Topic 4

Question 1

Define E factor

Answer 1

• a metric for assessing the efficiency and greenness of existing and new processes
• the mass ratio of total waste to products produced

E factor = total waste produced/total products produced

(waste produced/kg of product)

Question 2

Solvent recovery strategies? (5)

Answer 2

1. Recycling solvent - distillation is the most common
2. Use continuous reactors instead of batch reactors- higher heat/mass transfer rates + shorter reaction times -> less solvent used
3. Biosynthetic process - enzymes as catalyst, highly selective and biosynthetic reactions normally carried out in water
4. Solid state chemistry - no solvent used, high product purity produced, novel and not used commercially to date
5. Telescoping - reduce number of process steps and unit operations, e.g. sertraline (Zoloft) by Pfizer steps reduced from 3 to 1

Question 3

Method of solvent use reduction?

Answer 3

• use of green engineering and chemistry practices
• improve process development and solvent selection
• e.g. BMS optimized the process of making Taxol -> elimated 10 solvents, 6 drying steps and 11 chemical transformations + used enzymes as catalyst

Question 4

What is distillation?

Answer 4

• used for separation of components in a liquid solution
• dependent on the distribution of the components in the vapour and liquid phase
• all components are present in both phases
• the vapour phase is created from the liquid phase by vapourization at its boiling point
• basic requirement for separation is: the composition of the vapour is different from the liquid with which it is in equilibrium at the liquid boiling point

Question 5

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properties of a solvent mixture?

Answer 5

• no fixed boiling point
• has bubble point and dew point
• bubble point: temperature at which first bubble appears
• dew point: temperature at which first drop of liquid appears

Question 6

what is vapour-liquid equilibrium constant?

Answer 6

Ki = yi/xi
yi: mol fraction of component i in vapour phase
xi: mol fraction of component i in liquid phase
- ratio of vapour to liquid mole fraction of a single component
- the greater the difference btween xi and yi, the better the separation

Question 7

1.

explain relative volatility

Answer 7

a = Ki/Kj
- the ratios of vapour-liquid equilibrium constants for a pair of components
- when a>1, separation is possible
- a expresses the degree of volatility of one component to the other

Question 8

Discuss distillation methods (3)

Answer 8

1. Single stage - equilibrium or flash distillation
   - occurs in a single stage
   - a liquid mixture is partially vapourized
   - the vapour is allowed to come to equilibrium with the liquid
   - the liquid and vapour phases are separated
   - can be batch or continuous
2. Single stage - simple batch or differential
   - liquid mixture heated up in a still
   - as liquid boils slowly, the vapour is removed as soon as it is formed
   - the vapour is condensed as the distillate
   - nothing is added until the run is complete
   - the first portion of vapour is richest in the lighter (more volatile) component
   - as distillation proceeds, the vapour becomes leaner in lighter component
   - complete separation is impossible
   - can be used for preliminary separation
3. Distillation with reflux/fractional distillation
   - a series of flash vapourisation stages arranged in series
   - vapur and liquid products from each stage frlow counter-currently to each other
   - in each stage, a vapour and a liquid stream enter, are mixed and equilibrated before leaving to the next stage
   - the lighter component increases in vapour going upwards and decrease in liquid going downwards
   - vapour from the top stage rich in the lighter component is withdrawn and condensed, while a portion of it is returned to the column as reflux
   - liquid at the bottom where reboiler is gets partially vapourised and rises up the column while remaining liquid rich in heavier component is withdrawn as bottom product

Question 9

Define azeotropes.

Answer 9

A liquid mixture of 2 or more substances that boils at a lower or higher temperature than any of its components, and that retains the same composition in the vapour state as in the liquid state.
AKA constant boiling mixture

• vapour has same proportions as liquid -> hence cannot be separated by distillation

Question 10

Batch distillation of binary azeotropic mixture at constant pressure?

Answer 10

• given same heat applied, the temperature will incnrease with vapour richer in lighter component
• once the compositions reaches azeotropic point, the temperature and composition will not change until all the liquid fully vapourizes
• the composition at azeotropic point is the point of maximum separation -> marking end of distillation

Question 11

explain azeotropic or extractive distillation

Answer 11

• used to separate azeotropic and small a mixtures
• difficult and energy intensive to separate
• involves the addition of an entrainer (solvent)
• entrainer forms azeotrope with one of the solvent to be separated
• this can generate more waste unless the entrainer can be easily reused and recycled

Question 12

How to separate azeotropic mixtures? (2)

Answer 12

1. Pervapouration (PV)
   - membrane-based process for separation of aqueous, azeotropic solvent mixtures (has water)
   - uses hydrophilic non-porous membrane tha tis highly selective to water
   - independent of vapour-liquid equilibrium of solvent mixture, hence is able to separate azeotropic mixture

2.Distillation - PV hybrid
- the mixture is sent to distillation column to separate mixture to azeotropic point
- vapour at azeotropic point is sent to PV unit where PV membrane separates out water and solvent
- able to achieve high solvent concentration, removes the need for additional solvent entrainer and improves efficiency of solvent recovery
e.g. in the case of IPA-water mixture, distillation increase IPA concentratoin until azeotropic point, then PV is used to remove water. 99.1wt% of IPA purity can be achieved. (72% overall operating cost saving on pfizer celecoxib)

Question 13

Economics of solvent recovery?

