CN106397410B - 5-hydroxytryptamine receptor agonist and preparation method and application thereof - Google Patents
5-hydroxytryptamine receptor agonist and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a 5-hydroxytryptamine receptor agonist, a preparation method and application thereof, and provides a (3a alpha, 4 beta, 7a alpha) -hexahydro-2- [4[4- (2-pyrimidinyl) -1- (piperazine)Alkyl) -butyl]-4, 7-methylene-1H-isoindole-1, 3(2H) -dione citrate monohydrate having the molecular formula C, preparation method and use thereof21H29N5O2·C6H8O7·H2And O. The monohydrate has the advantages of high stability and good solubility, is beneficial to the quality control of products, improves the dissolution rate of the preparation, is beneficial to the absorption and utilization of medicaments, can be conveniently prepared into various dosage forms, and is convenient to process, store and transport. The preparation method has the advantages of few steps, simple and convenient operation, high product yield, high purity and the like, and is very suitable for industrial application.
Description
Technical Field
The invention relates to tandospirone citrate monohydrate, a preparation method and application thereof. Belongs to the field of pharmaceutical chemistry.
Background
Tandospirone, the chemical name is (3a alpha, 4 beta, 7a alpha) -hexahydro-2- [4[4- (2-pyrimidinyl) -1- (piperazinyl) -butyl ] -4, 7-methylene-1H-isoindole-1, 3(2H) -diketone, and the structural formula is shown as follows; tandospirone is a 5-hydroxytryptamine receptor agonist, and is used for treating anxiety or other diseases accompanied with anxiety.
Tandospirone belongs to azaspirone drugs, and in brain, it can be intensively distributed in the hippocampus, septum, interpeduncular nucleus, amygdaloid nucleus and other cerebral marginal systems of emotional center and 5-HT of seamed glandular nucleus1AReceptors selectively bind by agonizing 5-HT1AThe autoreceptor regulates 5-hydroxytryptamine projected from the raphe nucleus to the hippocampus, inhibits the 5-hydroxytryptamine effect of the motility inhibition system, and exerts an anxiolytic effect. Compared with the proto-drug azaspirone and the buspirone of the same kind derivative, tandospirone has higher selective anxiolytic effect which is similar to diazepam, but has less toxic and side effects in the aspects of nerve motility function damage, drug abuse and the like than diazepam. Due to the specificity of action mechanism, tandospirone has the advantages of high medication safety, few side effects, no muscle relaxation and sedative effects, no dependence and withdrawal phenomenon after stopping taking medicine, no accumulation in vivo after long-term application and the like when being clinically used for treating anxiety disorder.
Besides the anxiolytic effect, the tandospirone has quite good application in the treatment or adjuvant treatment of other nervous system diseases. The tandospirone has a certain antidepressant effect, has a very obvious curative effect on patients with mixed anxiety and depression, and can improve the vegetative nerve symptoms such as irritable bowel syndrome, functional dyspepsia, postoperative nausea and vomiting and the like through the anxiolytic and antidepressant effects. It is also an effective drug for treating central nervous system ataxia, and can significantly improve the symptoms of cerebellar ataxia in patients. It is also effective in improving memory, treating age-related memory disorder, and significantly improving narrative memory, logical memory and spoken language association in patients with neurasthenia, senile dementia or schizophrenia. In addition, tandospirone has ocular hypotensive activity, and can be used for treating eye diseases caused by endothelial cell proliferation, inflammation, increase in vascular permeability or angiogenesis, such as diabetic retinopathy, age-related macular degeneration, retinal edema, glaucoma, etc. Therefore, the tandospirone has very high clinical application value and wide market prospect.
At present, the citrate of tandospirone, also called citrate (namely tandospirone citrate), is mostly used in clinical treatment. In order to ensure the stable quality of the drug and exert good therapeutic effects, the drug needs to have both high stability and good solubility. In the prior art, crystals of tandospirone citrate are commonly used. However, in the crystal form in the prior art, the solubility of the tandospirone citrate crystal form I is better, but the stability is relatively lower (see Chinese patent CN 102344442A); although the stability of the crystal form II and the crystal form III of tandospirone citrate is higher, the solubility of the crystal form II and the crystal form III of tandospirone citrate is relatively poor (see Chinese patent CN 103641817A and CN 103641818A). It can be seen that the stability and solubility (solubility) of a drug are a pair of conflicting requirements, namely: the improvement of the stability of the drug usually results in the deterioration of the solubility of the drug, which is also a common general knowledge in the art (see: luoydulou crown hua eds., (crystal form drug) page 45, fourth paragraph, final paragraph, and people health press, 2009). For tandospirone citrate, researchers always hope to find products with high stability and good solubility, so that the quality stability of the products is better ensured, and good treatment effect is achieved.
