A Strategy for Co-former Selection to Design Stable Co-amorphous Formations Based on Physicochemical Properties of Non-steroidal Inflammatory Drugs.

PURPOSE: This study aimed to investigate the physicochemical factors contributing to stable co-amorphous formations and to design a co-former selection strategy. METHODS: Non-steroidal inflammatory drugs were used as main components and/or co-formers. Physical mixtures of the materials were melted. Co-amorphization was characterized by the inhibition effect of the co-former on crystallization of the main component from the undercooled melt. The contribution of physicochemical factors to the co-amorphous formation was analyzed by multivariate analysis. Co-amorphous samples prepared by melting were subjected to thermal and spectroscopic analyses and the isothermal crystallization test. RESULTS: Naproxen (NAP) was employed as the main component having a rapid crystallization tendency. Some materials used as the co-former inhibited the crystallization of amorphous NAP; decreasing melting temperatures of the components was an indicator of co-amorphization. The contribution of some physicochemical features (e.g., crystallization tendency, glass transition temperature (Tg)/melting temperature and molecular flexibility) of the co-formers to a co-amorphous formation was suggested by multivariate analysis. Deviation of the glass transition temperature from the theoretical value and changes in the infrared spectra of the co-amorphous samples were correlated with intermolecular interaction. The crystallization behaviors of the co-amorphous samples depended on their Tg. CONCLUSIONS: The results showed a relationship between stable co-amorphous formation and the physicochemical features of the components, which should inform efficient co-former selection to design stable co-amorphous formations.

Anomalous role change of tertiary amino and ester groups as hydrogen acceptors in eudragit E based solid dispersion depending on the concentration of naproxen.

Eudragit E (EGE) is a basic polymer incorporating tertiary amino and ester groups. The role of the functional groups of EGE in the formation of solid dispersion (SD) with Naproxen (NAP) was investigated. The glass transition temperature (Tg) of EGE decreased with the plasticizing effect of NAP up to 20% weight ratio. Addition of NAP at over 30% induced a rise in Tg, with the maximum value being reached at 60% NAP. Further addition of NAP led to a rapid drop of the Tg. A dramatic difference of physical stability between the SDs including 60 and 70% NAP was confirmed. The SD including 70% NAP rapidly crystallized at 40 °C with 75% relative humidity, while the amorphous state could be maintained over 6 months in the SD with 60% NAP. The infrared and (13)C solid state-NMR spectra of the SDs suggested a formation of ionic interaction between the carboxylic acid of NAP and the amino group of EGE. The SD with 20% NAP raised the (13)C spin-lattice relaxation (T1) of the amino group, but it decreased with over 30% NAP. The change in the (13)C-T1 disappeared with 70% NAP. The (13)C-T1 of the ester group rose depending on the amount of NAP. From these findings, we concluded that the role as hydrogen acceptor shifted from the amine to the ester group with an increase in amount of NAP. Furthermore, the amino group of EGE did not contribute to the interaction at over 70% NAP. These phenomena could be strongly correlated with Tg and stability.

Anti-plasticizing effect of amorphous indomethacin induced by specific intermolecular interactions with PVA copolymer.

The mechanism of how poly(vinyl alcohol-co-acrylic acid-co-methyl methacrylate) (PVA copolymer) stabilizes an amorphous drug was investigated. Solid dispersions of PVA copolymer, poly(vinyl pyrrolidone) (PVP), and poly(vinyl pyrrolidone-co-vinyl acetate) (PVPVA) with indomethacin (IMC) were prepared. The glass transition temperature (Tg)-proportion profiles were evaluated by differential scanning calorimetry (DSC). General Tg profiles decreasing with the IMC ratio were observed for IMC-PVP and IMC-PVPVA samples. An interesting antiplasticizing effect of IMC on PVA copolymer was observed; Tg increased up to 20% IMC ratio. Further addition of IMC caused moderate reduction with positive deviation from theoretical values. Specific hydrophilic and hydrophobic interactions between IMC and PVA copolymer were revealed by infrared spectra. The indole amide of IMC played an important role in hydrogen bonding with PVA copolymer, but not with PVP and PVPVA. X-ray diffraction findings and the endotherm on DSC profiles suggested that PVA copolymer could form a semicrystalline structure and a possibility of correlation of the crystallographic nature with its low hygroscopicity was suggested. PVA copolymer was able to prevent crystallization of amorphous IMC through both low hygroscopicity and the formation of a specific intermolecular interaction compared with that with PVP and PVPVA.

