200528100 九、發明說明： 【發明所屬之技術領域】 本發明係關已知其INN爲恩丹西酮|(OI1dansetron)之 (±)1，2,3,9-四氣-9-甲基-3-[(2-甲基咪哩-1-基）甲 基]-4H-咔唑-4-酮之新穎多形物。 本發明亦關於製備該多形物之方法，含該多形物之醫 藥組成物以及其於治療及預防噁心與嘔吐之用途。 【先前技術】200528100 IX. Description of the invention: [Technical field to which the invention belongs] The present invention is known that its INN is (±) 1,2,3,9-tetraki-9-methyl- (OI1dansetron) A novel polymorph of 3-[(2-methylimid-1-yl) methyl] -4H-carbazol-4-one. The invention also relates to a method for preparing the polymorph, a medicinal composition containing the polymorph, and its use in the treatment and prevention of nausea and vomiting. [Prior art]
已知化合物（±)1，2,3,9-四氫-9-甲基- 3-[(2-甲基-1H-咪 唑-1-基）甲基]-4H-咔唑-4-酮之INN爲恩丹西酮 (ondansetron)且具有下列結構： 恩丹西酮係Known compound (±) 1,2,3,9-tetrahydro-9-methyl- 3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4- The ketone INN is ondansetron and has the following structure: Ondansetron
吐劑著稱。 GB 2 1 5 382 1專利揭示恩丹西酮、其鹽及溶劑化物。其 中，鹼式恩丹西酮之製備係詳述於數個實施例內。例如， 實施例4，說明鹼式恩丹西酮之製備係於二甲基甲醯胺中 以硫酸二甲酯進行甲基化；得該產物其於223 °C -2 24t下分 解。實施例7中，鹼式恩丹西酮係於水中將3-[(二甲基胺） 甲基]-1，2,3,9-四氫-9-甲基-4H-咔唑-4-酮鹽酸鹽以2·甲基 咪唑處理而得，該恩丹西酮之熔點爲221 °C -22 1.5 °C，接著 於甲醇中進行再結晶作用得到熔點爲23 PC -232 t之恩丹 西酮。實施例8，說明鹼式恩丹西酮之製備係於水中將 200528100 1 2 3 9 -四氯-9-甲基-3-亞甲基- -昨'卩坐-4-顧[以 2 -甲基咏口坐 處ί里ί妾著1 甲醇中進丫了再結晶作用，所得之恩丹西嗣具有 於2 3 2 °C - 2 3 4 °C下分解之熔點。實施例1 8 ’說明驗式恩丹 西_之製備係於DMF (二甲基甲醯胺）中將3-(氯甲 基）-1，2,3,9 -四氫-9 -甲基-4H-味卩坐-4-酮與 2 -甲基咪D坐反 應，接著經由管柱層析純化得到熔點爲228 °C -229 °C之恩丹 西酮。實施例19說明鹼式恩丹西酮之製備係於THF (四氫 呋喃）中將2,3,4,9-四氫-9-甲基- 3-[(2-甲基-1H-咪嗤-1-基） φ 甲基]-1H-咔唑順丁烯二酸鹽與2,3-二氯-5,6-二氰基-1，4-苯 -醌進行氧化作用，接著經由管柱層析純化得到熔點爲2 2 7 °C -2 2 8.5 °C之恩丹西酮。實施例20說明鹼式恩丹西酮之製 備係於THF中將2,3,4,9·四氫-9-甲基·3-[(2-甲基-1H-咪唑 -1-基）甲基]-1Η-昨卩坐-4·醇與2,3 - 一^氯- 5,6 - —^氛基-1，4 -本醒 進行氧化作用，接著經由管柱層析純化得到熔點爲227.5 °C -229°C之恩丹西酮。 GB 2220352、EP 385517 及 EP 276559 專利亦說明與上 φ 述專利之實施例7相關之恩丹西酮之製備，得到與該實施 例一致之熔點。 亦已有文獻說明其他製備恩丹西酮之方法，該等方法 產生之恩丹西酮具有下列熔點：於EP 22 1 629專利中，接 著經由管柱層析純化，該恩丹西酮於21 5°C -216°C分解；於 EP 2 1 9929專利中，接著經由管柱層析純化，該恩丹西酮於 2 1 6 °C -2 1 8 °C熔解且，接著於甲醇中再結晶，所得之恩丹西 酮於227.5 °C -228.5 °C熔解；以及，最後，於EP 2043 535專 利中’接著於甲醇中再結晶，所得之恩丹西酮於2 2 7 _ 2 2 8.5 200528100 ^ °C熔解。 亦即，上述所有參考文獻所述之恩丹西酮具有非常多 變之熔點其範圍自21 5°C至234 °C。經由管柱層析純化後其 熔點仍多變，自215 t至229 °C，而於甲醇中再結晶後該熔 點提高且集中於約230°C (227 °C -234°C )。 國際專利W Ο 0 3 0 9 3 2 6 0中揭示鹼式恩丹西酮之兩種結 晶形式，其中一種具有與上述參考文獻相似之熔點而另一 種則具有較高之熔點，分別稱爲Α形物及Β形物。Β形物 • 之熔點爲244±2°C且X-光粉末繞射圖譜以下列高峰爲特 -徵·· 11.0; 11.2; 14.9; 15.5; 15.9; 16·5; 20.6; 21.4; 23.1 ; 23·5; 24.2; 24.7; 24.8; 25.8; 26.9; 28.1。20。其製備法 係於回流溫度下將鹼式恩丹西酮溶解於乙醇或甲醇接著冷 卻。Α形物係以X -光粉末繞射圖譜爲特徵其具有下列高 峰：11.0; 11.2; 14.8; 15.4; 16.4; 20.6; 21.4; 23.2; 24.1 ; 24.7 ; 25.4 ; 25.9 ; 26.7 ; 27.8°2 0。A 形物之製備係於 Ν，Ν· 二甲基甲醯胺中使恩丹西酮再結晶以及於1 -丁醇中使恩丹 | 西酮再結晶。 所揭示恩丹西酮之多形物之製備僅爲數公克或最大爲 1 · 1公斤之規模。此外，儘管只得到少量的產物，其所需使 用的溶劑體積非常大（製備上述最大量之恩丹西酮，亦即 1.1公斤，需要60公升之溶劑），因而阻礙其大-規模之製 造。 因此建議取得新穎穩定之恩丹西酮多形物及可於工業 規模下製備該產物之方法。 【發明內容】 200528100 . 本發明之標的係提供已知其IN N爲恩丹西酮之三種不 同（±)1，2,3,9 -四氫-9 -甲基-3-[(2 -甲基-1H -咪唑-1-基）甲 基]-4H-咔唑-4-酮之多形物。 因此，本發明之第一部分係關於一種稱爲恩丹西酮之 新穎之多形物，後文稱爲C形物，其特徵爲使用C u之K« ! 射線呈現之X-光粉末繞射圖譜如第1圖。 本發明之第二部分係關於一種稱爲恩丹西酮之新穎之 多形物，後文稱爲D形物，其特徵爲使用Cu之K u I射線 # 呈現之X-光粉末繞射圖譜如第2圖。 ' 本發明之第三部分係關於一種稱爲恩丹西酮之新穎之 、多形物，後文稱爲E形物，其特徵爲使用Cu之Κ α ,射線呈 現之X-光粉末繞射圖譜如第3圖。 又本發明之一標的係製備該經命名爲恩丹西酮之C、D 及Ε形物新穎多形物之方法。Emetic is famous. The GB 2 1 5382 1 patent discloses ondansetron, its salts and solvates. Among them, the preparation of basic ondansetron is detailed in several examples. For example, Example 4 illustrates that the preparation of basic ondansetron is methylation with dimethylformamide in dimethylformamide; the product is obtained which is decomposed at 223 ° C-2 24t. In Example 7, the basic ondansetron is 3-[(dimethylamine) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4 in water. -Ketone hydrochloride is obtained by treatment with 2.methylimidazole. The melting point of the ondansetron is 221 ° C -22 