Therefore, the development of a new product of tandospirone citrate with high stability and good solubility is needed.
Disclosure of Invention
The invention aims to provide a novel product of tandospirone citrate with high stability and good solubility.
The invention provides tandospirone citrate monohydrate, the molecular formula of which is C21H29N5O2·C6H8O7·H2O; wherein, C21H29N5O2Is tandospirone, C6H8O7Is citric acid.
Further, the monohydrate has the structural formula:
further, the monohydrate is characterized by having a melting point of 168.0-169.0 ℃.
Furthermore, the absorption peak of the monohydrate is between 90 and 120 ℃ on a spectrum of TGA (thermogravimetric analysis) or DSC (differential scanning calorimetry), or the monohydrate loses weight by about 3.02 percent between 90 and 120 ℃.
Furthermore, in the X-ray powder diffraction of the monohydrate, the 2 theta diffraction angle has characteristic peaks at 18.2 +/-0.2 degrees, 19.1 +/-0.2 degrees, 21.2 +/-0.2 degrees, 22.3 +/-0.2 degrees, 22.8 +/-0.2 degrees, 26.3 +/-0.2 degrees and 30.6 +/-0.2 degrees.
Further, in the X-ray powder diffraction of the monohydrate, the main peak with the relative intensity I% of the characteristic peak of the 2 theta diffraction angle being more than or equal to 10% is as follows:
| 2θ | relative strength (I% ≧ 10%) |
| 6.6±0.2° | 10 |
| 11.3±0.2° | 19 |
| 13.7±0.2° | 24 |
| 15.0±0.2° | 20 |
| 18.2±0.2° | 100 |
| 19.1±0.2° | 10 |
| 20.5±0.2° | 12 |
| 22.0±0.2° | 48 |
| 22.3±0.2° | 26 |
| 24.1±0.2° | 15 |
| 25.2±0.2° | 30 |
| 26.3±0.2° | 19 |
| 27.2±0.2° | 48 |
| 30.1±0.2° | 22 |
It is another object of the present invention to provide a process for preparing the above monohydrate.
The invention also provides a preparation method of the monohydrate, which comprises the following steps: taking tandospirone citrate, adding water, heating to dissolve, cooling, stirring, separating solid, and drying to obtain the tandospirone citrate monohydrate.
Further, the mass-volume ratio of the tandospirone citrate to the water is 1: 3-15 g/mL; further, the mass-volume ratio of the tandospirone citrate to the water is 1: 5-10 g/mL; furthermore, the mass-volume ratio of the tandospirone citrate to the water is 1:7, 1:7.5 or 1:9 g/mL.
Further, the temperature for heating and dissolving is 50-100 ℃; the temperature of the cooling condition is 1-10 ℃; the stirring time is 1 to 8 hours.
The present invention also provides another preparation method of the above monohydrate, comprising the steps of: taking tandospirone citrate, adding water to form a suspension solution, stirring, separating solids, and drying to obtain the tandospirone citrate monohydrate.
Further, the mass-volume ratio of the tandospirone citrate to the water is 1: 1-18 g/mL; further, the mass-volume ratio of the tandospirone citrate to the water is 1: 2-15 g/mL; furthermore, the mass-volume ratio of the tandospirone citrate to the water is 1:4, 1:5, 1:8 or 1:10 g/mL.
Furthermore, the stirring temperature is 5-28 ℃, and the stirring time is 5-40 hours.
Furthermore, the drying temperature is 15-50 ℃, and the drying time is 2-8 hours.
The invention also provides the application of the monohydrate in preparing medicines for treating or preventing 5-hydroxytryptamine or/and norepinephrine reuptake related diseases.
Further, the drug is a 5-hydroxytryptamine regulator.
The invention also provides a pharmaceutical composition which contains the monohydrate as an active ingredient and also contains pharmaceutically common auxiliary materials or auxiliary ingredients.
The hydrate of the drug refers to a state of eutectic substance formed by hydration reaction between drug molecules and crystal water, and belongs to the category of polymorphism (see: luyandu crown hua main, ed., (crystal form drug) pages 92-96, and the people health press, 2009). The solubility of the hydrate may be increased or decreased compared to the anhydrous hydrate, such as: the solubility of the amoxicillin anhydrous hydrate is 67.6%, the solubility of the amoxicillin monohydrate is 83.5%, while the solubility of the amoxicillin dihydrate is only 15.8%, and the solubility of the amoxicillin trihydrate is 95.5% (see: luyangduo guan hua main edition, crystal form drug, page 45, people's health press, 2009). Therefore, it is not easy to screen out a product with high stability and good solubility from many hydrates.
