CN105061217A - Two crystal forms of sertraline citrate, and preparation methods thereof - Google Patents
Two crystal forms of sertraline citrate, and preparation methods thereof Download PDFInfo
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Abstract
The invention relates to the field of polymorphism researches of medicine synthesis, and concretely relates to a crystal form A and a crystal form B of sertraline citrate, and preparation methods thereof. The crystal form A and the crystal form B of sertraline citrate have the advantages of good medicinal performances, medicinal preparation requirement meeting, good dissolvability, high dissolubility, high stability and storage benefiting, so the requirement of medicine stability is met. The preparation methods have the advantages of simple operation, few steps, mild preparation conditions, small environmental protection pressure, and suitableness for industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry polymorphic research field, be specifically related to utilize different crystallization method to prepare sertraline citrate crystal formation body and synthesising process research thereof.
Background technology
Polymorphism refers to that solid matter is with two or more different spaces arrangement mode, the phenomenon with the solid state of different physicochemical property of formation.In drug research field, polymorphic further comprises the polycomponent such as organic solvate, hydrate crystalline form.Medicine heteromorphism extensively exists in drug discovery process, is the intrinsic characteristic of organic micromolecule compound.Small-molecule drug can have unlimited many crystal accumulation mode-polymorphics in theory, and research shows, time and the resource of the discovery quantity of polymorph in pharmaceuticals and the research of its input are in direct ratio.Polymorphism is not only subject to space structure and the functional group performance of molecule itself, in molecule and the control of the internal factor such as intermolecular interaction, it is also selected by medicine synthesising process design, crystallization and purification condition, pharmaceutical adjunct, the impact of preparation process route and method of granulating and the aspects such as condition of storage, wrapping material factor.Different crystal forms has distinct colors, fusing point, solubleness, dissolving out capability, chemical stability, reactivity, mechanical stability etc., and these physical and chemical performances or processability directly have influence on safety, the effective performance of medicine sometimes.Therefore the important research content that crystal formation is studied and control becomes in drug development process.By the actual blood level selecting the polymorphic with different solubilities and/or intrinsic dissolution rate just advantageously can affect medicine.
Sertraline citrate, chemistry (1S, 4S) – 4 – (3,4 – dichlorophenyl) – 1,2,3,4 – tetra-hydrogen – N – first base – 1 – naphthylamines citrate monohydrate by name.Sertraline citrate is a kind of selective serotonin reuptake inhibitor.Its mechanism of action is relevant to the suppression of axoneuron serotonin reuptake transporter with it.Under clinical dosage, Sertraline blocks human blood platelets to the picked-up of serotonin.Research prompting Sertraline is a kind of potent and optionally neurone serotonin reuptake inhibitor, only has minor way to norepinephrine and Dopamine HCL.Sertraline is used for the treatment of the related symptoms of dysthymia disorders, comprises with anxiety, to have or without the dysthymia disorders of manic history.After satisfactory effect, continue to take Sertraline and effectively can prevent the recurrence of dysthymia disorders and send out again.Sertraline is also used for the treatment of obsession.After satisfactory effect, continue to take the recurrence that Sertraline can prevent obsession initial symptoms effectively.
My company has applied for that in 2002 Sertraline and salt and they thereof are used for the treatment of the purposes of mammal premature ejaculation, Authorization Notice No. CN1091096.Sertraline citrate is optionally 5-HT reuptake inhibitor, its mechanism of action is to 5-HT re-uptake by Selective depression nervus centralis presynaptic membrane, its local content is increased, and then the suppression ejaculation effect of especially AH 5-HT in reinforcement brain, therefore obviously can extend ejaculation latency, improvement quality of life, effectively treat premature ejaculation.
