Search

Polymorphism presents a challenge to pharmaceutical industry to produce drugs of consistent quality. Polymorphic conversion occurs due to various sources like change in the temperature, presence of air, mechanical stress, humidity and lead to formation of new polymorph. Their presence can adversely affect the bioavailability, stability, safety and efficacy of the pharmaceutical products. To avoid these adverse effects, detection of polymorphic impurity is needed. Identification of polymorphic impurity can be done by various techniques either alone or in combination. The PXRD technique identifies different crystal phases by their unique diffraction patterns by capturing the three dimensional diffraction patterns in a two dimensional plot. DSC is a thermal method of analysis which is used to study thermal transitions. Infrared and Raman spectra identify a pure crystal form from different crystalline forms of the same organic compound. NMR spectroscopy indicates the presence of configurational or conformational multiplicity present in the solid state. Optical microscopy determines the optical properties and morphological properties of particles. Scanning Electron Microscopy determines surface topography and type of crystals (Polymorphism and crystal habit). HSM is an analytical technique enables the solid state characterization of materials by combining the properties of microscopy and thermal analysis. When single technique fails to identify the polymorphs, then combination techniques are used. DSC-FTIR technique gives spectroscopic and thermodynamic information about a solid or liquid sample undergoing thermal modification. DSC-PXRD allows simultaneous measurements of thermochemical and thermophysical events, while following changes in crystalline structure(polymorphism) during these events. This article briefly reviews, the importance of detection of polymorphism in pharmaceuticals, types of polymorphism and its characterization. [ABSTRACT FROM AUTHOR]

Chiral amines are essential motifs in pharmaceuticals, agrochemicals, and specialty chemicals. While traditional chemical routes to chiral amines often lack stereoselectivity and require harsh conditions, biocatalytic methods using engineered enzymes can offer high efficiency and selectivity under sustainable conditions. This review discusses recent advances in protein engineering of transaminases, oxidases, and other enzymes to improve catalytic performance. Strategies such as directed evolution, immobilization, and computational redesign have expanded substrate scope and enhanced efficiency. Furthermore, process optimization guided by techno-economic assessments has been crucial for establishing viable biomanufacturing routes. Combining state-of-the-art enzyme engineering with multifaceted process development will enable scalable, economical enzymatic synthesis of diverse chiral amine targets., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Vikhrankar et al.)

Accurate estimation of in vivo clearance in human is pivotal to determine the dose and dosing regimen for drug development. In vitro-in vivo extrapolation (IVIVE) has been performed to predict drug clearance using empirical and physiological scalars. Multiple in vitro systems and mathematical modeling techniques have been employed to estimate in vivo clearance. The models for predicting clearance have significantly improved and have evolved to become more complex by integrating multiple processes such as drug metabolism and transport as well as passive diffusion. This chapter covers the use of conventional as well as recently developed methods to predict metabolic and transporter-mediated clearance along with the advantages and disadvantages of using these methods and the associated experimental considerations. The general approaches to improve IVIVE by use of appropriate scalars, incorporation of extrahepatic metabolism and transport and application of physiologically based pharmacokinetic (PBPK) models with proteomics data are also discussed. The chapter also provides an overview of the advantages of using such dynamic mechanistic models over static models for clearance predictions to improve IVIVE., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Accurate prediction of drug target activity and rational dosing regimen design require knowledge of drug concentrations at the target. It is important to understand the impact of processes such as membrane permeability, partitioning, and active transport on intracellular drug concentrations. The present study aimed to predict intracellular unbound atorvastatin concentrations and characterize the effect of enzyme-transporter interplay on these concentrations. Single-pass liver perfusion studies were conducted in rats using atorvastatin (ATV, 1 µM) alone at 4°C and at 37°C in presence of rifampin (RIF, 20 µM) and 1-aminobenzotriazole (ABT, 1 mM), separately and in combination. The unbound intracellular ATV concentration was predicted with a five-compartment explicit membrane model using the parameterized diffusional influx clearance, active basolateral uptake clearance, and metabolic clearance. Chemical inhibition of uptake and metabolism at 37°C proved to be better controls relative to studies at 4°C. The predicted unbound intracellular concentration at the end of the 50-minute perfusion in the +ABT , +ABT+RIF, and the ATV-only groups was 6.5 µM, 0.58 µM, and 5.14 µM, respectively. The predicted total liver concentrations and amount recovered in bile were within 0.94-1.3 fold of the observed value in all groups. The fold difference in total liver concentration did not always extrapolate to the fold difference in predicted unbound concentration across groups. Together, these results support the use of compartmental modeling to predict intracellular concentrations in dynamic organ-based systems. These predictions can provide insight into the role of uptake transporters and metabolizing enzymes in determining drug tissue concentrations., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)