制药工程专业英语课文翻译1 5 11 13 16单元原文加翻译

Unit 1 Production of Drugs Depending on their production or origin pharmaceutical agents can be split into three groups: I .Totally synthetic materials (synthetics)， ?.Natural products，and ? .Products from partial syntheses (semi-synthetic products). The emphasis of the present book is on the most important compounds of groups I and ?一thus Drug synthesis. This does not mean，however，that natural products or other agents are less important. They can serve as valuable lead structures，and they are frequently needed as starting materials or as intermediates for important synthetic products. Table 1 gives an overview of the different methods for obtaining pharmaceutical agents. 1单元生产的药品 其生产或出身不同药剂可以分为三类: 1。完全(合成纤维)合成材料， ?。天然产物，和 ?。产品从(半合成产品)的部分合成。 本书的重点是团体的最重要的化合物?和?一所以药物合成。这并不意味着，但是，天然产品或其他代理人并 不太重要。它们可以作为有价值的领导结构，他们常常为原料，或作为重要的合成中间体产品的需要。 表1给出了获取药剂的不同方法的概述。 Table 1 Possibilities for the preparation of drugs Methods Examples 1. Total synthesis -over 75 % of all pharmaceutical agents (synthetics) 2. Isolation from natural sources (natural products): 2.1 Plants -alkaloids;enzymes;heart glycosides;polysaccharides;tocopherol; steroid precursors (diosgenin, sitosterin);citral (intermediate product for vitamins A, E，and K) 2.2 Animal organs一enzymes;peptide hormones;cholic acid from gall; insulin) from the pancreas;sera and vaccines 2. 3 Other sources一cholesterol from wool oils;L-amino acids from keratin and gelatine hydrolysates 3. Fermentation一antibiotics;L-amino acids;dextran; targeted modifications on steroids， e.g. 11-hydroxylation; also insulin, interferon, antibodies, peptide hormones，enzymes，vaccines 4. Partial synthetic modification of natural products (semisynthetic agents): 一alkaloid compounds;semisynthetic /3-lactam antibiotics;steroids;human insulin Several therapeutically significant natural products which were originally obtained from natural sources are today more effectively -i. e. more economically -prepared.. by total synthesis. Such examples include L-amino acids， Chloramphenicol，Caffeine, Dopamine， Epinephrine，Levodopa, peptide hormones，Prostaglandins，D-Penicillamine， Vincamine， and practically all vitamins. 表1对药物的可能性准备 方法举例 1。全合成，超过75,的药剂(合成纤维) 2。分离(天然产物)天然来源: 2.1植物-生物碱;酶;心甙，多糖，维生素E; 类固醇的前体(薯蓣皂素，sitosterin)，柠檬醛(中间产品 维生素A，E和K) 2.2动物器官一酶;肽激素;胆酸从胆;胰岛素)从 胰脏;血清和疫苗 2。从角蛋白和明胶L -氨基酸;三一胆固醇从羊毛油脂的其他来源 水解 3。一抗生素发酵; L -氨基酸，葡聚糖，对类固醇有针对性的修改， 例如11 -羟基化;也胰岛素，干扰素，抗体，肽 激素，酶，疫苗 4。部分合成修改(半合成剂)天然产品: 一生物碱化合物;半合成/ 3-内酰胺类抗生素;类固醇;人胰岛素 其中几个重要的治疗作用最初是从天然产品天然来源获得更有效的今天，我。大肠杆菌更经济的准备..由全合成。 这样的例子包括L-氨基酸，氯霉素，咖啡因，多巴胺，肾上腺素，左旋多巴，肽类激素，前列腺素，D -青霉胺， 长春胺，以及几乎所有的维生素。 Over the last few years fermentation - i. e. microbiological processes has become extremely important. Through modern technology and results from genetic selection leading to the creation of high performance mutants of microorganisms， fermentation has already become the method of choice for a wide range of substances. Both Eukaryonts (yeasts and moulds)and Prokaryonts(single bacterial cells，and actinomycetes)are used microorganisms. The following product types can be obtained: 1. cell material (single cell protein)， 2. enzymes， 3. primary degradation products (primary metabolites)， 4. secondary degradation products (secondary metabolites). 在过去的几年里发酵-岛大肠杆菌微生物过程变得极其重要。通过现代技术和基因选择的结果导致了 突变体的微生物创造高性能，发酵，已成为首选方法各种各样的物质。这两个Eukaryonts(酵母菌 和霉菌)和Prokaryonts(单细胞细菌，放线菌和)用于微生物。下列产品类型可以得到: 1。细胞的物质(单细胞蛋白)， 2。酶， 3。主要降解产物(主要代谢物)， 4。二级降解产物(次生代谢物)。 Disregarding the production of dextran from the mucous membranes of certain microorganisms，e. g. Leuconostoc mesenteroides，classes 2 and 3 are the relevant ones for the preparation of drugs. Dextran itself，with a molecular weight of 50,000 ~ 100,000，is used as a blood plasma substitute. Among the primary metabolites the L-amino acids from mutants of Corynebacterium glutamicum and Brevibacterium flavum are especially interesting. From these organisms some 350， 000 tones of monosodium L-glutamate (food additive)and some 70，000 tones of L-lysine(supplement for vegetable proteins)are produced. Further important primary metabolites are the purina nucleotides，organic acids， lactic acid，citric acid，and vitamins，for example vitamin B,2 from Propionibacterium shermanii. Among the secondary metabolites the antibiotics must be mentioned first. The following five groups represent a yearly worldwide value of US-$17 billion: 不顾来自某些微生物，大肠杆菌粘膜生产的葡聚糖克明串珠mesenteroides，2和3级是毒品有关的准备工作。 葡聚糖本身5万〜10万分子量，是用作血浆代用品。其中主要来自谷氨酸棒杆菌代谢产物和黄色短杆菌突变体的L -氨基酸特别有趣。从这些味精约35万吨L -谷氨酸(食品添加剂)生物体和L -赖氨酸(用于植物蛋白补充)约70,000 吨的生产。此外重要的初级代谢产物的普瑞纳核苷酸，有机酸，乳酸，柠檬酸和维生素，例如维生素B，从丙酸 shermanii 2。 其中次生代谢产物的抗生素必须首先提到。以下五组代表了美国每年170亿美元的全球价值: penicillins ( Penicillium chrysogenum )， cephalosporins ( Cephalosporium acremonium )， tetracyclines ( Streptomyces aureofaciens )， erythromycins ( Streptomyces erythreus )， aminoglycosides (e. g. streptomycin from Streptomyces griseus). About 5000 antibiotics have already been isolated from microorganisms，but of these only somewhat fewer than 100 are in therapeutic use. It must be remembered，however，that many derivatives have been modified by partial synthesis for therapeutic use;some 50，000 agents have been semisynthetically obtained from户lactams alone in the last decade. Fermentations are carried out in stainless steel fermentors with volumes up to 400 m3. To avoid contamination of the microorganisms with phages etc. the whole process has to be performed under sterile conditions. Since the more important fermentations occur exclusively under aerobic conditions a good supply of oxygen or air(sterile)is needed. Carbon dioxide sources include carbohydrates，e. g. molasses，saccharides，and glucose. Additionally the microorganisms must be supplied in the growth medium with nitrogen-containing compounds such as ammonium sulfate，ammonia，or urea，as well as with inorganic phosphates. Furthermore，constant optimal pH and temperature are required. In the case of penicillin G， the fermentation is finished after 200 hours，and the cell mass is separated by filtration. The desired active agents are isolated from the filtrate by absorption or extraction processes. The cell mass，if not the desired product，can be further used as an animal feedstuff owing to its high protein content. 青霉素(青霉) 头孢菌素(头孢枝顶) 四环素(金色链霉菌) (链霉菌) erythromycins 氨基糖苷类(如链霉素从灰色链霉菌)。 关于抗生素已经分离出的微生物，但其中只有不到有些治疗使用。必须记住，但是，许 5000100 多衍生工具已被用于治疗使用部分合成修改约剂已被取得户内酰胺在过去;50,000semisynthetically 十年孤独。发酵都是在不锈钢发酵罐出来的量高达立方米。为了避免与噬菌体等微生物污染的400 全过程都必须在无菌条件下进行。由于更重要的发酵只发生在有氧条件下的氧气或空气好电源(无菌) 是必要的。二氧化碳的来源包括碳水化合物，大肠杆菌克糖蜜，糖和葡萄糖。另外必须提供的微生物 在与含氮如硫酸铵，氨水或尿素化合物生长介质，以及与无机磷酸盐。此外，不断最适和温度是pH 必需的。在青霉素的情况下，发酵完成小时后，细胞的质量是由过滤分离。所需的活性剂是G200 隔离的滤液吸收或提取工艺。大规模的细胞，如果不理想的产品，可进一步用作动物，由于其蛋白质 含量高的饲料。 By modern recombinant techniques microorganisms have been obtained which also allow production of peptides which were not encoded in the original genes. Modified E. coli bacteria make it thus possible to produce A- and B- chains of human insulin or proinsulin analogs. The disulfide bridges are formed selectively after isolation，and the final purification is effected by chromatographic procedures. In this way human insulin is obtained totally independently from any pancreatic material taken from animals. Other important peptides，hormones，and enzymes，such as human growth hormone (HGH)，neuroactive peptides， somatostatin，interferons，tissue plasminogen activator (TPA)，lymphokines，calcium regulators like calmodulin，protein vaccines，as well as monoclonal antibodies used as diagnostics，are synthesized in this way. The enzymes or enzymatic systems which are present in a single microorganism can be used for directed stereospecific and regiospecific chemical reactions. This principle is especially useful in steroid chemistry. Here we may refer only to the microbiological 11-a- hydro xylation of progesterone to 11-a-hydroxyprogesterone，a key product used in the synthesis of cortisone. Isolated enzymes are important today not only because of the technical importance of the enzymatic saccharification of starch，and the isomerization of glucose to fructose，They are also significant in the countless test procedures used in diagnosing illness，and in enzymatic analysis which is used in the monitoring of therapy. A number of enzymes are themselves used as active ingredients. Thus preparations containing proteases (e. g. chymotrypsin，pepsin，and trypsin)，amylases and lipases， mostly in combination with synthetic antacids，promote digestion. Streptokinase and urokinase are important in thrombolytics，and asparaginase is used as a cytostatic agent in the treatment of leukemia. 利用现代微生物重组技术已获得这也让其中不是在原来的基因编码多肽的生产。改性大肠杆菌从而使可能产生 A型和B -人胰岛素或胰岛素原类似物链。二硫键形成的选择性分离后，最终由色谱净化工序的影响。通过这种方 式获得的人类胰岛素完全独立采取任何从动物胰腺材料。 其他重要肽，激素和酶，如人类生长激素(hGH)，神经活性肽，生长抑素，干扰素，组织型纤溶酶原激活 物(tPA)，淋巴因子，如钙调节钙调蛋白，蛋白疫苗，以及作为诊断用单克隆抗体是合成了这种方式。 这些酶或微生物在一个单一的酶系统，目前可用于立体定向和regiospecific化学反应。这个原则是有用的， 尤其是在化学类固醇。在这里，我们只能引用的微生物十一水电黄体酮xylation至11人羟，一个关键的产品在可 的松合成。隔离酶是重要的，不仅因为淀粉的酶法糖化技术重要性的今天，和葡萄糖异构果糖，他们也都在无数次 试验在诊断疾病所用的程序显着，在酶的分析，在使用监测治疗。 数量的酶本身作为活性成分。因此，含有蛋白酶制剂(如糜蛋白酶，胃蛋白酶和胰蛋白酶)，淀粉酶和脂肪 酶的合成主要是在与抗酸药相结合，促进消化。链激酶和尿激酶溶栓是重要的，是天冬酰胺酶在治疗白血病细胞生 长剂。 