However, the tandospirone citrate monohydrate has the advantages of high stability and good solubility, is beneficial to the quality control of products, improves the dissolution rate of the preparation, is beneficial to the absorption and utilization of medicaments, can be conveniently prepared into various dosage forms, and is convenient to store and transport; in addition, the method has the advantages of few steps, simple and convenient operation, high product yield, high purity and the like, and is very suitable for industrial application.
The medicine is used for treating central nervous system diseases and eye diseases, and comprises medicines for treating various diseases such as anxiety, depression, neurasthenia, post-traumatic stress disorder, premenstrual dysphoric disorder, attention deficit disorder, panic disorder, autism, insomnia, schizophrenia, age-related memory disorder, senile dementia, obsessive-compulsive syndrome, obesity, bulimia nervosa or deficiency, Tourette syndrome, chronic fatigue syndrome, vasomotor flushing, ***e or alcohol addiction, sexual dysfunction, borderline personality disorder, Raynaud's syndrome, urinary incontinence, pain, Parkinson's disease, epilepsy, glaucoma, diabetic retinopathy, age-related macular degeneration or retinal edema.
The pharmaceutically acceptable auxiliary materials or auxiliary components are common excipients or auxiliary materials which are well known in the field and used for preparing the preparation. The excipients or adjuvants commonly used in oral preparations or external preparations include, but are not limited to, fillers (diluents), lubricants (glidants or antiadherents), dispersants, wetting agents, binders, regulators, solubilizers, antioxidants, bacteriostats, emulsifiers, disintegrants, etc. Binders such as syrup, acacia, gelatin, sorbitol, tragacanth, starch slurry, povidone, cellulose derivatives (such as microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose, or hydroxypropylmethylcellulose, etc.), and the like; fillers such as lactose, dextrin, starch and its derivatives, cellulose derivatives, inorganic calcium salts (such as calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, etc.), mannitol, agar powder, etc.; lubricants such as aerosil, stearic acid and its salts (e.g., magnesium stearate, etc.), talc, hydrogenated vegetable oils, polyethylene glycols, and the like; disintegrants such as starch and its derivatives (e.g., sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.), crospovidone, cellulose derivatives, and the like; wetting agents such as sodium lauryl sulfate, water, alcohols or other organic solvents, and the like. The common excipients or auxiliary materials for the injection of the invention include but are not limited to: antioxidants such as sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, dibutylbenzoic acid, and the like; bacteriostatic agents such as phenol, benzyl alcohol, cresol, hydroxypropylmethyl ester, chlorobutanol, and the like; regulators such as hydrochloric acid, citric acid, potassium (sodium) hydroxide, buffers (including sodium dioxyphosphate, disodium hydrogen phosphate, etc.), and the like; emulsifiers such as polysorbate 80, sorbitan fatty acid, pluronic F-68, lecithin, soy lecithin, and the like; solubilizers such as tween 80, bile, glycerol, and the like.
In addition, the active ingredient can be mixed with pharmaceutically acceptable sustained or controlled release carrier to prepare sustained or controlled release preparation according to the preparation method of sustained or controlled release preparation well known in the art. For example, the active ingredients are coated with retardant or microencapsulated and then made into pellets, including sustained-release pellets or controlled-release pellets. The sustained and controlled release carrier comprises but is not limited to an oil-fat doping agent, a hydrophilic colloid, a coating retarder and the like, wherein the oil-fat doping agent is selected from any one or the combination of glyceryl monostearate, hydrogenated castor oil, mineral oil, polysiloxane or dimethyl siloxane; the hydrophilic colloid is selected from any one or combination of sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, PVP, acacia, tragacanth or carbopol; the coating retarder is selected from any one of Ethyl Cellulose (EC), hydroxypropyl methyl cellulose (HMPC), polyvinylpyrrolidone (PVP), Cellulose Acetate Phthalate (CAP), acrylic resin or their combination.
The preparation form of the composition can be liquid preparation, gas preparation, solid preparation and semisolid preparation, and common preparation forms such as aromatic water agent, solution, injection, mixture, lotion, liniment, aerosol, spray, powder, pill, tablet, capsule, membrane, ointment, suppository, paste and the like are preferred.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a TGA spectrum of tandospirone citrate monohydrate of the present invention.
FIG. 2 is a DSC chart of tandospirone citrate monohydrate of the present invention.