1.5 ° C, and then recrystallization in methanol to obtain the melting point 23 PC -232 t Tannone. Example 8 illustrates that the preparation of basic ondansetron is 200528100 1 2 3 9 -tetrachloro-9-methyl-3-methylene--yesterday '卩 坐 -4- 顾 [以 2- Methyl yung mouth sits in a litre and recrystallizes in 1 methanol. The resulting ondanazepam has a melting point that decomposes at 2 3 2 ° C-2 3 4 ° C. Example 1 8 'illustrates that the preparation of the ondansetine was performed in DMF (dimethylformamide) with 3- (chloromethyl) -1,2,3,9-tetrahydro-9-methyl The reaction of -4H-Misoza-4-one with 2-methylimidazozone was followed by purification by column chromatography to obtain ondansetron with a melting point of 228 ° C -229 ° C. Example 19 illustrates that the preparation of basic ondansetron is based on the preparation of 2,3,4,9-tetrahydro-9-methyl- 3-[(2-methyl-1H-imidamine- 1-yl) φmethyl] -1H-carbazole maleate is oxidized with 2,3-dichloro-5,6-dicyano-1,4-benzene-quinone, and then through the column Purification by chromatography gave ondansetron with a melting point of 2 7 ° C-2 2 8.5 ° C. Example 20 illustrates that the preparation of basic ondansetron is based on 2,3,4,9 · tetrahydro-9-methyl · 3-[(2-methyl-1H-imidazol-1-yl) in THF. Methyl] -1Η-yttriol-4 · ol and 2,3 -a ^ chloro-5,6-— ^ amino-1,4-benzyl are oxidized, followed by purification by column chromatography to obtain the melting point Ondansetron is 227.5 ° C -229 ° C. GB 2220352, EP 385517, and EP 276559 patents also describe the preparation of ondansetron related to Example 7 of the above-mentioned patent, and obtain melting points consistent with this example. Other methods of preparing ondansetron have also been described in the literature. The ondansetron produced by these methods has the following melting point: in the patent EP 22 1 629, followed by purification by column chromatography, the ondansetron is obtained in 21 Decomposed at 5 ° C -216 ° C; in EP 2 1 9929 patent, and then purified by column chromatography, the ondansetron is melted at 2 16 ° C-2 1 8 ° C, and then reconstituted in methanol. Crystallized, the resulting ondansetron was melted at 227.5 ° C -228.5 ° C; and, finally, in the EP 2043 535 patent, followed by recrystallization in methanol, the ondansetron was obtained at 2 2 7 _ 2 2 8.5 200528100 ^ ° C melting. That is, ondansetron described in all of the above references has a very variable melting point ranging from 21 5 ° C to 234 ° C. After purification by column chromatography, its melting point is still variable, from 215 t to 229 ° C. After recrystallization in methanol, the melting point increases and is concentrated at about 230 ° C (227 ° C -234 ° C). International patent W 0 0 3 0 9 3 2 6 0 discloses two crystalline forms of basic ondansetron, one of which has a melting point similar to the above reference and the other has a higher melting point, which are called Α Shape and B-shape. Form B • Melting point is 244 ± 2 ° C and the X-ray powder diffraction pattern is characterized by the following peaks-11.0; 11.2; 14.9; 15.5; 15.9; 16.5; 20.6; 21.4; 23.1; 23 5; 24.2; 24.7; 24.8; 25.8; 26.9; 28.1.20. It is prepared by dissolving basic ondansetron in ethanol or methanol at reflux temperature and then cooling. Form A is characterized by X-ray powder diffraction pattern, which has the following peaks: 11.0; 11.2; 14.8; 15.4; 16.4; 20.6; 21.4; 23.2; 24.1; 24.7; 25.4; 25.9; 26.7; 27.8 ° 2 0. Form A was prepared by recrystallizing ondansetron in Ν, Ν · dimethylformamide and recrystallizing ondan | cionone in 1-butanol. The polymorphs of the disclosed ondansetron are prepared on a scale of only a few grams or a maximum of 1.1 kilograms. In addition, although only a small amount of the product