CN108440449B - Eutectic of hydrochlorothiazide and proline and preparation method thereof - Google Patents
Eutectic of hydrochlorothiazide and proline and preparation method thereof Download PDFInfo
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- CN108440449B CN108440449B CN201810340303.6A CN201810340303A CN108440449B CN 108440449 B CN108440449 B CN 108440449B CN 201810340303 A CN201810340303 A CN 201810340303A CN 108440449 B CN108440449 B CN 108440449B
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- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/15—Six-membered rings
- C07D285/16—Thiadiazines; Hydrogenated thiadiazines
- C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
- C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
- C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
- C07D285/26—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals
- C07D285/28—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached in position 3
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a hydrochlorothiazide drug and proline pharmaceutical co-crystal and a preparation method thereof, and relates to the field of pharmaceutical co-crystals. The composition of the hydrochlorothiazide-proline eutectic is [ C7H8N3O4S2Cl·C5H9NO2]The basic structural unit is formed by one hydrochlorothiazide molecule and one proline molecule. The eutectic crystal belongs to an orthorhombic system and has a space group ofPca21. Hydrochlorothiazide and proline are used as raw materials, and a solvent volatilization method and a cooling method are adopted to prepare the pharmaceutical co-crystal. The pharmaceutical co-crystal improves the solubility of hydrochlorothiazide and lays a foundation for improving the bioavailability and the drug effect of the hydrochlorothiazide. The preparation method of the pharmaceutical cocrystal is simple and easy, has low cost, and is convenient for large-scale production.
Description
Technical Field
The invention relates to the field of pharmaceutical co-crystals, in particular to a pharmaceutical co-crystal of hydrochlorothiazide and proline and a preparation method thereof.
Background
The pharmaceutical co-crystal is a new co-crystal formed by combining a pharmaceutical active ingredient and a physiologically acceptable co-crystal former in the same crystal lattice in a non-covalent bond form such as a hydrogen bond. The pharmaceutical co-crystal is used as a novel pharmaceutical entity, does not change the covalent structure of the drug molecules, realizes the innovation of the drug by regulating and controlling the crystal structure, greatly shortens the research and development period of the drug, and prolongs the property date of the drug. Pharmaceutical co-crystals have received a high degree of attention in recent years from both academia and industry due to unique developmental advantages and potential commercial value.
Hydrochlorothiazide (HCT) is colorless crystal or white crystalline powder with molecular formula of C7H8N3O4S2Cl as a drug for the treatment of essential hypertension, mainly by natriuresis, reducing blood volume negativeThe load plays a role in reducing blood pressure. However, according to the Biopharmaceutics Classification System (BCS), hydrochlorothiazide belongs to the BCS-IV class of drugs, and has problems of low solubility and poor permeability, resulting in low bioavailability of hydrochlorothiazide, which limits its clinical application to some extent. The dissolving property of the hydrochlorothiazide is improved by a co-crystallization technology, so that the treatment effect of the hydrochlorothiazide can be improved. The selection of the co-crystal former is a critical step in order to obtain the desired pharmaceutical co-crystal. Proline is white crystalline powder, is very easy to dissolve in water, has no toxic or side effect, and is an ideal eutectic forming substance. According to the invention, hydrochlorothiazide and proline are co-crystallized through a crystal engineering technology, so that hydrochlorothiazide-proline eutectic is prepared. By utilizing the characteristic that the water solubility of the proline is much higher than that of the hydrochlorothiazide, the method lays a foundation for improving the bioavailability of the hydrochlorothiazide by enhancing the solubility of the hydrochlorothiazide on the premise of not changing the pharmacological action of the hydrochlorothiazide drug for reducing the blood pressure.
Disclosure of Invention
The invention aims to provide a hydrochlorothiazide-proline pharmaceutical co-crystal (hereinafter referred to as hydrochlorothiazide-proline co-crystal) and a preparation method thereof, and the hydrochlorothiazide-proline co-crystal is characterized in structure and tested for solubility. The dissolving property of the hydrochlorothiazide is improved by preparing a pharmaceutical co-crystal.
