TW533203B - New crystalline form of omeprazole - Google Patents
New crystalline form of omeprazole Download PDFInfo
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- TW533203B TW533203B TW087120725A TW87120725A TW533203B TW 533203 B TW533203 B TW 533203B TW 087120725 A TW087120725 A TW 087120725A TW 87120725 A TW87120725 A TW 87120725A TW 533203 B TW533203 B TW 533203B
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- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 title claims abstract description 89
- 229960000381 omeprazole Drugs 0.000 title claims abstract description 86
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 208000018522 Gastrointestinal disease Diseases 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 101000870363 Oryctolagus cuniculus Glutathione S-transferase Yc Proteins 0.000 claims description 2
- 238000011282 treatment Methods 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- -1 4-fluorenoxy-3, 5-diamidino-2-pyridyl Chemical group 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- SAOHCOFTVLEOCB-UHFFFAOYSA-K tris(2,4,6-tribromophenoxy)bismuthane Chemical compound [Bi+3].[O-]C1=C(Br)C=C(Br)C=C1Br.[O-]C1=C(Br)C=C(Br)C=C1Br.[O-]C1=C(Br)C=C(Br)C=C1Br SAOHCOFTVLEOCB-UHFFFAOYSA-K 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 3
- 210000004211 gastric acid Anatomy 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 2
- 238000004279 X-ray Guinier Methods 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 210000003296 saliva Anatomy 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- DSPHFASHOJAOKN-UHFFFAOYSA-N 1-[(7-oxobenzo[a]phenalen-2-yl)amino]anthracene-9,10-dione Chemical compound C1=CC2=CC(NC3=C4C(=O)C5=CC=CC=C5C(C4=CC=C3)=O)=CC(C=3C(=CC=CC=3)C3=O)=C2C3=C1 DSPHFASHOJAOKN-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010019375 Helicobacter infections Diseases 0.000 description 1
- 206010035148 Plague Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 238000001237 Raman spectrum Methods 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002325 prokinetic agent Substances 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