Finally mention must be made of the important use of enzymes as `biocatalysts’in chemical reactions where their stereospecificity and selectivity can be used. Known examples are the enzymatic cleavage of racemates of N-acetyl-D， L-amino acids to give L-amino acids， the production of 8-aminopenicillanic acid from benzylpenicillin by means of penicillinamidase and the aspartase-catalysed stereospecific addition of ammonia to fumaric acid in order to produce L-aspartic acid. In these applications the enzymes can be used in immobilized forms-somehow bound to carriers - and so used as heterogeneous catalysts. This is advantageous because they can then easily be separated from the reaction medium and recycled for further use. Another important process depending on the specific action of proteases is applied for the production of semisynthetic human insulin. This starts with pig insulin in which the alanine in the 30-position of the B-chain is replaced by a threonine tert-butyl ester by the selective action of trypsin. The insulin ester is separated，hydrolyzed to human insulin and finally purified by chromatographic procedures. Sources for enzymes include not only microorganisms but also vegetable and animal materials. In Table 1 it was already shown that over 75%of all pharmaceutical agents are obtained by total synthesis. Therefore knowledge of the synthetic routes is useful. Understanding also makes it possible to recognize contamination .of the agents by intermediates and by- products. For the reason of effective quality control the registration authorities in many countries demand as essentials for registration a thorough documentation on the production process. Knowledge of drug syntheses provides the R&D chemist with valuable stimulation as well. There are neither preferred structural classes for all pharmaceutically active compounds nor preferred reaction types. This implies that practically the whole field of organic and in part also organometallic chemistry is covered. Nevertheless，a larger number of starting materials and intermediates are more frequently used，and so it is useful to know the possibilities for their preparation from primary chemicals. For this reason it is appropriate somewhere in this book to illustrate a tree of especially important intermediates. These latter intermediates are the key compounds used in synthetic processes leading to an enormous number of agents. For the most part chemicals are involved which are produced in large amounts. In a similar way this is also true for the intermediates based on the industrial aromatic compounds toluene， phenol and chlorobenzene. Further key compounds may be shown in a table which can be useful in tracing cross-relationships in syntheses.f In addition to the actual starting materials and intermediates solvents are required both as a reaction medium and ,for purification via recrystallization. Frequently used solvents are methanol，ethanol，isopropanol，butanol，acetone， ethyl acetate，benzene，toluene and xylene. To a lesser extent diethyl ether，tetrahydrofuran，glycol ethers， dimethylformamide (DMF) and dimethyl sulphoxide (DMSO) are used in special reactions. 最后必须提到的，作为他们在那里`biocatalysts'in化学stereospecificity和选择性反应的酶可用于制造重要的 用途。著名的例子是对N -乙酰- D，L -氨基酸消旋给予L -氨基酸酶裂解，从青霉素生产8 -氨基青霉烷酸的 penicillinamidase手段和天冬氨酸酶，催化氨立体除了富马酸为了酸生产L -天门冬氨酸。 在这些酶可以在固定的形式使用的应用程序，在某种程度上势必运营商 - 等为异构催化剂。这是有利的， 因为他们可以很容易地分离反应介质和回收再利用。 另一个重要进程的具体行动蛋白酶是根据申请的半合成人胰岛素的生产。与猪胰岛素这将启动，其中在30 的B链的位置被替换为丙氨酸苏氨酸叔丁基由胰蛋白酶选择性作用酯。胰岛素酯分离，水解为人体胰岛素和程序， 最后由色谱纯化。 对酶的来源不仅包括微生物，而且蔬菜和动物材料。 在表1，已经显示，有超过75,是由药剂全合成获得。因此，合成路线的知识是有用的。认识也使我们能够 认识到污染。按中间体和副产品代理。为了有效的质量控制在许多国家的登记要领对生产过程的完整的文档要求登 记机关的原因。药物合成知识提供了宝贵的刺激研发化学家以及。 有没有首选的所有药学活性化合物，也反应类型结构类型的首选。这意味着几乎全部领域的有机和有机金属 化学中的一部分也被覆盖。不过，也有较大的起始原料和中间体数量较常用，所以它是非常有用的知道他们准备从 初级品的可能性。基于这个原因，它是在适当的地方， 说明 关于失联党员情况说明岗位说明总经理岗位说明书会计岗位说明书行政主管岗位说明书 这本书的重要中间体，尤其是树。后面这些中间体领导 到数目庞大的代理商合成工艺中的关键化合物。对于大多数的化学品是在涉及大量生产。以类似的方式，这也是对 工业芳香族化合物甲苯，苯酚和氯苯中间体为基础的真实。另一个关键的化合物可能会显示在表格可在追踪 syntheses.f交叉关系很有用 除了实际的起始原料和中间体溶剂作为反应介质要求和通过再结晶纯化，两者。常用的溶剂是甲醇，乙醇， 异丙醇，丁醇，丙酮，醋酸乙酯，苯，甲苯和二甲苯。在较小程度上乙醚，四氢呋喃，乙二醇醚，二甲基甲酰胺(DMF) 和二甲基亚砜(DMSO)的使用在特殊的反应。 Reagents used in larger amounts are not only acids (hydrochloric acid，sulfuric acid， nitric acid，acetic acid) but also inorganic and organic bases (sodium hydroxide，potassium hydroxide，potassium carbonate，sodium bicarbonate， ammonia，triethylamine，pyridine). Further auxiliary chemicals include active charcoal and catalysts. All of these supplementary chemicals (like the intermediates) can be a source of impurities in the final product. In 1969 the WHO published a treatise on `Safeguarding Quality in Drugs'.Appendix 2 is concerned with the `Proper Practice for Reparation and Safeguarding Quality in Drugs' (WHO Technical Report No. 418，1969，Appendix 2;No. 567， 1975，Appendix 1A). This has in the meantime become known as `Good Manufacturing Practices' or GMP rules，and these should now be obeyed in drug production. They form the basis for mutual recognition of quality certificates relating to the production of pharmaceuticals and for inspections of the production. facilities. For a long time the US drug authority，the Food and Drug Administration (FDA)，has issued regulations for the preparation of drugs analogous to the WHO rules，and it applies these strictly. Exports of drugs to the USA，like those of finished products，require regular inspection of the production facilities by the FDA. 5 It may merely be noted here that such careful control applies not only to the products， but also to the raw materials (control of starting Materials)，and also to the intermediates. Clearly. the technical and hygienic equipment of the production and the storage areas have to fulfill set conditions. Since only a few compounds，such as acetylsalicylic acid，paracetamol and vitamins，are prepared in large amounts， most of the actual production takes place in multi-purpose (multi-product) facilities. .Special care has to be taken to avoid cross-contamination by other products what can be effected by good cleansing of used apparatus. A careful description and definition of all stored intermediates and products is needed. Selected -from H. J. Roth and A. Kleemann, Pharmaceutical Chemistry, Vol. 1，Drug Synthesis, Ellis Horwood Limited，England, 1988. 在较大的数额使用的试剂，不仅酸(盐酸，硫酸，硝酸，醋酸)，而且无机和有机碱(氢氧化钠，氢氧化钾，碳酸 钾，碳酸氢钠，氨，三乙胺，吡啶)。进一步的辅助化学品包括活性炭和催化剂。这些(如中间体)补充品都可以 成为最终产品中杂质的来源。 1969年，世界卫生组织发表了`保障药品质量的论文中(WHO技术报告号418,1969，附录二，附录二是有关` 适当的做法的赔偿和保障药品质量。';号567,1975，附件1A)。这已成为在此期间为'良好生产规范'或GMP规则众 所周知的，现在应在这些药品生产服从。它们构成的质量有关的药品生产证书互认的生产和检验的基础。设施。 长期以来，美国药品管理局，美国食品和药物管理局(FDA)已发出的药品制剂类似于谁的规则规定，而且适用 于这些严格。向美国药物如成品者外，出口由FDA要求的生产设施进行定期检查。 5 它可能只是在此指出，这种严格控制不仅适用于产品，而且对原材料(原辅料控制)，同时还以中间体。清楚。 对生产和储存方面的技术和设备必须符合卫生规定的条件。 由于只有少数的化合物，如乙酰水杨酸，对乙酰氨基酚和维生素，是在大量的准备，在实际生产中最需要的多用 途(多产品)设施的地方。 。特别小心，注意避免交叉通过什么可以按所使用的仪器良好的清洁影响其他产品的污 染。经过仔细的描述和所有储存的中间体和产品的定义是必要的。 选择从黄建忠罗斯和A. Kleemann，药物化学，卷。 1，药物合成， 埃利斯霍伍德有限公司，英国，1988年。 6 Exercises 1. Answer the following questions: (1)How many groups can pharmaceutical agents be split into depending on their production or origin? (2)Can you illustrate any significant examples of pharmaceutical agents obtained by total synthesis? (3) What is the difference between the synthetic drugs and traditional Chinese herbal medicine? 2. Put the following into English: 3. Put the following into Chinese: Polysaccharide peptide hormone vaccine heterogeneous catalyst contamination plasma steroid penicillin metabolite 4. Fill in the blanks with the following verb words: derive term distinguish present compose Nucleic acids are polyanionic molecules of high molecular weight. These polymers are _____ of a sequence of subunits or nucleotides so that the whole is usually _____ a polynucleotide. The nucleic acids are of two main varieties， ribonucleic(RNA)and deoxyribonucleic (DNA).DNA is found primarily in the chromatin of the cell nucleus， whereas 90%of RNA is _____ in the cell cytoplasm and 10 0 o in the nucleolus. The two classes of nucleic acids are _____ primary on the basis of the five-carbon atom sugar or pentose present. Two general kinds of bases are found in all nucleic acids. One type is a derivative of the parent compound purine. Principle examples are guanine and adenine. The second class of bases found in all nucleic acids is _____ from the parent compound pyrimidine. 6习 题 快递公司问题件快递公司问题件货款处理关于圆的周长面积重点题型关于解方程组的题及答案关于南海问题 1。回答下列问题: (1)有多少组可以药剂成其生产或出身而定分裂, (2)你能说明所取得的全合成药剂任何重大的例子吗, (3)什么是之间的合成药物和传统中药的区别, 2。把以下内容翻译成英语: 3。把成中文如下: 多糖肽类激素疫苗非均相催化剂 青霉素类固醇代谢物污染血浆 4。填写以下动词的单词填空: 目前构成派生词区别 核酸是超高分子量聚阴离子分子。这些聚合物的一个亚基或核苷酸，使整个通常是一个多核苷酸序列 __________。核酸是两个主要品种，核糖核酸(RNA)和脱氧核糖核酸(DNA)的。DNA是主要 存在于细胞核内的染色质，而90,是_____的RNA在细胞的细胞质和细胞核中的10 0Ø。核酸类 _____两对五碳糖或戊糖原子现有基础上小学。一般两个种基地发现，在所有核酸。一类是母体化合 物嘌呤的衍生物。原理是鸟嘌呤和腺嘌呤的例子。在所有发现核酸碱基第二类是从母体化合物嘧啶 _____。 Unit 5 Drug Development (I) 1. Introduction Drug Development is a very complex process requiring a great deal of coordination and communication between a wide range of different functional groups. It is expensive， particularly in the later phases of clinical development，where studies involve hundreds of patients. It is currently estimated that the development of a new drug costs about$230 million(1987 dollars)and takes somewhere between 7 and 10 years from initiation of preclinical development to first marketing (excluding regulatory delays). Drug development is a high-risk business;although the rate is increasing，only about ONE out of every TEN new chemical entities studied in human beings for the first time will ever become a product. As a drug candidate progresses through development the risks of failure decrease as ‘hurdles’are overcome along the way. Typical reasons for failure include unacceptable toxicity，lack of efficacy，or inability to provide advantages over competitive products (Fig. 1). Attrition Rate of New Chemical Entities (NCE's) entering development. On average only about I in 400^1000 compounds synthesized enters development. Reasons for termination of development of NCE's (excluding anti-infectives) 1:Lack of efficacy 2: Pharmacokinetics 3: Animal toxicity 4: Miscellaneous 5: Adverse effects in man 6: Commercial reasons Fig. 1 Attrition rates and reasons for terminations 2. Planning for development Assessment of whether a drug candidate is likely to provide competitive advantages highlights the need first to have in place a set of product `goals' or target product profile. Particular attention should be paid to the differentiation from competitors. This is becoming 55 more and more critical with the increasing emphasis on limited formularies，healthcare costs， and pharmacoeconomics (discussed later in the chapter). A target profile will define the indication(s) that a drug candidate will be developed for， along with goals such as once a day dosing，faster onset of action，better side effect profile than a major competitor. The target profile can be