scholarly journals Analysis of Benzenoid Substitution Patterns in Small Molecule Active Pharmaceutical Ingredients

2019 ◽  
Author(s):  
Aleksandra Nilova ◽  
David Stuart
Keyword(s):  
Natural Product ◽  
Small Molecule ◽  
Structural Variation ◽  
Electrophilic Aromatic Substitution ◽  
Active Pharmaceutical Ingredients ◽  
Aromatic Substitution ◽  
Pharmaceutical Ingredients ◽  
Drug Substances

An analysis of benzenoid substitution patterns in small molecule active pharmaceutical ingredients (APIs) approved by the FDA reveals a preference for 1,4-substituted (<i>para</i>), 1-substituted (<i>mono</i>), 1,2,4-substituted, and 1,2-substituted (<i>ortho</i>) arenes. Notably, these substitution patterns are widely commercially available and readily accessible by electrophilic aromatic substitution (S<sub>E</sub>Ar), but more highly substituted and contra-electronic substitution patterns are severely underrepresented in drug substances. Finally, structural variation decreases with increasing substitution and there is a strong reliance on natural product scaffolds in drugs with more highly substituted benzenoid rings.

scholarly journals Analysis of Benzenoid Substitution Patterns in Small Molecule Active Pharmaceutical Ingredients

2019 ◽  
Author(s):  
Aleksandra Nilova ◽  
David Stuart
Keyword(s):  
Natural Product ◽  
Small Molecule ◽  
Structural Variation ◽  
Electrophilic Aromatic Substitution ◽  
Active Pharmaceutical Ingredients ◽  
Aromatic Substitution ◽  
Pharmaceutical Ingredients ◽  
Drug Substances

An analysis of benzenoid substitution patterns in small molecule active pharmaceutical ingredients (APIs) approved by the FDA reveals a preference for 1,4-substituted (<i>para</i>), 1-substituted (<i>mono</i>), 1,2,4-substituted, and 1,2-substituted (<i>ortho</i>) arenes. Notably, these substitution patterns are widely commercially available and readily accessible by electrophilic aromatic substitution (S<sub>E</sub>Ar), but more highly substituted and contra-electronic substitution patterns are severely underrepresented in drug substances. Finally, structural variation decreases with increasing substitution and there is a strong reliance on natural product scaffolds in drugs with more highly substituted benzenoid rings.

scholarly journals Analysis of Benzenoid Substitution Patterns in Small Molecule Active Pharmaceutical Ingredients

2020 ◽  
Vol 63 (22) ◽  
pp. 13389-13396 ◽  
Author(s):  
Aleksandra Nilova ◽  
Louis-Charles Campeau ◽  
Edward C. Sherer ◽  
David R. Stuart
Keyword(s):  
Small Molecule ◽  
Active Pharmaceutical Ingredients ◽  
Pharmaceutical Ingredients

scholarly journals Aspartate/asparagine-β-hydroxylase: a high-throughput mass spectrometric assay for discovery of small molecule inhibitors

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Lennart Brewitz ◽  
Anthony Tumber ◽  
Inga Pfeffer ◽  
Michael A. McDonough ◽  
Christopher J. Schofield
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
High Throughput ◽  
Solid Phase ◽  
Hypoxia Inducible Factor ◽  
Active Pharmaceutical Ingredients ◽  
Inhibition Assay ◽  
Pharmaceutical Ingredients ◽  
Epidermal Growth ◽  
Good Signal