533203 五、發明說明α) 發明範圍 本發明係關於5-曱氧基-2-[[(4-曱氧基-3, 5 -二曱基-2-吡啶基）曱基]亞磺醯基]-11 -苯并咪4之新穎結晶形式。 5-曱氧基-2-[[(4-曱氧基-3, 5-二曱基-2-吡啶基）曱基]亞 磺醯基]-lg-苯并咪唑之屬名稱之為奥美普拉唑，其新穎 結晶形式此後稱為奥美普拉峻形式A。此外，本發明尚關 於奥美普拉唑形式A在胃腸疾病治療上的用途，含奥美普 拉唑形式A的醫藥組合物及奥美普拉唑形式A的製備方法。 發明背景及前此技藝
化合物5-曱氧基-2-[[(4-曱氧基-3 ,5 -二甲基-2 -吡啶 基）曱基]亞磺醯基]-1H-苯并咪唑，其屬名為奥美普拉 唑，以及其治療上可接受的鹽於EP 5 1 2 9内敘述過。到目 前為止所知的奥美普拉唑之結晶形式之單晶體X光數據及 衍生的分子構造曾被Ohishi等於Acta Cryst. (1989)， C45， 1 92 1 - 1 9 23敘述過。此以公佈的奥美普拉唑的結晶形 式此後稱為奥美普拉唑B。
奥美普拉唾是質子泵抑制劑，即可有效地抑制胃酸分 泌，可用作抗潰瘍劑。從更普遍的意義說，奥美普拉唑可 用於哺乳動物，特別是人，的與胃酸有關的疾病的治療 圖解簡述 圖1為奧美普拉唑形式A之X光粉衍射圖。 圖2為奥美普拉唑形式B之X光粉衍射圖。 本發明說明 現已令人驚奇地發現，此奥美普拉唑物質可以一種以上
第5頁 533203 五、發明說明（2) ------ 的晶體形式存在。本發明目的在提供一種奥美普拉唑形 A。本發明另一目的提供實質上無其他奥美普拉唑之奥〃美" 普拉唑形式A之製法。用X光粉衍射（fRpD)作為區別奥^美並 拉峻形式A與其他結晶的或不結晶的奥美普拉唾的方法。 此外，本發明目的還在提供含奥美普拉唑形式A的醫藥調 配物。 >'。 奥美普拉峻形式Α是結晶形式，展現優良性質，如清楚 地分辨出來’較奥美普拉唑形式B更具熱動力安定性^較 少吸濕性，尤以在室溫下為然。奥美普拉唑形式A較奥^ 普拉唑形式B也展現較佳化學安定性，如熱安定性及光安 定性。 奥美普拉唑形式B在特定條件下可完全或部分轉化成奥 美普拉嗤形式A。奥美晋拉唾形式A與奥美普拉峻形式b相 比，其特點是更具熱動力安定性。 奥美普拉唑形式A的另一特點是實質上無吸濕性的。 奥美，曰拉17坐形式A的特點可措X光粉衍射圖上的位置及強 動以及單位晶胞參數找出。單位晶胞向量曾以精確 Guinier數據計算出。與奥美普拉唾形式b與奥美普拉唑形 式A之X光粉衍射圖數據及單位晶胞參數都不同於奥美普拉 σ坐形式A。疋以可用X光粉衍射區別奥美普拉σ坐形式A斑奧 美普拉唑形式B。 根據本發明，奥美普拉X7坐形式A之特點在提供如圖1所示 之X光粉衍射型，展現出如下的d值及強度：
533203 五、發明說明（3) 形式A 形式A — d-値 相對 d-値 相對 〇 (A) 強度 (A) 強度 9.5 VS 3.71 s 7.9 S 3.59 m 7.4 W 3.48 m 7.2 VS 3.45 s 6.0 m j.j 1 w 5.6 S 3.22 ' s 5.2 S 3.17 m ‘ 5.1 S 3.11 w 4.89 W 3.04 w 4.64 m 3.00 w 4.60 m 2.91 w 4.53 w 2.86 w 4.49 m 2.85 w 4.31 m 2.75 w 4.19 w 2.67 w 4.15 w 2.45 w 3.95 w 2.41 w _圓_1 533203 五、發明說明（4) 以由Bragg公式及強度計算出的d-值所確證的此等峰係 取自奥美普拉σ坐形式A之Guinier衍射圖。相對強度較不可 靠，是以用下述定義代替各值： — %相對強度* 定義 2 5- 1 0 0 vs(很強） 10-25 s(強） 3-10 m(中等） 1-3 w (弱） *相對強度是用固定縫測出的衍射圖導出。
本發明奥美普拉唑形式A以三斜單位晶胞用參數進一步 定性： a=10. 410(4)A b=10. 468(3)A c二9· 72 9 (4 )1 α 二 1 1 1 . 5 1 ( 3 )° /3 = 116.78(3)° r 二 9 0 · 7 7 ( 3 )。
奥美普拉ϋ坐形式A也可以R a m a n光譜定性，奥美普拉17坐形 式Α之特點在1 3 6 4公分時無光束，而此光束見於奧美普拉 唑形式B，並以8 42及8 3 6公分-1相對強度比值定性。奥美 普拉唑形式A之此比值（ 8 42公分-1光束強度/ 83 6公分-1光 束強度）小於1，而奥美普拉唑形式B之此比值大於1。 根據本發明還提供一種奥美普拉唑形式A的製法。 奥美普拉唑形式A可以緩慢結晶製得，而奥美普拉唑形
