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Biomedical subjects

Arvind K Bansal

Publications and source records attributed to Arvind K Bansal.

At least 19 recordsLinked to original sources

Modification of the crystal habit of celecoxib for improved processability.

Crystallization is often used in the pharmaceutical industry for purification and isolation of drugs, and also as a means of generating polymorphs or isomorphs. The aim of this study was to investigate the role of extrinsic crystallization parameters on the crystallized product, with special emphasis on improving the mechanical properties of acicular celecoxib. Celecoxib isomorphs were prepared using different techniques (solvent crystallization and vapour diffusion) and crystallization conditions (solvents, stirring, degree of supersaturation, crystallization temperature and seeding). Powder X-ray diffractometry, spectroscopic and thermal methods were used to investigate physical characteristics of crystals. Growth kinetics and aggregation dynamics of crystallization in polar and non-polar solvents were simulated using a dynamic light scattering method. The quick appearance of broad peaks over the range of 10-8000 nm in chloroform during crystallization simulation studies indicated faster aggregation in non-polar solvents. Aspect ratio, flow, compressibility and surface area of recrystallized products were also determined. Surface topography was determined by atomic force microscopy and the lath-shaped crystals (aspect ratio of 2-4) exhibited a roughness index of 1.79 in comparison with 2.92 for needles. Overall, the lath-shaped isomorphs exhibited improved flow and better compressibility.

Calorimetry, Differential Scanning↗

Quantification of olanzapine polymorphs using powder X-ray diffraction technique.

Accurate quantification of crystalline phases present in drug materials is becoming increasingly important, due to stringent regulatory concerns about polymorph characterization and control in drug substances and products. In the present study, a quantification method for polymorphic forms of olanzapine (OLZ) has been developed using powder X-ray diffraction (PXRD). Preferred orientation has been reported to be the major source of error in PXRD analysis, therefore, prior to development of a quantification method, pure polymorphic forms (I and II) of different size ranges were analyzed. Preferred orientation effect was found to decrease on using sieve fraction BSS # 120/240 for form I. In order to obtain good peak resolution in optimum time, the step time and step size were varied so as to optimize the scan rate. Among the five combinations selected, step size of 0.05 degrees with step time of 5s demonstrated identification of four characteristic peaks of form I in form II in 62 min. A calibration curve was constructed in the range of 0-100% (w/w) using the characteristic peak of form I at 18.48 degrees 2theta (I/I(0) 78.8%). The PXRD assay was reproducible and precise and displayed a LOD of 0.40% (w/w) and LOQ of 1.22% (w/w). Validation results showed excellent correlation between actual and predicted concentrations with R(2) 0.9999.

Antipsychotic Agents↗

Investigation on physicochemical and biological differences of cefpodoxime proxetil enantiomers.

Cefpodoxime proxetil (CP) is a prodrug of cefpodoxime acid (CA), and is supplied as racemic mixture of R- and S-enantiomers. CP has only 50% absolute bioavailability, and the reasons responsible for low bioavailability remain poorly understood. The present work ascertains physicochemical and biological properties of individual isomers of CP and explores their capacity to optimize delivery of CP. Both isomers showed similar pH stability behavior, but R-isomer was more susceptible to enzymatic metabolism compared to S-isomer, when incubated with enzymes collected from various segments of GIT. Based on the in vitro and in vivo results, use of S-isomer for development of a dosage form such as gastro-retentive dosage form can improve oral bioavailability of CP.

Administration, Oral↗

Investigation of factors responsible for low oral bioavailability of cefpodoxime proxetil.

Learning about the behavior of a drug in biological environment enables application of better formulation strategies to improve bioavailability of the same. Cefpodoxime proxetil (CP) is a prodrug, which is orally administered cephalosporin with only 50% absolute bioavailability. Despite previous studies, reasons responsible for low bioavailability of CP remain poorly understood. The present study tries to ascertain reasons for the low oral bioavailability of CP. The in vitro, in situ and ex vivo studies showed interesting results, where metabolism of CP into cefpodoxime acid (CA) inside the intestinal epithelial cell and preferential efflux of CA into lumen was identified as primary reason for low oral bioavailability of CP. Presence of specific carriers or transportation mechanism on the apical side membrane of enterocyte, than basal side of the same was observed.

