CN111747947A - Meloxicam-urea eutectic crystal and preparation method thereof - Google Patents
Meloxicam-urea eutectic crystal and preparation method thereof Download PDFInfo
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- CN111747947A CN111747947A CN202010753601.5A CN202010753601A CN111747947A CN 111747947 A CN111747947 A CN 111747947A CN 202010753601 A CN202010753601 A CN 202010753601A CN 111747947 A CN111747947 A CN 111747947A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/02—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of urea, its salts, complexes or addition compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/02—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of urea, its salts, complexes or addition compounds
- C07C273/14—Separation; Purification; Stabilisation; Use of additives
- C07C273/16—Separation; Purification
Abstract
The invention relates to the field of pharmaceutical co-crystals, in particular to a meloxicam-urea co-crystal and a preparation method thereof. The XRD characteristic diffraction peak of the meloxicam-urea eutectic appears at 8.448 degrees +/-0.2 degrees, 13.222 degrees +/-0.2 degrees, 14.896 degrees +/-0.2 degrees, 16.344 degrees +/-0.2 degrees, 17.161 degrees +/-0.2 degrees, 22.302 degrees +/-0.2 degrees, 25.342 degrees +/-0.2 degrees, 27.016 degrees +/-0.2 degrees and 28.179 degrees +/-0.2 degrees. The formation of the meloxicam-urea eutectic obviously improves the in vitro release rate of the meloxicam.
Description
Technical Field
The invention relates to the field of pharmaceutical co-crystals, in particular to a meloxicam-urea co-crystal and a preparation method thereof.
Background
Meloxicam is a new nonsteroidal anti-inflammatory analgesic (NSAIDs), mainly used for the treatment of arthritis and rheumatoid arthritis, has pharmacological actions such as anti-inflammatory, pain-relieving, fever-relieving, because the gastrointestinal tract and kidney adverse reaction is obviously reduced compared with the same type of drugs, meloxicam has replaced other nonsteroidal anti-inflammatory drugs in most countries. However, meloxicam has poor water solubility and high permeability, so that it is poorly absorbed and has low bioavailability. At present, the solubility of the insoluble drug is improved and the bioavailability is improved, and the preparation method is mainly used for preparing new drug formulations, such as liposome, microemulsion, eutectic crystal and the like.
Pharmaceutical co-crystals refer to co-crystal products that are Active Pharmaceutical Ingredients (APIs) that form co-crystals with one or more other ligands, either by covalent bonds, intermolecular forces, or otherwise. The introduction of the ligand can change a plurality of physical and chemical characteristics of the API, such as enhancing the dissolution rate of the drug, and the like, and can also improve the pharmacological specificity of the drug.
Common preparation methods of pharmaceutical cocrystals include grinding, sublimation, solvent evaporation, solvothermal, melting, suspension, and high-velocity gas flow. Qiupei 29130, etc. by a solvent volatilization method, adding acetaminophen and adefovir dipivoxil (the molar ratio is 1: 1) into acetonitrile, and fully stirring to volatilize the solvent to obtain the adefovir dipivoxil-acetaminophen eutectic. And (3) adding 50g of zirconium oxide into the itraconazole and the malonic acid (the molar ratio is 1: 1) in a grinding tank by using a grinding method such as a fondant method, and carrying out liquid-free grinding for 10min to prepare the itraconazole-malonic acid eutectic. Four kinds of pharmaceutical cocrystals of theophylline-glutaric acid, theophylline-salicylic acid, theophylline-cinnamic acid and theophylline-benzoic acid are prepared by using a high-speed airflow method in Sunpuo and the like.
In recent years, with the continuous exhibition of the advantages of pharmaceutical co-crystals in the aspects of changing the solubility of drugs, improving the curative effect of drugs, improving the bioavailability and the like, a plurality of new co-crystal drugs are gradually emerged, such as piroxicam-benzoic acid co-crystal, indomethacin-nicotinamide co-crystal, puerarin-pyrazinamide co-crystal and isoniazid-naringenin co-crystal. However, the meloxicam cocrystal has not been reported yet.
