Process for converting one polymorphic crystalline form of buspyrone hydrochloride into its other po

专利摘要:
"A process for conversion of one polymorphic crystalline form of buspirone into its other polymorphic crystalline form is described.
公开号:SU1731056A3
申请号:SU884356323
申请日:1988-08-26
公开日:1992-04-30
发明作者:Джеймс Бехме Роберт；Тим Кенслер Терри；Джин Миколасек Дуглас
申请人:Бристоль Мейерз Сквибб Компани (Фирма)；
IPC主号:

专利说明:

This invention relates to biologically active compounds, namely, buspirone hydrochloride - 8- (4- (4- / 2-pyrimidinyl) -1 -1-piperazinyl) -butyl / -8-azaspiro- (4,5) Dean 7,9-dione hydrochloride, in particular, to a method of transition of one of its polymorphic crystalline forms to another with obtaining a stable polymorphic modification that preserves biological activity.
A known method for producing bu.spiron hydrochloride is by condensation of spiran halides with a spiran-substituted glutarimide.
However, the resulting product may exist in different crystalline forms, making it difficult to standardize for pharmacological purposes.
The purpose of the invention is the creation of stable crystalline forms of buspirone hydrochloride with preservation of specific biological properties.
The goal is achieved by dissolving the substance in a certain organic solvent, followed by recrystallization at a certain temperature.
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Example 1. 8- / 4- / A- / 2-Pyrimidinyl / ™ 1 piperazinyl / butyl / -8-azaspiro / 4,5 / decane-7,9-dione hydrochloride, buspirone, HC1, conversion of polymorphs - Noah form Р188 in polymorphic form Р203 in xylene
To 50 ml of xylene, heated to boiling (138–139 ° C), 10 g of low melting polymorphic form of Buspirone HC1 P188 are added. The mixture is stirred at 138 ° C for 17 hours, then allowed to cool to 25 ° C.
The solid crystalline product is collected on a filter and dried under reduced pressure, yield 7.5 g, t „pl. 199 - 200 ° C (not corrected
Found,%: C 59.77; H 7.65j N, 16.60; Cl 8.40
C HJtNs02
HC1
C, 59.56; H 7.39 N
Calculated, 16.56; C1 8.09.
The IR spectrum (KBG) and the PMR spectrum (CDClj) are consistent with the DSC structure of the sample 10.68 mg 10 K / min, beginning 202.89 ° C.
Example 2, Conversion of the form of Buspirone HCl P188 to P203 to xylene / cyclohexanone.
A suspension of 5 g (0.0118 mol) of buspirone-HC P188 in 25 ml of xylene is heated to 138 ° C under a nitrogen atmosphere. 15 ml of cyclohexanone is added to this suspension, a clear solution is obtained. Heating is stopped and the solution is allowed to cool spontaneously. At 120 ° C, the solution darkens and crystallization proceeds at 115 ° C. After cooling to 24.5 ° C, the solid product is filtered, washed with anhydrous ether and dried under reduced pressure at 50 ° C. The yield of the high melting polymorphic form is 3.6 g, i.e. 201 - 202 ° C.
Found,%: C 59.42; 7.39; N 16.48 C1 8.34.
C2fHs ,,
Calculated,%: C 59.72; H 7.65; N 16.60; C1 8.40.
The IR spectrum (KBG) and IMP spectrum (CDCl) correspond to the structure.
DSC sample 1.45 mg 10 deg / min, the beginning of 201.3 ° C.
Example 3 Transformation of the polymorphic form of buspirone HCl P188 in T203 to cyclohexanone / xylene.
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A 250-ml round-bottom flask equipped with a cooler, a thermometer, and a magnetic stir bar.
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25
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40
45
5s
