200306312 玖、發明說明 【發明所屬之技術領域】 本發明係有關一種製備卡伯葛啉（Cab ergo line)晶形ϊ之 新穎製法。 【先前技術】 卡伯葛啉（cabergoline)是一種麥角啉（ergoline)衍生 物，其與D2多巴胺受體交互作用且具有不同有用之醫藥 活性，可用於治療血中泌乳激素過高、中樞神經系統（CNS) 病症及其它相關疾病。 卡伯葛啉爲卜（（6-丙烯基麥角啉- 8yS-基）-羰基）4-(3-二 甲基胺基丙基）-3 -乙基脲之普通名’於US 4,526,892說明 且請求專利。卡伯葛啉分子之合成也報告於E u r. J . M e d . C hem.，24,421，（1989)及 GB-2，103,603-B。 卡伯葛啉晶形I類似卡伯葛啉，對促泌乳激素具有顯著 抑制作用，且具有治療性質，而可用於治療異常促泌乳激 素濃度相關之病理情況，因此可用於人類用藥及/或動物用 藥。單獨或組合之卡伯葛啉於治療可逆性阻塞性呼吸道疾 病、控制眼壓以及治療青光眼也具有活性。卡伯葛啉也可 用於動物用藥領域做爲抗促泌乳激素劑，以及大爲減少脊 椎動物的繁殖。卡伯葛啉之若干用途例如說明於 W099/48484，WO99/3 60 95，US 5 7 0 5 5 1 0，WO9 5 /0 5 1 7 6， EP 04 0,3 2 5 ° 卡伯葛啉晶形I特別可用於治療帕金森氏症（P D )、腿抖 動症候群（RLS)，以及用於治療如進行性核上麻痺（PSP)以 及多重系統性萎縮（MS A)等疾病。 5 312/發明說明書(補件)/92-06/92105467 200306312 卡伯葛啉晶形i屬於卡伯葛啉之無水非溶劑合物形，晶 形Ϊ首先係由乙醚結晶製備，例如述於I 1 F armaco，5 0(3), 175-178(1995) 〇 另一種透過甲苯溶劑合物形V製備卡伯葛啉晶形I之方 法述於 W001/70740。 爲了降低量產成本，高度需要改良卡伯葛啉晶形I之工 業製造產率，且避免冗長之製法。因此本發明之目的係使 用一種先前未曾使用之有機溶劑系統，獲得高度純質之卡 伯葛啉晶形I。有效製備高純度晶形I卡伯葛啉，就產業 成本以及環保考量而言皆有益。 【發明內容】 本發明係有關一種製備卡伯葛啉晶形I之新穎方法。 本發明方法包含新穎卡伯葛啉甲苯溶劑合物形式之製 備，及其單獨地轉化成爲卡伯葛啉晶形I。新穎卡伯葛啉 甲苯溶劑合物爲一種晶形，其特徵完整說明如下，爲方便 稱爲「晶形X」。 於另一態樣，本發明提供卡伯葛啉溶劑合晶形X，其當 去除溶劑合時，可快速且單獨地獲得卡伯葛啉晶形I。 於第四態樣，本發明提供製備卡伯葛啉溶劑合晶形X之 製法，以及由卡伯葛啉溶劑合晶形X製備卡伯葛啉晶形I 之製法。 【實施方式】 根據本發明，晶形I之製法可容易地始於粗產物，該粗 產物係由甲苯/庚烷或甲苯/己烷混合物之結晶，透過新穎 卡伯葛啉溶劑合晶形X而製備。本晶形I製法比老式製法 6 312/發明說明書(補件)/92·06/92105467 200306312 優異，卡伯葛啉溶劑合晶形X可快速且單獨地轉化成晶形 I。也提供新穎卡伯葛啉溶劑合晶形X、其新穎凝膠媒介製 法，及其轉化成結晶性卡伯葛啉晶形I之製法。 特性描述 X光粉末繞射（XRD)用於決定新穎卡伯葛啉溶劑合晶形 X之特性，且與晶形I及V比較。晶形X去溶劑合且相轉 化成爲晶形I，係經由溶劑合物置於X光繞射計之特殊光 試管，於升高溫度於高度真空經歷一段時間進行硏究。 也可對晶形V及X獲得差異掃描量熱計（DSC)分佈圖， 來顯示此等溶劑合物之獨特性質。 X光繞射分析 粉末X光繞射係使用西門子（s i e m e η s) D 5 0 0 0粉末繞射計 或伊奈兒（I n e 1)多用途繞射計進行。對西門子D 5 0 0 0粉末 繞射計，原始資料係對2 Θ値爲2至5 0，以0.0 2 0階及每階 時間兩秒測定。對伊奈兒多用途繞射計，樣本係置於鋁樣 本容器，原始資料係同時對全部2 Θ値收集1 0 0 0秒時間獲 得。如此所得資料顯示於下表I至表III。 可被加熱且可透過真空幫浦抽真空之特殊光試管用於 伊奈兒多用途繞射計硏究晶形X之去溶劑合以及晶形X之 相轉化成爲晶形I之表現。晶形X去溶劑合且相轉化成爲 晶形I之表現係於4 3 °C及9 4.8 kP a真空硏究。甲苯之蒸氣 壓極局’需要局度真空才能有效去除溶劑。用於晶形X去 溶劑合以及相轉化成爲晶形I，伊奈兒多用途繞射計經過 程式化，每半小時收集X光繞射資料1〇分鐘時間，總實 驗時間兩小時4 0分（包括資料的收集）。 312/發明說明書(補件)/92-06/92105467 7 200306312 溶劑合晶形X之X光粉末繞射樣式（圖1)顯示一種具有 有用的獨特峰之結晶結構，顯示於下表I。200306312 发明 Description of the invention [Technical field to which the invention belongs] The present invention relates to a novel method for preparing Cabergoline crystal form ϊ. [Prior technology] Cabergoline is an ergoline derivative that interacts with the D2 dopamine receptor and has different useful medical activities. It can be used to treat high levels of prolactin in the blood and central nervous system. System (CNS) disorders and other related diseases. Kappaline is the common name of ((6-propenylergoline-8yS-yl) -carbonyl) 4- (3-dimethylaminopropyl) -3 -ethylurea, as described in US 4,526,892 And request a patent. The synthesis of kappaline molecules is also reported in Eu r. J. Me d. C hem., 24,421, (1989) and GB-2, 103,603-B. Kappaline Form I is similar to Kappaline, has significant inhibitory effects on prolactin, and has therapeutic properties. It can be used to treat pathological conditions related to abnormal prolactin concentrations, so it can be used in human and / or animal