Disclosure of Invention
The invention aims to provide a meloxicam-urea eutectic crystal and a preparation method thereof, and the meloxicam-urea eutectic crystal is characterized in structure and tested for in vitro release rate.
The invention solves the technical problems through the following technical scheme:
the meloxicam-urea eutectic crystal comprises meloxicam and eutectic ligand urea.
The eutectic compound is a meloxicam-urea 1:1 eutectic.
The XRD characteristic diffraction peak of the meloxicam-urea eutectic appears at 8.448 degrees +/-0.2 degrees, 13.222 degrees +/-0.2 degrees, 14.896 degrees +/-0.2 degrees, 16.344 degrees +/-0.2 degrees, 17.161 degrees +/-0.2 degrees, 22.302 degrees +/-0.2 degrees, 25.342 degrees +/-0.2 degrees, 27.016 degrees +/-0.2 degrees and 28.179 degrees +/-0.2 degrees.
The preparation method of the meloxicam-urea eutectic crystal comprises the following steps: and weighing the meloxicam and the urea according to the molar ratio of 1:1, placing the meloxicam and the urea into a mortar, and grinding for 6 hours to obtain the dry-ground meloxicam-urea eutectic.
Or, the preparation method of the meloxicam-urea eutectic crystal comprises the following steps: weighing meloxicam and urea according to the molar ratio of 1:1, adding DMF, carrying out ultrasonic reaction at 60 ℃ for 2h to obtain a yellow transparent solution, carrying out rotary evaporation to remove DMF, and drying to obtain the meloxicam-urea eutectic crystal subjected to ultrasonic reaction.
In the above preparation method of the meloxicam-urea eutectic, the amount of DMF is DMF: 15: 1 of meloxicam, wherein the ratio is mL: g. In the preparation method of the meloxicam-urea eutectic, the ultrasonic reaction power is 250W, and the ultrasonic frequency is 40 KHz.
The beneficial effect of the invention is that,
the invention provides a novel meloxicam-urea eutectic crystal and a preparation method thereof. The preparation method adopts meloxicam and urea as initial components, adopts two methods of grinding method and solvent ultrasonic method to prepare high-purity eutectic, and characterizes the prepared eutectic by SEM, DSC, XRD and Raman spectrum technology.
In vitro release studies show that the cumulative release rates of meloxicam and the eutectic thereof in the artificial gastric juice are 75.2% and 92.0% respectively at 3h, and the cumulative release rate of the eutectic is 1.22 times of that of the bulk drug; the accumulative release rates of the meloxicam and the eutectic thereof in the artificial intestinal juice are 20.6 percent and 25.0 percent respectively at 3h, and the accumulative release rate of the eutectic is 1.21 times of that of the raw material medicines. Therefore, the formation of the meloxicam-urea eutectic significantly improves the in vitro release rate of meloxicam.
Drawings
FIG. 1 is an IR chart of meloxicam, urea, dry-milled cocrystal, and ultrasonic-reacted cocrystal.
Fig. 2 is an optimization graph of ultrasound time (a) and power (B).
Fig. 3 is SEM images of meloxicam (a) and cocrystal (B).
Figure 4 is a DSC chart of meloxicam, urea and co-crystals.
Figure 5 is an XRD pattern of meloxicam, urea and co-crystals.
Figure 6 is a Raman plot of meloxicam and co-crystals.
Fig. 7 is a graph comparing the in vitro release of meloxicam and its co-crystals in artificial gastric fluid (a) and artificial intestinal fluid (B).
Figure 8 is the XRD pattern of the meloxicam-urea cocrystal prepared in example 1 (dry process).
Figure 9 is the XRD pattern of the meloxicam-urea cocrystal prepared in example 3 (wet process).