50 ml of cyclohexanone are placed in the tube and the nitrogen inlet tube. The solvent is heated to 155 ° C and 5 g (0.0118 mol) of the low-melting polymorphic form of buspirone HCl PI88 is added, which dissolves immediately. Throughout the experiment, nitrogen was barurized through the solution. 125 ml of xylene is added to this solution and the solution is slowly cooled below 155 ° C. Crystallization occurs when the temperature drops to 100 ° C. The suspensions are allowed to cool to room temperature overnight and then the white solid is filtered, washed with anhydrous ether and dried in vacuo at 50 ° C to obtain 4 g of polymorphic form P203, m.p. 202 - 204 ° С.
Found,%: C 59.85; H 7.55; N 16.63; C1 8.29.
C, VH3,
Calculated,%: C 59.77; H 7.65; N 16.60; C1 8.40.
The IR spectrum (KBG) and PMR spectrum (CDClj) correspond to the structure
DSC sample, 1.62 mg, 10 deg / min, beginning 202.1 ° C.
PRI me R 4. The transformation of the form of buspirone, HCl P188 to P203 in butanol-1 "
5 g of the molimorphic form of buspirone.HCl PI88 is dissolved in 25 ml of hot n-butanol (mp. 118 ° C) and heated at boiling in a nitrogen atmosphere for 1 hour. Heating is stopped and the solution is allowed to slowly cool and crystallize. The mixture is allowed to reach room temperature, at which the bellows crystalline product is filtered, washed with several portions of dry ether and dried under reduced pressure at 50 ° C to obtain 3.9 g of the polymorphic form of the HC1 P 203 buspyron, mp. 201 - 203 ° C. Found,%: C 59.69; H 7.74; N 16.87; C1 8.52.
Cr (1SC WHC1,
Calculated,%: C 59.77; H 7.65; N 16.60; C1 8.40.
The IR spectrum (KBG) and PMR spectrum (CDClg) correspond to the structure.
DSC sample 4.88 mg, 10 deg / min, beginning 203.3 ° C.
Example 6. Large-scale obtaining of the form of buspirone hydrochloride P203.
In a 12 liter 4-necked round-bottomed flask equipped with a reflux condenser, stirrer, with a shaft and blades of stainless steel, a thermometer and a tube
To inject nitrogen located below the level of the solvent, 2500 ml of xylene and 500 g (1.185 mol) of buspirone HCl are placed (approx. 1). The suspension is heated to boiling, while at the same time passing nitrogen through the solution. When the temperature in the flask reaches 137 ° C, 1500 ml of cyclohexanone are added in a thin stream (approx. 2). The suspension is heated by refluxing until a clear solution is formed and at the top and on the walls of the flask HC1 Buspirone (approx. 3) remains. Heating is removed and the contents of the flask are allowed to cool spontaneously. After 20 minutes, when the contents of the flask cool down to 114 ° C, crystals begin to form. At 110 ° C, crystallization proceeds very quickly and the mixture becomes thick (approx. 4) The mixture is allowed to cool overnight in a nitrogen atmosphere and then the high melting polymorph is filtered off, washed 500 ml of xylene followed by 3-200 ml of diethyl ether. After drying at 60 ° C under vacuum to constant weight, 476.5 g of polymorphic form of buspirone HC1 P203 (95.3% recovery) are obtained, m.p. 201 - 202 ° С, DSC 10 deg / / min, beginning of 199.7 ° С „
Found,%: C 59.73; H 7.59; N Go, 45; C1 8.40,
C2, H3, N502-HC1,
Calculated,%: C 59.77; H 7.65; N 16.60; C1 8.40,
The IR spectrum and the PNR spectrum correspond. structure.
Notes
1 "The starting material can only be P188,
2. With this addition, the temperature in the flask drops to 130 ° C,
3, Clear solution is obtained
at 136 - 137 ° C for 20 - 30 minutes,
4. A sample was taken and dried to determine the melting point.
With the capillary method of determining the melting point in a bath heated to 190 ° C, no melting is observed. This shows the completeness of the transformation into a high-melting polymorphic form, which is confirmed by differential scanning calorimetry.
Get the form of buspirone hydrochloride R188.
Example 7. Conversion of the form of buspirone HC1 P203 to R188 in isopropanol.

