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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.

Controlling the physicochemical properties of a drug formulation is important for proper drug efficacy, since in the gastrointestinal tract many drugs undergo dissolution, limiting their efficacy. Factors affecting a drug's physicochemical properties include its crystal habit. Therefore, we predicted the crystal habit by molecular simulation for the purpose of controlling crystal morphology. In this study, we used aspirin as a model compound. By performing simulations based on known crystal structure data, we trained the simulation algorithm to produce the cubic and plate-like morphologies of crystals actually obtained. By these methods, we showed that the crystal plane of the crystal form actually obtained coincides with the characteristic crystal plane obtained by simulation. Furthermore, to consider the influence of the crystallization solvent on crystal growth, we simulated adsorption of solvent molecules on characteristic crystal planes. The difference in adsorption energy of the solvent molecules prevents the aspirin molecules from attaching to the crystal plane. As a result, we concluded that the crystal habit was caused by the difference in growth rate of the crystal plane. By applying the methods developed in this research, the growth of crystal planes can be predicted by molecular simulation, making it possible to efficiently obtain crystal forms with optimal physical properties for drug development. We believe that further development of this approach will lead to dramatic decreases in the cost and duration of drug development.

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.

Freshly prepared amorphous solid dispersions (ASDs) may not be in an equilibrium mixed state, as high-temperatures and/or solvents are generally used during their preparation. In this study, tolbutamide (TLB) and acetaminophen (AAP) were transformed into ASDs using hydroxypropylmethylcellulose acetate succinate, Eudragit E100 (E100), Soluplus, and Kollidon VA64 using the melt-quench method to observe their phase stability at 5, 25, 40, and 60 °C. Time-dependent phase separation was observed for all the drug and excipient combinations under all investigated storage conditions. The phase separation of the E100/TLB and Soluplus/TLB ASDs was faster under high-temperature storage conditions, whereas the opposite trend was observed with the other ASDs. In the above-mentioned stability studies, phase separation kinetics of the E100/TLB and Soluplus/TLB ASDs appeared to be dominated by molecular mobility due to the low glass transition temperature (Tg) of both the drug and polymer, whereas departure from equilibrium was a dominating factor for the other ASDs. The Tg of the mixed phase just after preparation could be used as an indicator for predicting phase separation after long-term storage, as the mixing ratio calculated from the Tg was in agreement with that after storage for certain ASDs.

Raman spectroscopy is potentially an extremely useful tool for the understanding of drug-polymer interactions in solid dispersions. This is examined and demonstrated for the case of solid dispersions of nifedipine in a polymeric substrate. Solid dispersions consisting of nifedipine and polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer (Soluplus®) were prepared by freeze drying, melting and solvent evaporation at drug loadings of 10, 30, 50, 70 and 90% w/w. Drug-polymer interactions in the amorphous solid dispersion were estimated by Raman spectroscopy. The correlation between the solid state stability of the drug in a solid dispersion and the extent of drug-polymer interaction was monitored by X-ray diffractometry. The miscibility limit of nifedipine-Soluplus® was found to be 30% w/w drug loading for all preparation methods. The drug was found to interact with Soluplus®, through a hydrophilic interaction identified by infrared spectroscopy and a hydrophobic interaction which could be quantified by Raman spectroscopy. The average extent of the drug-polymer interaction in the studied amorphous samples at equivalent drug loading was similar, regardless of the preparation method. Inhomogeneities in samples prepared by melting contributed to a wider variation in drug-polymer interaction and poorer solid state stability, in terms of its crystallization tendency. Raman spectroscopy was shown to be a useful technique in classifying miscibility levels based on the hydrophobic interaction between the drug and the polymer. Different drug loadings showed varying degrees of drug-polymer interaction, and hence variable solid state stability of the solid dispersion.

