植田 圭祐

We aimed to elucidate the dissolution mechanism of solid dispersions (SDs) according to the carrier polymers used. Nifedipine (NIF) and polymers dissolved simultaneously from NIF/Eudragit® S (EUD-S), NIF/Eudragit® L (EUD-L), and NIF/hypromellose (HPMC)/EUD-S spray-dried samples (SPDs). In contrast, NIF dissolved separately from polymers from NIF/HPMC and NIF/HPMC/EUD-L SPDs due to the formation of an amorphous NIF-rich interface. Solid-state NMR spectroscopy indicated that NIF-EUD interactions were stronger than NIF-HPMC interactions. NIF/HPMC SPD exhibited weak interactions thus, it failed to inhibit phase separation during the dissolution process and control NIF dissolution. The hygroscopicity of SPDs was higher with HPMC mixing and increased substitution ratio of methacrylic acid in EUD. Moreover, solid-state NMR spectroscopy revealed that the NIF-EUD interactions were hindered to a large extent by the absorbed water. During the dissolution process of NIF/HPMC/EUD-L SPD, the introduction of water to the NIF-EUD-L interaction site could induce the phase separation and poor controllability of NIF dissolution. Water-induced phase separation should be considered based on molecular-level characterization to obtain SDs with enhanced drug dissolution. An investigation of the molecular state change caused by the absorbed water using solid-state NMR spectroscopy will be helpful in understanding the dissolution mechanism of SDs.

Mycophenolic acid (MPA), an immunosuppressant drug, possesses antimicrobial, anticancer, and antipsoriatic activities. However, the use of MPA in therapeutic applications is limited to its poor oral bioavailability, low aqueous solubility, and undesired gastrointestinal side effects. Polymeric micelles are a drug delivery system that has been used to enhance the water solubility of pharmaceuticals. In this work, poloxamer 407 (P407) and MPA were conjugated via an ester linkage resulting in a P407-MPA conjugate. The P407-MPA conjugate was investigated for micellization, particle size, size distribution, MPA release in phosphate buffer (pH 7.4) and human plasma, and antipsoriatic activity. 1H-nuclear magnetic resonance suggested that polymeric micelles formed from the P407-MPA conjugate exposed its polyethylene oxide chain to the aqueous environment while restricting the conjugated MPA within the inner core. The P407-MPA conjugate has an improved micellization property with the over 12-fold lower critical micelle concentration compared to P407. The conjugate exhibited an enzyme-dependent sustained-release property in human plasma. Finally, the conjugate exhibited an improved antiproliferation activity in tumor necrosis factor-α-induced HaCaT cells, which is an in vitro psoriasis model. Therefore, the prepared P407-MPA conjugate, with an improved aqueous solubility and biological activity of MPA, has the potential to be further developed for psoriasis treatment.

In the present study, the molecular state of drug-rich amorphous nanodroplets was evaluated using NMR techniques to reveal the mechanism underlying the crystallization inhibition of drug-rich amorphous nanodroplets by a polymer. Ibuprofen (IBP) with a low glass transition temperature was used for direct characterization of drug-rich amorphous nanodroplets. Highly supersaturated IBP formed IBP-rich amorphous nanodroplets through phase separation from aqueous solution. Increasing the concentration of hypromellose (HPMC) in the aqueous solution contributed to the inhibition of IBP crystallization and maintenance of supersaturation at IBP amorphous solubility. Solution 1H NMR measurements of IBP supersaturated solution containing IBP-rich amorphous nanodroplets clearly showed two kinds of 1H peaks derived from the dissolved IBP in bulk water phase and phase-separated IBP in IBP-rich amorphous nanodroplets. NMR spectral analysis indicated that HPMC did not affect the chemical environment and mobility of the dissolved IBP. However, 1H spin-spin relaxation time measurements clarified that the dissolved IBP in the bulk water phase was exchanged with the IBP-rich amorphous nanodroplets with an exchange lifetime of more than 10 ms. Moreover, the 1H peaks of HPMC partially disappeared due to the formation of IBP-rich amorphous nanodroplets, suggesting that a part of HPMC distributed into the IBP-rich amorphous nanodroplets from the bulk water phase. The incorporation of HPMC significantly changed the chemical environment of the phase-separated IBP in the IBP-rich amorphous nanodroplets and strongly suppressed molecular mobility. The resulting molecular mobility suppression effectively inhibited IBP crystallization from the IBP-rich amorphous nanodroplets. Thus, direct investigation of drug-rich amorphous nanodroplets using NMR can be a promising approach for selecting appropriate pharmaceutical excipients to suppress drug crystallization in supersaturated drug solutions.