Answer 13

**solvent recovery is only done when it is both environmentally and economically feasible

Savings:
- purchase of fresh solvent
- disposal of spent solvent
- transport

Cost:
- capital
- energy
- storage

only when savings> cost does it make sense to have solvent recovery

• capital investment includes tank-farms, piping and recovery equipment
• not easy to justify with small volume waste-streams. the streams may or may not be pooled for recovery
• solvent recovery often done batchwise hence increase requirement for tankage (storage of solvent waste and recycled waste)
• solvents are treated as a batch and released as a batch as opposed to being integrated with the API manufacturing process

Question 13

disadvantages of distillation?

Answer 13

• generation of waste -> release of greenhouse gas co2
• high energy requirements
• inadequate condensing of distillate (overhead) products
• other inefficiencies

Question 14

Expain Life Cycle Approach (LCA) + 3 impacts

Answer 14

• determines the environmental impact of a process
• the environmental impact inclides assessing energy and emissions associated with:
• production of solvent
• use of solvent
• treatment and disposal of wastes

resource consumption
global warming
workplace safety
exo-toxicity
human toxicity

Question 15

1.

GMP for solvent recovery?

Answer 15

• validation is required for solvent recovery processes if the recovered solvents will be used in processes from which they did not originate from -> elimiate the risk of cross contamination
• solvents from processes that require dedicated facilities are not recovered for reause in other product families
• recycled solvents shown and documented to not affect API purity or intermediates

Question 16

Explain PAT

Answer 16

It is a system for designing, analyzing and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality.

USFDA: a framework to support innovation and efficiency in;
- pharmaceutical development
- manufacturing, and
- quality assurance
it is founded on process understanding to facilitate innovation and risk-based regulatory decisions by USFDA

Paradigm shift in ensuring quality:
Fixed process model
variable raw material input -> fixed process -> variable output
VS
Variable process model
variable raw material input -> variable process -> consistent output
variable process model is better, achieved by varying process parameters based on raw material characteristics to achieve consistent quality

Mission of PAT
PAT enables:
- QbD, ICH8-intro to concept of design space
- process validation, ICH9-continual improvement

**the central point of PAT is to generate product quality information in real time

**real time tests on critical quality attributes throughout manufacturing process

Question 17

Explain QbD

Answer 17

It is a systematic, scientific, risk-based and proactive approach to the pharmaceutical product and process development through commercialization. It is a comprehensive understading of how product attributes and process are related to product performance.

Quality is not a result of passing the final testing. It comes from intentionally developing product and process to consistently produce specific predefined attributes.

Elements of QbD:
- understand how attributes of raw materials and process parameters affect quality of final product
- establish in-process controls or make adjustments to the process without affecting the quality of the final product
- analyse potential risks involved before start of manufacturing + analyse data colleccted during manufacturing to anticipate and preduct imminent process issues

Question 18

Process validation?

Answer 18

stage 1. process design
stage 2. process qualification
stage 3. continued process verification

Question 19

types of in-ine testing?

Answer 19

In-line: no removal of sample
On-line: sample diverted away from main process, analyzed and may be returned
At-line: sample removed and analyzed close to process
Off-line: sample removed and analyzed away from process

Question 20

Common PAT tools?

Answer 20

1. thermocouples and pressure sensors
2. spectroscopic tools: NIR, MIR, Raman
3. Laser: FBRM

Spectroscopic tools:
- measures specific functional groups found in API, intermediates and raw materials
- qualitative trending and quantitative determination of component of interest
- probes connect spectrometer to process for real time measurement

Question 20

In-line FTIR monitoring of asymmetric hydrogenation reaction

Answer 20

• chiral catalyst used to convert achiral enamine amide to freebase product of desired chirality
• reaction conducted under 100psig of H2 at 50degC and normally takes about 15-21 hours to complete
• HPLC conventionally used to determine end of reaction

Disadvantages of HPLC:
- time consuming and requires sample removal which is hazardous
- longer reaction times can cause product degradation, reducing product yield
To solve, use in-line NIR. As in-line NIR was implemented to monitor drying process, it can minimize sampling handling and product degradation.

FTIR conventional method of analysis:
- use in-line Fourier Transformed-Infra Red specroscopy for monitoring hydrogenation process
- insert FTIR probe into reaction vessel
- spectra will show distinct peaks from starting enamine amide (1620/cm) and product freebase (1660/cm)
- apply chemometric analysis of data to obtain real-time reaction profiles