Shuji Noguchi

Investigation of internal structure of fine granules by microtomography using synchrotron X-ray radiation

Computed tomography (CT) using synchrotron X-ray radiation was evaluated as a non-destructive structural analysis method for fine granules. Two kinds of granules have been investigated: a bromhexine hydrochloride (BHX)-layered Celphere CP-102 granule coated with pH-sensitive polymer Kollicoat Smartseal 30-D, and a wax-matrix granule constructed from acetaminophen (APAP), dibasic calcium phosphate dehydrate, and aminoalkyl methacrylate copolymer E (AMCE) manufactured by melt granulation. The diameters of both granules were 200-300 μm. CT analysis of CP-102 granule could visualize the laminar structures of BHX and Kollicoat layers, and also visualize the high talc-content regions in the Kollicoat layer that could not be detected by scanning electron microscopy. Moreover, CT analysis using X-ray energies above the absorption edge of Br specifically enhanced the contrast in the BHX layer. As for granules manufactured by melt granulation, CT analysis revealed that they had a small inner void space due to a uniform distribution of APAP and other excipients. The distribution of AMCE revealed by CT analysis was also found to involve in the differences of drug dissolution from the granules as described previously. These observations demonstrate that CT analysis using synchrotron X-ray radiation is a powerful method for the detailed internal structure analysis of fine granules.

Evaluation of Crystallization Behavior on the Surface of Nifedipine Solid Dispersion Powder Using Inverse Gas Chromatography

PurposeTo investigate crystallization behavior on the surface of amorphous solid dispersion powder using inverse gas chromatography (IGC) and to predict the physical stability at temperatures below the glass transition temperature (Tg).MethodsAmorphous solid dispersion powder was prepared by melt-quenching of a mixture of crystalline nifedipine and polyvinylpyrrolidon (PVP) K-30. IGC was conducted by injecting undecane (probe gas) and methane (reference gas) repeatedly to the solid dispersion at temperatures below Tg. Surface crystallization was evaluated by the retention volume change of undecane based on the observation that the surface of the solid dispersion with crystallized nifedipine gives an increased retention volume.ResultsOn applying the retention volume change to the Hancock-Sharp equation, surface crystallization was found to follow a two-dimensional growth of nuclei mechanism. Estimation of the crystallization rates at temperatures far below Tg using the Avrami-Erofeev equation and Arrhenius equation showed that, to maintain its quality for at least three years, the solid dispersion should be stored at −20°C (Tg − 65°C).ConclusionsIGC can be used to evaluate crystallization behavior on the surface of a solid dispersion powder, and, unlike traditional techniques, can also predict the stability of the solid dispersion based on the surface crystallization behavior.

Design and evaluation of microwave-treated orally disintegrating tablets containing polymeric disintegrant and mannitol.

Microwave (MW) treatment was used to develop a formulation process for the preparation of wet molded orally disintegrating tablets (ODTs) consisting of mannitol and polymeric disintegrant with improved hardness and disintegration properties. The wet molded tablets were prepared in accordance with the conventional methods and subsequently heated by MW irradiation to induce the swelling of the tablet. Croscarmellose sodium, crospovidone, and low-substituted hydroxypropylcellulose (L-HPC) were evaluated for their use with this technology. NBD-020, which is a grade of L-HPC, provided the better hardness and disintegration results. In addition, the crystalline forms of mannitol impacted on hardness and disintegration properties of the ODT upon MW irradiation. The effects of the disintegrant ratio, δ and β crystalline mannitol ratio, amount of water, and compression force on the ODT properties were evaluated using the design of experiment method. MW-induced swelling was enhanced by an increase in the disintegrant ratio. Although the hardness of the tablet increased following MW treatment, the disintegration time became less than that of the MW-untreated tablets as the β-mannitol ratios increased. Taken together, the results indicated that the polymeric disintegrant greatly improved the properties of the molded tablets in combination with MW treatment.