The purpose of this study was to identify and characterize new crystalline bulking agents applicable to freeze-dried pharmaceuticals. Thermal analysis of heat-melt sugar and sugar alcohol solids as well as their frozen aqueous solutions showed high crystallization propensity of meso-erythritol and D-mannitol. Experimental freeze-drying of the aqueous meso-erythritol solutions after their cooling by two different methods (shelf-ramp cooling and immersion of vials into liquid nitrogen) resulted in cylindrical crystalline solids that varied in appearance and microscopic structure. Powder X-ray diffraction and thermal analysis indicated different crystallization processes of meso-erythritol depending on the extent of cooling. Cooling of the frozen meso-erythritol solutions at temperatures lower than their Tg' (glass transition temperature of maximally freeze-concentrated phase, -59.7°C) induced a greater number of nuclei in the highly concentrated solute phase. Growth of multiple meso-erythritol anhydride crystals at around -40°C explains the powder-like fine surface texture of the solids dried after their immersion in liquid nitrogen. Contrarily, shelf-ramp cooling of the frozen solution down to -40°C induced an extensive growth of the solute crystal from a small number of nuclei, leading to scale-like patterns in the dried solids. An early transition of the freezing step into primary drying induced collapse of the non-crystalline region in the cakes. Appropriate process control should enable the use of meso-erythritol as an alternative crystalline bulking agent in freeze-dried formulations.

The purpose of the present study was to investigate the applicability of the Zwietering equation to coning phenomena which often occur during dissolution testing. The minimum rotation speed at which coning phenomena disappeared (no coning rpm, NCrpm) was experimentally determined for various particle and fluid properties in a compendium paddle apparatus with a round-bottom unbaffled vessel. The particle size, relative density and kinematic viscosity exponents in the Zwietering equation were optimized for NCrpm. The particle size and relative density exponents were found to be similar with those for the general tank configurations of cylindrical flat-bottom baffled vessels. However, the kinematic viscosity exponent was significantly different. The equation obtained in this study showed sufficient accuracy (r(2)=0.98, average error=12rpm) to estimate the occurrence of coning. The Zwietering equation was found to be applicable to the coning phenomena in the compendium paddle apparatus.

The lack of protocols to predict the physical stability has been one of the most important issues in the use of amorphous solid dispersions. In this paper, the crystallization behaviors of pharmaceutical glasses, which have large variations in their crystallization tendencies, have been investigated. Although each compound appears to have a wide variation in their crystallization time, the initiation time for crystallization could be generalized as a function of only Tg/T, where Tg and T are the glass transition temperature and storage temperature, respectively. All compounds in which crystallization was mainly governed by temperature had similar activation energies for crystallization initiation, ca. 210-250 kJ/mol, indicating that physical stability at any temperature is predictable from only Tg. Increased stability is expected for other compounds, where crystallization is inhibited by an large energetic barrier, and stochastic nucleation plays an important role in initiating crystallization. The difference in the dominant factor, either temperature or pressure, appeared to correlate with the nucleation mechanism, and this could be determined by a cool-heat cycle after melting using thermal analysis. This conclusion should make prediction of physical stability of amorphous formulations easier, although the investigation was conducted under ideal conditions, which eliminated surface effects.

The morphology of spray-dried particles composed of psicose and hydroxypropyl methylcellulose was modified by adding ammonium bicarbonate (ABC) to the solution. The surface structure of the particles was altered by immediate transformation of ABC to gaseous components during the spray drying. As a result, low-density microparticles with a petaloid surface structure, which was controllable by changing the evaporation rate of ABC, was obtained. This technique should be useful for modifying characteristics of solid particles for pulmonary drug delivery. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1309–1313, 2014

Magnesium Stearate (MgSt) is a widely used lubricant for preventing tablet compression trouble. It is known that the powder characteristic of MgSt is different among MgSts manufactured by different methods and conditions. These differences affect blending efficiency with pharmaceutical additives. The purpose of this study is to evaluate the physicochemical properties of MgSt by thermal effusivity sensor for in-process monitoring of powder blending. MgSts having different physicochemical properties and granulated sugar spheres were used for model excipients. V-blender was used for powder blending. Thermal effusivity values of each of the ingredients in the blend were measured using one of the sensors prior to placing the ingredient in the blender. The effect of magnesium stearate addition to uniform ingredients can be clearly identified using the sensors. Compared to effusivity data and powder density, effusivity data correlated with the powder characteristics of magnesium stearate. These results suggested that effusivity can be used for end point detection of blending process for various magnesium stearates with sugar sphere. When various magnesium stearates were added to the granule, required time for achieving homogeneous powder blend was different. Blending behavior would be affected by the physicochemical characters. Blend uniformity and blended states of granules containing magnesium stearate can be detected nondestructively without intricate sampling process. Thermal effusivity sensors are an efficient tool to monitor the real time blending behavior of pharmaceutical ingredients.

