CN104649921B - A kind of gabapentin and adipic acid eutectic and preparation method thereof - Google Patents
A kind of gabapentin and adipic acid eutectic and preparation method thereof Download PDFInfo
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- CN104649921B CN104649921B CN201510018303.0A CN201510018303A CN104649921B CN 104649921 B CN104649921 B CN 104649921B CN 201510018303 A CN201510018303 A CN 201510018303A CN 104649921 B CN104649921 B CN 104649921B
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Abstract
nullThe present invention relates to a kind of gabapentin and adipic acid pharmaceutical co-crystals and preparation method thereof，Gabapentin and adipic acid form 2:1 eutectic，Its X-ray powder diffraction pattern is 8.9 ± 0.2，9.2±0.2，10.4±0.2，14.8±0.2,16.0±0.2,17.0±0.2，17.5±0.2，17.8±0.2，19.0±0.2，19.9±0.2，20.8±0.2，21.3±0.2，22.7±0.2，23.4±0.2，23.9±0.2，24.5±0.2，25.4±0.2，25.8±0.2,28.2±0.2，31.8±0.2，33.8±0.2，There is a series of characteristic peak in the positions such as 35.2 ± 0.2.Form eutectic and improve crystal habit, improve the physicochemical properties such as bulk density, dissolubility.Improve drug bioavailability.
Description
Technical field
The invention belongs to technical field of pharmaceutical co-crystal, be specifically related to a kind of gabapentin and adipic acid eutectic and system thereof
Preparation Method.
Background technology
Eutectic is a kind of Supramolecular self assembly system, is mutual between thermodynamics, kinetics and molecular recognition three
The result of balance.In eutectic system, intermolecular interaction is mainly hydrogen bond, halogen key, pi accumulation effect
And Van der Waals force.Research finds, not only only exists single intermolecular force between eutectic constituent element, also by
Multi-acting force reaches balance each other, thus constitutes and stablize lattice.
In recent years, the research to the solid forms of active pharmaceutical ingredient has become as of new drug development and design
Importance, and the most potential cocrystallization technology is introduced pharmaceutical industry, eutectic is permissible as one
Improve the new tool of the physicochemical properties of active pharmaceutical ingredient fast and effectively, the most increasingly cause domestic
The extensive concern of outer researcher.Eutectic technology is possible not only to improve ion-type or non-ionic activity ingredient
Physicochemical property, it is also possible to be greatly shortened the research cycle of new drug development and manpower and fund cost, it is thus achieved that have
The drug products of independent intellectual property right.
Gabapentin, English name Gabapentin, molecular formula is C9H12NO2, chemical name 1-aminomethyl-hexamethylene
Alkane acetic acid (1-Aminomethyl-1-Cyclohexaneacetic Acid), is γ-aminobutyric acid (GABA)
Derivant, relative molecular mass 171.24, structural formula is shown below.
Gabapentin is a kind of new antiepileptic drugs, Warner-Lambert company of the U.S. first develop,
Trade name Neurotin, in 1993 first Britain list, after in succession the U.S., Canada, France,
The listing of majority state in the world such as German, Italian, Japanese, U.S. FDA ratifies this medicine for fainting from fear and spasm
Curative, it may also be used for prevention of migraine, treatment Algopsychalia, some tremble, anxiety, Bipolar emotion barrier
Hindering, gabapentin thus becomes first medicine being approved for treating all neuropathic pain disorders.At English
State, gabapentin is approved for treating all neuropathic pains the most.In China, the tablet of gabapentin and
Capsule is ratified through country SFDA November calendar year 2001, carries out clinical trial as two kind new medicines.
Document reported that gabapentin had three kinds of anhydride crystal formations, also a monohydrate, two kinds of chloros half
Hydrate, a semihydrate and the heptahydrate under high pressure existed.Experiment records gabapentin at 25 DEG C
Dissolubility in pure water is 0.1205g/ml, but bioavailability is relatively low.Change crystal formation and can increase molten further
Xie Du, rate of dissolution, drug disposition permeability etc..And then the bioavailability of change medicine, therefore, exploitation
Gabapentin eutectic has important meaning.