FIG. 3 is a TGA spectrum of tandospirone citrate prepared according to the method disclosed in the prior art (CN101880274A example 8).
FIG. 4 is a DSC chart of tandospirone citrate prepared according to the method disclosed in the prior art (CN101880274A example 8).
FIG. 5 is an X-ray powder diffraction pattern of tandospirone citrate monohydrate of the present invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
EXAMPLE 1 preparation of tandospirone citrate monohydrate
Weighing 50g of tandospirone citrate, adding 350mL of water, heating to 100 ℃, continuing to stir for 0.5 hour after complete dissolution, stopping heating, cooling at 1 ℃ and stirring for 1 hour, separating out solids, filtering, and vacuum drying at 50 ℃ for 2 hours to obtain 50.3g of tandospirone citrate monohydrate, wherein the yield is 97.5%, and the purity is 99.90%; mass spectrum shows ESI m/z: 383.
the melting point was measured as: 168.0-169.0 ℃.
The tandospirone citrate monohydrate of the invention is taken for elemental analysis, and the results are shown in table 1:
TABLE 1 elemental analysis results
| Element(s) | N％ | C％ | H％ |
| C21H29N5O2·C6H8O7·H2Theoretical value of O | 11.80 | 54.63 | 6.62 |
| Measured value of the product of the invention | 11.80 | 54.58 | 6.67 |
Determination of loss on drying: the product of the invention is dried to constant weight at 105 ℃, and the weight is reduced by 3.03%; and (3) analyzing moisture: the sample is measured for water content according to a Karl moisture determination method, and the result is 3.06%; the two results are substantially identical, indicating that the product of the invention contains 1 molecule of water.
Thermal analysis: the products of the invention were subjected to TGA (thermogravimetric analysis) and DSC (differential scanning calorimetry) tests, the results of which are shown in figures 1 and 2. TGA (thermogravimetric analysis) and DSC (differential scanning calorimetry) of the existing product (cf. CN10188027A example 8) are shown in fig. 3 and 4.
The result shows that the product of the invention has an absorption peak between 90 and 120 ℃, and the weight loss of the product of the invention is about 3.02 percent in the interval, while the existing product has no absorption peak and corresponding weight loss step before 150 ℃; by contrast with the existing products, the product of the invention is also described to contain crystallization water or crystallization solvent, while the existing products do not contain crystallization water or crystallization solvent.
The X-ray powder diffraction result of the tandospirone citrate monohydrate of the invention measured by Cu Kalpha radiation is shown in figure 5, and the relevant diffraction data are shown in Table 2.
TABLE 2X-ray powder diffraction results
Wherein, the main relevant diffraction data of the relative intensity I% is more than or equal to 10% is shown in the table 3.
TABLE 3X-ray powder diffraction results
The above test results prove that the product of the invention contains 1 molecule of crystal water, and the structural formula is as follows:
example 2 preparation of tandospirone citrate monohydrate
Weighing 50g of tandospirone citrate, adding 250mL of water, heating to 90 ℃, continuing to stir for 0.5 hour after complete dissolution, stopping heating, cooling at 8 ℃, stirring for 6 hours, separating out solids, filtering, and ventilating and drying at 40 ℃ for 6 hours to obtain 50.5g of tandospirone citrate monohydrate, wherein the yield is 98.0%, and the purity is 99.92%.
The results of the tests of the product, such as elemental analysis, drying weight loss, moisture determination, thermal analysis and the like, show that the tandospirone citrate monohydrate is obtained by the method.
Example 3 preparation of tandospirone citrate monohydrate
Weighing 50g of tandospirone citrate, adding 500mL of water, heating to 50 ℃, continuing to stir for 0.5 hour after complete dissolution, stopping heating, cooling at 2 ℃, stirring for 4 hours, separating out solids, filtering, and vacuum drying at 15 ℃ for 8 hours to obtain 50.4g of tandospirone citrate monohydrate, wherein the yield is 97.8%, and the purity is 99.91%.
The results of the tests of the product, such as elemental analysis, drying weight loss, moisture determination, thermal analysis and the like, show that the tandospirone citrate monohydrate is obtained by the method.
Example 4 preparation of tandospirone citrate monohydrate
Weighing 50g of tandospirone citrate, adding 375mL of water, heating to 75 ℃, continuing to stir for 0.5 hour after complete dissolution, stopping heating after stirring, cooling at 4 ℃ and stirring for 2 hours, separating out solids, filtering, and drying in vacuum at 30 ℃ for 4 hours to obtain 50.2g of tandospirone citrate monohydrate, wherein the yield is 97.4%, and the purity is 99.89%.