Detailed Description
The invention will be further described with reference to the accompanying drawings and specific embodiments so that those skilled in the art may better understand the invention, but the invention is not limited thereto.
In the embodiment of the invention, the preparation of the artificial gastric juice and intestinal juice comprises the following steps: artificial gastric juice (pH 1.2) and intestinal juice (pH 6.8) were prepared as specified in the chinese pharmacopoeia (four parts) of the 2015 edition.
Example 1 preparation of Meloxicam-Urea cocrystal
And (3) dry grinding: 0.8785g of meloxicam and 0.15g of urea (the molar ratio of meloxicam to urea is 1: 1) are precisely weighed and placed in a mortar, and the mixture is ground for 6 hours, thus obtaining the dry grinding eutectic.
Example 2 preparation of Meloxicam-Urea cocrystal
An ultrasonic reaction method: respectively and precisely weighing 0.8785g of meloxicam and 0.15g of urea (the molar ratio of meloxicam to urea is 1: 1), adding 15ml of DMF, and respectively carrying out the following steps: reacting at 40 deg.C and 60 deg.C for 2h at 250W and 40 KHz; and a second condition: 250W, 40KHz, 60 ℃, and carrying out ultrasonic reaction for 1h, 2h and 3 h; and (3) carrying out a third condition: carrying out ultrasonic reaction for 2h at the temperature of 60 ℃ at 250W, 200W, 150W and 40 KH; obtaining a yellow transparent solution, removing DMF by rotary evaporation, and drying to obtain the ultrasonic reaction eutectic.
EXAMPLE 3 preparation of Meloxicam-Urea cocrystals
An ultrasonic reaction method: 0.8785g of meloxicam and 0.15g of urea are precisely weighed (the molar ratio of meloxicam to urea is 1: 1), 15ml of DMF is added, ultrasonic reaction is carried out for 2h (250W, 40KHz condition) at 60 ℃ to obtain yellow transparent solution, DMF is removed by rotary evaporation, and the ultrasonic reaction eutectic is obtained after drying.
Characterization and in vitro release rate experiments were performed on the meloxicam-urea cocrystals prepared in the above examples, as follows:
characterization of 1 Meloxicam-Urea cocrystal
1.1 scanning electron microscopy analysis: and respectively weighing 5mg of meloxicam raw material medicine and 5mg of eutectic crystal, and carrying out scanning electron microscope analysis.
1.2 differential scanning calorimetry analysis, taking a blank crucible as a reference, weighing 10mg of meloxicam reference substance, heating at a rate of 10 ℃/min under the protection of nitrogen, and recording the DSC curve of the reference substance at 15-600 ℃. DSC curves of urea and co-crystals were recorded by the same method.
1.3X-ray powder diffraction analysis: cu/k alpha (lambda is 1.5418nm) is used as a radiation source, the scanning speed and the step length are respectively 0.1s/step and 0.02 degrees, the scanning is carried out within the range of 5-50 degrees, and the working condition of a power supply is 40kV and 40 mA.
1.4 Raman spectrum under the wavelength of 633nm and 532nm of an exciter, the content of meloxicam raw material medicines and the content of eutectic in 100-4000 cm are respectively measured-1The raman spectrum of (a).
2. Determination of in vitro Release
Precisely weighing 10mg of meloxicam raw material medicine, respectively placing the meloxicam raw material medicine into 900mL of artificial intestinal juice and artificial gastric juice, respectively sampling 10mL (supplementing dissolution medium with the same volume immediately after sampling) at 37 ℃ and 75r/min for 5 min, 10min, 15 min, 20 min, 30 min, 40 min, 60 min, 80 min, 100 min, 120 min, 140 min, 160 min, 180 min, 200min, immediately filtering, and collecting the subsequent filtrate as a sample solution. The absorbance at 362nm was determined using the corresponding dissolution medium as a blank. According to a method for measuring the dissolution rate of meloxicam tablets in the' Chinese pharmacopoeia (second part) of 2015 edition, control working solutions with concentrations of 8.0 mug/mL and intestinal juice as media are respectively prepared. And respectively measuring the absorbance values of the test sample and the working solution at 362nm by adopting an ultraviolet spectrophotometry and taking a corresponding dissolution medium as a blank. The release was calculated according to equation (1). An appropriate amount of meloxicam-urea eutectic powder (about 10mg of meloxicam) is precisely weighed, and the dissolution rates in artificial intestinal juice and artificial gastric juice are determined by the same method.
