WO2008006298A1

WO2008006298A1 - Novel crystal form of doripenem, preparation method and uses thereof

Info

Publication number: WO2008006298A1
Application number: PCT/CN2007/002066
Authority: WO
Inventors: Yuan Yu; Wuchun Zhou; Dayong Xu; Yu Huang; Zhongrong Liu; Bogang Li; Hongying Zhou; Mei Zhang; Chengwang Duan
Original assignee: Chengdu Di'ao Jiuhong Pharmaceutical Factory
Priority date: 2006-07-03
Filing date: 2007-07-03
Publication date: 2008-01-17
Also published as: CN101466713A

Abstract

A novel crystal of (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(3S,5S)-5-sulfamoylaminomethylpyrrolidin-3-yl]thio-1-methyl-1-carba-2-penem-3-carboxylic acid or a hydrate thereof (hereinafter, abbreviated as doripenem). In the diffraction pattern in powder X-ray diffraction, the crystal has main peaks at diffraction angles(2ϑ)=6.46,15.27,16.41,17.49,20.72,23.05 and 25.38(degrees)±0.1. At room temperature, the crystal is more thermodynamically stable, its dissolubility is higher, the crystal can be produced in industry with simple process and lower cost. A medicament composition containing the novel crystal of doripenem, preparation method and the uses in the manufacture of a medicament for the prevention of infection thereof.

Description

多尼培南的新结晶及其制备方法和用途技术领域 New crystal of doripenem and preparation method and use thereof

本发明涉及药物新晶型，具体来说涉及多尼培南—— (lR,5S，6S)-6-[ (1R)-1- 羟乙基] -2- [ (3S, 氨磺酰氨基曱基吡咯烷 -3-基]硫基- 1-曱基 -1-碳代 -2- 青霉烯 -3-羧酸或其水合物的新结晶，及其制备方法；还涉及多尼培南新晶型在制备抗感染药物中的用途以及含有多尼培南新晶型的药物组合物。背景技术 The present invention relates to a novel crystalline form of a drug, in particular to doripenem - (lR,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(3S, sulfamoylamino) New crystals of decylpyrrolidin-3-yl]thio-1-1-mercapto-1-carbo-2-penems-3-carboxylic acid or a hydrate thereof, and a preparation method thereof; Use of Nanxin crystal form in preparing anti-infective drugs and pharmaceutical composition containing new form of doripenem.

由下式表示多尼培南是一个新的 1 β -甲基碳青霉烯抗生素 ,2位侧链是氨基横酰胺取代的四氢吡咯环。构效关系研究表明，多尼培南侧链氨基的酰化或磺酰化有利于抗菌活性的增加，对革兰氏阳性菌的抑制活性高于美洛培南，对革兰氏阴性菌的抑制活性高于亚胺培南,对亚胺培南耐药菌也有效,对丝氨酸 β - 内酰胺酶和腎脱氢肽酶稳定,可用于脑部、肾脏和肺部的严重感染的治疗【中国新药杂志 2003年第 12卷第 9期 700-703】。 It is represented by the following formula that doripenem is a novel 1 β-methyl carbapenem antibiotic, and the 2-position side chain is an aminotransamide-substituted tetrahydropyrrole ring. The structure-activity relationship study showed that the acylation or sulfonylation of the side chain amino group of doripenem was beneficial to the increase of antibacterial activity, and the inhibitory activity against Gram-positive bacteria was higher than that of meropenem, against Gram-negative bacteria. It has higher inhibitory activity than imipenem, is also effective against imipenem-resistant bacteria, stable to serine β-lactamase and renal dehydropeptidase, and can be used for the treatment of severe infections in the brain, kidneys and lungs. Chinese Journal of New Drugs, Vol. 12, No. 9, 2003, 700-703].

中国专利 CN92111069.3以及 CN200510021270.1 涉及多尼培南的制造，但仅涉及了其无定形粉末的制备，多尼培南无定形粉末在保存过程中的稳定性差，在通常的环境下长时间保存时，会产生变色、而且纯度下降的问题。为此, 中国专利 CN1048248C和 CN1192030C涉及了多尼培南的四种结晶及其制造方法，四种结晶分别命名为 I、 II、 III、 IV型结晶，分别具有以下所示的特征衍射角度（2 Θ ) 的峰： Chinese patents CN92111069.3 and CN200510021270.1 relate to the manufacture of doripenem, but only to the preparation of its amorphous powder. The stability of the polyaniline amorphous powder during storage is poor, and it is long in the usual environment. When stored, there is a problem of discoloration and a decrease in purity. To this end, Chinese patents CN1048248C and CN1192030C refer to the four crystals of doripenem and their manufacturing methods. The four crystals are named I, II, III, IV crystals, respectively, and have the characteristic diffraction angles shown below (2 Θ ) Peak:

I型： 7.32, 14.72、 18.62、 20.42、 21.1、 22.18、 23.88、以及 29.76(度） II型: 6.06、 12.2、 14.56、 17.0、 18.38、 20.68、 24.38、 24.60、 25.88、以及 30.12(度)。 Type I: 7.32, 14.72, 18.62, 20.42, 2.11, 22.18, 23.88, and 29.76 (degrees) Type II: 6.06, 12.2, 14.56, 17.0, 18.38, 20.68, 24.38, 24.60, 25.88, and 30.12 (degrees).

III型： 6.78、 6.96、 15.74、 17.92、 21.16、 23.56、以及 25.80(度)。 Type III: 6.78, 6.96, 15.74, 17.92, 21.16, 23.56, and 25.80 (degrees).

IV型: 13.04、 14.98、 15.88、 16.62、 20.62、 21.06、 22.18、 23.90、 26.08、 28.22、以及 29.98(度；)。 Type IV: 13.04, 14.98, 15.88, 16.62, 20.62, 21.06, 22.18, 23.90, 26.08, 28.22, and 29.98 (degrees;).

( X-射线衍射的测定条件： CuKa线、 1.54A (单色器）、管电压 40KV、 (Measurement conditions for X-ray diffraction: CuKa line, 1.54A (monochromator), tube voltage 40KV,

1 1

确认本管电流 25mA )。 Confirmation Tube current 25mA).

在这四种晶型中， I、 II、 III型稳定性不好，只有 IV型是其中稳定性最好的晶型。而 IV型晶型必须由 III型结晶干燥的方法获得，优选是加热并减压下干燥获得，制备工艺复杂、制备成本高。 Among the four crystal forms, type I, II, and III are not stable, and only type IV is the most stable crystal form. The type IV crystal form must be obtained by the method of crystal drying of type III, preferably by heating and drying under reduced pressure, and the preparation process is complicated and the preparation cost is high.

因此，在本领域，仍有必要研究热力学稳定性更好、溶解性更好、可工业化生产、制备成本更低的多尼培南新晶型及其制剂，和它们制备方法，以保证原料药及其制剂在制备和储存中的稳定性以提高药物质量、临床疗效。发明内容 Therefore, in the field, it is still necessary to study the new crystal form of doripenem and its preparation with better thermodynamic stability, better solubility, industrial production, and lower preparation cost, and preparation methods thereof to ensure the raw material medicine The stability of its preparation in preparation and storage to improve the quality of the drug and clinical efficacy. Summary of the invention

为了克服上述缺陷，本发明的目的在于提供稳定性优良的一种多尼培南的新型结晶（以下称之为 V型结晶），在该结晶的粉末 X线衍射的衍射图中，在衍射角度（2 Θ ) =6.46、 15.27、 16.41、 17.49、 20.72、 23.05及 25.38 (度) ± 0. 1处有特征吸收峰。 In order to overcome the above drawbacks, an object of the present invention is to provide a novel crystal of doripenem (hereinafter referred to as V-type crystal) excellent in stability, in the diffraction pattern of powder X-ray diffraction of the crystal, at a diffraction angle (2 Θ ) = 6.46, 15.27, 16.41, 17.49, 20.72, 23.05 and 25.38 (degrees) ± 0.1 There are characteristic absorption peaks.

