Derivation of the Extended Kawakita Equation for Estimating the Yield State of Powder in Die.

For powder compaction, the Kawakita equation has been used to estimate the powder behavior inside the die. The compression pressure exerted on powders is not homogeneous because of the friction on the die wall. However, the yield pressure and porosity estimated using the Kawakita equation are defined based on the assumption that homogeneous voids and compression pressure are distributed throughout the powder bed. In this study, an extended Kawakita equation was derived by considering the variation in the compression pressure as it corresponds to the distance from the loading punch surface. The yield time section estimated from the extended Kawakita equation was wider than that which was estimated via the classical equation. This result is consistent with the assumptions used to derive the extended Kawakita equation. Furthermore, a comparison of the porosity changes before and after the yield pressure was applied indicate that the direct cause of the yield is the spatial constraints of the powder particles. Equivalent stresses were defined to clarify the critical factor that constitutes the extended Kawakita equation. As a result, "taking into account the die wall friction" was considered to be the critical factor in the extended Kawakita equation. As these findings were theoretically determined by the extended Kawakita equation, a useful model was derived for a better understanding of powder compaction in die.

Development of Fast Disintegrating Tablets Containing Loxoprofen Sodium by HYDROFLASH Manufacturing Method.

In order to create and offer superior pharmaceuticals for consumers who wish to be relieved of headache and fever as soon as possible, we established HYDROFLASH manufacturing method that enables us to offer fast disintegration tablets containing loxoprofen sodium (LX), which are difficult to disintegrate. As a result of screening excipients, tablets using mannitol showed the fastest disintegration time, about 2 min. From the result of viscosity measurement, we found that LX produced higher viscosity when dissolved in water. This suggests that tablets containing LX disintegrate slower by inhibiting the penetration of water into the tablet due to the viscosity caused of LX. Therefore, we created a manufacturing method to make it easy for water to penetrate the tablet. It is possible to achieve fastest disintegration in about 30 s for tablets containing LX by granulating in a fluidized-bed with spraying of the dispersion of light anhydrous silicic acid (LASA). LX-containing tablets manufactured by the HYDROFLASH method disintegrated immediately after contact with water. Furthermore, it was observed that LASA was uniformly dotted on the surface of tablets by HYDROFLASH method, compared with other manufacturing methods. We considered that by fluidized-bed granulation with LASA dispersion (HYDROFLASH manufacturing method), water permeates through LASA on the tablet surface regardless of viscosity of LX. Futhermore, LX-containing tablets by the HYDROFLASH method showed that the dissolution rate of LX was nearly 100% at 5 min after starting the test. We considered that the initial dissolution became faster because of the fast disintegration.

Fabrication and Characterization of Pectin Films Containing Solid Lipid Nanoparticles for Buccal Delivery of Fluconazole.

Fluconazole (FZ) is a potential antifungal compound for treating superficial and systemic candidiasis. However, the use of conventional oral drug products has some limitations. The development of buccal film may be a potential alternative to oral formulations for FZ delivery. The present study involved the development of novel FZ-loaded solid lipid nanoparticles (FZ-SLNs) in pectin solutions and the investigation of their particle characteristics. The particle sizes of the obtained FZ-SLNs were in the nanoscale range. To produce pectin films with FZ-SLNs, four formulations were selected based on the small particle size of FZ-SLNs and their suitable polydispersity index. The mean particle sizes of all chosen FZ-SLNs formulations did not exceed 131.7 nm, and the mean polydispersity index of each formulation was less than 0.5. The properties of films containing FZ-SLNs were then assessed. The preparation of all FZ-SLN-loaded pectin films provided the mucoadhesive matrices. The evaluation of mechanical properties unveiled the influence of particle size variation in FZ-SLNs on the integrity of the film. The Fourier-transform infrared spectra indicated that hydrogen bonds could potentially form between the pectin-based matrix and the constituents of FZ-SLNs. The differential scanning calorimetry thermogram of each pectin film with FZ-SLNs revealed that the formulation was thermally stable and behaved in a solid state at 37 °C. According to a drug release study, a sustained drug release pattern with a burst in the initial stage for all films may be advantageous for reducing the lag period of drug release. All prepared films with FZ-SLNs provided a sustained release of FZ over 6 h. The films containing FZ-SLNs with a small particle size provided good permeability across the porcine mucosa. All film samples demonstrated antifungal properties. These results suggest the potential utility of pectin films incorporating FZ-SLNs for buccal administration.

