制药工程专业英语第1、5、6、7、9、11、13、16、21、24、25单元文章翻译(吴达俊庄思永)

Unit 1 Production of DrugsAbout 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.关于5000抗生素已经分离出的微生物，但其中只有不到100有些治疗使用。

Unit 1 Production of DrugsDepending on their production or origin pharmaceutical agents can be split into three groups:I .Totally synthetic materials (synthetics)，Ⅱ.Natural products，andⅢ.Products from partial syntheses (semi-synthetic products).The emphasis of the present book is on the most important compounds of groups I and Ⅲ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.Table 1 Possibilities for the preparation of drugsMethods Examples1. 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 forvitamins A, E，and K)2.2 Animal organs一enzymes;peptide hormones;cholic acid from gall; insulin) from thepancreas;sera and vaccines2. 3 Other sources一cholesterol from wool oils;L-amino acids from keratin and gelatinehydrolysates3. Fermentation一antibiotics;L-amino acids;dextran; targeted modifications on steroids，e.g. 11-hydroxylation; also insulin, interferon, antibodies, peptidehormones，enzymes，vaccines4. Partial synthetic modification of natural products (semisynthetic agents):一alkaloid compounds;semisynthetic /3-lactam antibiotics;steroids;human insulinSeveral 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.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).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: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.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.Finally mention must be made of the important use of enzymes as `biocatalyst s’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. Thereforeknowledge 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.fIn 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.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. 5It 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.Unit 5 Drug Development (I)1. IntroductionDrug Development is a very complex process requiring a great deal ofcoordination and communication between a wide range of different functionalgroups. It is expensive，particularly in the later phases of clinical development，where studies involve hundreds of patients. It is currently estimated that thedevelopment of a new drug costs about$230 million(1987 dollars)and takessomewhere between 7 and 10 years from initiation of preclinical development tofirst marketing (excluding regulatory delays). Drug development is a high-riskbusiness;although the rate is increasing，only about ONE out of every TEN newchemical 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 overco me 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 averageonly about I in 400^1000 compoundssynthesized enters development.Reasons for termination of development of NCE's(excluding anti-infectives)1:Lack of efficacy2: Pharmacokinetics3: Animal toxicity4: Miscellaneous5: Adverse effects in man6: Commercial reasonsFig. 1 Attrition rates and reasons for terminations2. Planning for developmentAssessment 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 productionToxicology Acute&subacute toxicology Long term and repro-toxicologyClinical Phase I Phase ll Phase lll Analysis data and report Phase lV ReviewRegulatory Submission and updating of clinical trial application prepare submit AuthorityMAA/NDA Regulatory ApprovalPost marketing SurverillancePharmaceuticsDevelopment and stability testing Prepare labellingDrug metabolismand pharmacokinetics Animal ADME* Healthy humans Human patientsActivities likely to be on the critical path are shown in bold* Absorption , Distribution , Metabolism , ExcretionFig. 2 The major processes in new drug developmentThe 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 Ⅱ( initial efficacy and safety and dose finding studies in patients)，and Phase Ⅲ(studies in several hundred patients). There then follows assembly of a marketing application dossier for subsequent review by country regulatory authorities.3. Chemical developmentRapid 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 different methods so as to identify the optimum route for synthesizing the compound. ‘Optimum’here may mean a 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 developmentThe 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. PharmacologyBefore 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 issuedto 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 evaluationThe 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 of14 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 tumours②in 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 thesephases. 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.Unit 6 Isolation of Caffeine from TeaIn this experiment，Caffeine will be isolated from tea leaves. The major problem of the isolation is that caffeine does not occur alone in tea leaves，but is accompanied by other natural substances from which it must be separated. The major component of tea leaves is cellulose，which is the major structural material of all plant cells. Cellulose is a polymer of glucose. Since cellulose is virtually insoluble in water，it presents no problems in the isolation procedure. Caffeine，on the other hand，is water soluble and is one of the major substances extracted into the solution called "tea.”Caffeine comprises as much as 5 percent by weight of the leaf material in tea plants. Tannins also dissolve in the hot water used to extract tea leaves. The term tannin does not refer to a single homogeneous compound，or even to substances which have similar chemical structure. It refers to a class of compounds which have certain properties in common. Tannins are phenolic compounds having molecular weights between 500 and 3000. They a re widely used to "tan”leather. They precipitate alkaloids'z and proteins from aqueous solutions. Tannins are usually divided into two classes: those which can be hydrolyzed and those which cannot. Tannins of the first type which are found in tea generally yield glucose and gallic acid when they are hydrolyzed. These tannins are esters of gallic acid and glucose. They represent structures in which some of the hydroxyl groups in glucose have been esterified by digalloyl groups. The non-hydrolyzable tannins found in tea are condensation polymers of catechin. These polymers are not uniform in structure，but catechin molecules are usually linked together at ring positions 4 and 8.When tannins are extracted into hot water，the hydrolyzable ones are partially hydrolyzed，meaning that free gallic acid is also found in tea. The tannins，by virtue of their phenolic groups，and gallic acid by virtue of its carboxyl groups，are both acidic. If calcium carbonate，a base，is added to tea water，the calcium salts of these acids are formed. Caffeine can be extracted from the basic tea solution with chloroform，but the calcium salts of gallic acid and the tannins are not chloroform soluble and remain behind in the aqueous solution.The brown color of a tea solution is due to flavonoid pigments and chlorophylls，as well as their respective oxidation products. Although chlorophylls are somewhat chloroform soluble，most of the other substances in tea are not. Thus，the chloroform extraction of the basic tea solution removes nearly pure caffeine. The chloroform is easily removed by distillation(by 61'C)to leave the crude caffeine. The caffeine may be purified by recrystallization or by sublimation.68Catechin Gallic AcidIn a second part of this experiment，Caffeine will be converted to a derivative. A derivative of a compound is a second compound，of known melting point，formed from the original compound by a simple chemical reaction. In trying to make a positive identification of an organic compound，it is often customary to convert it into a derivative. If the first compound，Caffeine in this case，and its derivative both have melting points which match those reported in the chemical literature (e.g.，a handbook)，it is assumed that there is no coincidence and that the identity of the first compound，Caffeine，has been definitely established.Caffeine is a base and will react with an acid to give a salt. Using salicylic acid，a derivative salt of Caffeine，Caffeine salicylate，will be made in order to establish the identity of the Caffeine isolated from tea leaves.Special Instructions Be careful when handling chloroform. It is a toxic solvent，and you should not breathe it excessively or spill it on yourself. When discarding spent tea leaves，do not put them in the sink because they will clog the drain. Dispose of them in a waste container.Procedure Place 25g of dry tea leaves，25g of calcium carbonate powder，and 250ml of water in a 500ml three neck round bottom flask equipped with a condenser for reflux. Stopper the unused openings in the flask and heat the mixture under reflux for about 20 minutes. Use a Bunsen burner to heat. While the solution is still hot，filter it by gravity through a fluted filter using a fast filter paper such as E&D No. 617 or S&S No. 595. You may need to change the filter paper if it clogs.Cool the filtrate (filtered liquid)to room temperature and，using a separatory funnel，extract it twice with 25ml portions of chloroform. Combine the two portions of chloroform in a 100ml round bottom flask，Assemble an apparatus for simple distillation and remove the chloroform by distillation. Use a steam bath to heat. The residue in the distillation flask contains the caffeine and is purified as described below (crystallization). Save the chloroform that was distilled. You。

