森部 久仁一

A novel amorphous solid dispersion (ASD) of poorly water-soluble nobiletin (Nob) with highly water-soluble methyl hesperidin (MeHes) was developed. Mixtures of Nob and excipients (MeHes, cellulose derivatives, and synthetic polymers) were processed by hot-melt extrusion (HME). Powder X-ray diffraction analysis proved that most of the HME products were fully amorphized. In dissolution studies, Nob-MeHes ASD showed a prominently higher Nob concentration than other HME products with polymeric excipients. Nob concentration upon dissolution of Nob-MeHes ASD was 400 and 7.5 times higher than that upon dissolution of crystalline Nob and a Nob-MeHes physical mixture, respectively. In addition, Nob-MeHes ASD showed good preservation stability for 6 months under an accelerated condition of 40 °C and 80% relative humidity. Permeation studies using a Caco-2 cell monolayer showed that Nob-MeHes ASD markedly increased the amount of Nob transported. In mice, the plasma Nob concentration and accumulated amount of Nob in various tissues drastically increased after administration of Nob-MeHes ASD. This is the first successful application of MeHes, with a relatively low glass-transition temperature, as an excipient for an ASD formulation prepared by hot-melt extrusion. The drastic improvement in Nob concentration with a small-molecule excipient may be an important finding.

In this study, the resveratrol spray-dried emulsions were developed using a quality-by-design approach. Further, the product and process factors that affected the quality of the spray-dried emulsions were analyzed and illustrated using an Ishikawa diagram. The product and process risks were prioritized using a risk-ranking system. The low methoxyl pectin (LMP) amount, caprylic/capric glyceride (CCG) amount, homogenization time, homogenization speed, inlet temperature, pump speed, drying airspeed, and de-blocking speed were observed to be the eight highest risk factors. Further, the criticality of these eight factors on the responses was determined using the Plackett–Burman design. Increasing the LMP amount increased the particle size, whereas increasing the CCG amount enhanced the drug-loading capacity and drug dissolution at 5-min intervals (Q 5 ) and decreased the moisture content. Q 5 was positively affected by the homogenization speed and pump speed; however, it was negatively affected by the LMP amount. The spraying efficiency was affected by the pump speed and the LMP amount. Further, the risk level of the homogenization time, inlet temperature, drying airspeed, and de-blocking speed were reduced. However, the LMP amount, CCG amount, homogenization speed, and pump speed were observed to remain at high risk and require further investigation. The risk assessment and Plackett–Burman design mitigated the risks and identified the critical factors that affected the quality of the resveratrol spray-dried emulsions and the spray-drying process.

We focused on the crystal structure of cyclodextrin (CD) to develop new solid CD complexes. There are two large spaces in the columnar structure of CD crystals: one inside a CD cavity and another between CD columns. New solid CD complexes can be designed by incorporating guest drugs between the CD columns. We succeeded in preparing a solid drug/[polyethylene glycol (PEG)/γ-CD-polypseudoraxane (PPRX)] complex by a sealed-heating method via the gas phase. A drug/(PEG/γ-CD-PPRX) complex has a structure in which PEGs are included in a γ-CD cavity, and guest drugs are incorporated between the γ-CD columns. Screening by a sealed-heating method determined that a variety of guest drugs with varying molecular size and log P could be incorporated into the spaces between γ-CD columns, following a stoichiometric rule. Another method, via solid phase using cogrinding and subsequent heating, was developed to prepare drug/(PEG/γ-CD-PPRX) complex. This method enabled us to prepare the complex with a thermally unstable drug, as well as a drug/(PEG/α-CD-PPRX) complex not formed using the sealed-heating method. Both the structure and molecular state of each drug in the complexes were characterized by powder X-ray diffraction and solid-state NMR measurements. The dissolution character and thermal stability of the drug incorporated in the complex could be improved by the specific complex formation. The solid CD complexes thus developed have potential for drug-encapsulation and as drug-release carriers, owing to their unique structural and pharmaceutical properties.

An aminoalkyl methacrylate copolymer, Eudragit® E (EUD-E), has gained tremendous attention as a solid dispersion carrier because it efficiently stabilizes drugs in the amorphous state. Furthermore, EUD-E remarkably enhances drug dissolution in water. This review focuses on the interaction between drugs and EUD-E in solution, which contributes to the enhancement of drug concentration. Studies examining interactions between acidic drugs and EUD-E in organic solvents have revealed that the interaction occurs predominantly by electrostatic interaction, including hydrogen bonding and dipolar interactions. Other studies on interactions in aqueous solution found evidence for strong electrostatic interactions between acidic drugs and EUD-E in ion exchange experiments. 1H-NMR studies using high-resolution magic-angle spinning, nuclear Overhauser effect spectroscopy, diffusion, and relaxation time measurements successfully identified the interaction site and strength in aqueous solution. Hydrophobic and ionic interactions occurred between drugs and EUD-E. The conformation of EUD-E, which was affected by the ionic strength and pH of the aqueous media, also influenced the interaction. The knowledge discussed in this review will be helpful in designing solid dispersion formulations with EUD-E, which will efficiently enhance drug concentration and subsequent absorption into the body.

To improve the solubility of the drug nifedipine (NI), NI-encapsulated lipid-based nanoparticles (NI-LNs) have been prepared from neutral hydrogenated soybean phosphatidylcholine and negatively charged dipalmitoylphosphatidylglycerol at a molar ratio of 5/1 using by roll grinding and high-pressure homogenization. The NI-LNs exhibited high entrapment efficiency, long-term stability, and enhanced NI bioavailability. To better understand their structures, cryo transmission electron microscopy and atomic force microscopy were performed in the present study. Imaging from both instruments revealed that the NI-LNs were bicelles. Structures prepared with a different drug (phenytoin) or with phospholipids (dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoylphosphatidylcholine) were also bicelles. Long-term storage, freeze-drying, and high-pressure homogenization did not affect the structures; however, different lipid ratios, or the presence of cholesterol, did result in liposomes (5/0) or micelles (0/5) with different physicochemical properties and stabilities. Considering the result of long-term stability, standard NI-LN bicelles (5/1) showed the most long-term stabilities, providing a useful preparation method for stable bicelles for drug delivery.

We investigated the effect of polymer composition on nifedipine (NIF) dissolution through molecular-level characterization of NIF/hypromellose (HPMC)/Eudragit S (EUD-S) ternary solid dispersions. The dissolution rates and molecular states of NIF and polymers were evaluated in NIF/HPMC/EUD-S spray-dried samples (SPDs) with different polymer compositions. Blending of HPMC and EUD-S improved the dissolution property of each polymer. Moreover, polymer blending enhanced NIF dissolution from the NIF/polymer SPD with EUD-S/polymer wt % of 50-75%. NIF dissolved simultaneously with polymers from the NIF/polymer SPDs with high EUD-S/polymer wt %. In contrast, NIF and polymers separately dissolved from the NIF/polymer SPDs with EUD-S/polymer wt % of 10-25%, exhibiting a significantly reduced NIF dissolution rate. Fourier transform-infrared and solid-state NMR measurements revealed that HPMC and EUD-S formed molecular interactions with NIF via different interaction modes. Comprehensive analysis by spectroscopic measurements and modulated differential scanning calorimetry showed that the molecular interaction between NIF and EUD-S was stronger than that between NIF and HPMC. Furthermore, the 13C-spin-lattice relaxation time measurements revealed that EUD-S effectively restricted the molecular mobility of NIF compared with HPMC. The molecular interaction between NIF and EUD-S led to the simultaneous and fast dissolution of NIF with EUD-S from the NIF/polymer SPD with high EUD-S loading. Thus, enhanced NIF dissolution was ascribed to the fast dissolution properties of the blended polymer and to polymer-controlled NIF dissolution through the strong molecular interaction between NIF and EUD-S. To achieve efficient optimization of the formulation of polymer-blended solid dispersion with desired drug dissolution, it is necessary to consider both polymer-polymer and drug-polymer intermolecular interactions.

