Organometallic iridium complexes have been reported as water oxidation catalysts (WOCs) in the presence of ceric ammonium nitrate (CAN). One challenge for all WOCs regardless of the metal used is stability. Here we provide evidence for extensive modification of many Ir-based WOCs even after exposure to only 5 or 15 equiv of Ce(IV) (whereas typically 100-10000 equiv are employed during WOC testing). We also show formation of Ir-rich nanoparticles (likely IrO(x)) even in the first 20 min of reaction, associated with a Ce matrix. A combination of UV-vis and NMR spectroscopy, scanning transmission electron microscopy, and powder X-ray diffraction is used. Even simple IrCl(3) is an excellent catalyst. Our results point to the pitfalls of studying Ir WOCs using CAN.
Process safety groups in the pharmaceutical
industry are important
components of active pharmaceutical ingredient (API) development through
its life cycle from discovery to commercial scale. The pharmaceutical
process safety laboratory staff conduct a series of tests to identify
chemically unstable reagents, intermediates and solvents, and mixtures
to ensure that the proposed operating conditions provide a sufficient
safety margin from the onset of undesired and potentially catastrophic
thermal decomposition. Across several pharmaceutical companies, the
methods used for these assessments and how results and conclusions
are made are widespread (vide infra). A working group
was created with members from several pharmaceutical companies within
the International Consortium for Innovation and Quality in Pharmaceutical
Development (IQ), with the goal of precompetitive collaboration and
to understand each of the participating companies’ procedures
and assessment regarding process safety. Each company was invited
to provide input using a blind survey format. This was done in the
interest of making this knowledge accessible for the participating
companies and the wider community of other pharma and chemical companies
and even academic institutions in the US and throughout the world.
This article provides the results of this in-depth survey of the members
of the IQ Consortium thermal hazard working group. General issues
around different tools used to assess thermal hazard risk and questions
regarding staffing and tech transfer of process safety data/information
from development to manufacturing were addressed. A snapshot of how
various assessment strategies are employed as a function of stage
of development (early, mid, and late) is also presented.
A commercial process to manufacture sotorasib (AMG 510),
a first-in-class
KRASG12C inhibitor, is described. Development efforts focused
on rendering a fit-for-purpose early-phase route into a viable long-term
commercial process through the reduction of side reactions to improve
yield and product quality, as well as reducing cycle times of crystallization
processes by improving particle properties and filtration times. These
improvements were key to ensuring clinical supply and commercial launch.
The final route consists of five synthetic operations from starting
material
M-1, including a telescoped
two-step sequence, and a final form-setting crystallization.
This
article describes the process characterization and development
of models to inform a process control strategy to prepare (R,R)-epoxy ketone 2, an intermediate
in the manufacture of carfilzomib. Model calibration for relevant
unit operations and the development of a dynamic integrated flowsheet-level
model in gPROMS FormulatedProducts software enabled investigation
of the impact of process disturbances and model uncertainties on the
critical quality attributes (CQAs) and identification of critical
process disturbances and failure modes to guide a process control
strategy. The model development was similar to that described in the
previous parts of this series, but with the added complexity of comparing
two distinct kinetic formulations for the epoxidation reaction. The
main CQAs for this process were (1) the conversion of enone 1 (target ≥99.0 mol % conversion) and (2) the purity
target for solids prior to cake wash (target ≥97.5% purity
by weight). Conversion of enone was not always achieved with the expected
disturbances: whereas 99.5% conversion was expected for normal operating
conditions, 97.2% conversion was predicted for the worst-case combination
of disturbances. The chiral purity of crystalline (R,R)-epoxy ketone 2 was not always achieved
with the expected disturbances: 98.2% purity was expected for normal
operating conditions, and 96.7% purity was expected for the worst-case
combination of disturbances. These analyses allowed for rank ordering
of critical process parameters that impact conversion and suitable
manipulated variables to develop a robust process control strategy
for the manufacturing scheme.
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