本发明所称的多尼培南新晶型化合物是 (lR,5S,6S)-6- [ (1R)-1-羟乙基] -2- [ (3S，5S)-5-氨磺酰氨基曱基吡咯烷 -3-基 ]硫基-1-曱基 -1-碳代 -2-青霉烯 -3-羧酸或其水合物的新晶型。 The novel form of doripenem known in the present invention is (lR,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(3S,5S)-5-sulfamoyl A new crystalline form of aminomercaptopyrrolidin-3-yl]thio-1-indenyl-1-carbo-2-penem-3-carboxylic acid or a hydrate thereof.

上述结晶的粉末 X-射线衍射的衍射图中，由于 X-射线衍射测定时，测定 , 的仪器或测定的条件，对于所测得的峰而言会稍有测定误差。具体来说， 2 Θ 值的误差在 ± 0. 1 以内。本实验采用四川大学分析测试中心的 X-射线衍射仪 DX-1000,测定 IV型结晶的 2 Θ值与专利公开的 2 Θ值完全吻合,误差在土 0.1以内。但根据仪器的精密度 ,2 Θ值的测定误差有时也可以为约士 0.2。 In the diffraction pattern of the X-ray diffraction of the above-mentioned crystal powder, the measurement or the conditions of the apparatus or measurement by X-ray diffractometry have a slight measurement error with respect to the measured peak. Specifically, the error of the 2 Θ value is within ± 0.1. In this experiment, the X-ray diffractometer DX-1000 of the Analysis and Testing Center of Sichuan University was used to determine that the 2 Θ value of the type IV crystal is completely consistent with the 2 Θ value disclosed in the patent, and the error is within 0.1. However, depending on the precision of the instrument, the measurement error of the 2 Θ value may sometimes be about 0.2.

本发明所述的多尼培南的晶型，其含有不少于 2分子的结晶水，进一步地，其含有 2分子的结晶水，其熔融点为 175 ± 2°C , 差示扫描量热吸热峰值分别在 98-115°C和 160-170°C。 The crystal form of doripenem according to the present invention contains not less than 2 molecules of crystal water, and further, it contains 2 molecules of crystal water having a melting point of 175 ± 2 ° C, differential scanning calorimetry The endothermic peaks were 98-115 ° C and 160-170 ° C, respectively.

研究发现，在室温条件下，准确地说当温度在 50°C以下时，本发明的 V 型结晶相当稳定，而当温度升至 50°C以上时，在 98-115°C出现吸热峰， V型结晶发生转变，成为 IV型结晶，因此，在 160-170 °C出现吸热峰，与这种变化是吻合的。 It has been found that, at room temperature, the V-type crystal of the present invention is quite stable when the temperature is below 50 ° C, and the endothermic peak appears at 98-115 ° C when the temperature rises above 50 ° C. V-type crystals change to become type IV crystals. Therefore, an endothermic peak appears at 160-170 °C, which is consistent with this change.

如附图 4、附图 5所示，在 DSC (示差扫描量热法)的图谱中显示， IV型结晶与 V型结晶的熔点 (分解起始温度)分别是 174.38°C和 176.74°C , 在分解之前的熔融过程中， IV型结晶有一个吸热峰（ 169.31 °C )，溶解焓为 64.47焦耳 / 克，而 V型结晶有两个吸热峰（98.63Ό和 164.78Ό )，溶解焓分别为 85.34焦耳 /克和 113.2焦耳 /克，说明 V型结晶转变为 IV型结晶的过程是熵增的过程，也就是说 V型结晶与 IV型结晶相比，处于更 ^的能级，在室温下具有更好的热力学稳定性和储存稳定性。本发明还提供一种药物组合物，其含有权利要求 1至 5任一项所述的多尼培南新晶型，所述药物组合物为口服制剂注射制剂、外用制剂或局部给药制剂形式。 As shown in FIG. 4 and FIG. 5, in the DSC (differential scanning calorimetry) pattern, the melting points (decomposition initiation temperatures) of the type IV crystal and the type V crystal are 174.38 ° C and 176.74 ° C, respectively. In the melting process before decomposition, the type IV crystal has an endothermic peak (169.31 °C), the dissolved enthalpy is 64.47 joules/gram, and the V-type crystal has two endothermic peaks (98.63 Ό and 164.78 Ό), dissolved 焓The process is 85.34 joules / gram and 113.2 joules / gram, respectively, indicating that the process of converting V-type crystal into type IV crystal is a process of entropy increase, that is, V-type crystal is at a higher energy level than IV-type crystal. Better thermodynamic stability and storage stability at room temperature. The present invention also provides a pharmaceutical composition comprising the novel form of doripenem according to any one of claims 1 to 5, which is in the form of an oral preparation for injection preparation, a topical preparation or a topical preparation. .

优选的，是口服制剂或注射制剂。所述口服制剂含有权利要求 1至 5任一项所述的多尼培南新晶型，以及药学上可接受的药用辅料、载体或助剂，所述的药学上可接受的药用辅料、载体或助剂是乳糖，硬脂酸，淀粉，明胶，硬脂酸镁，十二烷基硫酸钠，羧曱基淀粉钠，微晶纤维素中的至少一种。 Preferably, it is an oral preparation or an injection preparation. The oral preparation containing the novel form of doripenem according to any one of claims 1 to 5, and a pharmaceutically acceptable pharmaceutical excipient, carrier or adjuvant, the pharmaceutically acceptable pharmaceutical excipient The carrier or adjuvant is at least one of lactose, stearic acid, starch, gelatin, magnesium stearate, sodium lauryl sulfate, sodium carboxymethyl starch, and microcrystalline cellulose.

所述注射制剂含有权利要求 1至 5任一项所述的多尼培南新晶型，以及药学上可接受的药用辅料、载体或助剂，所述的药学上可接受的药用辅料、载体或助剂是明胶、甘露醇，山梨醇，甘氨酸，碱性氨基酸以及有机酸的弱碱盐中的至少一种。 The injection preparation contains the novel form of doripenem according to any one of claims 1 to 5, and a pharmaceutically acceptable pharmaceutical excipient, carrier or adjuvant, the pharmaceutically acceptable pharmaceutical excipient The carrier or adjuvant is at least one of gelatin, mannitol, sorbitol, glycine, a basic amino acid, and a weak base salt of an organic acid.

或者，所述的注射制剂仅由权利要求 1至 5任一项所述的多尼培南新晶型组成。由于本发明的新晶型在室温条件很稳定，当将其制备成粉针剂的时候甚至可以不需要加入其他药用辅料或助剂 ,只需在使用时加注射用蒸餾水溶解即可，这在临床上具有很大的优势。 Alternatively, the injectable preparation is composed only of the new form of doripenem according to any one of claims 1 to 5. Since the new crystal form of the present invention is stable at room temperature, it is not even necessary to add other medicinal adjuvants or auxiliaries when preparing the powder form, and it is only necessary to dissolve it by using distilled water for injection. Clinically, it has great advantages.

更进一步，上述的口服或注射制剂，每制剂单位含有 0.1 - 4g权利要求 1 所述的多尼培南的新晶型。 Further, the above oral or injectable preparation contains 0.1 - 4 g of the new crystalline form of doripenem of claim 1 per unit of preparation.