In equation (1): 8.0 concentration of meloxicam control solution (. mu.g/mL), 900 volume of dissolution medium (mL), AXIs the absorbance of the test article, ARAs absorbance of the control, M is the sample volume (mg).
3 results
3.1 screening of preparation method of Meloxicam-Urea cocrystal
3.1.1 screening of preparation method of Meloxicam-Urea cocrystal
The IR diagram of meloxicam, urea, dry milled co-crystal and ultrasound reacted co-crystal is shown in figure 1. As can be seen from FIG. 1, the characteristic absorption in the infrared of the C ═ O bond of meloxicam is present at 1550cm-1The characteristic absorption peak of the N-H bond is about 3300cm-1To (3). While urea has O-H … N bond, so 1700cm-1Infrared absorption (neutral carboxylic acid groups) with strong C ═ O bonds and weak C — O bond absorption at 1200cm-1Nearby. Compared with a single component, the IR spectrum of 2 eutectics is 400-3000 cm-1There was little change in the range, almost a summation of the meloxicam and urea profiles. It can be seen from the IR spectra of the dry-process ground eutectic and the ultrasonic reaction eutectic that both methods can prepareThe eutectic crystal and an IR image of the eutectic crystal by the ultrasonic reaction method show an obvious characteristic peak displacement phenomenon, which proves that the eutectic crystal of meloxicam is formed. The formation of the eutectic of meloxicam and urea is caused by the formation of hydrogen bonds between meloxicam and urea, and the characteristic peak does not disappear after the formation of the hydrogen bonds, but the corresponding characteristic peak is correspondingly shifted and changed due to the change of the bond energy or bond length. Therefore, the meloxicam-urea eutectic (simply referred to as the eutectic) is preferably prepared by an ultrasonic reaction method.
3.1.2 optimization of preparation of Meloxicam-Urea eutectic by ultrasonic reaction
Factors influencing the ultrasonic reaction method include: reaction temperature, sonication time and power. The influence of reaction temperature, ultrasonic time and power on eutectic formation is examined by a single-factor optimization method, and an IR (infrared) image of the eutectic is generated as a judgment standard. The prepared meloxicam-urea eutectic IR image is examined at 40, 60 and 80 ℃ according to the method of the ultrasonic reaction method in example 1, the fixed power is 250W, the frequency is 40KHz, and the ultrasonic reaction is 2 h. The results show that the reaction temperature effect is insignificant in the range of 40-80 ℃. Therefore, 60 ℃ is used as the reaction temperature. The effect of ultrasonic time (250w, 40KHz) and power (time 2h, frequency 40KHz) on eutectic formation was examined at 60 deg.C, and the results are shown in FIGS. 2A and 2B. As can be seen from fig. 2A, when the reaction is performed for 1 hour, the characteristic absorption of meloxicam still exists in the obtained cocrystal, and after the reaction exceeds 2 hours, the prepared cocrystal has no characteristic absorption of meloxicam and has a new absorption peak, the preparation speed is considered comprehensively, and the ultrasonic time is selected to be 2 hours. As can be seen from FIG. 2B, the speed of eutectic formation increases with increasing ultrasonic power, and the reaction can be completed rapidly at a power of 250W. Therefore, the optimal preparation conditions of the meloxicam-urea eutectic are as follows: the reaction temperature is 60 ℃, the ultrasonic time is 2h, and the power is 250W.