At present, Sertraline treatment premature ejaculation is still in clinical investigation phase at home and abroad, not yet gets permission listing.A large amount of clinical study shows, Sertraline can significant prolongation ejaculation latency, improvement quality of life, and treatment premature ejaculation determined curative effect, side effect are little, better tolerance.According to the literature, 36 routine penises insert Patients with Premature Ejaculation sertraline oral 100mg or the placebo respectively that namely intravaginal ejaculated less than 2 minutes, continuous treatment is after 4 weeks, placebo and test group intravagina ejaculation latency are respectively by within 46 ± 41 seconds, being increased to 2.27 ± 3.78 minutes and 4.27 ± 5.68 minutes before treating, life quality satisfaction rate is respectively 19.4% and 41.7%, compares all that there were significant differences for two groups.The adverse reaction rate for the treatment of group compared with placebo without significant difference.
Sertraline citrate initiates kind for my company, does not relate to the crystal formation of sertraline citrate raw material used in CN1091096 patent.
Have nothing to do in crystal data storehouse, Cambridge (CambridgeCrystallographicDataCentre, CCDC) in the crystal formation data of sertraline citrate.
Summary of the invention
One aspect of the present invention provides 2 kinds of crystal formations of sertraline citrate.
The first crystal formation of sertraline citrate provided by the invention, this crystal formation called after A crystal formation.There is obvious charateristic avsorption band at 2 θ angles of the X-ray powder diffraction pattern of this crystal being about the places such as 8.49,10.76,11.77,13.05,14.59,16.20,20.25,20.83,22.60,23.35 and 26.54.Concrete X powder diffraction figure is shown in Fig. 1.The infrared spectra of this crystal as shown in Figure 2.
Sertraline citrate the second crystal formation provided by the invention, this crystal formation called after B crystal form.There is obvious charateristic avsorption band at 2 θ angles of the X-ray powder diffraction pattern of this crystal being about the places such as 14.20,14.86,15.65,16.62,17.23,18.22,19.98,21.14,24.69,27.32,28.64,29.69 and 30.83.Concrete X powder diffraction figure is shown in Fig. 3.The infrared spectra of this crystal as shown in Figure 4.
The present invention provides the preparation method of these two kinds of sertraline citrate crystal formations on the other hand.Be specially:
Method 1: get sertraline citrate 50.0g, adds 95% ethanol of 250ml, is heated to 60-70 DEG C and is dissolved to clarification, keep 10 minutes, stop heating and dripping 7500ml water, be down to room temperature, keep stirring 24h, filter, the sertraline citrate A crystal formation that normal temperature drying under reduced pressure obtains for 12 hours.
Preferably, the ratio of described solvent load and sertraline citrate is 4ml ~ 10ml: 1g.
Preferably, the ratio of described second alcohol and water is 1:20 ~ 30.
Preferably, the insulated and stirred time is 10 minutes.
Method 2: get sertraline citrate 50.0g, adds 95% ethanol of 300ml, is heated to 60-70 DEG C and is dissolved to clarification, keeps 10 minutes, stops heating being down to room temperature, keeps stirring 24h, filters, the sertraline citrate B crystal form that normal temperature drying under reduced pressure obtains for 12 hours.
Preferably, the ratio of described solvent load and sertraline citrate is 4ml ~ 10ml: 1g.
Preferably, the insulated and stirred time is 10 minutes.
Advantage of the present invention is, sertraline citrate crystal form A of the present invention and crystal form B have good performance, and bioavailability is high; Or/and have good performance in stability, fulfilling medicinal formulation requirements, is conducive to storing, thus meets the requirement of medicine stability; Described preparation method is easy and simple to handle, and step is less, and environmental protection pressure is little, is applicable to suitability for industrialized production.
Crystal form A of the present invention is through product clinical 1 phase, clinical 2 phases, the Bioequivalence Test checking of GMP Workshop Production, and clinical efficacy is obvious, and untoward reaction is few.
Sertraline citrate crystal form A of the present invention and crystal form B and pharmaceutically acceptable vehicle make applicable oral, without digestive tube injection or by the tablet of intranasal administration or coated tablet, particle, Sublingual tablet, capsule, suppository, emulsion, ointment, painting skin glue, injection formulations, oral liquid.Described vehicle comprises conventional weighting agent, disintegrating agent, tackiness agent etc.Described weighting agent is as conventional weighting agents such as starch, lactose, Microcrystalline Cellulose, dextrin, N.F,USP MANNITOL, magnesium oxide, calcium sulfate.Described disintegrating agent is as carboxymethyl cellulose and the conventional disintegrating agent such as salt, cross-linked carboxymethyl cellulose and salt thereof, polyvinylpolypyrrolidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose thereof.Described tackiness agent is as typical binders such as polyvidone, Vltra tears, starch slurries.Described lubricant is as Magnesium Stearate, calcium stearate etc.