Optimization and Advantages of Molded Tablets Using Trehalose as a Binder.

Molded tablets are manufactured by molding wet powder at low pressure and drying. Typically, water-soluble polymers are used as a binder; however, the ratio to achieve both tablet strength and rapid disintegration is limited, and designing an optimal formulation according to the active ingredients can be challenging. In addition, production may be temporarily interrupted owing to the adherence of wet powder to the inside of the mortar, which can hamper stable production. Therefore, optimization was performed by design of experiments to utilize the disaccharide trehalose as a binder for molded tablets. We formulated placebo tablets with high tablet strength and rapid disintegration. On examining the tablet interior, we confirmed the formation of solid bridges between particles and high porosity, suggesting that trehalose can be used as a binder for molded tablets. The viscosity of the trehalose saturated solution was lower than that of the polyvinyl alcohol (PVA) solution (3.8 wt%). Moreover, the trehalose formulation exhibited a significantly lower wet powder adhesion rate to the upper punch than the PVA formulation. This study provided valuable results for the future formulation design of molded tablets.

Promoting Activity of Terpenes on Skin Permeation of Famotidine.

Famotidine (FMT) is a competitive histamine-2 (H2) receptor antagonist that inhibits gastric acid secretion for the treatment of Gastroesophageal reflux disease. To study the promoting effect and mechanism of terpenes, including l-menthol, borneol, and geraniol, as chemical enhancers, FMT was used as a model drug. Attenuated total reflectance-Fourier transform IR spectroscopy (ATR-FTIR) and differential scanning calorimetry (DSC) were used to explore the effects of terpenes on the skin. Hairless mouse skin was mounted on Franz-type diffusion cell, and skin permeation experiment of FMT hydrogel was carried out. The results suggested that the thermodynamic activity influenced the permeability of the drug, and the main mechanism of terpenes to enhance skin permeation of the drug was based on increasing the fluidity of the intercellular lipids. Moreover, it was revealed that l-menthol simultaneously relaxed the packing structure and lamellar structure, whereas geraniol had a great influence on the lamellar structure only. Collectively, all terpenes had a promoting effect on skin permeation of FMT, indicating their potential as chemical enhancers to change the microstructure of stratum corneum and improve the permeation of FMT through the skin, and it has great potential to be used in transdermal formulations of FMT.

Characterization of co-amorphous carvedilol-maleic acid system prepared by solvent evaporation.

The aim of this study was to enhance the solubility and stability of the water-insoluble drug carvedilol (CAR) with maleic acid (MLE) to create a co-amorphous system by a solvent evaporation method. Phase diagrams of co-amorphous CAR-MLE, constructed from peak height in the Fourier-transform infrared (FTIR) spectra and the glass transition temperature (Tg) from differential scanning calorimetry (DSC) measurements, revealed that the optimal molar ratio of CAR to MLE was 2:1. The FTIR spectra indicated that the secondary amine-derived peak of CAR and the carboxy group-derived peak of MLE disappeared in the CAR:MLE (2:1) co-amorphous system. DSC measurements showed that the endothermic peaks associated with the melting of CAR and MLE disappeared and a Tg at 43 °C was apparent. Furthermore, the solubility of CAR tested using the shaking flask method for 24 h at 37 °C was 1.2 µg/mL, whereas that of the co-amorphous system was approximately three times higher, at 3.5 µg/mL. Finally, the stability was evaluated by powder- X-ray diffraction at 40 °C; no clear diffraction peaks originating from crystals were observed in the amorphous state until after approximately three months of storage. These results indicate that co-amorphization of CAR with MLE improved the solubility of CAR while maintaining its stability in an amorphous form.

Formulation of Biopharmaceutical Dry Powder Inhaler Using the Void Forming Index (VFI) to Detect and Avoid Powder Caking in Dry Powder Inhaler Formulations.