We present the absorption improvement mechanism of fenofibrate (FFB), a Biopharmaceutics Classification System (BCS) class II drug, from self-microemulsifying drug delivery systems (SMEDDS), centered on improving the diffusion of FFB through the unstirred water layer (UWL). Four SMEDDS formulations containing Labrafac™ lipophile WL 1349 (WL1349) or Labrafil® M 1944CS (M1944) oils and NIKKOL HCO-40 (HCO40) or NIKKOL HCO-60 (HCO60) surfactants were prepared. Every SMEDDS formulation formed microemulsion droplets of approximately 30 nm. In vitro tests showed that the microemulsion droplets containing M1944 had relatively small FFB solubilization capacities, causing larger amounts of FFB to be dissolved in the bulk water phase, compared to the droplets containing WL1349. The diffusivity of the microemulsion droplets through the mucin solution layer was enhanced when using HCO40 compared to HCO60. The oral absorption in rats was the highest when using the SMEDDS formulation containing M1944 and HCO40. High FFB distribution in the bulk water phase and fast diffusion of microemulsion droplets through the mucus layer contributed to the efficient delivery of FFB molecules through the UWL to the epithelial cells, leading to enhanced FFB absorption.

The morphology and stability of amorphous nanoparticles of glibenclamide (GLB) prepared by the antisolvent method using different methods of adding hypromellose (HPMC) were evaluated. Nano-A was prepared by the injection of a dimethyl sulfoxide (DMSO) solution of GLB into the HPMC solution, whereas nano-B was obtained by the injection of a DMSO solution of GLB and HPMC into water. Cryogenic transmission electron microscopy, field-emission scanning electron microscopy, and field-emission transmission electron microscopy, including energy dispersive X-ray spectrometry, revealed that the particles of the nano-A and nano-B samples are hollow spheres and nonspherical nanoparticles, respectively. Powder X-ray diffraction and solid-state NMR measurements showed that GLB is present in an amorphous state in both nano-A and nano-B. The weight ratios of HPMC in the GLB/HPMC nanoparticles were 11 and 16% for nano-A and nano-B, respectively, as determined by solution-state NMR. The glass transition temperatures (Tg) of nano-A and nano-B evaluated using differential scanning calorimetry were lower by about 10 °C compared to that of amorphous GLB, presumably because of a Tg confinement effect and the surface coverage and mixing of HPMC, as suggested by the inverse gas chromatography experiment. GLB crystallization during storage was suppressed more strongly in nano-B than nano-A, owing to the higher amount of HPMC and the higher miscibility between GLB and HPMC. It is suggested that the diffusion rate of the solvent during nanoprecipitation determined the nanoparticle properties. In nano-A, the precipitation of GLB first occurred at the outer interface because of the rapid diffusion of the solvent. Thus, hollow spherical particles with HPMC preferentially located near the surface were formed. On the other hand, the diffusion of the solvent in nano-B was suppressed because of the presence of HPMC, yielding small nonspherical nanoparticles with a high miscibility of GLB and HPMC.

© 2018 Elsevier B.V. In this work, the effect of saccharin (SAC) addition on the dissolution and supersaturation level of phenytoin (PHT)/Eudragit® E (EUD-E) solid dispersion (SD) at neutral pH was examined. The PHT/EUD-E SD showed a much slower dissolution of PHT compared to the PHT/EUD-E/SAC SD. EUD-E formed a gel layer after the dispersion of the PHT/EUD-E SD into an aqueous medium, resulting in a slow dissolution of PHT. Pre-dissolving SAC in the aqueous medium significantly improved the dissolution of the PHT/EUD-E SD. Solid-state13C NMR measurements showed an ionic interaction between the tertiary amino group of EUD-E and the amide group of SAC in the EUD-E gel layer. Consequently, the ionized EUD-E could easily dissolve from the gel layer, promoting PHT dissolution. Solution-state1H NMR measurements revealed the presence of ionic interactions between SAC and the amino group of EUD-E in the PHT/EUD-E/SAC solution. In contrast, interactions between PHT and the hydrophobic group of EUD-E strongly inhibited the crystallization of the former from its supersaturated solution. The PHT supersaturated solution was formed from the PHT/EUD-E/SAC SD by the fast dissolution of PHT and the strong crystallization inhibition effect of EUD-E after aqueous dissolution.

We investigated the formation and stabilization mechanisms of indomethacin (IMC)/poloxamer 407 nanosuspensions. Stable nanosuspensions were prepared via 24 h wet-milling of three IMC forms (γ form, α form, and amorphous) with poloxamer 407. Cryogenic-transmission electron microscopy images of nanoparticles obtained using γ-form IMC indicated a rhombic-plate shape. In contrast, needle-like nanoparticles were observed in the nanosuspensions of α-form and amorphous IMC. Suspended-state cross polarization 13C NMR and Raman measurements directly detected the molecular states of IMC in nanosuspensions. IMC existed in its initial crystal form when γ-form and α-form IMC were used amorphous IMC transformed into crystalline α-form IMC. Suspended-state 13C pulse saturation transfer NMR measurements revealed the molecular state of poloxamer 407 on the surface of IMC crystals. The polypropylene oxide group adsorbed to the IMC crystal surface via hydrophobic interactions, while the polyethylene oxide group on the surface was as flexible as that in polymeric micelles. The equilibrium of poloxamer 407 between micelle and nanocrystal surfaces was slower than the NMR time scale, which could stabilize the dispersion of the nanoparticles in water. The time interval evaluation during the wet-milling process revealed that α-form IMC nanocrystals could be efficiently prepared via wet-milling using amorphous IMC as the starting material.

The 3-D morphology of doxorubicin (DOX)–loaded liposomes with a size of circa 100 nm was characterized by atomic force microscopy in an aqueous environment. Prolate liposomes appear in accordance with linear expansion of DOX fiber bundles precipitated inside liposomes. Oblate and concave liposomes were simultaneously observed with increased DOX concentrations however, their morphologies were not readily determined by 2-D cryo-TEM imaging. Precise data analysis of the 3-D parameters of each liposome allowed semiquantitative evaluation of the transformation of spherical liposomes into nonspherical—prolate, oblate, and concave liposomes. In addition, nonspherical liposomes became spherical on the replacement of the liposomal outer phase consisting of a sucrose solution, with water and subsequent water influx. All spherical liposomes transformed into oblate and concave liposomes with a return to hyperosmotic conditions, when transferred from water to sucrose solution. Furthermore, the concave liposomes did not appear under DOX incubation conditions (65°C), which could be due to the amorphous and supersaturated DOX inside the liposomes that restrained liposomal shrinkage. As atomic force microscopy has improved our ability to image 3-D morphologies of liposomes in various conditions, it is an alternative analytical tool to cryo-TEM and may have future applications in regulatory tests for quality control and assurance.