第8頁 533203 五、發明說明（5) 式B是以快速結晶製得。奥美普拉唑形式A可以任何形式的 奥美普拉唑或任何形式的奥美普拉唑混合物在非質子溶劑 例如曱醇内於約室溫作長時間結晶i重結晶製得。此長時 間的例包括，但不限於，數小時，例2小時，至達數週。 適宜的溶劑是烷基醇，特別是含1 -4個碳原子的低醇。 奥美普拉唑形式A也可用任何形式的奥美普拉唑或其任 何形式的混合物於室溫懸浮於適宜的溶劑較長時間製得。 適宜的溶劑的例包括，但不限於，曱醇，乙醇，丙酮，醋 酸乙酯，曱基第三-丁基醚，甲苯或其任何混合物。此長 時間的例包括，但不限於，數小時，例2小時，至達數 週。 根據本發明所製得的奥美普拉唑形式A是實質上無其他 晶體及非晶體形式的奥美普拉唾，如奥美普拉σ坐形式B。 實質上無其他形式的奥美普拉唑意為奥美普拉唑形式Α含 少於1 0 %，較佳是少於5 %，的其他形式的奥美普拉17坐，例 如奥美普拉唑形式B。 奥美普拉嗤形式A與其他固體形式的奥美普拉嗤，如奧 美普拉唑形式B，的混合物也展現有利性質，如較奥美普 拉唑形式B更有化學安定性。含特定量（重量比）奥美普拉 唑形式A的混合物較含少量（重量比）奥美普拉唑形式A的混 合物也更有化學安定性。此類含奥美普拉唑形式A的混合 物可以，例如，將根據本發明製備的奥美普拉唑形式A與 其他固以形式的奥美普拉唑，例如以前此技藝方法製備的 奥美普拉唑形式B，混合製備。
第9頁 533203 五、發明說明（7) 化合物可用於治療牛皮癖以及幽門螺旋菌（Helicobacter) 感染及與此有關的疾病的治療。本發明化合物也可用於哺 乳動物，包括人，感染性疾病的治#。 給予病人有效劑量的本發明奥美普拉嗤形式A可經由任 何適宜的途徑給予。例如可使用經口或非經腸調配物。劑 形包括膠囊，錠，分散液，懸浮液等，例如腸塗覆的膠囊 及/或錠，膠囊及/或含奥美普拉唑腸塗覆小丸的錠。於所 有劑形中，奥美普拉唑形式A都可與其他適宜的成分混 合。 根據本發明，還提供一種醫藥組合物，其含有奥美普拉 唑形式A作為活性成分，以及醫藥上可接受的載劑，稀釋 劑，或賦形劑，及視需要用的其他成分。含其他製療成分 的組合物特別有益於治療H e 1 i c 〇 b a c t e r感染。本發明還提 供奥美普拉唑形式A在製造藥物以用於治療與胃酸有關的 疾病上的用途，及治療與胃酸有關的疾病的方法，此發包 括給予患該疾病的病人治療有效量的奥美普拉峻形式A。 本發明組合物包括適於經口或非經腸給予的組合物。此 等組合物可製成習用的單位劑形，並可以已知的製藥技術 製備。 ， 在實行本發明時，最宜的給予途徑及奥美普拉唑形式A 劑量的大小需視要治的疾病的性質及嚴重性而定。劑量及 投藥頻率也因個別病人的年齡，體重，及反應而定。有 Z〇1 1 i n g e r - E 1 1 i s ο η徵候群的病人可能有特別需要，例如 較一般病人的劑量為高。孩童及有肝病的病人以及長期治
533203 五、發明說明（8) 療的病人以較一般劑量為低為宜。是以，在某些情形下， 而用下述β塁範圍之外的劑量。此等較高及較低劑量仍包 括在本發明範圍内。 一 曰一般而言，經口劑形可包括5毫克至25〇毫克總每天劑 量，可以單一劑量或均分成數劑量給予。較佳的劑量是1 〇 宅克至8 0毫克。 本發明化合物可作為活性成分與醫藥上的載劑以習用技 術混合，如W0 9 6/0 1 6 23及ΕΡ 24 7 9 83所述之調配物，今 一併附上供參考。 也可用合併治療，其包括奥美普拉唑形式Α及其他活性 成分’可以獨立劑形或一個固定劑形使用。此種活性成勿 的例包括抗菌化合物，非類固醇抗炎劑，抗酸劑’藻酸^ 及親動力劑（prokinetic agents)。 >· 下述實例進一步說明本發明化合物，即奥美普拉 & ，十， A的製備，但並非限制前述或下面申請專利範圍戶斤t 明範圍。 實例 實例j
奥美普拉唾形式A之製備 p H 將奥美普拉唑（55. 8克）加於含氨（1.3毫升；25%)之a +，然夜 (3 4 8晕升）内。然後將懸浮液於暗處授掉近4 5小时 表 過濾。濾過物於3 0 °C在減壓（< 5毫巴）下乾燥1 8小時° 出：43· 9克。 實例2 - " —-— >
第12頁 533203
五、發明說明（9) 奥美普拉唑形式B之製備 將奥美普拉唑（50克）於50 °C加於含氨（〇· 7亳升；25%) 甲醇（7 50毫升）内。然後將溶液過濾'在約20分鐘肉J ( 里N冷至〇 它。過濾生成之結晶，用冰冷的甲醇洗，然後乾焊。 /、 〉慮過 物於40 °C在減壓（<5毫巴）下乾燥24小時。產出：39克。 實例3 使用X光粉衍射作奥美普拉唑形式A及奥美普拉唑形式B定 性
X光衍射分析是根據標準方法完成，此法見，例如， Bunn, C. W. (1948), Chemical Crystallography, Clarendon Press, London ；或Klug, Η. P. &
Alexander, L. E. (1974), X-Ray Diffraction Procedures, John Wiley and Sons, New York 。奥美普 拉唑形式A及形式B的單位晶胞參數用” TRE0Rn程式，by Werner, P. -E., Eriksson, L. and Westdahl, M., J.
