CN103130683A - Polymorphism of methocarbamol dihydric phosphate and preparation method thereof - Google Patents
Polymorphism of methocarbamol dihydric phosphate and preparation method thereof Download PDFInfo
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- CN103130683A CN103130683A CN2013100950048A CN201310095004A CN103130683A CN 103130683 A CN103130683 A CN 103130683A CN 2013100950048 A CN2013100950048 A CN 2013100950048A CN 201310095004 A CN201310095004 A CN 201310095004A CN 103130683 A CN103130683 A CN 103130683A
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- dihydrogen phosphate
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Abstract
The invention relates to a polymorphism corresponding to 3-(o-methoxyphenoxy)-2-hydroxypropyl amino-acid ester dihydric phosphate (methocarbamol dihydric phosphate), and a preparation method and application thereof. A medicament containing the polymorphism can be used for treating muscle sprain, lumbar muscle strain and ischialgia. The polymorphism has peak characterization results of an X-ray powder diffraction pattern shown as Figure 1, nuclear magnetic resonance absorption spectra shown as Figures 2-4, a thermogravimetry-differential thermal analysis curve shown as Figure 5, an infrared spectrum absorption curve shown as Figure 8 and mass spectra shown as Figure 6 and Figure 7. The crystal form H of the methocarbamol dihydric phosphate, prepared by the invention, contains one crystalline water and has the characteristic of high stability; and the crystallization process is simple and convenient to implement production/transportation/storage, and conforms to the requirements for medicament preparation.
Description
Technical field
The present invention relates to a kind of polymorphic form of 3-(o-methoxyphenyl)-2-hydroxypropyl amino acid ester dihydrogen phosphate (methocarbamol dihydrogen phosphate) and its preparation method and application, contain this crystal formation medicine and can be applicable to treat muscle sprain, lumbar muscle strain, sciatica.
Background technology
In Chinese patent CN101863917A(publication No.) in to have put down in writing 3-(o-methoxyphenyl)-2-hydroxypropyl amino acid ester (methocarbamol) be a kind of active drug for the treatment of muscle epitonos, spasm, the symptom such as tetanic, treatment such as muscle sprain, lumbar muscle strain, sciatica, prolapse of lumbar intervertebral disc in obvious effective rate very high.But because methocarbamol itself is insoluble in water, water-soluble is only 1:210, has been subject to the corresponding detrimentally affect that causes in clinical middle application.
Patent CN101863917A provides methocarbamol has been carried out structural modification, the synthetic phosphatic method of methocarbamol, although improved solubleness, but the synthetic methocarbamol dihydrogen phosphate structure that obtains is fluffy, less stable, easily transition, not yet report relevant for the stable polymorphic of methocarbamol dihydrogen phosphate at present.
Summary of the invention
The object of the invention is to overcome the prior art above shortcomings, and polymorphic of a kind of methocarbamol dihydrogen phosphate and preparation method thereof is provided.
After the synthetic methocarbamol dihydrogen phosphate of the present invention, its polymorphic is studied.The problem of the methocarbamol dihydrogen phosphate less stable that obtains for original technology is by using the polymorphic that makes the methocarbamol dihydrogen phosphate after appropriate solvent dissolving, decrease temperature crystalline, filtration drying.
A kind of polymorphic form of methocarbamol dihydrogen phosphate provided by the invention is referred to as crystal formation H, contains a crystal water, and fusing point is: 119-122 ℃; Have following peak in the X ray diffracting spectrum of methocarbamol dihydrogen phosphate crystal formation H:
Methocarbamol dihydrogen phosphate crystal formation H's
1HNMR has following peak:
δ=3.76(s,3H),4.06-4.19(m,4H),4.50-4.57(m,1H),6.57(br?s,2H),6.85-7.02(m,4H)。
Methocarbamol dihydrogen phosphate crystal formation H's
13CNMR has following peak:
δ=55.63,62.47,67.58,71.83,112.60,114.11,120.77,121.64,147.73,149.25,156.32。
Methocarbamol dihydrogen phosphate crystal formation H's
31PNMR has following peak:
δ=-1.55。
The mass spectrum of methocarbamol dihydrogen phosphate crystal formation H goes out the peak:
+c?ESI:m/z=322(M+1),643(2M+1)，
-c?ESI:m/z=319(M-1),641(2M-1)。
The thermogravimetric differential thermal analysis result of methocarbamol dihydrogen phosphate crystal formation H is:
The DTG curve has following peak: 86.8 ℃, and 216.8 ℃, 285.9 ℃; The corresponding weightlessness of TG curve is 5.37%, 19.88%, 41.73%.Wherein, weightlessness 5.37% shows that methocarbamol dihydric salt crystal formation H contains a water molecules 86.8 ℃ the time.