Patent both domestic and external the most all concentrates on the synthesis of gabapentin, for the monomer of gabapentin eutectic without specially
Profit report.Crystal Growth and Design, reports 13 kinds of gabapentins in 2008,9 (1): 378-385
Eutectic (salt), and done further research to wherein 5 kinds, the part of these five kinds of novel co-crystal is respectively 3-hydroxyl
Yl benzoic acid, 4-HBA, salicylic acid, 1-hydroxy-2-naphthoic acid and RS-mandelic acid.Cryst.Growth
Des.2011, reports five kinds of new gabapentin eutectic things in 11,2,325 2334, between its part is respectively
Phthalic acid, phthalic acid, L-glutaminate, p-phthalic acid and trimesic acid.But it is above multiple common
Brilliant part is all aromatics carboxylic acid, and part can produce material poisonous and hazardous to human body human body metabolism, no
It is suitable for clinic.In document and be not written out the detailed synthetic method of eutectic, and the multiplex mixing of its eutectic synthetic process
Solvent, some needs to regulate pH value, and this makes the synthesis of eutectic difficult and complicated.
Adipic acid, C6H10O4, it is the dicarboxylic acids of a kind of six carbon, is that conventional eutectic forms part, and
Adipic acid has no side effect, and is that the medicine that human body is suitable for forms component.The present invention synthesis gabapentin and oneself two
The eutectic of acid, effectively changes the brilliant habit of gabapentin so that it is from the bar-shaped bulk that changes into, dissolubility significantly improves.
Eutectic can change crystal with adipic acid with complex state with the presence of some gabapentin molecules after dissolving in the solution
Form in the solution, this makes the bioavailability of gabapentin improve further.
Summary of the invention
The invention provides eutectic of a kind of gabapentin-adipic acid and preparation method thereof, with gabapentin as medicine
Thing active component, adipic acid is the part that eutectic is formed, and prepares a kind of gabapentin-adipic acid medicine altogether
Crystalline substance, molecular formula is (C9H12NO2)2C6H10O4.The physico of gabapentin is improved by forming pharmaceutical co-crystals
Learn character and bioavailability, the multiformity of developing drug molecule.
The eutectic thing of described gabapentin-adipic acid, its X-ray powder diffraction pattern at the angle of diffraction 2 θ is
8.9 ± 0.2,9.2 ± 0.2,10.4 ± 0.2,14.8 ± 0.2,16.0 ± 0.2,17.0 ± 0.2,17.5 ± 0.2,17.8
± 0.2,19.0 ± 0.2,19.9 ± 0.2,20.8 ± 0.2,21.3 ± 0.2,22.7 ± 0.2,23.4 ± 0.2,23.9
± 0.2,24.5 ± 0.2,25.4 ± 0.2,25.8 ± 0.2,28.2 ± 0.2,31.8 ± 0.2,33.8 ± 0.2,35.2
Characteristic peak is had at ± 0.2 degree.As it is shown in figure 1, these characteristic peaks are different from the feature of gabapentin and adipic acid
Peak, illustrates to define eutectic.
The gabapentin that the present invention obtains-adipic acid eutectic, its molecule proportioning is gabapentin: adipic acid=2:1,
In its eutectic molecule, 2 gabapentin molecules and 1 adipic acid molecule form gabapentin by hydrogen bond action
-adipic acid eutectic basic structural unit；Eutectic is by the amino of gabapentin and self carboxylic acid and adipic acid
Forming hydrogen bond between hydroxy-acid group, hydrogen bond action form is respectively N-H ... O and O-H ... O.