Filmy solid dispersion of terfenadine (TFD), fenofibrate (FFB), and carbamazepine (CBZ) and methacrylic acid methyl methacrylate copolymer (Eudragit®) was prepared by evaporating their solution. Raman and IR measurements for the filmy samples were performed. Concentration profile of TFD, FFB, and CBZ in solid dispersions was evaluated by their characteristic peaks, and then their diffusion rate constants were calculated. The start point of the crystallization peak under isothermal condition was determined by XRD–DSC. Viscoelastic character of Eudragit® was evaluated by dynamic mechanical analysis (DMA). The distribution map of drugs in their solid dispersions showed the diffusion state of drugs during storage. The concentration profile of TFD, FFB, and CBZ in the solid dispersion was calculated from obtained mapping data. The diffusion rate constant of both drug in Eudragit® EPO was higher than that in Eudragit® RLPO. The induction period of crystallization from amorphous CBZ was gradually delayed with increasing amounts of Eudragit®. The IR peak due to C=O was shifted to higher wave number; it suggested that there were some molecular interactions between CBZ and Eudragit®. From the results of the change in the interaction of drug-Eudragit®, it may be concluded that the diffusivity of drug molecule in polymer closely related to the delay of the induction period of crystallization of amorphous. DMA measurement clarified the difference in the viscosity of Eudragit® having different functional groups and molecular mass. These results suggested that the retardation of crystallization by Eudragit® could be related to the sample viscosity.

As psicose cannot be spray dried because of its low glass transition temperature (Tg), additives have been used to manufacture spray-dried particles. Its thermodynamic miscibility with each additive was evaluated by thermal analysis and C solid-state nuclear magnetic resonance. Aspartame was miscible with psicose at all ratios, and spray-dried particles were obtained when Tg of the mixture was higher than the outlet temperature of the spray dryer, where 30 wt % of psicose was loaded. poly(vinylpyrrolidone) and cluster dextrin were partially miscible with psicose, with a maximum loading of 40 wt %. When polymeric excipients were used, their mixing behavior with psicose was affected by the dynamic factor during the spray drying, that is, enhanced phase separation due to the molecular-weight difference. The Tg value of the polymer-rich phases, which were likely to form shell layers on the surfaces, played an important role in determining availability of the spray-dried particles. Hydroxypropyl methylcellulose (HPMC) offered a very effective loading capacity of 80 wt %, due to distinct phase separation to form shell phase with a very high Tg. Because molecular weight of HPMC was the smallest among the polymeric excipients, the thermodynamic miscibility seemed to affect the dynamic phase separation. These results provide useful information for preparing multicomponent spray-dried particles. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:518–529, 2013

Component crystallization and physical collapse during freeze-drying of aqueous solutions containing protein-stabilizing L-arginine and citric acid mixtures were studied. Freeze-drying microscopy (FDM) and thermal analysis of the solute-mixture frozen solutions showed collapse onset at temperatures (T(c)) approximately 10°C higher than their T(g)'s (glass transition temperatures of the maximally freeze-concentrated solute phase). Experimental freeze-drying of these solutions at a low chamber pressure showed the occurrence of physical collapse at shelf temperatures close to or slightly higher than the T(c). Slower ice sublimation at higher chamber pressures induced the physical collapse from lower shelf temperatures. The large effect of chamber pressures on the collapse-inducing shelf temperatures confirmed significance of the sublimation-related heat loss on the sublimation interface temperature during the primary drying. Drying of the single-solute L-arginine solution resulted in cake-structure solids composed of its anhydrous crystal. Thermal and powder X-ray diffraction (PXRD) analysis suggested slow crystal nucleation of L-arginine dihydrate in the frozen solutions. Characterization of the frozen solutions and freeze-dried solids should enable rational formulation design and process control of amino acid-containing lyophilized pharmaceuticals.

