CN103497195A - Conivaptan-hydrochloride novel crystal form and preparation method thereof - Google Patents
Conivaptan-hydrochloride novel crystal form and preparation method thereof Download PDFInfo
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- CN103497195A CN103497195A CN201310495851.3A CN201310495851A CN103497195A CN 103497195 A CN103497195 A CN 103497195A CN 201310495851 A CN201310495851 A CN 201310495851A CN 103497195 A CN103497195 A CN 103497195A
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- C07D487/04—Ortho-condensed systems
Abstract
The invention relates to the field of medicinal chemistry, and discloses a conivaptan-hydrochloride novel crystal form and a preparation method of the conivaptan-hydrochloride novel crystal form. The conivaptan-hydrochloride novel crystal form is single in crystal form, high in purity, good in stability, high in solubility and bioavailability, capable of restraining arginine vasopressin V1a and V2 receptors, and capable of being used for preparing medicine for treating hyponatremia. The preparation method of the conivaptan-hydrochloride novel crystal form is simple to operate, avoids complex and fussy crystallization processing conditions, enables solvents to be recycled, is low in production cost, and is suitable for industrial production. Products meet medicinal standards and good in stability.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, relate to specifically a kind of hydrochloric acid conivaptan new crystal and preparation method thereof.
Background technology
The 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 of ratifying Astellas Pharma US company on December 29th, 2005, trade(brand)name Vaprisol, for the injection liquid of 20mg/4mL, its indication is mainly used in the normal hyponatremia of Q volume of blood (often occurring together in syndrome of inappropriate secretion of antidiuretic hormone patient, thyroprivia patient, hypoadrenia patient or pulmonary disorder patient) and heavy body hyponatremia inpatient's treatment.Within 2007, FDA approval conivaptan increases indication-Hypervolemia hyponatremia, within 2008, ratifies to increase again the infusion solutions of 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)-yl) carbonyl] phenyl } xenyl-2-carboxamide hydrochloride, cas number is 168626-94-6, English name is Conivaptan Hydrochloride, and structural formula is as shown in formula I:
Crystal formation is one of important factor affected drug quality, curative effect and preparation processing performance.Polymorphism, refer to same compound, by controlling its different formation condition, can form two or more molecule space arrangement mode, thereby produce the phenomenon of different solid crystals.The different crystal forms of same compound, its chemical constitution is identical, but microcosmic crystalline structure difference, thereby cause them to there are differences on mode of appearance, physico-chemical property and biological activity.These characteristics directly affect the preparation processing performance of medicine, and can affect stability, solubleness and the bioavailability of medicine, and then have influence on quality, security, validity and the application thereof of medicine.Japanese Patent JP2001002678 has reported the preparation process of hydrochloric acid conivaptan δ type crystallization, adopted 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 shows that fusing point is about 277 ℃.Japanese Patent JP2002087962 has reported the preparation process of hydrochloric acid conivaptan α type crystallization, after being about to δ type crystallization that patent JP2001002678 make and heating in ethanol it is suspended, cooling crystallization is the alpha-crystal form of hydrochloric acid conivaptan, and DSC shows that fusing point is about 290 ℃.Yet the crystallization of taking in Japanese Patent JP2001002678 and JP2002087962 and crystal formation preparation method have used mixed solvent, operate complicatedly, solvent be difficult for to reclaim, and crystal formation purity is low, and preparation technology's environmental protection and economy are poor.Therefore, study and prepare single, pure hydrochloric acid conivaptan crystal formation compound and have great importance.
Summary of the invention
In view of this, the present invention seeks to by crystallographic method, study, find and hydrochloric acid conivaptan new crystal is provided, its preparation method is provided simultaneously.
At first, the present invention, by crystallographic method, studies, finds and provide hydrochloric acid conivaptan high purity to stablize crystalline form.
Basically pure hydrochloric acid conivaptan new crystal provided by the invention, its X-ray powder diffraction pattern as shown in Figure 1, has X-ray powder diffraction chromatogram characteristic parameter (2-Theta and d as shown in the table
error ± 0.2):
Basically pure hydrochloric acid conivaptan new crystal provided by the invention, as shown in Figure 2, the differential thermal analysis (DSC) of hydrochloric acid conivaptan new crystal shows and has 1 endotherm(ic)peak its differential thermal analysis curve, its Peak peak value is 325.91 ℃.
