東 顕二郎

Polymeric micelles are invaluable media as drug nanocarriers. Although knowledge of an interaction between the micelles is a key to understanding the mechanisms and developing the superior functions, the interaction potential surface between drug-incorporated polymeric micelles has not yet been quantitatively evaluated due to the extremely complex structure. Here, the interaction potential surface between drug-entrapped polymeric micelles was unveiled by combining a small-angle scattering experiment and a model-potential-free liquid-state theory. Triblock copolymer composed of poly(ethylene oxide) and poly(propylene oxide) was investigated over a wide concentration range (0.5-10.0 wt %). Effects of the entrapment of a water-insoluble hydrophobic drug, cyclosporin A, on the interaction were explored by comparing the interactions with and without the drug. The results directly clarified the high drug carrier efficiency in terms of the interaction between the micelles. In addition, an investigation based on density functional theory provided a deeper insight into the monomer contribution to the extremely stable dispersion of the nanocarrier.

70-90% of recently developed new drug candidates are poorly soluble in water, which creates a series of thorny challenges in developing its oral dosage forms, resulting in low bioavailability. In pre-formulation study, various specialized formulations have been developed to improve drug solubility. Intermolecular interactions between drug and excipients in the formulations can modify the drug state and achieve the improvement of drug solubility. Therefore, the understanding of intermolecular interaction is essential to design formulations with higher quality and to assure the quality as a pharmaceutical product. Solid-state NMR has attracted much attention as a promising method to evaluate the molecular state of a drug and the interaction between a drug and excipient in its formulation. I have applied solid-state NMR and its characteristic technique, namely magic-angle spinning (MAS), for various specialized formulations including amorphous solid dispersion, supersaturated solution, drug-loaded organic nanotube, and drug nanosuspension. The intermolecular interactions of drug and excipient in amorphous solid dispersion have been identified by 13C and 15N solid-state NMR. High-resolution MAS determined the interaction modes of drug and excipient in a supersaturated solution. The two-step dissolution profile of drug from organic nanotube was understood, based on the molecular states revealed by the combination of various solid-state NMR techniques. A suspended-state NMR clarified the nanostructure of drug nanoparticles dispersed in water. It is expected that more qualified pharmaceutical formulations with improved drug solubility can be designed based on the remarkable development of recent solid-state NMR technology.

We studied optimized conditions for preparing ternary hot extrudates (HEs) of glibenclamide (GLB)/polyvinylpyrrolidone (PVP)/sodium dodecyl sulfate to generate stable nanocrystal suspensions following aqueous dispersion. Raman and solid-state NMR measurements of ternary HEs prepared by altering HE conditions revealed that GLB crystallinity in HEs reduced with increased extrusion temperature and count and decreased screw speed. Aqueous dispersions of all HEs temporarily formed GLB nanoparticles with a diameter of 75-420 nm. The suspension from the HEs with the low GLB crystallinity (<22%) precipitated after 4-h storage, while the HEs with the high GLB crystallinity (>22%) formed stable nanocrystal suspension. Interestingly, the number of GLB nanoparticles <150  nm was different despite aqueous dispersion of HEs with similar GLB crystallinity, reflecting the different GLB crystalline size in those HEs. Although both the crushing by shear force and GLB dissolution into PVP reduced GLB crystalline size, the crushing GLB crystal by the shear force has a relatively high ability to decrease GLB crystalline size without excess amorphization of GLB. Performing the hot extrusion at a low temperature, a high screw speed, and maximizing extrusion count with GLB crystallinity >22% led to formation of small and stable nanocrystal suspensions.

© 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim RNA-based therapeutics is a promising approach for curing intractable diseases by manipulating various cellular functions. For eliciting RNA (i.e., mRNA and siRNA) functions successfully, the RNA in the extracellular space must be protected and it must be delivered to the cytoplasm. In this study, the development of a self-degradable lipid-like material that functions to accelerate the collapse of lipid nanoparticles (LNPs) and the release of RNA into cytoplasm is reported. The self-degradability is based on a unique reaction “Hydrolysis accelerated by intra-Particle Enrichment of Reactant (HyPER).” In this reaction, a disulfide bond and a phenyl ester are essential structural components: concentrated hydrophobic thiols that are produced by the cleavage of the disulfide bonds in the LNPs drive an intraparticle nucleophilic attack to the phenyl ester linker, which results in further degradation. An oleic acid-scaffold lipid-like material that mounts all of these units (ssPalmO-Phe) shows superior transfection efficiency to nondegradable or conventional materials. The insertion of the aromatic ring is unexpectedly revealed to contribute to the enhancement of endosomal escape. Since the intracellular trafficking is a sequential process that includes cellular uptake, endosomal escape, the release of mRNA, and translation, the improvement in each process synergistically enhances the gene expression.

