Understanding the solid-state forms of fenofibrate - A spectroscopic and computational study

The aim of this study was to investigate the structure of different solid-state forms of fenofibrate, a drug that lacks strong intermolecular interactions such as hydrogen bonding. In addition to a structural analysis of crystalline and amorphous fenofibrate using infrared and Raman spectroscopy combined with density functional theory calculations [B3LYP 6-31G(d)], solid-state changes that occur upon recrystallization of amorphous fenofibrate were monitored and described using in situ Raman spectroscopy. A comparison of the calculated vibrational spectra of a fenofibrate monomer and two dimer structures with the experimental vibrational spectra of crystalline and amorphous fenofibrate revealed conformational differences in the orientation of the two benzyl rings in the fenofibrate molecule and structural differences between the different solid-state forms in aliphatic parts of the drug molecule. The spectroscopic analysis suggests that non-hydrogen-bonded drug molecules are likely to exhibit more random molecular orientations and conformations in the amorphous phase since the weak intermolecular interactions that occur between such molecules can easily be disrupted. In situ Raman spectroscopy and multivariate analysis revealed multiple solid-state forms of fenofibrate, including the metastable crystalline form II, which were structurally analyzed with reference to the quantum chemical calculations. Overall, the study showed that vibrational spectroscopy, multivariate analysis, and quantum chemical modeling are well suited to investigate and characterize the structure of drug substances that exhibit only small structural differences between different solid-state forms.     

Solid-state properties and dissolution behaviour of tablets containing co-amorphous indomethacin–arginine

Co-amorphous drug formulations provide the possibility to stabilize a drug in its amorphous form by interactions with low molecular weight compounds, e.g. amino acids. Recent studies have shown the feasibility of spray drying as a technique to manufacture co-amorphous indomethacin–arginine in a larger production scale. In this work, a tablet formulation was developed for a co-amorphous salt, namely spray dried indomethacin–arginine (SD IND–ARG). The effects of compaction pressure on tablet properties, physical stability and dissolution profiles under non-sink conditions were examined. Dissolution profiles of tablets with SD IND–ARG (TAB SD IND–ARG) were compared to those of tablets containing a physical mixture of crystalline IND and ARG (TAB PM IND–ARG) and to the dissolution of pure spray dried powder.Concerning tableting, the developed formulation allowed for the preparation of tablets with a broad range of compaction pressures resulting in different porosities and tensile strengths. XRPD results showed that, overall, no crystallization occurred neither during tableting nor during long-term storage. Dissolution profiles of TAB SD IND–ARG showed an immediate release of IND by erosion. The solubility of crystalline IND was exceeded by a factor of about 4, which was accompanied by a slow crystallization. For TAB PM IND–ARG, an in situ amorphization of IND in the presence of ARG was observed. As a result, a supersaturation was obtained, too, followed by a faster crystallization compared to TAB SD IND–ARG. In conclusion, the AUC_24h of TAB SD IND–ARG was twofold higher than the AUC_24h of TAB PM IND–ARG. Interestingly, different plateaus were obtained for TAB SD IND–ARG, TAB PM IND–ARG and pure SD IND–ARG after 24 h dissolution, which could be explained by the formation of different polymorphic forms of indomethacin.     

On the role of salt formation and structural similarity of co-formers in co-amorphous drug delivery systems

Co-amorphous drug delivery systems based on amino acids as co-formers have shown promising potential to improve the solubility and bioavailability of poorly water-soluble drugs. Potential salt formation is assumed to be a key molecular interaction responsible for amorphous stability and increased solubility. However, little is known about the importance of the overall structure of the co-former. In this study, the structurally related amino acids arginine (basic) and citrulline (neutral) were chosen together with four model drugs (acidic furosemide and nitrofurantoin; basic cimetidine and mebendazole) to investigate the importance of salt formation versus structural similarity of co-formers. Drug-amino acid mixtures were ball milled at a molar ratio of 1:1. Generally, arginine showed a higher tendency to successfully form co-amorphous systems with the model drugs compared with citrulline, irrespective of assumed salt formation. Salt forming mixtures showed much higher T_gs, faster dissolution rates, higher solubility and physical stability compared to the corresponding non-salt forming mixtures. In conclusion, structural similarity of the co-formers does not lead to similar co-former performance for a given drug. Salt formation is not a prerequisite for the formation of a co-amorphous system, but if a co-amorphous salt system is formed, improved dissolution rate and physical stability are observed.     

