TWI359128B - New crystalline form v of agomelatine, a process f - Google Patents
New crystalline form v of agomelatine, a process f Download PDFInfo
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- TWI359128B TWI359128B TW095128302A TW95128302A TWI359128B TW I359128 B TWI359128 B TW I359128B TW 095128302 A TW095128302 A TW 095128302A TW 95128302 A TW95128302 A TW 95128302A TW I359128 B TWI359128 B TW I359128B
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- agomelatine
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- YJYPHIXNFHFHND-UHFFFAOYSA-N agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 title claims description 13
- 229960002629 agomelatine Drugs 0.000 title claims description 13
- 238000000034 method Methods 0.000 title claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 239000013078 crystal Substances 0.000 claims description 9
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 6
- 206010022437 insomnia Diseases 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 208000019888 Circadian rhythm sleep disease Diseases 0.000 claims description 4
- 208000001456 Jet Lag Syndrome Diseases 0.000 claims description 4
- 206010016256 fatigue Diseases 0.000 claims description 4
- 208000033915 jet lag type circadian rhythm sleep disease Diseases 0.000 claims description 4
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 4
- 208000012672 seasonal affective disease Diseases 0.000 claims description 4
- 208000019116 sleep disease Diseases 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- 208000027559 Appetite disease Diseases 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 208000010643 digestive system disease Diseases 0.000 claims description 3
- 208000000044 Amnesia Diseases 0.000 claims description 2
- 208000026139 Memory disease Diseases 0.000 claims description 2
- 208000019695 Migraine disease Diseases 0.000 claims description 2
- 206010033664 Panic attack Diseases 0.000 claims description 2
- 208000018737 Parkinson disease Diseases 0.000 claims description 2
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 230000032683 aging Effects 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 238000010586 diagram Methods 0.000 claims description 2
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- 208000024714 major depressive disease Diseases 0.000 claims description 2
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- 208000023060 memory loss Diseases 0.000 claims description 2
- 230000003340 mental effect Effects 0.000 claims description 2
- 206010027599 migraine Diseases 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
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- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 claims 1
- 230000036506 anxiety Effects 0.000 claims 1
- 239000003183 carcinogenic agent Substances 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 230000002490 cerebral effect Effects 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 239000002955 immunomodulating agent Substances 0.000 claims 1
- 229940121354 immunomodulator Drugs 0.000 claims 1
