CN103497195B - Conivaptan-hydrochlonovel novel crystal form and preparation method thereof - Google Patents
Conivaptan-hydrochlonovel novel crystal form and preparation method thereof Download PDFInfo
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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- C07D487/04—Ortho-condensed systems
Abstract
The present invention relates to medicinal chemistry art, disclose Conivaptan-hydrochlonovel novel crystal form and preparation method thereof.Conivaptan-hydrochlonovel novel crystal form crystal formation of the present invention is single, purity is high, good stability, solubleness and bioavailability are high, can suppress arginine vasopressin V1a and V2 acceptor, can be used for preparation treatment hyponatremia medicine.The preparation method of Conivaptan-hydrochlonovel novel crystal form of the present invention is simple to operate, avoids complexity, loaded down with trivial details crystallization treatment condition, and solvent cycle uses, and production cost is low, and be applicable to suitability for industrialized production, obtained product meets medicinal standard, good stability.
Description
Technical field
The present invention relates to medicinal chemistry art, relate to a kind of Conivaptan-hydrochlonovel novel crystal form and preparation method thereof specifically.
Background technology
Hydrochloric acid conivaptan is a kind of non-peptide class double inhibitor of arginine vasopressin (AVP) V1a and V2 acceptor.FDA is early than the hydrochloric acid conivaptan listing ratifying AstellasPharmaUS company on December 29th, 2005, trade(brand)name Vaprisol, for the injection liquid of 20mg/4mL, its indication is mainly used in the treatment of the normal hyponatremia of Q volume of blood (often occurring together in syndrome of inappropriate secretion of antidiuretic hormone patient, patients with hypothyroidism, hypoadrenia patient or Pulmonary Disease patients) and heavy body hyponatremia inpatient.FDA in 2007 ratifies conivaptan increases indication-Hypervolemia hyponatremia, within 2008, ratifies again the infusion solutions increasing new formulation-20mg/100mL.
The chemistry of hydrochloric acid conivaptan is called N-{4-[(2-methyl-4,5-glyoxalidine also [4,5-d] [1]-benzazepine-6 (1H)-Ji) carbonyl] phenyl } xenyl-2-carboxamide hydrochloride, cas number is 168626-94-6, English name is ConivaptanHydrochloride, and structural formula is as shown in formula I:
Crystal formation is one of important factor affecting drug quality, curative effect and preparation processing performance.Polymorphism, refers to same compound, by controlling its different formation condition, can form two or more molecule space arrangement mode, thus producing the phenomenon of different solid crystals.The different crystal forms of same compound, its chemical constitution is identical, but microcosmic crystalline structure is different, thus causes them to there are differences in mode of appearance, physico-chemical property and biological activity.These characteristics directly affect the preparation processing performance of medicine, and can affect the stability of medicine, solubleness and bioavailability, and then have influence on the quality of medicine, security, validity and application thereof.Japanese Patent JP2001002678 reports the preparation process of hydrochloric acid conivaptan δ type crystallization, have employed the mixed solvent system of acetonitrile, methyl alcohol, water, obtain the δ crystal formation of hydrochloric acid conivaptan through repeatedly decompression and air distillation, cooling crystallization, DSC display fusing point is about 277 DEG C.Japanese Patent JP2002087962 reports the preparation process of hydrochloric acid conivaptan α type crystallization, after heating in ethanol make it be suspended by the δ type crystallization that patent JP2001002678 is obtained, cooling crystallization is the alpha-crystal form of hydrochloric acid conivaptan, and DSC shows fusing point and is about 290 DEG C.But the crystallization taked in Japanese Patent JP2001002678 and JP2002087962 and crystal formation preparation method employ mixed solvent, operate complicated, solvent not easily reclaims, and crystal form purity is low, and environmental protection and the economy of preparation technology are poor.Therefore, study and prepare single, pure hydrochloric acid conivaptan crystal-form compound and have great importance.
Summary of the invention
In view of this, the present invention seeks to by crystallographic method, study, find and Conivaptan-hydrochlonovel novel crystal form is provided, provide its preparation method simultaneously.
First, the present invention, by crystallographic method, studies, finds and provide hydrochloric acid conivaptan high purity to stablize crystalline form.
Substantially pure Conivaptan-hydrochlonovel novel crystal form provided by the invention, its X-ray powder diffraction pattern as shown in Figure 1, has X-ray powder diffractogram characteristic parameter (2-Theta and d as shown in the table
error ± 0.2):
Substantially pure Conivaptan-hydrochlonovel novel crystal form provided by the invention, as shown in Figure 2, differential thermal analysis (DSC) display of Conivaptan-hydrochlonovel novel crystal form has 1 endotherm(ic)peak to its differential thermal analysis curve, and its Peak peak value is 325.91 DEG C.