It is mandatory to detect the powder cohesiveness of biopharmaceutical dry powder inhaler (Bio-DPI) formulations and their effect on their performance. Normally, Bio-DPI formulations consist of highly cohesive components with higher drug amounts than small molecules. Herein, a formulation study of a high-drug-ratio Bio-DPI was performed, detecting the risk of powder caking in DPI formulations. The Bio-DPI formulation was manufactured via the spray-dry method followed by mixing with excipients. Powder caking was detected through the void forming index (VFI), which was calculated using pressure drop measured by inverse gas chromatography (iGC). Since VFI can be used to evaluate the structural changes induced by powder caking over time with less than 1 g of sample, VFI is considered suitalbe to apply for DPI formulation screening. The risk of powder caking was detected in spray dryed particles at more than 45% relative humidity (RH) humidity condition, mannitol (as a carrier particle) and magnesium stearate (as a lubricant) were added to the formulations. With formulation screening, addition of more than 40% of mannitol was suggested to reduce the risk of powder caking. Selected DPI formulation remained higher emitted ratio (95.6%), than spray dried particle (52.5%) at 25 °C 65% RH condition for 1-month storage. In conclusion, VFI measurement is useful for selecting the DPI formulation by mitigating powder caking risk with limited samples.

Selection of Small Amounts of Glidant Capable of Improving the Tensile Strength of Ibuprofen Tablets.

This study examined the selection of small amounts of excipients capable of improving the compactability of ibuprofen, thereby enabling the miniaturization of ibuprofen tablets. Various glidants in amounts of 1% of the total volume were added to dry surface-modified ibuprofen, and the tensile strengths of the resulting tablets were evaluated. The characteristics of the excipients that affected the tensile strengths of the tablets were then extracted using a tensile strength prediction model. We confirmed that the effective angle of the internal friction of the mixed powder, the coating form of the glidant, the packing fraction of the raw material, and the mixed powder affect the tensile strength of the tablet. A smooth particle layer was formed on the surface of the ibuprofen particles when a glidant with a packing fraction of <0.05 was used. In the sample with a smooth particle layer, the angle of the critical state line increased significantly and the tensile strength improved. We inferred that the smoothness of the particle layer allowed the ibuprofen particles to come into close contact with each other. Consequently, the number of junctions increased, and the frictional force between the particles improved, resulting in tablets with improved tensile strengths. In conclusion, the compactability of ibuprofen was improved by adding 1% glidant with a packing fraction of <0.05. The reduction in excipients will allow the creation of smaller tablets, making them easier to swallow. Therefore, the medication adherence of customers will be improved.

Understanding Crystal Cleavability and Physical Properties of Crystal Surfaces Using in Silico Simulation.

In the drug formulation process, compound dissolution rate and wettability may be improved by grinding. However, there is no method to understand the effects of the wettability of the crystal facets of the ground product. Here, acetylsalicylic acid (ASA) was used to evaluate the changes in crystal morphology and dissolution rate by jet milling using powder X-ray diffraction and in silico simulation. Several cleavage facets were observed in cube crystals, and the (0 0 2) facet was observed in plate crystals. Furthermore, the dissolution rate of the ground samples per unit area decreased with the cleavage of the (1 0 0) and (0 0 2) facets. The polar surface energy of the ground sample decreased with increasing grinding pressure. The simulation results showed that the absolute attachment energy of the (1 0 0) and (0 0 2) facets was lower than that of the other crystal facets. Moreover, atoms with low polarity were present on the crystal surface of (0 0 2). The wettability and dissolution rate of the (0 0 2) facet were worse than those of the (1 0 0) facet. It was suggested that the dissolution rate of the ground sample was affected by the wettability of the crystal facet caused by the cleavage. The cleavability and wettability may be understood by simulation.

Manufacturability and Properties of Granules and Tablets Using the Eco-Friendly Granulation Method Green Fluidized Bed Granulation Compared to Direct Compression.

This study aimed to compare the manufacturability and granule and tablet properties of green fluidized bed granulation (GFBG) and of direct compression (DC). Acetaminophen was used as a low compactability model drug. The process time of GFBG to produce final mixtures was comparable to that of DC, and thus GFBG could be considered a simple process. DC could not produce 30% drug load tablets owing to poor granule flowability, whereas no problems were observed in the GFBG tableting process up to 80% of drug load. Tablets prepared with GFBG showed higher tensile strength than those prepared using DC. Compactability evaluation results show that the yield pressure of the granules prepared with GFBG was significantly lower than that of DC, suggesting that the granules prepared with GFBG were easily plastically deformed. Moreover, tablets prepared with GFBG showed fast disintegration, which was faster than that of DC. We conclude that GFBG produces granules with higher drug content and desired physicochemical properties at low cost.