Raman mapping for kinetic analysis of crystallization of amorphous drug based on distributional images.

The feasibility of Raman mapping for understanding the crystallization mechanism of an amorphous drug was investigated using described images. The crystallization tendency of amorphous indomethacin under dry condition at 30 °C was kinetically evaluated by means of Raman mapping and X-ray powder diffraction (XRPD) with change in the calculated crystallinities. Raman images directly revealed the occurrence of particle size-dependent non-uniform crystallization; slow crystallization of large particles, but fast crystallization of small particles. Kinetic analysis by fitting to the Kolmogorov-Johnson-Mehl-Avrami equation was performed for the crystallization profiles of both Raman mapping and XRPD data. For the Raman mapping data, the distribution of large particles was characterized and examined. The kinetic parameters calculated from the whole Raman image area agreed well with those of XRPD, suggesting accurate prediction of both techniques for the entire crystallization. Raman images revealed the change in the crystallization mechanism for the focused area; the large particles showed a reduced crystallization rate constant and an increase in the dimensional crystal growth exponent. Raman mapping is an attractive tool for quantitative and kinetic investigation of the crystallization mechanism with distributional images.

Process monitoring of ultrasound compaction as a small-scale heating process.

Ultrasound compaction is a simple small-scale heating process. The aim of this study was to elucidate the polymer phase transition process during ultrasound compaction by process monitoring. Morphological change with heat occurs when ultrasound energy is supplied. Monitoring of the process revealed changes in both punch position and the pressure of the die in terms of the polymer's phase transition process. The optimum ultrasound energy for complete transition could be detected by a sudden increase in the pressure on the lower punch. Such optimum energy clearly depended on the polymer's glass transition temperature (Tg), suggesting that Tg is the predominant parameter in the ultrasound compaction process. Optimization of ultrasound energy based on monitoring profiles is a promising way to obtain a desirable product by thermoplastic treatment with minimal thermal degradation due to excess supply of energy.

Physicochemical characterization and structural evaluation of a specific 2:1 cocrystal of naproxen-nicotinamide.

Physicochemical characterization and structural evaluation of a 2:1 naproxen-nicotinamide cocrystal were performed. The 2:1 cocrystal showed rapid naproxen dissolution and less water vapor adsorption, indicating better pharmaceutical properties of naproxen. The unique 2:1 cocrystal formation was evaluated by solid-state nuclear magnetic resonance (NMR). The assignments of all H and (13) C peaks for naproxen and the cocrystal were performed using dipolar-insensitive nuclei enhanced by polarization transfer and (1) H-(13) C cross-polarization (CP)-heteronuclear correlation (HETCOR) NMR measurements. The (13) C chemical shift revealed that two naproxen molecules and one nicotinamide molecule existed in the asymmetric unit of the cocrystal. The (1) H chemical shifts indicated that the carboxylic group of the naproxen in the cocrystal was nonionized, and the CH-π interaction between naproxens was very strong. From the (1) H-(13) C CP-HETCOR NMR spectrum with contact time of 5 ms, two different synthons, carboxylic acid-amide and carboxylic acid-pyridine ring, were found between naproxen and nicotinamide. Single-crystal X-ray analysis, which supported the solid-state NMR results, clarified the geometry and intermolecular interactions in more detail. The structure is unique among pharmaceutical cocrystals because each carboxyl group of the two naproxens formed different intermolecular synthons.

Crystallization of sucrose glass under ambient conditions: evaluation of crystallization rate and unusual melting behavior of resultant crystals.