本发明还提供所述多尼培南新晶型的制备方法，该方法包括以下步驟， a. 将多尼培南粗品溶于水中，以及 The present invention also provides a method for preparing the novel form of the doripenem, the method comprising the steps of: a. dissolving the crude product of doripenem in water, and

b. 在权利要求 1所述结晶作为晶种的存在下，从步骤（a )所得的水溶液中析出结晶，过滤，真空干燥得到结晶。 b. In the presence of the crystal of claim 1 as a seed crystal, crystals are precipitated from the aqueous solution obtained in the step (a), filtered, and dried under vacuum to obtain crystals.

多尼培南新晶型晶种的获得：将多尼培南粗品溶于水中，用有机溶剂萃取氷溶液，有机溶剂可以是酮类溶剂：丁酮、曱基异丁基酮等脂肪族酮类；醚类： ***、异丙醚、丁醚等脂肪族醚；酯类：乙酸乙脂、乙酸异丙酯等脂肪族酯类；醇类：正丁醇、异丁醇、仲丁醇、戊醇、己醇、辛醇等脂肪族醇类； [¾代烃类：二氯曱烷、三氯曱烷等代烃类。萃取分离后的水溶液于低温下 (约 -10 ~ 40°C) 析出 V型结晶。通过控制结晶温度，可得到单一的 V型结晶。 Obtaining a new crystal form of doripenem: Dissolve the crude product of doripenem in water and extract the ice solution with an organic solvent. The organic solvent may be a ketone solvent: an aliphatic ketone such as butanone or decyl isobutyl ketone. Ethers: aliphatic ethers such as diethyl ether, diisopropyl ether, and dibutyl ether; esters: aliphatic esters such as ethyl acetate and isopropyl acetate; alcohols: n-butanol, isobutanol, sec-butanol, Aliphatic alcohols such as pentanol, hexanol, and octanol; [3⁄4 generation hydrocarbons: hydrocarbons such as dichloromethane, trichlorodecane, and the like. The extracted aqueous solution is precipitated at a low temperature (about -10 to 40 ° C) to form a V-form crystal. By controlling the crystallization temperature, a single V-type crystal can be obtained.

由于本发明的多尼培南新晶型可以直接得到，不需要从其他晶型通过减压干燥等步骤转变而来，因此， V型结晶的制备成本更低。 Since the novel form of the doripenem of the present invention can be directly obtained, it is not required to be converted from other crystal forms by a step of decompression drying, and therefore, the preparation cost of the V-type crystal is lower.

本发明还提供所述的多尼培南新晶型结晶在制备抗感染药物中的应用。本发明提供的多尼培南新晶型作为活性成分用于以前采用碳青霉烯类 (尤其是多尼培南)的药物的任何一种药剂的用途，特别在制备治疗抗感染药物中的应用。该新晶型具有广普的抗菌活性，对革兰氏阴性菌和革兰氏阳性菌都有效。主要用于呼吸***感染包括医院获得性肺炎、呼吸器相关性肺炎、腹内感染、泌尿生殖***感染、骨关节及皮肤软组织感染、皮肤深度感染、眼及耳鼻喉感染、其它严重感染如手术后二次感染、败血症等疾病的治疗。附图说明 The invention also provides the use of the novel crystal form of doripenem in preparing an anti-infective drug. The use of the novel form of doripenem provided by the present invention as an active ingredient for any of the agents previously using carbapenems (especially doripenem), especially in the preparation of anti-infective drugs application. The new crystal form has broad antibacterial activity and is effective against both Gram-negative and Gram-positive bacteria. Mainly used for respiratory infections including hospital acquired pneumonia, respirator-associated pneumonia, intra-abdominal infection, genitourinary infection, bone and joint and skin and soft tissue infections, deep skin infections, eyes and ear and nose Laryngeal infection, other serious infections such as secondary infection after surgery, sepsis and other diseases. DRAWINGS

图 1实施例 2所得的 V型结晶的粉末 X线衍射的衍射图； Figure 1 is a diffraction pattern of X-ray diffraction of a V-type crystal powder obtained in Example 2;

图 2实施例 3所得的 V型结晶室温存放 1月后的粉末 X线衍射的衍射图；图 3实施例 2所得的 V型结晶室温存 6月后的粉末 X线衍射的衍射图；图 4实施例 2所得的 V型结晶的 DSC图； 2 is a diffraction pattern of powder X-ray diffraction after storage of V-type crystal obtained in Example 3 at room temperature for 1 month; FIG. 3 is a diffraction pattern of powder X-ray diffraction after leaving the V-type crystal obtained in Example 2 at room temperature for 6 months; a DSC chart of the V-form crystal obtained in Example 2;

图 5 1¥型结晶的08(：图； Figure 5 1 ¥ crystal crystallization 08 (: Figure;

图 6实施例 2所得的 V型的结晶红外光 if "图； Figure 6 shows the V-type crystalline infrared light obtained in Example 2;

图 7 IV型结晶的结晶红外光讲图； Figure 7 is a crystalline infrared light diagram of type IV crystal;

图 8实施例 2所得的 V型结晶的 TGA分析图。 Fig. 8 is a TGA analysis chart of the V-form crystal obtained in Example 2.

显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。 It is apparent that various other modifications, substitutions and changes can be made in the form of the above-described embodiments of the present invention.

以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。发明的具体实施方式 The above content of the present invention will be further described in detail below by way of specific embodiments of the embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Techniques based on the above teachings of the present invention are all within the scope of the present invention. DETAILED DESCRIPTION OF THE INVENTION

【实施例 1】多尼培南粗品的制备： [Example 1] Preparation of crude doripenem:

多尼培南可以用以前的已知方法合成。如用 CN200510021270.1公开的方法获得多尼培南粗品。也可以用以下方法制备： Doripenem can be synthesized using previously known methods. The crude product of doripenem is obtained by the method disclosed in CN200510021270.1. It can also be prepared by the following method:

(1)、巯基吡咯烷衍生物的制备 (1) Preparation of decylpyrrolidine derivatives

将 (2S，4S)-1-对硝基苄氧羰基 -2-(N-对硝基苄氧羰基 -N-氨磺酰氨基）曱基 -4-乙酰硫基吡咯烷 50克 (81.8亳摩尔)溶于 200毫升四氢呋喃,：水浴下滴加 6克氢氧化锂的 20毫升水溶液，滴加完毕后继续搅拌 120分钟,用 6当量盐酸酸化, 析出固体粘稠物,将之用乙酸乙酯溶解后再加入乙醇,冷冻、沉淀出淡黄色无定形固体粉末 32克,收率 68.8%。 (2S,4S)-1-p-Nitrobenzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N-sulfamoylamino)indolyl-4-acetylthiopyrrolidine 50 g (81.8 亳) Mol) is dissolved in 200 ml of tetrahydrofuran, and a 6 ml aqueous solution of 6 g of lithium hydroxide is added dropwise in a water bath. After the completion of the dropwise addition, stirring is continued for 120 minutes, acidified with 6 equivalents of hydrochloric acid, and a solid viscous material is precipitated, and ethyl acetate is used. After the dissolution, ethanol was added, and 32 g of a pale yellow amorphous solid powder was frozen and precipitated, and the yield was 68.8%.