- 230000002584 immunomodulator Effects 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 claims 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 claims 1
- 229960003987 melatonin Drugs 0.000 claims 1
- 208000020685 sleep-wake disease Diseases 0.000 claims 1
- 230000035882 stress Effects 0.000 claims 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 8
- -1 N-[2-(7-methoxy-1-indenyl)ethyl]acetamidine Chemical compound 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 208000008589 Obesity Diseases 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 235000020824 obesity Nutrition 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 229910000420 cerium oxide Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
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- 239000008187 granular material Substances 0.000 description 2
- 229960001021 lactose monohydrate Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 2
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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- 150000001412 amines Chemical class 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- C07C231/00—Preparation of carboxylic acid amides
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- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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Description
九、發明說明： 【發明所屬之技術領域】 本發明係關於一種式（I)之阿戈美拉汀或N-[2-(7-甲氧基-1-莕基）乙基]乙醯胺之新晶形V:
其製備方法及包含其之醫藥組合物。 【先前技術】 阿戈美拉汀或Ν-[2·(7-甲氧基-i_莕基）乙基]乙醢胺具有 重要之藥理性質。 其確實具有雙重特徵’一方面為褪黑激素能系統受體之 激動劑，及另一方面為5-HT2c受體之拮抗劑。此等性質在 中樞神經系統中及尤其在嚴重抑鬱症、季節性情感障礙 症、睡眠障礙、心血管病變、消化系統病變、失眠症及由 時差產生之疲勞、食慾障礙及肥胖之治療中賦與活性。 阿戈美拉汀，其製備及其治療用途在歐洲專利說明書EP 0 447 285中已有所描述。 鑒於此化合物之醫藥價值，能夠獲得具有極高純度、具 有適當界定’較佳可再現之晶形之該化合物是很重要的， 其因此用溶解及調配物來展示出重要特徵且充分穩定以允 許其長期存儲而對溫度、光、濕度或氧含量無特別要求。 專利說明書EP 0 447 28 5從7-甲氧基-1-四氫莕酮開始， 以八個步驟描述阿戈美拉汀之製備。然而，彼文獻並未以 113099.doc 1359128 可再現方式規定用於獲得以展示彼等特徵之形式之阿戈美 拉汀的條件。 【發明内容】 申請者現已開發出一種新的合成方法，其允許獲得以適 當界定、較佳可再現、尤其對於溶解及調配物展示出重要 特徵之晶形之阿戈美拉汀。 更特定言之，本發明係關於式⑴之化合物之晶形v，其 中由以下粉末X射線繞射圖表表徵、用Siemens D5005繞射 計（銅對陰極）量測及以内部平面距離d、布拉格（Bragg's)角 度2Θ、強度及相對強度（表示成最大強度射線之百分比）來 表示： 2-θ〇指數 指數 強度(％) 9.84 8.979 17 12.40 7.134 15 13.31 6.646 19 15.14 5.848 18 15.98 5.543 18 16.62 5.329 19 17.95 4.939 100 18.88 4.697 65 20.49 4.332 24 20.99 4.228 34 23.07 3.852 39 23.44 3.792 36 24.28 3.663 58 25.10 3.545 19 26.02 3.422 15 26.82 3.322 19 27.51 3.239 16
本發明亦係關於一種製備式（I)之化合物之晶形V的方 法，其方法之特徵在於阿戈美拉汀經受據稱"具有高能"之 113099.doc 13,59128
機械研磨。 根據本發明之結晶步驟中，有可能使用由任何方法所獲 侍之式（I)之化合物。 本發明亦係關於製備式⑴之化合物之晶形V的另一種方 法，其方法之特f攻在於將阿戈美纟汀加熱直至完全熔化， 接著立即置於室溫中及同時添加少量新近預備的式⑴之化 合物之晶形V，且將混合物冷卻直至完全結晶。 較佳地，在根據本發明之彼第二種結晶方法中，將阿戈 美拉、汀於110°c熔化》 在根據本發明之彼第二種方法中所添加之晶形V之量較 佳包含之阿戈美拉汀之重量在1/100與1/50間。 根據本發明之彼第二結晶步驟中，有可能使用由任何方 法所獲得之式（I)之化合物。 獲得彼晶形之優勢在於其允許製備具有一致及可再現之
組合物之醫藥職物，纟因此對於溶解展示出重要特徵， 當該醫藥調配物用於口服投藥時，獲得彼晶形尤其有利。 對如此獲得之形HV之藥理研究已表明其對於中框神經 系統及對於微循環具有實質活性，使得其得以證實阿戈美 拉汀之晶形V對於治療精神緊 重抑鬱症、季節性情感障礙 張、睡眠障礙、焦慮症、嚴 、心企管病變、消化系統病 變、失眠症及由於時差所引起之疲勞、精神分裂症、恐慌 發作、憂鬱症、食射章礙、肥胖、失眠症、疼痛、精神性 失常、癲癇症、糖尿病、帕金森氏症、老年癡呆症、與正 常或病理性衰老相關之各種失調 症、偏頭痛、記憶力喪 113099.doc <s 失、阿茲海默氏病症及大腦循環失調症有效。在另一方面 之活性中’表明阿戈美拉汀之晶形V可用於治療性功能障 礙' 其具有抑制排卵及免疫調節之性質、及其適合用於治 療癌症。 阿戈美拉汀之晶形V較佳用於治療嚴重抑鬱症、季節性 情感障礙、睡眠障礙、心血管病變、失眠症及由時差引起 之疲勞、食慾障礙及肥胖。 本發明亦係關於醫藥組合物，其包括作為活性成份之阿 戈美拉>丁之晶形V連同一或多種合適的惰性、無毒之賦形 劑。根據本發明之醫藥組合物中，提到，尤其適於口服、 非經腸（靜脈内或皮下）或鼻腔投藥之醫藥組合物、錠劑或 糖衣藥丸、顆粒、舌下錠、明膠膠囊、口含劑、栓劑、乳 劑、軟膏劑、皮凝膠、注射製劑、飲用懸浮液及可崩解糊 劑。 可根據失調症之性質及嚴重性、投藥路徑及患者之年齡 及體重調整有效劑量《在一或多次投藥過程中，劑量以每 天自0.1 mg至1 g變化。 【實施方式】 以下實例說明但不以任何方式限制本發明。