Compressibility and dissolution property of mefenamic acid, which exhibited poorly binding and water soluble properties, was improved by the mechanofusion process using dry inorganic materials. The surface free energy of coated particles and the hardness and dissolution rate of compressed tablets were investigated. The polar component of the surface free energy for mefenamic acid particle was increased by coated with inorganic material, and the hardness and dissolution rate of compressed tablet increased as the polar component of processed powder increased. Hence improvements of compressibility and dissolution property would be attributed to an increase of the hydroxyl groups presented on the particle surface. The surface interaction between mefenamic acid and inorganic material was studied by infrared spectroscopy. As a result, we found that mechanofusion process could produce physicochemical surface interactions between amino and carbonyl groups of mefenamic acid and hydroxyl groups of inorganic materials.

By co-grinding with β-cyclodextrin and drugs, it is suggested that drugs were included to β-cyclodextrin cavity. Ground mixture is amorphous, so that it is difficult to analyze the effect of co-grinding. This study was brought out molecular states of ground mixture and effect of co-grinding. It is suggested that change of molecular states by co-grinding was according to structure of drugs.

Inhalation has been regarded as a promising method for systematic drug delivery as well as treatment of pulmonary diseases. However, difficulty in controlling the powder characteristics is one of the major problems in this field that prevents wide application of the inhalation technology. Herein, strategies to obtain highly dispersive powders are presented, in which it was achieved by both physical and chemical approaches. Notably, addition of wrinkle structures on the particle surface significantly improved the powder dispersity. This technique may enable development of carrier-free nanoparticle inhalation therapy.

Nedocromil sodium has a number of known hydrate states, a monohydrate, a trihydrate and a heptahemihydrate, including an amorphous state. Effect of grinding on the hydration states of nedocromil sodium crystals was studied. After grinding the trihydrate, heptahemihydrate was observed in the ground sample, even though, the water content in the ground sample was not sufficient to cover the heptahemihydrate’s hydration level. On the other hand, in the ground heptahemihydrate, trihydrate was existed. Apparent activation energies (ΔE) for hydrates, monohydrate→anhydrate, trihydrate→monohydrate and heptahemihydrate→amorphous(anhydrate), were calculated using TG data. ΔE for the dehydration of heptahemihydrate was significantly lower than that of other hydrates. Obtained ΔE data explained the inter-conversion behavior of nedocromil sodium induced by grinding.

The purpose of this study was to identify and characterize new crystalline bulking agents applicable to freeze-dried pharmaceuticals. Thermal analysis of heat-melt sugar and sugar alcohol solids as well as their frozen aqueous solutions showed high crystallization propensity of meso-erythritol and D-mannitol. Experimental freeze-drying of the aqueous meso-erythritol solutions after their cooling by two different methods (shelf-ramp cooling and immersion of vials into liquid nitrogen) resulted in cylindrical crystalline solids that varied in appearance and microscopic structure. Powder X-ray diffraction and thermal analysis indicated different crystallization processes of meso-erythritol depending on the extent of cooling. Cooling of the frozen meso-erythritol solutions at temperatures lower than their Tg' (glass transition temperature of maximally freeze-concentrated phase, -59.7°C) induced a greater number of nuclei in the highly concentrated solute phase. Growth of multiple meso-erythritol anhydride crystals at around -40°C explains the powder-like fine surface texture of the solids dried after their immersion in liquid nitrogen. Contrarily, shelf-ramp cooling of the frozen solution down to -40°C induced an extensive growth of the solute crystal from a small number of nuclei, leading to scale-like patterns in the dried solids. An early transition of the freezing step into primary drying induced collapse of the non-crystalline region in the cakes. Appropriate process control should enable the use of meso-erythritol as an alternative crystalline bulking agent in freeze-dried formulations.