The purposes of above-mentioned sertraline citrate polymorphs body provided by the invention in the medicine of the related symptoms and premature ejaculation disease of preparing Cure of depression.
Accompanying drawing explanation
Fig. 1: the X-ray powder diffractogram of the embodiment of the present invention 1 sertraline citrate crystal form A.
Fig. 2: the infrared spectrogram of the embodiment of the present invention 1 sertraline citrate crystal form A.
Fig. 3: the X-ray powder diffractogram of the embodiment of the present invention 2 sertraline citrate crystal form B
Fig. 4: the infrared spectrogram of the embodiment of the present invention 2 sertraline citrate crystal form B.
The average drug-time curve figure of Fig. 5: 18 oral Sertraline Citrate in Beagles of experimenter (by test preparation) and assistant Lip river multiple (reference preparation) Sertraline afterwards
Embodiment
In order to introduce the present invention in more detail, providing and followingly preparing example.But scope of the present invention is not limited to this.
Experiment condition:
It should be noted that, in powdered sample X ray diffracting spectrum, the specific crystal formation of the diffraction spectrogram obtained by crystalline compounds is distinctive often, and wherein the relative intensity of bands of a spectrum (especially at low angle) may because of the difference of the relative content of crystallization condition, particle diameter, mixture and other test condition and the advantage orientation effect produced and changing.Therefore, the relative intensity of diffraction peak to for crystal be not distinctive, when judging whether identical with known crystal formation, should be noted that position instead of their relative intensity at peak.In addition, should note keeping organic conception when judging that whether crystal formation is the same, because be not that a diffracted ray represents a thing phase, but a set of specific " d-I/I
1" data just represent a certain thing phase.Should be noted also that in the qualification of mixture, because under content, degradation factor can cause the disappearance of portion diffracts line, now, without the need to relying in high-purity sample the whole bands of a spectrum observed, even bands of a spectrum may be also distinctive to given crystal.
embodiment 1: the preparation of sertraline citrate crystal form A:
Get sertraline citrate 50.0g, add 95% ethanol of 200ml, be heated to 60-70 DEG C and be dissolved to clarification, keep 10min, stop heating and dripping 6000ml water, be down to room temperature, keep stirring 24h, filter, the sertraline citrate crystalline powder that normal temperature drying under reduced pressure obtains for 12 hours.Measure through X-ray powder diffraction, showing the crystal formation obtained is crystal form A.Concrete peak position is as shown in table 1 below.
Table 1: the X-ray powder diffraction data of the embodiment of the present invention 1 sertraline citrate crystal form A
Carry out other tests to the sample obtained, the infrared spectra obtained as shown in Figure 2.
Carry out solubility test to the sample obtained, result is: sertraline citrate crystal form A sample is soluble in ethanol (11%, g/ml), is slightly soluble in 0.1mol/L hydrochloric acid soln (0.2%, g/ml), atomic water-soluble (0.01%, g/ml)
embodiment 2: the preparation of sertraline citrate crystal form B:
Get sertraline citrate 50.0g, add 95% ethanol of 500ml, be heated to 60-70 DEG C and be dissolved to clarification, keep 10min, stop heating being down to room temperature, keep stirring 24h, filter, the sertraline citrate crystalline powder that normal temperature drying under reduced pressure obtains for 12 hours.Measure through X-ray powder diffraction, showing the crystal formation obtained is crystal form B.Concrete peak position is as shown in table 2 below.
Table 2: the X-ray powder diffraction data of the embodiment of the present invention 2 sertraline citrate crystal form B
Carry out other tests to the sample obtained, the infrared spectra obtained as shown in Figure 4.
