JP5658751B2 - 1−(β−D−グルコピラノシル)−4−メチル−3−[5−(4−フルオロフェニル)−2−チエニルメチル]ベンゼンのための結晶化方法 - Google Patents
1−(β−D−グルコピラノシル)−4−メチル−3−[5−(4−フルオロフェニル)−2−チエニルメチル]ベンゼンのための結晶化方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/04—Carbocyclic radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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Description
oscillation episode)及び少なくとも1つの機械的粒度縮小エピソード(particle size reduction episode)を含むと、狭い粒度分布を有する結晶性1−(β−D−グルコピラノシル)−4−メチル−3−[5−(4−フルオロフェニル)−2−チエニルメチル]ベンゼン半水和物(すなわち化合物(I))を得ることができることが見出された。そのようにして得られる結晶性化合物(I)は狭い粒度分布ならびに向上した流動性、嵩密度及びタップ密度性を有することが見出された。
●加熱前の出発温度
●加熱時間、加熱の速度及び温度/時間分布
●最高温度及びその持続時間(温度保持段階)
●冷却時間、冷却の速度及び温度/時間分布
●冷却後の最終的な温度。
solution)ことができる。振幅は、所望の溶解度の差に依存して5℃〜20℃の範囲であることができる。振幅は、各温度振動エピソードに関して同じか又は異なることができる。
a)化合物(I)が全部溶解し得る許す濃度及び温度条件下で、溶媒系中の化合物(I)の溶液を調製し;
b)該溶液を、溶液が準安定区域内にあるような温度に冷却し;
c)化合物(I)の溶液に化合物(I)の結晶を播種し;
d)化合物(I)の溶液を冷却して化合物(I)の結晶の懸濁液を得;
e)かくして形成される結晶懸濁液を、せん断機を用いる機械的粒度縮小に供し;
f)化合物(I)の結晶懸濁液を加熱して微粒子を溶解し;
g)段階d)、e)及びf)を1〜6回繰り返し;
h)化合物(I)の結晶懸濁液を室温もしくはそれより低温に冷却し;
i)かくして生成する化合物(I)の結晶を濾別する
連続段階を含んでなる結晶性化合物(I)の製造方法に関する。
●段階b):温度は52℃〜56℃の範囲、特に約54℃である
●段階c):約0.5%の量で化合物(I)の極微結晶を播種
●段階d):冷却は36℃〜40℃の温度、特に約38℃への立方温度分布に従う
●段階e):高せん断機を用いる湿式磨砕
●段階f):結晶性化合物(I)の懸濁液を52℃〜56℃の温度、特に約55℃に加熱する
●段階h):化合物(I)の結晶懸濁液を室温又はそれより低温、特に0℃に冷却する。
化合物(I)(1.59g)を播種し、混合物を2時間撹拌した。反応混合物を、下記の立方温度低下に従って冷ました:
●20分かけて52.4℃に
●20分かけて49.0℃に
●20分かけて44.4℃に
●20分かけて38℃に。
●25分かけて54.0℃に
●25分かけて52.4℃に
●25分かけて47.1℃に
●25分かけて38℃に。
●25分かけて54.0℃に
●25分かけて52.4℃に
●30分かけて41.4℃に
●105分かけて0℃に。
図1:4つの温度振動エピソード及び4つの機械的粒度縮小エピソードのグラフ図。
図2:温度振動及び湿式磨砕のグラフ図。
図3:古典的な冷却又は非−溶剤結晶化により得られる化合物(I)の粒度分布。
図4:実施例1に記載された温度振動及び高せん断機を用いる湿式磨砕を用いて得られる化合物(I)の粒度分布。
Claims (12)
- 溶媒系中の1−(β−D−グルコピラノシル)−4−メチル−3−[5−(4−フルオロフェニル)−2−チエニルメチル]ベンゼン半水和物の結晶懸濁液が少なくとも1つの加熱及び冷却サイクル並びに少なくとも1つの湿式磨砕による機械的粒度縮小のサイクルを受け、ここで該溶媒系が酢酸エチル、酢酸1−メチルエチル又はそれらの混合物から選ばれ、該溶媒系が0%から20%の水を含んでなる、1−(β−D−グルコピラノシル)−4−メチル−3−[5−(4−フルオロフェニル)−2−チエニルメチル]ベンゼン半水和物結晶の製造方法。
- 加熱及び冷却サイクルが加熱段階及び対応する冷却段階を含む請求項1に従う方法。
- 加熱段階が冷却段階に先行する請求項2に従う方法。
- 加熱及び冷却サイクルが湿式磨砕による機械的粒度縮小のサイクルに先行する請求項3に従う方法。
- 加熱及び冷却サイクル及び湿式磨砕による機械的粒度縮小のサイクルを互いに独立して繰り返す請求項3に従う方法。
- a)1−(β−D−グルコピラノシル)−4−メチル−3−[5−(4−フルオロフェニル)−2−チエニルメチル]ベンゼン半水和物が全部溶解し得る濃度及び温度条件下で、溶媒系中の1−(β−D−グルコピラノシル)−4−メチル−3−[5−(4−フルオロフェニル)−2−チエニルメチル]ベンゼン半水和物の溶液を調製し;
b)該溶液を、溶液が準安定区域内にあるような温度に冷却し;