制药工程专业英语9单元课文翻译第一篇：制药工程专业英语9单元课文翻译Thoughout recorded纵观历史记载，细菌感染的人口定期付出沉重的收费。

鼠疫菌的“黑死病”鼠疫的1347-1351期间，估计有25万人在亚洲和欧洲死亡。

美国公共卫生服务统计为1910年和1920年的节目，在这个早在本世纪结核病死亡每1000名美国居民中的一个。

即使在今天，主要是在发展中国家，结核分枝杆菌仍然是主要死亡原因由于在单染性病，全世界每年杀害超过三百万Such 整个脊椎动物进化过程中的这种不懈的微生物攻击，挑起了一个令人惊讶的复杂的保护性免疫系统的进化。

随着人类的外观，最终到达一个物种可以设法协助先天和后天免疫系统，避免感染。

通过利用微生物的抗原成分（疫苗和马血清抗毒素的产生），然后微生物次生代谢产物（抗生素），已成为人类善于预防和治疗许多以前致命的微生物疾病。

Within在短短的几十年，抗感染药药典的可用性突然提供了人类的潜力，以提高他们的生存前景下不断微生物拦河坝规避自然的经过时间考验的，活的或死的进化范式。

那些以前会屈服于成员现在可以存活时间较长的疫苗和抗生素的帮助助剂-抗感染免疫系统一起工作。

实际上，人类对这些助剂的就业可以作为例证在他们的免疫防御系统的自我做作的演变看。

Once当爵士亚历山大·弗莱明发现青霉素的效用已经证明，从发掘出的天然来源的其他抗生素乱舞紧随其后。

其中一些被证明适用于治疗疾病，通常经过化学改性，以提高天然化合物的效力，安全性或药代动力学AlphaFor对于大多数在过去50年中，看来，医学获得了强大的手上的细菌病。