AbstractThe human 2-oxoglutarate dependent oxygenase aspartate/asparagine-β-hydroxylase (AspH) catalyses the hydroxylation of Asp/Asn-residues in epidermal growth factor-like domains (EGFDs). AspH is upregulated on the surface of malign cancer cells; increased AspH levels correlate with tumour invasiveness. Due to a lack of efficient assays to monitor the activity of isolated AspH, there are few reports of studies aimed at identifying small-molecule AspH inhibitors. Recently, it was reported that AspH substrates have a non-canonical EGFD disulfide pattern. Here we report that a stable synthetic thioether mimic of AspH substrates can be employed in solid phase extraction mass spectrometry based high-throughput AspH inhibition assays which are of excellent robustness, as indicated by high Z’-factors and good signal-to-noise/background ratios. The AspH inhibition assay was applied to screen approximately 1500 bioactive small-molecules, including natural products and active pharmaceutical ingredients of approved human therapeutics. Potent AspH inhibitors were identified from both compound classes. Our AspH inhibition assay should enable the development of potent and selective small-molecule AspH inhibitors and contribute towards the development of safer inhibitors for other 2OG oxygenases, e.g. screens of the hypoxia-inducible factor prolyl-hydroxylase inhibitors revealed that vadadustat inhibits AspH with moderate potency.

scholarly journals Recent Advanced of Multiple Unite Pellet System (MUPS) Technology in Formulation of Pharmaceutical Products: A Review

2020 ◽  
Vol 9 (10) ◽  
pp. 20202-20214
Author(s):  
V. K . Chatap ◽  
Deshbandhu Joshi
Keyword(s):  
Oral Route ◽  
Pharmaceutical Products ◽  
Active Pharmaceutical Ingredients ◽  
Blood Profile ◽  
Pharmaceutical Ingredients ◽  
Solid Dosage ◽  
Drug Substances ◽  
Form Design ◽  
Multiple Unit ◽  
User Friendly

The oral route of drug administration is the most important and most user-friendly route of administration. In recent years, Multiple Unit Pellet Systems (MUPS) tablets are widely used in solid dosage form design. MUPS is considered to provide pharmacokinetic advantages compared to monolithic dosage forms. Combination of drug substances and release profiles can be provided by formulating the MUPS tablets with different pellet qualities or combining pellets with drugs in powder or granulated form. MUPS tablet contains several hundred of coated pellets of active pharmaceutical ingredients which delivered the drug at predetermined rate and absorption to provide constant blood profile. MUPS are easily administered as disintegratable tablet which disperse into their subunits across the stomach and the small intestine, leading to predictable oral transition and constant bioavailability.

scholarly journals Shortening Synthetic Routes to Small Molecule Active Pharmaceutical Ingredients Employing Biocatalytic Methods

2021 ◽  
Author(s):  
Stefan Simić ◽  
Erna Zukić ◽  
Luca Schmermund ◽  
Kurt Faber ◽  
Christoph K. Winkler ◽  
...  
Keyword(s):  
Small Molecule ◽  
Active Pharmaceutical Ingredients ◽  
Pharmaceutical Ingredients ◽  
Synthetic Routes

Reversed-Phase High Performance Liquid Chromatographic Analysis of Three First Line Anti-Tuberculosis Drugs

2019 ◽  
Vol 69 (12) ◽  
pp. 3590-3592
Author(s):  
Nela Bibire ◽  
Romeo Iulian Olariu ◽  
Luminita Agoroaei ◽  
Madalina Vieriu ◽  
Alina Diana Panainte ◽  
...  
Keyword(s):  
High Performance ◽  
Biological Fluids ◽  
Gradient Elution ◽  
High Performance Liquid Chromatographic ◽  
Reversed Phase ◽  
Assay Method ◽  
Active Pharmaceutical Ingredients ◽  
First Line ◽  
Pharmaceutical Ingredients ◽  
Liquid Chromatographic