The results of the tests of the product, such as elemental analysis, drying weight loss, moisture determination, thermal analysis and the like, show that the tandospirone citrate monohydrate is obtained by the method.
EXAMPLE 5 preparation of tandospirone citrate monohydrate
Weighing 50g of tandospirone citrate, adding 450mL of water, heating to 50 ℃, continuing to stir for 0.5 hour after complete dissolution, stopping heating, cooling at 10 ℃, stirring for 8 hours, separating out solids, filtering, and vacuum drying at 15 ℃ for 8 hours to obtain 50.2g of tandospirone citrate monohydrate, wherein the yield is 97.4%, and the purity is 99.91%.
The results of the tests of the product, such as elemental analysis, drying weight loss, moisture determination, thermal analysis and the like, show that the tandospirone citrate monohydrate is obtained by the method.
Example 6 preparation of tandospirone citrate monohydrate
Weighing 50g of tandospirone citrate, adding 500mL of water, suspending the solid in the water at 10 ℃, stirring for 24 hours, filtering, and drying in vacuum at 30 ℃ for 5 hours to obtain 49.8g of tandospirone citrate monohydrate, wherein the yield is 96.6%, and the purity is 99.92%.
The results of the tests of the product, such as elemental analysis, drying weight loss, moisture determination, thermal analysis and the like, show that the tandospirone citrate monohydrate is obtained by the method.
Example 7 preparation of tandospirone citrate monohydrate
Weighing 50g of tandospirone citrate, adding 100mL of water, suspending the solid in the water at 28 ℃, stirring for 30 hours, filtering, and drying in vacuum for 6 hours at 15 ℃ to obtain 50.3g of tandospirone citrate monohydrate, wherein the yield is 97.6%, and the purity is 99.90%.
The results of the tests of the product, such as elemental analysis, drying weight loss, moisture determination, thermal analysis and the like, show that the tandospirone citrate monohydrate is obtained by the method.
Example 8 preparation of tandospirone citrate monohydrate
Weighing 50g of tandospirone citrate, adding 750mL of water, suspending the solid in the water at 5 ℃, stirring for 10 hours, filtering, and drying in air at 50 ℃ for 8 hours to obtain 49.9g of tandospirone citrate monohydrate, wherein the yield is 96.8%, and the purity is 99.91%.
The results of the tests of the product, such as elemental analysis, drying weight loss, moisture determination, thermal analysis and the like, show that the tandospirone citrate monohydrate is obtained by the method.
Example 9 preparation of tandospirone citrate monohydrate
Weighing 50g of tandospirone citrate, adding 400mL of water, suspending the solid in the water at 20 ℃, stirring for 20 hours, filtering, and drying in vacuum at 45 ℃ for 2 hours to obtain 50.1g of tandospirone citrate monohydrate, wherein the yield is 97.2%, and the purity is 99.91%.
The results of the tests of the product, such as elemental analysis, drying weight loss, moisture determination, thermal analysis and the like, show that the tandospirone citrate monohydrate is obtained by the method.
EXAMPLE 10 preparation of tandospirone citrate monohydrate
Weighing 50g of tandospirone citrate, adding 200mL of water, suspending the solid in the water at 25 ℃, stirring for 40 hours, filtering, and drying in vacuum for 8 hours at 15 ℃ to obtain 50.0g of tandospirone citrate monohydrate, wherein the yield is 97.0%, and the purity is 99.90%.
The results of the tests of the product, such as elemental analysis, drying weight loss, moisture determination, thermal analysis and the like, show that the tandospirone citrate monohydrate is obtained by the method.
EXAMPLE 11 preparation of tandospirone citrate monohydrate
50g of tandospirone citrate is weighed, 250mL of water is added, the solid is suspended in the water at the temperature of 15 ℃, stirred for 5 hours, filtered and dried in vacuum at the temperature of 25 ℃ for 6 hours, and then 50.1g of tandospirone citrate monohydrate is obtained, the yield is 97.2%, and the purity is 99.89%.
The results of the tests of the product, such as elemental analysis, drying weight loss, moisture determination, thermal analysis and the like, show that the tandospirone citrate monohydrate is obtained by the method.
EXAMPLE 12 preparation of Capsule products
TABLE 4 raw material ratio of the capsule
| Tandospirone citrate monohydrate | 3g |
| Starch | 200g |
| Microcrystalline cellulose | 5g |
| Is made into | 1000 granules |
According to the proportion shown in the table 4, the tandospirone citrate monohydrate and the starch are uniformly mixed by an equivalent incremental method, then are uniformly mixed with the microcrystalline cellulose, and are granulated and filled into capsules to obtain the tandospirone citrate.