medicine. . Kappaline, alone or in combination, is also active in the treatment of reversible obstructive respiratory disease, control of intraocular pressure, and treatment of glaucoma. Kappaline can also be used in the field of animal medicine as an anti-prolactin agent, and it can greatly reduce the reproduction of spinal animals. Some uses of Kappaline are described in, for example, W099 / 48484, WO99 / 3 60 95, US 5 7 0 5 5 1 0, WO9 5/0 5 1 7 6, EP 04 0,3 2 5 ° Kappaline Form I is particularly useful for the treatment of Parkinson's disease (PD), leg tremor syndrome (RLS), and for diseases such as progressive supranuclear palsy (PSP) and multiple systemic atrophy (MS A). 5 312 / Explanation of the Invention (Supplement) / 92-06 / 92105467 200306312 Kappaline's crystal form i belongs to the anhydrous non-solvate form of Kappaline. The crystal form Ϊ is first prepared by crystallization from ether, as described in I 1 F Armaco, 50 (3), 175-178 (1995). Another method for preparing Kappaline crystal form I through toluene solvate form V is described in W001 / 70740. In order to reduce mass production costs, it is highly desirable to improve the industrial manufacturing yield of Kappaline Form I and avoid lengthy manufacturing methods. It is therefore an object of the present invention to obtain a highly pure Kappaline Form I using an organic solvent system that has not previously been used. Effective preparation of high-purity crystal form I kappaline is beneficial in terms of industrial cost and environmental considerations. [Summary of the Invention] The present invention relates to a novel method for preparing kappaline crystal form I. The process of the present invention comprises the preparation of a novel kappaline toluene solvate form and its separate conversion to kappaline form I. The novel kappaline toluene solvate is a crystalline form, and its characteristics are fully explained below. For convenience, it is referred to as "crystal form X". In another aspect, the present invention provides Kappaline solvated crystalline Form X, which, when solvated is removed, can quickly and separately obtain Kappaline crystalline Form I. In a fourth aspect, the present invention provides a method for preparing Kappaline solvate crystalline form X, and a method for preparing Kappaline solvate crystalline form X. [Embodiment] According to the present invention, the preparation method of the crystal form I can be easily started from the crude product, which is prepared from the crystallization of a toluene / heptane or toluene / hexane mixture through the novel kappaline solvent crystalline form X . This crystal form I method is superior to the old method 6 312 / Invention Specification (Supplement) / 92 · 06/92105467 200306312, and the kappaline solvated crystalline form X can be quickly and individually transformed into the crystal form I. Also provided is a novel kappaline solvate crystalline form X, a novel method for preparing a gel medium, and a method for converting it into crystalline