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Norfloxacin is a special compound. Its hydrate form seems to be more soluble in water than in the anhydrate form. To investigate the hydration behavior of norfloxacin, the moisture-sorption analysis of anhydrous norfloxacin in different humidities was determined by using differential scanning calorimetry and thermogravimetric analysis. The contents of free water and bound water in the moisture-equilibrated norfloxacin were estimated quantitatively by using a curve-fitting program. Fourier transform infrared microspectroscopy with or without thermal analyzer was used to examine the structural change and dehydration process of norfloxacin in different humidities. The result indicates that the water content sorbed to anhydrous norfloxacin changed lightly below 51% relative humidity (RH) but increased markedly beyond 51% RH. The content of free water in the moisture-equilibrated norfloxacin was nearly to zero below 55% RH, but increased dramatically in high humidity. The content of bound water also enhanced gradually with the external humidity and reached to a constant of one unit after > 75% RH. When norfloxacin anhydrate transformed to its hydrate, the infrared peak intensity at 1732 and 1253 cm(-1) assigned to the C=O and C-O groups of carboxylic acid decreased gradually with the increase of water content, but the infrared peak intensity at 1584 and 1339 cm(-1) corresponding to asymmetric and symmetric carboxylates increased. Furthermore, the peak at 2553 cm(-1) assigned to the NH(+)(2) also appeared clearly and shifted from 2558 cm(-1) in higher water content and humidity. The main functional groups of norfloxacin changed from COOH to COO(-) and NH to NH(+)(2), attributable to the proton transfer from COOH group to NH group. This suggests that the hydration can induce the interaction between norfloxacin molecules from hydrogen bonding to ionic bonding by a proton-transfer process in the solid state.

The impact of thermal stress on indomethacin (IMC)–nicotinamide (NIC) cocrystal formation with or without neat cogrinding was investigated using differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) microspectroscopy, and simultaneous DSC–FTIR microspectroscopy in the solid or liquid state. Different evaporation methods for preparing IMC–NIC cocrystals were also compared. The results indicated that even after cogrinding for 40 min, the FTIR spectra for all IMC–NIC ground mixtures were superimposable on the FTIR spectra of IMC and NIC components, suggesting there was no cocrystal formation between IMC and NIC after cogrinding. However, these IMC–NIC ground mixtures appear to easily undergo cocrystal formation after the application of DSC determination. Under thermal stress induced by DSC, the amount of cocrystal formation increased with increasing cogrinding time. Moreover, simultaneous DSC–FTIR microspectroscopy was a useful one-step technique to induce and clarify the thermal-induced stepwise mechanism of IMC–NIC cocrystal formation from the ground mixture in real time. Different solvent evaporation rates induced by thermal stress significantly influenced IMC–NIC cocrystal formation in the liquid state. In particular, microwave heating may promote IMC–NIC cocrystal formation in a short time. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2386–2395, 2014

The influence of compression force to inner core tablet or to outer coating layer of the compression‐coated tablet on the function of time‐controlled disintegration was investigated. The inner core tablet was directly compacted by sodium diclofenac (model drug) and ethylcellulose (EC) with 4.6‐μm particle size was used as an outer coating layer. The immersion time of the compression‐coated tablet previously soaked in pH 1.2 solution to simulate the residence time of the tablet in the GI tract affecting the dissolution behavior of the compression‐coated tablet was also investigated. The effect of the amount of the outer coating layer used on the drug release was examined. The results indicate that sodium diclofenac released from these compression‐coated tablets exhibited a longer lag of a period about 16.3 h in both distilled water and pH 6.8 buffer solution, followed by a different drug release behavior. The lag time was independent of the pH of dissolution medium, and the immersion time in pH 1.2 solution. After that lag time, the outer shell of the compression‐coated tablets broke into two halves to make a rapid drug release. However, the drug release behavior of the soaked tablet in pH 6.8 buffer solution was dependent on the immersion time. The compression force 2 to the inner core tablet influenced the release behavior of drug less, but > 200 kg/cm 2 might delay the lag time. The lag time of the compression‐coated tablets was linearly correlated with the compression force to the outer coating layer ( r = 0.9896). We also found that the more the amount of outer coating layer added, the longer the lag time obtained. The study demonstrates that the time‐controlled disintegration of the compression‐coated tablet was effectively controlled by the compression force applied and the amount of outer coating layer added. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:2005–2009, 2001