The potential for inhibiting recrystallization with Eudragit® L (EUD-L), hypromellose acetate succinate (HPMC-AS), and polyvinylpyrrolidone-co-vinylacetate (PVP-VA) on amorphous felodipine (FLD) at low polymer loading was investigated in this study. The physical stabilities of the FLD/polymer amorphous solid dispersions (ASDs) were investigated through storage at 40 °C. The HPMC-AS and PVP-VA strongly inhibited FLD recrystallization, although EUD-L did not effectively inhibit the FLD recrystallization. The rotating frame 1H spin-lattice relaxation time (1H-T1ρ) measurement clarified that EUD-L was not well mixed with FLD in the ASD, which resulted in weak inhibition of recrystallization by EUD-L. In contrast, the HPMC-AS and PVP-VA were well mixed with the FLD in the ASDs. Solid-state 13C spin-lattice relaxation time (13C-T1) measurements at 40 °C showed that the molecular mobility of the FLD was strongly suppressed when mixed with polymer. The reduction in the molecular mobility of FLD was in the following order, starting with the least impact: FLD/EUD-L ASD, FLD/HPMC-AS ASD, and FLD/PVP-VA ASD. FLD mobility at the storage temperature, evaluated by 13C-T1, showed a good correlation with the physical stability of the amorphous FLD. The direct investigation of the molecular mobility of amorphous drugs at the storage temperature by solid-state NMR relaxation time measurement can be a useful tool in selecting the most effective crystallization inhibitor at low polymer loading.

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.

固体NMRはアカデミアや製薬企業などで医薬品原薬や製剤の分析に汎用的に使える実用的な手法の一つになりつつある。また、新しい試料管や測定手法の開発など固体NMR技術は著しく進歩しおり、製剤研究における固体NMRの応用は益々広まっていくと予想される。本稿では、我々が各種固体NMR手法を用いて様々な原薬・製剤の評価を行ったケーススタディーを示しながら、最近の固体NMR研究と今後の展望について概説する.

<p>Antisolvent法により2種の方法で，難水溶性薬物glibenclamide（GLB）及び安定化剤hypromellose（HPMC）からなる非晶質ナノ粒子を調製した．調製法Aでは，GLBを溶解させたDMSO溶液をHPMC水溶液に対して注入し，nano-A懸濁液を得た．調製法BではGLB及びHPMCを共に溶解させたDMSO溶液を蒸留水に対し注入し，nano-B懸濁液を得た．Nano-A及びnano-Bの形態はそれぞれ球形の中空粒子と非球形の中実粒子であった．Nano-Aと比較しnano-Bにおいて昇温過程中の高いGLB非晶質安定化が認められた．これはnano-B中のHPMCとGLBの混和性がnano-Aと比較して高いためと推察された．ナノ粒子中のGLB非晶質の安定性は調製法に依存したGLBとHPMCの混和性の影響を大きく受けることが示された．</p>

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.

Levofloxacin (LVFX), a broad-spectrum antibacterial agent from the fluoroquinolone family, is universally prescribed with antipyretics, including paracetamol (APAP) analogs. In this study, a new drug-drug cocrystal of LVFX and an APAP analog was developed using a grinding and heating approach. Among 9 APAP analogs, only metacetamol (AMAP) was able to form a cocrystal with LVFX, with a stoichiometric ratio of 1:1. This cocrystal was obtained from a eutectic melt of anhydrous LVFX and AMAP after complete desorption of water from LVFX hemihydrate. The crystal structure of the cocrystal was determined by single-crystal X-ray structural analysis. Unlike LVFX hydrates, the LVFX-AMAP cocrystal did not form a channel structure where water molecules reside in LVFX hydrates. Thus, the LVFX-AMAP cocrystal did not undergo hydration under high relative humidity conditions during vapor sorption-desorption analysis and physical stability tests. LVFX photostability was improved by cocrystallization when compared with that of the hemihydrate because of hydrogen bond formation between the hydroxyl group of AMAP and the N-methylpiperazine group of LVFX, which is possibly involved in LVFX photodegradation. The LVFX-AMAP cocrystal, which is superior to LVFX hydrates in both pharmacological and physicochemical properties, is expected to be a useful solid form.

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.

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.

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.

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.

<p>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.</p>

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.

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.

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.