kappaline form I. Characteristic description X-ray powder diffraction (XRD) is used to determine the characteristics of the novel kappaline solvate crystal form X, and it is compared with the crystal forms I and V. Form X is desolvated and phase-converted to form I, which is placed in a special light test tube of an X-ray diffractometer via a solvate, and is studied at elevated temperature and high vacuum for a period of time. Differential scanning calorimeter (DSC) profiles can also be obtained for crystal forms V and X to show the unique properties of these solvates. X-Ray Diffraction Analysis The powder X-ray diffraction system was performed using a Siemens (Siemén) D 5 0 0 0 powder diffractometer or an Iner (I n e 1) multipurpose diffractometer. For the Siemens D 5 0 0 0 powder diffractometer, the original data is 2 to 50 for 2 Θ 値, measured at 0.0 2 0 steps and two seconds per step time. For the Iner multi-purpose diffractometer, the sample was placed in an aluminum sample container, and the original data was collected simultaneously for all 2 Θ 値 for 1,000 seconds. The data thus obtained are shown in Tables I to III below. A special light test tube that can be heated and evacuated through a vacuum pump is used in an Iner multi-purpose diffractometer to investigate the desolvation of Form X and the transformation of Form X into Form I. Form X was desolvated and the phase transition into Form I was performed at 4 3 ° C and 9 4.8 kP a under vacuum. The vapor pressure of toluene requires a partial vacuum to effectively remove the solvent. For desolvation of crystal form X and phase inversion to form I, the Iner multi-purpose diffractometer is programmed to collect X-ray diffraction data every half an hour for 10 minutes, and the total experimental time is 2 hours and 40 minutes (including data Collection). 312 / Description of the Invention (Supplements) / 92-06 / 92105467 7 200306312 The X-ray powder diffraction pattern of solvated crystal form X (Figure 1) shows a crystalline structure with a useful unique peak, as shown in Table I below.
表I X光繞射資料，晶形X 角 2Θ 強度 Cps X 1 000 強度 % 7.988 6 8 9 9 100.00 10.937 837 11.97 12.067 477 6.82 14.927 22 13 3 1.66 17.162 2603 37.25 17.320 3 163 45.26 19.938 855 12.22 21.075 2 720 38.92 23.892 137 1 19.61 26.779 1086 15.54 卡伯葛啉晶形I : 之X光粉末繞射樣式（圖2)顯示一* ®結 晶結構其帶有下表 II顯示之獨特峰。 表II X光繞射資料，晶形I 角 強度 強度 2Θ Cps X 1000 % 9.870 445 8 99.86 10.497 1498 3 3.55 12.193 1244 27.86 14.707 1556 34.86 16,658 1743 39.94 16.721 1644 36.83 18.707 4464 100.00 20.822 2 3 3 0 52.19 22.688 1172 26.25 24.652 234 1 52.44 W Ο 0 1 / 7 0 7 4 0所述已知卡伯葛啉甲苯溶劑合晶形V之X 光粉末繞射樣式（圖3 )爲一種帶有獨特峰之結晶結構’不 於下表ΠΙ 312/發明說明書(補件)/92-〇6/92105467 200306312Table IX light diffraction data, crystal form X angle 2Θ intensity Cps X 1 000 intensity% 7.988 6 8 9 9 100.00 10.937 837 11.97 12.067 477 6.82 14.927 22 13 3 1.66 17.162 2603 37.25 17.320 3 163 45.26 19.938 855 12.22 21.075 2 720 38.92 23.892 137 1 19.61 26.779 1086 15.54 X-ray powder diffraction pattern (Figure 2) of Kappaline Form I (Figure 2) shows a * crystalline structure with unique peaks shown in Table II below. Table II X-ray diffraction data, crystal form I angular intensity 2Θ Cps X 1000% 9.870 445 8 99.86 10.497 1498 3 3.55 12.193 1244 27.86 14.707 1556 34.86 16,658 1743 39.94 16.721 1644 36.83 18.707 4464 100.00 20.822 2 3 3 0 52.19 22.688 1172 26.25 24.652 234 1 52.44 W 〇 0 1/7 0 7 4 0 The X-ray powder diffraction pattern of the known kappaline toluene solvate crystalline form V (Figure 3) is a crystalline structure with a unique peak. Table III 312 / Invention Specification (Supplement) / 92-〇6 / 92105467 200306312
表111 X光繞射資料，晶形V 角 2Θ 強度 Cps X 1000 強度 % 8.866 5 9 3 0 100.00 12.287 705 11.88 16.375 1440 24.28 18.171 1169 19.71 18.991 1167 19.67 21.043 12 14 20.47 24.938 75 1 12.66 此等資料明白指出卡伯葛啉晶形X爲一種新穎結晶多形 性溶劑合物，其易藉XRD而與先前技藝說明之已知溶劑合 物V區別。 於前述條件下，晶形X去溶劑合且相轉變成爲晶形I之 表現（圖6)，顯示大部分晶形X(以主峰位於7.9 8 8度2Θ爲 特徵）於30分鐘以內轉變成爲晶形1(以9.8 7 0及1 8.7 07度 2 Θ峰爲特徵）。藉主7.9 8 8度2 Θ峰完全消失之指示，此種 轉形係於1小時內完成。 圖6明白顯示由晶形X去溶劑合以及相轉形成爲晶形I 之有利動力學。此項資料也證實由晶形X製造晶形I可在 顯著極短時間內達成。 差異掃描量熱計分析（DSC) 差異掃描量熱計分佈圖係得自美特樂托雷多（Mettler-丁〇16(1〇) 8 2 2 £差異掃描量熱計。資料係以加熱速率i〇°C/分 鐘於25 °C至150°C間收集。使用40微升之氣密密封鋁盤， 銘盤室上有一個針刺孔。晶形X之差異掃描量熱計分佈圖 (圖4)顯示主吸熱事件之發生係取中於5 3 °C，接著爲較次 要且變寬之吸熱事件，取中於7 4 °C。前者係對應於晶形X 與甲苯之共熔形式，而後者則關聯經由氣化逐漸損失甲 9 312/發明說明書(補件)/92-06/92105467 200306312 苯。用於本發明之目的，共熔熔化定義爲含溶劑之固體轉 變成爲均質液態溶液，而與該固體結合之溶劑並無任何顯 著損失。 晶形V之差異掃描量熱計分佈圖（圖5 )顯示單〜吸熱事 件，取中於66 °C。此種吸熱事件係對應於晶形v於甲苯共 熔熔化。 比較圖4與圖5，也顯示晶形X與晶形v之獨特性質。 本發明之製造卡伯葛啉晶形I之方法以藉由從甲苯/庚院 結晶爲其特性。也可使用己烷取代庚烷。但庚燒就毒力學 性質而言爲較佳，更適合醫藥用途。 該製造方法包含將卡伯葛啉於室溫溶解於適量甲苯，較 佳用量相對於每克卡伯葛啉爲2.5至4.0克甲苯，更佳爲 約3.5克甲苯/克卡伯葛啉。 用作爲起始物料之卡伯葛啉可爲經由Eur. J. Med. Chem·，24, 421’（1989)所述合成方法獲得之油；或可爲由 前述參考文獻所得程序獲得之卡伯葛啉任一種結晶形或其 混合物，包括晶形I晶體。 所得溶液冷卻至低於-1 〇 °C溫度及攪拌隔夜，較佳至少 攪拌1 8小時。 於隔夜持續時間，卡伯葛啉於甲苯溶液轉變成爲凝膠， 該凝膠用於本發明之目的定義爲雙折射固體與懸浮液內部 飽和溶液平衡之稠厚非牛頓懸浮液，然後添加冷庚烷或己 烷至凝膠，較佳添加量相對於每克凝膠相卡伯葛啉約爲1 〇 至2 0克。 如此添加冷庚烷或己烷定名爲「淬熄」凝膠相。其表示 10 312/發明說明書(補件)/92-06/92105467 200306312 庚院或己院對卡伯葛琳甲苯溶液之極爲強力的抗溶劑性 質。此等性質主要係經由消除隨後固相轉變成爲可能比晶 形X更穩定的晶形的驅動力，而將例如前述凝膠等固體懸 浮液凍結於特定固態。 庚院或己院添加時’凝膠轉變成更容易懸浮的漿液，漿 液於低於周圍溫度之溫度下攪拌。此種情況下，獲得甲苯 溶劑合晶形X ’該晶形可藉一般程序回收，例如於減壓下 藉過濾或藉離心過濾回收，接著使用純庚烷或己烷洗滌固 體而去除殘餘母液或自由態甲苯。所得晶形X當由母液移 出時極爲不穩定’於周圍儲存條件下未施加任何熱量，於 24小時以內大致完全轉變成爲晶形I。 但藉此特定方式所得晶形〗晶體可含有製藥用途所無法 接受之殘餘甲苯’因此將固體於真空烘箱加熱較佳，俾將 甲苯含量降至可接受的範圍。此種乾燥過程可利用任一種 適當手段達成’乾燥過程例如（但非限制性）加熱固體，降 低固體周圍環境壓力或其組合。乾燥壓力及乾燥時間並無 狹窄限制。乾燥壓力較佳約爲1 0 1 kP a或以下。但隨著乾 燥壓力的下降，乾燥溫度降低及/或乾燥時間縮短。特別對 使用高沸溶劑（如甲苯）濕潤之固體，真空乾燥將允許使用 較低乾燥溫度。壓力與溫度之最理想組合可由甲苯之蒸氣 壓相對於溫度作圖、以及乾燥器設計上之相關因素決定。 乾燥時間只需讓甲苯含量降至製藥可接受的含量即可。當 固體經加熱而去除溶劑，例如於烘箱加熱時，較佳選用不 超過約1 5 0 °C之溫度。 另外，可於經由組合去溶劑合及乾燥步驟過濾之後所得 11 312/發明說明書(補件)/92-06/92105467 200306312 溶劑合晶形X，直接製備晶形I卡伯葛啉。若晶形x去溶 劑合及相轉化成爲晶形I之動力學太過快速，則可進行組 合操作，而無需如前段所述，對乾燥過程之方案做任何修 改。 根據本發明方法製備之卡伯葛啉晶形I晶體較佳具有多 形性純度大於95%，更佳大於98%，產率超過90% w/w ’ 比較W 0 0 1 / 7 0 7 4 0之方法所得產率約6 0 %。 甲苯溶劑合晶形X亦爲本發明之目的。晶形X之X光粉 末繞射樣式（圖1 )顯示結晶結構。此項資料指示卡伯葛啉 溶劑合晶形X易藉XRD及DSC區別。本發明之溶劑合X 爲一種真溶劑合形式，具有每莫耳卡伯葛啉約0.5莫耳甲 苯之固定組成。經由觀察X R D及D S C光譜，易知晶形X 與WOO 1 /7 0 74 0所述之已知半溶劑合晶形有顯著差異。 (實施例） 下列實施例說明此處所述卡伯葛啉固態形式製備方法 之進一步細節。此等細節說明係落入本發明之範圍，且係 供舉例說明本發明而非限制其範圍。除非另行指示，否則 全部百分比係以重量計。 