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.

The present study evaluated the specific intermolecular interactions between carbamazepine (CBZ) and substituents of hypromellose acetate succinate (HPMC-AS), as well as the mechanism of inhibition of recrystallization of solid dispersions (SDs) using Fourier-transform infrared (FTIR) and solid-state nuclear magnetic resonance (NMR) spectroscopy. CBZ and HPMC derivatives, including HPMC, hypromellose acetate (HPMC-A), and hypromellose succinate (HPMC-S), were spray-dried to prepare CBZ/polymer spray-dried samples (SPDs). CBZ/HPMC SPD and CBZ/HPMC-A SPD recrystallized within 10 days at 60 °C and 0% relative humidity, whereas CBZ/HPMC-S SPD maintained its amorphous state for a longer period. FTIR and solid-state NMR measurements using 13C cross polarization (CP), 1H single-pulse, and 1H-15N CP-based heteronuclear single quantum correlation filter experiment with very fast magic angle spinning (MAS) at 70 kHz identified molecular interactions in CBZ/polymer SPDs. Although the HPMC backbone and substituents did not interact notably with CBZ and disrupt CBZ-CBZ intermolecular interactions (formed in the amorphous CBZ), acetate and succinate substituents on HPMC-A and HPMC-S disrupted CBZ-CBZ intermolecular interactions through formation of CBZ/polymer interactions. The acetate substituent formed a hydrogen bond with the NH2 group of CBZ, whereas the succinate substituent formed molecular interactions with both the C═O and NH2 groups of CBZ. Formation of relatively strong molecular interactions between CBZ and the succinate substituent followed by disruption of CBZ-CBZ intermolecular interactions effectively stabilized the amorphous state of CBZ in CBZ/HPMC-S SPD. The correlation between CBZ-polymer interactions and ability of polymers to effectively inhibit CBZ recrystallization is reflected in various commercial HPMC-AS. For example, HPMC-AS LF grade, containing higher amounts of the succinate group, was found to effectively inhibit the recrystallization of CBZ through strong molecular interactions as compared with the HPMC-AS HF grade. The present study demonstrated that a detailed investigation of molecular interactions between the drug and the polymer using FTIR and solid-state NMR spectroscopy could contribute to a suitable selection of the SD carrier.

We investigated the effect of variation in the molecular weight of hypromellose (HPMC) on the oral absorption of fenofibrate (FFB) nanocrystal. Four types of HPMC with different molecular weights and sodium dodecyl sulfate (SDS) were used as dispersion stabilizers for FFB nanocrystal suspension. Wet-milling of FFB crystal with HPMC and SDS formed diamond-shaped FFB nanocrystals with approximately 150 nm diameter. HPMC was strongly adsorbed onto the FFB nanocrystal interface, and the amount of HPMC adsorbed was not dependent on the molecular weight of HPMC. However, the decrease in the molecular weight of adsorbed HPMC led to an improvement in the permeability of FFB nanocrystal through the mucin layer. The decrease in molecular weight of HPMC enhanced the flexibility of FFB nanocrystal interface and effectively inhibited its interaction with mucin. This led to faster diffusion of FFB nanocrystal through mucin. In vivo oral absorption studies showed rapid FFB absorption from FFB nanocrystal formulations using HPMC of low molecular weights. The present study revealed that the molecular weight of the dispersion stabilizer for drug nanocrystal formulation should be taken into consideration to achieve improved absorption of poorly water-soluble drugs after oral administration.