Carry out solubility test to the sample obtained, result is: sertraline citrate crystal form B sample dissolution in ethanol (1%, g/ml), soluble,very slightly in 0.1mol/L hydrochloric acid soln (0.01%, g/ml), hardly water-soluble (being less than 0.01%, g/ml)
embodiment 3: the preparation of sertraline citrate crystal form A:
Get sertraline citrate 50.0g, add 95% ethanol of 500ml, be heated to 60-70 DEG C and be dissolved to clarification, keep 10min, stop heating and dripping 10000ml water, be down to room temperature, keep stirring 24h, filter, the sertraline citrate crystalline powder that normal temperature drying under reduced pressure obtains for 12 hours.Measure through X-ray powder diffraction, show the crystal formation obtained consistent with the crystal formation of embodiment 1.Concrete peak position is as shown in table 1 below.
Table 3: the X-ray powder diffraction data of the embodiment of the present invention 3 sertraline citrate crystal form A
Carry out infrared test to the sample obtained, the infrared spectra obtained is consistent with Fig. 2.
embodiment 4: the preparation of sertraline citrate crystal form B:
Get sertraline citrate 50.0g, add 95% ethanol of 200ml, be heated to 60-70 DEG C and be dissolved to clarification, keep 10min, stop heating being down to room temperature, keep stirring 24h, filter, the sertraline citrate crystalline powder that normal temperature drying under reduced pressure obtains for 12 hours.Measure through X-ray powder diffraction, show the crystal formation obtained consistent with the crystal formation of embodiment 2.Concrete peak position is as shown in table 2 below.
Table 4: the X-ray powder diffraction data of the embodiment of the present invention 4 sertraline citrate crystal form B
Carry out infrared test to the sample obtained, the infrared spectra obtained is as consistent in Fig. 4.
Obvious the present invention disclosed herein is through taking into full account to realize above-mentioned target, but should be appreciated that one of ordinary skill in the art can propose many improvement and embodiment, therefore, claims cover all these improvement falling into the spirit and scope of the invention and embodiments.
embodiment 5: the stability test of the sertraline citrate of crystal form A, crystal form B
1, influence factor test:
Get crystal form A and the crystal form B sample of sertraline citrate, carry out influence factor test respectively, respectively at inspection by sampling in 0 day, 5 days, 10 days, 30 days.Influence factor test conditions is as follows: (1) high temperature test: 60 DEG C, and weighing bottle split shed is placed; (2) high wet test: 25 DEG C, RH92.5%, weighing bottle split shed is placed.(3) exposure experiments to light: 4500Lx ± 500Lx, weighing bottle split shed is placed.
Result: between 0 to 30 day probation, sample is high temperature 60 DEG C, and place the detected result of the related substance of sample after 30 days compared with 0 day initial results, the total impurities of crystal form A is increased to 0.09% by 0.00%, and the total impurities of crystal form A is increased to 0.02% by 0.00.Sample is placed in 25 DEG C, in the fixed temperature and humidity incubator of relative humidity 92.5%, places after 30 days, related substance detected result indifference compared with 0 day initial results of sample.Illumination 30 days, related substance detected result indifference compared with 0 day initial results of sample.
Between 0 to 30 day probation, under high temperature 60 DEG C, high humidity, illumination condition, the enantiomer of each time point does not detect.
Between 0 to 30 day probation, under high humidity, illumination condition, appearance color does not change, and under hot conditions, medicine color gradually becomes light yellow by white.
Found out by above-mentioned result, under high temperature 60 DEG C of conditions, two kinds of crystal form samples less stables, related substance has increased slightly.And under illumination, super-humid conditions, two kinds of crystal formation quality are very stable, do not change.
2, accelerated stability test
Get the sertraline citrate sample of the crystal form A of three batches of pilot scales, put RH75%(NaCl saturated solution) in, and to be positioned over room temperature be in the constant incubator of 40 DEG C.Measure in January, February, March, sampling in June by stability high spot reviews project.
Result: this product three batch sample commercially available back, 40 DEG C, investigate 6 months under relative humidity 75%RH condition, every inspection target is without considerable change, and wherein related substance variation range is that 0.72%(is minimum) ~ 0.91%(is the highest).The variation range of content is that 98.8%(is minimum) ~ 99.2%(is the highest), do not show obvious downtrending.Show that the sertraline citrate of crystal form A has good stability at accelerated stability 6 middle of the month.