refined and revised as a drug candidate moves through development and new data on the drug candidate or competitors become available. The logical next steps are to define the development strategy，for example，which indications to develop first，which countries to aim to market the drug in and then to define the core clinical studies necessary to achieve regulatory approval and commercial success. This chapter will describe the main activities required for successful development of a new drug. All these activities， many of which are interdependent，need to be carefully planned and co-ordinate. Speed to market with collection of high quality data is critical for success. The path of activities which determine the time it will take to get to registration is called， in project management terms，the critical path. It is vital to plan and prepare before studies begin and to monitor and manage problems so as to ensure that the critical path remains on schedule. With increased economic pressures and competitive intensity it is important for companies to explore ways to shorten this critical path. Running activities in parallel，or overlapping studies which would usually run sequentially，often involves an increase in risk but the dividends in time-saving can make such strategies worthwhile. The critical path for development of a new drug generally runs through the initial synthesis of compound，subacute toxicology studies，and then the clinical program. A chart showing the critical path activities for a typical drug candidate is shown in Fig. 2. Chemistry chemical Synthesis Route selection Pilot plant,scale up and stability testing Manufacturing plant production Toxicology Acute&subacute toxicology Long term and repro-toxicology Clinical Phase I Phase ll Phase lll Analysis data and report Phase lV Review Regulatory Submission and updating of clinical trial application prepare submit Authority MAA/NDA Regulatory Approval Post marketing Surverillance Pharmaceutics Preclinical,clinical and commercial formulation Development and stability testing Prepare labelling Drug metabolism and pharmacokinetics Animal ADME* Healthy humans Human patients Activities likely to be on the critical path are shown in bold * Absorption , Distribution , Metabolism , Excretion Fig. 2 The major processes in new drug development The following sections highlight the objectives and activities of drug development work.Activities within each technical discipline are described broadly in chronological order.At any one time，work in all these disciplines may be proceeding in parallel. The timing and outcome of much of the work has direct impact on work in other disciplines. The major phases of drug development are Preclinical ( studies required before the compound can be dosed in humans)，Phase I (clinical studies usually in healthy human volunteers ) Phase ? ( initial efficacy and safety and dose finding studies in patients)，and Phase ? (studies in several hundred patients). There then follows assembly of a marketing application dossier for subsequent review by country regulatory authorities. 3. Chemical development Rapid development of a drug candidate is dependent on the availability of sufficient quantity of the compound. The purity of compound needs to reach certain standards in order for it to be used in safety (toxicology)，pharmaceutical，and clinical studies. Initially，chemists will work on a small to medium scale to investigate production of the compound by several Optimum’ here may mean a different methods so as to identify the optimum route for synthesizing the compound. ‘ combination of several factors，for example，most efficient， cheapest safe，or that producing minimal waste. Analysis of the final product as well as intermediates and impurities plays a key role in identifying the best method of synthesis. Development and validation of analytical methods are necessary to support process development and guarantee the purity of the drug substance. In some cases levels of impurities may be unacceptably high and either improved purification procedures will need to be developed or the synthetic process may require significant alterations. The main aim is to ensure that the composition of compound is understood and that ultimately the material that is prepared is as pure as possible. As a drug candidate progresses through development，larger and larger amounts of compound are required. The amount of material required for different tests will often depend on the actual potency and dosage form of the compound. A pilot plant can be regarded as a mini-manufacturing set-up. Before transferring to a pilot plant，extensive evaluation and testing of the chemical synthesis is undertaken to ensure that any changes and hazards are minimized. Procedures are optimized，particular attention being paid to developing environmentally acceptable ways of disposing of waste products. Commercial production of bulk drug substance for production of a drug，once approved and marketed，will likely take place on a larger scale or at a registered manufacturing plant. 4. Formulation development The dosage form of a drug is the form by which it is administered to the patient. There are a vast array of possible dosage forms ranging from transdermal patches to inhalers to intranasal medicines. The more common dosage forms include oral tablets or capsules，oral liquids，topical ointments or creams，and injectables. The dosage form or forms chosen for a particular drug candidate will be defined in the target profile. Sometimes a more simple dosage form，for example an oral solution，is chosen for early 57 clinical studies in human beings. This may save time and upfront costs at an early，high-risk stage of the drug development process. Later clinical studies would use the expected marketed dosage form. Whatever the dosage form，the combination of drug and other materials which constitute it must fulfil certain criteria. One of the most important is that of adequate stability. That means a predetermined potency level must remain after，for example，two or three years. The stability data generated on a dosage form will determine its shelf-life and recommended storage conditions. Early in development the shelf-life may be limited to several months. This will not be a problem provided it is sufficient to cover use of the drug over the duration of the clinical study or studies. 5. Pharmacology Before a drug candidate is given to man，its pharmacological effects on major systems are often investigated in a number of species. The body systems studied include cardiovascular， respiratory，and nervous systems;the effects on gross behavior can also be studied. Experiments are sometimes conducted to see whether the drug candidate interferes with the actions of other medicines which，because of their specific effects or because of their common use，are likely to be taken concurrently with the drug candidate. Any synergism or antagonism of drug effects should be investigated，and any necessary warning issued to clinical investigators.(It may be judged necessary to investigate such effects further in clinical studies，and any potential or proven drug interactions are likely to be noted in the product labeling for the drug.) It may also be appropriate to identify a substance for possible use in the management of overdosage，particularly if the therapeutic margin of the drug candidate is small. 6. Safety evaluation The objective of animal toxicology testing，carried out prior to the administration of a drug to man，is to reject compounds of unacceptable toxicity and to identify potential target organs and timings for adverse effects of the drug. This means that in early human studies these organs and tissues can be monitored with particular attention. It is important to establish whether toxic effects are reversible or irreversible，whether they can be prevented and，if possible，the mechanism of the toxicological effects. It is also important to interrelate drug response to blood levels in humans and blood levels in various animal species. The toxicological studies required for the evaluation of a drug candidate in man will be relevant to its proposed clinical use in terms of route of administration and duration of treatment of the clinical studies. The size and frequency of the doses and the duration of the toxicology studies are major determinants of permissible tests in man. Countries， including UK，USA，Australia，and Nordic countries，have regulatory guidelines which relate the duration of treatment allowed in man to the length of toxicity studies required in two species. Points from the guidelines are referenced in the subsequent sections. 