CN108069945A - A kind of Alfuzosin novel crystal forms - Google Patents
A kind of Alfuzosin novel crystal forms Download PDFInfo
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- CN108069945A CN108069945A CN201711496428.XA CN201711496428A CN108069945A CN 108069945 A CN108069945 A CN 108069945A CN 201711496428 A CN201711496428 A CN 201711496428A CN 108069945 A CN108069945 A CN 108069945A
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- alfuzosin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of Alfuzosin novel crystal forms, belong to bulk pharmaceutical chemicals preparing technical field.The technical scheme is that：A kind of Alfuzosin novel crystal forms, X-ray powder diffraction have for 7.78,9.68,10.14,12.40,13.58,16.29,16.78,18.24,19.52,20.63,22.65,25.19,26.82,27.16 positions compared with strong absworption peak in 2 θ.The present invention provides a kind of Alfuzosin novel crystal forms with fine solubility and stabilization, for the bulk pharmaceutical chemicals that have provided of preparation of Alfuzosin preparation.
Description
Technical field
The present invention relates to a kind of Alfuzosin novel crystal forms, belong to bulk pharmaceutical chemicals preparing technical field.
Background technology
Hyperplasia of prostate（hyperplasia of prostate）, it is commonly referred to as benign prostatic hyperplasis（benign
Prostatic hyperplasia, BPH）It is one of middle-aging male common disease, it is cumulative with population in the world astogeny onset of illness
It is more.The incidence of hyperplasia of prostate is incremented by with the age, and with advancing age, the symptoms such as dysuria increase most of patients therewith
Add.
Hypertrophy of the prostate is also known as hyperplasia of prostate.Symptom is mainly shown as two groups of symptoms, and one kind is irritation sign of bladder;Separately
One kind is the obstructive symptoms generated by hyperplasia forefront adenemphraxis urinary tract.Irritation sign of bladder：Frequent micturition, urgent urination, enuresis nocturna increase and
Urge incontinence.Frequent micturition is the early signal of hyperplasia of prostate, and especially enuresis nocturna number, which increases, more clinical meaning.The disease has three
A main feature：Prostate volume increases;Bladder outlet obstruction;There are the lower urinary tract symptoms such as dysuria, frequent micturition, urgent urination.
Alfuzosin hydrochloride, chemical name：N- [3- [(4- amino -6,7- dimethoxy -2- quinazolyls)-methylamino]
Propyl] tetrahydrochysene -2- furoyl amine hydrochlorates.For treating benign prostatic hyperplasis illness.2.5mg specification.
It is found in the research process of Alfuzosin ordinary tablet, Alfuzosin belongs to small dimension preparation, and ordinary tablet is being made
In standby process, first, uniformity of dosage units is not easy up to standard, second is that after long-term storage, slice, thin piece moisture absorption is serious, while related substance
Rise protrudes, and influences the safely, effectively property of tablet.Further study show that existing Alfuzosin raw material is easy to moisture absorption, moisture absorption
Related substance rise afterwards.
The content of the invention
The object of the present invention is to provide a kind of stabilization, the Alfuzosin novel crystal forms with resistance to moisture pick-up properties.
Technical solution：
The technical scheme is that：
A kind of Alfuzosin novel crystal forms, the X-ray powder diffraction of the crystal form are 7.78,9.68,10.14,12.40 in 2 θ,
13.58,16.29,16.78,18.24,19.52,20.63,22.65,25.19,26.82,27.16 positions have compared with strong absworption peak.
The preparation method of crystal form of the present invention, prepares according to the following steps：
Alfuzosin crude product is dissolved in the ethyl alcohol of 50-60% by the first step；
The preferred technical solution of this step, the concentration of prepared solution is 18-26%（Quality percent by volume）.
Second step at room temperature, first step Alfuzosin crude product amount 7-10% is added in into first step solution（Weight percent）
Activated carbon, stirring 1-1.5 it is small when, filtering；
Under the stirring of 3rd step, second step filtrate is cooled to -10 to -3 DEG C and is kept, ethanol-acetone is slowly added dropwise thereto and mixes
Bonding solvent, the volume that mixed solvent is added dropwise is the 60-100% of first step solvent volume；Fast cooling has white to -14 to -18 DEG C
Color solid be precipitated, continue stir 3-6 it is small when；
The preferred technical solution of this step, the speed that ethanol-acetone mixed solvent is added dropwise are 0.80-1.6ml/ minutes.
