Improvement in Inhalation Properties of Theophylline and Levofloxacin by Co-Amorphization and Enhancement in Its Stability by Addition of Amino Acid as a Third Component.

Co-amorphous systems are amorphous formulations stabilized by the miscible dispersion of small molecules. This study aimed to design a stable co-amorphous system for the co-delivery of two drugs to the lungs as an inhaled formulation. Theophylline (THE) and levofloxacin (LEV) were used as model drugs for treating lung infection with inflammation. Leucine (LEU) or tryptophan (TRP) was employed as the third component to improve the inhalation properties. The co-amorphous system containing THE and LEV in an equal molar ratio was successfully prepared via spray drying where reduction of the particle size and change to the spherical morphology were observed. The addition of LEU or TRP at a one-tenth molar ratio to THE-LEV did not affect the formation of the co-amorphous system, but only TRP acted as an antiplasticizer. The Fourier transform infrared spectroscopy spectra revealed intermolecular interactions between THE and LEV in the co-amorphous system that were retained after the addition of LEU or TRP. The co-amorphous THE-LEV system exhibited better in vitro aerodynamic performance than a physical mixture of these compounds and permitted the simultaneous delivery of both drugs in various stages. The co-amorphous THE-LEV system crystallized at 40 °C, and this crystallization was not prevented by LEU. However, THE-LEV-TRP maintained its amorphous state for 1 month. Thus, TRP can act as a third component to improve the physical stability of the co-amorphous THE-LEV system, while maintaining the enhanced aerodynamic properties.

Dissolution-permeation of hot-melt extruded amorphous solid dispersion comprising an experimental grade of HPMCAS.

Background and purpose: Physicochemical properties of an amorphous solid dispersion (ASD) comprising an experimental grade of hydroxypropyl methylcellulose acetate succinate (HPMCAS-MX) with lower glass transition temperature have been previously investigated. This study aimed to evaluate applicability of HPMCAS-MX to hot-melt extrusion (HME) and dissolution-permeation performance of prepared ASDs using MicroFLUX. Review approach: A physical mixture of indomethacin (IMC) and HPMCAS-MX or -MG (a commercial grade with higher transition temperature) at 20:80 weight ratio was hot-melt extruded to prepare an ASD (IMC-MX and IMC-MG, respectively). The dissolution-permeation performance and the stability of the ASDs were measured. Key results: A torque reduction at 120 °C implied that IMC-MX transformed into an amorphous state at this temperature, but IMC-MG required around 170 °C. This result was supported by Raman mapping of the the HME samples. IMC-MG and IMC-MX remained in an amorphous state at 40 °C for three months. The initial dissolution rate and solubility of the ASDs were higher than that of crystalline IMC. The apparent permeability of IMC from IMC-MX and IMC-MG was comparable but was approximately two-fold higher than that from crystalline IMC. Conclusion: HPMCAS-MX enabled HME process at a lower temperature and improved the dissolution-permeation performance of indomethacin.

Formation of Hemihydrate Crystal form Overcomes Milling Issue Induced by Exposed Functional Groups on Cleavage Plane for a Y5 Receptor Antagonist of Neuropeptide Y.

This study aimed to investigate the crystal forms of an originally designed Y5 receptor antagonist of neuropeptide Y. Polymorphic screening was performed via solvent evaporation and slurry conversion using various solvents. The obtained crystal forms α, ß, and γ were characterized by X-ray powder diffraction analysis. Thermal analysis determined that forms α, ß, and γ were hemihydrate, metastable and stable forms, respectively; the hemihydrate and the stable forms were candidates. To arrange the particle size, forms α and γ were subjected to jet milling. However, form γ could not be milled because of powder stiction to the apparatus, whereas form α could be. To investigate this mechanism, single-crystal X-ray diffraction analysis was performed. The crystal structure of form γ was characterized by two-dimensional hydrogen bonding between neighboring molecules. This revealed that the functional groups forming hydrogen bonds were exposed on the cleavage plane of form γ. The three-dimensional hydrogen-bonding network with water stabilized the hemihydrate form, α. These results indicate that the hydrogen bondable groups exposed on the cleavage plane of form γ should result in stiction of the powder and adherence to the apparatus. It was concluded that crystal conversion is a method to overcome the milling issue.

Baloxavir Marboxil Shows Anomalous Conversion of Crystal Forms from Stable to Metastable through Formation of Specific Solvate Form.