Altered Media Flow and Tablet Position as Factors of How Air Bubbles Affect Dissolution of Disintegrating and Non-disintegrating Tablets Using a USP 4 Flow-Through Cell Apparatus.

This study investigated how air bubbles in media affect tablet dissolution in a flow-through cell system (USP 4) using disintegrating (USP prednisone) and non-disintegrating (USP salicylic acid) tablets. Cell hydrodynamics were studied using particle image velocimetry (PIV) and computational fluid dynamics (CFD). The PIV analysis showed periodic changes in the local flow corresponding to the discharge and suction of the pump cycles. The absence of prior deaeration induced small air bubbles in the media and lower maximum flow during the cycle, explaining the slower dissolution of the USP salicylic acid tablets. Bubbles, occurring during the USP prednisone tablets study, induced the transition of floating disintegrated particles towards the cell outlet, whereas the particles precipitated to form a white layer on the glass beads used in the study with prior deaeration. CFD analysis showed local flow variation in multiple positions of small (ID 12 mm) and large (ID 22.6 mm) cells, explaining the different rates of dissolution of prednisone tablet particles depending on their distribution. These results emphasize the importance of prior deaeration in dissolution studies using a flow-through system. Bubbles in the flow-through cell system affected tablet dissolution by reducing the area in contact with the media (wettability), lowering the maximum instantaneous flow (pressure buffering), and altering the position of disintegrated particles in the cell.

Impact of Magnesium Stearate Content: Modeling of Drug Degradation Using a Modified Arrhenius Equation.

To accelerate drug development, the pharmaceutical industry is working to shorten and improve studies on stability. The Accelerated Stability Assessment Program (ASAP) incorporating the humidity-corrected Arrhenius equation as an accelerated methodology has been proposed for both drug substances and drug products. In this study, the effect of magnesium stearate (MgSt) content on the chemical stability of acetylsalicylic acid was evaluated as a model system of drug-excipient compatibility studies using ASAP. In the acetylsalicylic acid powder blends, temperature and humidity showed a first-order linear response to the natural logarithm of the reaction rate constant, and MgSt content also showed a first-order linear response. A polynomial model was built in which temperature, humidity, and MgSt content were independent each other. The fitting index of the model, the coefficient of determination, was 0.9567, which was a good fit. In the long-term stability study (25 °C/60% relative humidity, 6 months), there was good agreement in total between measured values and model-predicted values. Using this model, we inferred that the degradation rates were depended on MgSt content at the fixed temperature and humidity because the micro-environmental pH of the excipient was catalytically affected. Applying this model equation can significantly reduce the duration of formulation design and stability studies and save time and costs in drug development.

Degradation Pathway of a Taxane Derivative DS80100717 Drug Substance and Drug Product.

The degradation pathway of a taxane derivative and anticancer agent, DS80100717, was investigated. Several degradants were generated under acidic, basic, and oxidative stress conditions in solution. The chemical structures of eight degradants of DS80100717 were elucidated using MS and NMR. The major degradant of the DS80100717 drug substance derived by heating in solid-state was the N-oxide form via oxidation and C2'-epimer of the side chain via acid hydrolysis. We proposed previously unreported degradation pathways of DS80100717 with taxane derivatives such as paclitaxel, docetaxel, and cabazitaxel.

Synthesis and Characterization of Cholesteryl Conjugated Lysozyme (CHLysozyme).

Hydrophobic interaction is important for protein conformation. Conjugation of a hydrophobic group can introduce intermolecular hydrophobic contacts that can be contained within the molecule. It is possible that a strongly folded state can be formed in solution compared with the native state. In this study, we synthesized cholesteryl conjugated lysozyme (CHLysozyme) using lysozyme and cholesterol as the model protein and hydrophobic group, respectively. Cholesteryl conjugation to lysozyme was confirmed by nuclear-magnetic resonance. Differential-scanning calorimetry suggested that CHLysozyme was folded in solution. CHLysozyme secondary structure was similar to lysozyme, although circular dichroism spectra indicated differences to the tertiary structure. Fluorescence measurements revealed a significant increase in the hydrophobic surface of CHLysozyme compared with that of lysozyme; CHLysozyme self-associated by hydrophobic interaction of the conjugated cholesterol but the hydrophobic surface of CHLysozyme decreased with time. The results suggested that hydrophobic interaction changed from intramolecular interaction to an intermolecular interaction. Furthermore, the relative activity of CHLysozyme to lysozyme increased with time. Therefore, CHLysozyme likely forms a folded state with an extended durability of activity. Moreover, lysozyme was denatured in 100% DMSO but the local environment of tryptophan in CHLysozyme was similar to that of a native lysozyme. Thus, this study suggests that protein solution stability and resistance to organic solvents may be improved by conjugation of a hydrophobic group.