The space group of the gabapentin that the present invention obtains-adipic acid eutectic structure cell is anorthic system, its axial lengthShaft angle a=69.13 ° ± 0.03 °,
β=74.96 ° ± 0.03 °, γ=83.52 ° ± 0.03 °.The monocrystalline using the mecrury software eutectic to obtaining carries out powder
The simulation of end diffracting spectrum adds, and the XRD figure spectrum that XRD figure spectrum and the experiment obtained directly obtains fits like a glove,
As shown in Figure 2.
Gabapentin of the present invention-adipic acid eutectic, its fusing point is 124 DEG C～130 DEG C, as shown in Figure 3.
Differ markedly from the fusing point of gabapentin, adipic acid.The gabapentin that the present invention obtains-adipic acid eutectic, its
Brilliant habit is bulk, as shown in Figure 5.
Gabapentin of the present invention-adipic acid eutectic is with ethanol as solvent, is obtained by solution crystallization.
The solution crystallization preparation method of gabapentin of the present invention-adipic acid eutectic, step is as follows:
At 30-40 DEG C, gabapentin and the adipic acid that mol ratio is 1:1～1:2 is placed in crystallizer, adds molten
Agent, in system, solute gabapentin+adipic acid gross mass content (solute/solution) is 10～20%；Constant temperature stirs
Mix 1h, make gabapentin and adipic acid dissolve at a higher temperature and be fully contacted in the solution, and then formed
Eutectic；2-3h is down to 10-15 DEG C by 30-40 DEG C, gradually provides degree of supersaturation, allows eutectic be formed further also
Gradually grow up；Growing the grain 1-2h, consumes residue degree of supersaturation, improves the yield of eutectic.Filter magma, be dried,
Obtain the eutectic of gabapentin-adipic acid.
Formed in experimental verification, foregoing invention is pure eutectic.This novel co-crystal changes gabapentin
Brilliant practise (bar-shaped become block), improve heap close.Experiment records, and the dissolubility of novel co-crystal is about 0.14g/ml,
Improve 16.7% than the dissolubility of gabapentin, rate of dissolution also improves.Additionally, eutectic is molten
May exist with complex ion state in liquid, this can change the permeability of medicine, may improve the biological utilisation of medicine
Degree.
The device information of the monitoring eutectic structure in the present invention is as follows:
1, eutectic structure is measured by Rigaku Rigakur mono-axisraPidH X-ray single crystal diffractometer
2, pressed powder diffraction XRD is to be measured by RigakuD/MAx2500X ray powder diffractometer
3, differential scanning calorimeter, Mei Tele company of the U.S., model DSC 1/500,10 DEG C/min of heating rate.
Nitrogen protection gas 100mL/min.
Accompanying drawing explanation
Fig. 1: gabapentin, adipic acid, the XRD figure of eutectic；
The XRD figure that the XRD figure spectrum of Fig. 2: the eutectic that experiment obtains calculates with the simulation of eutectic single crystal data；
The DSC figure of Fig. 3: eutectic；
The Electronic Speculum figure of Fig. 4: eutectic；
Fig. 5: the XRD figure of embodiment product.
Detailed description of the invention
Embodiment 1:
Accurately weighing 1.71g gabapentin and 2.92g adipic acid, mol ratio is that 1:2,41.67g ethanol is in 80ml
In crystallizer, Solute mass content 10%, constant temperature stirring 1h at 40 DEG C；
Temperature is down to 10 DEG C by 30 DEG C by 2h；
Constant temperature stirring 1h at 15 DEG C.Filter, washing with alcohol, be dried, i.e. obtain eutectic.
The product XRD figure prepared is as it is shown in figure 5, be pure eutectic.Brilliant habit is as shown in Figure 4；DSC shows it
Fusing point is 126 DEG C；At 25 DEG C, the dissolubility in water is 0.1395g/ml.
Embodiment 2:
Weighing 3.42g gabapentin 2.92g adipic acid, mol ratio is that 1:1,25.36g ethanol crystallizes in 50ml
In device, Solute mass content 20%, constant temperature stirring 1h at 40 DEG C；
Temperature is down to 15 DEG C by 40 DEG C by 3h；
15 degrees Celsius of lower constant temperature stirring 2h.Filter, washing with alcohol, be dried, i.e. obtain eutectic.