In this study, the time-dependent evolution of amorphous probucol nanoparticles was characterized by cryogenic transmission electron microscopy (cryo-TEM) and atomic force microscopy (AFM). The nanoparticles were formed by dispersing ternary solid dispersions of probucol in water. Spray drying and cogrinding were used to prepare a spray-dried sample (SPD) and two ground-mixture samples (GM(I) and GM(II)) of probucol (PBC) form I and form II/hypromellose/sodium dodecyl sulfate ternary solid dispersions. The amorphization of PBC in the SPDs and GMs was confirmed using powder X-ray diffraction (PXRD) and solid-state 13C nuclear magnetic resonance (NMR) spectroscopy. Additionally, differential scanning calorimetry showed that relatively small amounts of PBC nuclei or PBC-rich domains remained in both GMs. Then, the physical stability of drug nanoparticles formed after aqueous dispersion in the SPD and GM suspensions during storage at 40 °C was characterized. Cryogenic transmission electron microscopy was used to monitor the evolution of the amorphous PBC nanoparticles in the SPD and GM suspensions during storage. Spherical nanoparticles smaller than 30 nm were observed in all of the suspensions just after dispersion. The size of the particles in the SPD suspension gradually increased but remained on the order of nanometers and retained their spherical shape during storage. In contrast, both GM suspensions evolved through three morphologies, spherical nanoparticles that gradually increased in size, needle-like nanocrystals, and micrometer-sized crystals with various shapes. The evolution of the nanoparticles suggested that their stability in the GM suspension was lower than in the SPD suspension. PXRD analysis of the freeze-dried suspensions of the particles showed that the PBC in the nanoparticles of the SPD suspension was in the amorphous state just after dispersion, while a small fraction of the PBC in the nanoparticles of the GM suspension exhibited a crystal phase and selectively crystallized to its initial crystal form during storage. AFM force-distance curves also demonstrated the existence of crystal phase PBC in the spherical nanoparticles in the GM suspension just after dispersion. The molecular state of PBC in the ternary solid dispersion was dependent on the preparation method (either completely amorphized or incompletely amorphized with residual nuclei or drug-rich domains) and determined the potential mechanisms of PBC nanoparticle evolution after aqueous dispersion. These findings confirm the importance of the molecular state on the particle evolution and the physical stability of the drug nanoparticles in the suspension. Cryo-TEM and AFM measurements provide more direct insight for designing solid dispersion formulations to produce stable amorphous drug nanosuspensions that efficiently improve the solubility and bioavailability of poorly water-soluble drugs.

Drug-rich amorphous nanodroplets have great potential to improve intestinal absorption of poorly water-soluble drugs. Spray-dried samples (SPDs) of glibenclamide (GLB) with hypromellose (HPMC) or hypromellose acetate succinate (HPMC-AS, grade AS-LF and AS-HF) were prepared to investigate how GLB-rich amorphous nanodroplets form during the dissolution of solid dispersions. The co-spray drying of AS-LF significantly enhanced GLB dissolution from the SPD, leading to the temporary formation of GLB-rich amorphous nanodroplets. However, the droplets gradually coarsened as AS-LF fails to inhibit coarsening. In contrast, the addition of HPMC to the SPD failed to aid GLB-rich amorphous nanodroplet formation during dissolution. The failure of formation of GLB-rich amorphous nanodroplet was caused by slow GLB dissolution, due to the poor controllability of the GLB dissolution by HPMC. The addition of AS-HF to the SPD produced amorphous GLB particles that contained a large amount of AS-HF during dissolution. Gel-like particles formed instead of GLB-rich amorphous nanodroplets. When the SPD containing AS-LF was dissolved in AS-HF solution, stably-dispersed GLB-rich amorphous nanodroplets were successfully formed owing to rapid GLB dissolution from the SPD containing AS-LF and strong coarsening inhibition by AS-HF. Formulation optimization considering both aqueous dissolution of the solid dispersion and the inhibition of nanodroplet coarsening achieved stably-dispersed drug-rich amorphous nanodroplets.