Administration, Oral↗

Analytical techniques for quantification of amorphous/crystalline phases in pharmaceutical solids.

The existence of different solid-state forms such as polymorphs, solvates, hydrates, and amorphous form in pharmaceutical drug substances and excipients, along with their downstream consequences in drug products and biological systems, is well documented. Out of these solid states, amorphous systems have attracted considerable attention of formulation scientists for their specific advantages, and their presence, either by accident or design is known to incorporate distinct properties in the drug product. Identification of different solid-state forms is crucial to anticipate changes in the performance of the material upon storage and/or handling. Quantitative analysis of physical state is imperative from the viewpoint of both the manufacturing and the regulatory control aimed at assuring safety and efficacy of drug products. Numerous analytical techniques have been reported for the quantification of amorphous/crystalline phase, and implicit in all quantitative options are issues of accuracy, precision, and suitability. These quantitative techniques mainly vary in the properties evaluated, thus yielding divergent values of crystallinity for a given sample. The present review provides a compilation of the theoretical and practical aspects of existing techniques, thereby facilitating the selection of an appropriate technique to accomplish various objectives of quantification of amorphous systems.

Calorimetry↗

Devitrification of amorphous celecoxib.

The purpose of this research was to analyze the devitrification of amorphous celecoxib (CEL) in the presence of different stressors (temperature, pressure, and/or humidity) encountered during processing of solid dosage forms. Amorphous CEL was prepared in situ in the analytical instruments, as well as in laboratory, by quench-cooling of melt process, and analyzed by dynamic mechanical thermal analysis, differential scanning calorimetry, microscopy, and Fourier-transform infrared spectroscopy. Amorphous CEL prepared in situ in the analytical instruments was resistant to crystallization under the influence of temperature and/or pressure, because of its protection from the external environment during preparation. These samples exhibited structural relaxation during annealing at 25 degrees C/0% relative humidity (RH) for 16 hours. Generation of amorphous CEL in the laboratory resulted in partially crystalline samples, because of exposure to environmental temperature and humidity, resulting in incomplete vitrification. Subjection to thermal stress favored crystallization of amorphous CEL into metastable polymorphic forms, which were not obtained by solvent recrystallization approach. Temperature and humidity were identified as the major factors promoting devitrification of amorphous CEL, leading to loss of solubility advantage. Exposure to International Conference on Harmonization-specified accelerated stability storage conditions (40 degrees C/75% RH) resulted in complete devitrification of amorphous CEL within 15 days. The phase-transformation process of amorphous CEL along the temperature scale was examined visually, as well as spectrally. This propensity for devitrification of amorphous CEL seemed to depend on the strength of differential molecular interactions between the amorphous and crystalline form.

Celecoxib↗

Unbiased membrane permeability parameters for gabapentin using boundary layer approach.

The present study was performed to determine the relative contribution of both passive and nonpassive transport processes in jejunal absorption of gabapentin. The oral absorption of gabapentin was studied using in situ single pass intestinal perfusion technique in fasted rats. Unbiased intrinsic membrane absorption parameters such as maximal flux, Michaelis constant, carrier permeability, and membrane permeability were calculated using a modified boundary layer model. Gabapentin intestinal perfusion results indicate that its jejunal absorption in rats occurs via a nonpassive process, with no significant passive absorption component, as demonstrated by saturable absorption kinetics and its concentration-dependent permeability. A good correlation (r2 = 0.88) between observed human absorption fraction and calculated (from in situ rat intestine) human absorption fraction was obtained.

Algorithms↗

Bioinformatics in microbial biotechnology--a mini review.