The preferred technical solution of this step, mixing speed are 160-200 revs/min.
The volume ratio of both the preferred technical solution of this step, ethanol-acetone in the mixed solvent is 1:（0.5-1.0）.
4th step filters, and filter cake is washed with the 3rd step ethanol-acetone mixed solvent, and filter cake is spread out, 35 DEG C of vacuum drying.
The preferred technical solution of this step, filter cake are washed 3 times with ethanol-acetone mixed solvent, and each dosage is the first step
The 8-10% of quantity of solvent.
Illustrate the X-ray diffractogram of Fig. 1 Alfuzosin novel crystal forms of the present invention.
Useful achievement：The present invention provides a kind of Alfuzosin novel crystal forms with fine solubility and stabilization, are Ah husband
The bulk pharmaceutical chemicals that the preparation of azoles piperazine preparation has provided.And crystal form of the present invention, there is very strong moisture resistant ability.
Crystal form prepared by preparation method of the present invention has good granularity and mobility, without crushing and can sieve,
It is directly used in the preparation of preparation.Avoid loss of material and the related substance liter caused by mechanical impact caused by crushing
It is high.
Embodiment：The embodiment of the present invention is prepared with Alfuzosin crude product by the prior art, its is pure for high performance liquid chromatography detection
It spends for 92.89%.
Embodiment 1,
18g Alfuzosin crude products are dissolved in the ethanol water of 100ml 50% by the first step；
Second step at room temperature, 1.26g activated carbons is added in into first step solution, when stirring 1 is small, filtering；
Under the stirring of 3rd step, second step filtrate is cooled to -10 DEG C and is kept, 60ml ethanol-acetones are slowly added dropwise thereto and mix
The speed of ethanol-acetone mixed solvent was added dropwise as 0.80ml/ minutes in bonding solvent, and fast cooling has white solid analysis to -14 DEG C
Go out, continue stirring 3 it is small when, mixing speed be 160 revs/min；In mixed dissolution, the body of both ethanol-acetone in the mixed solvents
Product is than being 1:0.5；
4th step filters, and filter cake ethanol-acetone mixed solvent described in the 3rd step that temperature is -14 DEG C washs three times, uses every time
8ml, filter cake are spread out, 40 DEG C of vacuum drying.
The X-ray powder diffraction figure of the present embodiment product is shown in attached drawing 1, and high performance liquid chromatography detection purity is 99.96%, is received
Rate is that 92.64%, D90 is 91.2 microns.
Embodiment 2,
26g Alfuzosin crude products are dissolved in the ethanol water of 100ml 60% by the first step；
Second step at room temperature, 2.6g activated carbons is added in into first step solution, when stirring 1.5 is small, filtering；
Under the stirring of 3rd step, second step filtrate is cooled to -3 DEG C and is kept, 100ml ethanol-acetones are slowly added dropwise thereto and mix
The speed of ethanol-acetone mixed solvent was added dropwise as 1.6ml/ minutes in bonding solvent, and fast cooling has white solid analysis to -18 DEG C
Go out, continue stirring 6 it is small when, mixing speed be 200 revs/min；In mixed dissolution, the body of both ethanol-acetone in the mixed solvents
Product is than being 1:1.0.
4th step filters, and filter cake ethanol-acetone mixed solvent described in the 3rd step that temperature is -18 DEG C washs three times, often
Secondary dosage 10ml, filter cake are spread out, 35 DEG C of vacuum drying.
The X-ray powder diffraction figure of the present embodiment product is shown in attached drawing 1, and high performance liquid chromatography detection purity is 99.98%, is received
Rate is that 92.18%, D90 is 68 microns.
Embodiment 3,
24g Alfuzosin crude products are dissolved in the ethyl alcohol of 100ml 55% by the first step；
Second step at room temperature, 2.16g activated carbons is added in into first step solution, when stirring 1.2 is small, filtering；
Under the stirring of 3rd step, second step filtrate is cooled to -5 and is kept, the mixing of 85ml ethanol-acetones is slowly added dropwise thereto
The speed of ethanol-acetone mixed solvent was added dropwise as 1.3ml/ minutes in solvent, and fast cooling has white solid precipitation to -16 DEG C,
Continue stirring 4.5 it is small when, mixing speed be 180 revs/min；The volume ratio of both ethanol-acetone in the mixed solvents is 1:
0.8。
4th step filters, and filter cake ethanol-acetone mixed solvent described in the 3rd step that temperature is -16 DEG C washs three times, often
Secondary dosage 9ml, filter cake are spread out, 35 DEG C of vacuum drying.
