12 Things to Avoid During Process Scale-Up（12件需要在工艺放大避免的情况）

beiwei5du

12Things to Avoid During Process Scale-Up

12件需要在工艺放大避免的情况

1 - Avoid reactions that require highly specialized equipment, or that areknown to be hazardous and require special safety facilities, such as nitrationreactions. At a minimum, obtain full calorimetric data and compare it to themaximum heat removal rate of the reactor. If necessary,consider tolling out such reactions to companies that specialize in them.
1、避免需要高度特制设备的反应，即众所周知被认为危险的和需要特殊安全设施的反应，比如硝化反应。至少，需要获取全面的热量数据并将其和反应釜最大的热转移率比较。如果有必要，将这些危害反转包至那些专业的公司。
2 - Avoid "all-in and heat" operation - adding all reagents to thevessel and then heating up. While this is usually fine at the lab bench,possible exothermic reactions can create a thermal runaway situation at largerscales where heat removal rates are much slower. At unexpectedly hightemperatures, exothermic decomposition reactions can take over, putting thereaction beyond any chance of operator control. Rapid gas evolution cancompound the problem. It is better to design reactions so they can be controlledby slow addition of a limiting reagent at a rate that matches equipment coolingcapacity. As a corollary to this rule, never add the catalyst to a reactionmixture last.

2、避免“一次加入并加热”操作-即将所有的试剂加入到反应釜，然后加热。尽管在实验室，这种操作很通常很好。但是在大规模生产并且热转移率相对较低的情况下，放热反应可能造成热击穿现象。在超出预期的高温下，放热分解反应将占主导，使反应超出操作人员可控范围。急速的气体释放会加剧问题。所以最好能依据设备冷却性能，设计能够通过控制“限制物料”添加速率从而实施控制的反应。根据这条原则推论，禁止将催化剂直接加入到反应混合物中。
3 - Never heat a reactor without agitation. It can create hot spots thatcan erupt in violent boiling when the mixer is turned on. Never stop theagitator until a reaction mixture has cooled to a safe temperature.

3、绝不在不搅拌的情况下加热反应釜。这将形成过热点，并在搅拌桨启动的情况下造成剧烈的爆沸。绝不在反应混合物降低到安全温度之前停止搅拌桨。
4 - Do not operate a reactor less than 50°C from the known onset temperature ofan exotherm that might run out of control.

4、禁止在可能失控的放热反应的已知起始温度50摄氏度以下操作反应釜。

5 - Avoid having to add solids to a reacting mixture. Manual addition can beextremely dangerous, and screws and conveyors for large scale solids additionare unreliable and expensive. Do not add solids to a hot or refluxing mixture.（？？？？？）

5、避免直接加入固体到反应混合液，手工加料会十分危险，并且大规模的固体添加的螺杆加料和传送带加料不可靠并且十分昂贵。禁止将固体物料加入到热的或者回流的混合物中。
6 - Never develop a process that relies on evaporating to dryness or to very low volumes. Although this is a useful laboratory technique, most large-scalereactors have a minimum mixing level about 20% of their capacity.

6、禁止开发依靠蒸馏手段蒸馏至干燥或浓缩至过低容量的工艺。虽然这是一种有用的试验技术，大部分大规模反应釜拥有大约其容量20%的最小搅拌体积。

7、Avoid reactions that must beisolated ”immediately” such as kinetic resolution  of some enantiomers. At the manufacturingscale, production isolation alone can take up to 24 hours. Make sure the productslurry is stable for a sufficient length time.

7、避免必须立即分离的化学反应，比如某些对映异构体的动态拆分。在工厂生产规模，仅生产分离一项就需花费24小时，确保产品浆液在足够长的时间内稳定。

8、Avoid using methylenechloride or other halogenated solvents that are considered environmentalhazards. At the manufacturing scale, waste treatment or removal costs can oftenkill a process. Also see page 6-44 for a list of solvents limited for pharmaceuticaluse by the FDA. The use of phosphates should be minimized for similar reasons.

8、避免使用被认为环境危害物的二氯甲烷或者其他卤化类溶剂。在工厂生产规模，废物治理或去除费用能杀死一个工艺。可在6-44页参考FDA制定的制药限制使用溶剂清单。由于相同的理由，磷酸盐的使用也应该被尽量降低。

9、Avoid hot filtration or polishfiltration of highly saturated solutions. Solids can crash outquickly in pipes or lines and clog the filter and other equipment. To preventthis in the plant, lines often have to be steam-traced,or preheated.