Thermal Fourier transform infrared (FT-IR) microspectroscopy was used to investigate the conformational isomerization of captopril in the solid state. The result indicates that the IR peak intensity of captopril for original bands decreased dramatically at 102 degrees C, but for new bands it increased with the rise of temperature. The frequency of C=O stretching mode for carboxylic acid and for amide was located at a higher wavenumber of 1747 cm(-1) and at a lower frequency of 1591 cm(-1) as compared with the general compound, suggesting the existence of trans isomer of captopril in the solid state by intramolecular hydrogen bonding. Beyond 102 degrees C, several new bands at 1720, 1645, and 1610 cm(-1) were observed with the rise of temperature, indicating the coexistence of a cis isomer. However, the cis isomer could transform gradually to the trans isomer after cooling. The thermodynamics of equilibrium mixture of cis/trans isomers were also studied. The trans isomer was more stable than the cis isomer, but the cis isomer was favored at the higher temperature.

To investigate the physicochemical characteristics, thermodynamics, possible sublimation process and kinetics of nitroxoline, differential scanning calorimetry (DSC), isothermal thermogravimetry (TG), and Fourier transform infrared (FTIR) microspectroscopy equipped with a micro hot-stage of DSC microscopy assembly (simultaneous DSC-FTIR method) were used. The DSC result indicates that nitroxoline exhibited a sharp endothermic peak at 182 degrees C with enthalpy of 103.1 J/g due to the melting point of nitroxoline. A sublimation behavior of nitroxoline was found from 129 degrees C by gradual weight loss in TG curve. However, the nonisothermal DSC-FTIR method reveals that the temperature at 95 degrees C was the onset temperature of nitroxoline sublimation. A significant difference between DSC-FTIR method and TG analysis suggests that the simultaneous DSC-FTIR method was more sensitive than that of the TG analysis to detect the beginning temperature of nitroxoline sublimation. The sublimation kinetics of nitroxoline determined by isothermal TG analysis evidenced that the zero-order kinetics was followed over the sublimation time. The sublimation enthalpy correction was also carried out by a group additivity approach for the estimation of heat capacity. The enthalpy of nitroxoline sublimation estimated was 86.14 KJ/mol at 298.15 K.

The physicochemical properties of 9,10-anthraquinone-2-carboxylic acid (AQCA) were investigated by thermal analysis, powder X-ray diffraction pattern, solubility, and partition coefficient. The chemical structure of AQCA was confirmed by the data from UV, Fourier transform IR (FTIR), and NMR analyses. Solubility and partition coefficient data were pH dependent. A new methanolic solvate of AQCA that lost 9.34% of its initial weight from 70 to 100 degrees C was found by thermogravimetric analysis. Sublimation of AQCA occurred at temperatures > 250 degrees C and needle-like crystals (Form I) were formed. The water solubility of AQCA increased with temperature; its heat of solution was 32.7 kJ/mol. A differential scanning calorimetry-FTIR microscopic system correlated a thermal phase transition with structural changes due to loss of methanol from the solvate, and three-dimensional FTIR spectra indicated that the process was complete by 100 degrees C. The kinetics of desolvation and sublimation from each crystal form of AQCA were determined. The activation energy of desolvation of methanol from solvate was 425.8 kJ/mol, and the activation energy of sublimation from Form I or desolvated crystals was 182.7 kJ/mol.

