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kilomentor | 01 September, 2008 17:00
The sulfate salt is the second most common pharmaceutical salt behind the hydrochloride. Bisulfate salts are quite acidic so the base from which one is made 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 which two moles of amine are protonated by each of the two protons of H2SO4. The pKas of sulphuric acid are –3 and 1.92 with 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 an, at least 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 sufuric 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 was 96.5%) was collected by filtering and washed once with ether. The solid had a mp: 1113.5-116.5° C. (recrystallized from methanol).
This example illustrates the addition of the base to the organic solution of sulphuric acid in methanol. Although a small amount of methyl hydrogen sulphate 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
Example 11-(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% with a yield of approximately 90%.
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 with 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 trihvdrate.
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 formed 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 a non-defined hydrate. A slurry of the so obtained salt 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% RH) provides the title compound.
This example replaces the ethanol with methanol and is in most particulars very much the same. Here unhydrated gas was used in the drying ad 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 4 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate
1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (15.4 kg, 1 equivalent) is dissolved in ethanol (78 L) and the mixture is heated at 50°C. Aqueous sulfuric acid (1M, 1.1 equivalents) is added during minutes. The crystallization is initiated by a wet seed of Example 1 (1%) as described below. The suspension is cooled to 1°C with a cooling rate of 14C°/h and maintained at this temperature at least 11 hours before filtration and washing with aqueous ethanol (50 % W/W, 50 L). The solid is dried at 30°C under a wet stream of nitrogen (33-40% RH) to provide the title compound with a purity of 99.4% with a yield of approximately 79%.
The wet seed used in the above procedure is prepared by mixing - 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate (Example 1,) with a saturated solution (421 9) of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate (Example 1, 73.9 9) in aqueous ethanol (50 % W/W, 810 9).
Example 5
1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulphate dihvdrate
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% RH), 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 dihvdrate (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 dihvdrate (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.
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
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 anti-solvents 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.
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 sulphate is a high molecular weight molecule that should give an insoluble sulphate 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 sulphate salts because sulphate 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 mol) was added a solution of sulfuric acid (5.438 g; 55.45 mol) 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 sulfate counterion. In this example sulfuric acid in acetonitrile is used
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 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.
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<>
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