3.2 characterization of Meloxicam-Urea cocrystal
3.2.1 SEM analysis
SEM images of meloxicam (A) and cocrystal (B) are shown in FIG. 3. As can be seen from fig. 3A, meloxicam is in the shape of a stone under an electron microscope, and disordered fine particles exist on the surface; in fig. 3B, the rod-like structure of dense hemp can be observed, which is uniform, regular, and stable, indicating that eutectic is formed.
3.2.2 DSC analysis
The results of DSC analysis of meloxicam, urea and cocrystal are shown in figure 4. Meloxicam has a melting point of 254 deg.C and is melted and decomposed simultaneously. As can be seen from FIG. 4, meloxicam starts to melt at 254 deg.C and shows a characteristic absorption peak at 268 deg.C; the melting point of urea is 132.7 ℃, and a characteristic absorption peak appears at 140 ℃; in a DSC curve of the meloxicam-urea eutectic, the characteristic peak of meloxicam disappears, the peak intensity of urea is obviously reduced, and new endothermic peaks appear at about 187 and 261 ℃. Probably caused by the formation of meloxicam-urea eutectic and the reduction of the melting point of meloxicam.
3.2.3 XRD analysis
The XRD patterns of meloxicam, urea and co-crystal are shown in fig. 5. As can be seen from fig. 5, the characteristic peaks of meloxicam exhibited strong peaks at 13.168, 15.016, 18.708, 19.413 and 26.011 °, especially at 26.011 °; urea at 22.404, 29, 529, 35, 689, 37.359, 45.631 and 49.590 °, with a strong peak at 22.404 °; and the characteristic peaks of meloxicam and urea in the eutectic basically disappear, and new characteristic peaks appear at 8.448, 13.222, 14.896, 16.344, 17.161, 22.302, 23.404, 25.342, 27.016 and 28.179 degrees, which indicates that meloxicam and urea form the eutectic rather than the simple superposition of 2 substances.
3.1.5 Raman Spectroscopy
The Raman spectrum is an effective analysis method for identifying polymorphic substances, is complementary with the infrared spectrum, has obvious characterization advantages for molecules without polarity and symmetry, and is a Raman spectrogram of meloxicam and eutectic crystals at excitation wavelengths of 532nm and 633nm in figure 6. As can be seen from the results of FIG. 6, when the excitation wavelength is 532nm, the characteristic peak of meloxicam mainly appears at 725-1100 cm-1And 772, 864, 1008, 1051cm-1Exhibit strong absorption, and in the eutectic diagram these absorptions disappear, at 878, 1017, 1056cm-1New characteristic peaks appear; when the excitation wavelength is 633nm, the characteristic peak of meloxicam mainly appears at 1100-1750 cm-1And is 1166, 1310, 1541, 1604cm-1Shows strong absorption, and the intensity of the absorption peaks in a eutectic chart is remarkably reduced and is 878, 1017 and 1056cm-1A new characteristic peak appears at the position, and the wet-process eutectic not only obviously reduces the strength of the peak, but also enables 1500-1750 cm-1The peak shape between the two changes, indicating that the meloxicam and the urea form a eutectic crystal.
3.2 determination of in vitro Release
After oral administration, the drug is generally absorbed in the stomach or small intestine. The pH value of the stomach in the fasting state of a human is about 1.2, the pH value of the intestine is about 6.8, the internal environment of the stomach and the small intestine is simulated artificially in the experiment, the absorbance values of reference working solution with artificial gastric juice and intestinal juice as media and the concentration of 8.0 mug/mL are 0.6059 and 0.5824 respectively according to the dissolution rate determination method of meloxicam tablets in China pharmacopoeia (second part) of 2015 edition, the measured absorbance values of the test solution at each time point are substituted into the formula (1), the release rate is calculated, and the cumulative release rate of meloxicam and eutectic crystal is shown in figure 7. Fig. 7A shows that the cumulative release rates of meloxicam and the cocrystal thereof in the artificial gastric juice are 75.2% and 92.0% respectively at 3h, and the cumulative release rate of the cocrystal is 1.22 times of that of the bulk drug; and figure 7B shows that at 3h, the cumulative release rates of the meloxicam and the cocrystal thereof in the artificial intestinal juice are 20.6% and 25.0%, respectively, and the cumulative release rate of the cocrystal is 1.21 times of that of the raw material drug thereof. Therefore, the formation of the meloxicam-urea eutectic significantly improves the in vitro release rate of meloxicam.
