The
production of polyisobutylene with Lewis acid catalysts has
been in widespread use for over 60 years, but no validated molecular-level
understanding of the reaction mechanism exists. We have computed initiation
and propagation reaction pathways for isobutylene polymerization under
industrially relevant conditions with an AlCl3/H2O initiator from density functional theory calculations. The initiator/catalyst
complex we identified is fundamentally different from the putative
complex identified in the literature, which typically assumes that
the AlCl3OH2 complex is the active catalyst.
We found that the reaction pathway with the AlCl3OH2 complex is infeasible due to unreasonably high energy barriers.
Our calculations indicate that a minimum of two AlCl3 groups
and one H2O molecule is required to initiate the reaction
and that the complex must produce a highly acidic proton. It is the
extreme acidity of the complex that is crucial for successful initiation
of the reaction. The active catalyst moiety we identified produces
low-energy-barrier pathways for both initiation and propagation steps.
This complex was identified using the growing-string method to identify
possible reaction pathways with various AlCl3/H2O complexes. The initiation reaction with our proposed complex was
observed to occur naturally in an ab initio molecular dynamics simulation
under typical operating conditions, confirming the activity of the
complex.
Traditional
pharmaceutical manufacturing operates around a supply
chain that is subject to complex logistics and is vulnerable to spikes
in demand and interruptions. In this context, continuous pharmaceutical
manufacturing in portable, refrigerator-sized factories is a promising
solution with applications in battlefield medicine, pandemic response,
and mitigation of local medical emergencies. A new iteration of the
pharmacy on demand initiative is hereby presented, involving the development
of equipment and processes for the manufacture of ciprofloxacin HCl
with commercialization in mind. This article covers the implementation
and the feedback control strategies for downstream manufacturing,
as well as the results of the first end-to-end continuous manufacturing
campaign. The results involve a significant leap from prior iterations,
consistently attaining drug substance specifications in a fully automated
process and with a 4-fold increase in the process throughput over
the most recent iteration.
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