The molecular formula of the hydrochlorothiazide-proline eutectic is [ C7H8N3O4S2Cl·C5H9NO2]The basic structural unit is formed by one hydrochlorothiazide molecule and one proline molecule. The hydrochlorothiazide-proline eutectic belongs to an orthorhombic system, and the space group isPca21The unit cell parameters are: a = 20.30-20.70, b = 9.50-9.90, c = 8.06-8.46, a = β = γ = 90 °. The characteristic diffraction peaks of PXRD appear at 8.619 DEG +/-0.2, 14.718 DEG +/-0.2, 15.842 DEG +/-0.2, 18.262 DEG +/-0.2, 19.159 DEG +/-0.2, 21.497 DEG +/-0.2, 22.938 DEG +/-0.2, 23.782 DEG +/-0.2 and 30.501 DEG +/-0.2. Or the characteristic diffraction peaks of PXRD appear in 8.619 degrees plus or minus 0.1, 14.718 degrees plus or minus 0.1, 15.842 degrees plus or minus 0.1, 18.262 degrees plus or minus 0.1, 19.159 degrees plus or minus 0.1, 21.497 degrees plus or minus 0.1, 22.938 degrees plus or minus 0.1, 23.782 degrees plus or minus 0.1, 30.501 degrees plus or minus 0Position 1. Or its PXRD characteristic diffraction peak appears at 8.619 °, 14.718 °, 15.842 °, 18.262 °, 19.159 °, 21.497 °, 22.938 °, 23.782 °, 30.501 °.
The preparation method of the hydrochlorothiazide-proline eutectic is realized by the following steps:
mixing the hydrochlorothiazide bulk drug with proline, adding ethanol, stirring, filtering, standing the filtrate to separate out a solid phase substance, and collecting the solid phase substance to obtain the hydrochlorothiazide-proline eutectic crystal.
Further, the preparation method of the hydrochlorothiazide-proline eutectic is realized according to the following steps:
putting the hydrochlorothiazide raw material medicine and proline in a flask according to the molar ratio of 1:1, adding ethanol to completely dissolve the mixture powder, stirring for 3-5 h, filtering, standing the filtrate for 3-5 days, and collecting a solid phase substance to obtain the hydrochlorothiazide-proline eutectic crystal.
The preparation method of the hydrochlorothiazide-proline eutectic is realized by the following steps:
putting the hydrochlorothiazide raw material medicine and proline in a flask according to the molar ratio of 1:1, adding ethanol to completely dissolve the mixture powder, heating and stirring for 3-5 h, filtering while hot, standing the filtrate, cooling to room temperature, and separating out a solid phase substance to obtain the hydrochlorothiazide-proline eutectic.
The invention relates to a preparation method of hydrochlorothiazide-proline eutectic, which takes hydrochlorothiazide raw material medicines and proline as initial components, adopts a solvent volatilization method and a cooling method to prepare high-purity eutectic, and performs X-ray single crystal diffraction, TG, DSC, PXRD and other related characterization and dissolution rate determination on a eutectic sample. The result shows that the molecular formula of the hydrochlorothiazide-proline eutectic is [ C ]7H8N3O4S2Cl·C5H9NO2]The prepared drug cocrystal has high purity and crystallinity, can be kept stable for a long time without deterioration, and has larger dissolution rate.
The preparation method is simple and feasible, mild in reaction conditions, high in yield and purity, low in cost and capable of being used for expanded production.
Drawings
Fig. 1 is a molecular structural diagram of the hydrochlorothiazide-proline eutectic of the present invention.
FIG. 2 shows a hydrogen bonding mode of the hydrochlorothiazide-proline eutectic of the present invention.
Fig. 3 is a PXRD pattern comparison of hydrochlorothiazide and proline starting materials with the hydrochlorothiazide-proline co-crystal obtained in example two.
Fig. 4 is a comparison of the simulated PXRD spectrum of the software and the spectrum of the hydrochlorothiazide-proline co-crystal obtained in example two.
FIG. 5 is a TG-DSC curve of the hydrochlorothiazide-proline co-crystal obtained in example two.
Fig. 6 is a comparison graph of the dissolution rates of hydrochlorothiazide-proline eutectic and hydrochlorothiazide bulk drug in buffer solution.