A suspension of 5 g of the polymorphic form of buspirone HC P203 (0.118 mol) in 1 7 ml of isopropanol is heated at 40 to 420 ° C for 20 hours. The suspension is cooled to ambient temperature, the solid product is filtered, washed with several portions of non-full ether and dried under reduced
JQ pressure at 50 ° С to obtain 4 g of the polymorphic form of buspirone HCl P188, t, pl. 190 - 192 ° С (not corrected).
Found,%: C 59.87; H 7.49; N 16.56; C1 8.17,
15 C H3, N 02-HC1,
Calculated,%: C 59.77; H 7.65; N 16.60; C1 8.40,
The IR spectrum (KBG) and the PMR spectrum (ASCS) correspond to the structure.
20 DSC sample 3.03 mg, 10 deg / min, onset 189.6 ° С,
Example8. Transformation of the form of buspirone HC1 P203 to P188 in acetonitrile
25 A suspension of 5 g (0.0118 mol) of the form of buspirone HCl P203 in 25 ml of acetonitrile is heated at reflux until complete dissolution.
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thirty
35
40
The solution is allowed to cool to 60 ° C and crystallization occurs at this temperature. The reaction mixture is stirred at 60 ° C for 22 hours and then cooled to 25.5 ° C. The solid product is filtered off and washed with THF. After drying under reduced pressure at 50 ° C, 3.8 g of the polymorphic form of buspirone HCl P188 are obtained, that is, gai 189-191 ° C
Found,%: C 59.50; H 7.46; N 16.60; C1 8.25
C2, H, N502. HCl,
Calculated,%: C 59.77; H 7.65; N 16.60; C1 8.40.
IR spectrum (KBG) and PMR spectrum (CDC13) correspond to the structure “
DSC sample 6.55 mg, 10 deg / min, start 190 ° C,
Example 9. Conversion of the form of buspirone HCl P203 to P188 in methyl ethyl ketone.
Suspension of 5 g (0.0118 mol) of the nolymorphic form of buspirone. HCl T203 in 25 ml of methyl ethyl ketone is heated to boiling in 1 hour. The solid product does not dissolve. The suspension is cooled to 60 ° C and stirred at this temperature for 25 hours. During this time, the solid product dissolves. After cooling to ambient temperature, the solid product is filtered,
45
55
washed with several portions of anhydrous ether and dried under reduced pressure at 50 ° C to obtain 2.5 g of the polymorphic form of buspirone P188, mp. 189 - 190dS.
Found,%: C 59.61; H 7.62; N 16.24; C1 8.30.
C ,, HwNfOtHCl,
Calculated,%: C 59.77; H 7.65; N 16.60; C1 8.40,
The IR spectrum (KBG) and PMR spectrum (CDC1) correspond to the structure.
DSC sample 3.81, 10 deg / min, the beginning of 189.3 ° C.
Example 10. Large-scale production of the form of buspirone hydrochloride R188.
A 30-gallon (113–6 l) glass reactor was charged with 47.6 kg of isopropyl alcohol, 17.0 kg of buspirone (a bododium base) and 4.4 kg of 37% hydrochloric acid with constant stirring. The mixture is heated to boiling and Dargo + G-60 0.85 kg is added. The resulting hot mixture is filtered through a filter with an auxiliary layer of particles and washed with 8.0 kg of hot isopropyl alcohol. The resulting solution is slowly cooled and stirred for 24 hours at approximately 25 ° C. The resulting pasty mixture is then cooled, the white solid is separated and dried at 60tfC under reduced pressure.
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five
five
Yield: 16.86 kg, 91% buspirone hydrochloride R188.
Thus, the proposed method allows one to obtain stable crystalline forms of buspirone hydrochloride, which, under industrial conditions, preserve their specific characteristics during storage, which is important for pharmacology.

权利要求:
Claims (2)
[1]
1. A method of converting one polymorphic crystalline form of buspirone hydrochloride to another of its polymorphic crystalline form, characterized in that the initial form of buspirone hydrochloride is dissolved in an organic solvent and subjected to recrystallization at 118-155 ° C to obtain a high-melting polymorphic form or at 60 ° C for obtain a low melting polymorphic form.
[2]
2. Pop-up method 1, characterized in that xylene, butanol or xylene / cyclohexanone is used as an organic solvent to obtain a high-melting form and isopropanol, acetonitrile or methyl ethyl ketone to obtain a low-melting polymorphic crystalline form of buspirone hydrochloride.

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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US07/090,302|US4810789A|1987-08-28|1987-08-28|Process for buspirone hydrochloride polymorphic crystalline form conversion|

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