A 2,2-diphenyl-1-picrylhydrazyl radical (DPPH˙) was successfully solubilised in water by β-cyclodextrin (β-CD). DPPH˙/β-CD thus obtained was demonstrated to be a powerful tool to evaluate the antioxidative activity of water-soluble antioxidants, such as ascorbate and Trolox, in aqueous buffer solutions.

The purpose of the present study was to investigate the applicability of the Zwietering equation to predict the occurrence of coning phenomena for non-spherical, porous, and swell-able particles in the paddle dissolution test. For non-spherical particles, the minimum rotation speed at which the coning phenomena disappear (no coning rpm, NCrpm) was appropriately predicted by using the Stokes diameter or the short side length of the particles. For porous and swell-able particles, NCrpm was appropriately predicted by using the Stokes density of the particles. The accuracy of the Zwietering equation was sufficient to be used for development of a dissolution test method.

Fragility is a measure of the departure from non-Arrhenius behavior for supercooled liquids and glasses, and various simple methods are available for its quantification. However, the obtained values usually do not agree with each other. One of the purposes of this study was to compare the fragility values obtained by different methodologies. Thermodynamic fragility (FT) is a simple concept that is evaluated from the heat capacity change at the glass transition temperature (Tg). Dynamic fragility is evaluated using three methodologies in this study: extrapolation of the configurational entropy (Sc) to the Kauzmann temperature (Tk) (FDC), ramp-rate dependence of Tg (FDTg), and that of the fictive temperature (Tf) (FDTf). FT and FDC of 19 pharmaceutical compounds were correlated, whereas FDTg and FDTf did not correlate with either of them. This result seems reasonable because both FT and FDC are calculated from thermodynamic parameters in the quasi-equilibrium state, but FDTg and FDTf are likely affected by kinetics as well. Another goal of this study was to find the correlation between the glass-forming ability (GFA) and fragility. FDTg was shown to correlate with GFA, presumably because both were determined on the balance of thermodynamic and kinetic factors. This correlation suggests that fragile glass has low GFA. Furthermore, the relevance of fragility to isothermal crystallization is discussed. Compounds with small FDTg and FDTf tended to exhibit pressure-controlled crystallization, for which better storage stability can be expected relative to temperature-controlled compounds. Fragility was shown to be a useful parameter practically as well as scientifically.

Isothermal microcalorimetry was used to evaluate excipient compatibility of solid dosage form. Oxybutynin hydrochloride and cefaclor were used as model drugs for compatibility test with excipients. The calorimetric data for compatibility test were compared with those of HPLC data. Evaluation of compatibility between drug and excipient of solid dosage form might be possible to use isothermal microcalorimetry instead of conventional method. By using microcalorimetric method, the evaluation of the compatibility between drug and excipient could be successfully performed with a simple operation in a short time. The application of the isothermal microcalorimetry would be useful for the screening test of the drug compatibility with excipients.

Glass ampoule breakage during the freeze-drying process was prevented by the addition of sodium chloride to the formulation of lyophilization products of sodium thiopental. In order to clarify the ampoule breakage prevention mechanism, the physicochemical behavior of the freeze-drying process was monitored by simultaneous XRD-DSC measurements and thermal mechanical analysis (TMA). During the freezing process of formulated solution, the smaller heat of fusion of crystallized ice with the addition of sodium chloride was observed in comparison to that without sodium chloride. Although a greater amorphous portion remained, a higher crystal habit of hexagonal ice was reproducibly observed in the XRD patterns with the addition of sodium chloride during the freezing process. In the measurement of TMA, the scattering of the thermal expansion rate of formulated solution was significantly reduced by the addition of sodium chloride. These observations indicated that the addition of sodium chloride minimized the scattering of the thermal expansion rate and might be a cause for the inhibition of glass ampoule breakage during the freeze-drying process.

