Method optimization of hydrophilic interaction chromatography separation of nucleotides using design of experiment approaches I: Comparison of several zwitterionic columns.

A systematic method in hydrophilic interaction chromatography (HILIC) was developed for the separation of four monophosphate nucleotides using design of experiment (DOE) approaches. Three HPLC parameters, the buffer concentration (ammonium acetate concentration), gradient time, and temperature, were evaluated within the quality design framework, and the effects on chromatographic parameters were investigated. Four zwitterionic columns (ZIC-HILIC, ZIC-cHILIC, NUCLEODUR HILIC, and PC HILIC) were used to separate four nucleotides, and the HPLC conditions for each column were successfully optimized, although PC HILIC did not give peaks that were suitable for optimization. In addition, it was proved that optimized HPLC conditions differed from column to column even when the same types of zwitterionic sulfobetaine-functionalized columns were applied. This tendency was explained by differences in the separation characteristics of each column, the thickness of the water-enriched layer on the surface of the silica supports, and the pH. DOE for development of the HPLC method provides an effective explanation of the interactions among the variable parameters, especially in HILIC mode. Finally, a robust analytical method could be established by setting the optimum parameters. Among the employed columns, ZIC-cHILIC provided the widest range of suitable analytical conditions. NUCLEODUR HILIC was difficult to build a robust analytical method since the elution order of cytidine monophosphate and guanosine monophosphate was reversed.

Application of near-infrared spectroscopy to optimize dissolution profiles of tablets according to the granulation mechanism.

We developed a method for the optimization of dissolution properties of solid oral dosage forms manufacturing using high shear wet granulation (HSWG) by using near-infrared spectroscopy (NIRS) with chemometrics in small-scale experiments. The changes in rheology and NIR spectra of the granules were monitored to verify the granulation mechanism and determine the suitable water amount for model formulation during the HSWG. Tablets were manufactured by altering the added water amount to investigate the impact of the granulation mechanism on drug product qualities. Model formulation granules were prepared with 10-20% w/w water in a funicular state, corresponding to the plateau region in score plots obtained by principal component analysis (PCA). The dissolution rate of model formulation tablets manufactured with more than 20% w/w of water was significantly delayed while tablets manufactured with 15% w/w water showed 100% dissolution at 15 min. NIRS and PCA are applicable to the optimization of dissolution properties via the process understanding of HSWG at the early formulation development stage and could facilitate drug development.

Application of spherical silicate to prepare solid dispersion dosage forms with aqueous polymers.

The objective of this study is to prepare and characterize solid dispersions of nifedipine (NP) using porous spherical silicate micro beads (MB) that were approximately 100 µm in diameter with vinylpyrrolidone/vinyl acetate copolymer (PVP/VA) and a Wurster-type fluidized bed granulator. Compared with previously reported solid dispersion using only MB, the supersaturation of NP dissolved from the proposed system of MB and PVP/VA was maintained during dissolution tests. The proposed system produced a solid dispersion product coated on MB, and morphology was maintained after the coating process to prepare solid dispersion; therefore, the powder characteristics, such as flowability of the proposed solid dispersion product, was tremendously preferable to that of the conventional spray-dried solid dispersions of NP with PVP/VA, expecting to make the consequent manufacturing processes easy for development. Another advantage in the terms of manufacturing is its simple process to prepare solid dispersion by spraying the drug and polymer that were dissolved in an organic solvent onto a MB in a Wurster-type fluidized bed granulator, thus, simplifying the optimization and scale-up with ease.

Practical approach to prepare solid dispersion drug product using spherical silicate.

The purpose of this study is to establish a novel approach for preparing a solid dispersion drug product using spherical silicate by a Wurster-type fluidized bed granulator. The spherical silicate used in this study has porous structure and ideal particle size for loading by a Wurster-type fluidized bed granulator. As model drugs, ibuprofen (IBU), indomethacin (IMC), and phenytoin (PNT) were used and the proposed approach was applied to prepare amorphous drug. All drugs could be loaded on the spherical silicate in an amorphous state. On the other hand, spray drying of spherical silicate suspended in IBU solution was conducted to prepare amorphous product of IBU as a reference; however, complete amorphization was not achieved. Dissolution profiles of each drug after loading on spherical silicate by a Wurster-type fluidized bed granulator were evaluated, and dramatic improvement of dissolution was observed compared with those of crystalline drug. In the proposed approach, specific surface area and particle size of spherical silicate were determined as a key factors to contribute to high yield of amorphous product.