Comparative test example:
weighing 20g of tandospirone citrate, adding 140mL of water, heating to 70 ℃, cooling to 40 +/-5 ℃ after complete dissolution, adding 100mL of acetone and 100mL of ether while stirring, continuously cooling to room temperature, stirring for 1 hour at 5 +/-5 ℃, separating out a solid, filtering, and drying in vacuum for 2 hours at 50 ℃ to obtain 19.6g of tandospirone citrate 4/5 hydrate, wherein the yield is 95.6%.
Mass spectrum shows ESI m/z: 383.
the comparative test products were taken for elemental analysis and the results are shown in Table 5.
TABLE 5 elemental analysis results
| Element(s) | N％ | C％ | H％ |
| C21H29N5O2·C6H8O7·4/5H2Theoretical value of O | 11.87 | 54.96 | 6.59 |
| Measured value of the product of the invention | 11.88 | 54.94 | 6.58 |
Determination of loss on drying: drying the comparative test product at 105 ℃ to constant weight, with a weight reduction of 2.42%; and (3) analyzing moisture: the water content of the comparative test product is measured according to a Karl moisture measurement method, and the result is 2.45 percent; the results were essentially identical, indicating that the comparative test product contained 4/5 molecules of water.
Thermal analysis: TGA (thermogravimetric analysis) and DSC (differential scanning calorimetry) tests are carried out on the comparative test product, and the results show that the comparative test product has an absorption peak at 80-115 ℃, and the comparative test product has a weight loss of about 2.44% in the interval.
The above test results are combined, and it can be proved that the comparative test product contains 4/5 molecular crystal water, and its structural formula is:
it can be seen that changing the process steps or process conditions of the preparation method will result in a hydrate product different from the present invention.
To illustrate the advantageous effects of the present invention, the present invention provides the following test examples:
test example 1 solubility test
Test groups: the tandospirone citrate monohydrate of the present invention;
the existing product is as follows: refer to the method disclosed in the prior document (CN101880274A example 8) to prepare tandospirone citrate.
Weighing 2g of a sample, placing the sample in 20mL of water at 25 +/-2 ℃, and strongly shaking for 10 seconds every 1 minute; dissolution was observed within 3 minutes. When no solute particles are visible, the solution is considered to be completely dissolved; if visible solute particles exist, adding 5 times of water, and repeating the operation until the solute particles are completely dissolved; recording the total water consumption and time; the results are shown in Table 6.
TABLE 6 results of solubility test
The solubility test result shows that compared with the existing product, the water solubility of the product of the invention is obviously improved, and the product is more beneficial to the use of the preparation.
Test example 2 stability Effect test
Test groups: the tandospirone citrate monohydrate of the present invention;
the existing product is as follows: refer to the method disclosed in the prior document (CN101880274A example 8) to prepare tandospirone citrate.
(1) Test for influencing factor
The examination conditions are strong light irradiation (4500 +/-500 lx), high temperature (60 ℃), high humidity (relative humidity 92.5%, 25 ℃), tandospirone monohydrate of the present invention and the existing product are respectively placed for 10 days under different examination conditions, sampling and measuring are carried out for 5 days and 10 days, and the results are compared with the data of the same batch of samples of 0 day, which are shown in table 7.
TABLE 7 results of influential factor test
Test results show that the content and impurities of the tandospirone citrate monohydrate have no obvious change under the conditions of high temperature, high humidity and illumination, the stability is better, and the stability and controllability of the product quality are more favorably realized; the existing product has poor stability to light, heat and humidity, particularly under strong light irradiation, the impurities of the product are obviously increased, and the stability of the product is relatively poor.
(2) Stability study under different humidity conditions
The tandospirone monohydrate of the invention and the existing product were allowed to stand at room temperature for 10 days under different relative humidity conditions (75%, 92.5%), sampled for 5 and 10 days, respectively, and compared with the data of the same batch of samples for 0 day, and the results are shown in table 8.
TABLE 8 stability test results under different humidity conditions
Test results show that the tandospirone citrate monohydrate is placed for 10 days under different relative humidity conditions, the moisture content of a sample is not obviously changed, and the data of the sample is basically consistent with that of a batch of samples in 0 day, so that the tandospirone citrate monohydrate is good in stability, beneficial to long-term stable storage and convenient to transport, does not need to control the humidity particularly when a preparation is prepared, and is easier to prepare the preparation; the moisture content of the existing product is obviously increased under the conditions of different relative humidity, which shows that the existing product is unstable to humidity and has hygroscopicity.