58 Initially，the pharmacological effects of increasing doses of the test substances are established in acute toxicity studies in small numbers of animals，generally using two routes of administration (one being that used in man). Results provide a guide to the maximum tolerated doses in subsequent chronic. toxicity tests，aid selection of dose levels，and identify target organs. The main aim of the subsequent sub-acute toxicity tests is to determine whether or not the drug candidate is adequately tolerated after administration to animals for a prolonged period as a guide to possible adverse reactions in man. Two to four week (daily dosing) studies are required，using the same route of administration as in man，in two species (one non-rodent)prior to administration of the compound to man. Three dose levels are usually necessary:the low daily dose should be a low multiple of the expected therapeutic dose，and the highest dose should demonstrate some toxicity. A general guide for the evaluation of new chemical entities would be that toxicology studies of a minimum duration of 14 days are required to support single-dose exposure of a new drug candidate in normal volunteers in Phase 1. Toxicology studies of 30 days duration are required to support clinical studies of 7 to 10 days duration. Clinical studies of greater than 7 to 10 days up to 30 days duration require the support of at least 90 days toxicology studies. These requirements illustrate the need to plan ahead in drug development. The duration and approximate timings for future clinical trials need to be considered well in advance in order to schedule and conduct the appropriate toxicology studies to support the clinical program and avoid any delays. Two types of safety test are used to detect the ability of the drug candidate to produce tumours in man. The first are short-term in vitro genotoxicity tests，for example bacterial tests. The second are long-term animal carcinogenicity studies which are conducted in mice and rats;their length of often 2 years covers a large part of the lifespan of the animal. Mice and rats are used because of their relatively short life span，small size，and ready availability. Also，knowledge，which has accumulated concerning spontaneous diseases and tumours? in particular strains of these species，helps greatly in the interpretation of‘ results. Long-term toxicology and carcinogenicity studies are conducted in order to obtain approval to test and finally to market a product for chronic administration to man. These studies may need to start during the late preclinical/ early clinical phase in order to `support' the subsequent clinical program. Long-term toxicity studies will normally include toxicity studies of six and twelve months duration in two species (one non-rodent).Any toxicity previously detected may be investigated more closely，for example extra enzymes looked at in blood samples. Reproductive toxicology is that part of toxicology dealing with the effect of compounds on reproduction-fertility， foetal abnormalities，post-natal development. Prior to clinical studies in women of child-bearing age，regulatory authorities require teratology data from two species (normally rat and rabbit)as well as clinical data from male volunteers. No reproductive data are required prior to clinical studies in male subjects. The effects of 59 compounds on reproduction differ with the period of the reproductive cycle in which exposure takes place and studies are designed to look at these phases. Teratology`'' studies are designed to detect foetal abnormalities，fertility studies to investigate the compounds' effect on reproductive performance，And peri- and post-natal studies to study the development of pups. Selected from F. D. King，’Medicinal Chemistry Principles and Practice ’ the Royal Society of Chemistry Thomas , Graham House G. B. , 1994. 5单元 药物研发(I) 1。简介 药品开发是一个非常复杂的过程，需要一个协调和沟通不同功能之间的群体广泛很大。它是昂贵的，特别是在 临床开发的后期阶段，在研究涉及的数百名病人。据估计，目前约2.3亿美元(1987美元)的新药开发成本，并 采取介于7和10多年的临床前开发阶段开始，首先市场(不包括监管滞后)。药物开发是一项高风险业务，虽然利率不断上升，大约只有每十个新的化学研究在人类首次实体开展会不会成为一个产品。作为候选药物的进步，通过发展'的失败降低风险hurdles'are克服前进的道路上。失败的典型原因包括不可接受的毒性，缺乏有效性，或不能提供比其他竞争产品的优点 (图1)。 损耗率的新化学实体 (竞争性考试的)进入发展。平均 只有约400 ^ 1000我在化合物 合成进入发展。 原因的罗富国教育学院的发展终止 (不包括抗感染药) 1:缺乏疗效 2:药代动力学 3:动物毒性 4:杂项 5:在人的不良影响 6:商业上的原因 图。 1磨损率和终止的原因 2。发展规划 候选药物是否有可能提供有竞争力优势的评估首先需要强调的地方有一个产品'的目标，目标产品或配置文件集。应特别注意支付给竞争者形成差异。这已成为55个，并与有限的处方，医疗费用，以及药物经济学(本章稍后讨论)日益重视更为关键。 配置文件将确定一个目标指示(县)，将候选药物开发以及诸如每日一次给药的目标，起效更快的行动，更好地侧比主要竞争对手效应特征。目标配置文件可以通过完善和发展为移动和候选药物的候选药物或竞争对手成为可用的新数据修改。合乎逻辑的下一个步骤是确定发展战略，例如，有适应症先发展，哪些国家向市场为目标的药物，然后确定要达到的核心监管机构的批准和商业成功的临床研究。 本章将描述一个成功的新药开发所需的主要活动。所有这些活动，其中许多是相互依存，需要认真规划和协调。速度与高品质的数据收集到的市场是成功的关键。该活动确定的时间会去登记被称为项目管理方面，关键路径，路径。这是非常重要的 计划 项目进度计划表范例计划下载计划下载计划下载课程教学计划下载 和准备，并在研究开始监控和管理问题，以确保关键路径如期进行。增加经济压力和竞争强度，重要的是企业，探讨如何缩短这一关键路径。并行运行的活动，或重叠研究，这将通常按顺序运行，往往涉及的风险增加，节省时间，但分红可以使这种战略值得的。 用于药物开发的一个新的关键路径通常贯穿初步合成的化合物，亚急性毒性研究，然后临床计划。图表显示了一个典型的候选药物的关键路径上的活动图所示。 2。 化学化学合成路线的选择试验厂，规模和稳定性测试制造工厂生产 急性及亚急性毒理学毒理学长期和再现毒理学 第一阶段会期临床阶段微光分析数据和报告相低压回顾 监管意见书和临床试验申请更新准备提交管理局 甲基丙烯酸/新药审批管理 上市后Surverillance 药物临床前，临床和商业配方 发展和稳定的测试准备标签 药物代谢 动物药代动力学和操作ADME *健康人的人类患者 活动可能是在关键路径上以粗体显示 *吸收，分布，代谢，排泄 图。 2，在新药开发的主要过程 以下各节突出了每个技术学科的目标和药物开发work.Activities活动中介绍了大致按时间顺序order.At任何一个时间，在所有这些领域的工作可能是平行进行。的时间和大量的工作成果对其他学科的工作有直接的影响。药物开发的主要阶段是临床前(前化合物所需的研究，可在人体剂量)，第一阶段(通常在健康志愿者的临床研究)的 ?期(初始疗效和安全性和治疗剂量调查研究)，及?期(在几百病人的研究)。然后讲述了一个有上市申请档案大会由国家监管当局随后的审查。 3。化工发展 候选药物的快速发展是建立在足够数量的化合物可依赖。该化合物的纯度需要达到一定的 标准 excel标准偏差excel标准偏差函数exl标准差函数国标检验抽样标准表免费下载红头文件格式标准下载 ，以便它在安全使用(毒理学)，制药和临床研究。最初，化学家将在小到中等规模的调查数，以便确定该化合物合成路线的最佳方法不同，该化合物的生产。'最佳'这里可能意味着多种因素的组合，例如，最有效，最便宜的安全，或产生最少的废物。最终产品以及中间体和杂质分析在确定最佳的合成方法的关键作用。开发和分析方法验证是必要的支持过程的发展，保证原料药的纯度。 在某些情况下，杂质含量高得令人无法接受，要么提高净化程序，将需要开发或合成过程可能需要大量的改变。其主要目的是确保组成的化合物，最终理解和准备的材料是尽可能纯净。 作为候选药物开发的进展，复合数额越来越大的需要。材料的数量不同的测试规定，往往取决于实际效力和剂量的复合形式。一个实验工厂内可被视为一个小型制造业设置。才转一个试验工厂，广泛的评估和测试，进行化学合成，以确保任何改变和危害降至最低。程序的优化，特别注重发展产品的废物处置环境可接受的方式。为一次批准和销售的药品，生产原料药进行商业化生产，将可能采取更大规模的或在地方登记的制造工厂。 4。配方开发 一个是药物剂型，它是由病人的管理，以形成。有可能的剂量从贴剂到吸入到鼻腔药品形式繁多。较常见的剂型包括口服片剂或胶囊，口服液，外用药膏或面霜，和注射剂。剂型或特定候选人所选择的药物形式将目标配置文件中定义。 有时，一个更简单的剂型，例如一个口服液，是选择提前57人类临床研究。这可节省在早期，高风险的药物开发过程的前期阶段，时间和成本。随后的临床研究将使用预期销售剂型。 无论是什么剂型，药物和构成它必须符合一定标准的其他材料的组合。最重要的之一是足够的稳定性。这意味着，必须预先确定的水平后继续效力，例如，两年或三年。稳定剂型上产生的数据将决定其保质期和储存条件的建议。于早期发展的保质期可能仅限于数个月。这不会是一个问题，只要是足以应付使用的药物在临床研究或学习的时间。 5。药理 前候选药物是考虑到人，对大型系统的药理作用研究往往在一个物种的数目。身体系统的研究，包括心血管，呼吸和神经系统;总值行为的影响也有待研究。 有时进行实验，看看是否与这些候选药物，由于其具体效果，或者因为他们的共同使用，有可能采取与其他药物同时候选药物的行为干预。任何协同或拮抗作用的药物作用，应进行调查，并发出警告任何必要的临床调查。(这可能被认为有必要探讨进一步的临床研究这些影响，以及任何潜在的或行之有效的药物相互作用可能在产品上发现在药物标签。) 这也可能是适当的，以确定在管理方面可能的过量使用一种物质，特别是如果该候选药物治疗幅度很小。 6。安全性评价 对动物毒理学测试的目标，开展前的一个男子药品监督管理局，是拒绝不可接受的毒性化合物，并确定为潜在的药物不良反应的靶器官和时序。这意味着，在研究这些早期人类器官和组织，可特别注意监测。重要的是要确定是否有毒或不可逆转的影响是可逆的，他们是否可以预防的，如果可能的话，毒性作用的机制。这也是很重要的相互联系药物的反应水平在人类血液和各种动物的血液水平。 对于在人候选药物评价所需的毒理学研究将有关其建议的管理和治疗的临床研究，临床使用期限途径方面。的大小和剂量频率和持续时间的毒理学研究允许在人测试的主要因素。国家，包括英国，美国，澳大利亚和北欧国家，其中有涉及在男人的毒性研究两个物种所需要的长度允许疗程监管指引。百分点，从准则被引用在随后的章节。 58最初，测试物质增加剂量的药理作用是建立在急性毒性研究在动物小数目，一般采用两种给药途径(一个是在人使用)。结果提供了一个指南，在随后的慢性最大耐受剂量。毒性试验，援助的剂量水平的选择和确定目标器官。 在随后的亚急性毒性试验的主要目的是确定是否有足够的候选药物，给药后为，作为对人类可能产生的不良反应在长期指导动物的耐受性。两到四个星期(每日剂量)的研究是必需的，使用与男子相同的路线的管理，在两个物种(一非啮齿类)之前，该化合物对人的管理。三个剂量水平通常必要的:每天低剂量应是所期望的治疗剂量低倍数，最高剂量应表现出一定的毒性。 一种新的化学实体评价的一般指南将是一个为期14天以上毒理学研究需要支持正常的志愿者在第一阶段的单剂量接触一个新的候选药物。为期30天的毒理学研究是必需的，以支持7至10天时间的临床研究。超过7至 10天至30天的时间更多临床研究需要有至少90天的毒理学研究的支持。这些要求说明需要计划在药物向前发展。 的时间及今后的临床试验的近似时序需要考虑，以便提前做好安排，并进行相应的毒理学研究，以支持临床程序， 并避免任何延误。 两种类型的安全测试是用来检测的候选药物在人的能力产生肿瘤。第一类是短期的体外遗传毒性试验来看，例 如细菌试验。第二类是动物长期致癌性是在小鼠和大鼠进行了研究;他们往往二年长度覆盖了动物寿命的很大一部 分。小鼠和大鼠的使用，因为他们的寿命相对较短，体积小，随时可用性。此外，知识，积累了自发的疾病及有关 这些物种的特定菌株?肿瘤，大大有助于在'结果的解释。 长期毒理学和致癌性研究是为了获得批准，试验，终于向市场推出了人类对慢性管理的产品。这些研究可能需 要后期临床前/早期临床阶段的开始，以'支持'随后的临床计划。长期毒性试验通常包括毒性研究的6到12个月，两 个物种的持续时间(一个非啮齿类)。任何毒性，可调查发现以前更加紧密，例如额外的酶在血液样本看。 生殖毒理学则是一对繁殖的化合物，生育，胎儿畸形，产后处理毒理学发展的影响的一部分。之前，在生育 年龄的妇女的临床研究，监管部门需要从两个物种(通常大鼠和家兔)以及从男性志愿者的临床资料畸形的数据。 没有生育的数据之前，必须在男性受试者临床研究。 59个化合物对生殖的影响不同的生殖周期中，暴露发生和研 究的目的是看看这些阶段的时期。畸形`''研究的目的是检测胎儿畸形，生殖研究，以探讨该化合物对繁殖性能的影 响，城郊和产后的研究，研究幼崽的发展。 从fd选定国王的，药物化学原理与实践'皇家学会 化学托马斯，格雷厄姆府湾湾，1994年。 Exercises 1 .Answer the following questions: (1)Why do people consider the discovery of the novel drug is a long，expensive and tortuous process with no guarantee of success? (2) How many major processes are there in new drug development? (3) What has been achieved in the novel drug development in the past century? (4) Please list the disadvantages or barriers in Chinese novel drug development. 2. Put the following into English: 3. Put the following into Chinese: pharmacokinetics assessment optimum highlight regulatory approval preclinical pharmacology side effect excretion safety evaluation 4. Fill the blanks with the following words: Pharmacodynamics toxicology pharmacognosy Pharmacotherapeutics pharmacokinetics pharmacy ____ is a descriptive science concerned with the physical characteristics of natural drugs，primarily those derived from plants and animals. ____ is the art and science of preparing，compounding，and dispensing medicines. ____ is the study of the way drugs are absorbed into the body，their metabolism by the body，and the way they are excreted. ____ is the study of the actions of drugs on living organisms and can itself be further subdivided. It borrows freely from the experimental techniques of physiology，biochemistry， microbiology，pathology，genetics，immunology and cellular and molecular biology. Research in this area of pharmacology is at the very frontier of medical knowledge. It studies the ways in which drugs interact with the molecular structures(such as enzymes，cell receptors，and genetic material) that make up the machinery of living tissue. As knowledge has expanded，several of these subareas have developed specialized journals， such as the Journal of Molecular Pharmacology and the Journal of Biochemical pharmacology. Knowledge of precisely how drugs affect the chemistry of the cell has permitted the deliberate design of new drugs to treat formerly untreatable diseases. ____ deals with the use drugs in the prevention and treatment of disease，while ____ deals with the adverse effects of drugs. 练习 1。回答下列问题: (1)为什么人们考虑新药物的发现是一个没有成功的保证长期的，昂贵的和曲折的过程, (2)有多少主要过程是在新药开发呢, (3)什么一直在新药开发取得了过去一个世纪, (4)请列出的缺点或中国新药开发的障碍。 2。把以下内容翻译成英语: 3。把成中文如下: 药代动力学评价优化突出监管部门的批准 临床前药理副作用排泄安全性评价 4。填写以下单词填空: 药效毒理学药学 Pharmacotherapeutics药药房 ____是一种描述性科学与主要是来自植物和动物的天然药物，物理特性有关。____是艺术和准备，复合，并配 发药物科学。 ____是这些药物进入体内，被人体的新陈代谢，以及它们排出的方式吸收方式的研究。 ____是药物 对生物体的行动本身，可以进一步细分研究。它借用自由地从生理学，生物化学，微生物学，病理学，遗传学，免 疫学，细胞和分子生物学实验技术。在这方面的研究药理学是在非常前沿的医学知识。它研究的方法，使药物相互 作用的分子结构(如酶，受体细胞和遗传物质)构成的活组织机制。由于知识不断扩大，其中有几个子区域发展， 如分子药理学杂志和杂志生化药理专业刊物。 ，正是药物如何影响细胞的化学知识已批准新的药物来治疗前精心设 计无法治愈的疾病。 ____在预防和治疗疾病使用的药物处理，而与药物的 PART 3 INDUSTRIAL PHARMACY Unit 11 Tablets (The Pharmaceutical Tablets Dosage Form) Role in Therapy The oral route of drug administration is the most important method of administering drugs for systemic effects. Except in cases of Insulin therapy，the parenteral route is not routinely used for self-administration of medications. The topical route of administration has only recently been employed to deliver drugs to the body for systemic effects，with two classes of marketed products: Nitroglycerin for the treatment of angina and scopolamine for the treatment of motion sickness'. Other drugs are certain to follow，but the topical route of administration is limited in its ability to allow effective drug absorption for systemic drug action. The parenteral roue of administration is important in treating medical emergencies in which a subject is comatose or cannot swallow，and in providing various types of maintenance therapy for hospitalized patients. Nevertheless，it is probable that at least 90 0 o of all drugs used to produce systemic effects are administered by the oral rote. When a new drug is discovered，one of the first questions a pharmaceutical company asks is whether or not drug can be effectively administered for its intended effect by the oral route. If it cannot， the drug is primarily relegated to administration in a hospital setting or physician's office. If patient self- administration cannot be achieved，the sales of the drug constitute only a small fraction of what the market would be otherwise. Of drugs that are administered orally，solid oral dosage forms represent the preferred class of product. The reasons for this preference are as follows. Tablets and capsules represent unit dosage forms in which one usual dose of the drug has been accurately placed. By comparison， liquid oral dosage forms，such as syrups，suspensions，emulsions，solutions，and elixirs，are usually designed to contain one dose of medication in 5 to 30 ml. The patient is then asked to measure his or her own medication using a teaspoon， tablespoon，or other measuring device. Such dosage measurements are typically in error by a factor ranging from 20 0 o to 50% o when the drug is self-administered by the patient. Liquid oral dosage forms have other disadvantages and limitations when compared with tablets. They are much more expensive to ship (one liquid dosage weighs 5 g or more versus 0. 25 to 0. 4 g for the average tablet)，and breakage or leakage during shipment is a more serious problem with liquids than with tablets. Taste masking of the drug is often a problem (if the drug is in solution even partially). In addition，liquids are less portable and require much more space per number of doses on the pharmacist's shelf. Drugs are in general less 118 stable (both chemically and physically) in liquid form than in a dry state and expiration dates tend to be shorter. Careful attention is required to assure that the product will not allow a heavy microbiologic burden to develop on standing or under normal conditions of use once opened(preservation requirements).There are basically three reasons for having liquid dosage forms of a drug:(1)The liquid form is what the public has come to expect fox certain types of products (e. g. cough medicines).(2) The product is more effective in a liquid form (e. g.，many adsorbents and antacids). (3) The drug(s) are used fairly commonly by young children or the elderly，who have trouble swallowing the solid oral dosage forms. Properties The objective of the design and manufacture of the compressed tablet is to de liver orally the correct amount of drug in the proper form at or over the proper time and in the desired location，and to have its chemical integrity protected to that point. Aside from the physical and chemical properties of the medicinal agent (s)to be formulated into a tablet，the actual physical design，manufacturing process，and complete chemical makeup of the tablet can have a profound effect on the efficacy of the drug(s)being administered. A tablet(1)should be an elegant product having its own identity while being free of defects such as chips，cracks， discoloration，contamination，and the like;(2) should have the strength to withstand the rigors of mechanical shocks(5) encountered in its production， packaging，shipping，and dispensing; and (3) should have the chemical and physical stability to maintain its physical attribute over time. Pharmaceutical scientists now understand that various physical properties of tablets can undergo change under environmental or stress conditions，and that physical stability，through its effect on bioavailability in particular，can be of more significance and concern in some tablet systems than chemical stability. On the other hand，the tablet(1)must be able to release the medicinal agent(s) in the body in a predictable and reproducible manner and (2) must have a suitable chemical stability over time so as not to allow alteration of the medicinal agent(s). In many instances，these sets of objectives are competing. The design a of tablet that emphasizes only the desired medicine effects may produce a physically inadequate product. The design of a tablet emphasizing only the physical aspects may produce tablets of limited and varying therapeutic effects. As one example of this point，Meyer and associates present information on 14 Nitrofurantoin products，all of which passed the compendia physical requirements， but showed statistically，significant bioavailability differences. Selected from Lachman Leon et al. The Theory and Practice可Industrial Pharmacy, 3 rd ed., Lea and Febiger, Philadelphia, 1986. 第3部分工业药物 11单元 片(该药片剂型)的治疗作用 在口服给药途径是全身作用的药物管理最重要的方法。除胰岛素治疗的情况下，常规肠外路由不用于 自药物管理。行政专题路线只是最近被用来传送药物的系统性影响的机构，两个上市产品类:用于心 绞痛和东莨菪碱用于运动病的治疗硝酸甘油治疗。其他药物一定会跟进，但政府外用途径在于，它能 够让全身药物作用的有效药物的吸收有限。行政肠外roue在处理医疗紧急情况，其中一个主题是昏 迷或不能吞咽，住院，并为维持治疗患者的各类重要。不过，很可能至少有90 0用于生产系统影响 O的所有药物通过口服死记硬背管理。当一个新的药物被发现，在一家制药公司要求的第一个问题是， 是否得到有效的药物可以用于其预定的口服效果管理。如果不能，该药物主要是降级到政府在医院设 置或医生的办公室。如果病人自我管理，就不可能实现，该药物的销售只占一个什么样的市场，否则 将是一小部分。那是口服药物，口服固体制剂产品的首选代表类。这种偏好的原因如下。片剂和胶囊 代表哪一个单位剂量的药物常用剂量已准确地放置形式。相比之下，口服液等剂型，糖浆，混悬剂， 乳剂，解决 方案 气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载 和药酒，通常设计为包含一个药物剂量5至30毫升。然后问病人是衡量他或她自己 的药物使用一茶匙，汤匙，或其他测量设备。在这种剂量测量误差通常由20〜0度至50,O当药物 自我管理因素的病人。 口服液剂型有其他的缺点和局限性，当与药片。他们更昂贵的船舶(一液用量重5克与0或更多。 25 0 4。对于普通片剂G)和运输过程中破损或渗漏是一个比片液体更严重的问题。品味的药往往是 掩盖问题(如在溶液中的药物，即使是部分)。此外，液体移植性较差，需要更多的每对药剂师的货 架剂量数空间。毒品在一般不太稳定，118液态形式(包括化学和物理)，比在干燥状态和过期日期 往往较短。需要认真注意，以确保该产品将不会允许一个沉重的负担，发展微生物站立或根据一旦打 开(保存要求)正常使用条件基本上有三种具有液体剂型药物的原因:。(1)液体形式是公众所期 望的产品(如咳嗽药)某些类型的狐狸。(2)该产品是在液体中更多的形式(例如，许多吸附剂和 制酸剂)有效。 (3)药物(s)是用于儿童或老人，谁吞咽困难的固体口服剂型相当普遍。 属性 在设计和制造的压缩片的目的是去肝口服药物在达到或超过适当的时间和所需的位置适当的形式正 确的金额，并有完整的保护，其化学这一点。除了从药用剂的物理和化学性质(县)制定成片，实际 的物理设计制造过程，以及完整的片剂的化学成分可能对药物(s)的有效性产生深远的影响被管理。 甲片(1)应该是一个高雅的产品有它自己的身份而被如薯片，裂缝，变色，污染的缺陷，等等;(2)应该有实力能够承受机械冲击的严峻考验(5)中遇到的生产，包装，运输和分配，以及(3)应具有的化学和物理稳定性随着时间的推移，以维持它的物理属性。医药科学家们现在明白，片剂各种物理性能进行生物利用度的变化，特别是在环境或压力的条件，并通过其物理稳定性的影响，可以为更多的意义和化学稳定性比一些片剂系统的关注。 另一方面，片剂(1)必须能够在体内释放的药物剂(s)在可预测和可重复性的方式和(2)必须有一个合适的化学稳定性随着时间的推移，以便不容许改变药用剂(s)。在许多情况下，这些目标的集竞争。片剂的设计，强调只有所需的药物的效果可能会产生身体不足的产物。一个只注重物质方面片剂设计可能会产生不同的治疗效果有限，而且片。作为其中的一个点，迈耶和联营公司14呋喃妥因的产品，所有这些都通过汇编物理要求，但统计表明，生物利用度差异显着目前的信息的例子。 选自拉克曼莱昂等。理论与实践可工业药剂， 第三编。，Lea和Febiger，费城，1986年。 Exercise 1. Answer the following questions. (1)How many kinds of the route of drug administration are there? (2) Can you present these usual dosage forms of the drug that are administered orally? (3) How is an evaluation of a tablet's properties made? 2. Complete the passage below. Solid ____ dosage forms are delivery systems presented as solid dose units readily administered by mouth. The group includes ____，____ ，____ ，and ____ , as well as bulk or unit-dose powder and granules. The group constitutes the most popular form of presentation，and tablets and capsules account for the greatest number of preparations in this category. The prime reasons for this popularity includes:easy of accurate (yet versatile) ____ ，good ____ and ____ stability，competitive unit production costs，and an elegant distinctive appearance resulting in a high level of patient acceptability. Among the potential disadvantages are irritant effects on the gastrointestinal mucosa by some solids and the possibility of bioavailability problems caused by the fact that both ____ (in most causes)and ____ must take place before the drug is a available for absorption. 3. Put the following into Chinese. absorption action treat medication medicine pharmaceutical compress quality quantity uniformity measure composite 4. Put the following into English. 练习 1。回答下列问题。 (1)如何对药物给药途径有多少种, (2)你认为目前这些药物通常是口服剂型, (3)如何评价是一个片的属性呢, 2。完成以下的段落。 ____固体剂型为口服固体剂量容易管理的单位提交的运载系统。该集团包括____,____,____和____，以及大量或单位剂量粉末和颗粒。本集团构成了最流行的表现形式，片剂和胶囊的筹备工作最大的此类账户。这个大受欢迎的首要原因包括:精确的(但灵活)____，____和____稳定性好，有竞争力的单位生产成本，独特的外观和优雅的病人在接受高层次造成容易。在可能的缺点是对一些固体胃肠黏膜和的事实，这两个____(多数原因)和____前必须进行药物的吸收是一个可导致生物利用度问题的可能性有刺激性作用。 3。把成中文以下。 治疗药物的吸收作用 医药制药压缩质量 量均匀性测量复合材料 4。把以下内容翻译成英语。 Unit 13 Sterile Products Sterile Products Sterile products are dosage forms of therapeutic agents that are free of viable microorganisms. Principally，these include parenteral，ophthalmic，and irrigating preparations. Of these，parenteral products are unique among dosage forms of drugs because they are injected through the skin or mucous membranes into internal body compartment. Thus，because they have circumvented the highly efficient first line of body defense，the skin and mucous membranes，they must be free from microbial contamination and from toxic components as well as possess an exceptionally high level of purity. All components and processes involved in the preparation of these products must be selected and designed to eliminate，as much as possible，contamination of all types，whether of physical，chemical， or microbiologic origin. Preparations) for the eye，though not introduced into internal body cavities，are placed in contact with tissues that are very sensitive to contamination. Therefore，similar standards are required for ophthalmic preparations). Irrigating solutions(M are now also required to meet the same standards as parenteral solutions because during an irrigation procedure，substantial amounts of these solutions can enter the bloodstream directly through open blood vessels of wounds or abraded mucous membranes. Therefore，the characteristics and standards presented in this chapter for the production of large-volume parenteral solutions apply equally to irrigating solutions. Sterile products are most frequently solutions or suspensions，but may even be solid pellets for tissue implantation. The control of a process to minimize contamination for a small quantity of such a product can be achieved