was obtained, the volume of the solvent needed was very large (to produce the largest amount of ondansetron mentioned above, that is, 1.1 kg, requiring 60 liters of solvent), thus hindering its large-scale production. It is therefore proposed to obtain novel and stable ondansetron polymorphs and methods for preparing the products on an industrial scale. [Abstract] 200528100. The subject of the present invention provides three different (±) 1,2,3,9-tetrahydro-9-methyl-3-[(2- Polymorphs of methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one. Therefore, the first part of the present invention relates to a novel polymorph called ondansetron, hereinafter referred to as C-shaped, which is characterized by X-ray powder diffraction using K «rays of Cu. The map is shown in Figure 1. The second part of the present invention relates to a novel polymorph called ondansetron, hereinafter referred to as D-shaped, which is characterized by the X-ray powder diffraction pattern presented by Cu u I-ray # of Cu As shown in Figure 2. '' The third part of the present invention relates to a novel, polymorphic substance known as ondansetron, hereinafter referred to as the E-shaped substance, which is characterized by the use of Cu κ α and X-ray powder diffraction by rays. The map is shown in Figure 3. Another subject of the present invention is a method for preparing the novel polymorphs of C, D and E forms named ondansetron.
本發明之另一部分係一種含有任何經命名爲恩丹西酮 之C、D及Ε形物新穎多形物之醫藥組成物。 φ 本發明之另一部分係將該經命名爲恩丹西酮之C、D 及Ε形物新穎多形物用於製造用以治療及預防噁心與喔吐 之藥物之用途。 又本發明之另一部分係治療及預防手術後之噁心與嘔 吐之治療方法以及控制由放射線療法及細胞毒性化療引起 之噁心與嘔吐之治療方法。 〔發明之詳細說明〕 本發明標的之該三種恩丹西酮多形物，可由其X -光粉 末繞射圖譜予以識別。 200528100 Ί 秦 , 與本發明第一部分相關之c形物，其特徵爲其χ_光粉 末繞射圖譜於1 4 · 9 7及2 0 · 8 6 ° 2 0處呈現兩個特有的高峰以 及於6.5°2 0以下未呈現高峰。較次要方面，該相亦以25.50。2 0 處之局峰爲特徵。與本發明之另外兩個標的多形物的繞射 圖譜相較下，C形物之繞射圖譜於5-3 0°2 (9之角度間呈現 出較少數目之高峰。表1顯示於C形物之X-光粉末繞射圖 譜中所觀察到之高峰，其係採用下述用以提供該繞射圖譜 之條件。該表1進一步包含該高峰之相對強度數値作爲附 • 加資料。Another aspect of the invention is a pharmaceutical composition containing any of the novel polymorphs of the C, D and E forms named ondansetron. φ Another part of the present invention is the use of the novel polymorphs of C, D, and E named ondansetron for the manufacture of medicines for the treatment and prevention of nausea and vomiting. Yet another aspect of the present invention is a method of treating and preventing nausea and vomiting after surgery, and a method of controlling nausea and vomiting caused by radiation therapy and cytotoxic chemotherapy. [Detailed description of the invention] The three ondansetron polymorphs of the present invention can be identified by their X-ray powder diffraction patterns. 200528100 Ί Qin, a c-shaped object related to the first part of the invention, which is characterized by its χ_ light powder diffraction pattern showing two unique peaks at 1 4 · 9 7 and 2 · 8 6 ° 2 0 and at No peak below 6.5 ° 2 0. In a lesser aspect, this phase is also characterized by a local peak at 25.50.20. Compared with the diffraction patterns of the other two polymorphs of the present invention, the diffraction pattern of the C-shaped object shows a smaller number of peaks at an angle of 5-3 0 ° 2 (9. Table 1 shows in The peak observed in the X-ray powder diffraction pattern of the C-shaped object is based on the following conditions used to provide the diffraction pattern. Table 1 further includes the relative intensity number of the peak 高峰 as additional information .
