solution is then slowly warmed until E6070
crystallizes from solution. The solution may be warmed to about 100° C.
Typically crystal formation occurs at temperatures of about 70° C. Preferred
rates of warming typically range from about 30 minutes to 5 hours. Longer or
shorter times may be used, particularly depending upon the batch size. E6070
may not crystallize as readily from highly dilute solutions.
To enhance crystallization, an anti-solvent may be
used in the method of making the crystalline E6070 or to recrystallize
crystalline E6070. The recrystallization procedure is described in Example 5.
In the above method, the anti-solvent may be added to the aqueous suspension
before sulfuric acid addition or to the solution after sulfuric acid addition
and the optional filtration step. Useable anti-solvents and their use are known
in the art. Typical anti-solvents include water-miscible antisolvents such as,
for example, methanol, ethanol, 1-propanol, 2-propanol, acetone and mixtures
thereof. When an anti-solvent is used, the solution may become cloudy. It is
generally not necessary to warm the solution to as high of temperatures as when
just using an aqueous solution.
Comment:
The procedure above illustrates forming a bisulfate from water. Filtration or other clarification of the formed solution is illustrated. Removing insolubles removes nuclei that can catalyze improper nucleation. The example illustrates that a bisulfate salt in water may actually be supersaturated but the rate of nucleation may be impracically slow. Heating the solution increases the rate of nucleation and causes the insoluble salt to come out. If the sulfate is a high molecular weight molecule that should give an insoluble sulfate in water, perhaps heating will enhance the rate of seed formation as here.
The procedure above illustrates forming a bisulfate from water. Filtration or other clarification of the formed solution is illustrated. Removing insolubles removes nuclei that can catalyze improper nucleation. The example illustrates that a bisulfate salt in water may actually be supersaturated but the rate of nucleation may be impracically slow. Heating the solution increases the rate of nucleation and causes the insoluble salt to come out. If the sulfate is a high molecular weight molecule that should give an insoluble sulfate in water, perhaps heating will enhance the rate of seed formation as here.
The use of an
antisolvent is also illustrated. Note that water-miscible organics are often antisolvents
for sulfate salts because sulfate salts are so hydrophilic.
Tizanidine Monosulfate
(5-chloro-4-f2-imidazolin-2-ylamino')-2,l,3-benzothiadiazole monosulfate )
In a second preparation, tizanidine monosulfate was prepared by the
following method: to solid tizanidine (9.957 g; 39.24 mmol) was added a solution
of sulfuric acid (5.438 g; 55.45 mmol) in acetonitrile (175 mL). The yellow
solid rapidly converted to a white crystalline solid. The mixture was heated to
60°C and stirred for 90 minutes. The mixture was cooled to room temperature and
the solid was subsequently filtered and washed with additional acetonitrile (50
mL). The solid was collected via filtration and air-dried.
Tizanidine monosulfate comprises a 1:1 ratio of ionized tizanidine to bisulfate
counterion. In this example sulfuric acid in acetonitrile is used for crystallization.
Rosiglitazone Sulfate
Example 1:
5-[4-[2-(N-methyl-N-(2-pyridyl)amino) ethoxy]benzyl]
thiazolidine-2,4-dione sulfate
5-[4-[2- (N-Methyl-N-(2-pyridyl)amino) ethoxy]benzyl]thiazolidine-2,4-
dione (20.0 g) in glacial acetic acid (50 ml) was stirred and heated to 75°C
until a clear solution 5 was observed. Concentrated sulfuric acid (1. 5 ml) was
added and the stirred solution cooled to 21 °C. After evaporation of the solvent
under reduced pressure, methanol (100 ml) was added and the mixture stirred at
21°C for 48 hours. The solid was collected by filtration, washed with methanol
(50 ml) and dried under vacuum to give 5-[4-[2-(N-
methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione sulfate (10.7 g) as a crystalline solid.
methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione sulfate (10.7 g) as a crystalline solid.