with relative ease. As the quantity of product increases，the problems of controlling the process to prevent contamination multiply. Therefore，the preparation of sterile products has become a highly specialized area in pharmaceutical processing. The standards established，the attitude of personnel，and the process control must be of a superior level. vehicles By far the most frequently employed vehicle for sterile products is water，since it is the vehicle for all natural body fluids. The superior quality required for such use is described in the monograph on Water for Injection in the USP. Requirements may be even more stringent for some products，however. One of the most inclusive tests for the quality of water is the total solids content，a gravimetric evaluation of the dissociated and undissociated organic and inorganic substances present in the water. However，a less time-consuming test，the elevtrolytic measurement of conductivity of the water，is the one most frequently used. Instantaneous measurements can 132 be obtained by immersing electrodes in the water and measuring the specific conductance , a measurement that depends on the ionic content of the water. The conductance may be expressed by the meter scale as conductivity in micromhos ，resistance in megohms , or ionic content as parts per million (ppm)C" of sodium chloride. The validity of this measurement as an indication of the purity of the water is inferential in that methods of producing high-purity water，.such as distillation and reverse osmosis，can be expected to remove undissociated substances along with those that are dissociated. Undissociated substances such as pyrogens，however，could be present in the absence of ions and not be disclosed by the test. Therefore，for contaminants other than ions，additional tests should be performed. Additional tests for quality of Water for Injection with permitted limits are described in the USP monographs. When comparing the total solids permitted for Water for Injection with that for Sterile Water for Injection，one will note that considerably higher values are permitted for Sterile Water for Injection. This is necessary because the latter product has been sterilized，usually by a thermal method，in a container that has dissolved to some extent in the water. Therefore，the solids content will be greater than for the nonsterilized product. On the other hand，the 10 ppm total solids officially permitted for Water for Injection may be much too high when used as the vehicle for many products. In practice. water for Injection normally should not have a conductivity of more han 1 micromho(I megohm，approximately 0. 1 ppm NaCI ). Added Substances. Substances added to a product to enhance its stability are essential for almost every product. Such substances include solubilizers，antioxidants，chelating agents，buffers，tonicity contributors，antibacterial agents，antifungal agents，hydrolysis inhibitors，antifoaming agents，and numerous other substances for specialized purposes. At the same time，these agents must be prevented from adversely affecting the product. .In general，added substances must be nontoxic in the quantity administered to the patient. They should not interfere with the therapeutic efficacy nor with the assay of the active therapeutic compound. They must also be present and active when needed throughout the useful life of the product. Therefore， these agents must be selected with greatcare，and they must be evaluated as to their effect upon the entire formulation.- An extensive review of excipients used in parenteral products and the means for adjusting pH of these products has recently been published and should be referred to for more detailed information. Formulation The formulation of a parente.ral product involves the combination of one or more ingredients with a medicinal agent to enhance the convenience，acceptability，or effectieness of the product. Rarely is it preferabl6 to dispense a drug singly as a sterile dry powder unless the formulation of a stable liquid preparation is not possible. On the other hand，a therapeutic agent is a chemical compound subject to the physical and chemical reactions characteristic of the class of compounds to which it belongs. Therefore，a careful evaluation must be made of every combination of two or more 133 ingredients to ascertain whether or not adverse interactions occur，and if they do，of ways to modify the formulation so that the reactions are eliminated or minimized. The formulation of sterile products is challenging，therefore， to the knowledge and ingenuity of the persons responsible. The amount of information available to the formulator concerning the physical and chemical properties of a therapeutic agent，particularly if it is a new compound，is often quite meager. Information concerning basic properties muse be obtained，including molecular weight，solubility，purity，colligative properties，and chemical reactivity，before an intelligent approach to formulation can begin. Improvements in formulation are a continuing‘ process，since important properties of a drug or of the total formulation may not become evident until the product has been stored or used for a prolonged time: However，because of the extensive test documentation required by the U. S. Food and Drug Administration (FDA)，only outstanding formulations can be justified for continuance to the state of a maketed product. Production The production process includes all of the steps from the accumulation and combining of the ingredients of the formula to the enclosing of the product in the individual container for distribution. Intimately associated with these processes are the personnel who carry them out and the facilities in which they are performed. The most ideally planned processes can be rendered ineffective by personnel who do not have the right attitude or training，or by facilities that do not provide an efficiently controlled environment. To enhance the assurance of successful manufacturing operation，all process steps must be carefully reduced to writing after being shown to be effective. These written process steps are often called standard. operating procedures (SOPs)?.No extemporaneous changes are permitted to be made in these procedures;any change must go through the same approval steps as the original written SOP. Further，extensive records must be kept to give assurance at the end of the production process that all steps have been performed as prescribed，an aspect emphasized in the FDA's Good Manufacturing Practices. Such in-process control is essential to assuring the quality of the product，since these assurances are even more significant than those from product release testing. The production of .a quality product is a result of the continuous，dedicated effort of the quality assurance，一production，and quality control personnel within the plant in developing，performing，and confirming effective sops. Selected from Lachman Leon et al. The Theory and Practice of Industrial Pharmacy, 3rd ed.，Lea and Febiger, Philadelphia，1986. 无菌产品的单位13 无菌产品 无菌产品是可行的微生物属于免费治疗药物剂型。主要是，这些包括胃肠，眼科以及灌溉准备。其中， 肠外产品深受毒品剂型独一无二的，因为他们是通过皮肤或粘膜进入人体内部隔间膜注入。因此，因 为他们有规避的体魄，对皮肤和粘膜高效的第一线，他们必须从微生物污染和有毒成份，以及拥有的 纯度极高的水平。所有组件及这些产品的筹备工作进程，必须选择和设计，以消除，尽可能，所有类 型的污染，无论是物理，化学或微生物的起源。 虽然不是筹备工作进入体腔内部引入了眼睛，，)被放置在与组织的联系是非常敏感的污染。因 此，类似的标准都需要眼科制剂)。 冲洗液(男，现在也需要，因为在灌溉过程肠外解决方案以满足相同的标准，这些解决方案可以 大量通过伤口进入血管或磨损开放粘膜的血液直接。因此，呈现的特点和标准在这个大批量生产章肠 外解决方案同样适用于灌溉的解决方案。 无菌产品是最常见的解决方案或暂停，但甚至可能用于组织植入固体颗粒。一个过程的控制，尽 量减少对此类产品少量可相对容易地实现了污染。由于产品的增加，过程控制，以防止污染的问题， 乘以数量。因此，无菌产品的制备已成为一个高度专业化的制药加工区。该标准建立，人员的态度，和过程控制必须是一个高水准。 车辆 到目前为止，最常用的无菌产品汽车是水，因为它是所有自然体液车辆。优质的使用需要的是这样描述的水专着在美国药典注射。要求可能更严格的一些产品，但是。 在对水的质量最具包容性的测试之一是总固形物含量，是游离的和未解离有机和无机物质在水中 的重量评价。然而，耗时少试验，水的电导率测量，是一个最常用的。瞬时测量可以得elevtrolytic 到浸泡在水中的电极和电导率测量，测量，关于水的离子含量而定。电导可表示，作为每百万132 之一)的氯化钠“部分，至于在电导率，电阻兆欧，或离子含量米的规模。(百万分Cmicromhos 作为水的纯净度适应症这种测量的有效性推理在生产高纯度水的方法。如蒸馏和反渗透，可以预料，随着除去那些游离未解离的物质。未解离如热原物质，然而，可存在于离子的情况下，不被披露的考验。因此比其他离子污染物，应进行更多的测试。 在水质允许的限度与注射额外的测试中描述了美国药典专着。当允许使用比较水与注射用无菌水 注射液总固体，人会注意到，相当值越高，无菌注射用水许可。这是必要的，因为后者的产品已消毒，通常由热法在一个完全溶解在水中的一些程度的容器。因此，固形物含量会比在产品nonsterilized更大。另一方面，的总固形物正式允许使用注射用水可能过于高时，作为车用许多产品。在10 ppm 实践中。注射用的水通常应该不会有更多的韩一(我兆欧，约。的氯化钠)导电。micromho01 ppm 新增物质。 物质添加到产品，以提高其稳定性是几乎每一个产品的关键。这些物质包括增溶剂，抗氧剂，螯合剂，缓冲器，强壮贡献者，抗菌剂，抗菌剂，水解剂，消泡剂，以及许多其他专门用途的物质。与此同时，这些药物必须防止产生不利影响的产品。。一般而言，增加物质，必须在管理，以病人的数量无毒。 他们不应该干预治疗效果，也不符合化合物的积极治疗法。他们也必须存在和活跃的时候整个产品的使用寿命需要。因此，这些药物必须选择与，他们必须就其对整个制定一种产品所使用的greatcare.-赋形剂肠外广泛的审查和调整这些产品的值影响评价手段已出版，并应转介到更详细的信息。pH 配方 一个产品配方涉及到一个或多个代理药用成分的组合，以提高便利性，可接受性，或产parente.ral 品。很少是免除无菌干粉作为单独的药物，除非在一个稳定的液体制剂配方effectienesspreferabl6 是不可能的。 另一方面，一个治疗剂是一种化学化合物受到物理和化学反应的化合物类的特性在它所属。因此， 仔细评估必须由两个或两个以上的每成分的组合，以确定是否发生不良的相互作用，如果他们133 做，如何修改，以便消除或尽量减少的反应是制定。无菌产品的配方是具有挑战性，因此，对知识和责任人的聪明才智。 的信息提供给有关的配方治疗剂的物理和化学性能，尤其是当它是一种新的化合物，金额往往是 相当贫乏。有关信息的基本属性得到灵感，包括分子量，溶解度，纯度，依数性质，化学反应，在一个聪明的办法，就可以开始制定。在配方改进是一种持续的过程，因为一种药物或总配方可能不会' 明显重要的属性，直到该产品已被储存或使用时间过久:然而，由于广泛的测试文件要求由美国食品和药物管理局()，只有优秀的配方可以说得过去持续到一个产品的状态。FDAmaketed 生产 生产过程包括所有从积累的步骤公式的成分，结合到产品的封闭在分配个别货柜。与这些进程密切相关的人员是谁的贯彻落实和执行中，他们的设施。最完美的计划过程可以失效的人员谁不有正确的态度或培训，或设施，没有提供一个有效的控制环境。 为了提高成功的制造运作的保证，所有工艺步骤必须小心以书面记录后，证明是有效的。这些书 面处理步骤通常称为标准。。作业程序()?没有即席更改允许在这些程序的，任何改变必须 SOP 经过书面正本为的批准步骤相同。此外，广泛的记录必须保存给在生产过程结束时保证，所有SOP 的步骤已经按照规定，这方面强调，在的良好生产规范。这就是必须保证产品的质量，因为这FDA 些保证是从产品甚至比那些显着的发行测试过程控制。生产各种。高质量的产品是一个连续的，质量保证，一生产，并在植物的质量控制人员在开发，实施和确认有效的专用努力的结果。SOP 选自拉克曼莱昂等。的理论与实践工业制药， 第三版。，和，费城，年。 LeaFebiger1986 Exercise 1. Answer the following questions: (1)Can you tell the difference in quality control between the, oral tablet and sterile products injected. 135 (2) How is the quality of sterile products assured in-process? (3) What is the standard operating procedure (SOPs)? (4) How is the water for injection usually prepared? 