Detailed Description
The first embodiment is as follows: the molecular formula of the hydrochlorothiazide-proline eutectic is [ C ]7H8N3O4S2Cl·C5H9NO2]The basic structural unit is formed by one hydrochlorothiazide molecule and one proline molecule. The hydrochlorothiazide-proline eutectic belongs to an orthorhombic system, and the space group isPca21The unit cell parameters are: a = 20.5038 a, b = 9.7066 a, c = 8.2625 a, α = β = γ = 90 °. The characteristic diffraction peaks of PXRD appear at 8.619 degrees, 14.718 degrees, 15.842 degrees, 18.262 degrees, 19.159 degrees, 21.497 degrees, 22.938 degrees, 23.782 degrees and 30.501 degrees.
The hydrochlorothiazide-proline eutectic in the embodiment is formed by bonding one hydrochlorothiazide molecule and one proline molecule together through a hydrogen bond. As shown in figure 1, two molecules are connected by two N-H … O hydrogen bonds, wherein H atom on N1 of hydrochlorothiazide molecule is used as hydrogen bond donor to form hydrogen bond with O5 in proline molecule as hydrogen bond acceptor, and H atom on N4 in proline molecule is used as hydrogen bond donor to form hydrogen bond with O1 in hydrochlorothiazide molecule as hydrogen bond acceptor.
The second embodiment is as follows: the preparation method of the hydrochlorothiazide-proline eutectic is implemented according to the following steps:
putting hydrochlorothiazide raw material medicines and proline into a round-bottom flask according to a molar ratio of 1:1, adding ethanol into the round-bottom flask, heating in a water bath at 30 ℃, stirring for 3-5 hours, filtering, standing and volatilizing the filtrate for 3-5 days, and collecting a solid phase substance to obtain the hydrochlorothiazide-proline eutectic crystal.
The hydrochlorothiazide-proline eutectic crystal prepared by the embodiment has good chemical stability, high purity and high yield.
The third concrete implementation mode: the difference between the present embodiment and the second embodiment is that the solid-to-liquid ratio of the mixed powder to ethanol is (0.080-0.085) g (8-10) mL, and other steps and parameters are the same as those of the second embodiment.
The fourth concrete implementation mode: this embodiment is different from the second embodiment in that the filtrate is left at room temperature for 4 days and then the solid phase is collected. Other steps and parameters are the same as those in the second embodiment.
The fifth concrete implementation mode: the preparation method of the hydrochlorothiazide-proline eutectic is implemented according to the following steps:
putting the hydrochlorothiazide raw material medicine and proline into a round-bottom flask according to a molar ratio of 1:1, adding ethanol into the round-bottom flask, heating in a 70 ℃ water bath, stirring for 3-5 h, filtering while hot, cooling the filtrate to room temperature, and separating out a solid phase substance to obtain the hydrochlorothiazide-proline eutectic.
The sixth specific implementation mode: the difference between the present embodiment and the fifth embodiment is that the solid-to-liquid ratio of the mixed powder to ethanol is (0.080-0.085) g to (5-8) mL, and other steps and parameters are the same as those of the fifth embodiment.
The first embodiment is as follows: the preparation method of the hydrochlorothiazide-proline eutectic is implemented according to the following steps:
placing 59.5 mg of hydrochlorothiazide raw material medicine and 23 mg of proline in a round bottom flask according to the mol ratio of 1:1, adding 9 mL of ethanol into the mixed powder, heating in a water bath at 30 ℃, stirring for 4 hours, filtering, standing the filtrate for 4 days, and collecting a solid phase substance to obtain the hydrochlorothiazide-proline eutectic crystal.
In the embodiment, the hydrochlorothiazide-proline eutectic prepared by a solvent volatilization method is a colorless columnar crystal, and a single crystal sample can be selected from the colorless columnar crystal to perform X-ray single crystal diffraction measurement, so that the accurate structure of the hydrochlorothiazide-proline eutectic is analyzed.