<p>We have developed suspension-state NMR to evaluate the molecular states of drug nanosuspension directly without drying. In this commentary, the case studies by suspended-state NMR which evaluated two kinds of drug nanosuspensions were introduced. At first, an indomethacin/poloxamer 407 nanosuspension where indomethacin was in crystalline state was investigated. Secondly, a piroxicam/poloxamer 407 nanosuspension where crystalline and amorphous piroxicam coexisted was studied. The molecular states of poloxamer 407 located at the solid-liquid interface of drug nanoparticle and water were different between the drug nanosuspension using indomethacin and piroxicam. Finally, the structure of drug nanosuspension and the solid-liquid interface was discussed.</p>

We examined the effect of hot-melt extrusion condition on the physical stability of the solid dispersion prepared using partially hydrolyzed polyvinyl alcohol (PVOH). The hot-melt extrusion of indomethacin (IMC) and PVOH mixed at the weight ratio of 3 : 7, 5 : 5 and 7 : 3 was performed either at 170 or 190°C to prepare the IMC/PVOH hot-melt extrudate (HME). Differential scanning calorimetry represented that IMC was mixed with PVOH on a scale of several tens of nanometer in all the HMEs with different weight ratio. 13C solid-state NMR measurement revealed that an intermolecular interaction was formed between a carboxylic group of IMC and a hydroxy group of PVOH in the HMEs. The intermolecular interaction in the HMEs was stronger at the higher extrusion temperature. At the low IMC loading, the IMC molecules could be mixed with the amorphous PVOH at the molecular level, and the remained PVOH without interaction formed the crystal phase. On the other hand, at the high IMC loading, most PVOH could be amorphized by the interaction with IMC, and the excess IMC which did not interact with PVOH formed the IMC-rich domain. The IMC/PVOH HME at the weight ratio of 7 : 3 extruded at higher extrusion temperature showed higher physical stability of amorphous IMC compared with that extruded at lower extrusion temperature. The hot-melt extrusion process at higher temperature provided the rapid melting of PVOH crystal phase, resulted in the homogeneous mixing with IMC and the formation of stronger intermolecular interaction.

© 2017 Elsevier B.V. Various ternary Guest 2/(Guest 1/γ-cyclodextrin (CD)) complexes were prepared using a cogrinding and subsequent heating method, wherein Guest 1 was incorporated in the cavity of γ-CD and Guest 2 was incorporated into the intermolecular spaces between γ-CD columns. Dissolution fluxes of Guest 1 and Guest 2 from all ternary complexes were almost identical. The dissolution flux of flurbiprofen (Guest 1) from the ternary complexes depended on the solubility of Guest 2 drugs (naproxen &lt; ketoprofen &lt; ethenzamide) in the dissolution medium of pH 1.2. It is noteworthy that the dissolution flux of flurbiprofen from the ternary complexes with ketoprofen and ethenzamide as Guest 2 drugs was further enhanced compared with that from the flurbiprofen/γ-CD inclusion complex. The ternary complex of the acidic drug ketoprofen as Guest 1 and the neutral drug hydrocortisone as Guest 2 showed an increased dissolution flux, which was dependent on the increase in pH of the dissolution medium. The pH-dependent dissolution should reflect the solubility of ketoprofen/γ-CD inclusion complex in each dissolution medium. These results indicated that the dissolution flux of the ternary γ-CD complexes could be controlled by selecting the appropriate Guest 1 and Guest 2 species.

This review considers advances in the understanding of active pharmaceutical ingredient polymorphism since around 2010 mainly from a structural view point, with a focus on twelve model drugs. New polymorphs of most of these drugs have been identified despite that the polymorphism of these old drugs has been extensively studied so far. In addition to the conventional modifications of preparative solvents, temperatures, and pressure, more strategic structure-based methods have successfully yielded new polymorphs. The development of analytical techniques, including X-ray analyses, spectroscopy, and microscopy has facilitated the identification of unknown crystal structures and also the discovery of new polymorphs. Computational simulations have played an important role in explaining and predicting the stability order of polymorphs. Furthermore, these make significant contributions to the design of new polymorphs by considering structure and energy. The new technologies and insights discussed in this review will contribute to the control of polymorphic forms, both during manufacture and in the drug formulation. (C) 2016 Elsevier B.V. All rights reserved.

We investigated the phase separation behavior and maintenance mechanism of the supersaturated state of poorly water-soluble nifedipine (NIF) in hypromellose (HPMC) derivative solutions. Highly supersaturated NIP formed NIF-rich nanodroplets through phase separation from aqueous solution containing HPMC derivative. Dissolvable NIF concentration in the bulk water phase was limited by the phase separation of NIF from the aqueous solution. HPMC derivatives stabilized the NIP-rich nanodroplets and maintained the NIF Super saturation with phase-separated NIP for several hours. The size of the NIF-rich phase was different depending on the HPMC derivatives dissolved in aqueous solution, although the droplet size had no correlation with the time for which NIF supersaturation was maintained without NIP crystallization. HPMC acetate and HPMC acetate succinate (HPMC-AS) effectively maintained the NIF supersaturation containing phase-separated NIF compared with HPMC. Furthermore, HPMC-AS stabilized NIF supersaturation more effectively in acidic conditions. Solution H-1 NMR. measurements of NIF-supersaturated solution revealed that HPMC derivatives distributed into the NIF-rich phase during the phase separation of NIP from the aqueous solution. The hydrophobicity of HPMC derivative strongly affected its distribution into the NIF-rich phase. Moreover, the distribution of HPMC-AS into the NIP-rich phase was promoted at lower pH due to the lower aqueons solubility of HPMC-AS. The distribution of a large amount of HPMC derivatives into NIF-rich phase induced the strong inhibition of NIF crystallization from the NIF-rich phase. Polymer distribution into the drug-rich phase directly monitored by solution NMR technique can be a useful index for the stabilization efficiency of drug-supersaturated solution containing a drug-rich phase.

This study investigated how the process parameters of wet-granulation affect the properties of solid dispersions (SDs), such as dissolution and physical stability. SDs of nilvadipine (NIL) and hypromellose prepared by spray-drying were wet-granulated and dried under various conditions. The NIL concentration at 4 h and area under the curve from dissolution tests were taken to indicate dissolution. Then, the NIL crystallinity calculated from powder X-ray diffraction patterns of SD granules stored at 60 degrees C for 3 months was evaluated to indicate physical stability. A statistical analysis revealed that the amount of granulation liquid (w/w%) and the ratio of water to ethanol in the liquid (v/v%) significantly affected the dissolution property, and that the drying temperature had a significant effect on the physical stability. Although exposure to water makes the wet-granulation process seem less suitable for granulating a SD, the results indicated that the process can be used to develop SD granules by selecting appropriate conditions, such as a lower proportion of granulation liquid, a higher water to ethanol ratio in the liquid, and a higher drying temperature. (C) 2017 Elsevier B.V. All rights reserved.

© 2017 Elsevier Ltd We report the full assignment of1H and13C NMR signals belonging to α-glucosyl rhoifolin (Rhf-G), a novel transglycosylated compound synthesized from a flavone glycoside, rhoifolin, as well as its chemical structure. Furthermore, we report the complete NMR signal assignment for another transglycosylated compound, α-glucosyl rutin (Rutin-G), as the signals corresponding to its sugar moieties had not been identified. Electrospray ionization-mass spectrometry along with multiple NMR methods revealed that Rhf-G possesses three sugar moieties in its chemical structure. The additional glucose was bound directly via a transglycosylation to rhoifolin at position 3a of the sugar moiety. Interestingly, intramolecular hydrogen bonds in the basic Rhf-G and Rutin-G skeletons were confirmed by HMBC experiments. These findings will be helpful for comprehensive NMR studies on transglycosylated compounds in food, cosmetic, and pharmaceutical fields.

