Agitated filter-dryers (AFDs) are
commonly used for performing
both filtration and drying operations in the manufacture of active
pharmaceutical ingredients (APIs) and intermediates. Successful scale-up
from the laboratory to manufacturing AFD equipment requires that physical
properties specifications such as particle size be consistently met
in addition to chemical purity specifications. Depending on the API–solvent
system and equipment operational parameters, undesired attrition or
agglomeration may occur, so an improved understanding of these phenomena
upon scale-up is of key importance. In this paper, we describe recent
advances in laboratory methods, based on material characterization
methods common to drug product formulation development, to better
assess the risk of agglomeration and attrition potential upon scale-up.
These methods provide data to evaluate solid behavior, in both wet
and dry states, associated with processing in an AFD. For agglomeration
prediction, the application of mixer torque rheometry for measuring
the propensity to form granules or agglomerates of API wet cake is
described as well as how to categorize agglomeration risk based on
the output of this testing. For measuring attrition propensity, the
application of powder rheometry is described, and risk categories
are proposed. For both testing methods, good agreement was seen between
laboratory predictions and actual behavior upon scale-up. For compounds
evaluated as high risk for attrition or agglomeration, alternate drying
protocols are recommended to mitigate risk. In addition, progress
on enhancing cycle times for difficult to dry materials is discussed.
Several routes to bisulfite adduct 2 were explored, the most efficient of which involved vinyl Grignard addition to 2-indanone followed by ozonolysis and workup with aqueous NaHSO 3 to effect reduction and bisulfite formation in a single pot. The safety and calorimetry of this ozonolysis reaction was studied, and the safe scale-up to 3 kg of olefin is described. The utility of bisulfite adduct 2 as an aldehyde surrogate in a reductive amination reaction is also described.
N-Vinyl-O-benzyl urethane was prepared for use as a starting material in a multistep synthesis of a drug candidate. After unsuccessful attempts to employ non-Curtius options to prepare this intermediate, we decided to assess the thermodynamic and kinetic parameters of the acyl azide Curtius rearrangement and trapping of the intermediate isocyanate.
A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxabicyclo[3.2.1]octane motif is prepared from commercially available 2,3,4,6-tetra-O-benzyl-D-glucose, with nucleophilic hydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate 39. A cocrystalline complex of the amorphous solid 1 with L-pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality.
Preparation of Grignard reagents from organic halides and magnesium pose potential safety hazards on scale-up due to their high exothermic potential which can lead to overpressurization, discharge of contents, or explosion. One of the main challenges arises in ensuring the reaction has initiated before excessive accumulation of organic halide occurs or that the reaction does not stall and then reinitiate. Specifically, in production-scale equipment, it is sometimes difficult to ascertain whether initiation has occurred at all and whether it is safe to proceed. By using in situ infrared technology (FTIR), we have developed a method for safer scale-up of Grignard chemistry that can definitively identify that initiation has occurred. The process would involve adding approximately 5% of the organic halide charge and waiting for the initiation to occur using an in situ FTIR probe. FTIR spectroscopy can be used to monitor the accumulation of the halide and reveal when initiation occurs by the resulting decrease in the infrared absorbance. Once it has been determined that the organic halide has reacted as a result of the initiation, it is safe to proceed with the remaining halide charge. The organic halide concentration can then be continuously monitored after initiation to ensure the reaction does not stall or to halt the feed if it does stall. Further, it was shown that IR can be used to quantify the amount of water that is present in THF which is needed to confirm that the THF is dry. The IR results along with reaction calorimetry and ventsizing data are discussed.
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