The infrared absorption spectrum wave number of methocarbamol dihydrogen phosphate crystal formation H is with cm
-1For unit is respectively:
444.6，541.1，584.9，626.3，753.1，774.7，839.2，914.7，937.1，989.7，1034.1，1049.3，1080.9，1105.7，1126.6，1142.4，1168.2，1182.8，1229.5，1242.7，1254.8，1292.6，1335.6，1362.9，1395.5，1406.7，1423.2，1439.7，1460.3，1507.1，1595.0，1618.4，1714.3，2284.0，2591.1，2840.9，2940.9，2976.3，3000.8，3203.4，3328.7，3465.1。
The preparation method of methocarbamol dihydrogen phosphate crystal formation H provided by the invention is:
The methocarbamol dihydrogen phosphate is dissolved in single solvent or mixed solvent, is heated to more than 50 ℃, be chilled to the normal temperature crystallize out after the dissolving fully, obtain crystal formation H after filtering rear 60 ℃ of dry 12h.
Described in the present invention, single solvent refers to: alcoholic solvent, specifically a kind of in methyl alcohol, ethanol, propyl alcohol, Virahol; Described mixed solvent refers to: the mixed solvent of a kind of composition in a kind of and water in above-mentioned alcoholic solvent, acetone, ethyl acetate, methylene dichloride, or two kinds of solvents that mix formation in above-mentioned alcoholic solvent.
Advantage of the present invention and beneficial effect:
The methocarbamol dihydrogen phosphate crystal formation H that the present invention obtains contains a crystal water, has the high characteristics of stability, and this crystallization technique is simple, is convenient to production and transport and stores, and meets the requirement of medicine preparation.
Description of drawings
Fig. 1 is the X-ray powder diffraction collection of illustrative plates of methocarbamol dihydrogen phosphate crystal formation H;
Fig. 2 is the proton nmr spectra of methocarbamol dihydrogen phosphate crystal formation H;
Fig. 3 is the carbon-13 nmr spectra of methocarbamol dihydrogen phosphate crystal formation H;
Fig. 4 is the nucleus magnetic resonance phosphorus spectrum of methocarbamol dihydrogen phosphate crystal formation H;
Fig. 5 is the thermogravimetric differential thermal analysis curve of methocarbamol dihydrogen phosphate crystal formation H;
Fig. 6 is that the mass spectrum positive ion of methocarbamol dihydrogen phosphate crystal formation H goes out peak figure;
Fig. 7 is that the mass spectrum negative ion of methocarbamol dihydrogen phosphate crystal formation H goes out peak figure;
Fig. 8 is the infrared absorpting light spectra of methocarbamol dihydrogen phosphate crystal formation H.
Embodiment
One, the preparation of methocarbamol dihydrogen phosphate crystal formation H
0.50g methocarbamol dihydrogen phosphate is dissolved in the mixed solvent of 2.5mL ethanol and 2.5mL water, is heated to 60 ℃, get settled solution, the standing room temperature that is cooled to is filtered after crystallize out, and 60 ℃ of dry 12h obtain crystal formation H, and fusing point is 121-122 ℃.
0.25g methocarbamol dihydrogen phosphate is dissolved in the mixed solvent of 1.5mL Virahol and 1.5mL water, is heated to 65 ℃, get settled solution, the standing room temperature that is cooled to is filtered after crystallize out, and 60 ℃ of dry 12h obtain crystal formation H, and fusing point is 121-122 ℃.
Embodiment 3
It is in the solvent of 4: 1 that 40.26g methocarbamol dihydrogen phosphate is dissolved in 200mL second alcohol and water proportioning, be heated to boil, backflow 30min treats the solution clarification, the standing room temperature that is chilled to of stopped heating, change 5 ℃ of refrigerator insulation 3h crystallizatioies over to complete after having crystal to separate out, after filtering, 60 ℃ of dry 12h of filter cake get crystal formation H, and fusing point is: 119-121 ℃.