( 2 )、保护的吡咯烷硫基碳青霉烯的制备 (2) Preparation of protected pyrrolidinyl carbapenem

将（lR,5R,6S)-6- [ (1R)-1-羟乙基] -2-二苯氧磷酰氧基 -1-曱基 -1-碳代 -2- 青霉浠 -3-羧酸对硝基苄基酯 (17.82克, 30 毫摩尔)和 (2S,4S)-1-对硝基苄氧羰基 -2-(N-对硝基苄氧叛基 -N-氨磺酰氨基)曱基 -4-巯基吡咯烷 (22克, 38.66 毫摩尔）溶于 250毫升 DMF,)水浴冷却下加入二异丙基乙胺 (7.23毫升, 42.5毫摩尔），120 分钟后，反应混合物用乙酸乙酯稀释,依此用 1 当量盐酸、饱和碳酸氢钠和饱和食盐水洗涤,无水硫酸钠干燥后浓缩至小体积,加入曱苯沉淀出固体,过滤、干燥得淡黄色无定形固体粉末 27克 (收率 98.5%)。 (lR,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-diphenoxyphosphoryloxy-1-mercapto-1-carbo-2-penicillin-3 - p-nitrobenzyl carboxylate (17.82 g, 30 mmol) and (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-(N-p-nitrobenzyloxy-N-sulfonate Acylamino)hydrazino-4-mercaptopyrrolidine (22 g, 38.66 mmol) dissolved in 250 ml of DMF, and then added to diisopropylethylamine (7.23 ml, 42.5 mmol) in a water-cooling bath. The mixture was diluted with ethyl acetate, and then washed with 1N hydrochloric acid, saturated sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, and then evaporated to a small volume. A pale yellow amorphous solid powder of 27 g (yield 98.5%) was obtained.

(3 )、脱保护 (3), deprotection

将（lR,5R,6S)-2- [ (3S,5S)小对硝基苄氧羰基 -5-( N-对硝基苄氧 -N-氨磺酰氨基)曱基吡咯烷- 3-基]硫基 -6- [ (1R)- 1-羟乙基] -1-曱基 -1-碳代 -2-青霉烯 -3-羧酸对硝基苄酯 (10克, 10.95毫摩尔)溶于 180毫升四氢呋喃中,加入 120 毫升水和 10克 10%钯 /碳 (含水量 54%)，于 0.5MPa氢气压下搅拌 4小时后，反应混合物过滤除去催化剂,加入 1.4克六水氯化镁,再加入 300毫升四氢呋喃分相，分出水相后加入三倍体积的异丙醇，冷冻，将沉淀物减压干燥得（lR,5S，6S)-6- [ (1R)-1-羟乙基 ] -1- [ (3S,5S)-5-氨磺酰氨基曱基吡咯烷 -3-基 ]硫基 -1-甲基 -1- 碳代 -2-青霉烯 -3-羧酸的白色粉末 2.269g (多尼培南粗品)。 (lR,5R,6S)-2-[(3S,5S) small p-nitrobenzyloxycarbonyl-5-(N-p-nitrobenzyloxy-N-sulfamoylamino)decylpyrrolidine-3- Thio-6-[(1R)-1-hydroxyethyl]-1-mercapto-1-carbo-2-penems-3-carboxylic acid p-nitrobenzyl ester (10 g, 10.95 m Mole) was dissolved in 180 ml of tetrahydrofuran, 120 ml of water and 10 g of 10% palladium/carbon (54% water content) were added, and stirred under a hydrogen pressure of 0.5 MPa for 4 hours, the reaction mixture was filtered to remove the catalyst, and 1.4 g of hexahydrate was added. Magnesium chloride, adding 300 ml of tetrahydrofuran phase separation, separating the aqueous phase, adding three volumes of isopropanol, freezing, and drying the precipitate under reduced pressure to obtain (lR, 5S, 6S)-6-[(1R)-1-hydroxyl Ethyl]-1-[(3S,5S)-5-sulfamoylaminodecylpyrrolidin-3-yl]thio-1-methyl-1-carbo-2-penem-3-carboxylate Acid white powder 2.269 g (donipenem crude).

【实施例 2】本发明多尼培南新晶体的制备 [Example 2] Preparation of Dominican New Crystal of the Present Invention

1、晶种的制备：将多尼培南粗品 10克加入 100毫升蒸榴水中，用 40毫升乙酸乙酯萃取 3次，将水溶液在室温（8 - 13 °C )下放置一夜，析出晶体，过滤，室温真空干燥得晶种。 1. Preparation of seed crystals: 10 g of crude product of doripenem was added to 100 ml of distilled water, extracted three times with 40 ml of ethyl acetate, and the aqueous solution was allowed to stand at room temperature (8 - 13 ° C) overnight to precipitate crystals. Filtration, vacuum drying at room temperature to obtain seed crystals.

2、新晶体的制备：将多尼培南粗品 10克加入 200毫升蒸馏水中，在 50 2. Preparation of new crystals: Add 10 grams of crude doripenem to 200 ml of distilled water at 50

± 5°C下加热溶解，加入 0.5克针用活性炭脱色 10分钟，过滤，将滤、液冷却至 0 - 5Ό后，加入 20毫克 V型结晶的晶种，搅拌 4小时使结晶析出，然后緩锾. 滴加 100毫升异丙醇，滴加完毕后降温至 -1(TC继续晶析熟化一夜，然后滤出结晶。所得的结晶用 80%的异丙醇水（20毫升）洗净后，在室温下减压（20 ~ 30mmHg )干燥约 7小时，即得到多尼培南的 V型结晶。 HPLC法含量测定： 99.89 %。 Dissolve and dissolve at ± 5 ° C, add 0.5 g of needle and decolorize with activated carbon for 10 minutes, filter, and filter the liquid to 0 - 5 Torr, add 20 mg of V-crystal seed crystals, stir for 4 hours to precipitate crystals, then slow 100. Add 100 ml of isopropanol dropwise, and after cooling, cool down to -1 (TC continues to crystallize for one night, then filter out the crystals. The obtained crystals are washed with 80% isopropanol water (20 ml). After drying at room temperature under reduced pressure (20 ~ 30 mmHg) for about 7 hours, the V-form crystal of doripenem was obtained. HPLC content determination: 99.89 %.

粉末 X线衍射测定条件： CuK a线， 1.54A (单色器）、管电压 40KV、管电流 25mA。所得结晶的粉末 X线衍射测定结果示于图 1中。就所得的结晶而言，粉末 X线^ "射的衍射图中，在衍射角度（2 Θ ) =6.411、 15.229、 16.369、 17.446、 20.688、 23.056及 25.337 (度) ± 0.1处有特征吸收峰。此外,在衍射角度（2 Θ ) =11.262、 12.222、 12.880、 14.507、 18.458、 19.374、 21.751、 23.660、 24.530、 24.890、 25.911、 27.257、 27.992、 29.284、 30.831、 33.954、 39.096土 0.1处有较低峰。 Powder X-ray diffraction conditions: CuK a line, 1.54A (monochromator), tube voltage 40KV, tube current 25mA. The results of the X-ray diffraction measurement of the obtained crystal powder are shown in Fig. 1. With respect to the obtained crystal, in the diffraction pattern of the powder X-ray, there were characteristic absorption peaks at diffraction angles (2 Θ ) = 6.411, 15.229, 16.369, 17.446, 20.688, 23.056, and 25.337 (degrees) ± 0.1. In addition, there are lower peaks at diffraction angles (2 Θ ) = 11.262, 12.222, 12.880, 14.507, 18.458, 19.374, 21.751, 23.660, 24.530, 24.890, 25.911, 27.257, 27.992, 29.284, 30.831, 33.954, 39.096 .