Novel computational study on π-stacking to understand mechanistic interactions of Tryptanthrin analogues with DNA

Based on recently published initial experimental results on the intercalation of a class of broad spectrum antiparasitic compounds, we present a purely theoretical approach for determining if these compounds may preferentially intercalate with guanosine/cytosine (GC)-rich or adenosine/thymidine (TA)-rich regions of DNA. The predictive model presented herein is based upon utilization of density functional theory (DFT) to determine a priori how the best intercalator may energetically and sterically interact with each of the nucleoside base pairs. A potential new method using electrostatic potential maps (EPMs) to visually select the best poses is introduced and compared to the existing brute-force center of mass (COM) approach. The EPM and COM predictions are in agreement with each other, but the EPM method is potentially much more efficient. We report that 4-azatryptantrin, the best intercalator, is predicted to favor π-stacking with GC over that of TA by approximately 2–4?kcal/mol. This represents a significant difference if one takes into account the Boltzmann distribution at physiological temperature. This theoretical method will be utilized to guide future experimental studies on the elucidation of possible mechanism(s) for the action of these antiparasitic compounds at the molecular level.     

A double-blind,multi-centre comparison of naproxen and indomethacin in acute musculoskeletal disorders

Summary

A double-blind, multi-centre trial was carried out in 191 patients with acute musculoskeletal conditions to compare the efficacy of naproxen and indomethacin. Patients were randomly allocated to receive either 250 mg naproxen or 50 mg indomethacin twice daily. Treatment was for 7 or 14 days. The results, assessed by the patients'¹ subjective responses, showed that statistically significant improvements in pain, mobility and general condition were produced by both drugs from the first day of treatment. Improvement continued throughout the treatment period but there was no significant difference in the degree or rate between the two drug groups. Twenty-seven patients {13 on naproxen; 14 on indomethacin) withdrew from the study because of side-effects.     

A theoretical study on interactions between mitoxantrone as an anticancer drug and DNA: application in drug design

This research is an effort to further understand the physicochemical interaction between the novel drug, mitoxantrone (MTX) and its biologic receptor, DNA. The ultimate goal is to design drugs that interact more with DNA. Understanding the physicochemical properties of the drug as well as the mechanism by which it interacts with DNA, it should ultimately allow the rational design of novel anti-cancer or anti-viral drugs. Molecular modelling on the complex formed between MTX and DNA presented that this complex was indeed fully capable of participating in the formation of a stable intercalation site. Furthermore, the molecular geometries of MTX and the DNA bases (adenine, guanine, cytosine and thymine) were optimized with the aid of the B3LYP/6-31G* method. The properties of the isolated intercalator and its stacking interactions with the adenine...thymine (AT) and guanine...cytosine (GC) nucleic acid base pairs were studied with the DFTB method (density functional tight-binding), an approximate version of the DFT method, that was extended to cover the London dispersion energy. The B3LYP/6-31G* stabilization energies of the intercalator...base pair complexes were found 10.06 kcal/mol and 21.64 kcal/mol for AT...MTX and GC...MTX, respectively. It was concluded that the dispersion energy and the electrostatic interaction contributed to the stability of the intercalator.DNA base pair complexes. The results concluded from the comparison of the DFTB method and the Hartree-fock method point out that these methods show close results and support each other.     

Vibrational spectroscopic study of salbutamol hemisulphate

Salbutamol hemisulphate is a relatively selective β₂‐adrenergic agonist and is used as a bronchodilator. In this work, we present a detailed vibrational spectroscopic investigation of salbutamol hemisulphate using mid‐infrared and near‐infrared Fourier‐transform (NIR‐FT) Raman spectroscopies. These data are supported by quantum chemical calculations, which allow us to characterise the vibrational spectra of this compound reasonably. As such, this study could be viable for examining the way in which this drug interacts with its target molecules. Copyright © 2009 John Wiley & Sons, Ltd.     

Mechanistic studies on the drug metabolism and toxicity originating from cytochromes P450

Abstract

Cytochromes P450 are oxidizing enzymes; a few families of cytochromes P450 are implicated in drug metabolism. These enzymatic reactions involve many processes including (i) prodrug to drug conversion, (ii) easy excretion of drug, (iii) generation of reactive metabolites, many of which cause toxicity. In this review, the fundamental biochemical mechanisms associated with the conversion of drugs into the useful or toxic metabolites have been discussed. The mechanisms can be established with the help of many experimental methods like mass spectral analysis, NMR and in vitro analysis etc. Computational methods provide detailed atomic level information, which is generally not available from experimental studies. Thus, the in silico efforts in elucidating the molecular mechanisms are complementary to the known experimental methods and are often clearer (especially in providing 3D information about the metabolites and their reactions). Quantum chemical methods and molecular docking become especially very useful. This review includes five case studies, which explain how the atomic level details were obtained to explore the reaction mechanisms of drug metabolism by cytochromes P450.     