實例1 : Ν·【2-(7-甲氧基-1-萘基）乙基】乙醢胺之晶形V 將100 g Ν-[2-(7-甲氧基-ΐ_萘基）乙基]乙醯胺置於行星式 球農機象之機械研磨機中約6小時及所獲得之固體由 以下粉末X射線繞射圖表表徵及用Siemens D5005繞射計 (鋼對陰極）量測及以内部平面距離d、Bragg's角度2Θ、強 113099.doc 1359128 度及相對強度（表示成最大強度射線之百分比）來表示： 2-θ(°)指數 指數 強度(％) 9.84 8.979 17 12.40 7.134 15 13.31 6.646 19 15.14 5.848 18 15.98 5.543 18 16.62 5.329 19 17.95 4.939 100 18.88 4.697 65 20.49 4.332 24 20.99 4.228 34 23.07 3.852 39 23.44 3.792 36 24.28 3.663 58 25.10 3.545 19 26.02 3.422 15 26.82 3.322 19 27.51 3.239 16
實例2 : N-[2_(7-甲氧基-1-莕基）乙基】乙醯胺之晶形V 將4 g N-[2-(7-曱氧基-1-莕基）乙基]乙醯胺置於在110°C 之通風恆溫箱内。在110°C 1小時後，立即將製品置於室溫 中及用0.05 g由高啤^械研磨獲得的結構純之N-[2-(7-甲氧 基-1-莕基）乙基]乙醯胺之晶形V接種。5分鐘後，完成結晶 且所獲得之固體由以下粉末X射線繞射圖表表徵、用 Siemens D5005繞射計（銅對陰極）量測及以内部平面距離 d、Bragg's角度2Θ、強度及相對強度（表示成最大強度射線 之百分比）來表示： 113099.doc 10- 1359128
2-θ(°)指數 d(A)指數 強度(％) 9.84 8.979 17 12.40 7.134 15 13.31 6.646 19 15.14 5.848 18 15.98 5.543 18 16.62 5.329 19 17.95 4.939 100 18.88 4.697 65 20.49 4.332 24 20.99 4.228 34 23.07 3.852 39 23.44 3.792 36 24.28 3.663 58 25.10 3.545 19 26.02 3.422 15 26.82 3.322 19 27.51 3.239 16 實例3 :醫藥組合物 製備1000粒錠劑之調配物，每粒錠劑包含之劑量為25 . mg : 實例1或2之化合物....................................... 25 g 乳糖單水合物................................. 62 g _ 硬脂酸鎂.......................................................1.3 g 玉米澱粉.......................................................26 g 麥芽糊精........................................................9 g 無水膠狀二氧化矽........................................ 0-3 g A型羥基乙酸澱粉鈉...................................... 4 g 硬脂酸........................................................ 2.6 g 實例4 :醫藥組合物 r 製備1000粒錠劑之調配物，每粒錠劑包含之劑量為25 113099.doc • 11 - 1359128 mg : 實例1或2之化合物............................................25 g 乳糖單水合物...............................................62 g 硬脂酸鎂.......................................................1.3 g 聚乙稀0比洛_.................................................. 9 g 無水膠狀二氧化矽.........................................0.3 g 纖維素羥乙酸鈉............................................30 g 硬脂酸.........................................................2.6 g 113099.doc -12·
Claims (1)
1359128 .公/豕 十、申請專利範圍： L----J 1. 一種式（I)之阿戈美拉汀之晶形V，
NHCOMe (I) 其由以下粉末X射線繞射圖表表徵，用一繞射計（銅對陰 極）量測及以内部平面距離d、布拉格（Bragg's)角’度2Θ、 強度及相對強度（表示成最大強度射線之百分比）來表 示： 2-θ〇指數 d(A)指數 強度(％) 9.84 8.979 17 12.40 7.134 15 13.31 6.646 19 15.14 5.848 18 15.98 5.543 18 16.62 5.329 19 17.95 4.939 100 18.88 4.697 65 20.49 4.332 24 20.99 4.228 34 23.07 3.852 39 23.44 3.792 36 24.28 3.663 58 25.10 3.545 19 26.02 3.422 15 26.82 3.322 19 27.51 3.239 16
2. 一種製備如請求項1之式（I)之化合物之晶形V的方法·，其 特徵在於阿戈美拉汀經受一據稱具有’'高能"之機械研 磨。 3. —種製備如請求項1之式（I)之化合物之晶形V的方法，其 113099.doc 1359128 特徵在於將阿戈美拉汀加熱直至完全熔化，接著立即置 於至溫且㈣添加少量新鮮製備的式⑴之化合物之晶形 v，且將混合物冷卻直至完全結晶。 .4. -種醫藥組合物，其包括作為活性成份之如請求項κ 阿戈美拉汀之晶形V，與一或多種醫藥上可接受之惰 性、無毒載劑組合。 5_如請求項4之醫藥組合物，其用於製造治療褪黑素能失 • 調症之藥劑。 6.如凊求項4之醫藥組合物’其用於製造治療睡眠障礙、 精神緊張、焦慮症、季節性情感障礙或嚴重抑鬱症、心 血管病變、消化系統病變、失眠症及由於時差所引起的 、 疲勞、精神分裂症、恐慌發作、憂#症、食慾障礙、肥 . 胖、失眠症、精神性失常、癲癇症、糖尿病、帕金森氏 症、老年癡呆症、與正常或病理性衰老相關之各種失調 症、偏頭痛、記憶力喪失、阿兹海默氏病症、大腦循環 • 失調症，及治療性功能障礙、作為排印抑制劑、免疫調 節劑及癌症之藥劑。 113099.doc