含水率 Moisture content

理论值 (二水合物）： 7.89% Theoretical value (dihydrate): 7.89%

热失重分析 ( TGA )测定值： 8.052% Thermogravimetric analysis (TGA) measured value: 8.052%

示差扫描量热法测得（DSC )熔融点： 176.74 °C Differential scanning calorimetry (DSC) melting point: 176.74 °C

将本发明的新结晶与 IV型结晶的结晶红外光谱图进行比较如图 6、图 7 及下表所示，两者是完全不同的。表 1 本发明多尼培南新晶型红外光语数据 Comparing the crystalline infrared spectra of the novel crystals of the present invention with the type IV crystals is completely different as shown in Figures 6, 7 and the table below. Table 1 Infrared optical data of the new crystal form of Doripenem of the present invention

吸收峰波数吸收峰波数 Absorption peak wave number absorption peak wave number

( cm"¹ ) ( cm"¹ ) 吸收峰强 ( cm" ¹ ) ( cm" ¹ ) absorption peak intensity

基团和振动类型 Group and vibration type

(IV型） (本发明 V型）度 (Type IV) (V type of the invention)

3531.8 3465.2 s 分子内氢键締合 0-H伸缩振动 3531.8 3465.2 s intramolecular hydrogen bond association 0-H stretching vibration

3391.2 3344.4 m 吡咯环 N-H伸缩振动 3391.2 3344.4 m pyrrole ring N-H stretching vibration

3260.0 3167.3 s 分子间氢键締合 0-H伸缩振动 3260.0 3167.3 s Intermolecular hydrogen bond association 0-H stretching vibration

与 N原子相连的 C-H不对称伸 C-H asymmetric extension connected to N atom

3077.8 m 3077.8 m

缩振动 Shrinking vibration

2949.9 s 甲基中 C-H不对称伸缩振动 2949.9 s methyl group C-H asymmetric stretching vibration

2923.1 2923.1 s 亚甲基中 C-H不对称伸缩振动 2923.1 2923.1 s methylene group C-H asymmetric stretching vibration

2853.4 2853.8 s 亚曱基中 C-H对称伸缩振动 2853.4 2853.8 s 曱曱 C C-H symmetric stretching vibration

1712.4 1737.2 s 中 C=0伸缩振动 1712.4 1737.2 s Medium C=0 stretching vibration

1629.8 m β内酰胺中 C=0伸缩振动 1629.8 m β-lactam C=0 stretching vibration

1567.1 1587.3 s C=C伸缩振动 1567.1 1587.3 s C=C stretching vibration

1454.4 1459.1 m 甲基中 C-H不对称变形振动 1454.4 1459.1 m methyl group C-H asymmetric deformation vibration

1377.1 1375.2 s 曱基中 C-H对称变形振动 1377.1 1375.2 s 曱 base C-H symmetric deformation vibration

1348.8 1319.0 1348.8 1319.0

1319.7 1281.6 1319.7 1281.6

s -S0₂-的不对称伸缩振动 Asymmetric stretching vibration of s -S0 ₂ -

1277.2 1259.5 1277.2 1259.5

1262.9 1262.9

1161.1 1148.1 s -S0₂-的对称伸缩振动 1161.1 1148.1 s -S0 ₂ - Symmetrical stretching vibration

1090.3 1073.9 m 仲醇 C-0伸缩振动 1090.3 1073.9 m secondary alcohol C-0 stretching vibration

1070.1 1050.0 m 叔胺的 C-N伸缩振动 1070.1 1050.0 m C-N stretching vibration of tertiary amine

928.6 943.0 m 氛基中 OH非平面变角振动 928.6 943.0 m OH non-planar angular vibration

763.1 765.2 m 吡咯环 N-H非平面摇摆 763.1 765.2 m pyrrole ring N-H non-planar rocking

核磁共振数据 Nuclear magnetic resonance data

¾ MR(D₂0) 3⁄4 MR (D ₂ 0)

δ 1.0029- 1.0150(d,J=7.26Hz,3H， C₄ 上的甲基中的三个质子）, 1.0721-1.0827(d,J=6.36Hz,3H , - CH(OH)CH₃ 上的曱基中的三个质子）, 1.5203-1.5703(m,lH , C β 质子）， 2.5026-2.5529(m,lH , C α质子）, 3.1362-3.1877(m,lH, C₄ c质子)， 3.1965-3.2339(m,lH, C₂ ⁷ β质子)， 3.1965-3.2339 (m,lH， -CH₂-NHS0₂NH₂上亚甲基中的一个质子), 3.2539- 3.2680(m, 1H， C₆上的质子) ,3.3118-3.3439(dd, 14.82、 4.38Hz,lH, -CH₂-MIS0₂NH₂上亚曱基中的一个盾子) ,3.4819-3.5143(dd，12.54、 7.08Hz,lH, C ct质子)，3.7021-3.752 l(m,lH， C α质子) ,3.8254-3.8677(m,lH, α质子) ,4.0128-4.0605(m,lH, C₅上的质子）, 4.0128-4.0605(m,lH, -CH(OH)CH₃中叔碳上的质子)。 δ 1.0029- 1.0150 (d, J = 7.26 Hz, 3H, three protons in the methyl group on C ₄ ), 1.0721-1.0827 (d, J = 6.36 Hz, 3H, - CH(OH) CH ₃ Three protons in the base), 1.5203-1.5703 (m, lH, C β proton), 2.5026-2.5529 (m, lH, C α proton), 3.1362-3.1877 (m, lH, C ₄ c proton), 3.1965- 3.2339 (m, lH, C ₂ ⁷ β proton), 3.1965-3.2339 (m, lH, - proton of -CH ₂ -NHS0 ₂ NH ₂ on a methylene group), 3.2539- 3.2680 (m, 1H, C ₆ Proton), 3.3118-3.3439 (dd, 14.82, 4.38 Hz, lH, -CH ₂ -MIS0 ₂ NH ₂ on a shield in the subunit), 3.4819-3.5143 (dd, 12.54, 7.08 Hz, lH, C Ct proton), 3.7021-3.752 l (m, lH, C α proton), 3.8254-3.8677 (m, lH, alpha proton), 4.0128-4.0605 (m, lH, proton on C ₅ ), 4.0128-4.0605 (m , lH, a proton on the tertiary carbon of -CH(OH)CH ₃ ).

1³C NMR(D₂0) δ 15.755(4 位上曱基碳原子)， 20.0508(-CH(OH)CH₃上的甲基碳原子),1 ³ C NMR (D ₂ 0) δ 15.755 (4-position fluorenyl carbon atom), 20.0508 (methyl carbon atom on -CH(OH)CH ₃ ),

32.6738(砒咯环 C位碳原子)， 39.2167(砒咯环 C位碳原子)， 42.4220(4位碳原子）， 43.0565(-CH₂-NHSO₂NH₂ 中碳原子）， 52.1510(砒咯环位碳原子）,32.6738 (C-position carbon atom of the fluorene ring), 39.2167 (C-position carbon atom of the fluorene ring), 42.4220 (4-position carbon atom), 43.0565 (carbon atom in -CH ₂ -NHSO ₂ NH ₂ ), 52.1510 (砒环 ring) Bit carbon atom),

55.8778(5 位碳原子)， 58.7527(6 位碳原子)， 59.5722(砒咯环 C 位碳原子),55.8778 (5-position carbon atom), 58.7527 (6-position carbon atom), 59.5722 (砒-ring ring C-position carbon atom),

65.0312(-CH(OH)CH₃中叔碳原子)， 133.6914(2位碳原子)， 138.1061(3位碳原子)， 167.6282(2位½碳原子)， 176.5966(7位羰基碳原子)。 65.0312 (tertiary carbon atom in -CH(OH)CH ₃ ), 133.6914 (2 carbon atom), 138.1061 (3 carbon atom), 167.6282 (2 position 1⁄2 carbon atom), 176.5966 (7-position carbonyl carbon atom).