表 1 2 Θ 〇 1/1〇 7.1 8 96 10.96 100 13.13 34 14.97 36 16.08 39 16.42 34 19.73 19 20.86 41 21.82 20 24.08 70 24.70 47 25.50 52 26.73 30 27.59 20 28.97 22 200528100 使用C u之Κ α !射線，C形物呈現之X -光粉末繞射圖譜 參照第1圖。 與本發明第二部分相關之D形物，其特徵爲其X-光粉 末繞射圖譜於 11.29°; 14.58°; 17.16°; 18.89°; 20.28°; 21.22°; 25.06°及27.49°2(9處呈現高峰。表2顯示於〇形物之乂-光 粉末繞射圖譜中所觀察到之高峰。該表2進一步包含該高 峰之相對強度數値作爲附加資料。Table 1 2 Θ 〇 〇1 / 1〇7.1 8 96 10.96 100 13.13 34 14.97 36 16.08 39 16.42 34 19.73 19 20.86 41 21.82 20 24.08 70 24.70 47 25.50 52 26.73 30 27.59 20 28.97 22 200528100 Using κ α α rays of Cu, The X-ray powder diffraction pattern of the C-shaped object is shown in FIG. 1. The D-shaped object related to the second part of the present invention is characterized in that its X-ray powder diffraction pattern is 11.29 °; 14.58 °; 17.16 °; 18.89 °; 20.28 °; 21.22 °; 25.06 ° and 27.49 ° 2 (9 Table 2 shows the peaks. Table 2 shows the peaks observed in the ray-light powder diffraction pattern of the 0-shaped object. The table 2 further includes the relative intensity number 该 of the peaks as additional information.
表2 2 Θ (°) 1/1〇 5.58 16 7.10 99 7.26 49 10.77 58 10.92 86 11.29 60 13.23 50 13.65 15 14.58 43 14.74 24 15.23 2 1 15.38 23 15.92 30 16.22 37 16.48 42 17.16 18 -10- 200528100 - 15 18 20^28_ 39 32 21.22 __ 40 2J^98_ 24 22.84 _ 16 17 24J1__ 74 9.4/7^ 68 — 2^06,—-- 100 26^0}__ 40 2_6JJ_ . 39 26JJ__ 31 24 27.49 25 2 7^__ 21 28.75 20 18 討圖 -光粉 0 (此 峰以 物之 使用C u之Κ α 1射線’ D形物呈現之X -光粉末繞彳 譜參照第2圖。 與本發明第三部分相關之E形物’其特徵爲其X 末繞射圖譜於 6.29°; 11.09°; 11.88°; 12.69°; 14.97°2 最接近之高峰亦呈現於C形物之繞射圖譜）處呈現高 及於24.96° ; 15.17°20呈現雙峰。下表3顯示於E形 -11- 200528100 X-光粉末繞射圖譜中所觀察到之高峰。該表3進一步顯示 該高峰之相對強度數値作爲附加資料。Table 2 2 Θ (°) 1 / 1〇5.58 16 7.10 99 7.26 49 10.77 58 10.92 86 11.29 60 13.23 50 13.65 15 14.58 43 14.74 24 15.23 2 1 15.38 23 15.92 30 16.22 37 16.48 42 17.16 18 -10- 200528100-15 18 20 ^ 28_ 39 32 21.22 __ 40 2J ^ 98_ 24 22.84 _ 16 17 24J1__ 74 9.4 / 7 ^ 68 — 2 ^ 06, --- 100 26 ^ 0} __ 40 2_6JJ_. 39 26JJ__ 31 24 27.49 25 2 7 ^ __ 21 28.75 20 18 Discussion-Light powder 0 (This peak is based on the use of Cu κ α 1-ray 'D-shaped object X-ray powder winding spectrum shown in Figure 2. Related to the third part of the present invention The E-shaped object 'is characterized in that the X-ray diffraction pattern is 6.29 °; 11.09 °; 11.88 °; 12.69 °; 14.97 ° 2 The closest peak is also present in the C-shaped object's diffraction pattern). 24.96 °; 15.17 ° 20 showed double peaks. Table 3 below shows the peaks observed in the E-shape -11-200528100 X-ray powder diffraction pattern. The table 3 further shows the relative intensity number of the peak as additional information.
表3 2 θ η Ι/Ι〇 6.29 17 7.06 67 10.50 16 11.09 100 11.88 13 12.69 16 13.10 32 13.57 16 14.97 48 16.33 53 16.93 17 17.40 15 18.58 13 19.28 19 20.71 38 21.08 23 21.28 30 22.10 20 24.12 48 24.7 1 41 24.96 60 25.17 87 25.73 24 26.65 34 26.93 21 28.18 19 28.53 17 29.34 15 29.76 15 -12- 200528100 _ 使用Cu之Κα 1射線’ E形物呈現之χ-光粉末繞射圖譜 參照第3圖。 ’ 有益地’ E形物亦可由工業規模上具有再現性之方法 予以製備’其可產生市場上最理想之恩丹西酮結晶形，因 此，爲較佳之形式。 該X -光粉末繞射圖譜係經由C U之Κ α !射線獲得，其 係利用具有Ge主要單光儀之INELCPS-120裝置以及發射 幾何中樣本係位於0 · 5 mm直徑之林德曼玻璃毛細管中。於 φ 決定該高峰位置之誤差可經評估爲±〇.〇5°2 0。 ， 於拉曼光譜（Raman spectra)之低頻區（15至150cm·丨間） 亦可區分出C、D及E形多形物間之差異，如第4圖所示。 C與D形物之拉曼光譜彼此較爲相似，且其於光譜上清楚 地顯示出與E形物間之差異。因此拉曼技術並不適合用於 區別C形物及D形物，儘管其可將此兩形與E形物作一區 該拉曼光譜係使用具有氬雷射之Job in-Y von T64000設 φ 備而得，且使用514.5nm之激發波與30至35mW間之雷射 功率進行測定。 本發明之三種多形物所呈現之熔點範圍爲 240-247 °C。該熔點係由DSC，根據熔點高峰測定，其係使用具有 孔蓋之鋁坩堝以1 0 °C /分鐘之加熱速率進行。考慮到本發明 之三種多形物的熔點相似，以及鹼式恩丹西酮熔解時會釋 放出2-甲基咪唑，因此無法將熔點視爲區分本發明之三種 多形物的特徵。 下列詳細說明製備本發明之三種稱爲C、D及E形多 -13- 200528100 _ 形物的方法。 c形物可藉由於室溫下對鹼式恩丹西酮之飽和溶液添 加沉澱溶劑而獲得。詳言之，c形物可藉由下列方法予以 製備，包括： a) 室溫下製備鹼式恩丹西酮於二氯甲烷中之飽和溶液； b) 藉由添加C5-C7烷使結晶形沉澱；以及 c) 回收該結晶形。 較佳地，該C — C7烷係選自正-己烷或正-戊烷。 Φ D形物可藉由下列方法予以製備，包括： -a)於回流下將鹼式恩丹西酮溶於Ci-C4醇中； _ b)添加第三-丁基-甲基-醚接著進行冷卻；以及 c) 回收該結晶形。 較佳地，該醇爲甲醇。 本發明亦提供製造E形物之方法。該方法包括： a) 將恩丹西酮鹽酸鹽溶解於Ci-C3醇與水之混合物中； b) 藉由鹼化該溶液而使鹼式恩丹西酮沉澱； φ c)濾出該固體且以水洗滌； d) 於攪拌回流下將階段c)所得之以水濕化之固體懸浮於甲 醇中；以及 e) 回收該結晶形。 較佳地，該Ci-Ca醇爲甲醇。 階段b)之鹼化作用可以添加氫氧化鈉、氫氧化鉀或氨 水之方式進行。較佳地，該階段b)之鹼化作用係藉由添加 氨水溶液之方式進行。有利地，以氨水進行鹼化作用係產 生氯化銨作爲殘質，其比氯化鈉或氯化鉀更容易溶解於水 -14- 200528100 _ 及醇類中因此較易去除。 