Conivaptan-hydrochlonovel novel crystal form provided by the invention has comparatively satisfactory stability, thus bioavailability is high, in treatment hyponatremia, have good curative effect.In addition, Conivaptan-hydrochlonovel novel crystal form of the present invention has good performance in solubleness and anti-moisture absorption property, can fulfilling medicinal requirements well, is convenient to processing and the preservation of pharmaceutical preparation.
Present invention also offers the preparation method of the Conivaptan-hydrochlonovel novel crystal form of applicable suitability for industrialized production, with anhydrous methanol and acetonitrile, crystallization is carried out to hydrochloric acid conivaptan crude product.
Preferably, the preparation method of described Conivaptan-hydrochlonovel novel crystal form, specifically comprises
Hydrochloric acid conivaptan crude product is dissolved in heating in anhydrous methanol by step a) to be made it to dissolve, and activated carbon decolorizing, filters, filtrate evaporate to dryness;
Step b) adds acetonitrile, backflow, cooling, and filter, filtrate is drying to obtain.
Preferably, the ratio of the quality of the conivaptan of hydrochloric acid described in step a) crude product and the volume of described anhydrous methanol is 1g:10mL ~ 15mL.
Preferably, solvent temperature described in step a) is 35 DEG C ~ 40 DEG C.
Preferably, the ratio of the quality of the conivaptan of hydrochloric acid described in step b) crude product and the volume of described acetonitrile is 1g:20mL ~ 25mL.
Preferably, return time described in step b) is 3 hours ~ 5 hours.
Present invention also offers the application of described Conivaptan-hydrochlonovel novel crystal form in the medicine for the preparation for the treatment of hyponatremia.
Preferably, described hyponatremia is normal blood volume hyponatremia and heavy body hyponatremia.
The invention provides Conivaptan-hydrochlonovel novel crystal form and preparation method thereof.Conivaptan-hydrochlonovel novel crystal form crystal formation of the present invention is single, purity is high, good stability, solubleness and bioavailability are high, can suppress arginine vasopressin V1a and V2 acceptor, can be used for preparation treatment hyponatremia medicine.The preparation method of Conivaptan-hydrochlonovel novel crystal form of the present invention is simple to operate, avoids complexity, loaded down with trivial details crystallization treatment condition, and solvent cycle uses, and production cost is low, and be applicable to suitability for industrialized production, obtained product meets medicinal standard, good stability.
Accompanying drawing explanation
Fig. 1 shows the X-ray powder diffraction spectrogram of Conivaptan-hydrochlonovel novel crystal form, and ordinate zou is diffracted intensity (I), and unit is counting (counts); X-coordinate is diffraction angle (2 θ), and unit is degree;
Fig. 2 shows differential thermal analysis (DSC) figure of Conivaptan-hydrochlonovel novel crystal form, and ordinate zou is rate of heat flow, and unit is card/second; X-coordinate is temperature, and unit is DEG C.
Embodiment
The embodiment of the invention discloses Conivaptan-hydrochlonovel novel crystal form and preparation method thereof and application.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.Product of the present invention and method are described by preferred embodiment, related personnel obviously can not depart from content of the present invention, spirit and scope product as herein described and method are changed or suitably change with combination, realize and apply the technology of the present invention.
In order to understand the present invention further, below in conjunction with embodiment, the present invention is described in detail.
The present invention, by crystallographic method, studies, finds and provide Conivaptan-hydrochlonovel novel crystal form.
The present invention adopts the x-ray powder diffraction (XRPD) of generally acknowledging in the world study and characterize Conivaptan-hydrochlonovel novel crystal form.Adopt Japanese RigakuD/max-2550 Powder X-ray Diffractometer, at test parameter be: copper target, pipe stream 150mA, pipe pressure 40kV, sweep velocity 8 °/point, analyzes it under the condition that step-length is 0.02 °.Substantially pure Conivaptan-hydrochlonovel novel crystal form provided by the invention, its X-ray powder diffraction pattern as shown in Figure 1, has X-ray powder diffractogram characteristic parameter (2-Theta and d as shown in the table
error ± 0.2):
Table 1X-ray powder diffractogram characteristic peak
It should be noted that, for the X-ray powder diffraction peak of the above crystal formation, between a machine and another machine and between a sample and another sample, 2 θ of X-ray powder diffraction may slightly change, and its numerical value may differ about 1 unit, or differ about 0.8 unit, or differ about 0.5 unit, or differ about 0.3 unit, or differ about 0.1 unit, therefore given numerical value can not be considered as absolute.