【实施例 3】本发明多尼培南新晶体的重复制备： [Example 3] Repeated preparation of the new crystal of doripenem of the present invention:

为了确认上述实施例 1的重复性，利用实施例 2所得 V型结晶作为晶种进行重复试验。所得结晶的放置 1月的粉末 X线衍射测定结果示于图 2中，在衍射角度（2 Θ ) =6.471、 15.290、 16.402、 17.508、 20.748、 23.063及 25.396 (度）处有主峰。此外,在在衍射角度（2 Θ ) =11.275、 12.224、 12.894、 14.506、 18.444、 19.375、 21.739、 23.661、 24.528、 24.890、 25.911、 27.256、 27.981、 29.269、 30.804、 33.929、 39.081 ± 0.1处有较低峰。 In order to confirm the repeatability of the above Example 1, the V-type crystal obtained in Example 2 was used as a seed crystal for repeated tests. Placement of the obtained crystals The powder X-ray diffraction measurement results of 1 month are shown in Fig. 2, and there are main peaks at diffraction angles (2 Θ ) = 6.471, 15.290, 16.402, 17.508, 20.748, 23.063, and 25.396 (degrees). In addition, there are lower at diffraction angles (2 Θ ) = 11.275, 12.224, 12.894, 14.506, 18.444, 19.375, 21.739, 23.661, 24.528, 24.890, 25.911, 27.256, 27.981, 29.269, 30.804, 33.929, 39.081 ± 0.1 peak.

含水率：理论值（二水合物）： 7.89%,热失重分析（TGA )测定值： 8.003%。示差扫描量热法（DSC )测得熔点： 175.71 °C ; 红外光傳数据、核磁共振数据与实施例 2吻合。 Moisture content: theoretical value (dihydrate): 7.89%, thermogravimetric analysis (TGA) measured value: 8.003%. The melting point was measured by differential scanning calorimetry (DSC): 175.71 °C; the infrared light transmission data and the nuclear magnetic resonance data were in agreement with Example 2.

【实施例 4】本发明多尼培南新晶体的体外抗菌活性考察试验：本发明多尼培南新晶型对临床分离致病菌的体外抗菌活性，观察记录多尼培南新晶型、头孢他定和美罗培南对所试菌林 MIC值，计算 MC均值， MIC₅。， MIC_9Q, 及 MIC_range。受试菌株共计 40林菌，标准质控菌株：金黄色葡萄球菌 ATCC 25923、大肠埃希菌 ATCC 25922、铜绿假单孢菌 ATCC 27853; 临床分离菌株：包括以下菌株：铜绿假单孢菌 3株，大肠埃希菌 2株，大肠埃希菌 ESBLs 菌株 2株，肺炎克雷伯菌 4株，肺炎克雷伯菌 ESBLs 菌株 3株，阴沟肠杆菌 2株，对曱氧西林耐药金黄色葡萄球菌（MRSA ) 5株，对甲氧西林敏感金黄色葡萄球菌（MSSA ) 4株，对甲氧西林耐药表皮葡萄球菌（MRSE ) 6株，对曱氧西林敏感表皮葡萄球菌（MSSE ) 2株 ,· 产气肠杆菌 2株，变形杆菌 2株，其中 23林产 (3 -内酰胺酶（包括 ESBLs菌株）。以上菌株均为 2004 年 10 月至 2005年 1月在四川成都地区、北京地区收集的临床分离致病菌。在收集单位经 VITEK-60自动微生物鉴定仪鉴定再经本室，用 API 20E、20KE、 Staph 系列及常规方法重新鉴定。每林细菌在实验前经琼脂平板划单菌落分纯， 37°C隔夜新鲜培养的菌体适当稀释用于实验。 [Example 4] In vitro antibacterial activity test of the new crystal of doripenem of the present invention: In vitro antibacterial activity of the new form of doripenem of the present invention on clinical isolates of pathogenic bacteria, and observation of a new crystal form of doripenem, The MIC values of ceftazidime and meropenem against the tested strains were calculated and the mean MC value, MIC ₅ . , MIC _9Q , and MIC _range . A total of 40 strains of the tested strains, standard quality control strains: Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853; clinical isolates: including the following strains: Pseudomonas aeruginosa 3 2 strains of Escherichia coli, 2 strains of Escherichia coli ESBLs, 4 strains of Klebsiella pneumoniae, 3 strains of Klebsiella pneumoniae ESBLs, 2 strains of Enterobacter cloacae, resistant to oxoxacillin 5 strains of cocci (MRSA), 4 strains of methicillin-sensitive Staphylococcus aureus (MSSA), 6 strains of methicillin-resistant Staphylococcus epidermidis (MRSE), 2 strains of methicillin-sensitive Staphylococcus epidermidis (MSSE) 2 strains of Enterobacter aerogenes, 2 strains of Proteus, of which 23 forests (3 -lactamases (including ESBLs strains). The above strains were collected from Chengdu, Sichuan and Beijing in October 2004 to January 2005. The clinical isolates of pathogenic bacteria. The collection unit was identified by VITEK-60 automatic microbiological identification instrument and then re-identified by API 20E, 20KE, Staph series and conventional methods. Each forest bacteria was colonized by agar plate before the experiment. Pure, 37 ° C overnight cultured bacterial cells appropriately diluted fresh for experimentation.

多尼培南及其对照药美罗培南和头孢他定对所试细菌的体外抗菌活性试验 C_5Q, MIC₉₍₎，及 MICrange结果见表 2。多尼培南及其对照药美罗培南和头孢他定体外杀菌活性结果见表 3。表 2 多尼培南新晶体体外抗菌活性结果 In vitro antibacterial activity tests of doripenem and its reference drugs meropenem and ceftazidime against the tested bacteria C _5Q , MIC _{9 ()} , and MICrange results are shown in Table 2. The results of in vitro bactericidal activity of doripenem and its reference drugs meropenem and ceftazidime are shown in Table 3. Table 2 Results of in vitro antibacterial activity of new crystals of doripenem

MIC值（mg/L) MIC value (mg/L)

同同同同白 MICso MIC₉o MIC„ Same as the same MICso MIC ₉ o MIC

色 Color

*所试的 40株头孢他定 4 >128 0. 03->128 * 40 strains of ceftazidime tested 4 >128 0. 03->128

末上上上上 Upper and upper

菌本发明新晶型 0. 25 8 0. 06-16 The new crystal form of the invention 0. 25 8 0. 06-16

美罗培南 0. 125 8 0. 06-〉128 Meropenem 0. 125 8 0. 06->128

对头孢曲松耐药 Resistance to ceftriaxone

的 13株菌（头孢头孢他定 128 >128 2->128 13 strains of cephalosporin ceftazidime 128 >128 2->128

曲松 ΜΙΟ 本发明新晶型 8 16 0. 125-16 曲松 ΜΙΟ The new crystal form of the invention 8 16 0. 125-16

64mg/l) 美罗培南 8 32 0. 03->32 多尼培南新晶体体外杀菌活性（MBC ) 实验结果

64mg/l) Meropenem 8 32 0. 03->32 In vitro bactericidal activity (MBC) of doripenem new crystals

以上试验结果试验结果提示多尼培南新晶型的抗菌效果优于头孢他定和美罗培南。 The results of the above test results suggest that the antibacterial effect of the new form of doripenem is better than that of ceftazidime and meropenem.