有利地，該方法可使E形物以工業規模上完全地再現 性之方式獲得。再者，因鹼式恩丹西酮不需完全溶於醇中， 其不完全可溶於該溶劑，相較於先前技藝下其可以非常少 量之溶劑得到較多之產物。 E形物亦可藉由下列方法以實驗室規模予以製備，該 方法包括： a)於回流下將鹼式恩丹西酮溶於Ci-C4醇中； φ b)添加乙酸乙酯接著進行冷卻且於室溫下以緩慢蒸發進行 •濃縮；以及 _ c)回收該結晶形。 較佳地，該C — C4醇爲甲醇。 本發明任一多形物之回收係使用習知方法經由過濾出 該固體且將其乾燥而進行。 本發明中，「醇」係指甲醇、乙醇、正-丙醇、 異丙醇、正-丁醇。 φ 本發明中，「C5-C7烷」係指正-戊烷、正-己烷、正- 庚烷。 作爲用於製備本發明多形物之起始物之鹼式恩丹西酮 及恩丹西酮鹽酸鹽可藉由文獻中所述之任何方法予以製 備。較佳地，其係依照專利E S 2 0 4 3 5 3 5所述之一般方法予 以製備，該專利之工業應用係以鹽酸作爲催化劑，以異丙 醇及水之混合物作爲溶劑而進行，該方法可使恩丹西酮直 接以鹽酸鹽之形式單離出來。該鹼式恩丹西酮可依次由鹼 化該鹽酸鹽之溶液而得。 -15- 200528100 又本發明之標的爲一種醫藥組成物，其含有治療有效 量之任一稱爲C、D或E形恩丹西酮多形物以及適量之至 ’ 少一種賦形劑。 本發明提供之組成物可藉由任何適當途徑投予，但較 佳爲口服或非口服方式投予。 用於非口服或局部投予之組成物可呈注射溶液、靜脈 溶液、灌注、栓劑或經皮系統之形式。口服投予之醫藥組 成物可爲固體例如錠劑或膠囊，其可根據習知方式與醫藥 φ 可接受賦形劑予以製備，或爲液體例如水溶液或油溶液、 -糖漿、酏、乳液或懸浮液，其可根據習知方式與醫藥可接 受添加劑予以製備。 錠劑及注射或靜脈溶液分別爲口服及非口服投藥之較 佳形式。 用於投予恩丹西酮之C、D及E形物之特佳的醫藥形 式爲口服崩解錠劑（亦稱爲口服分散劑 (buccodispersable))。口服分散錠劑係指經口投予之未經包 φ 覆之錠劑其優點爲於吞下前即快速崩解。已有各類型之技 術可製造此種錠劑，且爲熟於此技藝者所知悉。特佳之技 術係揭示於國際專利申請案W0 03 103629號者。 該醫藥形式可含有2-10毫克劑量之任何C、D及E形 多形物。 根據習知之醫藥常規，用於錠劑形式之賦形劑可包含 稀釋劑、崩解劑、潤濕劑、潤滑劑、著色劑、調味劑或其 他習知之佐劑。因此，典型之錠劑賦形劑包含，例如，乳 糖、微晶纖維素、玉米澱粉、羥丙甲纖維素、硬脂酸鎂、 -16- 200528100 _ 聚乙二醇、聚乙烯基吡咯烷酮、甘露糖。 本發明之注射配方包含，較佳爲水溶液，具有習知之 用於注射配方之賦形劑包含檸檬酸鈉、檸檬酸、氯化鈉、 以及注射用水。 本發明之標的亦爲將C、D及E形多形物用於製造用 以治療及預防手術後噁心與嘔吐以及控制由放射線療法及 細胞毒性化療引起之噁心與嘔吐之藥物之用途。 本發明之標的亦爲治療及預防手術後噁心與嘔吐之治 φ 療方法以及控制由放射線療法及細胞毒性化療引起之噁心 -與嘔吐之方法，該方法係對有此需要之病患投予治療有效 .量之任何C、D或E形多形物，其較佳之劑量爲2-1 0毫克。 【實施方式】 實驗部分 下列實施例爲本發明之非-限制性說明。 〔實施例〕 合成實施例 • 實施例1 製備C形驗式恩丹西_ 將492毫克之鹼式恩丹西酮溶解於35毫升之二氯甲 烷。加入1 8毫升之正-己烷而見結晶沉澱。攪拌所得之懸 浮液10分鐘且過濾。將所得白色固體於40 °C下乾燥至恆 重。得137毫克之C形鹼式恩丹西酮（28%)。 實施例2 製備C形鹼式恩丹两酮 於20-22t下將146毫升之正·戊烷加至經攪拌之含有4 -17- 200528100 克鹼式恩丹西酮於二氯甲烷之2 8 4毫升溶液，並見結晶沉 澱。攬拌所得之懸浮液1 0分鐘且過濾。將所得白色固體於 4 0 °C下乾燥至恆重。得2克之C形鹼式恩丹西酮（50%)。 實施例3 製備D形鹼式恩丹西酮 於回流加熱下攪拌含有4克鹼式恩丹西酮於甲醇之 178毫升溶液直到完全溶解。緩慢加入509毫升之第三-丁 基-甲基-醚然後關掉熱源並使混合物於攪拌下緩慢冷卻至 鲁 20-22 °C。將所得懸浮液過濾並於40 °C下使所得白色固體乾 -燥至恆重。得2 · 4克之D形鹼式恩丹西酮（6 0 % )。 、實施例4 製備E形鹼式恩丹西酮（實驗室方法） 於回流加熱下攪拌含有4克鹼式恩丹西酮於甲醇之 200毫升溶液直到完全溶解。緩慢加入480毫升之乙酸乙酯 然後關掉熱源且使混合物緩慢冷卻至20-22 °C。停止攪拌並 將燒瓶打開使混合物緩慢濃縮2 0 - 3 0天直到結晶出現，將 φ結晶過濾然後在4(TC下乾燥。得1克之E形鹼式恩丹西酮 (25%)。 實施例5 製備E形鹼式恩丹西酮（工業設備方法） 於3 0°C下加熱含有16公斤恩丹西酮鹽酸鹽於80公升 甲醇與80公升水之經攪拌懸浮液直到完全溶解。以2小時 以上之時間加入6公升之25 %氨水，直到pH爲9。鹼式恩 丹西酮開始沉澱出來且將所得懸浮液加熱至3 5 °C以及於該 溫度下攪拌1小時。然後冷卻至22-25 t並離心該懸浮液。 -18- 200528100 將所得之塊狀物以水洗滌（2 x 4 0公升）且再懸浮於6 0公升 之水中。將懸浮液於351下攪拌30分鐘，冷卻至22_25°C 且再次離心，最後以水洗滌（2 X 40公升）。將經水濕潤之固 體懸浮於1 80公升之甲醇且使該混合物於攪拌下進行回流 1小時。但該懸浮流體並未達到溶解。使其冷卻至2 0 - 2 2 °C 以及攪拌懸浮液3 0分鐘。冷卻至〇 - 5 °C以及於室溫下攪拌 該懸浮液1小時。離心該懸浮液，然後所得之塊狀物以2 0 公升之冷甲醇洗滌。產物於6 0 °C下真空乾燥1 5小時。得 φ 10.8公斤之E形鹼式恩丹西酮（84%)。 -【圖式簡單說明】 、 第1圖顯示C形物之X-光粉末繞射圖譜。y軸代表強 度（以計數（counts)表示）以及X -軸代表角度20。 第2圖顯示D形物之X-光粉末繞射圖譜。 第3圖顯示E形物之X-光粉末繞射圖譜。 第4圖顯示C、D及E形物之低頻拉曼光譜 (low-frequency Raman spectrum)。y-軸顯示拉曼強度（以 φ A.U.(任意單位）表示）以及X-軸顯示頻率。 【主要元件符號說明】 無0 -19-Table 3 2 θ η I / 06.29 17 7.06 67 10.50 16 11.09 100 11.88 13 12.69 16 13.10 32 13.57 16 14.97 48 16.33 53 16.93 17 17.40 15 18.58 13 19.28 19 20.71 38 21.08 23 21.28 30 22.10 20 24.12 48 24.7 1 41 24.96 60 25.17 87 25.73 24 26.65 34 26.93 21 28.18 19 28.53 17 29.34 15 29.76 15 -12- 200528100 _ Refer to Figure 3 for the χ-light powder diffraction pattern presented by Cu κα 1-ray 'E shape. 'Beneficially' E-forms can also be prepared by reproducible methods on an industrial scale ', which produces the most desirable form of ondansetron on the market and is therefore the preferred form. The X-ray powder diffraction pattern is obtained via κ α! Rays of CU, which uses the INELCPS-120 device with a Ge single light meter and a Lindemann glass capillary with a sample system located at a diameter of 0.5 mm in the emission geometry. in. The error that determines the peak position at φ can be evaluated as ± 0.05 ° 20. It is also possible to distinguish the differences between C, D, and E-shaped polymorphs in the low-frequency region (between 15 and 150 cm ·) of Raman