Single dose pharmacokinetics of ketoprofen, indomethacin, and naproxen taken alone or with sucralfate

The effects of sucralfate on the rate and extent of absorption of ketoprofen, indomethacin, and naproxen were investigated in healthy volunteers. Six volunteers each received sucralfate (2 g) half an hour before a ketoprofen (50 mg) capsule, and, on another occasion, a ketoprofen (50 mg) capsule alone according to a 2 X 2 Latin square pattern of administration. The same design was used for studies with indomethacin (50 mg) capsules and naproxen (500 mg) tablets. Sucralfate decreased significantly (p less than 0.05) the maximum plasma concentrations (Cmax) of ketoprofen, indomethacin, and naproxen. Although the time necessary to attain Cmax (tmax) for the three drugs tended to increase, only for indomethacin was this increase significant. Sucralfate decreased significantly the rate of absorption (ka) of naproxen and indomethacin, but not that of ketoprofen; it had no significant effect on the elimination half-life and area under the plasma concentration as a function of time curves (AUC0----infinity) of the three drugs. Sucralfate thus decreases the Cmax and increases the tmax of ketoprofen, indomethacin, and naproxen without affecting their bioavailabilities.     

UV-vis and FTIR-ATR spectroscopic techniques to study the inclusion complexes of genistein with beta-cyclodextrins

The effect of beta-cyclodextrin (beta-CyD), (2-hydroxypropyl)-beta-cyclodextrin (HP-beta-CyD) and methyl-beta-cyclodextrin (Me-beta-CyD) complexation on the UV absorption of genistein (Gen) was studied in pure water. A phase solubility study was performed, according to the method reported by Higuchi and Connors, to evaluate the changes of isoflavone in the complexation state and the obtained diagrams suggested that it forms complexes with a stoichiometry of 1:1. Then, the solid complexes of genistein with these macrocycles in 1:1 molar ratio were prepared by the co-precipitation method and characterized by FTIR absorption spectroscopy in ATR geometry. The host-guest interactions have been evidenced by monitoring, in the FTIR-ATR spectra, the changes in some guest molecule bands relative to those observed in the spectra of the 1:1 physical mixtures and complexes. In particular, for the high-frequency O-H stretching band, a quantitative vibrational assignment of the observed sub-bands has been made. From the results, the inclusion phenomena have been discussed.     

Theoretical and experimental vibrational study of miconazole and its dimers with organic acids: application to the IR characterization of its inclusion complexes with cyclodextrins

The geometry, frequency and intensity of the vibrational bands of miconazole were derived from the density functional theory (DFT) calculations with the hybrid functional B3LYP and the 6-31G(d) basis set. Starting from the fully AM1 optimized geometries of miconazole/βCD/acids complexes, the miconazole/acid dimers were reoptimized at the B3LYP/6-31G(d) level. Three acids were studied: maleic, fumaric and l-tartaric acids. To begin with the vibrational spectral data obtained from solid phase in mid FT-IR spectrum of miconazole and its dimers are assigned based on the results of the normal modes calculations. All the observed spectra and the calculated ones are found to be in good agreement. In a second step, theoretical results allowed the assignment of FT-IR spectrum for the miconazole/HPγCD inclusion complex produced by supercritical carbon dioxide treatment and confirmed the inclusion of miconazole. The experimental spectra for the miconazole/HPγCD/acids complexes prepared by supercritical carbon dioxide processing were also assigned using theoretical results. The results confirmed the presence of a genuine inclusion complex and also the interaction between miconazole and the acid.     

A comparative study of electroporation and iontophoresis for percutaneous penetration of naproxen

Using side-by-side compartment diffusion cell and rat skin, the in vitro percutaneous penetration of naproxen by electroporation and iontophoresis with different energy was investigated and compared. Both electroporation and iontophoresis could obviously increase the penetration of naproxen through rat skin. The enhancing effect of electroporation was not always better than that of iontophoresis. The enhancing effect was dependent on the energy of the electrical field.     

Clinical evaluation of two daily doses of naproxen and indomethacin: result of a double-blind crossover trial

Summary

A double-blind crossover clinical trial is reported on the effects of naproxen in two doses, 500?mg. and 750?mg. daily, and 100?mg. indomethacin daily in 23 patients with classical rheumatoid arthritis, each drug being given for 1 week. The results show that there was little to choose between the drugs and that there was clinical equivalence between the two doses of naproxen. Radioactive pertechnetate (^99mTc) joint uptakes were depressed by both naproxen and indomethacin, indicating anti-inflammatory effect.     