【实施例 5】本发明多尼培南新晶体的稳定性考察试验 [Example 5] The stability test of the new crystal of doripenem of the present invention

考察本品对热的稳定性，将原料样品置于相对湿度为 75%的干燥器中，再置于 40°C恒温干燥箱中，分别于 1、 2、 3、 6月取样，考察性状、水分、含量、有关物质变化，结果见表 4。 Investigate the thermal stability of the product, place the raw material sample in a desiccator with a relative humidity of 75%, and then place it in a 40 °C constant temperature oven, and sample it at 1, 2, 3, and 6 months to investigate the traits. The results of water, content and related substances are shown in Table 4.

V型结晶室温存放 1月后和 6月后的粉末 X线衍射的衍射图与新制备的新型结晶的粉末 X线衍射图谱完全一致（如图 1 , 图 2, 图 3所示），证明 V 型结晶室温存放 6月后稳定性良好。 The diffraction pattern of powder X-ray diffraction after storage of V-type crystal at room temperature for 1 month and after 6 months is completely consistent with the powder X-ray diffraction pattern of the newly prepared new crystal (as shown in Fig. 1, Fig. 2, Fig. 3), which proves that V The crystals were stored at room temperature for 6 months and the stability was good.

表 4 本发明多尼培南新晶体高温高湿加速试验 Table 4 High temperature and high humidity accelerated test of the new crystal of Donibene in the present invention

^ 性状 ΐ 酸度比旋度 [α ] 含量（％) *i; ^ traits 酸 acidity specific rotation [α ] content (%) *i;

8.02 5.30 36.0 100.13 0.055 8.02 5.30 36.0 100.13 0.055

8.15 5.30 35.8 100.82 0.10 8.15 5.30 35.8 100.82 0.10

8.22 5.33 35.6 100.00 0.26 8.22 5.33 35.6 100.00 0.26

8.18 5.29 36.1 100.16 0.44 8.18 5.29 36.1 100.16 0.44

8.24 5.34 35.8 100.41 0.18 8.24 5.34 35.8 100.41 0.18

上述结果均显示本发明的新晶型是相当稳定的。 The above results all show that the new crystal form of the present invention is quite stable.

【实施例 6】本发明多尼培南新晶体的溶解性试验 [Example 6] Solubility test of the new crystal of doripenem of the present invention

温度 (。c ) Temperature (.c)

样品 Sample

30 35 40 30 35 40

V型结晶 31. 57 32. 14 Form V crystal 31. 57 32. 14

IV型结晶 19. 86 20. 63 一般认为，高熔点的晶型的溶解度小于低熔点的晶型，本试验的结果正好相反，提示在相对低温的条件下， V型结晶的稳定性大于 IV型结晶，此结果与差热分析的结果吻合。同时 IV型结晶在相同温度条件下溶解后，溶液的澄清度明显不及 V型结晶。 Form IV crystal 19. 86 20. 63 It is generally believed that the solubility of the high melting point crystal form is lower than that of the low melting point crystal form. The results of this test are reversed, suggesting that the stability of the V type crystal is greater than that of the IV type crystal under relatively low temperature conditions. The results are consistent. At the same time, after the type IV crystal is dissolved under the same temperature conditions, the clarity of the solution is obviously inferior to that of the V-form crystal.

【实施例 7】本发明多尼培南新晶体注射剂的制备： [Example 7] Preparation of Donicene New Crystal Injection of the Present Invention:

取多尼培南新晶型粉末，采用针剂制备工艺将其制成注射用粉针，每一个制剂包装的装量分别为 250mg, 500mg, 750mg和 1000mg。 The new crystalline form of doripenem was prepared into an injectable powder by an injection preparation process, and the dosage of each preparation package was 250 mg, 500 mg, 750 mg and 1000 mg, respectively.

【实施例 8】本发明多尼培南新晶体注射剂的制备： [Example 8] Preparation of Donicene New Crystal Injection of the Present Invention:

取多尼培南新晶型粉末，与甘露醇混合均匀，釆用针剂制备工艺将其制成注射用粉针，每一个制剂包装的装量为含多尼培南新晶型 250mg, 甘露醇 250mg_o Take the new crystal form of doripenem, mix it evenly with mannitol, and prepare it into the powder for injection with the preparation of injection. The dosage of each preparation package is 250mg of new form of doripenem, mannitol. 250mg _o

【实施例 9】本发明多尼培南新晶体片剂的制备 [Example 9] Preparation of Doripenem New Crystal Tablet of the Present Invention

本发明多尼培南新晶体 250g The new doripenem crystal of the invention 250g

HPMC Lvioo 30g HPMC Lvioo 30g

乳糖 70g Lactose 70g

硬脂酸镁 lg (共制成 1000片 ) 本发明多尼培南新晶体、 HPMC、乳糖混匀，以 75%乙醇为粘合剂制湿颗粒，过 22目筛， 50°C干燥 3h, 22目筛整粒，加入硬脂酸镁混匀压片，每片重 0.25g。用作抗菌药物。 Magnesium stearate lg (total 1000 pieces) The new crystal of doripenem, HPMC and lactose are mixed, and the wet granules are made of 75% ethanol as a binder, passed through a 22 mesh sieve, and dried at 50 ° C for 3 hours. The whole mesh was sieved through a 22-mesh sieve, and the magnesium stearate was mixed and compressed, and each tablet weighed 0.25 g. Used as an antibacterial drug.

本发明的多尼培南新晶型在室温下热力学稳定性更好、制备方法筒便，成本更低，原料药及其制剂在制备和储存中的稳定性良好，其药物质量、临床疗效均得到有效保证。另夕卜，由于其常温下优越的稳定性能，在制备粉针剂时，可以不添加药用辅料，对提高用药安全性和疗效都有好处，因此本发明的多尼培南新晶型为抗感染药物是供了一种新的途径。工业应用性 The novel form of doripenem of the invention has better thermodynamic stability at room temperature, the preparation method is convenient, the cost is lower, the stability of the raw material drug and its preparation in preparation and storage is good, and the drug quality and clinical curative effect are all good. Get a valid guarantee. In addition, due to its superior stability at room temperature, in the preparation of powder injections, it is possible to improve the safety and efficacy of the drug without adding a pharmaceutical excipient, and thus the new form of doripenem of the present invention is resistant. Infected drugs are a new way. Industrial applicability

本发明不仅提供了一种（lR,5S,6S)-6- [ (1R)-1-羟乙基 ] -2- [ (3S,5S)-5- 氨磺酰氨基甲基吡咯烷 -3-基]硫基小甲基 -1-碳代 -2-青霉烯 -3-羧酸或其水合物（以下筒称多尼培南）的新晶型，该结晶的粉末 X线衍射的衍射图中，在衍射角度（2 Θ ) =6.46、 15.27、 16.41、 17.49、 20.72、 23.05及 25.38 (度） ± 0.1处有主峰。还提供了含有多尼培南新晶型的药物组合物及制备多尼培南新晶型的方法和在制备抗感染药物中的用途。本发明新晶型室温下在热力学上更稳定、溶解性更好、可工业化生产、制备工艺筒单、制备成本更低。 The present invention not only provides (lR,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(3S,5S)-5-sulfamoylaminomethylpyrrolidine-3 a new crystalline form of a thiol-small methyl-1-carbo-2-penem-3-carboxylic acid or a hydrate thereof (hereinafter referred to as doripenem), which is powdered by X-ray diffraction In the diffraction pattern, there are main peaks at diffraction angles (2 Θ ) = 6.46, 15.27, 16.41, 17.49, 20.72, 23.05, and 25.38 (degrees) ± 0.1. Also provided are pharmaceutical compositions containing new forms of doripenem and methods of preparing novel forms of doripenem and use in the preparation of anti-infective agents. The new crystal form of the invention is thermodynamically more stable, has better solubility at room temperature, can be industrially produced, and has a simple preparation process and a lower preparation cost.