A single crystal sample with a suitable size and high quality was selected from the hydrochlorothiazide-proline eutectic prepared by the solvent evaporation method in example one, and X-ray single crystal diffraction measurement was performed. Scanning was carried out by means of an Xcalibur Eos diffractometer from Agilent, usa, with a Cu-ka radiation monochromator monochromatized by means of a graphite monochromator in the form of an omega scan. The current voltages required for the diffraction experiments were set at 40 mA and 50 kV. The results show that the molecular formula of the hydrochlorothiazide-proline eutectic in the embodiment is [ C ]7H8N3O4S2Cl·C5H9NO2]The basic structural unit is formed by one hydrochlorothiazide molecule and one proline molecule. The hydrochlorothiazide-proline eutectic belongs to an orthorhombic system, and the space group isPca21The unit cell parameters are: a = 20.5038 a, b = 9.7066 a, c = 8.2625 a, α = β = γ = 90 °. The characteristic diffraction peaks of PXRD appear at 8.619 degrees, 14.718 degrees, 15.842 degrees, 18.262 degrees, 19.159 degrees, 21.497 degrees, 22.938 degrees, 23.782 degrees and 30.501 degrees.
Example two: the preparation method of the hydrochlorothiazide-proline eutectic is implemented according to the following steps:
595 mg of hydrochlorothiazide bulk drug and 230 mg of proline are placed in a round bottom flask according to the molar ratio of 1:1, 60 mL of ethanol is added into the mixed powder, the mixture is heated and stirred in a 70 ℃ water bath for 2 hours, the mixture is filtered while hot, and the solid phase is collected after the filtrate is cooled to room temperature, so that the hydrochlorothiazide-proline eutectic crystal is obtained.
In the embodiment, the yield of the hydrochlorothiazide-proline eutectic prepared by the cooling method is 85.1%. The prepared hydrochlorothiazide-proline eutectic is white crystalline powder, has good chemical stability, can keep the framework structure of the crystal after being placed at room temperature for a long time, and does not have any deterioration phenomenon.
Purity determination of hydrochlorothiazide-proline eutectic:
PXRD diffraction experiments were performed on powder samples obtained by the cooling method of example two. PXRD diffraction data were measured using an X-ray diffractometer model D8 from BRUKER, Germany. And (3) testing conditions are as follows: the voltage of the Cu-Kalpha target tube is 40 kV, the tube current is 10 mA, and the scanning speed is 2 degrees/min. As shown in fig. 3, when the obtained hydrochlorothiazide-proline eutectic is compared with the raw material, the characteristic diffraction peak position and diffraction intensity are significantly changed, indicating that a new phase is generated.
In order to further determine the phase and purity of the hydrochlorothiazide-proline eutectic sample obtained by the cooling method, in this example, the PXRD spectrogram of the hydrochlorothiazide-proline eutectic sample is compared with the theoretical spectrogram of the hydrochlorothiazide-proline eutectic simulated by Mercury software according to crystal data obtained by an X-ray single crystal diffraction test. As shown in figure 4, PXRD characteristic diffraction peaks appear at 8.619 degrees, 14.718 degrees, 15.842 degrees, 18.262 degrees, 19.159 degrees, 21.497 degrees, 22.938 degrees, 23.782 degrees and 30.501 degrees, powder diffraction peaks are sharp and are matched with theoretical spectrogram diffraction peaks of a hydrochlorothiazide-proline eutectic sample, and the prepared hydrochlorothiazide-proline eutectic has high crystallinity and purity. On the basis, the hydrochlorothiazide-proline eutectic obtained in example two was subjected to thermal analysis by using a Netzsch STA 409PC synchronous thermal analyzer, and the thermogravimetric-differential scanning calorimetry (TG-DSC) thereof is shown in fig. 5. As can be seen from the figure, the resulting co-crystal is a homogeneous phase with a fixed melting point of 202 ℃.
Intrinsic Dissolution Rate (IDR) determination of hydrochlorothiazide-proline cocrystal:
IDRs of a hydrochlorothiazide-proline eutectic sample and a hydrochlorothiazide bulk drug are respectively measured in a phosphate buffer medium with pH = 7.4 by a ROTATING disk method, and the result is shown in figure 6. The figure shows that the IDR of the hydrochlorothiazide-proline eutectic is higher than that of hydrochlorothiazide, which indicates that the pharmaceutical eutectic can improve the solubility of the hydrochlorothiazide, and the research result provides scientific basis for improving the bioavailability and curative effect of the hydrochlorothiazide.