Embodiment 4
35.35g methocarbamol dihydrogen phosphate is dissolved in 95% ethanol of 180mL, be heated to boil, backflow 30min treats the solution clarification, the standing room temperature that is chilled to of stopped heating, change 5 ℃ of refrigerator insulation 4h crystallizatioies over to complete after having crystal to separate out, after filtering, 60 ℃ of dry 12h of filter cake get crystal formation H, and fusing point is 120-122 ℃.
0.62g methocarbamol dihydrogen phosphate is dissolved in the mixed solvent of 1.8mL ethanol and 1.8mL ethyl acetate, is heated to 50 ℃, get settled solution, the standing room temperature that is cooled to is filtered after crystallize out, and 60 ℃ of dry 12h obtain crystal formation H, and fusing point is 119-120 ℃.
Embodiment 6
0.41g methocarbamol dihydrogen phosphate is dissolved in the mixed solvent of 1.2mL ethanol and 1.2mL acetone, is heated to 50 ℃, get settled solution, the standing room temperature that is cooled to is filtered after crystallize out, and 60 ℃ of dry 12h obtain crystal formation H, and fusing point is 120-121 ℃.
0.60g methocarbamol dihydrogen phosphate is dissolved in the mixed solvent of 2.5mL Virahol and 2.5mL ethyl acetate, is heated to 50 ℃, get settled solution, the standing room temperature that is cooled to is filtered after crystallize out, and 60 ℃ of dry 12h obtain crystal formation H, and fusing point is 119-120 ℃.
0.25g methocarbamol dihydrogen phosphate is dissolved in the 1.5mL Virahol, is heated to 65 ℃, get settled solution, the standing room temperature that is cooled to is filtered after crystallize out, and 60 ℃ of dry 12h obtain crystal formation H, and fusing point is 121-122 ℃.
0.52g methocarbamol dihydrogen phosphate is dissolved in the 2.5mL dehydrated alcohol, is heated to 60 ℃, get settled solution, the standing room temperature that is cooled to is filtered after crystallize out, and 60 ℃ of dry 12h obtain crystal formation H, and fusing point is 121-122 ℃.
0.64g methocarbamol dihydrogen phosphate is dissolved in the 4mL anhydrous methanol, is heated to 50 ℃, get settled solution, the standing room temperature that is cooled to is filtered after crystallize out, and 60 ℃ of dry 12h obtain crystal formation H, and fusing point is 120-122 ℃.
Embodiment 11
0.74g methocarbamol dihydrogen phosphate is dissolved in the mixed solvent that the anhydrous methanol of the dehydrated alcohol of 2.5mL and 2.5mL forms, is heated to 60 ℃, get settled solution, the standing room temperature that is cooled to, filter after crystallize out, 60 ℃ of dry 12h obtain crystal formation H, and fusing point is 119-120 ℃.
Embodiment 12
0.72g methocarbamol dihydrogen phosphate is dissolved in the mixed solvent that the water of the dehydrated alcohol of 4.5mL and 0.5mL forms, is heated to 60 ℃, get settled solution, the standing room temperature that is cooled to, filter after crystallize out, 60 ℃ of dry 12h obtain crystal formation H, and fusing point is 119-121 ℃.
Embodiment 13
0.57g methocarbamol dihydrogen phosphate is dissolved in the mixed solvent that the water of the dehydrated alcohol of 3.5mL and 1.5mL forms, is heated to 60 ℃, get settled solution, the standing room temperature that is cooled to, filter after crystallize out, 60 ℃ of dry 12h obtain crystal formation H, and fusing point is 119-120 ℃.
Embodiment 14
0.28g methocarbamol dihydrogen phosphate is dissolved in the mixed solvent that the water of the dehydrated alcohol of 1.5mL and 3.5mL forms, is heated to 65 ℃, get settled solution, the standing room temperature that is cooled to, filter after crystallize out, 60 ℃ of dry 12h obtain crystal formation H, and fusing point is 120-122 ℃.