Synergetic role of polymer blending on dissolution of amorphous solid dispersion was investigated. Dissolution rates of hypromellose (HPMC) and methacrylic acid copolymer (EUD) from the HPMC/EUD spray-dried sample (SPD) were improved compared to those of each single polymer SPD. Differential scanning calorimetry measurements revealed that the structural change in HPMC following heating was inhibited by co-spray-drying with EUD, suggesting an intermolecular interaction between the polymers. C-13 solid-state nuclear magnetic resonance (NMR) spectroscopy detected the change induced in the hydroxyl group of HPMC by co-spray-drying with EUD. Moreover, the carbonyl peak shape of EUD in the C-13 NMR spectra differed between EUD SPD and HPMC/EUD SPD, indicating that the dimer structure of the carboxylic acid of EUD was partially disrupted by the interaction with HPMC. An intermolecular interaction occurred between HPMC and EUD. The hydrogen bond reformation likely improved the dissolution rates of the polymers. The ternary griseofulvin (GRF)/HPMC/EUD SPD showed a significantly higher supersaturation level of GRF than the mixtures containing equal amounts of binary GRF/HPMC and GRF/EUD SPDs. The change of interaction mode between polymers improved the dissolution of solid dispersion. Therefore, polymer blending based on interpolymer interactions could be a practical strategy for designing excellent solid dispersion formulations. (C) 2017 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.

Ascorbyl 2,6-dipalmitate (ASC-DP) and distearoyl phosphatidylethanolamine polyethylene glycol 2000 (DSPEPEG) formed stable nanoparticles at a molar ratio of less than or equal to 2:1 after dispersing the solvent-evaporated film in water. The mean particle sizes measured by dynamic light scattering were within the range of ca. 100-160 nm. Composition-dependent changes of the ASC-DP and DSPE-PEG molecular states within the film were analyzed by wide-angle X-ray diffraction and infrared (IR) and solid-state nuclear magnetic resonance (NMR) spectroscopy. Transmission electron microscopy (TEM) of nanoparticles revealed that ASC-DP/DSPE-PEG changed from a micelle to a disk and tubular structure as the molar ratio increased. Quantitative solution-state H-1 NMR measurements elucidated the structure of nanoparticle in water; the core could be composed of ASC-DP and hydrophobic acyl chains of DSPE, whereas the hydrophilic PEG chains of DSPE-PEG on the surface form the hydration shell to stabilize the nanoparticle dispersion in water. Cytotoxicity of ASC-DP against cancer cell lines was observed by using ASC-DP/DSPE-PEG nanoparticles, and no cytotoxicity against normal cells was found. Thus, the ASC-DP/DSPE-PEG formulation, with tumor cell specific cytotoxicity, can be applicable for cancer monotherapy or in combination with other anticancer drugs. (C) 2016 Elsevier B.V. All rights reserved.

In this study, a new preparation method was developed to obtain drug/(polyethylene glycol/cyclodextrin-polypseudorotaxane (PEG/CD-PPRX)) complexes in which drugs were incorporated into the intermolecular spaces of CD columns in PEG/CD-PPRXs. This method was solid-phase mediated and used cogrinding and subsequent heating. Guest drug and CD in PEG/CD-PPRX were amorphized by cogrinding, and then crystallization of CD was promoted by subsequent heating. A previously reported sealed-heating method using the gas phase was not applicable for poorly sublimated and thermally unstable drugs such as piroxicam (PXC) and hydrocortisone, whereas this new method allowed these drugs to be incorporated into the intermolecular spaces of gamma-CD columns. Furthermore, salicylic acid (SA) and salicylamide were successfully incorporated into the intermolecular spaces of CD columns using alpha-CD instead of gamma-CD. Powder X-ray diffraction and solution-state H-1 nuclear magnetic resonance measurements revealed that complexation followed the stoichiometric rule and that the size of the guest drug determined whether complexation occurred. Accurate control of preparation conditions (temperature and water content) was required to obtain complexes with high CD crystallinity. Changes in the molecular state and mobility of each component during the formation process of the PXC/(PEG/gamma-CD-PPRX) and SA/(PEG/alpha-CD-PPRX) complexes were evaluated using solid-state NMR measurements. Finally, dissolution enhancement and sublimation suppression of SA in the SA/(PEG/alpha-CD-PPRX) complex were demonstrated.

Developing a robust analytical HPLC-UV method to characterize a drug candidate during an early stage of development is a major challenge when not all impurity standards are available. Here, we report our efforts to devise an efficient strategy for HPLC method development using continuous screening of analytical parameters without impurity standards. This strategy uses small incremental changes in the mobile phase pH and column temperature to trace each impurity on an overlay chromatogram. We tested this method using benzocaine as the active pharmaceutical ingredient (API), and compounds with similar structures to represent unknown impurities. Despite the coelution of peaks, results identified the number of impurities and indicated the starting point and parameter variables of the ensuing optimization step. Further, we demonstrated that the retention time of each peak as a function of mobile phase pH accounts for the apparent pK(a) of known and unknown compounds in the presence of an organic solvent. This information is critically important to the selection of a robust pH range for HPLC methods. [GRAPHICS] .

© 2016 Elsevier Ltd. All rights reserved. The composite material formed by phytosterol ester (PSE) and γ-cyclodextrin (γ-CD) disperses readily in water and has been used to mask undesirable flavours. This paper elucidates the structure of the PSE/γ-CD particle. Cryogenic scanning electron microscopy and contact angle measurements showed that the PSE/γ-CD particles formed a capsule-like structure with a hydrophilic surface. A phase-solubility study using cholesteryl oleate (ChO), one of the components of PSE, showed that ChO formed a hydrophilic and stoichiometric inclusion complex with γ-CD at a molar ratio of 2:5. The structure of the PSE/γ-CD inclusion complex was similar to that of ChO/γ-CD, based on differential scanning calorimetry and powder X-ray diffractometry results. Thus, we propose that the PSE/γ-CD particle has a capsule-like structure wherein a hydrophobic PSE droplet is surrounded by an outer layer of the hydrophilic PSE/γ-CD inclusion complex.

Objectives Solid dispersion using Eudragit E PO (EPO) improves the dissolution of poorly water-soluble drugs in acidic solutions; however, the dissolution extremely decreases in neutral solutions. In this report, ternary solid dispersions containing probucol (PBC), EPO, and saccharin (SAC) were prepared to enable high drug dissolution at neutral pH. Methods Cryogenic-grinding was used to obtain ternary solid dispersions. Dissolution tests at neutral pH values were conducted to confirm the usefulness of the cryogenic-ground mixture (cryo-GM). The molecular state of each component and intermolecular interactions in the ternary cryo-GM were evaluated using powder X-ray diffraction (PXRD) and C-13 solid-state NMR including spin-lattice relaxation time evaluation. Key findings PBC dispersed in ternary cryo-GM had an improved dissolution in neutral solutions. PBC and SAC were in amorphous states in EPO polymer matrices. The weak hydrophobic interaction between PBC and EPO and the ionic bond or hydrogen bond between EPO and SAC were demonstrated. These two molecular interactions improved the dissolution of PBC in neutral solutions. Conclusion Preparation of ternary solid dispersion is a potential method of improving drug solubility and absorption.

