A5028212125- Granular flow and fluidized beds
- Innovative Microfluidic and Catalytic Techniques Innovation
- Microbial Metabolic Engineering and Bioproduction
- Pharmacogenetics and Drug Metabolism
- Chemistry and Chemical Engineering
- Biochemical and Molecular Research
- Particle Dynamics in Fluid Flows
- Computational Drug Discovery Methods
- Analytical Chemistry and Chromatography
- Crystallization and Solubility Studies
- Tuberculosis Research and Epidemiology
- Gene Regulatory Network Analysis
- Cancer Genomics and Diagnostics
- Synthetic Organic Chemistry Methods
- Pharmaceutical Economics and Policy
- Enzyme Catalysis and Immobilization
- Aerosol Filtration and Electrostatic Precipitation
- Pharmaceutical Quality and Counterfeiting
- Circadian rhythm and melatonin
- Fluid Dynamics and Heat Transfer
- Lung Cancer Treatments and Mutations
- Metallurgy and Material Forming
- Synthesis and biological activity
- Thermal and Kinetic Analysis
- Receptor Mechanisms and Signaling
Merck & Co., Inc., Rahway, NJ, USA (United States)
2023-2025
Rutgers, The State University of New Jersey
2016-2023
Cancer is a devastating disease that takes the lives of hundreds thousands people every year. Due to heterogeneity, standard treatments, such as chemotherapy or radiation, are effective in only subset patient population. Tumors can have different underlying genetic causes and may express proteins one versus another. This inherent variability cancer lends itself growing field precision personalized medicine (PPM). There many ongoing efforts acquire PPM data order characterize molecular...
We report the total synthesis of enlicitide decanoate, an orally bioavailable inhibitor proprotein convertase subtilisin/kexin type 9 that is being developed for treatment atherosclerotic cardiovascular disease. It a highly complex macrocyclic peptide with significant number nonpeptide structural elements presents daunting synthetic chemistry challenge. describe development convergent, efficient, and robust manufacturing process enables large-scale production enlicitide.
The rejection of process impurities from crystallizing products is an essential step for the purification pharmaceutical drugs and isolation active ingredients with right crystal quality attributes. While several impurity incorporation mechanisms have been reported in literature, frequency those actual industrial processes largely unknown. This work presents outcome a joint investigation by crystallization scientists two companies academic institution, on prevalence retention cooling...
A ketone fluorination/reduction dynamic kinetic resolution (DKR) was developed for a third-generation synthesis of belzutifan. This new process replaced precious metal catalyst with ketoreductase (KRED) in the DKR. Achieving this one-pot reaction required several rounds enzyme evolution that improved stability presence acetonitrile and methanol. To maintain development progress satisfy program timelines, around reaction, workup, isolation operations performed parallel ongoing modification,...
A convergent nucleophilic aromatic substitution (SNAr) was developed as the final step in an improved manufacturing process to belzutifan. The reaction performed water enable a reactive crystallization and direct isolation of drug substance toward green sustainable process. Due sensitivity vapor phase composition, engineering controls around headspace pressure sweep rate were tuned balance reactivity selectivity maximize product yield purity. Ultimately, our investigation resulted robust...
We report the process development for active pharmaceutical ingredient (API) step of commercial manufacturing route to nemtabrutinib (MK-1026), a reversible Bruton’s Tyrosine Kinase (BTK) inhibitor currently under investigation treatment several hematological malignancies. Significant improvements on efficiency were achieved by direct isolation leveraging optimal reaction conditions and synergistic API solubility in an ethanol/water system. In combination with additional robustness impurity...
Synchronization of biological functions to environmental signals enables organisms anticipate and appropriately respond daily external fluctuations is critical the maintenance homeostasis. Misalignment circadian rhythms with cues associated adverse health outcomes. Cortisol, downstream effector hypothalamic-pituitary-adrenal (HPA) activity, facilitates synchronization peripheral processes environment. Cortisol levels exhibit substantial seasonal rhythmicity, peak occurring during...
Our company has developed a robust and scalable process to synthesize an amino alcohol tosylate salt, penultimate intermediate in the synthesis of nemtabrutinib. A key reaction this synthetic sequence is reductive acetal ring opening using boron trifluoride diethyl etherate as Lewis acid triethylsilane reducing agent. Detailed mechanistic inquisition revealed that presence sulfolane, reduced by generate diborane active reductant. Diborane poses many safety hazards; it highly reactive,...
We describe the rapid end-game process development for first good manufacturing (GMP) delivery of 3C-like protease inhibitor MK-7845 (1), an experimental treatment SARS-CoV-2. Three operations, including amide-coupling, oxidation, and crystallization, were rapidly developed implemented on a kilogram scale to enable critical safety studies phase 1 clinical trials move forward highly accelerated timeline. Key success this undertaking was our focus purging key impurities formed in...
Abstract Agitated drying of pharmaceuticals remains a challenging manufacturing step due to the simultaneous heat transfer, mass and physicochemical changes occurring during process. This work focuses on transfer component by implementing discrete element method model dry particles in heated bladed mixer. Simulations varying material conductivities impeller agitation rates were conducted evaluate influence mean bed temperature distribution. The results indicated that increasing rate...
Nemtabrutinib (MK-1026) is a novel oral Bruton's tyrosine kinase (BTK) inhibitor for treatment of B-cell cancers. An initial synthetic supply route to generate ketone 3 relied on the generation highly reactive transient intermediate and use n-butyllithium. Cryogenic temperatures (−60 °C) were also required achieve modest 61% yield, with one major impurity, resulting from dehalogenation, accounting majority mass balance. alternative process was developed increase yield decrease dependence...
Abstract An understanding of heat transfer in a bladed mixer is important for drying pharmaceutical drug crystals. This study presents thermal imaging experiments the particle bed surface to investigate how impeller speed influences rate and uniformity transfer. Next, process simulated using discrete element method. The properties are lumped into an effective conductivity, that calibrated one speed. simulations show same trends generally agree well all agitated beds. However, obtain good...
Intermittent mixing, alternating agitation and no agitation, is an approach to maintain a high drying rate while minimizing particle breakage in agitated filter of the active pharmaceutical ingredient. In this study, effect intermittent mixing on heat transfer particles was examined using DEM simulations. The ratio (the fraction time agitator on) cycle number on/off cycles) represent extent allocation respectively. It observed that as increases from static bed, temperature uniformity...