The revolutionary growth in the computation speed and memory storage capability has fueled a new era in the analysis of biological data. Hundreds of microbial genomes and many eukaryotic genomes including a cleaner draft of human genome have been sequenced raising the expectation of better control of microorganisms. The goals are as lofty as the development of rational drugs and antimicrobial agents, development of new enhanced bacterial strains for bioremediation and pollution control, development of better and easy to administer vaccines, the development of protein biomarkers for various bacterial diseases, and better understanding of host-bacteria interaction to prevent bacterial infections. In the last decade the development of many new bioinformatics techniques and integrated databases has facilitated the realization of these goals. Current research in bioinformatics can be classified into: (i) genomics--sequencing and comparative study of genomes to identify gene and genome functionality, (ii) proteomics--identification and characterization of protein related properties and reconstruction of metabolic and regulatory pathways, (iii) cell visualization and simulation to study and model cell behavior, and (iv) application to the development of drugs and anti-microbial agents. In this article, we will focus on the techniques and their limitations in genomics and proteomics. Bioinformatics research can be classified under three major approaches: (1) analysis based upon the available experimental wet-lab data, (2) the use of mathematical modeling to derive new information, and (3) an integrated approach that integrates search techniques with mathematical modeling. The major impact of bioinformatics research has been to automate the genome sequencing, automated development of integrated genomics and proteomics databases, automated genome comparisons to identify the genome function, automated derivation of metabolic pathways, gene expression analysis to derive regulatory pathways, the development of statistical techniques, clustering techniques and data mining techniques to derive protein-protein and protein-DNA interactions, and modeling of 3D structure of proteins and 3D docking between proteins and biochemicals for rational drug design, difference analysis between pathogenic and non-pathogenic strains to identify candidate genes for vaccines and anti-microbial agents, and the whole genome comparison to understand the microbial evolution. The development of bioinformatics techniques has enhanced the pace of biological discovery by automated analysis of large number of microbial genomes. We are on the verge of using all this knowledge to understand cellular mechanisms at the systemic level. The developed bioinformatics techniques have potential to facilitate (i) the discovery of causes of diseases, (ii) vaccine and rational drug design, and (iii) improved cost effective agents for bioremediation by pruning out the dead ends. Despite the fast paced global effort, the current analysis is limited by the lack of available gene-functionality from the wet-lab data, the lack of computer algorithms to explore vast amount of data with unknown functionality, limited availability of protein-protein and protein-DNA interactions, and the lack of knowledge of temporal and transient behavior of genes and pathways.

Journal Article↗

Spray drying for generation of a ternary amorphous system of celecoxib, PVP, and meglumine.

Generation of amorphous forms of a poorly soluble drug by solid dispersion techniques has been a subject of intensive research for decades. Apart from the stability of the dispersions, development of a suitable production technology is a major challenge to the successful commercialization of these products. Coprocessing of celecoxib (CEL), poly(vinyl pyrrolidone), and meglumine by spray drying resulted in an amorphous drug product that provided enhanced solubility and stability to an otherwise poorly soluble crystalline form of CEL. The spray-drying process parameters were optimized to provide an amorphous product with required characteristics. The product was stable for 3 months under the accelerated stability storage conditions. This technique can serve as a suitable means for generating a ready-to-formulate amorphous drug-additive(s) composite that can be directly filled into hard gelatin capsules.

Air Pressure↗

Impact of solid-state properties on lubrication efficacy of magnesium stearate.

The advent of high-speed tableting and slug capsule-filling machines has ushered in an increasingly important role for the lubricants to enact during manufacturing of dosage forms. Although lubricants help in processing, they can also adversely affect the flow properties and dissolution profile of the drug. It is thus critical to maintain a balance between these two behaviors, by understanding the underlying mechanisms and using their optimum concentration in the formulation. The source and manufacturing process inculcate different solid-state properties to magnesium stearate, the most commonly used lubricant, leading to variations in its lubrication efficacy. However, there has been no complete study relating the lubrication efficacy of magnesium stearate to various levels of solid state. Hence, this study was aimed at comprehensively scrutinizing the role of molecular, particle, and bulk level properties of solid state on the lubrication efficacy of magnesium stearate. A method based on net work done during compression using texture analyzer, was developed and validated to analyze its performance. Particle and bulk-level properties were studied using microscopy, particle size analysis, and particle surface area determination, and molecular level was characterized using thermal, spectroscopic, and crystallographic methods. Interplay of solid-state characteristics such as particle size, degree of agglomeration, and crystal habit were found to markedly influence the lubrication potential of magnesium stearate.