A comprehensive study of the encapsulation and dissolution of the poorly water-soluble drug ibuprofen (IBU) using two types of organic nanotubes (ONT-1 and ONT-2) was conducted. ONT-1 and ONT-2 had similar inner and outer diameters, but these surfaces were functionalized with different groups. IBU was encapsulated by each ONT via solvent evaporation. The amount of IBU in the ONTs was 9.1 and 29.2 wt % for ONT-1 and ONT-2, respectively. Dissolution of IBU from ONT-1 was very rapid, while from ONT-2 it was slower after the initial burst release. One-dimensional (1D) H-1, C-13, and two-dimensional (2D) H-1-C-13 solid-state NMR measurements using fast magic-angle spinning (MAS) at a rate of 40 kHz revealed the molecular state of the encapsulated IBU in each ONT. Extremely mobile IBU was observed inside the hollow nanosapce of both ONT-1 and ONT-2 using C-13 MAS NMR with a single pulse (SP) method. Interestingly, C-13 cross-polarization (CP) MAS NMR demonstrated that IBU also existed on the outer surface of both ONTs. The encapsulation ratios of IBU inside the hollow nanospaces versus on the outer surfaces were calculated by waveform separation to be approximately 1:1 for ONT-1 and 2:1 for ONT-2. Changes in C-13 chemical shifts showed the intermolecular interactions between the carboxyl group of IBU and the amino group on the ONT-2 inner surface. The cationic ONT-2 could form the stronger electrostatic interactions with IBU in the hollow nanosapce than anionic ONT-1. On the other hand, 2D H-1-13C NMR indicated that the hydroxyl groups of the glucose unit on the outer surface of the ONTs interacted with the carboxyl group of IBU in both ONT-1 and ONT-2. The changes in peak shape and chemical shift of the ONT glucose group after IBU encapsulation were larger in ONT-2 than in ONT-1, indicating a stronger interaction between IBU and the outer surface of ONT-2. The smaller amount of IBU encapsulation and rapid IBU dissolution from ONT-1 could be due to the weak interactions both at the outer and inner surfaces. Meanwhile, the stronger interaction between IBU and the inner surface of ONT-2 could suppress IBU dissolution, although the IBU on the outer surface of ONT-2 was released soon after dispersal in water. This study demonstrates that the encapsulation amount and the dissolution rates of poorly water-soluble drugs, a class which makes up the majority of new drug candidates, can be controlled using the functional groups on the surfaces of ONTs by considering the host guest interactions.

The formation mechanism of drug nanoparticles was investigated using solid-state nuclear magnetic resonance (NMR) techniques for the efficient discovery of an optimized nanoparticle formulation. The cogrinding of nifedipine (NIF) with polymers, including hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP), and sodium dodecyl sulfate (SDS) was performed to prepare the NIF nanoparticle formulations. Then, solid-state NMR relaxometry was used for the nanometer-order characterization of NIF in the polymer matrix. Solid-state NMR measurements revealed that the crystal size of NIF was reduced to several tens of nanometers with amorphization of NIF by cogrinding with HPMC and SDS for 100 min. Similarly, the size of the NIF crystal was reduced to less than 90 nm in the 40 min ground mixture of NIF/PVP/SDS. Furthermore, 100 min grinding of NIF/PVP/SDS induced amorphization of almost all the NIF crystals followed by nanosizing. The hydrogen bond between NIF and PVP led to the efficient amorphization of NIF in the NIF/PVP/SDS system compared with NIF/HPMC/SDS system. The efficient nanosizing of the NIF crystal in the solid state, revealed by the solid-state NMR relaxation time measurements, enabled the formation of large amounts of NIF nanoparticles in water followed by the polymer dissolution. In contrast, excess amorphization of the NIF crystals failed to efficiently prepare the NIF nanoparticles. The solid-state characterization of the crystalline NIF revealed good correlation with the NIF nanoparticles formation during aqueous dispersion. Furthermore, the solid-state NMR measurements including relaxometry successfully elucidated the nanometer-order dispersion state of NIF in polymer matrix, leading to the discovery of optimized conditions for the preparation of suitable drug nanoparticles.

Chondroitin sulfate (CS) has been accepted as an ingredient in health foods for the treatment of symptoms related to arthritis and cartilage repair. However, CS is poorly absorbed through the gastrointestinal tract because of its high negative electric charges and molecular weight (MW). In this study, poly-ion complex (PIC) formation was found in aqueous solutions through electrostatic interaction between CS and polyamines - organic molecules having two or more primary amino groups ubiquitously distributed in natural products at high concentrations. Characteristic properties of various PICs generated by mixing CS and natural polyamines, including unusual polyamines, were studied based on the turbidity for PIC formation, the dynamic light scattering for the size of PIC particles, and ζ -potential measurements for the surface charges of PIC particles. The efficiency of PIC formation between CS and spermine increased in a CS MW-dependent manner, with 15 kDa CS being critical for the formation of PIC (particle size: 3.41 μm) having nearly neutral surface charge (ζ -potential: -0.80 mV). Comparatively, mixing tetrakis(3-aminopropyl)ammonium and 15 kDa of CS afforded significant levels of PIC (particle size: 0.42±0.16 μm) despite a strongly negative surface charge (-34.67±1.15 mV). Interestingly, the oral absorption efficiency of CS was greatly improved only when PIC possessing neutral surface charges was administered to mice. High formation efficiency and electrically neutral surface charge of PIC particles are important factors for oral CS bioavailability.

A novel type of spectrum, the one-dimensional power spectrum (1D-PS), was designed for the discrimination of adhesive packing tapes, i.e., kraft tapes. The 1D-PS offered complementary information to that provided by the improved two-dimensional PS (2D-PS), which was calculated using our previously established image processes combined with a two-dimensional fast Fourier transform (2D-FFT) to obtain information about the spatial periodicity within kraft tapes. The 1D-PS was calculated using a three-step image process: (i) the 2D-FFT was applied to 50 randomly selected areas in a transmitted light image; (ii) the obtained 2D-PSs were accumulated without applying a logarithmic transform; (iii) the wavenumber and the maximum intensity were plotted on the x-axis and y-axis, respectively. Through an intra-roll comparison, the 1D-PSs collected from single rolls showed similar profiles. In an inter-roll comparison, the 1D-PSs from 50 commercially available brand-name products were classified into 29 groups. The 1D-PSs contained other useful information than that provided by the improved 2D-PSs: they presented more peaks and absolute intensity with a wider range. The 1D-PSs enabled us to compare the spectra quickly and easily, owing to their unchanging profiles regardless of the orientation of the scanned images. A combined use of the 1D-PSs with the improved 2D-PSs-both spectrum types being convenient, rapid, non-destructive, and applicable to dirty and/or damaged samples-could further improve the identification of kraft tapes. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

© 2015 Published by Elsevier B.V. AbstractAmorphous solid dispersions of phenytoin (diphenylhydantoin: DPH) and glibenclamide (GBM) with Eudragit® S 100 (S100) were prepared by a spray-drying. At low drug loading ratios, DPH dissolved simultaneously with S100. However, at high drug loading ratios the DPH dissolution rates were significantly reduced in comparison with those of S100 because of the rapid crystallization of DPH during the dissolution test. All of the DPH molecules in the low drug loading spray-dried sample (SPD) intimately interacted with the S100 matrix. In the SPDs with high drug loadings, only some of the DPH molecules interacted with the S100 matrix, while the excess DPH formed DPH-rich domains. When these domains contacted the water during the dissolution test, the amorphous DPH were more easily transformed into a crystalline form. In contrast to the solid dispersion of DPH/S100, that of GBM/S100 showed the simultaneous dissolution independent of the drug loading ratio. GBM was retained in an amorphous state during the dissolution test even at high drug loadings, although GBM-rich domains were formed. The miscibility at the molecular level as well as the stability of the amorphous state of drug are crucial factors to enhance the drug dissolution rate by the simultaneous dissolution with the polymer.