spectra, as shown in Figure 4. The Raman spectra of the C-shaped and D-shaped objects are relatively similar to each other, and the spectra clearly show the difference from the E-shaped objects. Therefore, Raman technology is not suitable for distinguishing C-shaped and D-shaped objects, although it can be used as a region between the two-shaped and E-shaped objects. The Raman spectrum uses a Job in-Y von T64000 with argon laser set φ It was prepared and measured using an excitation wave of 514.5 nm and a laser power between 30 and 35 mW. The three polymorphs of the present invention exhibit melting points in the range of 240-247 ° C. The melting point was determined by DSC based on the melting point peak, which was performed using an aluminum crucible with a hole cover at a heating rate of 10 ° C / min. Considering that the melting points of the three polymorphs of the present invention are similar, and that 2-methylimidazole is released when the basic ondansetron is melted, the melting point cannot be regarded as a feature that distinguishes the three polymorphs of the present invention. The following is a detailed description of the methods for preparing three types of C-, D-, and E-shaped polymorphs of the present invention. Form c is obtained by adding a precipitation solvent to a saturated solution of basic ondansetron at room temperature. In particular, Form C can be prepared by the following methods, including: a) preparing a saturated solution of basic ondansetron in dichloromethane at room temperature; b) crystallizing by adding C5-C7 alkane Precipitation; and c) recovering the crystalline form. Preferably, the C-C7 alkane is selected from n-hexane or n-pentane. Φ D forms can be prepared by the following methods, including:-a) dissolving basic ondansetron in Ci-C4 alcohol under reflux; _ b) adding a third -butyl-methyl-ether followed by Cooling; and c) recovering the crystalline form. Preferably, the alcohol is methanol. The invention also provides a method for manufacturing an E-shaped article. The method includes: a) dissolving ondansetron hydrochloride in a mixture of Ci-C3 alcohol and water; b) precipitating basic ondansetron by basifying the solution; φc) filtering out the Solid and washed with water; d) suspending the water-wetted solid obtained in stage c) in methanol with stirring under reflux; and e) recovering the crystalline form. Preferably, the Ci-Ca alcohol is methanol. The alkalization in stage b) can be performed by adding sodium hydroxide, potassium hydroxide or ammonia. Preferably, the alkalization in stage b) is performed by adding an aqueous ammonia solution. Advantageously, ammonium chloride is used as a residue to produce ammonium chloride as a residue, which is easier to dissolve in water than sodium chloride or potassium chloride -14-200528100 _ and alcohols and is therefore easier to remove. Advantageously, this method allows the E-form to be obtained in a completely reproducible manner on an industrial scale. Furthermore, since basic ondansetron does not need to be completely soluble in alcohol, it is not completely soluble in the solvent, and it can obtain more products with a very small amount of solvent compared with the prior art. Form E can also be prepared on a laboratory scale by: a) dissolving basic ondansetron in Ci-C4 alcohol under reflux; φ b) adding ethyl acetate followed by cooling And concentrated by slow evaporation at room temperature; and c) recovering the crystal form. Preferably, the C-C4 alcohol is methanol. The recovery of any of the polymorphs of the present invention is performed by filtering out the solid and drying it using a conventional method. In the present invention, "alcohol" means methanol, ethanol, n-propanol, isopropanol, and