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.

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 ß 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 ß-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.

Preparation and evaluation of swelling induced-orally disintegrating tablets by microwave irradiation.

A major challenge in the development of orally disintegrating tablets (ODTs) is to achieve a good balance between tablet hardness and disintegration time. In this study, an advanced method was demonstrated to improve these opposing properties in a molded tablet using a one-step procedure that exploits the swelling induced by microwave treatment. Wet molded tablets consisting of the delta form of mannitol and silicon dioxide were prepared and microwave-heated to generate water vapor inside the tablets. This induced either swelling or shrinking of tablets, in the extent of each being dependent on tablet formulation and manufacturing conditions. A two-level full factorial design method was used to evaluate the effects of several variables in formulation and manufacturing conditions on the tablet properties, hardness, disintegration time and change in shape. The variables investigated in this study were: ratio of silicon dioxide in formulation, water volume added in granulation, ratio of water absorbed by silicon dioxide prior to granulation, and microwave irradiation time. Swelling of tablet by microwave irradiation was observed in the batches with high ratio of silicon dioxide and low levels of water volume. The disintegration time was clearly shortened by induction of the swelling, while tablet hardness increased. We demonstrated that the water vapor generated by microwave irradiation promoted a change in the crystalline form of mannitol from delta to beta, and that this may have contributed to an increase in tablet hardness. Additionally, it was found that new solid bridges were formed between the granules in the tablet via the pathway from dissolution of mannitol in water vapor to congelation, resulting in an increase in tablet hardness. Thus, both tablet hardness and disintegration properties of the molded tablets were improved by the proposed one-step method and the appropriate ranges for variables are indicated. In addition, multiple regression modeling was used to optimize formulation and manufacturing conditions, and the tablets obtained under these optimized conditions showed both swelling and desirable tablet properties. Therefore, we concluded that this one-step method using microwave irradiation would be a useful method for preparing the ODTs.

Dynamic evolution of the spectrum of long-period fiber Bragg gratings fabricated from hydrogen-loaded optical fiber by ultraviolet laser irradiation.

Long-period fiber Bragg gratings fabricated by exposure of hydrogen-loaded fiber to UV laser light exhibit large-scale dynamic evolution for approximately two weeks at room temperature. During this time two distinct features show up in their spectrum: a large upswing in wavelength and a substantial deepening of the transmission minimum. The dynamic evolution of the transmission spectrum is explained quantitatively by use of Malo's theory of UV-induced quenching [Electron. Lett. 30, 442 (1994)] followed by refilling of hydrogen in the fiber core and the theory of hydrogen diffusion in the fiber material. The amount of hydrogen quenched by the UV irradiation is 6% of the loaded hydrogen.

Thermal tuning of mechanically induced long-period fiber grating.

We have developed a wideband tunable optical filter that uses a long-period fiber grating (LPFG) in which both resonance wavelength and its signal attenuation can be adjusted. We create the grating mechanically by pressing a spring coil to an optical fiber. We achieve continuous fine tuning of wavelength and attenuation by varying the temperature of the LPFG. The adjustable ranges of the LPFG are more than 200 nm in resonance wavelength and more than 10 dB in signal attenuation.

Orally fast disintegrating tablets: developments, technologies, taste-masking and clinical studies.

Fast disintegrating tablets (FDTs) have received ever-increasing demand during the last decade, and the field has become a rapidly growing area in the pharmaceutical industry. Upon introduction into the mouth, these tablets dissolve or disintegrate in the mouth in the absence of additional water for easy administration of active pharmaceutical ingredients. The popularity and usefulness of the formulation resulted in development of several FDT technologies. This review describes various formulations and technologies developed to achieve fast dissolution/dispersion of tablets in the oral cavity. In particular, this review describes in detail FDT technologies based on lyophilization, molding, sublimation, and compaction, as well as approaches to enhancing the FDT properties, such as spray-drying, moisture treatment, sintering, and use of sugar-based disintegrants. In addition, taste-masking technologies, experimental measurements of disintegration times, and clinical studies are also discussed.