In a particular embodiment, in its x-ray diffraction pattern of Conivaptan-hydrochlonovel novel crystal form of the present invention, the relative peak intensities of each respective peaks does not depart from the relative peak intensities more than 20% of characteristic peak described in table 1.
The present invention also adopts differential thermal analysis (DSC) study and characterize Conivaptan-hydrochlonovel novel crystal form.Adopt Switzerland MettlerDSC1 thermal analyzer, optimum configurations: starting temperature 30 DEG C, final temperature 350 DEG C, temperature rise rate 10K/min, tests new crystal.Substantially pure Conivaptan-hydrochlonovel novel crystal form provided by the invention, as shown in Figure 2, differential thermal analysis (DSC) display of Conivaptan-hydrochlonovel novel crystal form has 1 endotherm(ic)peak to its differential thermal analysis curve, and its Peak peak value is 325.91 DEG C.
Invention is investigated the stability of the Conivaptan-hydrochlonovel novel crystal form provided.Result shows, Conivaptan-hydrochlonovel novel crystal form provided by the invention has comparatively satisfactory stability, thus bioavailability is high, in treatment hyponatremia, have good curative effect.In addition, official method is also adopted to have studied Conivaptan-hydrochlonovel novel crystal form water absorbability of the present invention and solubleness.Conivaptan-hydrochlonovel novel crystal form of the present invention has good performance in solubleness and anti-moisture absorption property, can fulfilling medicinal requirements well, is convenient to processing and the preservation of pharmaceutical preparation.
Present invention also offers the preparation method of the Conivaptan-hydrochlonovel novel crystal form of applicable suitability for industrialized production, with anhydrous methanol and acetonitrile, crystallization is carried out to hydrochloric acid conivaptan crude product.
Preferably, the preparation method of described Conivaptan-hydrochlonovel novel crystal form, specifically comprises
Hydrochloric acid conivaptan crude product is dissolved in heating in anhydrous methanol by step a) to be made it to dissolve, and activated carbon decolorizing, filters, filtrate evaporate to dryness;
Step b) adds acetonitrile, backflow, cooling, and filter, filtrate is drying to obtain.
Wherein, the ratio of the quality of the conivaptan of hydrochloric acid described in step a) crude product and the volume of described anhydrous methanol is preferably 1g:10mL ~ 15mL, is more preferably 1g:10mL.Namely every 1g hydrochloric acid conivaptan crude product preferably adds 10mL ~ 15mL anhydrous methanol, is more preferably and adds 10mL anhydrous methanol.
Preparation method's step a) hydrochloric acid conivaptan crude product of Conivaptan-hydrochlonovel novel crystal form of the present invention is dissolved in anhydrous methanol post-heating makes hydrochloric acid conivaptan dissolving crude product, and described solvent temperature is preferably 35 DEG C ~ 40 DEG C.
Conivaptan-hydrochlonovel novel crystal form is activated carbon decolorizing after anhydrous methanol heating for dissolving, filters, and collects filtrate evaporate to dryness.Wherein said evaporate to dryness is preferably the quick evaporate to dryness of solvent, is more preferably 35 DEG C ~ 40 DEG C water pump evaporated under reduced pressure.
The crystal of step a) evaporate to dryness in step b) after acetonitrile backflow is dissolved recrystallization.Wherein the ratio of the quality of the conivaptan of hydrochloric acid described in step b) crude product and the volume of described acetonitrile is preferably 1g:20mL ~ 25mL, is more preferably 1g:20mL.Namely every 1g hydrochloric acid conivaptan crude product adds 20mL ~ 25mL acetonitrile, more preferably adds 20mL acetonitrile.
Further, return time described in step b) is preferably 3 hours ~ 5 hours, is more preferably 4 ~ 5 hours.
According to the present invention, cooling after the backflow of step b) acetonitrile in the preparation method of described Conivaptan-hydrochlonovel novel crystal form, filter, filtrate drying obtains Conivaptan-hydrochlonovel novel crystal form.Wherein said drying is preferably drying under reduced pressure, is more preferably 60 DEG C of oil pump drying under reduced pressure.
The present invention is not particularly limited described pending hydrochloric acid conivaptan crude product, the method of open source literature at present can be adopted to obtain hydrochloric acid conivaptan crude product, as CN1040210C, JP8198879A and Org.ProcessRes.Dev.2005,9 (5), 593-598 and Heterocyles.2004,63 (5), 1113-1122.