The physical stability of amorphous drug in solid dispersion was estimated using differential scanning calorimetry (DSC). Tolbutamide (TB) and flurbiprofen (FBP) were selected as insoluble drugs in water. Polyvinylpyrrolidone (PVP) was selected as a polymer for solid dispersion. Solid dispersions of various ratios of TB or FBP and PVP-K25 were prepared by solvent evaporation method and the induction period of crystallization from amorphous drug in solid dispersion was measured by DSC. Compared with FBP, the induction period of crystallization from TB was delayed by an addition of PVP. The improvement of the physical stability by the addition of PVP-K25 was estimated from the activation energy of diffusion of drug molecules and the interfacial free energy between drug crystal and supercooled liquid of drug in solid dispersion. From thses results, the hindrance of the diffusivity of the drug molecule might be mainly affected the delay of the induction period of crystallization of TB and FBP.

We have developed the vacuum dryer attached XRD-DSC system and monitored manufacturing process of freeze-dried pharmaceutical product. The aim of this study is to apply the XRD-DSC system for the preformulation of freeze-dried injections. Gabexate mesilate was used as a model drug. Drug solution was frozen then heated to annealing temperature according to the process-controlling program. The XRD-DSC analyses were performed to monitor the crystallized spicies and their crystallinity of sample. When the solution was cooled slowly, peaks of gabexate mesilate and mannitol polymorph had been already observed during the cooling process while those crystallinity were low at fast cooling rate. As the drying underwent, intensity of ice peaks were getting weaker. At the cooling rate of 0.1°C min–1, the XRD profile of final product was revealed that the characteristic peaks of gabexate mesilate, mannitol δ-form and β-form were appeared. When the cooling rate was increased, the crystallinity of final products was decreased. From these results, it was confirmed that the XRD profiles during freeze-drying process significantly related to the final freeze-dried product. It is obvious that monitoring by XRD-DSC system is a quite effective way to simulate the manufacturing process and to optimize the qualified product.

A rapidly disintegration tablet in the oral cavity was prepared using a glycine as a disintegrant. Effect of disintegrant on the disintegration behavior of the tablet in the oral cavity was evaluated. Wetting time prepared from carboxymethylcellulose (NS-300) having the hardness of 4 kg was 3 s. Tablet containing NS-300 showed fastest disintegration compared to other formulations. These results suggested that NS-300 possessed excellent wetting nature and resulted in the rapid disintegration of tablet. Ethenzamide and ascorbic acid were added to the formulation, and their disintegration behavior were evaluated. Ethenzamide did not affect the disintegration property, however, ascorbic acid prolonged disintegration time. It was suggested that the tablet formulation containing NS-300 and glycine was highly applicable to water-insoluble drug, such as ethenzamide.

It is very difficult to follow rapid changes in polymorphic transformation and crystallization and to estimate the species recrystallized from the amorphous form. The aim of this study was to clarify the structural changes of amorphous terfenadine and to evaluate the polymorphs crystallized from amorphous samples using XRD–DSC and an atomic force microscope with a thermal probe (micro-TA). Amorphous samples were prepared by grinding or rapid cooling of the melt. The rapid structural transitions of samples were followed by the XRD–DSC system. On the DSC trace of the quenched terfenadine, two exotherms were observed, while only one exothermic peak was observed in the DSC scan of a ground sample. From the in situ data obtained by the XRD–DSC system, the stable form of terfenadine was recrystallized during heating of the ground amorphous sample, whereas the metastable form was recrystallized from the quenched amorphous sample and the crystallized polymorph changed to the stable form. Obtained data suggested that recrystallized species could be related to the homogeneity of samples. When the stored sample surface was scanned by atomic force microscopy (AFM), heterogeneous crystallization was observed. By using micro-TA, melting temperatures at various points were measured, and polymorph forms I and II were crystallized in each region. The percentages of the crystallized form I stored at 120 and 135 °C were 47 and 79%, respectively. This result suggested that increasing the storage temperature increased the crystallization of form I, the stable form, confirming the temperature dependency of the crystallized form. The crystallization behavior of amorphous drug was affected by the annealing temperature. Micro-TA would be useful for detecting the inhomogeneities in polymorphs crystallized from amorphous drug.

