Define E factor
- 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)
Solvent recovery strategies? (5)
- Recycling solvent - distillation is the most common
- Use continuous reactors instead of batch reactors- higher heat/mass transfer rates + shorter reaction times -> less solvent used
- Biosynthetic process - enzymes as catalyst, highly selective and biosynthetic reactions normally carried out in water
- Solid state chemistry - no solvent used, high product purity produced, novel and not used commercially to date
- Telescoping - reduce number of process steps and unit operations, e.g. sertraline (Zoloft) by Pfizer steps reduced from 3 to 1
Method of solvent use reduction?
- 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
What is distillation?
- 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
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properties of a solvent mixture?
- 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
what is vapour-liquid equilibrium constant?
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
1.
explain relative volatility
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
Discuss distillation methods (3)
- 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 - 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 - 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
Define azeotropes.
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
Batch distillation of binary azeotropic mixture at constant pressure?
- 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
explain azeotropic or extractive distillation
- 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
How to separate azeotropic mixtures? (2)
- 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)
Economics of solvent recovery?
**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
disadvantages of distillation?
- generation of waste -> release of greenhouse gas co2
- high energy requirements
- inadequate condensing of distillate (overhead) products
- other inefficiencies
Expain Life Cycle Approach (LCA) + 3 impacts
- 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
1.
GMP for solvent recovery?
- 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
Explain PAT
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
Explain QbD
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
Process validation?
stage 1. process design
stage 2. process qualification
stage 3. continued process verification
types of in-ine testing?
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
Common PAT tools?
- thermocouples and pressure sensors
- spectroscopic tools: NIR, MIR, Raman
- 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
In-line FTIR monitoring of asymmetric hydrogenation reaction
- 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
