Etsuo Yonemochi

Effect of Water-Soluble Carriers on Dissolution Characteristics of Nifedipine Solid Dispersions

Solid dispersions of nifedipine (NP) with polyethylene glycols (PEG4000 and PEG6000), hydroxypropyl-β-cyclodextrin (HPβCD), and poloxamer 407 (PXM 407) in four mixing ratios were prepared by melting, solvent, and kneading methods in order to improve the dissolution of NP. The enhancement of the dissolution rate and the time for 80% NP dissolution T80% depended on the mixing ratio and the preparation method. The highest dissolution rate and the T80% as short as 15 min were obtained from PXM 407 solid dispersion prepared by the melting method at the mixing ratio of 1:10. The X-ray diffraction (XRD) patterns of solid dispersions at higher proportions of carriers demonstrated consistent with the results from differential scanning calorimetric (DSC) thermograms that NP existed in the amorphous state. The wettability and solubility were markedly improved in the PXM 407 system. The presence of intermolecular hydrogen bonding between NP and PEGs and between HPβCD and PXM 407 was shown by infrared (IR) spectroscopy.

Physicochemical properties of amorphous clarithromycin obtained by grinding and spray drying

In order to characterize the amorphous clarithromycin (CAM) obtained by grinding and spray drying, physicochemical properties (crystallinity, thermal behavior, stability and solubility parameters) were evaluated. From powder X-ray diffraction, it was estimated that the crystalline state of CAM was changed into an amorphous state by grinding and spray drying. In differential scanning calorimetry measurements, both broad and sharp peaks for crystallization were observed in ground samples, whereas spray dried samples showed one broad peak due to crystallization. As to the stability test under high humidity, structural difference was confirmed between ground CAMs and spray dried CAM. The heat of dissolution of ground CAMs was greater than that of intact CAM. In the solubility parameter measurement, the increase of the special term, deltas, indicated that the energy change was due to the polarity of the surface energy of the powder particles by grinding.

The use of near infra-red spectroscopy to detect changes in the form of amorphous and crystalline lactose

Abstract The suitability of near infra-red spectroscopy (NIR) to follow changes in both the amorphous and crystalline state of lactose at room temperature was investigated. Amorphous lactose samples were stored in sealed glass jars with saturated salt solutions to control the relative humidity. NIR spectra were recorded after various periods of storage and the data related to calorimetric and thermo-gravimetric assessments of the physical form of the material. Differentiation between crystalline and amorphous states of lactose was found possible by studying the shape and magnitude of regions of the near infra-red spectrum corresponding to combination and first overtone stretching frequencies of water. It was possible to follow changes in the amorphous, the onset of crystallisation and the solid state transition from β - to α -lactose. NIR with benefits of being non-invasive, non-destructive and operating at room temperature, has been shown to be a valuable tool with which to assess changes in the physical form of lactose.

Improved dissolution of ofloxacin via solid dispersion

Abstract The objective of this study was to improve the dissolution rate of a sparingly water soluble drug, ofloxacin, by solid dispersion systems with urea and mannitol. Differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD) analysis and infrared spectroscopy (IR) were performed to evaluate the physicochemical properties of the prepared solid dispersions. The dissolution rate of ofloxacin was markedly increased in solid dispersion of urea and mannitol. Solubility studies revealed a marked increase in the solubility of ofloxacin with an increase in urea concentration. Mannitol concentration had no effect on the solubility of ofloxacin. The PXRD study revealed that the crystallinity of ofloxacin was decreased as the ratio of drug to carrier was decreased. The results from DSC and IR indicated that there was no interaction between drug and carriers.

Cocrystallization and amorphization induced by drug–excipient interaction improves the physical properties of acyclovir

Although acyclovir is one of the most important antiviral drugs used today, there are several problems with its physical properties. The aim of this study is to prepare cocrystals or amorphous complex of acyclovir using drug-excipient interactions to improve the physical properties of the drug, especially its dissolution rate and transdermal absorption. Screening for formation of cocrystals and the presence of amorphous acyclovir was conducted with various pharmaceutical excipinents, with the use of the solution-crystallization method and liquid-assisted cogrinding. The potential cocrystalline phase and the amorphized complex were characterized by PXRD, TG/DTA, IR, DSC and HPLC techniques. The screening indicated that acyclovir formed novel cocrystals with tartaric acid and was amorphized with citric acid. The acyclovir-tartaric acid cocrystal (ACV-TA cocrystal) structure was determined from synchrotron X-ray powder diffraction data. T(g) of the amorphous acyclovir-citric acid compound (ACV-CA amorphous) was determined by DSC. The initial dissolution rate of the ACV-TA cocrystals was considerably faster than that of anhydrous acyclovir. In vitro skin permeation of ACV-CA amorphous from polyethylene glycol (PEG) ointment was remarkably higher than that of the crystalline acyclovir. We successfully improved the physical properties of acyclovir by the cocrystallization and amorphization techniques, using pharmaceutical excipients.

Evaluation of solid dispersions on a molecular level by the Raman mapping technique

Troglitazone containing two asymmetric carbons has four isomers. Crystalline troglitazone consists of two crystalline diastereomer-pairs, RR/SS and RS/SR, which have different melting points. Using a closed melting method, troglitazone-polyvinylpyrrolidone solid dispersions with various crystallinities were prepared. Raman spectroscopy and its mapping technique were applied to discriminate between the crystalline RR/SS, crystalline RS/SR and amorphous form of troglitazone in solid dispersions. The results of the Raman mapping of solid dispersions showed the co-existence of crystal and amorphous forms, and which diastereomer-pairs remained as crystals, in addition to the distribution of the drug. Moreover, the distribution of PVP could be illustrated from the Raman mapping data. Thus, Raman spectroscopy and its mapping technique are useful tools to evaluate crystal and amorphous states, including discrimination of crystalline diastereomer-pairs in solid dispersions. In addition, by describing the distribution of the drug and the carrier, it could be guessed how drug crystals become amorphous during preparation from the point of view of the distribution of the amorphous form of the drug substance and the carrier.