0.43g methocarbamol dihydrogen phosphate is dissolved in the mixed solvent that the water of the dehydrated alcohol of 3.0mL and 2.0mL forms, is heated to 50 ℃, get settled solution, the standing room temperature that is cooled to, filter after crystallize out, 60 ℃ of dry 12h obtain crystal formation H, and fusing point is 119-122 ℃.
Embodiment 16
0.39g methocarbamol dihydrogen phosphate is dissolved in the mixed solvent that the acetone of the Virahol of 2.5mL and 2.5mL forms, is heated to 60 ℃, get settled solution, the standing room temperature that is cooled to, filter after crystallize out, 60 ℃ of dry 12h obtain crystal formation H, and fusing point is 119-121 ℃.
Two, the polymorphous parametric measurement of methocarbamol di(2-ethylhexyl)phosphate sylvite
1, methocarbamol dihydrogen phosphate crystal formation H being carried out the test condition that X-ray powder diffraction characterizes is:
The X ray diffracting spectrum (as shown in Figure 1) of methocarbamol dihydrogen phosphate crystal formation H has following peak:
The condition of 2, methocarbamol dihydrogen phosphate crystal formation H being carried out nucleus magnetic resonance test is:
Instrument: the Bruker400M nmr spectrometer,
Solvent: DMSO-d
6,
Content:
1HNMR,
13CNMR,
31PNMR.
Methocarbamol dihydrogen phosphate crystal formation H's
1HNMR(is as shown in Figure 2) have a following peak:
δ=3.76(s,3H),4.06-4.19(m,4H),4.50-4.57(m,1H),6.57(br?s,2H),6.85-7.02(m,4H)。
Methocarbamol dihydrogen phosphate crystal formation H's
13CNMR(is as shown in Figure 3) have a following peak:
δ=55.63,62.47,67.58,71.83,112.60,114.11,120.77,121.64,147.73,149.25,156.32。
Methocarbamol dihydrogen phosphate crystal formation H's
31PNMR(is as shown in Figure 4) have a following peak:
δ=-1.55。
3, methocarbamol dihydrogen phosphate crystal formation H being carried out the mass spectroscopy condition is:
Instrument: Thermo Fisher Finnigan LCQ Advantage,
Method: LC-MS,
Ion source: ESI,
Mass charge ratio range: 50-2000.
The mass spectrum of methocarbamol dihydrogen phosphate crystal formation H goes out peak (as Fig. 6, shown in Figure 7):
+c?ESI:m/z=322(M+1),643(2M+1)，
-c?ESI:m/z=319(M-1),641(2M-1)。
4, methocarbamol dihydrogen phosphate crystal formation H being carried out thermogravimetric differential thermal (TG-DTG) analysis condition is:
The thermogravimetric differential thermal analysis result (as shown in Figure 5) of methocarbamol dihydrogen phosphate crystal formation H is:
The DTG curve has following peak: 86.8 ℃, and 216.8 ℃, 285.9 ℃; The corresponding weightlessness of TG curve is 5.37%, 19.88%, 41.73%.Wherein, weightlessness 5.37% shows that methocarbamol dihydric salt crystal formation H contains a water molecules 86.8 ℃ the time.
5, methocarbamol dihydrogen phosphate crystal formation H being carried out the infrared absorption test condition is:
Infrared absorption spectrum (as shown in Figure 8) wave number of methocarbamol dihydrogen phosphate crystal formation H is with cm
-1For unit is respectively:
444.6，541.1，584.9，626.3，753.1，774.7，839.2，914.7，937.1，989.7，1034.1，1049.3，1080.9，1105.7，1126.6，1142.4，1168.2，1182.8，1229.5，1242.7，1254.8，1292.6，1335.6，1362.9，1395.5，1406.7，1423.2，1439.7，1460.3，1507.1，1595.0，1618.4，1714.3，2284.0，2591.1，2840.9，2940.9，2976.3，3000.8，3203.4，3328.7，3465.1。
Reference
1, Chinese patent, publication No. CN101863917A.