Hydrochloric acid conivaptan new crystal provided by the invention has comparatively satisfactory stability, thereby bioavailability is high, aspect the treatment hyponatremia, has good curative effect.In addition, hydrochloric acid conivaptan new crystal of the present invention has good performance aspect solubleness and anti-moisture absorption property, and fulfilling medicinal requirements, be convenient to processing and the preservation of pharmaceutical preparation well.
The present invention also provides the preparation method of the hydrochloric acid conivaptan new crystal of applicable suitability for industrialized production, with anhydrous methanol and acetonitrile, hydrochloric acid conivaptan crude product is carried out to crystallization.
Preferably, the preparation method of described hydrochloric acid conivaptan new crystal, specifically comprise
Step a) is dissolved in heating in anhydrous methanol by hydrochloric acid conivaptan crude product to be made it to dissolve, and activated carbon decolorizing, filter the filtrate evaporate to dryness;
Step b) adds acetonitrile, refluxes, cooling, filters, and filtrate is drying to obtain.
Preferably, the ratio of the volume of the quality of the conivaptan of hydrochloric acid described in step a) crude product and described anhydrous methanol is 1g:10mL～15mL.
Preferably, solvent temperature described in step a) is 35 ℃～40 ℃.
Preferably, the ratio of the volume of the quality of the conivaptan of hydrochloric acid described in step b) crude product and described acetonitrile is 1g:20mL～25mL.
Preferably, return time described in step b) is 3 hours～5 hours.
The present invention also provides the application of described hydrochloric acid conivaptan new crystal in the medicine for the preparation of the treatment hyponatremia.
Preferably, described hyponatremia is normal blood volume hyponatremia and heavy body hyponatremia.
The invention provides hydrochloric acid conivaptan new crystal and preparation method thereof.Hydrochloric acid conivaptan new crystal crystal formation of the present invention is single, purity is high, good stability, solubleness and bioavailability high, can suppress arginine vasopressin V1a and V2 acceptor, can be used for preparation treatment hyponatremia medicine.The preparation method of hydrochloric acid conivaptan new crystal of the present invention is simple to operate, has avoided complicated, loaded down with trivial details crystallization treatment condition, and solvent cycle is used, and production cost is low, is applicable to suitability for industrialized production, and obtained product meets medicinal standard, good stability.
The accompanying drawing explanation
Fig. 1 shows the X-ray powder diffraction spectrogram of hydrochloric acid conivaptan new crystal, 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 hydrochloric acid conivaptan new crystal, and ordinate zou is rate of heat flow, and unit is card/second; X-coordinate is temperature, and unit is ℃.
Embodiment
The embodiment of the invention discloses hydrochloric acid conivaptan new crystal and preparation method thereof and application.Those skilled in the art can use for reference this paper content, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they all are deemed to be included in the present invention.Product of the present invention and method are described by preferred embodiment, the related personnel obviously can be within not breaking away from content of the present invention, spirit and scope to product as herein described with method is changed or suitably change and combination, realize and apply the technology of the present invention.
In order further to understand the present invention, below in conjunction with embodiment, the present invention is described in detail.
The present invention, by crystallographic method, studies, finds and provide hydrochloric acid conivaptan new crystal.
The present invention adopts generally acknowledged in the world x-ray powder diffraction (XRPD) to study and characterize hydrochloric acid conivaptan new crystal.Adopt Japanese Rigaku D/max-2550 powder x-ray diffraction instrument, at test parameter be: the copper target, pipe stream 150mA, pipe is pressed 40kV, and 8 °/minutes of sweep velocitys, analyzed it under the condition that step-length is 0.02 °.Basically pure hydrochloric acid conivaptan new crystal provided by the invention, its X-ray powder diffraction pattern as shown in Figure 1, has X-ray powder diffraction chromatogram characteristic parameter (2-Theta and d as shown in the table
error ± 0.2):
Table 1X-ray powder diffraction chromatogram characteristic peak
It should be noted that, X-ray powder diffraction peak for 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, perhaps differ about 0.5 unit, perhaps differ about 0.3 unit, or differ about 0.1 unit, therefore given numerical value can not be considered as absolute.
In specific embodiment, in its x-ray diffraction pattern of hydrochloric acid conivaptan new crystal of the present invention, the Relative Peak intensity of each respective peaks does not depart from the Relative Peak intensity of characteristic peak described in table 1 more than 20%.