Claims (6)
1. The pharmaceutical co-crystal of hydrochlorothiazide and proline is characterized in that the chemical formula of the pharmaceutical co-crystal is [ C ]7H8N3O4S2Cl·C5H9NO2]A basic structural unit is formed by one hydrochlorothiazide molecule and one proline molecule; the pharmaceutical co-crystal is an orthorhombic system, and the space group Pca21The unit cell parameters are:
α ═ β ═ γ ═ 90.00 °; the characteristic diffraction peaks of the pharmaceutical co-crystal PXRD appear at 8.619 DEG +/-0.2, 14.718 DEG +/-0.2, 15.842 DEG +/-0.2, 18.262 DEG +/-0.2, 19.159 DEG +/-0.2, 21.497 DEG +/-0.2, 22.938 DEG +/-0.2, 23.782 DEG +/-0.2 and 30.501 DEG +/-0.2.
2. The process for the preparation of the pharmaceutical co-crystal of hydrochlorothiazide with proline according to claim 1, characterized in that it is carried out according to the following steps:
mixing the hydrochlorothiazide bulk drug with proline, adding ethanol, stirring, filtering, standing the filtrate to separate out a solid phase substance, and collecting the solid phase substance to obtain the hydrochlorothiazide-proline pharmaceutical co-crystal.
3. The process for the preparation of the pharmaceutical co-crystal of hydrochlorothiazide with proline according to claim 1, characterized in that it is carried out according to the following steps:
mixing the hydrochlorothiazide raw material medicine and proline in a molar ratio of 1:1, placing the mixture in a round-bottom flask, adding ethanol into the mixed powder, heating in a water bath at 30 ℃, stirring for 3-5 hours, filtering, standing and volatilizing the filtrate for 3-5 days, and collecting a solid phase substance to obtain the hydrochlorothiazide and proline medicinal eutectic crystal.
4. The preparation method of the hydrochlorothiazide and proline pharmaceutical co-crystal according to claim 3, characterized in that the solid-to-liquid ratio of the mixed powder and ethanol is (0.080-0.085) g, (8-10) mL, and the solid phase is collected after standing for 4 days.
5. The process for the preparation of the pharmaceutical co-crystal of hydrochlorothiazide with proline according to claim 1, characterized in that it is carried out according to the following steps:
mixing the hydrochlorothiazide raw material medicine and proline in a molar ratio of 1:1, placing the mixture in a round-bottom flask, adding ethanol into the mixed powder, heating and stirring the mixture in a 70 ℃ water bath for 3-5 hours, filtering the mixture while the mixture is hot, standing the filtrate, cooling the filtrate to room temperature, and separating out a solid phase substance to obtain the hydrochlorothiazide and proline medicinal eutectic crystal.
6. The preparation method of the hydrochlorothiazide and proline pharmaceutical co-crystal according to claim 5, characterized in that the solid-to-liquid ratio of the mixed powder and ethanol is (0.080-0.085) g (5-8) mL.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017049294A1 (en) * | 2015-09-18 | 2017-03-23 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017049294A1 (en) * | 2015-09-18 | 2017-03-23 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
Non-Patent Citations (3)
| Title |
|---|
| Shanmukha Prasad Gopi et al..New Cocrystals of Hydrochlorothiazide: Optimizing Solubility and Membrane Diffusivity.《Cryst. Growth Des.》.2016,第17卷(第1期),第308-316页，Supporting Information第S1-S11页. * |
| 新型药物共晶的合成及表征;邢娇娇;《中国优秀硕士学位论文全文数据库工程科技I辑》;20111015(第10期);第B016-119页第12页第1.2.4节 * |
| 药物共晶的合成、表征与性质研究;张晓明;《中国优秀博士学位论文全文数据库工程科技I辑》;20160815(第8期);第B014-91页第10页第1.3节 * |
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