Isothermal crystallization of sucrose glass under ambient condition was investigated by powder X-ray diffraction, isothermal microcalorimetry, and water sorption/desorption analysis. Isothermal microcalorimetry measurements showed that the crystallization behavior was affected by the compression force applied to starting amorphous materials. The crystallization rate was analyzed by X-ray diffraction measurements to establish that the rate could well be explained by the Avrami-Erofeev equation. In the water sorption/desorption analysis, the weight change during the crystallization was elucidated by supposing that desorption proceeded from the crystallized part. The sucrose crystallized at relatively low temperature conditions showed completely different melting behavior from that of intact sucrose, although the crystal form was most likely to be identical. This difference could be explained by defects in the lattice structure produced during the crystallization and the desorption process. Correlation was found between the melting temperature and the water content just before the crystallization. Defects in the crystal structure were partially modified by annealing as has been found in relaxation studies of amorphous materials.

Solubilization behavior of a poorly soluble drug under combined use of surfactants and cosolvents.

The solubilization behavior of a poorly soluble model drug, phenytoin (PHT), under combined use of surfactants (sodium dodecyl sulfate (SDS), Tween 80) and cosolvents (dimethylacetoamide (DMA), ethanol, poly(ethylene glycol) 400 (PEG), glycerol) was examined. The solubility of PHT in the aqueous surfactant solutions increased linearly with increase of the surfactant concentration. The solubility of PHT in water-cosolvent mixtures roughly followed the log-linear model, which is widely accepted to explain the solubilization behavior of poorly soluble compounds in water-cosolvent mixtures, except for the case of glycerol, in which the solubility was minimal at 10% (w/v) of glycerol. When the cosolvents were added to the aqueous surfactant solutions, their effect on the solubility depended on the combination of the surfactant and the cosolvent. The most striking increase in solubility was observed with DMA, regardless of the type of surfactant. When ethanol was added, an increase in the solubility was observed with the Tween 80 solution, while a dramatic decrease was found with the SDS solution. The addition of glycerol or PEG to the surfactant solutions had only a minor impact on the solubility. These solubilization behaviors of PHT in the surfactant-cosolvent mixtures were partially explained by the solubility model introduced in our previous paper [Kawakami, K., Miyoshi, K., Ida, Y., 2004. Solubilization behavior of poorly soluble drugs with combined use of Gelucire 44/14 and cosolvent. J. Pharm. Sci. 93, 1471-1479]. Addition of the cosolvents to the surfactant solutions generally offered only a small advantage from the viewpoint of improving solubility because of the decrease in the solubilization capacity of the micelles.

Impact of the amount of excess solids on apparent solubility.

PURPOSE: The impact of excess solids on the apparent solubility is examined. METHODS: The apparent solubility of some model drugs was measured in various buffered solutions, with various amounts of excess solid. To help understand the dependence of the solubility on the amount of solid, we evaluated the dissolution and crystallization rates of indomethacin (IDM), one of the model drugs, at near-equilibrium conditions. RESULTS: In the case of IDM, the apparent solubility decreased with an increase in the solid amount at pH 5 and 6. On the other hand, it increased with an increase in the solid amount at pH 6.5 and 7. The crystallization and dissolution rates of IDM decreased and increased, respectively, with an increase in pH values, and became equal at between pH 6 and 7. Therefore, the apparent solubility was most likely to be affected by the balance between the crystallization and dissolution rates. The apparent solubility of other model drugs showed the same trend, although the dependency on the solid amount was not as significant as in the case of IDM. CONCLUSIONS: The apparent solubility was affected by the amount of solid for all the model drugs investigated. This was most likely to be caused by a competition between the crystallization and dissolution rates.

Effect of salt type on hygroscopicity of a new cephalosporin S-3578.