Claims

权利要求书 Claim

1、一种多尼培南—— (lR,5S,6S)-6- [ (1R)-1-羟乙基] -2- [ (3S,5S)-5-氨磺酰氨基甲基吡咯烷 -3-基 ]硫基 -1-甲基小碳代 -2-青霉烯 -3-羧酸或其水合物的新晶型，其特征在于，在该结晶的粉末 X线衍射的衍射图中，在衍射角度（2 Θ ) =6.46, 15.27、 16.41、 17.49、 20.72、 23.05及 25.38 (度) ± 0.1处有特征吸收峰。 1. A doripenem - (lR, 5S, 6S)-6- [(1R)-1-hydroxyethyl]-2-[(3S,5S)-5-sulfamoylaminomethylpyrrole A new crystalline form of alk-3-yl]thio-1-methyl small carbo-2-pyrimidine-3-carboxylic acid or a hydrate thereof, characterized by diffraction of powder X-ray diffraction of the crystal In the figure, there are characteristic absorption peaks at diffraction angles (2 Θ ) = 6.46, 15.27, 16.41, 17.49, 20.72, 23.05 and 25.38 (degrees) ± 0.1.

2、如权利要求 1所述的多尼培南的晶型，其含有不少于 2分子的结晶水。 The crystal form of doripenem according to claim 1, which contains not less than 2 molecules of water of crystallization.

3、如权利要求 2所述的多尼培南的晶型,其特征在于，其含有 2分子的结晶水。 The crystal form of doripenem according to claim 2, which contains 2 molecules of crystallization water.

4、如权利要求 1或 2所述的多尼培南的晶型，其熔融点为 175 ± 2°C。 4. The crystal form of doripenem according to claim 1 or 2, which has a melting point of 175 ± 2 °C.

5、如权利要求 1-4中任一项所述的多尼培南的晶型，差示扫描量热吸热峰值分别在 98-115 °C和 160-170°C。 The crystal form of doripenem according to any one of claims 1 to 4, wherein the differential scanning calorimetry peaks are 98-115 ° C and 160-170 ° C, respectively.

6、一种药物组合物，其特征在于：含有权利要求 1至 5任一项所述的多尼培南新晶型。 A pharmaceutical composition comprising the novel form of doripenem according to any one of claims 1 to 5.

7、如权利要求 6所述的药物组合物，其特征在于：所述药物组合物为口服制剂、注射制剂、外用制剂或局部给药制剂形式。 The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is in the form of an oral preparation, an injection preparation, a topical preparation or a topical preparation.

8、如权利要求 7所述的药物组合物，其特征在于：所述口服制剂含有权利要求 1至 5任一项所述的多尼培南新晶型，以及药学上可接受的药用辅料、载体或助剂。 The pharmaceutical composition according to claim 7, wherein the oral preparation contains the novel form of doripenem according to any one of claims 1 to 5, and a pharmaceutically acceptable pharmaceutical excipient. , carrier or auxiliary.

9、如权利要求 8所述的药物组合物，其特征在于：所述的药学上可接受的药用辅料、载体或助剂是乳糖，硬脂胶，淀粉，明胶，硬脂酸镁，十二烷基硫酸钠，羧甲基淀粉钠，微晶紆维素中的至少一种。 9. The pharmaceutical composition according to claim 8, wherein: the pharmaceutically acceptable pharmaceutical excipient, carrier or adjuvant is lactose, stearin, starch, gelatin, magnesium stearate, ten At least one of sodium dialkyl sulfate, sodium carboxymethyl starch, and microcrystalline cellulose.

10、如权利要求 7所述的药物组合物，其特征在于：所述注射制剂含有权利要求 1至 5任一项所述的多尼培南新晶型，以及药学上可接受的药用辅料、载体或助剂。 The pharmaceutical composition according to claim 7, wherein the injection preparation contains the new form of doripenem according to any one of claims 1 to 5, and a pharmaceutically acceptable pharmaceutical excipient. , carrier or auxiliary.

11、如权利要求 10所述的药物组合物，其特征在于：所述的药学上可接受的药用辅料、载体或助剂是甘露醇，山梨醇，甘氨酸，碱性氨基酸以及有机酸的弱碱盐中的至少一种。 The pharmaceutical composition according to claim 10, wherein the pharmaceutically acceptable pharmaceutical excipient, carrier or adjuvant is mannitol, sorbitol, glycine, basic amino acid and weak organic acid. At least one of the alkali salts.

12、如权利要求 7所述的药物组合物，其特征在于：所述的注射制剂由权利要求 1至 5任一项所述的多尼培南新晶型组成。 The pharmaceutical composition according to claim 7, wherein the injection preparation consists of the new form of doripenem according to any one of claims 1 to 5.

13、如权利要求 8、 10、 12任一项的药物组合物，其特征在于：所述口服或注射制剂每制剂单位含有 0.1 - 4g权利要求 1所述的多尼培南的新晶型。 The pharmaceutical composition according to any one of claims 8, 10, 12, wherein the oral or injectable preparation contains 0.1 - 4 g of the new crystalline form of doripenem according to claim 1 per unit of preparation.

14、制备权利要求 1所述结晶的方法，该方法包括以下步骤， 14. A method of preparing the crystallization of claim 1 comprising the steps of

a. 将多尼培南粗品溶于水中，以及 b. 在权利要求 1所述结晶作为晶种的存在下，从步骤（a )所得的水溶液中析出结晶，过滤，真空干燥得到结晶。 a. Dissolve the crude product of doripenem in water, and b. In the presence of the crystal of claim 1 as a seed crystal, crystals are precipitated from the aqueous solution obtained in the step (a), filtered, and dried under vacuum to obtain crystals.

15、制备权利要求 14所述晶种的方法，该方法包括以下步骤， 15. A method of preparing a seed crystal according to claim 14, the method comprising the steps of

将多尼培南粗品溶于水中，以及用有机溶剂萃取水溶液 2- 10次，萃取分离后的水溶液于低温下 (约 -10 ~ 40°C)析出 V型晶种。 The crude product of doripenem is dissolved in water, and the aqueous solution is extracted 2 to 10 times with an organic solvent, and the extracted aqueous solution is precipitated at a low temperature (about -10 to 40 ° C) to form a V-type seed crystal.

16、制备权利要求 15所述晶种的方法，其特征在于： 16. A method of preparing the seed crystal of claim 15 wherein:

萃取水溶液的有机溶剂可以是酮类溶剂：丁酮、甲基异丁基酮等脂肪族酮类；醚类：***、异丙醚、丁醚等脂肪族醚；酯类：乙酸乙脂、乙酸异丙酯等脂肪族酯类醇类：正丁醇、异丁醇、仲丁醇、戊醇、己醇、辛醇等脂肪族醇类；卤代烃类：二氯甲烷、三氯曱烷等代烃类。 The organic solvent for extracting the aqueous solution may be a ketone solvent: an aliphatic ketone such as methyl ethyl ketone or methyl isobutyl ketone; an ether: an aliphatic ether such as diethyl ether, diisopropyl ether or dibutyl ether; and an ester: ethyl acetate and acetic acid. Aliphatic ester alcohols such as isopropyl ester: aliphatic alcohols such as n-butanol, isobutanol, sec-butanol, pentanol, hexanol, and octanol; halogenated hydrocarbons: dichloromethane, trichlorodecane Equivalent hydrocarbons.

17、权利要求 1 - 5任一项所述的多尼培南新晶型结晶在制备抗感染药物中的应用。 Use of the novel crystal form of doripenem according to any one of claims 1 to 5 for the preparation of an anti-infective drug.