The present invention also adopts differential thermal analysis (DSC) to study and characterized hydrochloric acid conivaptan new crystal.Adopt Switzerland Mettler DSC1 thermal analyzer, the parameter setting: 30 ℃ of starting temperatures, 350 ℃ of final temperatures, temperature rise rate 10K/min, tested new crystal.Basically pure hydrochloric acid conivaptan new crystal provided by the invention, as shown in Figure 2, the differential thermal analysis (DSC) of hydrochloric acid conivaptan new crystal shows and has 1 endotherm(ic)peak its differential thermal analysis curve, its Peak peak value is 325.91 ℃.
The stability of the hydrochloric acid conivaptan new crystal provided also has been provided in invention.Result shows, hydrochloric acid conivaptan new crystal provided by the invention has comparatively satisfactory stability, thereby bioavailability is high, aspect the treatment hyponatremia, has good curative effect.In addition, also adopt official method to study hydrochloric acid conivaptan new crystal water absorbability of the present invention and solubleness.Hydrochloric acid conivaptan new crystal of the present invention has good performance aspect solubleness and anti-moisture absorption property, fulfilling medicinal requirements, be convenient to processing and the preservation of pharmaceutical preparation well.
The present invention also provides the preparation method of the hydrochloric acid conivaptan new crystal of applicable suitability for industrialized production, with anhydrous methanol and acetonitrile, hydrochloric acid conivaptan crude product is carried out to crystallization.
Preferably, the preparation method of described hydrochloric acid conivaptan new crystal, specifically comprise
Step a) is dissolved in heating in anhydrous methanol by hydrochloric acid conivaptan crude product to be made it to dissolve, and activated carbon decolorizing, filter the filtrate evaporate to dryness;
Step b) adds acetonitrile, refluxes, cooling, filters, and 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, more preferably 1g:10mL.Be that every 1g hydrochloric acid conivaptan crude product preferably adds 10mL～15mL anhydrous methanol, more preferably add the 10mL anhydrous methanol.
Preparation method's step a) hydrochloric acid conivaptan crude product of hydrochloric acid conivaptan new crystal of the present invention is dissolved in the anhydrous methanol post-heating makes hydrochloric acid conivaptan dissolving crude product, and described solvent temperature is preferably 35 ℃～40 ℃.
Hydrochloric acid conivaptan new crystal activated carbon decolorizing after the anhydrous methanol heating for dissolving, filter, and collects the filtrate evaporate to dryness.Wherein said evaporate to dryness is preferably the quick evaporate to dryness of solvent, more preferably 35 ℃～40 ℃ water pump evaporated under reduced pressure.
The crystal of step a) evaporate to dryness in step b) after acetonitrile reflux to dissolve recrystallization.Wherein the ratio of the volume of the quality of the conivaptan of hydrochloric acid described in step b) crude product and described acetonitrile is preferably 1g:20mL～25mL, more preferably 1g:20mL.Be that every 1g hydrochloric acid conivaptan crude product adds 20mL～25mL acetonitrile, more preferably add the 20mL acetonitrile.
Further, return time described in step b) is preferably 3 hours～and 5 hours, more preferably 4～5 hours.
According to the present invention, in the preparation method of described hydrochloric acid conivaptan new crystal, the step b) acetonitrile is cooling after refluxing, and filters, and the filtrate drying obtains hydrochloric acid conivaptan new crystal.Wherein said drying is preferably drying under reduced pressure, more preferably 60 ℃ of oil pump drying under reduced pressure.
The present invention is not particularly limited described pending hydrochloric acid conivaptan crude product, can adopt the current method of open source literature to make hydrochloric acid conivaptan crude product, as CN1040210C, JP8198879A and Org.Process Res.Dev.2005,9 (5), 593-598 and Heterocyles.2004,63 (5), 1113-1122.
Through high performance liquid phase (HPLC), analyze, it is equal that the preparation method of hydrochloric acid conivaptan new crystal of the present invention obtains hydrochloric acid conivaptan new crystal content > 99.0%, the related substance total amount is less than 0.5%, and the single impurity of any maximum is no more than 0.1%.
Hydrochloric acid conivaptan new crystal of the present invention carries out stability test through high temperature test and accelerated test, and test-results shows: hydrochloric acid conivaptan new crystal of the present invention all keeps original crystal formation constant, and content and total impurities also do not occur obviously to change.