Baloxavir marboxil is a novel cap-dependent endonuclease inhibitor of influenza. This study aimed to identify its polymorphs and their relationship with crystal engineering. Polymorph screening by evaporation gave forms I-III and solvate forms IV and V. Heating enabled the conversion of form III to form II, but did not enable that of forms I and II. The solvent-mediated transformation of the forms I-III by magnetic stirring in various solvents resulted in the formation of form I. These results indicate that form I is the stable form. However, all crystal forms transformed to form II after magnetic stirring in a 50% acetonitrile aqueous solution, which was not obtained from water or acetonitrile. The suspension in a 50% acetonitrile aqueous solution exhibited a novel X-ray diffraction pattern as shown in form VI. The measurement of the suspension by solid-state 13C-nuclear magnetic resonance revealed that the spectra of forms II and VI were similar. From these results, we conclude that the drug forms a solvate with both water and acetonitrile and spontaneously transforms to form II upon rapid desolvation under ambient conditions. This study elucidates the mechanism of unexpected convergence to a metastable form in a specific solvent and contributes to the crystal engineering of baloxavir marboxil.

Design of a Stable Coamorphous System Using Lactose as an Antiplasticizing Agent for Diphenhydramine Hydrochloride with a Low Glass Transition Temperature.

Coamorphous systems comprising small molecules are emerging as counterparts to polymeric solid dispersions. However, the glass transition temperatures (Tgs) of coamorphous materials are relatively low because of the lack of polymeric carriers with higher Tgs. This study aimed to investigate the applicability of lactose (LAC) as an antiplasticizing coformer to a coamorphous system. Diphenhydramine hydrochloride (DPH) was selected as a model drug (Tg = 16 °C). Differential scanning calorimetry showed a comelting point in addition to a decrease in the neat melting points depending on the composition of the physical mixtures, suggesting that the mixture of DPH-LAC was eutectic. The melting point of the eutectic mixture was calculated according to the Schröder-van Laar equation. The heat of fusion of the eutectic mixture was maximized at a 70:30 molar ratio of DPH to LAC; at this point, the melting peaks of the pure components disappeared. The heat flow profiles following the melting and cooling of DPH-LAC physical mixtures at the ratios from 10:90 to 90:10 showed a single Tg, suggesting the formation of a coamorphous system. Lactose showed a Tg of over 100 °C, and the Tg of DPH increased with the molar ratio of LAC; it was 84 °C at a 10:90 molar ratio of DPH to LAC. The Raman image indicated the formation of a homogeneous dispersion of DPH and LAC in the coamorphous system. Peak shifts in the infrared spectra indicated the presence of intermolecular interactions between the amino group of DPH and the hydroxyl group of LAC. Principal component analysis of the infrared spectra revealed a significant change at the 70:30 molar ratio of DPH to LAC, which was in agreement with the results of the thermal analysis. A stability test at 40 °C revealed rapid crystallization of the supercooled liquid DPH. The coamorphous samples containing 10-50% of LAC remained in an amorphous state for 21 days, and no crystallization was observed for the samples containing >60% of LAC for 28 days. The relatively lower Tg (less than 40 °C) of the coamorphous system containing 10-50% of LAC might have caused crystallization during storage. These findings indicate that LAC, which is a safe and widely used pharmaceutical excipient, can be applied to coamorphous systems as an antiplasticizing coformer.

Multiwell Raman plate reader for high-throughput biochemical screening.

Although Raman spectroscopy has been used for the quantitative analysis of samples in many fields, including material science, biomedical, and pharmaceutical research, its low sensitivity hindered the application of the analytical capability for high-throughput screening. Here, we developed a high-throughput Raman screening system that can analyze hundreds of specimens in a multiwell plate simultaneously. Multiple high numerical aperture (NA) lenses are assembled under each well in the multiwell plate to detect Raman scattering simultaneously with high sensitivity. The Raman spectrum of 192 samples loaded on a standard 384-well plate can be analyzed simultaneously. With the developed system, the throughput of Raman measurement was significantly improved (about 100 times) compared to conventional Raman instruments based on a single-point measurement. By using the developed system, we demonstrated high-throughput Raman screening to investigate drug polymorphism and identify a small-molecule binding site in a protein. Furthermore, the same system was used to demonstrate high-speed chemical mapping of a centimeter-sized pork slice.

Applicability of an Experimental Grade of Hydroxypropyl Methylcellulose Acetate Succinate as a Carrier for Formation of Solid Dispersion with Indomethacin.