n-butanol. φ In the present invention, "C5-C7 alkane" means n-pentane, n-hexane, and n-heptane. The basic ondansetron and ondansetron hydrochloride as starting materials for preparing the polymorph of the present invention can be prepared by any method described in the literature. Preferably, it is prepared according to the general method described in the patent ES 2 0 4 3 5 35, the industrial application of the patent is to use hydrochloric acid as a catalyst and a mixture of isopropanol and water as a solvent. Ondansetron can be isolated directly as the hydrochloride. The basic ondansetron can be sequentially obtained by basifying a solution of the hydrochloride. -15- 200528100 The subject of the present invention is a pharmaceutical composition containing a therapeutically effective amount of any of the polymorphs of ondansetron C, D or E and an appropriate amount of at least one excipient. The composition provided by the present invention can be administered by any appropriate route, but is preferably administered orally or parenterally. Compositions for parenteral or topical administration can be in the form of injectable solutions, intravenous solutions, infusions, suppositories, or transdermal systems. Pharmaceutical compositions for oral administration can be solids such as troches or capsules, which can be prepared in a conventional manner with pharmaceutical acceptable excipients, or can be liquids such as aqueous or oil solutions, syrups, tinctures, emulsions or suspensions Liquid, which can be prepared according to conventional methods and pharmaceutically acceptable additives. Lozenges and injection or intravenous solutions are the preferred forms of oral and parenteral administration, respectively. A particularly preferred pharmaceutical form for administration of Ondansetron in the C, D, and E forms is an oral disintegrating tablet (also known as an oral dispersing agent (buccodispersable)). Oral dispersible lozenge refers to an uncoated phial lozenge administered orally, which has the advantage of disintegrating quickly before swallowing. Various types of technology are available for making such lozenges and are known to those skilled in the art. The best technology is disclosed in International Patent Application No. WO 03 103629. The pharmaceutical form may contain any of the C, D, and E polymorphs in a dose of 2-10 mg. Excipients used in the form of lozenges may include diluents, disintegrants, wetting agents, lubricants, colorants, flavoring agents, or other conventional adjuvants, in accordance with conventional pharmaceutical practice. Therefore, typical lozenge excipients include, for example, lactose, microcrystalline cellulose, corn starch, hypromellose, magnesium stearate, -16- 200528100 _ polyethylene glycol, polyvinylpyrrolidone, mannose sugar. The injection formulation of the present invention includes, preferably an aqueous solution, and conventional excipients for injection formulations include sodium citrate, citric acid, sodium chloride, and water for injection. The subject matter of the present invention is also the use of C, D, and E-shaped polymorphs for the manufacture of drugs to treat and prevent postoperative nausea and vomiting, and to control nausea and vomiting caused by radiation therapy and cytotoxic chemotherapy. The subject of the present invention is also a treatment method for treating and preventing nausea and vomiting after surgery and a method for controlling nausea and vomiting caused by radiation therapy and cytotoxic chemotherapy. The method is to treat patients in need An effective amount of any C, D or E shaped polymorph, the preferred dosage is 2-10 mg. [Embodiment] Experimental section The following examples are non-limiting illustrations of the present invention. [Examples] Synthetic Examples • Example 1 Preparation of C-type test ondansi_ 492 mg of basic ondansetron was dissolved in 35 ml of dichloromethane. 