Ikuo Kushida

Supersaturation-Nucleation Behavior of Poorly Soluble Drugs and its Impact on the Oral Absorption of Drugs in Thermodynamically High-Energy Forms

In order to better understand the oral absorption behavior of poorly water-soluble drugs, their supersaturation-nucleation behavior was characterized in fasted state simulated intestinal fluid. The induction time (t(ind)) for nucleation was measured for four model drugs: itraconazole, erlotinib, troglitazone, and PLX4032. Supersaturated solutions were prepared by solvent shift method, and nucleation initiation was monitored by ultraviolet detection. The relationship between t(ind) and degree of supersaturation was analyzed in terms of classical nucleation theory. The defined supersaturation stability proved to be compound specific. Clinical data on oral absorption were investigated for drugs in thermodynamically high-energy forms such as amorphous forms and salts and was compared with in vitro supersaturation-nucleation characteristics. Solubility-limited maximum absorbable dose was proportionate to intestinal effective drug concentrations, which are related to supersaturation stability and thermodynamic solubility. Supersaturation stability was shown to be an important factor in determining the effect of high-energy forms. The characterization of supersaturation-nucleation behavior by the presented method is, therefore, valuable for assessing the potential absorbability of poorly water-soluble drugs.

Inhibition of crystal nucleation and growth by water‐soluble polymers and its impact on the supersaturation profiles of amorphous drugs

The impact of water-soluble polymers on drug supersaturation behavior was investigated to elucidate the role of water-soluble polymers in enhancing the supersaturation levels of amorphous pharmaceuticals. Hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and Eudragit L-100 (Eudragit) were used as representative polymers, and griseofulvin and danazol were used as model drugs. Supersaturation profiles of amorphous drugs were measured in biorelevant dissolution tests. Crystal growth rate was measured from the decrease in dissolved drug concentration in the presence of seed crystals. Nucleation kinetics was evaluated by measuring the induction time for nucleation. All experiments were performed in the presence and absence of polymers. The degree of supersaturation of the amorphous model drugs increased with an increase in the inhibitory efficiency of polymers against crystal nucleation and growth (HPMC > PVP > Eudragit). In the presence of HPMC, the addition of seed crystals diminished the supersaturation ratio dramatically for griseofulvin and moderately for danazol. The results demonstrated that the polymers contributed to drug supersaturation by inhibiting both nucleation and growth. The effect of the polymers was drug dependent. The detailed characterization of polymers would allow selection of appropriate crystallization inhibitors and a planned quality control strategy for the development of supersaturable formulations.

Solvent shift method for anti-precipitant screening of poorly soluble drugs using biorelevant medium and dimethyl sulfoxide.

96-well plate based anti-precipitant screening using bio-relevant medium FaSSIF (fasted-state simulated small intestinal fluid) is a useful technique for discovering anti-precipitants that maintain supersaturation of poorly soluble drugs. In a previous report, two disadvantages of the solvent evaporation method (solvent casting method) were mentioned: precipitation during the evaporation process and the use of volatile solvents to dissolve compounds. In this report, we propose a solvent shift method using DMSO (dimethyl sulfoxide). Initially, the drug substance was dissolved in DMSO at a high concentration and diluted with FaSSIF that contained anti-precipitants. To evaluate the validity of the method, itraconazole (ITZ) was used as the poorly soluble model drug. The solvent shift method resolved the disadvantages of the evaporation method, and AQOAT (HPMC-AS) was found as the most appropriate anti-precipitant for ITZ in a facile and expeditious manner when compared with the solvent evaporation method. In the large scale JP paddle method, AQOAT-based solid dispersion maintained a higher concentration than Tc-5Ew (HPMC)-based formulation; this result corresponded well with the small scale of the solvent shift method.

Evaluation of drug supersaturation by thermodynamic and kinetic approaches for the prediction of oral absorbability in amorphous pharmaceuticals

Supersaturation behavior of model drugs, danazol, griseofulvin, itraconazole, vemurafenib, and ER-34122, was analyzed by both thermodynamic and kinetic approaches to better understand the absorption characteristics of amorphous pharmaceuticals. For each amorphous drug, the extent of supersaturation during in vitro dissolution was proved to be similar to that in vivo, which was estimated from relative bioavailability data. The theoretical limit of supersaturation was thermodynamically calculated from several thermal properties and water sorption isotherms of amorphous solids. in vitro and in vivo supersaturation of amorphous vemurafenib was thermodynamically controlled and was in good agreement with the theoretical limit. On the contrary, the supersaturation ratio of the other four drugs was highly overestimated by the thermodynamic calculation. However, it was satisfactorily explained by considering supersaturation stability, which indicated how long supersaturation can be maintained without crystal nucleation. Supersaturation stability was evaluated by measuring the induction time for crystal nucleation kinetically. Concomitant use of thermodynamic and kinetic approaches is, therefore, invaluable in evaluating supersaturation behavior of amorphous materials and assessing development potential of poorly water-soluble drugs.

Investigation for the amorphous state of ER-34122, a dual 5-lipoxygenase/cyclooxygenase inhibitor with poor aqueous solubility, in HPMC solid dispersion prepared by the solvent evaporation method.