Hydrochloric acid conivaptan new crystal of the present invention is excellent performance aspect inhibition 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 of preparation treatment hyponatremia.Therefore the invention provides the application of described hydrochloric acid conivaptan new crystal in the medicine for the preparation of the treatment hyponatremia.
Further, described hyponatremia is normal blood volume hyponatremia and heavy body hyponatremia.
Hydrochloric acid conivaptan new crystal of the present invention can further be prepared into the various solid dosages of oral medicine, as tablet, and capsule or granule.
The medicinal preparations that is used for the treatment of hyponatremia of the present invention, comprise described hydrochloric acid conivaptan new crystal and pharmaceutical excipient.In these formulations, active compound mixes with at least one pharmaceutically acceptable inert excipient 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 is as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; Tackiness agent is as carboxymethyl cellulose, alginate, gelatin, Povidone, sucrose and gum arabic; Wetting Agent for Printing Inks is as glycerine; Disintegrating agent is 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 is as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sulfuric acid,monododecyl ester, sodium salt.
Embodiment 1: the preparation of hydrochloric acid conivaptan new crystal
Hydrochloric acid conivaptan crude product 1g is dissolved in the 12mL anhydrous methanol, and heating in water bath to 35～40 ℃ make it to dissolve, and adds gac 0.06g and enters, and insulated and stirred decolouring 20min, filter 35～40 ℃ of water pump evaporated under reduced pressure of filtrate; Add the 25mL acetonitrile, under rapid stirring, temperature rising reflux is 5 hours, is cooled to 15 ℃ of left and right, stirs after 1 hour and filters, and 60 ℃ of oil pump drying under reduced pressure of filter cake, to constant weight, obtain white solid powder 0.694g, yield 69.4%.Through HPLC, analyze, the related substance total amount of products obtained therefrom is 0.065%, maximum single assorted 0.046%(area normalization method).
Adopt Japanese Rigaku D/max-2550 powder x-ray diffraction instrument, at test parameter be: the copper target, pipe stream 150mA, pipe is pressed 40kV, and 8 °/minutes of sweep velocitys, analyzed described solid product under the condition that step-length is 0.02 °, and result is referring to Fig. 1.The powder x-ray diffraction collection of illustrative plates of the hydrochloric acid conivaptan new crystal that Fig. 1 is embodiment of the present invention acquisition.Fig. 1 shows to have following characteristic parameter:
Adopt Switzerland Mettler DSC1 thermal analyzer, the parameter setting: 30 ℃ of starting temperatures, 350 ℃ of final temperatures, temperature rise rate 10K/min, tested described product.Result is referring to Fig. 2.Differential thermal analysis (DSC) collection of illustrative plates of the hydrochloric acid conivaptan new crystal that Fig. 2 is embodiment of the present invention acquisition.The differential thermal analysis of this crystal formation (DSC) demonstration has 1 endotherm(ic)peak, and its Peak peak value is 325.91 ℃.
Embodiment 2: the preparation of hydrochloric acid conivaptan new crystal
Hydrochloric acid conivaptan crude product 20g is dissolved in the 200mL anhydrous methanol, and heating in water bath to 35～40 ℃ make it to dissolve, and adds gac 1.0g and enters, and insulated and stirred decolouring 30min, filter 35～40 ℃ of water pump evaporated under reduced pressure of filtrate; Add the 400mL acetonitrile, under rapid stirring, temperature rising reflux is 5 hours, is cooled to 15 ℃ of left and right, stirs after 1 hour and filters, and 60 ℃ of oil pump drying under reduced pressure of filter cake, to constant weight, obtain white solid powder 14.672g, yield 73.36%.Through HPLC, analyze, the related substance total amount of products obtained therefrom is 0.067%, maximum single assorted 0.042%(area normalization method).
Adopt Japanese Rigaku D/max-2550 powder x-ray diffraction instrument, Switzerland's Mettler DSC1 thermal analyzer to be analyzed described product, result shows, its product crystal formation prepared with embodiment 1 is consistent.