某些制药厂和研发机构决定减少对抗生素的发现成果，因为它的出现，医生的抗菌军火库是充足。

但疾病的性质已经证明并非如此。

The在多种抗生素耐药病原体的发病率迅速升级现在提高全球非常严重的问题。

这种发展突出了强大的进化能力的细菌种群的选择压力下的抗生素治疗。

Resistance抗药性问题被视为与革兰氏阴性（例如大肠杆菌）和革兰氏阳性菌（如金黄色葡萄球菌），但目前关注的最后一组的病原体。

制药行业专业英语1，药品生产质量管理规范GMP：Good ManufacturingPractice2，国家食品与药品监督管理局State Food and Drug Administration3，总则GeneralProvisions4，《中华人民共和国药品管理法》the DrugAdministration Law of the People's Republic of China 5，制剂Preparation6，原料药API: Active PharmaceuticalIngredient7，成品finished goods8，工序process9，机构与人员organization and personnel10，专业知识professional knowledge11，生产经验production experience12，组织能力organizational skill13，技术人员technical staff14，实施implementation15，药品生产pharmaceutical manufacturing16，质量管理quality management17，质量检验quality inspection18，专业技术培训professional and technicaltraining19，基础理论知识basic theoreticalknowledge20，实际操作技能practical operationskills 21，高生物活性highly potent22，高毒性high toxicity23，污染contamination24，考核评估assessment25，厂房与设施buildings and facilities 26，生产环境production environment 27，空气洁净级别clean air level28，昆虫insect29，洁净室（区）clean room(area)30，光滑smooth31，无裂缝no cracks32，无颗粒物脱落no particle shedding 33，耐受endure34，消毒disinfection35，无菌sterile36，交界处junction, joint37，弧形arc38，灰尘积聚dues accumulation 39，储存区store area40，生产规模production scale41，设备equipment42，物料material43，中间产品intermediate product 44，待验品quarantined material 45，交叉污染cross-contamination 46，管道pipeline, ductwork47，风口tuber48，公用设施, 公用工程utilities of publicservice 49，照明lighting50，照度illumination。

P61 Unit 5 药物研发药物代谢作用和药代动力学药物代谢和制药学研究需要建立一套关于化合物代谢和方式的知识，化合物水平及其代谢产物根据药物给予量和施用时间长度变化的方式（决定）。

在早期药物临床发展临床阶段,很少有代谢数据权威性的管理要求。

然而，新陈代谢研究有助于解释毒理学结果和研究设计，以及有助于将动物安全性效率数据进行外插。

在生物学流体或组织中需要开发测定法测量药物和主要代谢产物水平。

目的是快速开发可重现性方法。

高效液相色谱通常用于分离，但其他技术如气相色谱在试用时也可以使用。

例如检测法可以是紫外光，荧光测定法，电化学方法，质谱法。

当化合物的活性很高时，体液和组织液中仅存痕量物质，检测可能出现问题。

放射免疫测定法可以提供更高的灵敏度，以及在给定时间内有可能分析出更多的化合物。

然而，放射免疫测定法有可能花很长时间来显影，并且缺少特异性将是一个问题。

需要关于化合物/代谢物血浆浓度的信息来支持毒理学研究，以及帮助选择剂量水平。

有最初需要建立药代动力学的线性区域，即其中剂量对AUC可被认为是一个线性的范围。

对非线性原因的确定例如代谢饱和的吸收/消除将有助于理解毒理学或药理学现象。

临床学一旦已经完成并分析充分的动物试验，药物公司将决定是否将药物投入人体研究阶段。

这一步通常包括公司专家，临床研究者和临床委员会的批准，并且在某些国家，例如在美国，还需要政府机构如FDA（美国食品和药品监督管理局）的审查。

当出资公司向FDA提出一种新药的调查申请时，这种新药就首先被FDA 审查。

FDA必须在30天内让出资者知道以他们的判断这个临床研究是否足够安全。

如果足够安全，实际上IND可考虑在其中并且临床可以继续进行。

如果不安全，FDA会将这个临床研究暂停直到他们的担忧成功解决。

规划这个临床方案时，很重要的是参考目标性质并且探究药物的潜在临床效益，尽可能早地参考这些，以便去除掉未能达到预期效果的候选药物。

新候选药物最初在人体内试用应遵循以下主要原则：确定药物在人体内的安全性和耐受性。

1、生产的药品其生产或出身不同药剂可以分为三类：Ⅰ.完全（合成纤维）合成材料，Ⅱ.天然产物，和Ⅲ.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Ⅰ和Ⅲ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。

（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2.3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。

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）。

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。

P131-Unit1314制药工程-专英作业1.Sterile product are dosage forms of therapeutic agents that are free of viable microorganismsTranslations:无菌产品是不含微生物活体的治疗剂型。

2.Principally，these include parenteral,ophthalmic,and irrigating preparations。

主要包括非肠道，眼药，冲洗制剂3.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.其中，肠外给药在药物剂型中是独特的，因为它们是通过皮肤或粘膜注射到体内的4.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 highly level ofpurity.因此，因为它们穿过了人体的第一道防线，皮肤和粘膜，所以它们必须没有微生物的污染和有毒成分，以及具有非常高的纯度水平。

5.原文：All compontents 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. 翻译：在产品制备中涉及的所有组分和工艺流程必须要筛选和设计以尽可能消除各种类型的污染，无论是来自物理的，化学的，还是微生物的。

Unit 1 Production of DrugsDepending on their production or origin pharmaceutical agents can be split into three groups:I .Totally synthetic materials (synthetics)，Ⅱ.Natural products，andⅢ.Products from partial syntheses (semi-synthetic products).The emphasis of the present book is on the most important compounds of groups I and Ⅲ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，Ⅱ。

天然产物，和Ⅲ。

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Ⅰ和Ⅲ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。