c)1−(β−D−グルコピラノシル)−4−メチル−3−[5−(4−フルオロフェニル)−2−チエニルメチル]ベンゼン半水和物の溶液に1−(β−D−グルコピラノシル)−4−メチル−3−[5−(4−フルオロフェニル)−2−チエニルメチル]ベンゼン半水和物の結晶を播種し;
d)1−(β−D−グルコピラノシル)−4−メチル−3−[5−(4−フルオロフェニル)−2−チエニルメチル]ベンゼン半水和物の溶液を冷却して1−(β−D−グルコピラノシル)−4−メチル−3−[5−(4−フルオロフェニル)−2−チエニルメチル]ベンゼン半水和物の結晶の懸濁液を得;
e)かくして形成される結晶懸濁液を、せん断機を用いる機械的粒度縮小に供し;
f)1−(β−D−グルコピラノシル)−4−メチル−3−[5−(4−フルオロフェニル)−2−チエニルメチル]ベンゼン半水和物の結晶懸濁液を加熱して微粒子を溶解し;
g)段階d)、e)及びf)を1〜5回繰り返し;
h)1−(β−D−グルコピラノシル)−4−メチル−3−[5−(4−フルオロフェニル)−2−チエニルメチル]ベンゼン半水和物の結晶懸濁液を室温もしくはそれより低温に冷却し;
i)かくして生成する1−(β−D−グルコピラノシル)−4−メチル−3−[5−(4−フルオロフェニル)−2−チエニルメチル]ベンゼン半水和物の結晶を濾別する
連続段階を含んでなる請求項1の方法。 - 段階a)における溶媒系が0%から20%の水を含んでなる酢酸エチルである請求項6に従う方法。
- 段階a)における溶媒系が酢酸1−メチルエチル及び水の混合物である請求項6に従う方法。
- 段階b)における温度が54℃である請求項8に従う方法。
- 段階f)において1−(β−D−グルコピラノシル)−4−メチル−3−[5−(4−フルオロフェニル)−2−チエニルメチル]ベンゼン半水和物の結晶懸濁液を55℃に加熱する請求項9に従う方法。
- 段階d)、e)及びf)を1回繰り返す請求項10に従う方法。
- 段階h)において1−(β−D−グルコピラノシル)−4−メチル−3−[5−(4−フルオロフェニル)−2−チエニルメチル]ベンゼン半水和物の結晶懸濁液を0℃に冷却する請求項11に従う方法。
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EP09165125.7 | 2009-07-10 | ||
PCT/EP2010/059817 WO2011003976A1 (en) | 2009-07-10 | 2010-07-08 | CRYSTALLISATION PROCESS FOR 1-(ß-D-GLUCOPYRANOSYL)-4-METHYL-3-[5-(4-FLUOROPHENYL)-2-THIENYLMETHYL] BENZENE |
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EP2933255A1 (en) | 2014-04-17 | 2015-10-21 | LEK Pharmaceuticals d.d. | Novel crystalline form of 1-(beta-D-glucopyranosyl)-4- methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene |
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WO2011003976A1 (en) | 2011-01-13 |
AU2010270202A1 (en) | 2012-01-19 |
KR101532412B1 (ko) | 2015-06-29 |
CY1114404T1 (el) | 2016-08-31 |
EA022186B1 (ru) | 2015-11-30 |
SI2451797T1 (sl) | 2013-07-31 |
ES2416459T3 (es) | 2013-08-01 |
EP2451797B1 (en) | 2013-04-03 |
CN102482250B (zh) | 2014-11-19 |
US20120108824A1 (en) | 2012-05-03 |
AU2010270202B2 (en) | 2014-04-24 |
CN102482250A (zh) | 2012-05-30 |
KR20120046213A (ko) | 2012-05-09 |
PL2451797T3 (pl) | 2013-08-30 |
PT2451797E (pt) | 2013-06-25 |
DK2451797T3 (da) | 2013-06-24 |
JP2012532845A (ja) | 2012-12-20 |
US8772512B2 (en) | 2014-07-08 |
HRP20130561T1 (en) | 2013-07-31 |
EA201270153A1 (ru) | 2012-05-30 |
CA2767258A1 (en) | 2011-01-13 |
CA2767258C (en) | 2016-09-13 |
EP2451797A1 (en) | 2012-05-16 |
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