Embodiment 3: the stability experiment of hydrochloric acid conivaptan new crystal
The hydrochloric acid conivaptan new crystal sample that will obtain according to alpha-crystal form hydrochloric acid conivaptan and the embodiment of the present invention 2 of patent JP2002087962 embodiment 1 preparation, uncoveredly respectively divide placement, the stability of investigation sample under 60 ℃ of conditions of heating, 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, the hydrochloric acid conivaptan new crystal that the embodiment of the present invention 2 obtains is than alpha-crystal form hydrochloric acid conivaptan under 60 ℃ of conditions of high temperature, and foreign matter content is low, and stability is higher.
The crystalline state hydrochloric acid conivaptan sample that will obtain according to alpha-crystal form hydrochloric acid conivaptan and the embodiment of the present invention 2 of patent JP2002087962 embodiment 1 preparation, all adopt composite membrane for packaging medicine to pack, place 6 months under the condition of temperature 40 ℃ ± 2 ℃ (RH75% ± 5%).The 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, place HPLC after 6 months and detect related substance under accelerated test (40 ℃ ± 2 ℃ of temperature, RH75% ± 5%) condition, it is few that hydrochloric acid conivaptan new crystal provided by the invention is placed generation impurity than alpha-crystal form hydrochloric acid conivaptan, and stability is higher.
The explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof.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 improvement and modification also fall in the protection domain of the claims in the present invention.
Claims (10)
1. a hydrochloric acid conivaptan new crystal, is characterized in that, has X-ray powder diffraction chromatogram characteristic parameter (2-Theta and d as shown in the table
error ± 0.2):
2. crystal formation according to claim 1, is characterized in that, its differential scanning calorimetric analysis curve approximately 325.91 ℃ located endotherm(ic)peak.
3. the preparation method of the described hydrochloric acid conivaptan of claim 1 new crystal, is characterized in that, with anhydrous methanol and acetonitrile, hydrochloric acid conivaptan crude product carried out to crystallization.
4. preparation method according to claim 3, is characterized in that, comprises
Step a) is dissolved in heating in anhydrous methanol by hydrochloric acid conivaptan crude product to be made it to dissolve, and activated carbon decolorizing, filter the filtrate evaporate to dryness;
Step b) adds acetonitrile, refluxes, cooling, filters, and filtrate is drying to obtain.
5. preparation method according to claim 4, is characterized in that, 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.
6. preparation method according to claim 4, is characterized in that, solvent temperature described in step a) is 35 ℃～40 ℃.
7. preparation method according to claim 4, is characterized in that, 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.
8. preparation method according to claim 4, is characterized in that, return time described in step b) is 3 hours～5 hours.
9. the application of the described hydrochloric acid conivaptan of claim 1 new crystal in the medicine for the preparation of the treatment hyponatremia.
10. application according to claim 9, is characterized in that, described hyponatremia is normal blood volume hyponatremia and heavy body hyponatremia.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153168A (en) * | 2015-09-29 | 2015-12-16 | 上海天慈国际药业有限公司 | Preparation method of N-[4-(2-methyl-4,5-dihydro-3H-imidazo [4,5-d] [1] benzazepin-6-formyl) phenyl]-2-phenylbenzamide hydrochloride |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1040210C (en) * | 1993-07-21 | 1998-10-14 | 山之内制药株式会社 | Fused benzazepine derivative and pharmaceutical composition containing the same |
| JP2001002678A (en) * | 1999-06-17 | 2001-01-09 | Yamanouchi Pharmaceut Co Ltd | Crystal of condensed benzazepine derivative |
| JP2002087962A (en) * | 2000-09-12 | 2002-03-27 | Yamanouchi Pharmaceut Co Ltd | Readily water-soluble and stable composition |
-
2013
- 2013-10-21 CN CN201310495851.3A patent/CN103497195B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1040210C (en) * | 1993-07-21 | 1998-10-14 | 山之内制药株式会社 | Fused benzazepine derivative and pharmaceutical composition containing the same |
| JP2001002678A (en) * | 1999-06-17 | 2001-01-09 | Yamanouchi Pharmaceut Co Ltd | Crystal of condensed benzazepine derivative |
| JP2002087962A (en) * | 2000-09-12 | 2002-03-27 | Yamanouchi Pharmaceut Co Ltd | Readily water-soluble and stable composition |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153168A (en) * | 2015-09-29 | 2015-12-16 | 上海天慈国际药业有限公司 | Preparation method of N-[4-(2-methyl-4,5-dihydro-3H-imidazo [4,5-d] [1] benzazepin-6-formyl) phenyl]-2-phenylbenzamide hydrochloride |
| 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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