A New Method for Classification of Salts and Cocrystals Using Solid-State UV Spectrophotometry.

Salt and cocrystal formulations are widely used as techniques to improve physicochemical properties of compounds. Some spectrometric techniques to distinguish cocrystals from salts have been reported; however, it has not been possible to adapt these formulations with many compounds, because of limitations, high difficulty, and exceptions. Therefore, we focused on the possibility of UV spectrometry, which had not been reported as a classification technique for salts and cocrystals. The integration values of solid-state UV/visible (Vis) spectra of indomethacin salts were larger than those of physical mixtures of indomethacin and counter molecules, while that of indomethacin cocrystal was not large compared with that of the physical mixture. From these results, differences between a salt and a cocrystal were observed in their solid-state UV/Vis absorption spectra for indomethacin complexes. Therefore, it is suggested that solid-state UV/Vis absorption spectra can be used as a new technique to classify salts and cocrystals.

Development of microparticles coated with poly-γ-glutamic acid to improve oral absorption of a poorly water-soluble drug.

Novel microparticles coated with poly-γ-glutamic acid (PGA) were developed to improve the oral absorption of indomethacin (IM), a poorly water-soluble drug. Microparticles containing γ-IM (IMbulk-PGA) or crystal polymorph α-IM (IMpolymorph-PGA) were prepared. Additionally, microparticles were prepared containing α-IM without PGA (IMpolymorph without PGA). IMbulk-PGA and IMpolymorph-PGA exhibited better drug retention properties on mucin disks. Drug release rates from IMpolymorph-PGA and IMpolymorph without PGA were higher than from IM bulk powder, and drug release from IMbulk-PGA was also improved. Drug release from IMbulk-PGA could be improved with the use of Tween 80. In addition, PGA may influence the ionization of IM or affect specific molecular interactions. After the microparticles were administered orally to mice, IMbulk-PGA and IMpolymorph-PGA increased the plasma drug concentration more rapidly compared with IM bulk powder, but IMpolymorph without PGA did not increase the plasma drug concentration. It was considered that IMbulk-PGA and IMpolymorph-PGA rapidly reached the intestinal membrane through the mucus layer and IM was absorbed quickly. Because IMbulk-PGA and IMpolymorph-PGA showed a rapid increase in plasma drug concentration, IMbulk-PGA and IMpolymorph-PGA could be useful preparations to improve the gastrointestinal absorption of IM. Furthermore, IMbulk-PGA may maintain higher plasma drug concentrations than IMpolymorph-PGA.

Effect of sulfobutyl ether-ß-cyclodextrin and propylene glycol alginate on the solubility of clozapine.

Clozapine (CLZ) is an atypical antipsychotic medication used in the treatment of schizophrenia and is poorly soluble in water (0.05 mM). In this study, we have investigated the effect of ß-cyclodextrin (CD) and its derivatives on the solubility of CLZ. The solubility of the CLZ was measured to generate a phase solubility diagram, and the interaction between CLZ and sulfobutyl ether-ß-cyclodextrin (SBE-ß-CD) in aqueous solution was observed by 1H- and 2D rotating-frame Overhauser enhancement spectroscopy (ROESY)-NMR methods. Moreover, the synergistic effect of SBE-ß-CD and water-soluble polymers, including polyvinylpyrrolidone, hydroxypropyl methylcellulose, carboxymethylcellulose sodium salt, polyvinyl alcohol, sodium alginate, and propylene glycol alginate (PGA), on the solubility of CLZ was investigated. The results show that the solubility of CLZ with 1 w/v% PGA was 7.6 mM, which was almost four times greater than that of CLZ without PGA in a 15 mM SBE-ß-CD solution. In contrast, the solubility of CLZ with 1 w/v % PGA in an aqueous solution decreased by one-third relative to that of CLZ in a 15 mM SBE-ß-CD solution. 2D ROESY-NMR indicated that a CLZ/SBE-ß-CD/PGA ternary complex formed. It was found that the combination of PGA and SBE-ß-CD enhanced the solubility of CLZ.