The X-ray powder diffraction figure of the present embodiment product is shown in attached drawing 1, and high performance liquid chromatography detection purity is 99.99%, is received
Rate is that 92.92%, D90 is 28 microns.
Reference examples 1, Alfuzosin crude product, are dissolved repeatedly with 55% ethyl alcohol, filtering, until obtained powder high-efficient liquid phase color
Spectrum detection purity is 99.99%.
Embodiment 4 prepares Alfuzosin tablet with embodiment 1-3 and 1 product of reference examples by marumerization preparation method.
Prescription Alfuzosin 2.5g, lactose 32g, sodium carboxymethyl starch 14g, microcrystalline cellulose 40g, calcium citrate 15g,
Macrogol 4000 6g, magnesium stearate 1.5g prepare 1000 by following preparation methods
First step Alfuzosin crosses 80 mesh sieves, other auxiliary materials cross 60 mesh sieves respectively；
Second step weighs the Alfuzosin of the first step sieving of recipe quantity, the calcium citrate mixing with recipe quantity；Again with recipe quantity
Lactose, sodium carboxymethyl starch, polyethylene glycol, microcrystalline cellulose, mixing, by the use of 45% ethyl alcohol as wetting agent, 40 DEG C of vacuum are done
It is dry, cross 60 mesh sieves.
Particle prepared by 3rd step second step adds in the magnesium stearate of recipe quantity, tabletting.
Test example 1 uses 4 product of embodiment respectively, each 100, aluminum-plastic packaged, is placed in climatic chamber, 30 DEG C, relatively
Humidity 75% is stored 12 months, is taken out, is measured related substance respectively（High performance liquid chromatography）And dissolution rate.Measure situation records
In table 1.
Test example 1, respectively Example 1-3 and each 100 of reference examples 1-3 products, it is aluminum-plastic packaged, it is placed in climatic chamber
In, 30 DEG C, relative humidity 75% is stored 12 months, is taken out, and observes slice, thin piece appearance, and complete slice, thin piece is taken to measure related substance（It is high
Effect liquid phase chromatogram method）Degree.Measure situation is recorded in table 1.
Table 1
1 data explanation of table：Product of the embodiment of the present invention is stable during storage, and slice, thin piece appearance and related substance are almost
Do not change；And the related substance of reference examples product is raised, and tablet has different degrees of hygroscopic effect, than if any point
Or become loose, it is apparent to illustrate that technical solution of the present invention has played the stabilization of tablet.It is various in technical solution of the present invention
The reasonable compatibility of ingredient and and preparation method combination, very prominent effect is played for the stabilization of tablet, for clinic
Provide a kind of composition of safety and stability.
Test example 2 distinguishes Example 1-3 and each 100g of 1 product of reference examples, is placed in open culture dish, then is placed in
In climatic chamber, 30 DEG C, relative humidity 75% is stored 3 months, is taken out, and is weighed and is measured related content of material.Data record
In table 2.
2 data of table illustrate that crystal form has good anti-moisture absorption property obtained by the embodiment of the present invention.
Claims (8)
1. a kind of Alfuzosin novel crystal forms, which is characterized in that the X-ray powder diffraction of the crystal form is 7.78,9.68 in 2 θ,
10.14,12.40,13.58,16.29,16.78,18.24,19.52,20.63,22.65,25.19,26.82,27.16 positions have
Compared with strong absworption peak.
2. the preparation method of Alfuzosin novel crystal forms described in claim 1, which is characterized in that prepare according to the following steps：
Alfuzosin crude product is dissolved in the ethyl alcohol of 50-60% by the first step；
Second step at room temperature, first step Alfuzosin crude product amount 7-10% is added in into first step solution（Weight percent）Work
Property charcoal, stirring 1-1.5 it is small when, filtering；
Under the stirring of 3rd step, second step filtrate is cooled to -10 to -3 DEG C and is kept, ethanol-acetone is slowly added dropwise thereto and mixes
Bonding solvent, the volume that mixed solvent is added dropwise is the 60-100% of first step solvent volume；Fast cooling has white to -14 to -18 DEG C
Color solid be precipitated, continue stir 3-6 it is small when；
4th step filters, and filter cake is washed with the 3rd step ethanol-acetone mixed solvent, and filter cake is spread out, 35 DEG C of vacuum drying.