Calorimetry, Differential Scanning↗

Molecular interactions in celecoxib-PVP-meglumine amorphous system.

Stabilization of the amorphous form of a drug is conferred by additives that interact with it at the molecular level. Ternary systems of celecoxib, poly(vinyl pyrrolidone) (PVP) and meglumine were studied for molecular interactions responsible for enhanced drug stability and solubility in amorphous form. Meglumine was found to lower the glass transition temperature (T(g)) of the drug due to its plasticization effect. However, the presence of PVP masked its destabilizing effect and provided net anti-plasticization to the celecoxib-PVP-meglumine (7:2:1 w/w) ternary amorphous system. Positive deviation of the experimentally determined T(g mix) value for this composition, from those predicted by the Gordon-Taylor/Kelley-Bueche equation, inferred molecular interaction between the three species, which was also supported by band shifts from their Fourier-transform infra-red (FTIR) spectra. Further, shift of differential scanning calorimetry (DSC) melting endotherms of celecoxib in its amorphous systems from those observed for crystalline celecoxib confirmed the complexation between these components, which was also substantiated by molecular modelling studies that showed H-bonding of -S=O, 2-N of the pyrazole ring and -C-F groups of celecoxib with -O-H group of meglumine. These molecular interactions of amorphous celecoxib with meglumine were found to be the potential cause for enhanced stability and solubility of the celecoxib-PVP-meglumine ternary system.

Anti-Inflammatory Agents, Non-Steroidal↗

Differential molecular interactions between the crystalline and the amorphous phases of celecoxib.

We have investigated the differences in molecular interactions between the crystalline (ordered) and amorphous (disordered) phase of a poorly soluble drug, celecoxib. Molecular interactions in the crystalline phase were investigated with the help of Mercury software, using single crystal X-ray diffractometric data for celecoxib. A simulated annealing molecular dynamics approach was used for the assessment of altered molecular interactions in the amorphous phase. Crystalline celecoxib was found to contain an ordered network of H-bonding between all its electron donors (-S=O group, 2-N of pyrazole ring and -C-F) and the acceptor (-N-H). Amorphous celecoxib retained all these interactions in its disordered molecular arrangement, with a relatively stronger H-bonding between the interacting groups, as compared with crystalline celecoxib. However, these inter-molecular interactions differed in strength in the two solid-state forms. The altered configurations of the molecular arrangement in the two phases were supported by the shifts observed in the Fourier-transform infra-red vibrational spectra of respective states. These interactions could have strong implications on devitrification kinetics of amorphous celecoxib, and could further guide the choice of stabilizers for the amorphous form.

Celecoxib↗

Stability and solubility of celecoxib-PVP amorphous dispersions: a molecular perspective.

PURPOSE: The purpose of the current study is to evaluate the solubility advantage offered by celecoxib (CEL) amorphous systems and to characterize and correlate the physical and thermodynamic properties of CEL and its amorphous molecular dispersions containing poly(vinylpyrrolidone) (PVP). METHODS: The measurement of crystalline content, glass transition temperatures, and enthalpy relaxation was performed using differential scanning calorimetry. Solubility and dissolutions studies were conducted at 37 degrees C to elucidate release mechanisms. Further, the amorphous systems were characterized by polarized light microscopy and X-ray powder diffraction studies. RESULTS: The PVP content has a prominent effect on the stability and solubility profiles of amorphous systems. A dispersion of 20% w/w PVP with CEL resulted in a maxima in terms of solubility enhancement and lowering of relaxation enthalpy. The release of drug from amorphous molecular dispersions was found to be drug-dependent and independent of the carrier. CONCLUSIONS: The solubility enhancement and enthalpy relaxation studies with respect to PVP concentration helped in a better prediction of role of carrier and optimization of concentration in the use of solid dispersions or amorphous systems. The drug release mechanism is drug-controlled rather than carrier-controlled.