3, long-term stable experiment
Get the sertraline citrate sample of the crystal form A of three batches of pilot scales, put RH64%(NaCO
2saturated solution) in, and to be positioned over room temperature be in the constant incubator of 25 DEG C.Measure in March, June, September, December, 18 months, 24 months, 36 months sampling by stability high spot reviews project.
Result: this product three batch sample commercially available back, 25 DEG C, investigate 36 months under relative humidity 64%RH condition, every inspection target is without considerable change, and wherein related substance variation range is that 0.72%(is minimum) ~ 0.81%(is the highest).The variation range of content is that 99.32%(is minimum) ~ 100.02%(is the highest), do not show obvious downtrending.Show that the sertraline citrate of crystal form A had good stability 36 middle of the month.
embodiment 6: the Dissolution Rate Testing of the sertraline citrate of crystal form A, crystal form B
Get crystal form A respectively, crystal form B sertraline citrate takes identical prescription, technique prepares Sertraline Citrate in Beagle and distinguish the different of its solubility property from by dissolution determination, to evaluate the dissolution characteristic of the sertraline citrate of two kinds of crystal formations.Result is as following table.
The Sertraline Citrate in Beagle dissolution determination comparing result table of table 5 two kinds of crystal formations
As can be seen here, the sertraline citrate dissolution rate of crystal form A is fast, has reached stripping peak value when 10 minutes, and the dissolution rate of crystal form B is slightly slower than crystal form A, reaches the peak value of stripping in 20 minutes time.Therefore, more preferably the sertraline citrate of crystal form A carries out next step clinical trial.
Get crystal form A the sertraline citrate Sertraline Citrate in Beagle prepared and sertraline hydrochloride sheet prepared by identical prescription, technique again and distinguish the different of its solubility property, to evaluate the dissolution characteristic of two kinds of Sertralines by dissolution determination in two kinds of different dissolution mediums.Result is as following table.
Table 6 Sertraline Citrate in Beagle and sertraline hydrochloride sheet dissolution determination comparing result table
Prove through test, sertraline citrate is all better than sertraline hydrochloride in solubility property and dissolution rate two.1 gram of sertraline citrate is dissolvable in water in 13ml ethanol and 4.5ml chloroform, and 1 gram of sertraline hydrochloride is dissolvable in water in 70ml ethanol and 9ml chloroform.With 0.1mol/L hydrochloric acid soln for dissolution fluid, Sertraline Citrate in Beagle 15 minutes dissolution rates can reach 97%, and sertraline hydrochloride sheet 15 minutes dissolution rates only reach 90%.
embodiment 7: 2 clinical trial phase data of the sertraline citrate of crystal form A
Within 2005, treat the validity of premature ejaculation and the clinical trial of safety evaluation by Peking University First Hospital's sertraline citrate carried out about crystal form A of taking the lead, this test is adjustable according to dosage, the multiple center clinical study of randomized, double-blind, placebo parallel control designs.Plan has 180 experimenters to enter this research, is probabilistically assigned to test group and placebo group.Jointly completed (participating in the second stage of clinical other five hospitals is: The People's Hospital of Peking University, The Third Affiliated Hospital of Peking University, PLA General Hospital, Beijing Tongren Hospital, BEIJING CHAO-YANG HOSPITAL) by 6 hospitals.
This test enters to organize patient 178 example altogether, wherein, and sertraline citrate 118 example, placebo 60 example; Complete test all do not make a house call person 169 example, sertraline citrate 115 example, placebo 54 example; All patients all employs drugs and has carried out safety evaluation and therapeutic evaluation at least one times, enter Safety population, ITT [be ready treat (IntentToTreat))] crowd, 166 routine patients enter PP [meeting scheme (PerProtocol)] crowd.
Totally 9 routine patient's premature termination researchs, wherein test group (sertraline citrate) 3 example (2.54%), control group (placebo) 6 example (10%).The demographic data of two groups of patients, the aspects such as the baseline state of an illness, no difference of science of statistics, two groups have comparability.