2. Complete the passage below: Sterile product are dosage forms of therapeutic agent that are free of viable ____ , these include ____ ____ and ____ ，because they are injected through the ____ or ____ membranes into internal body，parenteral products must be free from ____ and from ____ . Sterile products are most frequently ____ or ____，the most frequently employed ____ for sterile product is ____ the quality of water for injection (WFI) is required by pharmacopeia，which is superior quality required，the natural water contain generally dissociated and undissciated ____ and ____ substances which they must be essentially removed and set a permitted limits，____ are products of matabolism of microorganisms，the removal of ____ is very important for water for injection. Water for injection is prepared by ____ or ____. 3. Put the following into Chinese: parenteral ophthalmic irrigating microoganisms contamination specialize conductivity pycogens 4. Put the following into English 5. Why the removal of pycogens is very important for WFI? 练习 1。回答下列问题: (1)你能告诉之间，口服片剂和无菌产品质量控制的不同注射。 135 (2)如何是无菌产品的质量保证在进程, (3)什么是标准作业程序(SOP)的, (4)如何准备通常是注射用水, 2。通过完成如下: 无菌产品是治疗药物剂型是可行的____自由，其中包括________和____的，因为他们是通过将人体内部的____ 或____膜注射，注射产品必须是自由和从________。 无菌产品是最常见的____或____,为无菌产品，是最常用的________的注射用水(WFI的)质量是由药典的要 求，这是优越的质量要求，一般的天然水含有游离和____和____ undissciated他们基本上必须拆除，并设置许可 限制,____物质是微生物matabolism产品，____搬迁是非常重要的注射用水。 注射用水制备了____或____。 3。把成中文如下: 肠外眼科灌溉microoganisms 污染专门导电pycogens 4。把以下内容翻译成英语 5。为什么pycogens注射用水去除是非常重要的, PART 4 PHARMACEUTICAL ENGINEERING第4部分制药工程 Unit 16 Reactor Technology Reactor technology comprises(D the underlying principles of chemical reaction engineering (CRE)and the practices used in their application. The focuses of reactor technology are reactor configurations，operating conditions，external operating environments， developmental history，industrial application，and evolutionary change. Reactor designs evolve from the pursuit of new products and uses，higher conversion，more favorable reaction selectivity，reduced fixed and operating costs，intrinsically safe operation，and environmentally acceptable processing. Besides stoichiometry and kinetics，reactor technology includes requirements for introducing and removing reactants and products，efficiently supplying and withdrawing heat，accommodating phase changes and material transfers，assuring efficient contacting of reactants，and providing for catalyst replenishment or regeneration. Consideration must be given to physical properties of feed and products (vapor，liquid，solid，or combinations)， characteristics of chemical reactions (reactant concentrations，paths and rates，operating conditions，and heat addition or removal)，the nature of any catalyst used (activity，life，and physical form)，and requirements for contacting reactants and removing products(flow characteristics，transport phenomena，mixing requirements，and separating mechanisms). All the factors are interdependent and be considered together. Requirements for contacting reactants and removing products are a central focus in applying reactor technology;other factors usually are set by the original selection of the reacting system， intended levels of reactant conversion and product selectivity，and economic and environmental considerations. Reactor Types and Characteristics Specific reactor characteristics depend on the particular use of the reactor as a laboratory， pilot plant，or industrial unit. All reactors have in common selected characteristics of four basic reactor types : the well-stirred batch reactor，the semibatch reactor，the continuous- flow stirred-tank reactor，and the tubular reactor (Fig. 1). Batch reactor A batch reactor is one in which a feed material is treated as a whole for a fixed period of time . Batch reactors may be preferred for small-scale production of high priced products， particularly if many sequential operations are employed to obtain high product yields，e. g., a process requiring a complex cycle of temperature-pressure-reactant additions. Batch reactors also may be justified when multiple，low volume products are produced in the same equipment Other reactants added continuously Reactants at Reactants at. neaagcooling indng cooli Feed Products Heating/cooling Feed Distance along reactor Heatin/cooling Fig. 1 Reactor types:(a) batch，(b) semibatch，(c) continues-flow stirred-tank，and (d) tubular 单元16反应堆技术 反应堆技术包括(D的化学反应工程(CRE)的基本原则和做法，他们的应用程序。反应堆技术的重点是反应器的 配置，运行条件，外部经营环境，发展历史，工业应用，改变和进化。反应堆从进化设计的新产品和用途，较高的 转换，追求更有利的反应选择性，降低经营成本固定，本质安全运行，符合环保要求的处理。 除了化学计量学和动力学，反应器技术，包括引进和消除反应物和产品，有效供给和撤消热，可容纳相变化和材 料转移，保证高效的反应物接触，并为催化剂提供补给或再生的要求。必须考虑到物理性质的饲料和产品(蒸气， 液体，固体或组合)，特性化学反应(反应物浓度，路径和速度，运行条件，热添加或删除)，在使用任何催化剂的 性质(活动，生活和身体表)，并负责联系反应物和删除产品(流量特性，传递现象，混合要求，并分离机制)的 要求。 所有的因素是相互依存，一并加以考虑。反应物的接触，消除产品的要求是在应用电抗器技术的核心焦点;其他 因素通常是由该反应系统的原始选择，反应物的转化率和目的产物的选择性，以及经济和环境因素的水平。 反应堆类型及特征 具体反应器特性取决于该反应堆作为一个实验室，中试，工业单位或特定用途。所有的反应堆有四个基本反应堆类 型共同选定的特点:良好的搅拌批式反应器，半批式反应器的，连续流CSTR反应器，管式反应器和(图1)。 批式反应器 批式反应器是在其中一个进料作为一个整体治疗一段固定的时期。批式反应器，可首选小规模生产的高价位产品， 尤其是当许多顺序操作受雇取得的产品产量高，大肠杆菌克，一个过程，需要对温度压力增加的复杂的反应周期。 批式反应器也可能是合理的时候多，低容量的产品在同一设备生产 其他反应物添加在连续反应物在反应物。 neaagcooling indng cooli饲料产品加热/冷却饲料沿堆Heatin /冷却距离 图。 1反应堆类型:(一)批次，(二)半批式，(三)继续流 搅拌坦克，和(d)管 153 equipment or when continuous flow is difficult，as it is with highly viscous or sticky solids- laden liquids，e. g., in the manufacture of polymer resins where molecular weight and product quality are markedly affected by increasing viscosity and heat removal demands. Because residence times can be more uniform in batch reactors，better yields and higher selectivity may be obtained than with continuous reactors. This advantage exists when undesired reaction products inhibit the reaction，side reactions are of lower order than that desired，or the product is an unstable or reactive intermediate. Batch reactors often are used to develop continuous processes because of their suitability and convenient use in laboratory experimentation. Industrial practice generally favors processing continuously rather than in single batches， because overall investment and operating costs usually are less. Data obtained in batch reactors，except for very rapid reactions，can be well defined and used to predict performance of large scale，continuous- flow reactors. Almost all batch reactors are well stirred ; thus，ideally，compositions are uniform throughout and residence times of all contained reactants are constant. Semibatch Reactor The semibatch reactor is similar to the batch reactor but has the additional feature of continuous addition or removal of one or more components. For example，gradual addition of chlorine to a stirred vessel containing benzene and catalyst results in higher yields 6f di- and trichlorobenzene than the inclusion of chlorine in the original batch. Similarly，thermal decomposition of organic liquids is enhanced by continuously removing gaseous products. 154 Constant pressure. can be maintained and chain-terminating reaction products removed from the system. In addition to better yields and selectivity，gradual addition or removal assists in controlling temperature particularly when the net reaction is highly exothermic. Thus，use of a semibatch reactor intrinsically permits more stable and safer operation than in a batch operation. Continuous-Flow Stirred-Tank Reactor In a continuous-flow stirred-tank reactor (CSTR)，reactants and products are continuously added and withdrawn. In practice，mechanical or hydraulic agitation is required to achieve uniform composition and temperature，a choice strongly influenced by process considerations，i. e., multiple specialty product requirements and mechanical seal pressure limitations. The CSTR is the idealized opposite of the well-stirred batch and tubular plug- flow reactors. Analysis of selected combinations of these reactor types can be useful in quantitatively evaluating more complex gas-，liquid-，and solid-flow behaviors. Because the compositions of mixtures leaving a CSTR are those within the reactor，the reaction driving forces， usually reactant concentrations，are necessarily low. Therefore， except for zero- and negative-order reactions，a CSTR requires the largest volume of the reactor types to obtain desired conversions. However，the low driving force makes possible better control of rapid exothermic and endothermic reactions. When high conversions of reactants are needed， several CSTRs in series can be used. Equally good results can be obtained by dividing a single vessel into compartments while minimizing back-mixing and short-circuiting. The larger the number of stages，the closer performance approaches that of a tubular .plug-flow reactor.， Tubular Reactor The tubular reactor is a vessel through which flow is continuous., usually at steady state， and configured so that conversion and other dependent variables are functions of position within the reactor rather than of time. In the ideal tubular reactor，the fluids flow as if they were solid plugs or pistons，and reaction time is the same for all flowing material at any given tube cross section;hence，position is analogous to time in the well-stirred batch reactor. tubular reactors -)resemble batch reactors in providing initially high driving forces， which diminish as the reactions piogress down the tubes. Flow in tubular reactors can be laminar，as with viscous fluids in small-diameter tubes， and greatly deviate from ideal plug-flow behavior，or turbulent，as with gases，and consequently closer to the ideal. Turbulent flow generally is preferred to laminar flow， because mixing is introduced in the direction of flow. For slow reactions and especially in small laboratory and pilot-plant reactors，establishing turbulent flow can result in inconveniently long reactors or may require unacceptably high feed rates. Depending on the consequences in process development and impact on process economics， compromises， though necessary，may not prove acceptable. 当设备或连续流是困难的，因为它具有高度粘性或粘性固体，液体拉丹，E.是克，在聚合物在分子量 和产品质量均显着增加粘度和散热需求影响树脂的生产。由于停留时间可在批式反应器，更好的产量 和较高的选择性，可取得更均匀比连续反应堆。这种优势时存在不良反应产物抑制反应，副反应是低 于预期的订单，或产品是一种不稳定或反应中间体。 批式反应器经常被用来发展，因为它们适于在实验室实验和方便使用连续过程。一般加工工业实 践中不断地有利于而不是单一的批次，因为整体投资和运营费用通常较少。在批式反应器获得的数据， 除了非常迅速的反应，可以明确界定，并用来预测大规模，连续流动反应器的性能。几乎所有的批式 反应器的搅拌好，因此，最理想的是，整个作品是统一和各反应物中的停留时间为常数。 半批式反应器 半批式反应器的类似的批式反应器，但连续添加或删除一个或多个组件的附加功能。