Algorithms↗

Effect of processing on Celecoxib and its solvates.

Pharmaceuticals mostly exist in crystalline form and exhibit the phenomenon of differential crystal packing and configurational arrangements of molecules, called polymorphism. Pharmaceutical processing by introducing significant amount of stress alters the molecular interactions in the system engendering polymorphic transformations. The energy supplied by these processing steps tends to overcome the energy barriers between different solid-state forms, thus yielding undesirable changes in the physicochemical and material characteristics of drugs or their dosage forms. Therefore, the role of these unit processes in solid-state transformations must be cautiously studied and if required appropriate controls should be used to monitor such events. The present study was aimed at studying the effect of major energy imparting pharmaceutical unit processes, like size reduction, wet granulation, consolidation, and compression on solid-state transformation of Celecoxib, a selective cyclooxygenase-II inhibitor and its N,N-dimethyl acetamide and N,N-dimethyl formamide solvated forms. A qualitative estimation of crystal transformation in processed samples was performed using DSC, microscopy, FTIR spectroscopy, and XRPD. FTIR was also applied for the development of a quantification method to find the percentage of transformation in N,N-dimethyl acetamide solvated form during compression.

Acetamides↗

Qualitative and quantitative analysis of clopidogrel bisulphate polymorphs.

This study deals with characterization and quantification of form I and form II of clopidogrel bisulphate (CLP), a selective and irreversible inhibitor of ADP-induced platelet aggregation. Thermal (DSC, TGA, HSM), crystallographic (XRD) and spectroscopic (FTIR) methods were used for characterization. After characterization of active pharmaceutical ingredient (API), these techniques were further used for identification of the polymorphic form present in three marketed formulations (tablets). FTIR method was successfully developed and validated for the quantification of form I in polymorph mixtures.

Chemistry, Pharmaceutical↗

Characterization of solid-state forms of celecoxib.

This study deals with the generation and characterization of various solid-state forms of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor. The drug was subjected to polymorphic screen using different solvents to explore the possibility of existence of different solid forms. N,N-Dimethyl acetamide (DMA) and N,N-dimethyl formamide (DMF) yielded solvates in 1:1 stoichiometric ratio. Quench cooling of the melt resulted in amorphous form of the drug. All these solid-state forms were characterized by thermoanalytical (DSC, TGA, HSM), crystallographic (XRD), microscopic (polarized, SEM), spectroscopic (FTIR), and elemental analysis techniques. Solubility and van't Hoff studies were carried out for their thermodynamic interpretation. Influence of morphology of different solid-state forms on flow behavior was also investigated. Molecular modeling studies were used to elucidate the interaction between solute and solvent molecules in the solvate.

Celecoxib↗

Enthalpy relaxation studies of celecoxib amorphous mixtures.

PURPOSE: The purpose of this study was to compare the structural relaxation and molecular mobility of amorphous celecoxib (CEL) with that of CEL amorphous mixtures consisting of various excipients and to study the effect of different excipients on the relaxation of high-energy amorphous systems. METHODS: The measurement of glass transition temperatures (Tg) and enthalpy relaxation were performed using differential scanning calorimetry. The interactions between drug and excipients and the absence of crystalline forms were further confirmed by conducting Fourier transform infrared spectroscopic and X-ray powder diffraction studies on same samples. RESULTS: All samples exhibited a single Tg value. Polymers had a prominent effect on the lowering of the relaxation rate in amorphous CEL. The lowering of the rate of relaxation was directly dependent on the concentration and type of polymer used. The total enthalpy required for relaxation was same, although additives affected the rate of relaxation. CONCLUSIONS: In absence of any specific interactions during Fourier transform infrared studies, it was concluded that the antiplasticizing activity of polymers is responsible for the stabilization of CEL amorphous systems. Glassy amorphous dispersions of CEL exhibited a complex type of relaxation pattern, which failed to fit in Kohlrausch-Williams-Watts equation with respect to calculation of relaxation time constants.

Calorimetry, Differential Scanning↗