Claims (7)
1. The meloxicam-urea eutectic crystal is characterized by comprising meloxicam and eutectic ligand urea.
2. The meloxicam-urea cocrystal of claim 1, wherein the cocrystal is a meloxicam-urea 1:1 cocrystal.
3. The meloxicam-urea cocrystal of claim 2, wherein: the XRD characteristic diffraction peak of the meloxicam-urea eutectic appears at 8.448 degrees +/-0.2 degrees, 13.222 degrees +/-0.2 degrees, 14.896 degrees +/-0.2 degrees, 16.344 degrees +/-0.2 degrees, 17.161 degrees +/-0.2 degrees, 22.302 degrees +/-0.2 degrees, 25.342 degrees +/-0.2 degrees, 27.016 degrees +/-0.2 degrees and 28.179 degrees +/-0.2 degrees.
4. The method of preparing a meloxicam-urea cocrystal according to claim 1, comprising the steps of: and weighing the meloxicam and the urea according to the molar ratio of 1:1, placing the meloxicam and the urea into a mortar, and grinding for 6 hours to obtain the dry-ground meloxicam-urea eutectic.
5. The method of preparing a meloxicam-urea cocrystal according to claim 1, comprising the steps of: weighing meloxicam and urea according to the molar ratio of 1:1, adding DMF, carrying out ultrasonic reaction at 60 ℃ for 2h to obtain a yellow transparent solution, carrying out rotary evaporation to remove DMF, and drying to obtain the meloxicam-urea eutectic crystal subjected to ultrasonic reaction.
6. The method of claim 5, wherein the amount of DMF is DMF: 15: 1 of meloxicam, wherein the ratio is mL: g.
7. The method for preparing the meloxicam-urea cocrystal according to claim 5, wherein the ultrasonic reaction power is 250W, and the ultrasonic frequency is 40 KHz.
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Citations (3)
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DE102007030695A1 (en) * | 2007-07-01 | 2009-01-08 | Sciconcept Gmbh | Co-crystal, useful e.g. to prepare a pharmaceutical formulation for the treatment of psychosis, neurological disorder and struma lymphomatosa, comprises an amino compound and urea as further component |
WO2009094155A1 (en) * | 2008-01-22 | 2009-07-30 | Thar Pharmaceuticals | In vivo studies of crystalline forms of meloxicam |
CN102036946A (en) * | 2008-05-21 | 2011-04-27 | 埃斯蒂文博士实验室股份有限公司 | Co-crystals of duloxetine and Cox-inhibitors for the treatment of pain |
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DE102007030695A1 (en) * | 2007-07-01 | 2009-01-08 | Sciconcept Gmbh | Co-crystal, useful e.g. to prepare a pharmaceutical formulation for the treatment of psychosis, neurological disorder and struma lymphomatosa, comprises an amino compound and urea as further component |
WO2009094155A1 (en) * | 2008-01-22 | 2009-07-30 | Thar Pharmaceuticals | In vivo studies of crystalline forms of meloxicam |
CN102036946A (en) * | 2008-05-21 | 2011-04-27 | 埃斯蒂文博士实验室股份有限公司 | Co-crystals of duloxetine and Cox-inhibitors for the treatment of pain |
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Title |
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P. CYSEWSKI: "Intermolecular interaction as a direct measure of water solubility advantage of meloxicam cocrystalized with carboxylic acids", 《JOURNAL OF MOLECULAR MODELING》 * |
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