Melting point: 184 - 189°C.
DSC: Tosser = 184.4°C, Tpeak = 189.1 °C Elemental Analysis: 15 Found: C;
52.96 H; 4.94 N; 10.23 S; 11.78 Theory: (C36H40N6O,oS3) C; 53. 19 H; 4.96 N;
10.34 S; 11.83
Comment:
In this example glacial acetic acid is used as the solvent for the free base and heating is required to get a clear solution. The experimentalist apparently expected the sulfate to precipitate at about ambient but it did not. It is important that in this example the basic group was tertiary because the combination of acetic acid and sulfuric acid could cause acetylation with primary or secondary amines. Undeterred the experimentalist removed some acetic acid under vacuum and replace it with the antisolvent methanol. This time cooling gave the desired solid derivative.
In this example glacial acetic acid is used as the solvent for the free base and heating is required to get a clear solution. The experimentalist apparently expected the sulfate to precipitate at about ambient but it did not. It is important that in this example the basic group was tertiary because the combination of acetic acid and sulfuric acid could cause acetylation with primary or secondary amines. Undeterred the experimentalist removed some acetic acid under vacuum and replace it with the antisolvent methanol. This time cooling gave the desired solid derivative.
Example 2:
5-[4-l2-(N-methyl-N-(2- pyridyl)amino) ethexylbenzyl] thiazolidine-2,4
20 dione sulfate
5- [4-[2-(N-Methyl-N-(2- pyridyl)amino)ethoxy]benzyl]
thiazolidine-2,4-dione (40.0 g) in glacial acetic acid (100 ml) was stirred and
heated to 70°C until a clear solution was observed. Concentrated sulfuric acid
(3.1 ml) was added and the mixture stirred for 10 minutes at 70°C, then cooled
to 21°C with stirring. The solvent was
evaporated under reduced pressure, followed by the addition of methanol
(100 ml) and the mixture was stirred at 21 °C until crystallization was
complete. The product was collected by filtration, washed with methanol (200
ml) and dried under vacuum over phosphorus pentoxide for 4 hours at 50°C to
give 5-[4-[2-(N-methyl-N-(2 pyridyl)amino)ethoxy] benzyl]thiazolidine-2,4-dione
sulfate (36.9 g) as an off white
crystalline solid.
Example 3:
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)
ethexy]benzyl] thiazolidine-2,4 dione sulfate
Concentrated sulfuric acid (1.94 ml) was added to a stirred suspension
of 5-[4- [2 35 (N-methyl-N-(2-pyridyl)amino) ethoxy]benzyl]
thiazolidine-2,4-dione (25.0 g) in methanol (1000 ml) at 56°C. The reaction
mixture was stirred at 60°C until a clear solution was observed, then cooled to
21 °C and stirred at this temperature for 16 hours.
The product was collected by filtration, washed with methanol (100 ml) and dried under vacuum at 21°C for 3 hours to afford 5-[4-[ 2-(N-methyl-N- (2 pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione sulfate (19.5 g) as a white crystalline solid.
The product was collected by filtration, washed with methanol (100 ml) and dried under vacuum at 21°C for 3 hours to afford 5-[4-[ 2-(N-methyl-N- (2 pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione sulfate (19.5 g) as a white crystalline solid.
Comment:
Since methanol turns out to be good for precipitating the product using it to dissolve the free base gives a simple procedure. In the plan, because the system is closed and inerted, the slurry can be cooled down to about -20°C without difficulty and without condensing water from the natural atmosphere. Also, in the plant, cooling wash liquid to -20°C is simple and can increase recoveries substantially.
Since methanol turns out to be good for precipitating the product using it to dissolve the free base gives a simple procedure. In the plan, because the system is closed and inerted, the slurry can be cooled down to about -20°C without difficulty and without condensing water from the natural atmosphere. Also, in the plant, cooling wash liquid to -20°C is simple and can increase recoveries substantially.
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