例如，氯逐步除 了激起比氯原批列入船只苯中含有较高的产量和催化剂结果6楼二和三氯苯。同样地，有机液体中的 热分解去除气态不断增强产品。 154恒压。可以继续保持和链终止反应，从系统中删除产品。除了更好的收益率和选择性，逐步增加 或去除协助控制温度尤其是当净反应是强放热反应。因此，一个半批式反应器本质上允许使用比在批 处理操作更稳定，更安全的操作。 连续流搅拌，反应釜 在连续流动搅拌，反应器(CSTR)，反应物和产品的不断增加和撤销。在实践中，机械或水力搅拌 须达到成分和温度均匀，强烈进程的考虑，选择一，影响了五，多专业的机械密封产品需求和压力的 限制。连续搅拌反应是良好的搅拌批次和管状推流式反应器的理想背道而驰。这些反应堆类型选择的 组合分析可定量评价是有用的更复杂的气体，液体和固体流的行为。 因为离开一个CSTR反应混合物的组成，反应器内的，反应驱动力，通常是反应物浓度，都必然 是低。因此，除了零和负序反应，需要一个CSTR反应的反应堆类型最大音量以获得所需的转换。 但是，低动力成为可能更好的快速放热和吸热反应的控制。当反应物高的转换是需要的，在一系列的 不同CSTRs都可以使用。同样良好的效果，市民可分为单船车厢，同时尽量减少返混及短路。数字 越大的阶段，是一个管状。推流式反应器接近性能接近。， 管式反应器管式反应器是船只通过该流是连续的。通常在稳定状态，配置，使加工成本和其他因变量 是反应器内，而不是时间的位置的功能。在理想管式反应器，流体流动，好像他们是坚实的插头或活 塞，反应时间是所有在任何给定的管截面流材料相同，因此，地位类似于时间在充分搅拌批式反应器。 管式反应器 - )像最初提供高驱动力，而降低，如反应piogress批式反应器下降管。 管式反应器流可层，与小直径管粘稠液体，并大大偏离理想推流式的行为，或湍流，与气体，因 此更接近理想。湍流一般要好于层流，因为混合是在流动方向介绍。对于较慢的反应，特别是在小型 实验室和中试反应器，建立湍流会导致反应堆不便或需要长期过高的进给率。根据在工艺开发和工艺 经济，妥协，虽然必要影响的后果，可能并不接受。 Multiphase Reactors多相反应器 Fig. 2 Multiple fixed-bed configurations:(a)adiabatic fixed-bed reactor，(b) tubular fixed beds，(c) staged adiabatic reactor with interbed heating (cooling)， (d) moving radial fixed-bed reactor， and (e) tickle beds in series 图。2多固定床配置:(一)绝热固定床反应器，(二)管 固定的床，(三)，上演了夹层加热(冷却)绝热反应器， (四)移动径向固定床反应器，以及(e)在系列病床痒痒 155 The overwhelming majority of industrial reactors are multiphase reactors. Some important reactor configurations are illustrated in Fig. 2 and Fig. 3. The names presented are often employed，but are not the only ones used. The presence of more than one phase，whether or not it is flowing，confounds analyses of reactors and increases the multiplicity of reactor configurations. Gases，liquids，and solids each flow in characteristic fashions，either dispersed in other ‘phases or separately. Flow patterns in these reactors are complex and phases rarely exhibit idealized plug-flow or well-stirred flow behavior. A fixed-bed reactor is packed with catalyst. If a single phase is flowing，the reactor can be analyzed as a tubular plug-flow reactor or modified to account for axial diffusion. If both liquid and gas or vapor are injected downward through the catalyst bed，or if substantial amounts of vapor are generated internally，the reactors are mixed-phase，downflow， and fixed-bed reactors. If the liquid and gas rates are so low that the liquid flows as a continuous film over the catalyst，the reactors are called trickle beds. Trickle beds have potential advantages of lower pressure drops and superior access for gaseous reactants to the catalyst; however restricted access can also be a disadvantage，e. g., where direct gas contact promotes undesired side reactions. At higher total flow rates，particularly when the liquid is prone to foaming，the reactor is a pulsed column. This designation arises from the observation that the pressure drop within the catalyst bed cycles at a constant frequency as a result of liquid temporarily blocking gas or vapor pathways. The pulsed column is not to be confused with the pulse reactor used to obtain kinetic data in which a pulse of reactant is introduced into a tube containing a small amount of catalyst. Downflow of reactants is preferred because reactors are more readily designed mechanically to hold a catalyst in place and are not prone to inadvertent excessive velocities， 其中，工业反应器绝大多数是多相反应器。一些重要的反应器配置图所示。 2和图。3。提出的名称为经常，但不是只用的。超过一相的存在，不论它是流动的，混淆反应堆和反应堆的配置增加了多样性分析。气体，液体和固体流中的每个特征的时尚，无论是分散在其他'相或分开。在这些反应器流态复杂，分阶段很少表现出理想化的推流式或福利搅拌流动的行为。 固定床反应器是挤满了催化剂。如果是单相流，反应器可以分析为管状推流式反应器或修改，以考虑轴向扩散。如果液体和气体或蒸气通过催化剂床层注入向下，或者大量的蒸气产生内部，反应堆的混合阶段，下行流和固定床反应器。如果液体和气体率如此之低，成为一个催化剂连续膜的液体流动，被称为滴流床反应器。涓流床有较低的压力下降以及向上级访问气态反应物催化剂的潜在优势，但受限制的访问也可以是一个缺点，大肠杆菌克，其中直接促进不受欢迎的气体接触面反应。 在较高的总流量，尤其是当液体很容易起泡，反应器是脉冲列。这一名称时说，在一个恒定的频率周期内催化剂床层压力下降导致的液体气体或蒸气暂时阻断通路的观察。脉冲列不被混淆用于获取其中一个脉冲的反应将含有少量的催化剂管引入动力学数据脉冲反应堆。 反应物是首选，因为下行流反应器的机械设计更容易在地方举行的催化剂，是不容易发生意外过量速度， Fig.3 Multiphase fluid and fluid-solids reactors: (a)bubble column (b)spray column，(c)slurry reactor and auxiliaries，(d)fluidization unit，(e)gas-liquid- solid fluidized reactor，(f) rotary kiln，and (g) traveling grate or belt drier 图3多相流体和流体固体反应堆: (一)气泡柱(二)喷柱，(三)浆态床和助剂，(四)流态化单位(五)气液固流化床反应器，(六)回转窑，以及(g)或皮带链条炉排干燥剂 which upset the beds. Upflow is used less often but has the advantage of optimum contacting between gas，liquid，and catalyst over a wilder range of conditions. Mixed-phase，upflow， and fixed-bed reactors offer higher liquid holdups and greater assurance of attaining uniform catalyst wetting and radial flow distribution，the consequences of which are' more uniform temperature distribution and greater heat transfer. At high liquid flow rates in these co-current fixed-bed reactors，gas becomes the dispersed phase and bubble flow develops ; flow characteristics are similar to those in countercurrent packed-column absorbers. At high gas rates，spray and slug flows can develop. Moving beds are fixed-bed reactors in which spent catalyst or reactive solids are slowly removed from the bottom and fresh material is added at the top. A fixed bed that collects solids impurities present in the feed or produced in the early reaction stages is a guard bed. If catalyst deposits are periodically burned or otherwise removed，the operation is cyclic，and the catalyst remaining behind the combustion front is regenerated. In bubble column reactors，gas bubble flow upward through a slower moving liquid. The bubbles，which rise in essentially plug flow，draw liquid in their wakes and thereby induce back-mixing in the liquid with which they have come in contact. Analogously，in spray columns，liquid as droplets descend through a fluid，usually gas. Both bubble and spray columns are used for reactions where high interfacial areas between phases are desirable. Bubble column reactors are used for reactions where the rate-limiting step is in the liquid phase，or for slow reactions where contacting is not critical. An important variant of the bubble column reactor is the loop reactor，commonly used for both multiphase and highly viscous systems. Loop reactors are distinguishable by their hydraulically or mechanically driven fluid recirculation，which offers the benefits of the well-stirred behavior of CSTRs and high average reactant concentrations of tubular reactors. Reactors are termed fluidized or fluid beds if upward gas or liquid flows，alone or in concert，are sufficiently high to suspend the solids and make them appear to behave as a liquid. This process is usually referred to as fluidization. The most common fluid bed is the gas-fluidized bed. With gas feeds，the excess gas over the minimum required for fluidization rises as discrete bubbles，through which the surrounding solids circulate. At higher gas rates，such beds lose their clearly defined surface，and the particles are fully suspended. Depending on the circumstances，these reactors are variously called riser， circulating- fluidized，fast-fluidized，or entrainment reactors. In ebullating-bed or gas-liquid-solid reactors，the solids are fluidized by liquid and gas，with gas primarily providing lifting power in the former，and liquid in the latter. These become slurry bubble column reactors (less precisely，slurry reactors)at high rates when the beds begin to lose their defined surfaces. Slurry bubble column reactors that contain finely powdered solids are often termed and treated as bubble column reactors because such suspensions are homogeneous. A reactor is termed a radial or panel-bed reactor when gas or vapor flow perpendicular to a catalyst-filled annulus or panel. These are used for rapid reactions to reduce stresses on the catalyst or to minimize pressure drops. Similar cross-flow configurations also are used for processing solids moving downward under gravity while a gas passes horizontally through them. Rotary kilns，belt dryers，and travelling grates are examples. Cross- flow reactors are not restricted to solids-containing systems. Venturis ，in which atomized liquids are injected across the gas stream，are effective for fast reactions and similarly for generating small gas bubbles in downward-flowing liquids where mass transport across the gas-liquid interface is limiting. Selected from R. E. Kirk & D. F. Othmer , Encyclopedia of Chemical Technology, 4th ed. , vol. 20, 1996, John Wiley & Sons，New York. 它扰乱了床。上流是不常使用，但在一个疯狂的条件范围内的最佳利益之间的气体，液体接触，和催 化剂。混合阶段，上流式和固定床反应器提供了更高的液体含率和更大的润湿和实现统一的催化剂径 向流分布的保证，其后果是更均匀的温度分布和更大的热传递。' 在这些合作在高电流固定床反应器液体流量，气体成为分散相和泡状流发展流动特性是在填充柱 ; 减震器类似的逆流。高瓦斯率，喷雾和塞流才能发展。移动床固定床反应器中固体废催化剂或反应性也慢慢从底部删除和新鲜的材料是在顶部添加。固定床，收集固体杂质存在于饲料或在早期阶段产生的反应是一个保护层。如果催化剂存款定期烧毁或以其他方式拆除，操作循环，催化剂，燃烧后余下的则是前再生。 在鼓泡塔反应器，气泡流过的液体向上缓慢移动。气泡，这在本质上塞流的兴起，吸引他们的流 动性，从而导致醒来后，在与他们有接触的液体混合。类似地，在喷柱，液体，通过流体液滴，通常气体下降。这两个泡沫和喷雾列用于反应在地区之间的高界面阶段是可取的。鼓泡塔反应器可用于在反应的限速步骤是在液相中，或在接触并不严重反应缓慢。一个重要的鼓泡塔反应器变种是循环反应器，一般为多相和高粘度的系统中。环流反应器是由液压或机械驱动的流体循环，提供了良好的搅拌和高的管式反应器反应物的平均浓度行为的利益区别开来。CSTRs 流化床反应器被称为流化床如果向上或气体或液体流动，单独或在演唱会，有足够高的固体暂停， 让他们似乎表现为液体。这个过程通常被称为流态化。最常见的是气体流化床流化床。随着汽油饲料，过流化作为离散气泡上升所需的最低限度，通过它周围的固体过剩气体流通。在较高的气率，病床等表面失去了明确界定，和粒子完全暂停。根据不同的情况下，这些所谓的提升管反应器是不同的，循环，流化床，快速流化床，或夹带反应堆。在床或气液固反应器中，固体流态化的液体和ebullating 气体，气体主要提供在前，并在后者液体提升力。这些成为浆鼓泡塔反应器在高利率(扣除准确地说，浆态床)当床开始失去其定义的表面。鼓泡浆态反应器中包含细微粉末状固体常被称为和鼓泡塔反应器处理，因为这种悬浮液均匀。 一个被称为径向反应器或面板床反应器时，气体或蒸汽流量垂直于催化剂填充环或面板。这些是 快速反应，以减少使用讲于催化剂或尽量减少压降。类似的横流的配置还用于处理固体在重力作用下向下运动，同时通过横向的气体通过他们。回转窑，皮带机和旅游炉排就是例子。横流式反应器不仅仅限于固体含系统。丘，其中在液体雾化气流注入，是有效的快速反应和产生同样在向下流动的液体的小气泡在质量上的气液界面的交通限制。 选择从再柯克,东风奥思默，化工技术百科全书， 第四版。，第一卷。日，年，约翰,出版，纽约。 201996WileySons Exercise 1. Answer the following questions: (1)What kinds of the reactor are often used in pharmaceutical factories? (2)What are the advantages and disadvantages of the Continuous-Flow Stirred- Tank reactor ? (3) Could you give some production examples that use multiphase reactors? (4) What kind of the reactor does a jacked fermentor belong to? 2. Translate the ” Tubular Reactor” section into Chinese. 3. Write a short essay to describe the multiplicity of multiphase reactor. 练习 1。回答下列问题: (1)什么类型的反应堆，还经常用于药厂, (2)有哪些优势和连续流搅拌，反应釜缺点是什么, (3)你能举出一些例子，生产，使用多相反应器, (4)什么样的反应器发酵罐属于一个劫持, 2。翻译的“管式反应器“为中国部分。 3。写一篇短文来描述多相反应器的多重性。