Quantitative evaluation of drug supersaturation and nanoparticle formation was conducted using in situ evaluation techniques, including nuclear magnetic resonance (NMR) spectroscopy. We prepared a ternary complex of carbamazepine (CBZ) with hydroxypropyl methylcellulose (HPMC) and sodium dodecyl sulfate (SDS) to improve the drug concentration. Different preparation methods, including grinding and spray drying, were performed to prepare the ternary component products, ground mixture (GM) and spray-dried sample (SD), respectively. Although CBZ was completely amorphized in the ternary SD; CBZ was partially amorphized with the remaining CBZ crystals in the ternary GM. Aqueous dispersion of the ternary GM formed nanoparticles of around 150 nm, originating from the CBZ crystals in the ternary GM. In contrast, the ternary SD formed transparent solutions without a precipitate. The molecular-level evaluation using NMR measurements revealed that approximately half a dose of CBZ in the ternary GM dispersion was present as nanoparticles; however, CBZ in the ternary SD was completely dissolved in the aqueous solution. The characteristic difference between the solid states, followed by different preparation methods, induced different solution characteristics in the ternary GM and SD. The permeation study, using a dialysis membrane, showed that the CBZ concentration dissolved in the bulk water phase rapidly reduced in the ternary SD dispersion compared to the ternary GM dispersion; this demonstrated the advantage of ternary GM dispersion in the maintenance of CBZ supersaturation. Long-term maintenance of a supersaturated state of CBZ observed in the ternary GM dispersion rather than in the ternary SD dispersion was achieved by the inhibition of CBZ crystallization owing to the existence of CBZ nanoparticles in the ternary GM dispersion. Nanoparticle formation, combined with drug amorphization, could be a promising approach to improve drug concentrations. The detailed elucidation of solution characteristics using in situ evaluation techniques will lead to the formation of useful solid dispersion and nanoparticle formulations, resulting in improved drug absorption. (C) 2015 Elsevier B.V. All rights reserved.

In this study, we examined the stabilization mechanism of drug supersaturation by hypromellose (HPMC) and polyvinylpirrolidone (PVP). The poorly water-soluble drugs, phenytoin (diphenylhydantoin, DPH), and its synthesized derivatives monomethylphenytoin (MDPH) and dimethylphenytoin (DMDPH) were used. DPH supersaturation was efficiently maintained by both HPMC and PVP. HPMC maintained the supersaturation of MDPH and DMDPH in a similar manner to that of DPH, whereas the ability of PVP to maintain drug supersaturation increased as follows: DPH &gt; MDPH &gt; DMDPH. Caco-2 permeation studies and nuclear magnetic resonance measurements revealed that the permeability and molecular state of the drug in a HPMC solution barely changed. In fact, the solubilization of the drug into PVP changed its apparent permeability and molecular state. The drug solubilization efficiency by PVP was higher and followed the order: DPH &gt; MDPH &gt; DMDPH. The different drug solubilization efficiencies most likely result from the different strengths in the intermolecular interaction between the DPH derivatives and PVP. The difference in the stabilization mechanism of drug supersaturation by HPMC and PVP could determine whether the efficient maintenance of the drug supersaturation was dependent on the drug species. (c) 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2574-2582, 2015

The crystallization behavior of a pharmaceutical drug in nanoparticles was directly evaluated by atomic force microscopy (AFM) force curve measurements in aqueous solution. A ternary spray-dried sample (SPD) was prepared by spray drying the organic solvent containing probucol (PBC), hypromellose (HPMC), and sodium dodecyl sulfate (SDS). The amorphization of PBC in the ternary SPD was confirmed by powder X-ray diffraction (PXRD) and solid-state 13C NMR measurements. A nanosuspension containing quite small particles of 25 nm in size was successfully prepared immediately after dispersion of the ternary SPD into water. Furthermore, solution-state 1H NMR measurements revealed that a portion of HPMC coexisted with PBC as a mixed state in the freshly prepared nanosuspension particles. After storing the nanosuspension at 25 degrees C, a gradual increase in the size of the nanoparticles was observed, and the particle size changed to 93.9 nm after 7 days. AFM enabled the direct observation of the morphology and agglomeration behavior of the nanoparticles in water. Moreover, AFM force-distance curves were changed from (I) to (IV), depending on the storage period, as follows: (I) complete indentation within an applied force of 1 nN, (II) complete indentation with an applied force of 1-5 nN, (III) partial indentation with an applied force of 5 nN, and (IV) nearly no indentation with an applied force of 5 nN. This stiffness increase of the nanoparticles was attributed to gradual changes in the molecular state of PBC from the amorphous to the crystal state. Solid-state C-13 NMR measurements of the freeze-dried samples demonstrated the presence of metastable PBC Form II crystals in the stored nanosuspension, strongly supporting the AFM results.

The chemical stability of suplatast tosilate (ST) was evaluated under dry conditions at 60 degrees C, with a focus on the polymorphic forms and crystal uniformity. The intact alpha-form, namely alpha-C type crystals, was crystallized rapidly by adding isopropyl ether into an ethanolic solution of ST. The alpha-C type crystals exhibited low stability at 60 degrees C. In addition to the alpha-C type crystals, two types of alpha-form crystals with different uniformities, namely alpha-A and alpha-B type crystals, were prepared. The alpha-A type crystals were prepared by conversion from the eta-form in aqueous acetone, while the alpha-B type crystals were prepared by recrystallization from 2-propanol at a low supersaturation level. The stability of the alpha-form crystals was as follows: alpha-A &gt; alpha-B &gt; alpha-C. The uniformity of ST crystals was determined according to the newly developed high performance liquid chromatography (HPLC) method. The alpha-C type crystals exhibited inferior chemical stability due to unstable crystalline phases. They showed preferential enrichment and exhibited a unique optical resolution phenomenon. The observed unstable crystalline phases were produced during the crystallization process. alpha-A type crystals, which had high regularity, exhibited excellent stability. Overall, we prepared and evaluated the structures of alpha-form crystals with different uniformities. (C) 2015 Elsevier B.V. All rights reserved.

A variable-temperature H-1 NMR study was performed to investigate the effects of the molecular weight of poly(ethylene glycol) (PEG) in PEG-lipids and cholesterol addition to the lipid bilayer on PEG chain flexibility at the liposomal surface. PEG-lipids, i.e.,L-alpha-distearoylphosphatidylethanolamine (DSPE)-PEG, with PEG molecular weights of 750, 2000, and 5000 were modified to liposomes of ca. 100 nm. The 1H NMR peak of PEG in DSPE-PEG was overlapped by broad and sharp peaks, corresponding to rigid and flexible PEG components, respectively. When the PEG molecular weight was increased, the PEG peak became sharp, indicating that long-chain PEGs were more flexible on the liposome surface. The proportion of flexible components projecting into the water phase increased as the PEG chain length increased. Peak sharpening also occurred when the cholesterol content was increased from 0 to 30 mol%, demonstrating that cholesterol incorporation into the lipid bilayer enhanced the PEG chain flexibility. In addition, the PEG chain flexibility significantly increased when cholesterol was delocalized in the lipid bilayer at concentrations above 20 mol%. Lateral diffusion of the lipid with the presence of cholesterol in the lipid bilayer significantly affected the PEG chain flexibility. (C) 2015 Elsevier B.V. All rights reserved.

A nanosuspension of piroxicam (PXC) and poloxamer 407 (poloxamer) prepared by the wet milling method was directly evaluated at the molecular level from the viewpoint of both solution and solid phases. C-13 solution-state NMR measurements revealed a reduction in the concentration of dissolved poloxamer in the nanosuspension. Furthermore, the fraction of dissolved poly(ethylene oxide) (PRO) chain, which is the hydrophilic part of poloxamer, was higher than that of dissolved poly(propylene oxide) (PPO) chain, the hydrophobic part. C-13 suspended-state NMR and Raman spectroscopies detected both solid-state PXC and poloxamer involved in the nanoparticles. Interestingly, the coexistence of crystalline and amorphous PXC in the nanoparticle was demonstrated. The yellow color of the nanosuspension strongly supported the existence of amorphous PXC. Changes in the peak intensity depending on the contact time in the suspended-state NMR spectrum revealed that the PEO chain of poloxamer in the nanoparticle had higher mobility compared with the PPO chain. The PRO chain should project into the water phase and form the outer layer of the nanoparticles, whereas the PPO chain should face the inner side of the nanoparticles. Amorphous PXC could be stabilized by intermolecular interaction with the PPO chain near the surface of the nanoparticles, whereas crystalline PXC could form the inner core.