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| CN101481321B (zh) * | 2009-02-27 | 2012-04-18 | 上海医药工业研究院 | 阿戈美拉汀卤化氢复合物及其制备方法 |
| CN101585779B (zh) * | 2009-03-10 | 2014-04-02 | 上海医药工业研究院 | 阿戈美拉汀的晶型vi及其制备方法和应用 |
| WO2011006387A1 (zh) * | 2009-07-11 | 2011-01-20 | 浙江华海药业股份有限公司 | 阿戈美拉汀的制备方法、阿戈美拉汀晶形及其制备方法 |
| CN102001959B (zh) * | 2009-09-01 | 2014-07-02 | 北京本草天源药物研究院 | 一种药物晶体及其制备方法和用途 |
| CN102050755B (zh) * | 2009-10-29 | 2014-11-05 | 重庆医药工业研究院有限责任公司 | 阿戈美拉汀的晶型及其制备方法 |
| CN101781226B (zh) | 2009-12-23 | 2012-03-28 | 天津泰普药品科技发展有限公司 | 阿戈美拉汀及其药物组合物 |
| WO2011154140A2 (en) | 2010-06-10 | 2011-12-15 | Gador S.A. | New process for the preparation of n-[2-(7-methoxy-1-naphthyl)-ethyl]acetamide and new crystalline form |
| CN102000583B (zh) * | 2010-11-18 | 2012-08-15 | 烟台万华聚氨酯股份有限公司 | 一种氯化氢氧化制氯气的催化剂及其制备方法 |
| CN102690209A (zh) * | 2011-03-23 | 2012-09-26 | 上海医药工业研究院 | 阿戈美拉汀的混晶(形式-ⅷ)、其制备方法、应用和包含其的药物组合物 |
| CN102690210A (zh) * | 2011-03-23 | 2012-09-26 | 上海医药工业研究院 | 阿戈美拉汀的新晶型ⅶ、其制备方法、应用和包含其的药物组合物 |
| CA3209613A1 (en) * | 2011-06-02 | 2012-12-06 | CHINOIN Zrt. | Novel processes for the preparation of prostaglandin amides |
| FR2978916B1 (fr) | 2011-08-10 | 2013-07-26 | Servier Lab | Composition pharmaceutique solide pour administration buccale d'agomelatine |
| WO2013082302A1 (en) | 2011-11-30 | 2013-06-06 | Ratiopharm Gmbh | Agomelatine-urea complex and crystalline forms thereof |
| CZ2012108A3 (en) | 2012-02-15 | 2013-02-27 | Zentiva Ks | A method for the manufacture of a polymorphously stable pharmaceutical composition containing agomelatine |
| CN103360275B (zh) * | 2012-03-30 | 2015-04-22 | 上海创诺制药有限公司 | 一种制备阿戈美拉汀ⅰ型晶体的方法 |
| EP2934502A1 (en) | 2012-12-21 | 2015-10-28 | Laboratorios Lesvi S.L. | Process for prepararing n-(2-(7-methoxy-1-naphthalenyl)ethyl) acetamide and solid forms thereof |
| FR3001894A1 (fr) | 2013-02-08 | 2014-08-15 | Servier Lab | Composition pharmaceutique solide pour administration buccale d'agomelatine |
| EP2810647A1 (en) | 2013-06-06 | 2014-12-10 | Zentiva, a.s. | Pharmaceutical formulations comprising agomelatine in the form of agomelatine co-crystal with an organic acid |
| ES2645223T3 (es) | 2013-06-06 | 2017-12-04 | Zentiva, K.S. | Formulaciones de agomelatina que comprenden agomelatina en forma de co-cristales |
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| WO2015124496A1 (en) | 2014-02-19 | 2015-08-27 | Synthon B.V. | Pharmaceutical composition comprising amorphous agomelatine |
| FR3033131B1 (fr) | 2015-02-26 | 2017-11-17 | Servitronique | Glissiere pour ses systemes de reglage coulissants et procede d'assemblage |
| EP3075724B1 (en) | 2015-03-31 | 2023-07-12 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Solid form of agomelatine |
| EP3466923A1 (en) | 2017-10-09 | 2019-04-10 | KRKA, d.d., Novo mesto | Process for the preparation of agomelatine in crystalline form |
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