Analyze through high performance liquid phase (HPLC), the preparation method of Conivaptan-hydrochlonovel novel crystal form of the present invention obtains the equal >99.0% of Conivaptan-hydrochlonovel novel crystal form content, and related substance total amount is less than 0.5%, and any maximum single impurity is no more than 0.1%.
Conivaptan-hydrochlonovel novel crystal form of the present invention carries out stability test through high temperature test and accelerated test, and test-results shows: Conivaptan-hydrochlonovel novel crystal form of the present invention all keeps original crystal formation constant, and obvious change does not also occur for content and total impurities.
Conivaptan-hydrochlonovel novel crystal form of the present invention is excellent performance in suppression arginine vasopressin V1a and V2 acceptor, and has good preservation and Treatment Stability, is applicable to medicament manufacture and standing storage, can be used for the medicine preparing treatment hyponatremia.Therefore the invention provides the application of described Conivaptan-hydrochlonovel novel crystal form in the medicine for the preparation for the treatment of hyponatremia.
Further, described hyponatremia is normal blood volume hyponatremia and heavy body hyponatremia.
Conivaptan-hydrochlonovel novel crystal form of the present invention can be prepared into the various solid dosages of oral medicine further, as tablet, and capsule or granule.
The medicinal preparations being used for the treatment of hyponatremia of the present invention, comprises described Conivaptan-hydrochlonovel novel crystal form and pharmaceutical excipient.In these formulations, active compound mixes with the pharmaceutically acceptable inert excipient of at least one or carrier, as Trisodium Citrate, calcium phosphate, weighting agent, tackiness agent, wetting Agent for Printing Inks, disintegrating agent, retarding agent, absorption enhancer, wetting agent, absorption agent or lubricant and their mixture.Wherein, weighting agent as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; Tackiness agent as carboxymethyl cellulose, alginate, gelatin, Povidone, sucrose and gum arabic; Wetting Agent for Printing Inks is as glycerine; Disintegrating agent as agar, calcium carbonate, potato starch or tapioca (flour), Lalgine, some silicate and sodium carbonate, low-substituted hydroxypropyl cellulose; Retarding agent solution is as paraffin; Absorption enhancer is as quaternary ammonium compounds; Wetting agent is as hexadecanol and glyceryl monostearate; Absorption agent is as white bole and bentonite; Lubricant as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sulfuric acid,monododecyl ester, sodium salt.
Embodiment 1: the preparation of Conivaptan-hydrochlonovel novel crystal form
Hydrochloric acid conivaptan crude product 1g is dissolved in 12mL anhydrous methanol, and heating in water bath to 35 ~ 40 DEG C make it to dissolve, and add gac 0.06g and enter, and insulated and stirred decolouring 20min, filters, filtrate 35 ~ 40 DEG C of water pump evaporated under reduced pressure; Add 25mL acetonitrile, under rapid stirring, temperature rising reflux 5 hours, is cooled to about 15 DEG C, and stir after 1 hour and filter, filter cake 60 DEG C of oil pump drying under reduced pressure, to constant weight, obtain white solid powder 0.694g, yield 69.4%.Analyze through HPLC, the related substance total amount of products obtained therefrom is 0.065%, and maximum list is mixed 0.046%(area normalization method).
Adopt Japanese RigakuD/max-2550 Powder X-ray Diffractometer, at test parameter be: copper target, pipe stream 150mA, pipe pressure 40kV, sweep velocity 8 °/point, analyze described solid product under the condition that step-length is 0.02 °, result is see Fig. 1.Fig. 1 is the powder x-ray diffraction collection of illustrative plates of the Conivaptan-hydrochlonovel novel crystal form that the embodiment of the present invention obtains.Fig. 1 display has following characteristic parameter:
Adopt Switzerland MettlerDSC1 thermal analyzer, optimum configurations: starting temperature 30 DEG C, final temperature 350 DEG C, temperature rise rate 10K/min, tests described product.Result is see Fig. 2.Fig. 2 is differential thermal analysis (DSC) collection of illustrative plates of the Conivaptan-hydrochlonovel novel crystal form that the embodiment of the present invention obtains.Differential thermal analysis (DSC) display of this crystal formation has 1 endotherm(ic)peak, and its Peak peak value is 325.91 DEG C.