Appl· Crystallogr· 1 8 ( 1 985 ) 3 6 7-3 70 所作的 X-光粉衍
射圖計算。奥美普拉唑形式A及形式b於衍射圖上的位置及 峰可分別用單位晶胞參數計算出的事實，證明單位晶胞是 正確的，衍射圖也顯示為純形式。圖1顯示根據本發g月實 例1所製的奥美普拉唑形式A之衍射圖，圖2顯示根據本發 明實例2所製的奥美普拉唑形式b之衍射圖。 以Bragg公式及強度計算出的d—值證實的峰係取自奥美 普拉咬形式A及形式B的衍射圖，見表1。於此表中，也列 出奥美普拉唑形式A及形式B的單位晶胞參數。相對強度較
第13頁 533203 五、發明說明（ίο) 不可靠，用如下的定義代替各值： %相對強度 定義 2 5- 1 0 0 vs(很強） 10-25 s (強） 3-10 m(中等） 1 w (弱） 表1中省略去衍射圖所發現的一些弱及視弱的峰。 表1.圖1及2所示之奥美普拉唾形式A及形式B的X光衍射 數據。奥美普拉唑形式A及形式B所示出的所有的峰可以下 述單位晶胞指示。
533203 五、發明說明（11) 形式A 形式B d-値 相對 d-値 相對 (A) 強度 〇 ㈧ 強度 9.5 VS 9.6 vs 7.9 S 8.0 m 7.4 W 7.9 m 7.2 VS 7.5 w 6.0 m 7.1 vs 5.6 S 5.9 m 5.2 S 5.6 m 5.1 S 5.3 s 4.89 W 5.1 s 4.64 m 4.54 m 4.60 m 4:48 s 4.53 w 4.41 m 4.49 m 4.14 w 4.31 m 3.75 s 4.19 w 3.57 m 4.15 w 3.47 s 3.95 w 3.40 w 3.71 s 3.28 s 3.59 m 3.22 m 3.48 m 3.02 w 3.45 s 2.97 w
mm 第15頁 533203 五、發明說明（12)
形式A 形式B d-値 相對 d-値 相對 0 ㈧ 強度 (A) 強度 1 W 2.87 W 3.22 S 2.37 W 3.17 m 3.11 W 3.04 W 3.00 W — 2.91 W 2.86 W 2.85 W 2.75 W 2.67 W 2.45 W 2.41 W 三斜單位晶胞是：
單位晶胞形式A 單位晶胞形式B 画_11 第16頁 533203 五、發明說明（13) a二 10. 410 ⑷又 b二1 0. 4 68 ( 3 )1 c-9. 729(4)A α 二 111. 51(3)° /3 二 1 1 6 . 7 8 ( 3 )。 r =90. 77 ( 3 )σ a-10. 257(10)1 b-10. 717(6)1 c-9. 694(10)1 α 二1 12. 14(7V 二 1 1 5 · 5 6 ( 5 )° r -91. 76(7)°
I 第17頁
Claims (1)
- 533203V；： i ： . i ； -1-:. —、. i -；·： "： .—年3月 日 修正_ 六、申請專利範圍 1 . 一種奥美普拉唑形式A，其特徵在於室溫下為熱動力 安定的且提供實質上展現如下d-值之X光粉繞射型： 形式A 形式A —— -.- (HI 相對 d-値 相對 (A) 強度 (A) 強度 9.5 vs 3.71 s 7.9 s 3.59 m 7.4 Wr 3.48 · m 7.2 vs 3.45 s 6.0 m 3.31 w 5.6 s 3.22 s 5.2 s 3,17 , m 5.1 s 3.11 , w 4.89 w 3.04 w 4·64 m 3.00 w 4.60 m 2.91 w 4.53 w / 2.86 w 4.49 應 m 2.85 w 4.31 m 2.75 w 4.19 w 2.67 w 4.15 w 2.45 w 3.95 w 2.41 wO:\55\55995-920311.ptc 第19頁 533203 _案號 87120725_年 3 月 曰__ 六、申請專利範圍 2 .根據申請專利範圍第1項之奥美普拉唑形式A，其特徵 在有如下的三斜單位晶胞參數： a-10. 410(4) A,b=10.468(3) A,c-9.729(4) A, α 二 111. 51(3)° ，/5 = 116.78(3)° ，” 9 0.7 7 ( 3 )。。 3 . —種製備根據申請專利範圍第1或2項之奥美普拉唑形 式A的方法，其包括的步驟是： a )於1 5 - 2 5 °C將任何形式的或任何形式混合物的奥美 普拉唑溶於或懸浮於適宜的溶劑内； b )任此溶液結晶至少2小時使用奥美普拉唑形式A引起 結晶，及 c )分離這樣製得的奥美普拉唑形式A。 4 .根據申請專利範圍第3項之方法，其特徵在於步驟a ) 所用的溶劑是選自包括甲醇，乙醇，丙酮，醋酸乙酯，甲 基第三-丁基醚，甲苯或其任何混合物。 5 .根據申請專利範圍第3或4項之方法，其中步驟b )係使 用奥美普拉唑形式A引起結晶而進行。 6 . —種根據申請專利範圍第1項之奧美普拉唑形式A，其 係以申請專利範圍第3至5項中任一項之方法所製備。 7. —種用於治療胃腸疾病的醫藥組合物，其包括治療有 效量的根據申請專利範圍第1或2項之奥美普拉唑形式A。O:\55\55995-920311.ptc 第20頁