A new polymorphic crystal form of indomethacin was precipitated from an aqueous solution of indomethacin and beta-cyclodextrin by titration with a 0.5 N HCl aqueous solution. Three polymorphs (alpha, beta, and gamma forms) and a new crystal form were differentiated with thermal analysis, infrared spectroscopy, powder X-ray diffractometry, thin-layer chromatography, elemental analysis, and Fourier transform infrared (FTIR) spectroscopy with a newly developed FTIR microscope equipped with a thermal analyzer. The new crystal polymorph of indomethacin exhibited endo- and exothermic peaks near 102.8 and 104.1 degrees C, respectively, because of phase transitions without weight loss, followed by two additional endothermic peaks at 151 and 158.9 degrees C, because of fusion. The differential scanning calorimetry-FTIR system can be used to examine the correlation between structural change of C = O stretching bands of this new polymorph and its thermal response. The new crystal form contained some gamma-form crystals, determined with an FTIR microscope equipped with a mapping option. Solid-state carbon-13 nuclear magnetic resonance spectra of the polymorphs of indomethacin were also examined.

An in vitro dissolution study has been carried out with a USP rotating paddle apparatus using the stepwise pH change method. The dissolution kinetics of two different matrix-type aminophylline slow-release (SR) tablets were compared. Both aminophylline SR tablets show similar release rates and slow release behavior. The bioavailability of these two aminophylline SR tablets was also evaluated in eight healthy male Chinese volunteers and correlated with in vitro dissolution results by moment analysis. The preliminary results suggest that there is no evidence indicating that the two different matrix types of aminophylline SR tablets are not bioequivalent, and a good in vitro–in vivo correlation for these aminophylline SR tablets may therefore be presumed.

Micronized sulfamethoxazole particles were microencapsulated using the gelatin-acacia complex conacervation method. The effects of the coacervation pH and the amount of formaldehyde used on the micromeritic parameters of the microcapsules were investigated. The particle-size and the wall thickness distributions were log-normal forms. As the pH was increased, the particle size decreased (8.5-28.5 micrometers). The porosity of various pH-adjusted microcapsules was between 0.158 and 0.277. The particle size of formalized microcapsules was larger than that of the unformalized microcapsules because formalization prevents shrinking of microcapsules during the dehydration and drying process. A smooth surface appeared on the unformalized microcapsule, but a net-like wrinkled structure was observed upon scanning the formalized one. Moreover, folding and invaginating structures were found on the spray-dried microcapsules. The optimum coacervation pH value was 3.5, at which the highest core content was obtained (77.5% w/w). Approximately 6.73 microgram of formaldehyde remained in 1 g of the microcapsules formalized with 50 ml of formaldehyde. The crystalline sulfamethoxazole in the microcapsules prepared by spray drying the coacervate slurries was changed into the amorphous form, while the microcapsules dried in the conventional manner showed the same sulfamethoxazole form as the starting substance.

Aqueous solutions of ethylenediamine and theophylline were spray dried to obtain solid particulates of theophylline--ethylenediamine complex to improve solubility of theophylline. Packing and flow properties of the spray-dried products were much improved when compared with those of original theophylline particles, due to their spherical shapes which were confirmed by a scanning electron microscope. The solubility of theophylline in the resultant products was found to be three to five times higher than that of original theophylline. The solubilities of the products decreased with increasing drying temperature and rotation speed of the atomizer, which was interpreted in terms of the contents of ethylenediamine in the products. The products were confirmed to be a mixture of aminophylline, alpha-aminophylline, and theophylline by X-ray analysis and NMR spectroscopy. The logarithm of the relative intensity of the X-ray diffraction peak of alpha-aminophylline to that of theophylline decreased linearly with drying temperature and rotation speed of the atomizer. Thermal decomposition of the spray-dried products involved liberations of crystal water at 100 degrees and ethylenediamine between 110 and 127 degrees. Liberation of ethylenediamine occurred via three steps for aminophylline, but with different steps for the spray-dried products.

