Unit Operation Selection and Optimization Problem
Statement
Problem 1 – Increased Utilization of Heterogeneous Catalysis in
Pharmaceutical Synthesis
Non-stoichiometric heterogeneous catalysis in pharmaceutical manufacture is extensively
used for hydrogenations, but for few other applications. Conversely, a wide range of
homogenous catalysts are available for a wide range of useful transformations, including
cross-couplings, ring closing metathesis, and asymmetric applications. Because
homogenous catalysts are not easily recoverable or recyclable, their cost can be
prohibitive either due to the complexity of a ligand or the use of a precious metal. If
synthetically useful homogenous catalysts could be made heterogeneous and recycled,
the overall process efficiency and cost would be greatly removed.
Exemplification of Problem
Palladium acetate is often used in coupling reactions in a soluble form (e.g., Heck and
Suzuki reactions). The palladium is subsequently wasted with mother liquors. There are
many available asymmetric catalysts available which typically involve a complex ligand
to which an ‘expensive’ element is bound (e.g., Ru, Rh, Pd, etc…). Both the ligand and
the metal are wasted, causing downstream waste management problems and wasting
precious natural resources. In some cases, metals become chelated by the active
pharmaceutical ingredient at levels above regulatory limits for daily exposure to patients,
causing inefficient reprocessing procedures. Biocatalysts are also available for a wide
range of transformations, but can be difficult to separate from liquors and are often
wasted.
In order to ‘green’ processes and conserve natural resources, the immobilization of useful
catalysts is sought. The following bullets provide a few possibilities for immobilization:
1. There are existing immobilized catalysts from the oil industry and fine chemical
industry which could possibly be applied to remove reagents from synthesis and
would immediately have a positive effect on synthesis. For example, the
reactions taking place in a catalytic converter in a car exhaust system are
extremely complex and very efficient. A review of catalysts used in these
industries and a comparison with pharmaceutically relevant reactions may result
in some ‘quick wins’.
2. Whilst some work has been done with palladium there is always room to improve
the generality, performance, leaching rates and cost of these systems.
Immobilized systems that hold all the reagents required for a Suzuki reaction for
example would equally be interesting. For instance, have pendant tethered
nucleophiles in place above the metal to promote the formation of the borate
complex just where it is needed and improve the performance of these systems
and reduce side reactions – basically move to a tailored metalo-enzyme system.
3. Lewis acid catalysis is a key area in chemistry that often suffers with difficult
waste streams/work-ups or metal related impurities in the downstream reactions.
Many of the rare earth lanthanides are superb clean catalysts in chemistry –
understanding how to immobilize them effectively to retain their activity is key.
Simply providing a SO3- ligand on polystyrene is not enough as these systems do
not always confer catalytic activity. Basic understanding of key reaction
pathways is required if we are to design a suitable support for lanthanide catalysis.
4. There are many biocatalysts which have no current immobilization options. A
generalized approach to immobilizing biocatalysts is sought.
Expected Output of Research
1. Review of available catalysts from petrochemical and fine chemical industry with
a view towards their potential utilization in pharmaceuticals.
2. Choice of useful reactions to investigate. GSK may be able to assist with model
substrates.
3. Exemplification of catalyst fixation for the useful reactions.
4. An understanding of scope and limitations of the developed solution – define any
issues with industrializing proposed solutions.
Problem 2 – The use of solvent resistant membranes for
pharmaceutical separations of interest
Separations in the pharmaceutical industry generally consist of distillations, extractions,
and crystallizations. Distillations are used to concentrate solutions for use in a
subsequent unit operation (e.g., reaction or crystallization), extractions are commonly
used to remove acid/base reagents, and crystallizations are typically used for the
purification of one organic molecule from others. Distillation, in particular, is energy
intensive and often must be done under vacuum conditions to preserve product purity.
Crystallizations are also energy intensive, particularly as products must be isolated and
dried.
Energy efficient separation methodologies are sought as complements and replacements
to distillation and crystallization.
Exemplification of Problem
There are three common ways that distillations are used in pharmaceutical processing.
1. To change one solvent for another in a process so subsequent unit operations can
be performed, or simply to concentrate one solvent-solute system. For instance, a
reaction is performed in THF but cannot be crystallized from THF due to poor
solubility. THF is solvent exchanged with 2-propanol, which is an excellent
crystallization solvent for the compound. Solute concentrations are often as high
as 30% w/w in such process.
2. Chromatographic separations. Chromatography, especially SMB, can provide
excellent separation selectivity for pharmaceutical and fine chemical molecules.
However, due to the dilutions required (often lower than 1%) large amounts of
solvent are used. These solvents are typically recovered using evaporators, which
are energy intensive and reduce the economic competitiveness of the process.
3. Solvent recovery. After a process has been run, solvents can be recovered and
reused in the process. This requires steam to drive distillation column reboilers,
and results in a significant energy expenditure. Solids are typically removed
through evaporators prior to entering a column to prevent fouling.
Also, several examples are available for crystallization:
1. Separation of desired product from undesirable organic compounds. These may
include impurities which have similar structures and molecular weights to the
desired product (e.g., undesired isomers). In addition, organic catalysts, reagents,
or ligands, with quite different molecular weights, may require removal prior to
progressing to a subsequent unit operation.
2. Separation of desired product from undesirable inorganic compounds. Many
reactions include low levels of homogeneous precious metal catalysts (for
instance palladium acetate), which requires removal due to its reactivity in
subsequent steps.
Solute concentrations in crystallization applications can vary from 4% to approximately
30%.
In both cases, it would be desirable to have more energy efficient unit operations which
would eliminate the need for significant heating, condenser, and drying costs.
Expected Output of Research
1. Survey of potential separation applications from what is known, and a map of
these against pharmaceutical problems.
2. Experimental demonstration of application for a specific pharmaceutical industry
problem (more specific examples can be provided by GSK)
3. Clear estimation of energy and mass savings relative to alternative.
4. Analysis of the application of the developed solution to other industry problems.
5. A clear industrialization path for the proposed solution.