Motoki Inoue

Solid dispersions of efonidipine hydrochloride ethanolate with improved physicochemical and pharmacokinetic properties prepared with microwave treatment

Drug absorption into the body is known to be greatly affected by the solubility of the drug itself. The active pharmaceutical ingredient efonidipine hydrochloride ethanolate (NZ-105) is a novel 1,4-dihydropyridine calcium antagonist that has a very low solubility in water. It is classified as a poorly soluble drug, and improvements in its solubility and higher bioavailability with oral administration are needed. In this study, employing microwave technology as a new means to improve solubility, we established a method for preparing solid dispersions using hydroxypropyl methylcellulose acetate succinate as a polymeric carrier and urea as a third component. This effective method has a treatment time of several minutes (simple) and does not require the use of organic solvents (low environmental impact). The third component, urea, acts to lower the melting point of NZ-105, which promotes amorphization. This greatly improves the solubility compared with the microwave-treated product of NZ-105/HPMC-AS binary system. The solid dispersion prepared with this method, in addition to evaluation in vitro, was tested in vivo using beagle dogs and shown to be effective from the eightfold improvement in absorption compared with NZ-105 alone based on the area under the curve.

Developmental considerations for ethanolates with regard to stability and physicochemical characterization of efonidipine hydrochloride ethanolate

Efonidipine hydrochloride ethanolate (NZ-105) is a novel 1,4-dihydropyridine derivative and Ca antagonist. Its chemical structure is distinctive, being a solvate composed of an equimolar adduct of ethanol and efonidipine hydrochloride, and it represents one of a few cases of solvates marketed as a pharmaceutical drug. The research presented in this paper used methods to assess its solid-state properties and included thermal analysis (thermogravimetry-differential thermal analysis, TG-DTA), Fourier transform infrared spectroscopy (FT/IR), evolved gas analysis-mass spectrometry (EGA-MS), environmental (low-vacuum) scanning electron microscopy (E-SEM), variable temperature powder X-ray diffraction, and single-crystal X-ray structure analysis, in order to clarify the thermal behavior of the hydrogen chloride and ethanol adducts of efonidipine in the study of the thermal stability of efonidipine hydrochloride ethanolate. Upon heating, efonidipine hydrochloride ethanolate first released ethanol and subsequently formed a decomposition product with the elimination of chloride ions. X-ray diffraction patterns and particulate forms were markedly altered after the release of ethanol, which suggested the interaction of ethanol molecules with chloride ions and efonidipine molecules within the crystal structure. Vastly different from efonidipine, the crystal structure of efonidipine hydrochloride ethanolate arranges the chloride ion within a basket-type conformation formed by the bulky diphenyl and phosphate groups. This distinctive crystal structure was thought to suppress the elimination of chloride ions and contribute significantly to the improved thermal stability of the compound.

Comparison of Chemical Behavior of Original and Generic Docetaxel Formulations as Non-alcoholic Preparations: Discussion about Diluent Solvents for Docetaxel

　Although generic anti-tumor agents are in wide clinical use, they have not in all cases been shown to be equivalent to the original agents after preparation. In the present study, original and generic docetaxel formulations were compared with respect to stability when prepared as a non-alcoholic solution for use. When the original formulation was diluted with physiological saline solution to make a non-alcoholic preparation, the concentration decreased with time, whereas no such decrease occurred when a preparation of the generic formulation was made in a similar manner. With both the original and generic formulations, no decrease in docetaxel concentration with time was found after dilution with 5% glucose solution. On the basis of these results, it is concluded that the behaviors of original and generic docetaxel formulations are not equivalent when prepared, but that the original and generic formulations can be taken to be equivalent if they are diluted with 5% glucose solution at preparation.

Discrimination and quantification of sulfathiazole polytypes using low-frequency Raman spectroscopy

Sulfathiazole forms II, III and IV are polytypes where common monolayers accumulate in different stacking modes. These polytypes are difficult to identify using conventional analytical techniques when they concomitantly crystallize. However, the use of low-frequency Raman spectroscopy enables discrimination of these polytypes and can determine the ratio of forms III and IV, which are the most challenging pair for quantification. A Hydrogen/deuterium exchange study suggests that characteristic patterns below 100 cm−1 predominantly come from differences of superstructure geometries, especially layer stacking, rather than hydrogen-bond geometries. This study demonstrates that low-frequency Raman spectroscopy has advantages for both polytypic discrimination and quantification.

Molecular State of Active Pharmaceutical Ingredients in Ketoprofen Dermal Patches Characterized by Pharmaceutical Evaluation

The molecular states of ketoprofen and the interaction between ketoprofen and other pharmaceutical excipients in the matrix layer were examined to determine their effect on the pharmaceutical properties of original and generic ketoprofen dermal patches (generic patches A and B). Molecular states of ketoprofen were evaluated using polarized light microscopy, Raman spectroscopy and powder X-ray diffraction. For the original ketoprofen patch, crystalline components were not observed in the matrix layer. However, crystalline ketoprofen was observed in the two generic ketoprofen patches. Moreover, the ketoprofen exhibited hydrogen bonding with the pharmaceutical excipients or patch materials in the generic products. Skin permeation of ketoprofen from the patches was evaluated using hairless mouse skin. Twelve hours after application, the original patch demonstrated the highest level of cumulative skin permeation of ketoprofen. This was followed by generic patch B while generic patch A showed the lowest level of permeation. Fluxes were calculated from the skin permeation profiles. The original patch was approx. 2.4-times faster compared with generic patch A and approximately 1.9-times faster compared with generic patch B. This investigation suggested that pharmaceutical properties such as skin permeability for these types of products are affected by the precipitation of crystalline ketoprofen in the matrix layer and the interaction of ketoprofen with the pharmaceutical excipients or patch materials.

Novel amino acid-based surfactant for silicone emulsification and its application in hair care products: a promising alternative to quaternary ammonium cationic surfactants

Quaternary ammonium cationic surfactants (ACSs) and N‐[3‐alkyl(12,14)oxy‐2‐hydroxypropyl]‐l‐arginine hydrochloride (N‐AOHPA) were used to emulsify silicone. The potential of the resulting emulsions in hair conditioning products was investigated.

Microanalysis of pharmaceutical cocrystals using a nano-spot method coupled with Raman spectroscopy

Recently, the formation of pharmaceutical cocrystals has attracted significant attention because it improves the physicochemical properties of active pharmaceutical ingredients (APIs). In this study, we developed a novel nano-spot method that can possibly reduce the API consumption for an exploring study of pharmaceutical cocrystals by using Raman spectroscopy. The study was performed as follows: (i) a small amount of the sample solution was deposited on the surface of a hydrophobized glass plate using a microsyringe, (ii) the droplet gradually shrank due to drying of the solvent, and a “microcrystal” was precipitated, and (iii) the molecular state of the microcrystal was evaluated by using Raman spectroscopy. By optimizing the hydrophobizing reagent and solvent for spotting samples, a fluorine-coating reagent and ethanol were determined to be the best combination for the nano-spot method. We used caffeine as a model API, and ten types of pharmaceutical ingredients were selected as cocrystal formers. To reduce the operation time, we used an automatic dispensing machine for nano-spotting. The resulting microcrystals were similar to the produced microcrystals manually dispensed out of the solution. Under the optimized conditions, characteristic Raman spectra were obtained from ca. 10 ng of microcrystals and were similar to previously reported results. The technique would be suitable for the early stage of new drug development in which the use of a candidate compound is strictly limited.