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-state 13C 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-state 1H 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>

Cancer-type organic anion transporting polypeptide 1B3 (Ct-OATP1B3) mRNA is a variant isoform of the liver-type OATP1B3. Because Ct-OATP1B3 mRNA shows an excellent cancer-specific expression profile in colorectal cancer (CRC), and that its expression levels are associated with CRC prognosis, it holds the potential to become a useful CRC detection and diagnosis biomarker. While the potential is currently justified only at the tissue level, if existence of Ct-OATP1B3 mRNA in CRC-derived extracellular vesicles (EVs) is validated, the findings could enhance its translational potential as a CRC detection and diagnosis biomarker. Therefore, this study aims at proving that Ct-OATP1B3 mRNA exists in CRC-derived EVs, and can be detected using serum specimens. To examine the possibility of Ct-OATP1B3 mRNA being existed in extracellular milieu, we isolated EVs from the human CRC (HCT116, HT-29, and SW480) cell lines, and prepared their cDNAs. The RT-PCR results showed that Ct-OATP1B3 mRNA was clearly present in EVs derived from the human CRC cell lines. Then, in order to further explore the possibility that Ct-OATP1B3 mRNA in CRC-derived EVs can be detected in serum, we isolated serum EVs derived from human CRC xenograft mice, and then performed RT-PCR. The results showed that Ct-OATP1B3 mRNA could be found in all serum EV and CRC tissue samples of the mice examined. Collectively, our findings, which show that Ct-OATP1B3 mRNA exists in EVs and can be detected in (at least) mouse serum, strengthen the potential use of Ct-OATP1B3 mRNA as a serum-based CRC biomarker.

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.

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<ketoprofen<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.

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 NIF 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 NIF-rich nanodroplets and maintained the NIF supersaturation with phase-separated NIF 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 NIF 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 1H NMR measurements of NIF-supersaturated solution revealed that HPMC derivatives distributed into the NIF-rich phase during the phase separation of NIF 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 NIF-rich phase was promoted at lower pH due to the lower aqueous 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 4h 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°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.

We report the full assignment of 1H and 13C 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. 13C 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 13C 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.

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 γ-CD columns. Furthermore, salicylic acid (SA) and salicylamide were successfully incorporated into the intermolecular spaces of CD columns using α-CD instead of γ-CD. Powder X-ray diffraction and solution-state 1H 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/γ-CD-PPRX) and SA/(PEG/α-CD-PPRX) complexes were evaluated using solid-state NMR measurements. Finally, dissolution enhancement and sublimation suppression of SA in the SA/(PEG/α-CD-PPRX) complex were demonstrated.

Ascorbyl 2,6-dipalmitate (ASC-DP) and distearoyl phosphatidylethanolamine polyethylene glycol 2000 (DSPE-PEG) 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. 100-160nm. 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 1H 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.

We have designed and synthesized colchicine-derived prodrug 7, which is composed of a 4-chlorocolchicine derivative, a dipeptide side chain cleavable by cathepsin B, a spacer containing a disulfide bond, and hydrophobic vitamin E. Prodrug 7 was capable of forming nanoparticles by self-assembly. Mean particle diameter evaluated by dynamic light scattering measurement was ca. 205 nm.

<p>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。</p>

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.

© 2016 American Chemical Society. Dimenhydrinate (DIM) is an important drug used for the prevention of motion sickness. Surprisingly, the crystal structure of DIM has not been determined over the last 67 years. In this study, we have attempted to determine the structure of DIM through single crystal X-ray structure analysis and confirmed the salt-cocrystal ambiguity. Because of the existence of proton transfer, DIM exists as a salt crystal. The crystal structure of DIM contains the anionic form of 8-chlorotheophylline whose existence was confirmed using density functional theory calculation. Other solid-state characterizations based on spectroscopy and thermal analysis were also conducted in order to fill the vacancy regarding the solid-state characterization. Kinetic and intrinsic solubility tests were also performed to evaluate the physicochemical properties of DIM raw material.

Dimenhydrinate (DIM) is an important drug used for the prevention of motion sickness. Surprisingly, the crystal structure of DIM has not been determined over the last 67 years. In this study, we have attempted to determine the structure of DIM through single crystal X-ray structure analysis and confirmed the salt-cocrystal ambiguity. Because of the existence of proton transfer, DIM exists as a salt crystal. The crystal structure of DIM contains the anionic form of 8-chlorotheophylline whose existence was confirmed using density functional theory calculation. Other solid-state characterizations based on spectroscopy and thermal analysis were also conducted in order to fill the vacancy regarding the solid-state characterization. Kinetic and intrinsic solubility tests were also performed to evaluate the physicochemical properties of DIM raw material.

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) (1)H, (13)C, and two-dimensional (2D) (1)H-(13)C 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 (13)C MAS NMR with a single pulse (SP) method. Interestingly, (13)C 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 (13)C 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 (1)H-(13)C 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.