(3) Accelerated test
Packaging the sample with aluminum-plastic composite film bag, placing in an accelerating condition (constant temperature and humidity incubator with temperature of 40 ℃ +/-2 ℃ and relative humidity of 75 +/-5%), sampling at the end of 1, 2, 3 and 6 months, and comparing with the result of the same batch of samples in 0 month; the test results are shown in Table 9.
TABLE 9 accelerated test results
Test results show that the product is placed for 6 months under the acceleration condition, the content and the moisture of the sample are not obviously changed, the impurity amount is not obviously increased, and the data of the sample in the same batch is basically consistent with the data of the sample in 0 month, which indicates that the product is stable under the acceleration condition; and the total amount of impurities of the existing product is increased by 1 time after the existing product is placed for 3 months under an accelerated condition, which indicates that the stability of the existing product is relatively poor.
The water content in the tables is the water content measured by the loss on drying method, and the content is the content of tandospirone citrate measured as an anhydrate.
The test result of the test example 2 shows that the content of the product of the tandospirone citrate monohydrate is not obviously reduced, the moisture is not obviously changed, the impurity amount is not obviously increased, the stability is good, and the product quality is stable and controllable under the conditions of high temperature, high humidity and illumination; the existing product has poor stability to light, heat and humidity, the impurities are obviously increased, especially under the high-humidity condition, the moisture content of the existing product is obviously increased, and the stability of the product is relatively poor.
Test example 3 dissolution test of preparation
Test group 1: the capsule product of example 12 of the present invention;
test group 2: taking tandospirone citrate (namely the existing product) prepared according to the existing document (CN101880274A example 8), and preparing the tandospirone citrate into capsules according to the method of the invention example 12 to obtain the capsules of the existing product.
The dissolution rate determination method comprises the following steps: according to a dissolution determination method (XC third method which is an appendix of the 2010 version of Chinese pharmacopoeia) by taking 0.1mol/L hydrochloric acid solution as a dissolution medium, rotating at 100r/min, operating according to the method, taking 5mL of solution after 15 minutes, filtering, adding a mobile phase to dilute into solution containing 5 mu g of tandospirone citrate per 1mL, and taking the solution as a test solution; and adding a proper amount of tandospirone citrate into the mobile phase to prepare a solution containing 5 mu g of tandospirone per 1mL, wherein the solution is used as a reference solution. Measuring according to chromatographic conditions under chromatographic content measurement item, and calculating the elution amount of each granule.
Test results show that in a dissolution medium of 0.1mol/L hydrochloric acid solution, the dissolution rates of the test group 1 and the test group 2 within 15min are 90% and 70% respectively; the product of the invention has ideal dissolution effect, is improved by about 1/3 compared with the existing product, and is obviously superior to the existing product. Therefore, the product of the invention has higher dissolution rate, is suitable for being prepared into various preparations, has high bioavailability, can ensure the medication effect and is more suitable for clinical application.
In conclusion, the tandospirone citrate monohydrate has the advantages of high stability and good solubility, is beneficial to the quality control of products, improves the dissolution rate of the preparation, is beneficial to the absorption and utilization of medicaments, can be conveniently prepared into various dosage forms, and is convenient to store and transport; in addition, the method has the advantages of few steps, simple and convenient operation, high product yield, high purity and the like, and is very suitable for industrial application.
Claims (19)
1. Tandospirone citrate monohydrate having the structural formula:
it is characterized in that the 2 theta diffraction angle in the X-ray powder diffraction has characteristic peaks at 6.6 +/-0.2 degrees, 11.3 +/-0.2 degrees, 13.7 +/-0.2 degrees, 15.0 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.6 +/-0.2 degrees, 18.2 +/-0.2 degrees, 19.1 +/-0.2 degrees, 21.2 +/-0.2 degrees, 22.3 +/-0.2 degrees, 22.8 +/-0.2 degrees, 26.3 +/-0.2 degrees and 30.6 +/-0.2 degrees.
2. A process for the preparation of the monohydrate of claim 1 characterized by the steps of: taking tandospirone citrate, adding water, heating to dissolve, cooling, stirring, separating solid, and drying to obtain the tandospirone citrate monohydrate.
3. The preparation method according to claim 2, wherein the mass-to-volume ratio of tandospirone citrate to water is 1: 3-15 g/mL.
4. The preparation method according to claim 2, wherein the mass-to-volume ratio of tandospirone citrate to water is 1: 5-10 g/mL.