Active pharmaceutical ingredients such as isoniazid, pyrazinamide and rifampicin are among the most important first-line anti-tuberculosis drugs. A simple, rapid and sensitive reversed phase-high performance liquid chromatographic assay method for the simultaneous determination of isoniazid, pyrazinamide and rifampicin has been developed. Separation of the interest compounds was achieved in a 10 min chromatographic run in gradient elution mode on a Zorbax SB-C18 stainless steel column (150 � 4 mm, 5 mm) using a guard column containing the same stationary phase. The gradient elution was carried out with a mobile phase of 10% CH3CN aqueous solution for channel A and 50% CH3CN in pH = 6.8 phosphate buffer (20 mM), to which 1.5 mL triethylamine were added for channel B. Quantification of the analyzed substances was carried out spectrophotometrically at 269 nm. Detection limits of 0.48 mg/L for isoniazid, 0.52 mg/L for pyrazinamide and 0.48 mg/L for rifampicin were established for the developed assay method. The present work showed that the proposed analysis method was advantageous for simple and rapid analysis of the active pharmaceutical ingredients in pharmaceuticals and biological fluids.

scholarly journals Numaswitch: an efficient high-titer expression platform to produce peptides and small proteins

AMB Express ◽  
2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bach-Ngan Nguyen ◽  
Florian Tieves ◽  
Thomas Rohr ◽  
Hilke Wobst ◽  
Felix S. Schöpf ◽  
...  
Keyword(s):  
Fermentation Broth ◽  
High Titer ◽  
New Technology ◽  
Active Pharmaceutical Ingredients ◽  
Pharmaceutical Ingredients ◽  
Expression Platform ◽  
Small Proteins ◽  
Production Platform ◽  
Β Amyloid ◽  
Cost Efficient

AbstractThe production of peptides as active pharmaceutical ingredients (APIs) by recombinant technologies is of emerging interest. A reliable production platform, however, is still missing due the inherent characteristics of peptides such as proteolytic sensitivity, aggregation and cytotoxicity. We have developed a new technology named Numaswitch solving present limitations. Numaswitch was successfully employed for the production of diverse peptides and small proteins varying in length, physicochemical and functional characteristics, including Teriparatide, Linaclotide, human β-amyloid and Serum amyloid A3. Additionally, the potential of Numaswitch for a cost-efficient commercial production is demonstrated yielding > 2 g Teriparatide per liter fermentation broth in a quality meeting API standard.

scholarly journals Diagnosis of Agglomeration and Crystallinity of Active Pharmaceutical Ingredients in Over the Counter Headache Medication by Electrospray Laser Desorption Ionization Mass Spectrometry Imaging

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 610
Author(s):  
Mariann Inga Van Meter ◽  
Salah M. Khan ◽  
Brynne V. Taulbee-Cotton ◽  
Nathan H. Dimmitt ◽  
Nathan D. Hubbard ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Mass Spectrometry Imaging ◽  
Laser Desorption ◽  
Ionization Mass Spectrometry ◽  
Ionization Mass ◽  
Active Pharmaceutical Ingredients ◽  
Laser Desorption Ionization ◽  
Over The Counter ◽  
Pharmaceutical Ingredients ◽  
Desorption Ionization

Agglomeration of active pharmaceutical ingredients (API) in tablets can lead to decreased bioavailability in some enabling formulations. In a previous study, we determined that crystalline APIs can be detected as agglomeration in tablets formulated with amorphous acetaminophen tablets. Multiple method advancements are presented to better resolve agglomeration caused by crystallinity in standard tablets. In this study, we also evaluate three “budget” over-the-counter headache medications (subsequently labeled as brands A, B, and C) for agglomeration of the three APIs in the formulation: Acetaminophen, aspirin, and caffeine. Electrospray laser desorption ionization mass spectrometry imaging (ELDI-MSI) was used to diagnose agglomeration in the tablets by creating molecular images and observing the spatial distributions of the APIs. Brand A had virtually no agglomeration or clustering of the active ingredients. Brand B had extensive clustering of aspirin and caffeine, but acetaminophen was observed in near equal abundance across the tablet. Brand C also had extensive clustering of aspirin and caffeine, and minor clustering of acetaminophen. These results show that agglomeration with active ingredients in over-the-counter tablets can be simultaneously detected using ELDI-MS imaging.

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