Claims (8)
1. the polymorphic of a methocarbamol dihydrogen phosphate, be referred to as crystal formation H, and the X-ray powder diffraction collection of illustrative plates of described methocarbamol dihydrogen phosphate crystal formation H has following peak:
2. polymorphic as claimed in claim 1, is characterized in that, the proton nmr spectra of methocarbamol dihydrogen phosphate crystal formation H has following peak,
1HNMR (400MHz, DMSO-d
6): δ=3.76 (s, 3H), 4.06-4.19 (m, 4H), 4.50-4.57 (m, 1H), 6.57 (br s, 2H), 6.85-7.02 (m, 4H); Carbon-13 nmr spectra has following peak,
13CNMR (400MHz, DMSO-d
6): δ=55.63,62.47,67.58,71.83,112.60,114.11,120.77,121.64,147.73,149.25,156.32; Nucleus magnetic resonance phosphorus spectrum has following peak,
31PNMR (400MHz, DMSO-d
6): δ=-1.55.
3. polymorphic as claimed in claim 1, is characterized in that, the mass spectrometry results of methocarbamol dihydrogen phosphate crystal formation H is ,+c ESI:m/z=322 (M+1), 643 (2M+1);-c ESI:m/z=319 (M-1), 641 (2M-1).
4. polymorphic as claimed in claim 1, is characterized in that, absorption peak wave number corresponding to infrared spectra of methocarbamol dihydrogen phosphate crystal formation H is with cm
-1For unit is respectively: 444.6,541.1,584.9,626.3,753.1,774.7,839.2,914.7,937.1,989.7,1034.1,1049.3,1080.9,1105.7,1126.6,1142.4,1168.2,1182.8,1229.5,1242.7,1254.8,1292.6,1335.6,1362.9,1395.5,1406.7,1423.2,1439.7,1460.3,1507.1,1595.0,1618.4,1714.3,2284.0,2591.1,2840.9,2940.9,2976.3,3000.8,3203.4,3328.7,3465.1.
5. polymorphic as claimed in claim 1, is characterized in that, thermogravimetric differential thermal (TG-DTG) analytic curve of methocarbamol dihydrogen phosphate crystal formation H has following peak: 86.8 ℃, and 216.8 ℃, 285.9 ℃; The corresponding weightlessness of TG curve is 5.37%, 19.88%, 41.73%.Wherein, weightlessness 5.37% shows that methocarbamol dihydric salt crystal formation H contains a water molecules 86.8 ℃ the time.
6. the preparation method of methocarbamol dihydrogen phosphate crystal formation H claimed in claim 1, it is characterized in that, the methocarbamol dihydrogen phosphate is dissolved in single solvent or mixed solvent, is heated to more than 50 ℃ to be chilled to the normal temperature crystallize out after dissolving fully, obtain crystal formation H after filtering 60 ℃ of dry 12h.
7. the method for claim 1 is characterized in that described single solvent refers to: alcoholic solvent, specifically a kind of in methyl alcohol, ethanol, propyl alcohol, Virahol; Described mixed solvent refers to: the mixed solvent of a kind of composition in a kind of and water in above-mentioned alcoholic solvent, acetone, ethyl acetate, methylene dichloride, or two kinds of solvents that mix formation in above-mentioned alcoholic solvent.
8. the application of methocarbamol dihydrogen phosphate crystal formation H claimed in claim 1 is for the preparation of the medicine for the treatment of muscle sprain, lumbar muscle strain, sciatica.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES8707179A1 (en) * | 1986-06-24 | 1987-07-16 | Lasa Lab | Metho-carbamol di:hydrogen phosphate prepn. |
| CN1823741A (en) * | 2005-12-28 | 2006-08-30 | 严洁 | Methocarbamol dry mixing suspension |
| CN101863917A (en) * | 2010-06-17 | 2010-10-20 | 天津市若围药物研究所 | Methocarbamol salt |
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2013
- 2013-03-22 CN CN2013100950048A patent/CN103130683A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES8707179A1 (en) * | 1986-06-24 | 1987-07-16 | Lasa Lab | Metho-carbamol di:hydrogen phosphate prepn. |
| CN1823741A (en) * | 2005-12-28 | 2006-08-30 | 严洁 | Methocarbamol dry mixing suspension |
| CN101863917A (en) * | 2010-06-17 | 2010-10-20 | 天津市若围药物研究所 | Methocarbamol salt |
Non-Patent Citations (1)
| Title |
|---|
| 邱志平和邱方利: "美索巴莫的结晶研究", 《浙江化工》, vol. 38, no. 9, 31 December 2007 (2007-12-31), pages 10 - 11 * |
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