5. The preparation method according to claim 2, wherein the mass-to-volume ratio of tandospirone citrate to water is 1:7, 1:7.5 or 1:9 g/mL.
6. The method according to claim 2, wherein the temperature for heating and dissolving is 50 ℃ to 100 ℃; the temperature of the cooling condition is 1-10 ℃; the stirring time is 1 to 8 hours.
7. A process for the preparation of the monohydrate of claim 1 characterized by the steps of: taking tandospirone citrate, adding water to form a suspension solution, stirring, separating solids, and drying to obtain the tandospirone citrate monohydrate.
8. The preparation method of the monohydrate of claim 7, wherein the mass-to-volume ratio of tandospirone citrate to water is 1: 1-18 g/mL.
9. The preparation method of the monohydrate of claim 8, wherein the mass-to-volume ratio of tandospirone citrate to water is 1: 2-15 g/mL.
10. The preparation method of the monohydrate of claim 9, wherein the mass to volume ratio of tandospirone citrate to water is 1:4, 1:5, 1:8 or 1:10 g/mL.
11. The method according to claim 7, wherein the stirring temperature is 5 ℃ to 28 ℃ and the stirring time is 5 hours to 40 hours.
12. The method of claim 7, wherein: the drying temperature is 15-50 ℃, and the drying time is 2-8 hours.
13. Use of a monohydrate of claim 1 in the manufacture of a medicament for the treatment or prevention of a 5-hydroxytryptamine or/and norepinephrine reuptake associated disorder.
14. The use of claim 13, wherein the medicament is a 5-hydroxytryptamine modulator.
15. The use according to claim 13, wherein the medicament is for the treatment of central nervous system and ocular disorders.
16. Use according to claim 13, said medicament being a medicament for the treatment of anxiety disorders, depression, neurasthenia, post-traumatic stress disorder, premenstrual dysphoric disorder, attention deficit disorder, panic disorder, autism, insomnia, schizophrenia, age-related memory disorders, senile dementia, obsessive-compulsive syndrome, obesity, bulimia nervosa or deficiency, tourette's syndrome, chronic fatigue syndrome, vasomotor flushing, ***e or alcohol addiction, sexual dysfunction, borderline personality disorder, raynaud's syndrome, urinary incontinence, pain disorders, parkinson's disease, epilepsy, glaucoma, diabetic retinopathy, age-related macular degeneration or retinal edema.
17. A pharmaceutical composition characterized by comprising the monohydrate of claim 1 as an active ingredient, and further comprising pharmaceutically commonly used adjuvants or auxiliary ingredients.
18. The tandospirone citrate monohydrate of claim 1, of the formula:
the characteristic is that the diffraction angle of 2 theta in the X-ray powder diffraction has the peak at 6.6 +/-0.2 degrees, 8.9 +/-0.2 degrees, 11.3 +/-0.2 degrees, 13.7 +/-0.2 degrees, 15.0 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.6 +/-0.2 degrees, 18.2 +/-0.2 degrees, 19.1 +/-0.2 degrees, 19.8 +/-0.2 degrees, 20.5 +/-0.2 degrees, 21.2 +/-0.2 degrees, 22.0 +/-0.2 degrees, 22.3 +/-0.2 degrees, 22.8 +/-0.2 degrees, 23.4 +/-0.2 degrees, 24.1 +/-0.2 degrees, 25.2 +/-0.2 degrees, 25.7 +/-0.2 degrees, 26.3 +/-0.2 degrees, 27.2 +/-0.2 degrees, 28.3 +/-0.2 degrees, 28.7 +/-0.2 degrees, 29.6 +/-0.2 degrees, 30.1 +/-0.2 degrees and 30.6 +/-0.2 degrees.
19. The tandospirone citrate monohydrate of claim 1, of the formula:
it is characterized by its X-ray powder diffraction pattern as shown in FIG. 5.
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| CN102344442A (en) * | 2011-08-04 | 2012-02-08 | 成都科瑞德医药投资有限责任公司 | Novel crystal form of tandospirone citrate and preparation method and application thereof |
| CN102351812A (en) * | 2008-12-01 | 2012-02-15 | 北京四环制药有限公司 | Methanesulfonic acid cinepazide crystal form III and preparation method thereof |
| CN103012430A (en) * | 2013-01-16 | 2013-04-03 | 湖北济生医药有限公司 | Mezlocillin sodium compound and medicine composition thereof |
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| CN103012430A (en) * | 2013-01-16 | 2013-04-03 | 湖北济生医药有限公司 | Mezlocillin sodium compound and medicine composition thereof |
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