Flow synthesis kinetics for lomustine, an anti-cancer active pharmaceutical ingredient

Abstract

Continuous flow synthesis of Active Pharmaceutical Ingredients (APIs) can offer access to process conditions that are otherwise hazardous when operated in batch mode, resulting in improved mixing and heat transfer,...

Parameter estimation and estimability analysis in pharmaceutical models with uncertain inputs

“…Kuu et al 7 Primary drying of 5% mannitol and 5% povidone Batch Y Sadikoglu and Liapis 8 Drying stages in bulk solution freeze-drying of pharmaceuticals in trays Batch Y Togkalidou et al 9 Cooling crystallization of a drug compound Batch Y Hermanto et al 10 Crystallization of L-glutamic acid polymorphs Batch N Velardi et al 11 Freeze-drying of bovine serum albumin, sucrose, and mannitol Batch Y Mortier et al 12 Drying behavior of single pharmaceutical granules Continuous Y Barrasso et al 13 Manufacturing of microcrystalline cellulose and tablets Continuous N Barrasso et al 14 Twin screw granulation process Continuous Y Selisteanu et al 15 Monoclonal antibody production using mammalian cell culture process Batch Y Gagnon et al 16 Drying of pharmaceutical particles containing calcium carbonate Batch N Garcıa-Munoz et al 17 Direct compression process for pharmaceutical tablets Continuous N Garg et al 18 Antisolvent crystallization for production of dexlansoprazole Batch Y Montes et al 19 Hoescht process for the synthesis of ibuprofen Batch Y Wang et al 20 Chinese hamster ovary cell metabolism to produce antibody Fed-batch N Cuthbertson et al 21 Enzymatic synthesis of amoxicillin Batch Y Lee et al 22 Kinetics, evaporation, and crystallization in the manufacturing of active pharmaceutical ingredients (API) Batch, continuous Y Maloney et al 23 Carfilzomib drug substance intermediate manufacturing Batch, continuous N Schenk et al 24 Multistage solid-liquid pharmaceutical process for urea compound synthesis Fed-batch N Diab et al 25 Flow synthesis kinetics for an anticancer API called Lomustine Continuous Y Grimard et al 26 Hot-melt extrusion process for the manufacturing of itraconazole tablets…”

“…squares (WLS) estimation, 7,9,13,14,16,20,24,25,29,31 which is applied when there are multiple dependent variables with different levels of variability.…”

Continuous Flow Synthesis of Anticancer Drugs

“…Recent efforts by Diab et al have furthermore investigated the reaction kinetics for the continuous synthesis of lomustine which adds further value to these efforts [50].…”

“…It is used as a first-line treatment for patients with locally advanced or metastatic non-small cell lung carcinoma (NSCLC) with EGFR sensitizing mutations and as a treatment for patients with EGFR T790M-mutation-positive NSCLC that has progressed on or after EGFR-TKI therapy. The recommended dose in the U.S. is one 80 mg tablet taken once daily [50,91,92].…”

Parameter Estimation and Estimability Analysis in Pharmaceutical Models with Uncertain Inputs

“…[7][8][9] In all the studies listed in Table 1, model inputs (independent variables) were assumed to be perfectly known during parameter estimation and all of the experimental uncertainty was assigned to the model outputs (dependent variables). This assumption enabled modelers to use either Least Squares (LS) 15,18,30 or Weighted Least Squares (WLS) estimation, 10,12,16,17,19,23,27,28,32,34 which is applied when there are multiple dependent variables with different levels of variability.…”