The product XRD figure prepared is as it is shown in figure 5, be pure eutectic.Its brilliant habit is identical with Fig. 4, and DSC shows
Its fusing point is 125 DEG C；At 25 DEG C, the dissolubility in water is 0.1401g/ml.
Embodiment 3:
Weighing 1.72g gabapentin 2.20g adipic acid, mol ratio is that 1:1.5,26.13g ethanol crystallizes in 50ml
In device, Solute mass content 15%, constant temperature stirring 1h at 35 DEG C；
Temperature is down to 12.5 DEG C by 40 DEG C by 2.5h；
Constant temperature stirring 1.5h at 15 DEG C.Filter, washing with alcohol, be dried, i.e. obtain eutectic.
The product XRD figure prepared is as it is shown in figure 5, be pure eutectic.DSC shows that its fusing point is 127 DEG C；Brilliant
Practising as block, at 25 DEG C, the dissolubility in water is 0.1397g/ml.
Embodiment 4:
Weigh 0.3087g gabapentin and 0.5063g adipic acid, mol ratio be 1:1.92,7.2502g ethanol in
In 20ml easymax crystallizer, Solute mass content 10.11%, constant temperature stirring 1h at 40 DEG C；
Temperature is down to 15 DEG C by 40 DEG C by 2h；
Constant temperature stirring 1h at 15 DEG C.Filter, washing with alcohol, be dried, i.e. obtain eutectic.
The product XRD figure prepared is as it is shown in figure 5, be pure eutectic.DSC shows, its fusing point is 126 DEG C.
Claims (3)
1. a gabapentin and adipic acid eutectic；2 gabapentin molecules and 1 adipic acid molecule pass through hydrogen bond
Effect composition gabapentin-adipic acid eutectic basic structural unit；The space group of eutectic structure cell is three oblique crystalline substances
System, its axial lengthShaft angle
A=69.13 ° ± 0.03 °, β=74.96 ° ± 0.03 °, γ=83.52 ° ± 0.03 °；Eutectic X-ray powder diffraction pattern
8.9 ± 0.2,9.2 ± 0.2,10.4 ± 0.2,14.8 ± 0.2,16.0 ± 0.2,17.0 ± 0.2,17.5 ± 0.2,
17.8 ± 0.2,19.0 ± 0.2,19.9 ± 0.2,20.8 ± 0.2,21.3 ± 0.2,22.7 ± 0.2,23.4 ±
0.2,23.9 ± 0.2,24.5 ± 0.2,25.4 ± 0.2,25.8 ± 0.2,28.2 ± 0.2,31.8 ± 0.2,33.8
The existing characteristics peak, position of ± 0.2,35.2 ± 0.2.
2. gabapentin as claimed in claim 1 and adipic acid eutectic, it is characterized in that described gabapentin-oneself two
Acid crystals is practised as bulk.
3. the gabapentin of claim 1 and the preparation method of adipic acid eutectic, is characterized in that: at 30-40 DEG C, will
Mol ratio is the gabapentin of 1:1～1:2 and adipic acid is placed in crystallizer, adds etoh solvent, molten in system
Matter gabapentin+adipic acid gross mass content is 10～20%；Constant temperature stirring 1h；2-3h is down to by 30-40 DEG C
10-15℃；Growing the grain 1-2h, filters magma, is dried, obtains the eutectic of gabapentin-adipic acid.
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Non-Patent Citations (2)
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| An Alternate Crystal Form of Gabapentin: A Cocrystal with Oxalic Acid;Mazal Wenger et al.;《Crystal Growth & Design》;20080320;第8卷(第5期);第1595-1598页 * |
| 药物共晶的最新研究进展;王义成 等;《药学进展》;20131231;第37卷(第3期);第120-130页 * |
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