Evaluate sertraline citrate treatment premature ejaculation validity and security clinical study by this multicenter of 6 weeks by a definite date, randomized, double-blind, placebo parallel control, result shows: after 2 weeks, administration 2-4 week is used for the treatment of Patients with Premature Ejaculation to Sertraline Citrate in Beagle successive administration is as required effective and safe.
Ejaculation latent period (minute) and time expand successful:
Before the treatment of sertraline citrate, placebo, meta ejaculation is respectively 1.20,1.17 minutes latent period, during treatment end (6 weeks), meta ejaculation is respectively 3.79,1.79 minutes latent period, and meta ejaculation extends 2.56,0.86 minutes latent period respectively.
Sexual life satisfaction degree significantly improves:
Before the treatment of sertraline citrate, placebo patients except few patients occasionally has satisfaction, most all without satisfied sexual life, after treatment, sexual intercourse satisfaction mean value is respectively 45.76%, 14.65%%, two groups of differences have statistical significance, and sertraline citrate, placebo patients have 64.47%, 17.02% patient to be improved in varying degrees respectively.
Spouse of patient sexual intercourse satisfaction result and sexual life satisfaction degree result basically identical.
Patient is with or without the change being satisfied with sexual life:
Treat front two groups of patients almost all without being satisfied with sexual life, after treatment, sertraline citrate group has the ratio being satisfied with sexual life to rise to 41.53%, and placebo group is then 13.33%.
Before and after two groups of tests, laboratory examination, Electrocardioscopy and adverse events situation are all close, and one routine abnormal liver function occurs sertraline citrate group.
Conclusion: it is that safety is with effective that the sertraline citrate of crystal form A is used for the treatment of premature ejaculation.
embodiment 8: the Bioequivalence Test of the sertraline citrate of crystal form A
Within 2003, Sertraline Citrate in Beagle human bioavailability and Bioequivalence Test are carried out by national drug Clinical research center Liaoning People's Hospital Shenyang Pharmaceutical University's drug metabolism and pharmacokinetics laboratory, this test adopts Liquid chromatography-tandem mass spectrometry coupling method, determine the oral Sertraline Citrate in Beagle by crystal form A of 18 healthy male subjects (by test preparation, Harbin Jiandi Medicine Science and Technology Development Co., Ltd. and Sanjing Pharmaceutical Co., Ltd., Hayao Group's development) and the multiple sheet (reference preparation in assistant Lip river, Dalian pfizer inc produces) after the not concentration of Sertraline in blood plasma in the same time, depict blood concentration-time curve.According to blood concentration-time data, adopt trapezoidal method to calculate AUC value, with semilog graphing method, calculate t1/2 by the concentration point eliminating phase end, and obtain main pharmacokinetic parameter.
18 health volunteers oral containing Sertraline 50mg by after test preparation and reference preparation, record the Tmax of Sertraline in blood plasma and be respectively 7.1 ± 2.3(means standard deviation, lower same) and 7.6 ± 2.2h, Cmax is respectively 12.07 ± 6.53 and 10.76 ± 3.21ng/ml, t1/2 is respectively 30.66 ± 10.86 and 31.92 ± 7.56h, calculate by trapezoidal method, AUC0-t be respectively 393.4 ± 195.4 and 396.7 ± 148.5ngh/ml, AUC0-∞ be respectively 453.0 ± 230.1 and 459.6 ± 188.5ngh/ml.Calculate with AUC0-t, the relative bioavailability average out to 97.7 ± 15.9% of Sertraline Citrate in Beagle.
Carry out variance analysis by after the main pharmacokinetic parameters Logarithm conversion of gained, and adopt Doubled haploid population and (1-2 α) fiducial interval method to carry out evaluation of bioequivalence further.Result shows: AUC0-t and Cmax of two kinds of preparations all refuses biological inequivalence hypothesis.Crediblely 87.9% ~ 105.8% of reference preparation relevant parameter is limited to by 90% of test preparation AUC0-t; 90% of Cmax is crediblely limited to 97.6% ~ 117.6% of reference preparation relevant parameter.Can think that two kinds of preparations have bioequivalence.