The Eudragit RS and polyethylene glycol 400 (PEG 400) blend polymer (EPG) membranes were prepared by the solvent casting method to pioneer a novel application of Eudragit RS to a thermo-sensitive material. The EPG membranes containing 2.5-10% PEG 400 (2.5-10% EPG) showed the glass transition temperatures (Tgs) around the body temperature (32-42 degrees C). Drug permeation studies through the EPG membranes were carried out using acetaminophen (AAP) and aminopyrine (AMP) as the model drugs. The permeability of AAP and AMP through the EPG membranes has been shown to be a discontinuous function of temperature, that is, their permeability increased steeply above the Tg of the membranes. The amount of AMP permeated at 42 degrees C was nearly eight times as much as that at 36 degrees C. Arrhenius plots of the steady-state permeability coefficient (P) of AAP indicated two straight lines that intersect at the Tg of the 10% EPG membrane. In the water uptake study for the 10% EPG membrane, the degree of the swelling for the membrane tended to increase with increasing temperature above the Tg of the membrane. The thermo-sensitive permeation mechanism for the EPG membranes might be based on the structure change of the membranes caused by the glass transition, so that the membranes could absorb more water. Considering the high biological safety of Eudragit RS and PEG 400, the EPG membranes might be used to develop a novel thermo-sensitive drug delivery system.

The crystalline state of drug substance, such as polymorphic forms and crystallinity, in the manufacturing process was analyzed by the Near Infrared Spectroscopy (NIR) calibrated with a set of blend mixture of polymorphs and amorphous samples. The crystalline state of drug substance in the mixture and the tablet was well analyzed by the NIR spectroscopy. However, the crystalline state of drug substance in the granule was determined only when there were no molecular interactions between the drug substance and the excipient since molecular interaction inhibited the accurate evaluation of crystalline state. Chemometrics and spectroscopic measurements will be a useful tool for the evaluation of crystalline state in dosage form when no molecular interaction occurs in the manufacturing process.

The initial dissolution rates of amorphous, partial crystalline and crystalline samples of terfenadine polymorphs (forms I and II) were measured by the rotating disk method. The heats of fusion due to crystalline fraction of samples were obtained by the differential scanning calorimetry (DSC) data taking into account the heat of crystallization and the heat capacity change at glass transition during the heating process. The logarithms of initial dissolution rates of different crystallinity samples were linearly correlated with the corrected heats of fusion, irrespective of the crystal forms.

Purpose. The aim of this study is to estimate the initialdissolution rate of drug substances by isothermal microcalorimetry. A theorywas presented on the basis of Gibbs free energy and the Noyes—Whitneyequation.

Purpose. The aim of this study was to clarify the quantitativerelationship between solubility, initial dissolution rate and heat of solution ofracemic compound and its enantiomers. Methods. Propranolol, propranolol HCl, tyrosine, and tryptophan wereused as typical chiral drugs. The heat of solution of chiral drug wasmeasured by an isothermal microcalorimeter and the heat of fusionwas measured by a DSC. The free energy difference for the dissolutionof drug was calculated from the solubility and initial dissolution ratedata. Results. The free energy difference and enthalpy difference of thedissolution between the racemic compound and enantiomer ofpropranolol, propranolol hydrochloride, tyrosine, and tryptophan were obtainedby the solubility, initial dissolution rate and heat of solution data. Agood linearity was observed in the free energy difference and theenthalpy difference for the dissolution of them, except for propranololHCl data. By considering the dissociation in solution, the data ofpropranolol HCl followed the regression line. Conclusions. The free energy difference of the dissolution was linearlydependent on the enthalpy difference for the racemic compound andits enantiomers. The results fit the theoretical equation. It could bepossible to estimate the solubility of chiral insoluble drug from thethermal data.

Heat of hydration of theophylline anhydrate to the monohydrate at 298 K was evaluated by three different methods. The values determined by heat of solution with a microcalorimeter and heat of dehydration with a differential scanning calorimeter were -9.34±0.65 and -9.82±0.48 kJ/mol, respectively. The values obtained directly with a heat conduction microcalorimeter under 97.3, 95.4 and 93.7% relative humidities were -9.48±0.49, -9.28±0.63 and -9.37±0.74 kJ/mol, respectively. From thermograms obtained with a microcalorimeter at the isothermal transition of theophylline anhydrate to monohydrate, hydration rates were analyzed by a deconvolution method. Hydration rates were in good agreement with those obtained by the Karl Fischer method. Hydration mechanisms were also analyzed on the basis of solid-state kinetic models and the transition followed a mechanism of random nucleation and two-dimensional growth of nuclei.