The maintenance mechanism of the supersaturated state of poorly water-soluble drugs, glibenclamide (GLB) and chlorthalidone (CLT), in hydroxypropyl methylcellulose acetate succinate (HPMC-AS) solution was investigated at a molecular level. HPMC-AS suppressed drug crystallization from supersaturated drug solution and maintained high supersaturated level of drugs with small amount of HPMC-AS for 24 h. However, the dissolution of crystalline GLB into HPMC-AS solution failed to produce supersaturated concentrations, although supersaturated concentrations were achieved by adding amorphous GLB to HPMC-AS solution. HPMC-AS did not improve drug dissolution and/or solubility but efficiently inhibited drug crystallization from supersaturated drug solutions. Such an inhibiting effect led to the long-term maintenance of the amorphous state of GLB in HPMC-AS solution. NMR measurements showed that HPMC-AS suppressed the molecular mobility of CLT depending on their supersaturation level. Highly supersaturated CLT in HPMC-AS solution formed a gel-like structure with HPMC-AS in which the molecular mobility of the CLT was strongly suppressed. The gel-like structure of HPMC-AS could inhibit the reorganization from drug prenuclear aggregates to the crystal nuclei and delay the formation of drug crystals. The prolongation subsequently led to the redissolution of the aggregated drugs in aqueous solution and formed the equilibrium state at the supersaturated drug concentration in HPMC-AS solution. The equilibrium state formation of supersaturated drugs by HPMC-AS should be an essential mechanism underlying the marked drug concentration improvement.

The purpose of this study was to characterize the non-aqueous nanosuspension of a hydrophilic drug prepared by bead milling for cutaneous application. Riboflavin was used as the model hydrophilic drug. The non-aqueous nanosuspensions were prepared by grinding riboflavin with zirconia beads using eight nonaqueous bases. The mean particle size of riboflavin in the suspensions ranged from 206 to 469 nm, as determined by the dynamic light scattering method. Among the well-dispersed samples, riboflavin nanosuspension prepared in oleic acid was selected for evaluation of the drug permeability through rat skin. The cumulative amount and permeation rate of riboflavin from the nanosuspension were approximately three times higher than those for unprocessed riboflavin in oleic acid. Fluorescence imaging of the riboflavin nanosuspension suggested improved penetration of riboflavin into the stratum corneum. Furthermore, the addition of polysorbate 65 or polyglyceryl-6 polyricinoleate to the nanosuspension prepared in oleic acid markedly improved the riboflavin dispersibility. These results show that the preparation of a nanosuspension in a non-aqueous base by bead milling is one of the simple methods to improve the skin permeability of hydrophilic drugs.

The equimolar complexation behavior of urea or thiourea with 2-alcoxybenzamides has been studied by theoretical calculations. Structural models for the calculation were constructed from the X-ray crystallographic structures of 2-methoxybenzamide (MB) crystal and 2-ethoxybenzamide (EB)-thiourea, MB-thiourea, and MB-urea equimolar cocrystals. Structural optimization for EB-urea equimolar cocrystal was performed by the density functional theory (DFT) method (B3LYP/6-31G** level) and the complexation energy was determined using the DFT with higher order basis set (6-31+G**). Energetic stabilization by the equimolar complexation was observed in the three equimolar complexes. The reason why the amide group of MB is out-of-plane in unprocessed MB crystals is well explained by the calculations. It was suggested that intermolecular hydrogen bonding increases in the out-of-plane structure of MB and that subsequently leads to stabilization in the crystal. The amide group of MB or EB was inplane by the complex formation with urea or thiourea. Finally, we predict the possibility of EB-urea equimolar complex formation in terms of the complexation energy.

The effects of drug-crystallization inhibitor in bile acid/lipid micelles solution on drug permeation was evaluated during the drug crystallization process. Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) was used as a drug-crystallization inhibitor, which efficiently suppressed dexamethasone (DEX) crystallization in a gastrointestinal fluid model containing sodium taurocholate (NaTC) and egg-phosphatidylcholine (egg-PC). Changes of molecular state of supersaturated DEX during the DEX crystallization process was monitored in real time using proton nuclear magnetic resonance (H-1 NMR). It revealed that DEX distribution to bulk water and micellar phases formed by NaTC and egg-PC was not changed during the DEX crystallization process even in the presence of HPMC-AS. DEX permeation during DEX crystallization was evaluated using dissolution/permeability system. The combination of crystallization inhibition by HPMC-AS and micellar encapsulation by NaTC and egg-PC led to considerably higher DEX concentrations and improvement of DEX permeation at the beginning of the DEX crystallization process. Crystallization inhibition by HPMC-AS can efficiently work even in the micellar solution, where NaTC/egg-PC micelles encapsulates some DEX. It was concluded that a crystallization inhibitor contributed to improvement of permeation of a poorly water-soluble drug in gastrointestinal fluid. (C) 2014 Elsevier B.V. All rights reserved.

Two polymorphic forms of a sulfathiazole (STZ):oxalic acid (OXA) 1:1 complex were successfully prepared by different cogrinding methods and characterized by multiple analytical techniques. Rod-milled and ball-milled ground mixtures had different powder X-ray diffraction patterns, showing polymorph formation of the STZ-OXA complex (complex A and complex B). The heat of fusion from differential scanning calorimetry curves and terahertz time-domain spectra helped differentiating the polymorphs. According to infrared spectra, C-13 NMR chemical shifts, and the relative intensities of N-15 NMR peaks, both polymorphs were salts where the proton of a -COOH group in OXA was transferred to a -NH2 group in STZ. High-resolution H-1 NMR and H-1-C-13 heteronuclear correlation NMR spectra indicated that complex B in powder form had a cocrystal type structure compared to complex A having a clathrate-type structure. Complex B structure suggested by solid-state NMR coincided well with the experimentally determined one, which was formed from three layers of thiazole rings, benzene rings, and OXAs, by using single-crystal X-ray diffraction (SC-XRD) measurement. Advanced solid-state NAIR spectroscopy measurements was useful to elucidate the structure of a polymorph, for which SC-XRD data are not available, by referring to the SC-XRD data of another polymorph.

Hydrocortisone (HC), a poorly water-soluble drug, was encapsulated within organic nanotubes (ONTs), which were formed via the self-assembly of N-{12-[(2-alpha,beta-D-glucopyranosyl) carbamoyl] dodecanyl}glycylglycylglycine acid. The stability of the ONTs was evaluated in ten organic solvents, of differing polarities, by field emission transmission electron microscopy. The ONTs maintained their stable tubular structure in the highly polar solvents, such as ethanol and acetone. Furthermore, solution-state H-1-NMR spectroscopy confirmed that they were practically insoluble in acetone at 25 degrees C (0.015 mg/mL). HC-loaded ONTs were prepared by solvent evaporation using acetone. A sample with a 3/7 weight ratio of HC/ONT was analyzed by powder X-ray diffraction, which confirmed the presence of a halo pattern and the absence of any crystalline HC peak. HC peak broadening, observed by solid-state C-13-NMR measurements of the evaporated sample, indicated the absence of HC crystals. These results indicated that HC was successfully encapsulated in ONT as an amorphous state. Improvements of the HC dissolution rate were clearly observed in aqueous media at both pH 1.2 and 6.8, probably due to HC amorphization in the ONTs. Phenytoin, another poorly water-soluble drug, also showed significant dissolution improvement upon ONT encapsulation. Therefore, ONTs can serve as an alternative pharmaceutical excipient to enhance the bioavailability of poorly water-soluble drugs. (C) 2014 Elsevier B.V. All rights reserved.