Sulfamethoxazole was microencapsulated with cellulose acetate phthalate and talc, colloidal silica, or montmorillonite clay by a spray-drying technique. The surface topography of the products varied with the type of excipient used and the pH of the suspending medium. The products without the excipient were coated with flake-like crusts, while the products containing the excipient tended to become well-rounded spheres. In addition, the crystalline form of sulfamethoxazole converted from Form I to an amorphism and Form II during the spray-drying process. This polymorphic transformation was attributed to the interaction of cellulose acetate phthalate with sulfamethoxazole. Increasing the concentration of cellulose acetate phthalate in the formulation increased the attainment of amorphism. Form II was also obtained by freeze and vacuum drying. Talc was the only excipient that contributed to polymorphism, which occurred in the alkaline suspension medium. Montmorillonite products prepared from the acidic medium exhibited an exothermic differential scanning calorimetry thermogram, which might be interpreted in terms of adsorption of the fused sulfamethoxazole with the internal surface of montmorillonite

Improved methods were developed for the preparation of enteric-coated microcapsules for tableting by a spray-drying technique, and the drug release behavior from the tableted microcapsules was investigated using a disintegration apparatus and a new in vitro method of simulating the GI tract. As a model system, ammonium solutions of sulfamethoxazole and cellulose acetate phthalate were spray dried using a centrifugal wheel atomizer at 140 degrees. Additives such as colloidal silica, montmorillonite clay, and talc were included in the formulations for spray drying. The influence of the additives on the particle diameter, density, packing properties, and compressibility of the product and on the release characteristics of the resultant tablet in vitro were investigated. The additives in the formulations greatly improved the flow properties of the spray-dried products, which could be tableted easily. Products from the nonadditive formulations could not be tableted due to their poor flowability. The hardness and disintegration rate of the tablet increased with increasing concentration of additives in the formulations. X-ray analysis and IR spectroscopy confirmed that the crystals of sulfamethoxazole in the spray-dried microcapsules with cellulose acetate phthalate were converted from Form I to Form II. In vitro release characteristics of the tablets were studied using a disintegrator (JP) in buffer solutions (pH 1.2 and 7.5) and distilled water. Enteric action of the spray-dried products was proved by comparison with the original nontreated powders. The additives in the tablet increased the release rate at the initial stage in all dissolution media used. A new in vitro release simulator was devised consisting of a flow-type dissolution container in which the pH of the medium was changed continuously from 1.2 to 7.0 to simulate the pH change of tablets exposed to the GI tract.

Aqueous slurries of aminopyrine and barbital (molecular ratio 2:1) containing various excipients such as colloidal silica, synthetic aluminum silicate, montmorillonite clay, corn starch, microcrystalline cellulose, hydroxypropylcellulose, methylcellulose, gelatin, and chitosan were spray-dried by a centrifugal wheel atomizer with various rotation speeds (10,000–40,000 rpm) at various temperatures (85–145 ± 5°). The spray-dried products were a mixture of aminopyrine–barbital complex (molecular ratio 1:1), aminopyrine, and the excipient used. The flowability and the packing property of the products were improved by compounding colloidal silica into the formulation used for spray-drying. The products with montmorillonite clay, chitosan, and a com starch–colloidal silica mixture were compressed directly into tablets. It was found that aminopyrine in the products was oxidized during spray-drying. The oxidation products were assumed to be a trace mixture of 5-oxo-2- methyl-4-dimethylamino-l -phenyl-3-pyrazoline carboxyaldehyde and miscellaneous oxidation products. Montmorillonite clay compounded in the formulation considerably prevented the oxidation of aminopyrine during spray-drying. The present study proposes an improved method for the preparation of solid particulates of aminopyrine–barbital complex for tableting, which combines the synthesis, drying, and agglomeration processes into a single process.