Clarithromycin form I determined by synchrotron X-ray powder diffraction

The structure of the metastable form I polymorph of the macrolide antibiotic clarithromycin, C(38)H(69)NO(13), was determined by a powder diffraction method using synchrotron radiation. The space group of form I is P2(1)2(1)2. The initial model was determined by a molecular replacement method using the structure of clarithromycin form 0 as a search model, and the final structure was obtained through Rietveld refinements. In the form I crystal structure, the clarithromycin molecules are aligned parallel along the a axis in a head-to-tail manner with intermolecular hydrogen bonds between the hydroxy O atoms. The dimethylamine groups of the clarithromycin molecule interdigitate between neighbouring head-to-tail clarithromycin alignments. The novel crystal packing found in form I provides a mechanism that describes the transformation of form 0 to form I.

Fine granules showing sustained drug release prepared by high-shear melt granulation using triglycerin full behenate and milled microcrystalline cellulose

This study aimed to prepare fine granules with a diameter less than 200μm and sustained drug release properties by melt granulation. Triglycerin full behenate (TR-FB) was examined as a new meltable binder (MB) by comparison of its properties with those of glycerin monostearate (GM), widely used as MB. The effect of milling microcrystalline cellulose (MCC), an excipient for melt granulation, on the granule properties was also investigated. TR-FB was more stable during heating and storage than GM, and produced smaller granules with narrower particle size distribution, larger yield in the 106-200μm range, uniform roundness and better sustained drug release profile than those prepared with GM. Granules prepared with milled MCC had almost the same physicochemical properties as those produced with intact MCC. However, milled MCC produced granules with a more rigid structure and smaller void space than intact MCC. Consequently, the granules produced with milled MCC showed better sustained drug release behavior than those prepared with intact MCC. We successfully prepared fine granules with sustained drug release properties and diameter of less than 200μm using TR-FB and milled MCC.

Polymorphic Transformation of Antibiotic Clarithromycin Under Acidic Condition

Clarithromycin (CAM) is a 14-membered semisynthetic macrolide antibiotic used to treat the infection of various bacteria including Helicobacter pylori. The polymorphic transformation of CAM form II crystals under acidic conditions is, however, still unclear, and was investigated using X-ray powder diffraction method. Gel of CAM, which was immediately formed by mixing form II crystals with the hydrochloric acid solution, transformed at first to unstable form A crystals and then to form B crystals. Both forms A and B crystals are hydrochloride salts. Analyses using Hancock-Sharp equation revealed that the mechanism of form B formation was three-dimensional growth of nuclei. The rate constant of the transformation indicated that the times for 95% of form A transforming to form B at 37 °C are 0.69, 1.90, and 3.79 h at pH 1.5, 2.5, and 3.4, respectively. These suggest that the transformation from form II to form B via gel and form A could occur on the surface of form II formulation of prolonged gastric residence time, in the case that the pH in stomach stays low.

Lipid nanoparticles with no surfactant improve oral absorption rate of poorly water-soluble drug.

A pharmacokinetic study was performed in rats to evaluate the oral absorption ratios of nanoparticle suspensions containing the poorly water-soluble compound nifedipine (NI) and two different types of lipids, including hydrogenated soybean phosphatidylcholine and dipalmitoylphosphatidylglycerol. NI-lipid nanoparticle (LN) suspensions with a mean particle size of 48.0 nm and a zeta potential of -57.2 mV were prepared by co-grinding combined with a high-pressure homogenization process. The oral administration of NI-LN suspensions to rats led to a significant increase in the NI plasma concentration, and the area under the curve (AUC) value was found to be 108 min μg mL⁻¹, indicating a 4-fold increase relative to the NI suspensions. A comparison of the pharmacokinetic parameters of the NI-LN suspensions with those of the NI solution prepared using only the surfactant polysorbate 80 revealed that although the AUC and bioavailability (59%) values were almost identical, a rapid absorption rate was still observed in the NI-LN suspensions. These results therefore indicated that lipid nanoparticles prepared using only two types of phospholipid with a mean particle size of less than 50 nm could improve the absorption of the poorly water-soluble drug.