Claims (10)
1. a crystal formation for sertraline citrate, the crystal formation of described sertraline citrate is crystal form A, crystal form B, and the crystal formation of described sertraline citrate is pure substantially.
2. the crystal formation of sertraline citrate according to claim 1, described crystal form A, large in its X-ray powder diffraction pattern is that 23.35 positions have peak about 2 θ; Or be greatly that a place of 8.49,10.76,11.77,13.05,14.59,16.20,20.25,20.83,22.60,23.35 and 26.54 positions or many places have peak about 2 θ in its X-ray powder diffraction pattern; Or its X-ray powder diffraction pattern substantially as shown in Figure 1.
3. the crystal formation of sertraline citrate according to claim 1, described crystal form B, large in its X-ray powder diffraction pattern is that 21.14 positions have peak about 2 θ; Or be greatly that a place of 14.20,14.86,15.65,16.62,17.23,18.22,19.98,21.14,24.69,27.32,28.64,29.69 and 30.83 positions or many places have peak about 2 θ in its X-ray powder diffraction pattern; Or its X-ray powder diffraction pattern substantially as shown in Figure 3.
4. sertraline citrate crystal form A according to claim 2, is characterized in that: described crystal form A has infrared spectra as shown in Figure 2 substantially.
5. sertraline citrate crystal form B according to claim 3, is characterized in that: described crystal form B has infrared spectra as shown in Figure 4 substantially.
6. the preparation method of sertraline citrate crystal form A according to claim 2, it is specially: get sertraline citrate 50.0g, add 95% ethanol of 250ml, be heated to 60 ~ 70 DEG C and be dissolved to clarification, keep 10 minutes, stop heating, and drip 7500ml water, be down to room temperature, keep stirring 24h, filter, normal temperature drying under reduced pressure obtains sertraline citrate crystal A crystal formation for 12 hours.
7. method according to claim 6, is characterized in that: the ratio of described 95% ethanol consumption and sertraline citrate is 4ml ~ 10ml: 1g; The volume ratio of 95% described second alcohol and water is 1:20 ~ 30.
8. the preparation method of sertraline citrate crystal form B according to claim 3, it is specially: get sertraline citrate 50.0g, add 95% ethanol of 300ml, be heated to 60-70 DEG C and be dissolved to clarification, keep 10 minutes, stop heating being down to room temperature, keep stirring 24h, filter, normal temperature drying under reduced pressure obtains sertraline citrate crystal B crystal form for 12 hours.
9. method according to claim 8, is characterized in that: the ratio of described 95% ethanol consumption and sertraline citrate is 4ml ~ 10ml: 1g.
10. the purposes of sertraline citrate according to claim 1 in the medicine of the related symptoms and premature ejaculation disease of preparing Cure of depression.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017000270A1 (en) * | 2015-07-01 | 2017-01-05 | 徐静 | Two crystal forms of sertraline citrate and preparation methods therefor |
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| WO2005012224A1 (en) * | 2003-07-15 | 2005-02-10 | Recordati Industria Chimica E Farmaceutica S.P.A. | Sertraline hydrochloride form ii and methods for the preparation thereof |
| CN1589256A (en) * | 1999-11-24 | 2005-03-02 | 特瓦制药工业有限公司 | Polycrystalline forms of sertraline hydrochloride and compeosition containing them, and method for preparing sertraline hydrochloride polycrystalline forms and amorphous matter |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1384816A (en) * | 1999-10-29 | 2002-12-11 | 西巴特殊化学品控股有限公司 | Polymorphic forms of sertraline hydrochloride |
| CN1589256A (en) * | 1999-11-24 | 2005-03-02 | 特瓦制药工业有限公司 | Polycrystalline forms of sertraline hydrochloride and compeosition containing them, and method for preparing sertraline hydrochloride polycrystalline forms and amorphous matter |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017000270A1 (en) * | 2015-07-01 | 2017-01-05 | 徐静 | Two crystal forms of sertraline citrate and preparation methods therefor |
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