Characterization of complexes between phenethylamine enantiomers and ß-cyclodextrin derivatives by capillary electrophoresis-Determination of binding constants and complex mobilities.

To optimize chiral separation conditions and to improve the knowledge of enantioseparation, it is important to know the binding constants K between analytes and cyclodextrins and the electrophoretic mobilities of the temporarily formed analyte-cyclodextrin-complexes. K values for complexes between eight phenethylamine enantiomers, namely ephedrine, pseudoephedrine, methylephedrine and norephedrine, and four different ß-cyclodextrin derivatives were determined by affinity capillary electrophoresis. The binding constants were calculated from the electrophoretic mobility values of the phenethylamine enantiomers at increasing concentrations of cyclodextrins in running buffer. Three different linear plotting methods (x-reciprocal, y-reciprocal, double reciprocal) and nonlinear regression were used for the determination of binding constants with ß-cyclodextrin, (2-hydroxypropyl)-ß-cyclodextrin, methyl-ß-cyclodextrin and 6-O-α-maltosyl-ß-cyclodextrin. The cyclodextrin concentration in a 50 mM phosphate buffer pH 3.0 was varied from 0 to 12 mM. To investigate the influence of the binding constant values on the enantioseparation the observed electrophoretic selectivities were compared with the obtained K values and the calculated enantiomer-cyclodextrin-complex mobilities. The different electrophoretic mobilities of the temporarily formed complexes were crucial factors for the migration order and enantioseparation of ephedrine derivatives. To verify the apparent binding constants determined by capillary electrophoresis, a titration process using ephedrine enantiomers and ß-cyclodextrin was carried out. Furthermore, the isothermal titration calorimetry measurements gave information about the thermal properties of the complexes.

Effect of Magnesium Stearate Mono- and Dihydrate Dispersibilities on Physical Properties of Tablets.

Magnesium stearate (MgSt), an essential lubricant in the manufacturing of tablets, is available in several hydrate forms with different qualities that affect the physical properties of tablets. This study examined MgSt mono- and dihydrates, and their effects on tablet dissolution, disintegration, and hardness. These effects were examined in terms of surface free energy and dispersibility. Dissolution, disintegration, and hardness were evaluated for tablets manufactured from powder mixtures of each MgSt hydrate form and other components, including ethenzamide as an active ingredient, using different mixing times. The surface energy was evaluated for MgSt mono- or dihydrate powder mixtures with a surface tensiometer. For dispersibility, the adhesion states of MgSt hydrates to other components were visually observed via near-infrared (NIR) chemical imaging. The dispersion behavior of MgSt hydrates was examined by quantitative evaluation of skewness and kurtosis of histograms, based on NIR images, and domain size estimated from their binary images. It was found that changes in those parameters related to dispersibility and dissolution differed between MgSt hydrates. This suggests that the quantitative determination of dispersibility of MgSt using NIR chemical imaging is a useful methodology for improving the understanding of tablet manufacturing blending processes.

Investigation of Discoloration of Furosemide Tablets in a Light-Shielded Environment.

We observed that uncoated furosemide tablets turned yellow in a light-shielded automatic packaging machine and discoloration of the furosemide tablets was heterogeneity and occurred on the surface of the tablets only. The machine was equipped with an internal blower to maintain a constant temperature. Therefore, we investigated the effect of air flow on the discoloration of the furosemide tablets using a blower in a dark environment. The color difference (ΔE) of the furosemide tablets increased linearly as the blowing time increased. We performed structural analysis of the yellow compound in the furosemide tablets by LC-MS and identified the compound as a hydrolysate of furosemide. This suggested that furosemide hydrolysis was accelerated by the air flow. The furosemide tablets were prepared with the most stable furosemide polymorph, form I. X-Ray powder diffractometry and IR spectroscopy showed that during tablet preparation, no crystal transition occurred to an unstable furosemide polymorph. Furthermore, IR spectroscopy showed that the crystal form of furosemide in the yellow portion of the tablets was form I. To elucidate the factors producing the discoloration, we investigated the effect of humidity and atmosphere (air, oxygen, and nitrogen) on the discoloration of the furosemide tablets. The results suggested that the discoloration of the furosemide tablets was accelerated by oxidation, although humidity did not affect the hydrolysis. Therefore, we concluded that the discoloration of the furosemide tablets in the automatic packing machine was caused by acceleration of oxidative degradation by air flow.