An easy-to-use approach for determining the disintegration ability of disintegrants by analysis of available surface area

With the aim of directly predicting the functionality and mechanism of disintegrants during the disintegration and dissolution of tablets, we investigated an analysis method based on available surface area, which is the surface area of a drug in a formulation in direct contact with the external solvent during dissolution. We evaluated the following disintegrants in this study: sodium starch glycolate (Glycolys), crospovidone (Kollidon CL), carboxymethylcellulose calcium (CMC-Ca), low-substituted hydroxypropylcellulose (L-HPC), and croscarmellose sodium (Ac-Di-Sol). When disintegrant was added to a 50% ethenzamide tablet formulation, an increase in the dissolution rate dependent on disintegrant concentration was observed, according to the type of disintegrant. In addition, the available surface area also differed between disintegrants. For Glycolys, CMC-Ca, and Ac-Di-Sol, a rapid increase in available surface area and a large increase in maximum available surface area (Smax) were observed due to high swellability and wicking, even when the disintegrant concentration was only 1.0%. In contrast, for Kollidon CL and LH-21, a gradual increase in available surface area was observed, depending on the disintegrant concentration. To evaluate the disintegrant ability, Δtmax and ΔSmax were calculated by subtracting peak time (tmax) at 5.0% from that at 1.0% and subtracting Smax at 1.0% from that at 5.0%, respectively, and it was found that the water absorption ratio had strong negative correlations with Δtmax and ΔSmax. Therefore, this study demonstrates that analysis of only available surface area and parameters thereby obtained can directly provide useful information, especially about the disintegration ability of disintegrants.

Newly developed surface modification punches treated with alloying techniques reduce sticking during the manufacture of ibuprofen tablets.

Sticking is a serious problem during the manufacturing process of tablets. In order to prevent this, we used alloying techniques to prepare metal hardening (MH) and electron beam processing infinite product (EIP) punches with rougher asperity of surfaces than a hard chrome plated (HCr) punch. This study evaluated the anti-sticking properties of the MH and EIP punches compared to the HCr punch, using quantitative scraper force measurements and visual observation, for the manufacture of ibuprofen (Ibu) tablets. The anti-sticking property mechanism of the MH and EIP punches was also confirmed. The amount of Ibu adhering to the punch surface was 66% lower for the MH and EIP punches than for the HCr punch, suggesting a superior anti-sticking property of the MH and EIP punches. The scraper force of the HCr punch was 2.60-4.28 N, while that for the MH and EIP punches was 0.54-1.64 N and 0.42-1.33 N, respectively. The result of X-ray photoelectron spectroscopy suggested that the anti-sticking property of the EIP punch was attributed by the rough asperity as well as existence of low friction substance carbon fluoride on the punch surface. In conclusion, this study provides new evidence for the mechanisms behind the superior anti-sticking property of the MH and EIP punches.

Impact of active ingredients on the swelling properties of orally disintegrating tablets prepared by microwave treatment

The impact of different active pharmaceutical ingredients (APIs) loading on the properties of orally disintegrating tablets (ODTs) prepared according to our previously reported microwave (MW) treatment process was evaluated using famotidine (FAM), acetaminophen (AAP), and ibuprofen (IBU). None of the APIs interrupted the tablet swelling during the MW treatment and the tablet hardness were improved by more than 20 N. MW treatment, however, led to a significant increase in the disintegration time of the ODTs containing IBU, but it had no impact on that of the ODTs containing FAM or AAP. This increased disintegration time of the ODTs containing IBU was attributed to the relatively low melting point of IBU (Tm=76 °C), with the IBU particles melting during the MW treatment to form agglomerates, which interrupted the penetration of water into the tablets and delayed their disintegration. The effects of the MW treatment on the chemical stability and dissolution properties of ODTs were also evaluated. The results revealed that MW treatment did not promote the degradations of FAM and AAP or delay their release from the ODTs, while dissolution of the ODTs containing IBU delayed by MW treatment. Based on these results, the MW method would be applicable to the preparation of ODTs containing APIs with melting points higher than 110 °C.