Copyright © 2018 American Chemical Society. 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, the13C-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>

© 2018 Elsevier Inc. Cytoplasmic DNA triggers cellular immunity via activating the stimulator of interferon genes pathway. Since DNA is degradable and membrane impermeable, delivery system would permit cytoplasmic delivery by destabilizing the endosomal membrane for the use as an adjuvant. Herein, we report on the development of a plasmid DNA (pDNA)-encapsulating lipid nanoparticle (LNP). The structural components include an SS-cleavable and pH-activated lipid-like material that mounts vitamin E as a hydrophobic scaffold, and dual sensing motifs that are responsive to the intracellular environment (ssPalmE). The pDNA-encapsulating LNP (ssPalmE-LNP) induced a high interferon-β production in Raw 264.7 cells. The subcutaneous injection of ssPalmE-LNP strongly enhanced antigen-specific cytotoxic T cell activity. The ssPalmE-LNP treatment efficiently induced antitumor effects against E.G7-OVA tumor and B16-F10 melanoma metastasis. Furthermore, when combined with an anti-programmed death 1 antibody, an extensive therapeutic antitumor effect was observed. Therefore, the ssPalmE-LNP is a promising carrier of adjuvants for cancer immunotherapy.

© 2018 The Pharmaceutical Society of Japan. 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.

難水溶性薬物の経口吸収性を改善する目的で、固体分散体を用いた薬物の溶解性改善が20世紀後半から検討されてきた。薬物の溶解性改善が必ずしも吸収性改善に結びつかないケースも存在することから、製剤からの薬物溶出挙動及び溶解状態を考慮した製剤設計が重要である。本稿では、固体分散体からの薬物溶出挙動および薬物の溶解状態に焦点をあて、添加剤の種類及び組成が薬物溶出に及ぼす影響について検討した結果を紹介する。(著者抄録)

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.

© 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.

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.

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.

Liposomal formulations of an anticancer drug, doxorubicin (DOX), which are on the market as the trade name of Doxil®, can reduce toxic side effects and improve drug accumulation at tumor tissues. Fibrous DOX bundles are precipitated in the inner water phase of liposomes, resulting in the elongation of the liposomes [1]. In this study, changes of three-dimensional morphology of DOX-loaded liposomes with the size of ca. 100 nm were investigated by atomic force microscopy (AFM) in an aqueous environment. The liposomes were sphere when the DOX loading amount was less than 10 mol% against total lipid concentration (Fig. 1A). At the DOX loading amount more than 20 mol%, the prolate liposomes were observed due to linearly expansion of DOX fiber bundles inside liposomes (Fig. 1B). The curved DOX fiber bundles were formed along the rim of lipid bilayer with further enhanced DOX concentration to give the oblate liposomes (Fig. 1C). It was also found that the replacement of outer phase from sucrose solution to H2O induced the water influx inside liposomes and changed the morphology of prolate and oblate liposomes into spherical ones. All spherical liposomes transformed into oblate ones with return to isotonic condition, from H2O to sucrose solution.

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 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 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.

難水溶性薬物の溶解性を改善する目的で、各種ポリマーを添加剤として用いた製剤処方検討が多数行われている。ポリマーによる薬物溶解性改善機構は、用いるポリマーの種類により異なり、それが薬物の膜透過性・吸収性に影響する。各種ポリマーによる薬物溶解性改善機構を分子レベルで明らかにすることで、ポリマー溶液からの薬物吸収性を予測することができ、これにより固体分散体をはじめとする固形製剤の設計をより効率的に進めることが可能である。本稿では、ポリマー溶液中の薬物分子状態を核磁気共鳴(NMR)法により評価した。そして、NMR法により推察された各ポリマーによる薬物溶解性改善機構と、薬物膜透過性との関連を考察した。(著者抄録)

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.

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.