18 ml of n-hexane was added and crystals were precipitated. The resulting suspension was stirred for 10 minutes and filtered. The resulting white solid was dried to constant weight at 40 ° C. This gave 137 mg of C-form basic ondansetron (28%). Example 2 Preparation of C-form basic ondanthionone At 20-22t, 146 ml of n-pentane was added to a stirred solution containing 4 -17- 200528 100 g of basic ondansetron in dichloromethane. 2 8 4 ml of solution and see crystal precipitation. The resulting suspension was stirred for 10 minutes and filtered. The resulting white solid was dried to constant weight at 40 ° C. 2 g of C-shaped basic ondansetron (50%) were obtained. Example 3 Preparation of D-form basic ondansetron A 178 ml solution containing 4 g of basic ondansetron in methanol was stirred under reflux until completely dissolved. Slowly add 509 ml of tert-butyl-methyl-ether and turn off the heat source and allow the mixture to cool slowly to 20-20 ° C with stirring. The resulting suspension was filtered and the resulting white solid was dried-dried to constant weight at 40 ° C. 2.4 g of D-form basic ondansetron (60%) were obtained. Example 4 Preparation of Form E basic ondansetron (laboratory method) Under reflux heating, a 200 ml solution containing 4 g of basic ondansetron in methanol was stirred until completely dissolved. 480 ml of ethyl acetate was slowly added and the heat source was turned off and the mixture was slowly cooled to 20-22 ° C. The stirring was stopped and the flask was opened to slowly concentrate the mixture for 20-30 days until crystals appeared. The φ crystals were filtered and dried at 4 ° C. 1 g of basic E ondansetron (25%) was obtained. Examples 5 Preparation of E-form basic ondansetron (industrial equipment method) Heat a stirred suspension containing 16 kg of ondansetron hydrochloride in 80 liters of methanol and 80 liters of water at 30 ° C until completely dissolved. For 2 hours or more, 6 liters of 25% ammonia water was added until the pH was 9. The basic ondansetron started to precipitate out and the resulting suspension was heated to 35 ° C and stirred at this temperature for 1 hour. Then cooled to 22-25 t and centrifuge the suspension. -18- 200528100 The resulting cake was washed with water (2 x 40 liters) and resuspended in 60 liters of water. The suspension was stirred at 351 for 30 minutes, Cool to 22-25 ° C and centrifuge again, and finally wash with water (2 X 40 liters). Suspend the water-wet solid in 180 liters of methanol and allow the mixture to reflux for 1 hour with stirring. But the suspension fluid and Not reaching dissolution. Allow to cool to 20-2 ° C and stir Liquid for 30 minutes. Cool to 0-5 ° C and stir the suspension for 1 hour at room temperature. Centrifuge the suspension and wash the resulting mass with 20 liters of cold methanol. The product is at 60 ° C Dry under vacuum for 15 hours. The E-shaped basic ondansetron (84%) of φ 10.8 kg was obtained.-[Simplified description of the figure], Figure 1 shows the X-ray powder diffraction pattern of the C-shaped object. The axis represents the intensity (expressed in counts) and the X-axis represents the angle 20. Figure 2 shows the X-ray powder diffraction pattern of the D-shaped object. Figure 3 shows the X-ray powder diffraction pattern of the E-shaped object. Figure 4 shows the low-frequency Raman spectrum of the C, D, and E objects. The y-axis shows the Raman intensity (in φ AU (any unit)) and the X-axis shows the frequency. Description of main component symbols] None 0 -19-