實施例1 ·卡伯葛啉溶劑合晶形X之製備 3克卡伯葛啉於裝配有頂攪拌系統之1 2 5毫升有夾套反 應器內，溶解於1 0 · 5克甲苯。當於每分鐘1 4 2轉攪拌下形 成澄淸溶液後，反應器冷卻至-1 8 °C設定點，俾於反應器內 達到-1 5 °C溫度。溶液攪拌隔夜（至少1 8小時時間）。此段 期間，溶液轉成稠厚凝膠。於另一分開反應器，4 5克庚烷 冷卻至-1 5 °C，然後以1 5分鐘時間移至含凝膠之反應器。 12 312/發明說明書(補件)/92-06/92105467 200306312 所得漿液於-1 5 °c攪拌3 . 5小時，隨後洩放物於減壓下操作 至過濾瓶內。濾餅以6毫升庚烷洗滌去除母液，自固體洗 滌去除過量甲苯。此等固體則留在過濾器上3 0分鐘時間。 固體藉XRD辨識爲晶形X，資料顯示於圖1及表1。以 純「不含甲苯」卡伯葛啉之初含量爲基準，產率約爲 102%(w/w)。 實施例2 ·卡伯葛啉晶形I之製備 實施例1所得溶劑合晶形X晶體置於真空烘箱內，置於 94.8 kPa真空下於環境溫度經歷2小時時間。然後溫度提 高至43°C，固體進一步乾燥24小時。又於6〇t乾燥24 小時。各乾燥期後，取得固體樣本進行XRD及溶劑含量分 析’指示於第一期乾燥（於環境溫度及高度真空）後，固體 轉成晶形I ’但甲苯含量非於產品規格範圍內。經第二期 乾燥（於43°C及高度真空下經歷24小時時間）後，固體符 合全部產品規格。乾燥後，所得晶形I藉X r D資料識別， XRD資料顯示於圖2。以純卡伯葛啉初含量爲基準，總產 率約爲9 3 %。檢定分析之多形性純度高於9 8 %。 【圖式簡單說明】 圖1爲X光粉末繞射（XRD)樣式，顯示根據實施例1製 造之卡伯葛啉溶劑合晶形X之峰特徵。 圖2爲X光粉末繞射（XRD)樣式，顯示根據實施例2之 卡伯葛啉晶形I之峰特徵。 圖3爲X光粉末繞射（XRD)樣式，顯示根據w〇〇1/7〇74〇 摘述之程序製備之原先甲苯溶劑合物（稱做爲晶形v )之峰 特徵。 312/發明說明書(補件)/92-06/92105467 13 200306312 圖4爲晶形X之差異掃描量熱計（DSC)分佈圖，顯示卡 伯葛啉與甲苯共熔熔化之相關熱事件。 圖5爲晶形V之差異掃描量熱計（DSC)分佈圖，顯示卡 伯葛啉與甲苯共熔熔化之相關熱事件。 圖6爲晶形X於43 °C於高度真空（94.8 k Pa)下去溶劑合 相轉形之經過時間分割之粉末X光資料。Table 111 X-ray diffraction data, crystal form V angle 2Θ intensity Cps X 1000 intensity% 8.866 5 9 3 0 100.00 12.287 705 11.88 16.375 1440 24.28 18.171 1169 19.71 18.991 1167 19.67 21.043 12 14 20.47 24.938 75 1 12.66 The card clearly indicates the card Bergerin crystal form X is a novel crystalline polymorphic solvate, which is easily distinguished from the known solvate V described in the prior art by XRD. Under the aforementioned conditions, the behavior of Form X desolvation and phase transformation to Form I (Figure 6) shows that most of Form X (characterized by the main peak at 7.9 8 8 degrees 2Θ) transformed to Form 1 (with 9.8 7 0 and 1 8.7 07 degrees 2 Θ peaks). Based on the indication that the peak of 7.9 8 8 degrees 2 Θ disappeared completely, this transformation was completed within 1 hour. Figure 6 clearly shows the favorable kinetics of desolvation and phase inversion from Form X to Form I. This data also confirms that Form I from Form X can be achieved in a significantly shorter time. Differential Scanning Calorimeter Analysis (DSC) The differential scanning calorimeter profile is from Mettler-Toledo (Mettler-Ding 〇16 (1〇) 8 2 2 £ Differential Scanning Calorimeter. Data are based on heating rate i0 ° C / min was collected between 25 ° C and 150 ° C. A 40 microliter hermetically sealed aluminum pan was used. There was a pinhole in the plate chamber. The profile of the differential scanning calorimeter of crystal form X (Figure 4) It is shown that the occurrence of the main endothermic event is taken at 5 3 ° C, followed by the lesser and wider endothermic event, taken at 7 4 ° C. The former corresponds to the eutectic form of crystal form X and toluene. The latter is related to the gradual loss of A 9 312 / Invention Specification (Supplement) / 92-06 / 92105467 200306312 benzene through gasification. For the purpose of the present invention, eutectic melting is defined as the transformation of solids containing solvents into homogeneous liquid solutions, The solvent