The transformation of a crystalline drug into an amorphous form is a promising way to enhance the oral bioavailability of poorly water-soluble drugs. Blending of a carrier, such as a hydrophilic polymer, with an amorphous drug is a widely used method to produce a solid dispersion and inhibit crystallization. This study investigates an experimental grade of hydroxypropyl methylcellulose acetate succinate, HPMCAS-MX (MX), as a solid dispersion carrier. Enhancement of thermal stability and reduction of the glass transition temperature (Tg) of MX compared with those of the conventional grade were evaluated through thermogravimetric analysis and differential scanning calorimetry (DSC). The formation of a homogeneous amorphous solid dispersion between MX and indomethacin was confirmed by X-ray powder diffraction analysis, DSC, and Raman mapping. It was observed that 10-30% MX did not act as an anti-plasticizer, but the utilization of >40% MX caused an increase in Tg and reduction of molecular mobility. This could be explained by a change in intermolecular interactions, inferred from infrared spectroscopy combined with principal component analysis. HPMCAS-MX exhibited similar performance to that of conventional-grade, HPMCAS-MG. Although HPMCAS-MX has thermal properties different from those of conventional-grade HPMCAS-MG, it retains its ability as a solid dispersion carrier.

New insight into transdermal drug delivery with supersaturated formulation based on co-amorphous system.

The objective of this study was to prepare a supersaturated formulation based on formation of a co-amorphous system of a drug and a coformer in order to enhance skin permeation. Atenolol (ATE) and urea (URE) were used as the model drug and the coformer, respectively. Thermal analysis of physical mixtures of ATE and URE showed decreases in the melting points and the formation of a co-amorphous system which was in a supercooled liquid state because of a low glass transition temperature. Supersaturated solutions of ATE and URE at different molar ratios in polyethylene glycol 400 (PEG400) were prepared. The precipitations were observed under storage at 25 °C for all formulations except for ATE-URE at 1:8 molar ratio which remained in the supersaturated state for 2 months. 1H NMR analysis confirmed the interactions between ATE and URE in PEG400. The ATE-URE supersaturated formulation showed higher permeability for mice skin than that of ATE saturated formulation, which was superior to the expected permeability from the degree of supersaturation. We concluded that co-amorphous based supersaturated formulation offers much promise for transdermal drug delivery.

Dynamic Polymorph Formation during Evaporative Crystallization from Solution: The Key Role of Liquid-Like Clusters as "Crucible" at Ambient Temperature.

Understanding the polymorph phenomenon for organic crystals is essential for the development of organic solid materials. Here, the fluorescence study of the evaporative crystallization of 1,3-dipyrrol-2-yl-1,3-propanedione boron difluoride complex (1), which has three polymorphs showing different emission profiles, is reported. The droplet of 1 in 1,2-dichloroethane showed blue emission just after dropping. Solids with bluish-green emission were observed. As time elapsed, a solid with red or orange emission was observed around the droplet. Time evolution of the fluorescence spectra, observed for the first time, implied that the molten state of 1 was observed by emission of an intermediate, even at ambient temperature. These findings suggested that the liquid-like cluster incidentally forms an ordered array as the crystallites nucleate. The liquid-like cluster can be considered as the "crucible" in the nucleation of polymorphs.

Hierarchical construction of SHG-active polar crystals by using multi-component crystals.

Organic salts composed of chiral amines and sulfonic acid with high hyperpolarizability allowed the construction of polar crystals with incorporated guest molecules. The polarity of the crystals was precisely regulated by employing suitable guest molecules. As a result, the crystals generated a strong second harmonic generation property.

A Structurally Variable Porous Organic Salt Based on a Multidirectional Supramolecular Cluster.

A porous organic salt (POS) composed of 2-sulfophenyl anthracene (2-SPA) and triphenylmetylamine (TPMA) forms five types of porous crystals, POS-a-e, by recognizing subtle differences in the molecular structure of incorporated guest molecules. This structurally variable POS was hierarchically designed on the basis of a supramolecular cluster with a directionally flexible linker formed by the organic salt. X-ray crystallographic analysis reveals that the salt forms six conformers attributable to rocking and rotational motions of the phenylene group in 2-SPA. The clusters form POS crystals through different porous networks according to the conformers. The POS crystals show a wide range of fluorescence spectra that are responsive to differences in the molecular and electronic structure of the guest molecule. This remarkable behavior has potential application in sensitive chemical sensors that are responsive to slight differences in molecular structures.

Linkage control between molecular and supramolecular chirality in 21-helical hydrogen-bonded networks using achiral components.

Chiral molecules preferentially form one-handed supramolecular assemblies that reflect the absolute configuration of the molecules. Under specific conditions, however, the opposite-handed supramolecular assemblies are also obtained because of flexibility in the bond length and reversibility of non-covalent interactions. The mechanism of the handedness selectivity or switching phenomenon remains ambiguous, and most phenomena are observed by chance. Here we demonstrate the construction of chiral hydrogen-bonded twofold helical assemblies with controlled handedness in the crystalline state based on crystallographic studies. Detailed investigation of the obtained crystal structures enabled us to clarify the mechanism, and the handedness of the supramolecular chirality was successfully controlled by exploiting achiral factors. This study clearly reveals a connection between molecular chirality and supramolecular chirality in the crystalline state.