Water sorption and near IR spectroscopy to study the differences between microcrystalline cellulose and silicified microcrystalline cellulose before and after wet granulation

Silicified microcrystalline cellulose (SMCC) has been shown to have advantages over conventional microcrystalline cellulose (MCC). These advantages are (i) improved tablet strength compared to that achieved with MCC, (ii) the retention of compressibility after wet granulation, whereas MCC produces weaker tablets after wet granulation, and (iii) superior flow properties than MCC. In this study gravimetric and calorimetric vapour sorption data and near IR spectroscopy have been used to study MCC and SMCC before and after wet granulation. It was found that MCC, SMCC and wet granulated SMCC had essentially identical physical structures (except for a size increase due to granulation). Wet granulated MCC had a different enthalpy of water sorption at low RH, and its near IR spectrum was different from the other samples in the region which relates to C-H bonding. It can be concluded that MCC and SMCC are of very similar structures, thus these analytical techniques cannot provide an explanation for the improvements in compressibility. However the change in compressibility in MCC after wet granulation may relate to the observed differences in internal bonding in this sample.

Evaluation of Amorphous Ursodeoxycholic Acid by Thermal Methods

AbstractPurpose. The purpose of this study was to characterize the amorphous state of ursodeoxycholic acid (UDCA) samples by using isothermal microcalorimetry, X-ray diffraction, infrared (IR) spectroscopy and solid state carbon 13 nuclear magnetic resonance (13C-NMR) spectroscopy, and to demonstrate the application of the thermal methods (microcalorimetry and differential scanning calorimetry (DSC)) for studying the amorphous state and clarifying the dissolution mechanism of UDCA. Methods. Amorphous UDCA was prepared by grinding and rapid cooling of the melts. The heat of solution of UDCA was measured by an isothermal heat-conduction twin microcalorimeter at 25.0°C. Some physicochemical properties of amorphous UDCA were also studied. Results. The intensities of X-ray diffraction peaks of crystalline UDCA decreased with an increase in grinding time. The heat levels of solution of crystalline UDCA and UDCA ground for 1 min were endothermic, and became exothermic with an increase in grinding time. A good correlation was obtained between the heat of solution and the heat of crystallization determined from the peak area in DSC. Although no significant difference was observed in X-ray diffraction patterns of amorphous UDCA prepared by the two methods, significant differences were recognized in DSC, IR and 13C-NMR, and the heat of solution indicated different values among the two samples. The stability of amorphous UDCA samples stored under 74.5% relative humidity at 40°C was found to depend upon the preparation methods. Conclusions. Different states of amorphous UDCA were obtained depending on the preparation method. The application of thermal methods to evaluate the amorphous state was demonstrated. The mechanism of dissolution of UDCA was discussed from the results of the heat of solution examination.

Differences in Crystallization Behavior Between Quenched and Ground Amorphous Ursodeoxycholic Acid

AbstractPurpose. To study the crystallization of ground and quenched ursodeoxycholic acid (UDCA) and to characterize their amorphous states. Methods. Amorphous UDCA was prepared by grinding and also by rapid cooling of the melt. These samples were characterized by powder X-ray diffraction (XRD), near IR spectra and dynamic water sorption. The heat associated with crystallization was measured in an isothermal microcalorimeter at 25°C at various relative humidities (RH) (50%−100%) and, in the presence of the vapour from a mixed solvent of ethanol and water (ethanol conc. 10%−100%). The specific surface area was calculated from krypton adsorption. Contact angles were measured by using a Wilhelmy plate to calculate the surface energy of the samples. Results. Ground and quenched samples yielded amorphous XRD patterns. Differential scanning calorimetry thermographs of the milled sample revealed that crystallization occurred at around 80°C, whereas the quenched sample did not crystallize. Exposure to humid air did not result in crystallization of either amorphous sample during the microcalorimetric experiments. In the presence of ethanol vapour, the ground sample did, but the quenched sample did not, crystallize. The amount of water sorption into the quenched sample was larger than that of the ground sample at low RH. The surface energy of the quenched material was different to that of the ground. Peak shifts were observed in the NIR spectra at around 1450, 2100 nm, allowing differentiation between the ground and quenched samples. Conclusions. It can be concluded that different molecular states of amorphous UDCA were obtained depending on the preparation method. The crystallisation of amorphous UDCA was related to the molecular state of disorder.

Enhanced Dissolution of Ursodeoxycholic Acid from the Solid Dispersion

AbstractSolid dispersions of a very slightly water-solubte drug, ursodeoxycholic acid (UDCA), were prepared using urea, mannitol, and PEG 6000 as a carrier, and the solubility of UDCA was determined in water-ethanol (1:1) mixed solvent as a function of UDCA-carrier ratio. The solubility of UDCA was slightly improved when urea or PEG 6000 was used as a carrier. The powder x-ray diffraction measurements revealed that UDCA did not exist in the crystalline state in the solid dispersions. Differential scanning calorimetry (DSC) studies showed that UDCA was able to dissolve in the melt of urea, mannitol, and PEG 6000. The effect of carriers of solid dispersions on the UDCA dissolution rate was examined. The dissolution rate of UDCA was markedly increased from the solid dispersions of urea, PEG 6000, and mannitol, respectively.