combined with the solid did not have any significant loss. The differential scanning calorimeter profile of Form V (Figure 5) shows a single ~ endothermic event, which is centered at 66 ° C. This endothermic event corresponds to the crystal form v at The toluene eutectic melts. Comparing Fig. 4 and Fig. 5, the unique properties of crystal form X and crystal form v are also shown. The invented method for producing Kappaline crystal form I is characterized by crystallization from toluene / heptane. Hexane can also be used instead of heptane. But heptane is better in terms of toxicological properties and more suitable for medical use The manufacturing method comprises dissolving kappaline in an appropriate amount of toluene at room temperature, preferably in an amount of 2.5 to 4.0 g of toluene per gram of kappaline, and more preferably about 3.5 g of toluene / g of kappaline. Kappaline used as a starting material may be an oil obtained by the synthetic method described in Eur. J. Med. Chem., 24, 421 '(1989); or it may be a Kappa obtained by the procedure obtained in the aforementioned reference. Any one of the crystalline forms of puertoline or a mixture thereof, including crystals of Form I. The resulting solution is cooled to a temperature below -10 ° C and stirred overnight, preferably for at least 18 hours. Over the duration of the overnight, Kappa morpholine in toluene The solution turns into a gel, which is used for the purpose of the present invention. It is defined as a thick non-Newtonian suspension in which the birefringent solids and the saturated solution inside the suspension are balanced, and then cold heptane or hexane is added to the gel, preferably Kappa Approx. 10 to 20 grams. The cold phase was added as "quenching" gel phase. It means 10 312 / Invention Specification (Supplement) / 92-06 / 92105467 200306312 Gengyuan or Jiyuan Extremely strong anti-solvent properties for the toluene solution of Kappa Gelin. These properties are mainly the freezing of solid suspensions such as the aforementioned gels by eliminating the driving force of the subsequent solid phase transition to a crystal form that may be more stable than Form X It is in a specific solid state. When Gengyuan or Jiyuan is added, the 'gel transforms into a slurry that is more easily suspended, and the slurry is stirred at a temperature lower than the surrounding temperature. In this case, the toluene solvated crystalline form X' can be obtained by ordinary Recycling by procedures such as filtration under reduced pressure or centrifugation, followed by washing the solids with pure heptane or hexane to remove residual mother liquor or free-form toluene. The obtained crystal form X is extremely unstable when it is removed from the mother liquor 'without substantially applying any heat under the surrounding storage conditions, and almost completely transformed into the crystal form I within 24 hours. However, the crystalline form obtained in this specific manner may contain residual toluene which is