Embodiment 2: the preparation of Conivaptan-hydrochlonovel novel crystal form
Hydrochloric acid conivaptan crude product 20g is dissolved in 200mL anhydrous methanol, and heating in water bath to 35 ~ 40 DEG C make it to dissolve, and add gac 1.0g and enter, and insulated and stirred decolouring 30min, filters, filtrate 35 ~ 40 DEG C of water pump evaporated under reduced pressure; Add 400mL acetonitrile, under rapid stirring, temperature rising reflux 5 hours, is cooled to about 15 DEG C, and stir after 1 hour and filter, filter cake 60 DEG C of oil pump drying under reduced pressure, to constant weight, obtain white solid powder 14.672g, yield 73.36%.Analyze through HPLC, the related substance total amount of products obtained therefrom is 0.067%, and maximum list is mixed 0.042%(area normalization method).
Adopt Japanese RigakuD/max-2550 Powder X-ray Diffractometer, Switzerland MettlerDSC1 thermal analyzer analyzes described product, result shows, it is consistent with the product form that embodiment 1 prepares.
Embodiment 3: the stability experiment of Conivaptan-hydrochlonovel novel crystal form
By the Conivaptan-hydrochlonovel novel crystal form sample that the alpha-crystal form hydrochloric acid conivaptan prepared according to patent JP2002087962 embodiment 1 and the embodiment of the present invention 2 obtain, uncoveredly respectively divide placement, investigate the stability of sample under heating 60 DEG C of conditions, investigating sample time is 10 days.Powder x-ray diffraction and HPLC detected result are in table 2.
Table 2 stability test result
As shown in Table 2, comparatively alpha-crystal form hydrochloric acid conivaptan is under high temperature 60 DEG C of conditions for the Conivaptan-hydrochlonovel novel crystal form that the embodiment of the present invention 2 obtains, and foreign matter content is low, and stability is higher.
The crystalline state hydrochloric acid conivaptan sample that the alpha-crystal form hydrochloric acid conivaptan prepared according to patent JP2002087962 embodiment 1 and the embodiment of the present invention 2 are obtained, all adopt composite membrane for packaging medicine to pack, place 6 months under the condition of temperature 40 DEG C ± 2 DEG C (RH75% ± 5%).HPLC detected result is in table 3.
Table 3 accelerated test study on the stability result
As shown in Table 3, crystalline state hydrochloric acid conivaptan provided by the invention and alpha-crystal form hydrochloric acid conivaptan, under accelerated test (temperature 40 DEG C ± 2 DEG C, RH75% ± 5%) condition, place HPLC after 6 months detect related substance, it is few that Conivaptan-hydrochlonovel novel crystal form provided by the invention places generation impurity compared with alpha-crystal form hydrochloric acid conivaptan, and stability is higher.
The explanation of above embodiment just understands method of the present invention and core concept thereof for helping.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improve and modify and also fall in the protection domain of the claims in the present invention.
Claims (5)
1. a hydrochloric acid conivaptan crystal formation, is characterized in that, has X-ray powder diffractogram characteristic parameter as shown in the table, 2-Theta error ± 0.2; With
error ± 0.2:
2. crystal formation according to claim 1, it is characterized in that, its differential scanning calorimetric analysis curve has endotherm(ic)peak at about 325.91 DEG C of places.
3. a preparation method for hydrochloric acid conivaptan crystal formation described in claim 1, is characterized in that, comprise
Hydrochloric acid conivaptan crude product a) is dissolved in heating in anhydrous methanol by step to be made it to dissolve, and activated carbon decolorizing, filters, filtrate evaporate to dryness;
Step b) add acetonitrile, backflow, cooling, filter, filtrate is drying to obtain;
Step a) described in the ratio of the quality of hydrochloric acid conivaptan crude product and the volume of described anhydrous methanol be 1g:10mL ~ 15mL;
Step a) described in solvent temperature be 35 DEG C ~ 40 DEG C;
Step b) described in the ratio of the quality of hydrochloric acid conivaptan crude product and the volume of described acetonitrile be 1g:20mL ~ 25mL;
Step b) described in return time be 3 hours ~ 5 hours.
4. the application of hydrochloric acid conivaptan-crystal formation described in claim 1 in the medicine for the preparation for the treatment of hyponatremia.
5. application according to claim 4, is characterized in that, described hyponatremia is normal blood volume hyponatremia and heavy body hyponatremia.
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| CN106442751A (en) * | 2016-08-24 | 2017-02-22 | 蚌埠丰原涂山制药有限公司 | Method for determining content of conivaptan hydrochloride by virtue of high performance liquid chromatography |
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| JP4461512B2 (en) * | 1999-06-17 | 2010-05-12 | アステラス製薬株式会社 | Crystals of condensed benzazepine derivatives |
| JP2002087962A (en) * | 2000-09-12 | 2002-03-27 | Yamanouchi Pharmaceut Co Ltd | Readily water-soluble and stable composition |
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