We examined the inhibitory effect of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) on drug recrystallization from a supersaturated solution using carbamazepine (CBZ) and phenytoin (PHT) as model drugs. HPMC-AS HF grade (HF) inhibited the recrystallization of CBZ more strongly than that by HPMC-AS LF grade (LF). 1D-H-1 NMR measurements showed that the molecular mobility of CBZ was clearly suppressed in the HF solution compared to that in the LF solution. Interaction between CBZ and HF in a supersaturated solution was directly detected using nuclear Overhauser effect spectroscopy (NOESY). The cross-peak intensity obtained using NOESY of HF protons with CBZ aromatic protons was greater than that with the amide proton, which indicated that CBZ had hydrophobic interactions with HF in a supersaturated solution. In contrast, no interaction was observed between CBZ and LF in the LF solution. Saturation transfer difference NMR measurement was used to determine the interaction sites between CBZ and HF. Strong interaction with CBZ was observed with the acetyl substituent of HPMC-AS although the interaction with the succinoyl substituent was quite small. The acetyl groups played an important role in the hydrophobic interaction between HF and CBZ. In addition, HF appeared to be more hydrophobic than LF because of the smaller ratio of the succinoyl substituent. This might be responsible for the strong hydrophobic interaction between HF and CBZ. The intermolecular interactions between CBZ and HPMC-AS shown by using NMR spectroscopy clearly explained the strength of inhibition of HPMC-AS on drug recrystallization.

Nano-formulation of poorly water-soluble drugs has been developed to enhance drug dissolution. In this review, we introduce nano-milling technology described in recently published papers. Factors affecting the size of drug crystals are compared based on the preparation methods and drug and excipient types. A top-down approach using the comminution process is a method conventionally used to prepare crystalline drug nanoparticles. Wet milling using media is well studied and several wet-milled drug formulations are now on the market. Several trials on drug nanosuspension preparation using different apparatuses, materials, and conditions have been reported. Wet milling using a high-pressure homogenizer is another alternative to preparing production-scale drug nanosuspensions. Dry milling is a simple method of preparing a solid-state drug nano-formulation. The effect of size on the dissolution of a drug from nanoparticles is an area of fundamental research, but it is sometimes incorrectly evaluated. Here, we discuss evaluation procedures and the associated problems. Lastly, the importance of quality control, process optimization, and physicochemical characterization are briefly discussed. © 2013 Bentham Science Publishers.

A solid dispersion (SPD) of carbamazepine (CBZ) with hydroxypropyl methylcellulose acetate succinate (HPMC-AS) was prepared by the spray drying method. The apparent solubility (37 degrees C, pH 7.4) of CBZ observed with the SPD was over 3 times higher than the solubility of unprocessed CBZ. The supersaturated solution was stable for 7 days. A higher concentration of CBZ in aqueous medium was also achieved by mixing with Poloxamer 407 (P407), a solubilizing agent. From permeation studies of CBZ using Caco-2 monolayers and dialysis membranes, we observed improved CBZ permeation across the membrane in the supersaturated solution of CBZ/HPMC-AS SPD. On the contrary, the CBZ-solubilized P407 solution exhibited poor permeation by CBZ. The chemical shifts of CBZ on the H-1 NMR spectrum from CBZ/HPMC-AS SPD solution were not altered significantly by coexistence with HPMC-AS. In contrast, an upfield shift of CBZ was observed in the CBZ/P407 solution. The spin-lattice relaxation time (T-1) over spin-spin relaxation time (T-2) indicated that the mobility of CBZ in the HPMC-AS solution was much lower than that in water. Meanwhile, the mobility of CBZ in P407 solution was significantly higher than that in water. NMR data indicate that CBZ does not strongly interact with HPMC-AS. CBZ mobility was suppressed due to self-association and microviscosity around CBZ, which do not affect permeation behavior. Most of the CBZ molecules in the CBZ/P407 solution were solubilized in the hydrophobic core of P407, and a few were free to permeate the membrane. The molecular state of CBZ, as evaluated by NMR measurements, directly correlated with permeation behavior.