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| PCT/SE1998/002028 WO1999008500A2 (en) | 1998-11-10 | 1998-11-10 | New crystalline form of omeprazole |
| BR9816067-2A BR9816067A (pt) | 1998-11-10 | 1998-11-10 | Forma a de omeprazol, omeprazol, processo para a preparação da forma a de omeprazol, formulação farmacêutica, uso de omeprazol, e, método de tratamento de distúrbios gastrointestinais. |
| CA002363810A CA2363810A1 (en) | 1998-11-10 | 1998-11-10 | New form of omeprazole |
| DE29823393U DE29823393U1 (de) | 1998-11-10 | 1998-11-10 | Neue kristalline Form von Omeprazol |
| EP98957255A EP0969819B1 (en) | 1998-11-10 | 1998-11-10 | New crystalline form of omeprazole |
| US10/076,225 US20020156284A1 (en) | 1998-11-10 | 2002-02-13 | Crystalline form of omeprazole |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE7804231L (sv) * | 1978-04-14 | 1979-10-15 | Haessle Ab | Magsyrasekretionsmedel |
| SE8301182D0 (sv) | 1983-03-04 | 1983-03-04 | Haessle Ab | Novel compounds |
| SE9002043D0 (sv) * | 1990-06-07 | 1990-06-07 | Astra Ab | Improved method for synthesis |
| ES2078447T3 (es) | 1990-06-15 | 1995-12-16 | Merck & Co Inc | Un procedimiento de cristalizacion para mejorar la estructura y el tamaño de los cristales. |
| US5877192A (en) * | 1993-05-28 | 1999-03-02 | Astra Aktiebolag | Method for the treatment of gastric acid-related diseases and production of medication using (-) enantiomer of omeprazole |
| SE9302396D0 (sv) * | 1993-07-09 | 1993-07-09 | Ab Astra | A novel compound form |
| SE9302395D0 (sv) * | 1993-07-09 | 1993-07-09 | Ab Astra | New pharmaceutical formulation |
| WO1995018612A1 (en) * | 1994-01-05 | 1995-07-13 | Aktiebolaget Astra | A method for treatment of psoriasis, by omeprazole or related compounds |
| US5856493A (en) * | 1995-02-06 | 1999-01-05 | Smithkline Beecham Corporation | Process for making novel form of paroxeting hydrochloride anhydrate |
| SE521100C2 (sv) * | 1995-12-15 | 2003-09-30 | Astra Ab | Förfarande för framställning av en bensimidazolförening |
| TW385306B (en) | 1996-11-14 | 2000-03-21 | Takeda Chemical Industries Ltd | Method for producing crystals of benzimidazole derivatives |
| SE510666C2 (sv) * | 1996-12-20 | 1999-06-14 | Astra Ab | Nya Kristallmodifikationer |
| SE9704183D0 (sv) | 1997-11-14 | 1997-11-14 | Astra Ab | New process |
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