Analytical methods for the monitoring of solid phase organic synthesis

Solid phase synthesis (SPS) is a powerful technique to assemble compound libraries in high-throughput parallel and combinatorial synthesis. The widespread applications of these techniques required the development of analytical methods for both structural elucidation and reaction monitoring. This review covers some recently developed techniques for on-bead analyses together with solution-state ones. Particular emphasis is devoted to software and hardware improvements for automated high-throughput analysis.     

A comparative study of flurbiprofen and indomethacin in rheumatoid arthritis

Summary

A double-blind, crossover study was carried out in 30 patients with active, classical or definite rheumatoid arthritis to compare the effect of 200?mg flurbiprofen per day with that of 100?mg indomethacin per day. Patients received, at random, each drug for a period of 2 weeks separated by a week's wash-out period on placebo. Assessments were made before the start of the trial and at weekly intervals of pain, morning stiffness, grip strength, articular index, walking time, and finger joint size. Patients' preference for any particular treatment period was recorded at the end of the trial. Laboratory investigations were carried out before and during the trial. Both drugs show statistically significant improvement over baseline assessments, although there was little difference between the two active treatment periods. More patients preferred the treatment period with flurbiprofen, and this was probably related to the fewer side-effects which were reported with this drug.     

Applications of density functional theory in COVID-19 drug modeling

The rapidly evolving Coronavirus 2019 (COVID-19) pandemic has led to millions of deaths around the world, highlighting the pressing need to develop effective antiviral pharmaceuticals. Recent efforts with computer-aided rational drug discovery have allowed detailed examination of drug–macromolecule interactions primarily by molecular mechanics (MM) techniques. Less widely applied in COVID-19 drug modeling is density functional theory (DFT), a quantum mechanics (QM) method that enables electronic structure calculations and elucidations of reaction mechanisms. Here, we review recent advances in applying DFT in molecular modeling studies of COVID-19 pharmaceuticals. We start by providing an overview of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs and targets, followed by a brief introduction to DFT. We then provide a discussion of different approaches by which DFT has been applied. Finally, we discuss essential factors to consider when incorporating DFT in future drug modeling research.     

Baseline risk of gastrointestinal disorders among new users of meloxicam,ibuprofen, diclofenac,naproxen and indomethacin

Meloxicam (Mobic^®) was introduced in the UK in 1996 as a nonsteroidal anti‐inflammatory drug (NSAID). To help evaluate the postmarketing experience with meloxicam in the UK, we used the General Practitioners Research Database (GPRD) to characterize the baseline risk of an upper gastrointestinal (GI) event among new users of meloxicam, ibuprofen, diclofenac, naproxen and indomethacin. We selected for analysis a random sample of 5000 meloxicam users, and 5000 users of each of the comparator NSAIDS except indomethacin, for which we selected 2500 subjects. Comparators were matched to meloxicam subjects on age and sex. We examined for each subject history of certain GI diagnoses and recent use of anti‐inflammatory drugs and acid‐suppressing drugs. We found that patients receiving meloxicam were at least twice as likely as patients receiving other NSAIDs to have a recent history of GI diagnoses or treatment. We conclude that in the UK meloxicam was used more often than other popular NSAIDs among patients who were at increased baseline risk of GI events. The occurrence of GI events among users of meloxicam, even at a relatively high frequency, therefore, would be expected based solely on this increased baseline risk. Copyright © 2000 John Wiley & Sons, Ltd.     

盐酸吗啡、咖啡因的FTIR检验及谱图解释

目的 提高用红外光谱法鉴定盐酸吗啡、咖啡因纯品、二者混合物的水平.方法 用红外光谱法有针对性地选择特征峰,探明盐酸吗啡、咖啡因红外光谱与结构的关系.结果 获得盐酸吗啡、咖啡因的特征峰.结论 该方法 克服了鉴定中的盲目性,重现性好,特异性强.     

A comparative gastroscopic study of lonazolac and indomethacin in healthy subjects

In 9 healthy volunteers the effects of a 14-day treatment with lonazolac 300 mg b.i.d. on gastric and duodenal mucosa have been endoscopically compared with those of indomethacin 75 mg b.i.d. in a double-blind placebo-controlled trial. Lonazolac and indomethacin induced significantly more gastric and duodenal mucosal injuries (1.9 +/- 0.4 and 1.7 +/- 0.3) compared to placebo (0.9 +/- 1.0) (p less than 0.05). The validity of different procedures in predicting the deleterious effects of nonsteroidal antiinflammatory drugs on the human upper gastrointestinal epithelium is discussed.