unacceptable for pharmaceutical use. Therefore, it is better to heat the solid in a vacuum oven to reduce the toluene content to an acceptable range. Such a drying process may be achieved by any suitable means such as (but not limited to) heating a solid, reducing the ambient pressure of the solid, or a combination thereof. There is no narrow limit on the drying pressure and drying time. The drying pressure is preferably about 101 kPa or less. However, as the drying pressure decreases, the drying temperature decreases and / or the drying time decreases. Especially for solids moistened with high boiling solvents such as toluene, vacuum drying will allow lower drying temperatures. The optimal combination of pressure and temperature can be determined by plotting the vapor pressure of toluene against temperature and related factors in the design of the dryer. The drying time only needs to reduce the toluene content to a pharmaceutically acceptable content. When the solid is heated to remove the solvent, such as in an oven, a temperature not exceeding about 150 ° C is preferred. In addition, 11 312 / Invention Specification (Supplement) / 92-06 / 92105467 200306312 solvated Form X can be obtained after filtering through a combination of desolvation and drying steps to directly prepare Form I Kappaline. If the kinetics of Form x Desolvent combination and phase transformation to Form I is too fast, the combination operation can be performed without any modification to the solution of the drying process as described in the previous paragraph. The kappaline crystal Form I crystal prepared according to the method of the present invention preferably has a polymorphic purity of greater than 95%, more preferably greater than 98%, and a yield of more than 90%. W / w 'Compare W 0 0 1/7 0 7 4 0 The yield obtained by this method is about 60%. The toluene solvated crystal form X is also an object of the present invention. The X-ray powder diffraction pattern of Form X (Figure 1) shows a crystalline structure. This data indicates that Kappaline solvated crystalline form X is easily distinguished by XRD and DSC. The solvate X of the present invention is a true solvate form and has a fixed composition of about 0.5 mole of toluene per mole of kappoline. By observing the X R D and D S C spectra, it is easy to see that the crystal form X is significantly different from the known semisolvent crystal form described in WOO 1/7 0 74 0. (Examples) The following examples illustrate further details of the method for preparing kappaline solid state forms described herein. These detailed descriptions are within the scope of the invention and are provided to illustrate the invention without limiting its scope. Unless otherwise indicated, all percentages are by weight. Example 1 Preparation of Kappaline Solvent-Soluble Crystalline Form X 3 g of Kappaline in a 125 ml jacketed reactor equipped with a top stirring system was dissolved in 10 · 5 g of toluene. After forming the hydrazone solution with agitation at 142 revolutions per minute, the reactor was cooled to a set point of -18 ° C, and was allowed to reach a temperature of -1 5 ° C in the reactor. The solution was stirred overnight (at least 18 hours). During this period, the solution turned into a thick gel. In a separate reactor, 45 g of heptane was cooled to -15 ° C, and then transferred to the gel-containing reactor over 15 minutes. 