9、避免高饱和溶液的热过滤或者精密过滤。固体会在管线中迅速撞击析出并堵塞过滤器和其他设备。为避免这些状态在工厂发生，管线常需蒸汽伴热管加热或者预热。

10、Avoid reverse phase-splits(where the phase you want to retain is on the bottom). They require the additionof another vessel to the equipment train, a considerable expense at themanufacturing scale, and add time to the process cycle. Likewise，do not pour reaction mixturesinto water to quench them. When scaled up, it will likely have to be the otherway around.

10、避免反相分层（即所需保留的液相在分相层下部）。这需要在设备链中增加容器，在工厂生产规模相对昂贵，并增加了工艺周期的时间。同样的，禁止将反应液倒入水中以终止反应，当工艺放大时，这种操作可能会适得其反。

11、Try to avoid usingchromatography for purification. While it is extremely useful in the lab, it isused commercially only for very high-value products or where there is no otherchoice. Even then chromatography requires very large amount ofsolvents and support material. Better to develop a salt or other crystallizableform.

11、尽量避免使用层析法纯化，尽管该法在实验室非常有用，但其仅在高附加值的产品或者没有其他选择的情况下使用。尽管那样，层析法需要大量的溶剂和支撑物，最好制成一种盐型或者可结晶型。

12、Don’t risk all of your rawmaterials or intermediates on one batch! Be prepared for the possibility thatthe batch, especially in a new process, may still hold surprise in spite ofyour careful preparations. Operator errors may also be more likely the firsttime through a new process.

12、不要冒险将所有的原料或者中间体用于一批产品！对所有的可能性尽量做好准备，特别对于新工艺，尽管做了仔细的准备，批生产仍存在出人意料的情况。操作错误在新工艺第一次实施中更有可能发生。

beiwei5du

刚翻译了这个，但是非化工出生，对其中好多观点还是不熟悉！网大家指导：
1、As a corollary to this rule, never add the catalyst to a reactionmixture last催化剂加入，可能还是看阶段，比如氢化反应，我在没有通氢之前，难道不能通过固体加料口直接加入？？？
2、Avoid having to add solids to a reacting mixture.如果这种不能？？该怎么加料？？？
3、Avoid reactions that must beisolated ”immediately” 什么是isolated immediately？
4、Avoid reverse phase-splits(where the phase you want to retain is on the bottom)反相分层很普遍啊，
5、lines often have to be steam-traced,or preheated.大家的管道加热是使用的什么方式呢？？？？
反正有各种理解不了的

syhorchid

谢谢分享

coriolan

谢谢分享

coriolan

beiwei5du 发表于 2015-8-22 21:00
刚翻译了这个，但是非化工出生，对其中好多观点还是不熟悉！网大家指导：
1、As a corollary to this rule ...

1、As a corollary to this rule, never add the catalyst to a reactionmixture last催化剂加入，可能还是看阶段，比如氢化反应，我在没有通氢之前，难道不能通过固体加料口直接加入？？？
这个应该从原文来看，你没通氢气之前，应该不属于他说的这种情况，原文的意思应该是说：所有的反应物混合后，直接加入催化剂可能会造成反应失控，氢化反应在没有通入氢气时加入催化剂反应不会进行，不属于此情况。
3、Avoid reactions that must beisolated ”immediately” 什么是isolated immediately？这一条我理解应该是在强调产品混合物状态下的稳定性，强调了工艺放大过程中要留出足够的处理时间，这一点不只是分离操作，对于其他加热、冷却等操作，都要考虑小试和工艺放大的差异，对于时间要求很苛刻的，放大过程中可能存在困难
其他几点，特别是反相分层，我也不理解，期待高人指点

beiwei5du

coriolan 发表于 2015-8-23 09:38
1、As a corollary to this rule, never add the catalyst to a reactionmixture last催化剂加入，可能还 ...

对于第二个问题你们是先加固体物料到反应釜中，再加入溶剂系统，还是反过来的呢？？？？

coriolan

beiwei5du 发表于 2015-8-26 21:39
对于第二个问题你们是先加固体物料到反应釜中，再加入溶剂系统，还是反过来的呢？？？？

我们是先加溶剂，再加固体物料

胜利者

呵呵