PURPOSE: Effect of salt type on hygroscopicity was evaluated using S-3578 salts. METHODS: The hydration behavior of a sulfate and a nitrate salt of S-3578 were evaluated by powder X-ray diffraction (PXRD), simultaneous measurement of PXRD-differential scanning calorimetry (DSC), moisture sorption analysis, simultaneous measurement of thermogravimetric/differential thermal analyses, and solid state 13C-nuclear magnetic resonance (C-NMR). RESULTS: The sulfate salt incorporated two types of lattice water to form a monohydrate or a trihydrate. Additional water could also be absorbed as channel water to expand the lattice structure. The activation energy for dehydration was very high, probably due to steric hindrance in the lattice structure. The nitrate salt incorporated only one water molecule per compound as the lattice water. The additional water was absorbed as channel water as observed for the sulfate salt. X-ray diffractograms showed little dependence on the salt type under the ambient condition. The hydration number was likely to be affected by the size of the counter acids. CONCLUSIONS: The hygroscopicity of S-3578 salts was significantly altered by the salt type. The difference in the amount of the lattice water could be explained in terms of the difference in the molecular size of the counter acids.

Solubilization behavior of poorly soluble drugs with combined use of Gelucire 44/14 and cosolvent.

Gelucire 44/14 is a surface-active excipient that can solubilize poorly soluble drugs. We investigated its solubilization behavior when coexisting with dimethylacetoamide (DMA) or dimethylsulfoxide (DMSO), both of which are also expected to enhance drug solubility. Gelucire was confirmed to form micelles by surface tension and fluorescence measurements both in water and water/cosolvent mixtures. Light-scattering measurements revealed that DMA and DMSO affect the micellar morphology in a different manner. DMA helped form large structures by being entrapped in the hydrophobic region of the micelles and/or inducing the aggregation. DMSO was likely to be anchored to the interfacial layer and did not induce micelle growth. Two model drugs, phenytoin and indomethacin, were employed to observe the solubilization behavior of poorly soluble drugs in Gelucire/cosolvent mixtures. The solubility of these drugs in the mixtures could be explained very well by using the new solubility model introduced in this article. Addition of cosolvents to the Gelucire solution did not enhance the solubility very much, and thus the combined use of cosolvents with Gelucire offered only little advantage from the viewpoint of solubility.

Direct observation of the enthalpy relaxation and the recovery processes of maltose-based amorphous formulation by isothermal microcalorimetry.

PURPOSE: The applicability of isothermal microcalorimetry (IMC) for evaluating enthalpy relaxation and recovery processes of amorphous material was assessed. METHODS: A maltose-based formulation was prepared by freeze-dry method. Differential scanning calorimetry (DSC) was used to investigate its glass transition and relaxation behaviors. IMC was applied to quantitatively analyze the relaxation and the recovery processes. The IMC data were analyzed using a derivative of the Kohlrausch-Williams-Watts equation. RESULTS: The glass transition temperature of the formulation and its fictive temperature stored at 15 degrees C for 1 year were 62 and 32 degrees C, respectively. DSC study showed that annealing below the fictive temperature increased the enthalpy recovery, but it was decreased by annealing at higher temperatures. IMC enabled direct observation of the heat flow during both the relaxation and the recovery processes. The decay constant for the recovery process (recovery time) was much smaller and less sensitive to the temperature than that for the relaxation process (relaxation time). CONCLUSIONS: IMC was successfully used to obtain quantitative information on both relaxation and recovery processes of amorphous material. The relaxation parameters obtained by this method could explain the thermodynamic behavior of the formulation.

Assessment of amorphous content by microcalorimetry.

The amorphous content of model drugs was evaluated by isotherm microcalorimetry. Two model drugs were employed; lactose as a hydrophilic one and erythromycin as a hydrophobic one. When amorphous lactose was loaded in a sample cell with a water vial, a sharp exothermic peak due to the crystallization was observed. When a mixture of the amorphous and the crystalline forms was loaded, the peak area of the exothermic heat flow was proportional to the amorphous content. Quantification could be done with much higher accuracy than by the X-ray powder diffraction method reported in earlier literature. When erythromycin was used as a model drug, the crystallization was not completed by water but by organic solvents, which can dissolve erythromycin. The most adequate solvent for erythromycin was acetonitrile, of which the suitability was elucidated in terms of solubility and vapor pressure. This is the first report in which the role of the vapor pressure on crystallization behavior is discussed. The time needed to obtain the crystallization peak was controlled by mixing acetonitrile with water. The strategy to obtain the crystallization peak by microcalorimetry, which enables quantification of the amorphous content with high accuracy, is discussed.