12 312 / Invention (Supplement) / 92-06 / 92105467 200306312 The resulting slurry was stirred at -15 ° C for 3.5 hours, and then the effluent was operated under reduced pressure into the filter bottle. The filter cake was washed with 6 ml of heptane to remove the mother liquor, and excess toluene was removed from the solid wash. These solids were left on the filter for 30 minutes. The solid was identified as Form X by XRD. The data are shown in Figure 1 and Table 1. Based on the initial content of pure "toluene-free" kappaline, the yield is approximately 102% (w / w). Example 2 Preparation of Kappaline Form I The solvated crystalline Form X crystal obtained in Example 1 was placed in a vacuum oven and placed under a vacuum of 94.8 kPa for 2 hours at ambient temperature. The temperature was then raised to 43 ° C and the solid was further dried for 24 hours. It was then dried at 60t for 24 hours. After each drying period, a solid sample was obtained for XRD and solvent content analysis ', indicating that after drying in the first period (at ambient temperature and high vacuum), the solid turned into crystal form I' but the toluene content was not within the product specification range. After the second phase of drying (24 hours at 43 ° C and high vacuum), the solid met all product specifications. After drying, the obtained crystal form I was identified by X r D data, and the XRD data is shown in FIG. 2. Based on the initial content of pure Kappaline, the total yield is approximately 93%. The polymorphic purity of the assay was higher than 98%. [Brief description of the figure] FIG. 1 is an X-ray powder diffraction (XRD) pattern, showing the peak characteristics of the kappaline solvate crystal form X manufactured according to Example 1. FIG. FIG. 2 is an X-ray powder diffraction (XRD) pattern showing peak characteristics of the kappaline crystal form I according to Example 2. FIG. FIG. 3 is an X-ray powder diffraction (XRD) pattern, showing peak characteristics of an original toluene solvate (referred to as a crystal form v) prepared according to the procedure summarized by WO1 / 07704. 312 / Invention (Supplement) / 92-06 / 92105467 13 200306312 Figure 4 is a differential scanning calorimeter (DSC) profile of Form X, showing the thermal events related to the eutectic melting of kappaline and toluene. Figure 5 is a DSC profile of Form V showing thermal events related to the co-melting and melting of kappafoline and toluene. Figure 6 shows the time-segmented powder X-ray data of the crystalline phase X at 43 ° C under a high vacuum (94.8 kPa).
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