Eleven guest drugs with planar structures were incorporated into the intermolecular spaces between polyethylene glycol/γ-cyclodextrin (γ-CD)-polypseudorotaxanes by a sealed-heating method. Drug incorporation changed the crystal packing of γ-CD from hexagonal- to monoclinic-columnar forms, without dependence on the guest species. The incorporation of guest drugs was size dependent and stoichiometric. Guest drugs with one benzene ring and maximum cross sectional areas of ca. 40-55 Å2exhibited a drug to γ-CD stoichiometry of 2:1. Meanwhile, the stoichiometry was 1:1 for drugs with 2-3 benzene rings and maximum cross sectional areas of ca. 60-75 Å2. More sterically bulky drugs (four and five benzene rings) did form complexes, though the complexation efficiency was insufficient to form stoichiometric complexes, due to steric hindrance. The volume of intermolecular space of the host was estimated to be larger than that of a β-CD cavity and as large as that of a γ-CD cavity. Hydrophobic and van der Waals interactions worked as driving forces for the complexation because polycyclic aromatic hydrocarbons with high log P values formed the complex. The dissolution property of the hydrophobic pharmaceutical drug naproxen was clearly improved by the complexation because naproxen existed in a monomolecular state in the complex. © 2014 American Chemical Society.

The inhibitory effect on drug crystallization in aqueous solution was evaluated using various forms of hydroxypropyl methylcellulose acetate succinate (HPMCAS). HPMCAS suppressed crystallization of carbamazepine (CBZ), nifedipine (NIF), mefenamic acid, and dexamethasone. The inhibition of drug crystallization mainly derived from molecular level hydrophobic interactions between the drug and HPMCAS. HPMCAS with a lower succinoyl substituent ratio strongly suppressed drug crystallization. The inhibition of crystallization was affected by pH, with the CBZ crystallization being inhibited at a higher pH due to the hydrophilization of HPMCAS derived from succinoyl ionization. The molecular mobility of CBZ in an HPMCAS solution was evaluated by 1D-H-1 NMR and relaxation time measurements. CBZ mobility was strongly suppressed in the HPMCAS solutions where strong inhibitory effects on CBZ crystallization were observed. The mobility suppression of CBZ in the HPMCAS solution was derived from intermolecular interactions between CBZ and HPMCAS leading to an inhibition of crystallization. The effect of HPMCAS on the drug dissolution rate was evaluated using an NIF/HPMCAS solid dispersion. The dissolution rate of NIF was increased when HPMCAS with a higher succinoyl substituent ratio was used. (C) 2014 Elsevier B.V. All rights reserved.

We investigated the drug solubilization mechanism of α-glucosyl stevia (Stevia-G) which was synthesized from stevia (rebaudioside-A) by transglycosylation.1H and13C NMR peaks of Stevia-G in water were assigned by two-dimensional (2D) NMR experiments including1H-1H correlation,1H-13C heteronuclear multiple bond correlation, and1H-13C heteronuclear multiple quantum coherence spectroscopies. The1H and13C peaks clearly showed the incorporation of two glucose units into rebaudioside-A to produce Stevia-G, supported by steviol glycoside and glucosyl residue assays. The concentration-dependent chemical shifts of Stevia-G protons correlated well with a mass-action law model, indicating the self-association of Stevia-G molecules in water. The critical micelle concentration (CMC) was 12.0 mg/mL at 37 °C. The aggregation number was 2 below the CMC and 12 above the CMC. Dynamic light scattering and 2D1H-1H nuclear Overhauser effect spectroscopy (NOESY) NMR experiments demonstrated that Stevia-G self-associated into micelles of a few nanometers in size with a core-shell structure, containing a kaurane diterpenoid-based hydrophobic core and a glucose-based shell. 2D1H-1H NOESY NMR measurements also revealed that a poorly water-soluble drug, naringenin, was incorporated into the hydrophobic core of the Stevia-G micelle. The Stevia-G self-assembly behavior and micellar drug inclusion capacity can achieve significant enhancement in drug solubility. © 2014 Elsevier B.V. All rights reserved.

The aim of this study was to confirm whether light anhydrous silicic acid (Aerosil) could exhibit a stabilizing effect on the physical stability of solid dispersion under humidified conditions. Ternary solid dispersions consist of 50% troglitazone, and various ratios of polyvinyl pyrrolidone and Aerosil were prepared using the co-milling method and then evaluated for their crystallizing behavior under storage conditions. The results showed that Aerosil has a stabilizing effect against crystallizing in the dihydrate of troglitazone under humidified conditions and has an appropriate ratio range (Troglitazone/PVP/Aerosil = 50/30-20/20-30) in the ternary solid dispersion, when considering total quality satisfaction such as physical stability and dissolution. Furthermore, it was found that hydrophobized Aerosil R805 has a stronger stabilizing effect than hydrophilic Aerosil 200. The stabilizing mechanism was discussed based on the comparative results and possible molecular interaction. (C) 2013 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved.

Molecular networks based on noncovalent bonds have resonant frequencies in the terahertz (THz) region. THz spectroscopy is a powerful tool for identifying molecular bonds, such as intermolecular or intramolecular hydrogen bonds, in pharmaceuticals. A THz chemical imaging (TCI) system was developed by combining a THz time-domain spectrometer with a translational stage to obtain two-dimensional distributions of molecular networks in tablet samples Since THz spectral peaks of pharmaceuticals are broad at room temperature, multicomponent chemical analysis with the TCI system has some limitations. In this paper, we describe multicomponent,chemical analysis of pharmaceuticals using a sample chamber cooled, by a cryostat. TCI measurement at low temperature sharpens spectral peaks and/or shifts peak frequencies, enabling us to determine the distribution of several kinds of pharmaceuticals in a tablet. The TCI system provides THz images of polymorphic form distribution of famotidine binding with D-mannitol in an over-the-counter pharmaceutical tablet. Furthermore, the molecular mechanics method was used to determine the vibrational modes of the peaks in the spectra of famotidine polymorphic forms. (C) The Author(s) 2014. Published by ECS. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 License (CC BY, http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse of the work in any medium, provided the original work is properly cited. All rights reserved.

The intermolecular interaction between mefenamic acid (MFA), a poorly water-soluble nonsteroidal anti-inflammatory drug, and Eudragit EPO (EPO), a water-soluble polymer, is investigated in their supersaturated solution using high-resolution magic-angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy. The stable supersaturated solution with a high MFA concentration of 3.0 mg/mL is prepared by dispersing the amorphous solid dispersion into a d-acetate buffer at pH 5.5 and 37 degrees C. By virtue of MAS at 2.7 kHz, the extremely broad and unresolved H-1 resonances of MFA in one-dimensional H-1 NMR spectrum of the supersaturated solution are well-resolved, thus enabling the complete assignment of MFA H-1 resonances in the aqueous solution. Two-dimensional (2D) H-1/H-1 nuclear Overhauser effect spectroscopy (NOESY) and radio frequency-driven recoupling (RFDR) under MAS conditions reveal the interaction of MFA with EPO in the supersaturated solution at an atomic level. The strong cross-correlations observed in the 2D H-1/H-1 NMR spectra indicate a hydrophobic interaction between the aromatic group of MFA and the backbone of EPO. Furthermore, the aminoalkyl group in the side chain of EPO forms a hydrophilic interaction, which can be either electrostatic or hydrogen bonding, with the carboxyl group of MFA. We believe these hydrophobic and hydrophilic interactions between MFA and EPO molecules play a key role in the formation of this extremely stable supersaturated solution. In addition, 2D H-1/H-1 RFDR demonstrates that the molecular MFA-EPO interaction is quite flexible and dynamic.