3. according to the preparation method of Alfuzosin novel crystal forms described in claim 2, which is characterized in that solution prepared by the first step
Quality concentration of volume percent is 18-26%.
4. according to the preparation method of Alfuzosin novel crystal forms described in claim 2, which is characterized in that ethyl alcohol-the third is added dropwise in the 3rd step
The speed of ketone mixed solvent is 0.80-1.6ml/ minutes.
5. according to the preparation method of Alfuzosin novel crystal forms described in claim 2, which is characterized in that the 3rd step mixing speed is
160-200 revs/min.
6. according to the preparation method of Alfuzosin novel crystal forms described in claim 2, which is characterized in that the 3rd step ethanol-acetone mixes
Volume ratio both in bonding solvent is 1:（0.5-1.0）.
7. a kind of composition containing crystal form described in claim 1, which is characterized in that in the composition of unit dose, contain Ah
Husband's azoles piperazine 2.5mg, lactose 32mg, sodium carboxymethyl starch 14mg, microcrystalline cellulose 40mg, calcium citrate 15mg, polyethylene glycol
4000 6mg, magnesium stearate 1.5mg.
8. the preparation method of composition described in claim 7, which is characterized in that prepared by following preparation methods：
First step auxiliary material crosses 60 mesh sieves respectively；
Second step weighs the Alfuzosin of the first step sieving of recipe quantity, the calcium citrate mixing with recipe quantity；Again with recipe quantity
Lactose, sodium carboxymethyl starch, polyethylene glycol, microcrystalline cellulose, mixing, by the use of 45% ethyl alcohol as wetting agent, 40 DEG C of vacuum are done
It is dry, cross 60 mesh sieves；
Particle prepared by 3rd step second step adds in the magnesium stearate of recipe quantity, tabletting.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201711496428.XA CN108069945A (en) | 2017-12-31 | 2017-12-31 | A kind of Alfuzosin novel crystal forms |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711496428.XA CN108069945A (en) | 2017-12-31 | 2017-12-31 | A kind of Alfuzosin novel crystal forms |
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| CN201711496428.XA Withdrawn CN108069945A (en) | 2017-12-31 | 2017-12-31 | A kind of Alfuzosin novel crystal forms |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107987043A (en) * | 2018-02-27 | 2018-05-04 | 威海贯标信息科技有限公司 | A kind of mycophenolate mofetil novel crystal forms |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1634066A (en) * | 2004-08-30 | 2005-07-06 | 鲁南制药股份有限公司 | Dispersible tablet of alfuzosin hydrochloride |
| WO2006090268A2 (en) * | 2005-02-28 | 2006-08-31 | Glenmark Pharmaceuticals Limited | Processes for the preparation of alfuzosin and salts thereof and novel crystalline forms of alfuzosin |
| US20070100143A1 (en) * | 2004-09-16 | 2007-05-03 | Hetero Drugs Limited | Crystalline alfuzosin base |
| CN107998090A (en) * | 2017-12-30 | 2018-05-08 | 威海贯标信息科技有限公司 | A kind of Alfuzosin tablet composition |
-
2017
- 2017-12-31 CN CN201711496428.XA patent/CN108069945A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1634066A (en) * | 2004-08-30 | 2005-07-06 | 鲁南制药股份有限公司 | Dispersible tablet of alfuzosin hydrochloride |
| US20070100143A1 (en) * | 2004-09-16 | 2007-05-03 | Hetero Drugs Limited | Crystalline alfuzosin base |
| WO2006090268A2 (en) * | 2005-02-28 | 2006-08-31 | Glenmark Pharmaceuticals Limited | Processes for the preparation of alfuzosin and salts thereof and novel crystalline forms of alfuzosin |
| CN107998090A (en) * | 2017-12-30 | 2018-05-08 | 威海贯标信息科技有限公司 | A kind of Alfuzosin tablet composition |
Non-Patent Citations (1)
| Title |
|---|
| 陈霰等: "盐酸阿夫唑嗪的改进合成方法", 《精细化工》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107987043A (en) * | 2018-02-27 | 2018-05-04 | 威海贯标信息科技有限公司 | A kind of mycophenolate mofetil novel crystal forms |
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