ER-34122, a poorly water-soluble dual 5-lipoxygenase/cyclooxygenase inhibitor, exists as a crystalline form. According to an Oak Ridge thermal ellipsoid plot drawing, carbonyl oxygen O (5) makes an intermolecular hydrogen bond with the hydrogen bonded to N (3) in the crystal structure. The FTIR and the solid-state 13C NMR spectra suggest that the network is spread out in the amorphous state and the hydrogen bonding gets weaker than that in the crystalline phase, because the carbonyl signals significantly shift in both spectra. When amorphous ER-34122 was heated, crystallization occurred at around 140°C. Similar crystallization happened in the solid dispersion; however, the degree of crystallization was much lower than that observed in the pure amorphous material. Also, the DSC thermogram of the solid dispersion did not show any exothermic peaks implying crystallization. The heat of fusion (ΔHf) determined in the pure amorphous material was nearly equal to that for the crystalline form, whereas the ΔHf value obtained in the solid dispersion was less than a third of them. These data prove that crystallization of the amorphous form is dramatically restrained in the solid dispersion system. The carbonyl wavenumber shifts in the FTIR spectra indicate that the average hydrogen bond in the solid dispersion is lower than that in the pure amorphous material. Therefore, HPMC will suppress formation of the intermolecular network observed in ER-34122 crystal and preserve the amorphous state, which is thermodynamically less stable, in the solid dispersed system.

Design, synthesis, and structure-activity relationships of a series of novel N-aryl-2-phenylcyclopropanecarboxamide that are potent and orally active orexin receptor antagonists.

Herein we describe the design, synthesis, and structure-activity relationships (SARs) of a novel phenylcyclopropane series represented by 7 and 33 b as antagonists of orexin 1 and orexin 2 receptors. With 4 serving as the initial lead for the development of orexin antagonists, exploration of SAR resulted in improved binding affinity for orexin 1 and orexin 2 receptors. Among the synthesized compounds, 33 b ((-)-N-(5-cyanopyridin-2-yl)-2-[(3,4-dimethoxyphenyl)oxymethyl]-2-phenylcyclopropanecarboxamide) exhibited potent in vitro activity and oral efficacy in animal sleep measurement experiments. The results of our study suggest that compound 33 b may serve as a valuable template for the development of new orexin receptor antagonists.

Frozen water phase method for log D measurement using a 96-well plate

In this study, a frozen water phase method for logD measurement using a 96-well plate was developed. In the case of logD measurement of compounds, the problem of octanol contamination often occurs; in lipophilic compounds, the concentration of the octanol phase is much higher than that of the water phase. When the water phase is separated from the octanol phase, a small amount of octanol phase contamination could strongly influence the concentration of the water phase. To avoid this problem, the frozen water phase method was developed. The water phase was frozen in liquid nitrogen and then the unfrozen octanol phase was removed. To remove the portion of the octanol remaining on the frozen water phase, the surface of the frozen water phase was washed with octanol and water/ethanol (50/50, v/v). The validity of the method was confirmed by results of commercially available drugs at the logD range from 0 to 4. Further, it was found that this method had the ability to evaluate the pH-logD profile of compounds in the range from pH 2 to pH 12. As a result, we developed the convenient and accurate method that is effective in preventing contamination with a wide dynamic range.

Quantitative crystallinity determination for E1010, a novel carbapenem antibiotic, using differential scanning calorimetry

Objectives  The objective of this study was to develop a quantitative crystallinity analysis method for the bulk drug of E1010 ((+)‐(4R,5S,6S)‐6‐[(R)‐1‐hydroxyethyl]‐3‐[(2S,4S)‐2‐[(R)‐1‐hydroxy‐1‐[(R)‐pyrrolidin‐3 ‐yl]methyl]pyrrolidin‐4‐yl]thio‐4‐methyl‐7‐oxo‐1‐azabicyclo[3.2.0]hept‐2‐ene‐2‐carboxylic acid monohydrochloride), a novel carbapenem antibiotic.

Crystal structure and dehydration behavior of E6070, a novel IKKβ protein kinase inhibitor for the treatment of rheumatoid arthritis

This study is focused on solving the crystal structure of E6070, a novel IKKβ protein kinase inhibitor, and characterizing its solid state. E6070 exists as a stable crystalline trihydrate (hydrate I) that undergoes two dehydration events on heating. Neither crystal form nor water content changed under the relative humidity range from 11% to 93% at 25 °C. Crystal transformation to hydrate II occurred in the first dehydration process beginning at ~70 °C followed by loss of almost all remaining crystal lattice water as heating continues up to 160 °C. The observed weight loss of the first step was significantly higher than two equivalents of water. The X-ray powder diffraction proved that the anhydrate is an amorphous form that reversibly reforms the original trihydrate when exposed to atmospheric moisture. Hydrate II more readily forms hydrate I than from the anhydrate. The activation energy of the second step accompanied with amorphism was approximately 1.5 times greater than that of the first. In addition, a gradual decline of activation energy depending on the extent of dehydration was observed, implying reversible conversion in both steps. Therefore, the trihydrate was considered suitable for further development as its solid state is controllable during the manufacturing processes and the shelf life.