A method of measuring the rate of water penetration into tablets was proposed in which a heat conduction microcalorimeter was employed. Heat evolved when the tablets were immersed in water. The rate of generation of the heat was determined by a deconvolution method. The rate of water penetration into tablets when they were placed in water was determined by assuming to correspond to the generation rate of heat. For model experiments of water penetration into tablets, hydrophilic MCC was used as a basic component of the tablet, and hydrophobic phenytoin as an active ingredient. The time required for total water penetration of MCC tablets increased with tablet compression pressure, and the rate of water penetration into the tablets increased with phenytoin content.

The present study aimed to clarify, by means of micro-spectroscopy, the mechanism of aggregation of particles into granules during high-shear granulation. We used two types of pharmaceutical granules prepared by high-shear granulator, one containing mefenamic acid and the other containing flavoxate hydrochloride as poorly soluble active pharmaceutical ingredients (APIs). Lactose, cornstarch, and microcrystalline cellulose were used as excipients; and hydroxypropyl cellulose (HPC) was used as the binding agent. The distributions of components in granules were visualized by mapping cross-sections of individual granules with techniques utilizing mid-infrared spectroscopy at the SPring-8 synchrotron radiation facility and micro-Raman spectroscopy. In the distribution maps of mefenamic acid granules, distributions of mefenamic acid, cornstarch, and microcrystalline cellulose overlapped; in flavoxate hydrochloride granules, on the other hand, distributions of flavoxate hydrochloride and lactose overlapped. Assessment of the surface free energy of each component found that ingredients with overlapping distribution had similar surface properties. Therefore, it was revealed that in high-shear granulation, in addition to the granulator operating conditions and general properties of the formulation itself (such as the solubility and particle size of each ingredient), the surface properties of the ingredients and their interrelationships were also factors that determined the aggregation behavior of the particles.

A practical protocol to obtain accurate heat capacity values of pharmaceutical compounds using modulated-temperature differential scanning calorimetry was established. Three pharmaceutical compounds, acetaminophen, indomethacin, and tri-O-methyl-β-cyclodextrin were used as model compounds. Powder samples did not produce reproducible results, presumably due to inclusion of gas in gap of powders that influenced the measured heat capacity and thermal homogeneity in the sample. Thus, the amorphous characteristics were evaluated using quench-cooled samples. Crystalline samples were obtained by partially melting the sample to allow recrystallization using the residual crystal as a template. Optimum sample mass was about 10 mg. Use of too small sample size resulted in poor reproducibility due to localization of the sample in the pan, while too large size resulted in low heat capacity values probably because of heterogeneity of the sample temperature. The optimum modulation period was in the range of 60 s and 90 s, to which the ramp rates of 2°C/min and 1°C/min, respectively, were applied. The ramp amplitude was less significant in the evaluation. This information should help in comprehending basic characteristics of pharmaceutical compounds.

Component crystallization and physical collapse during freeze-drying of aqueous solutions containing protein-stabilizing L-arginine and citric acid mixtures were studied. Freeze-drying microscopy (FDM) and thermal analysis of the solute-mixture frozen solutions showed collapse onset at temperatures (T(c)) approximately 10°C higher than their T(g)'s (glass transition temperatures of the maximally freeze-concentrated solute phase). Experimental freeze-drying of these solutions at a low chamber pressure showed the occurrence of physical collapse at shelf temperatures close to or slightly higher than the T(c). Slower ice sublimation at higher chamber pressures induced the physical collapse from lower shelf temperatures. The large effect of chamber pressures on the collapse-inducing shelf temperatures confirmed significance of the sublimation-related heat loss on the sublimation interface temperature during the primary drying. Drying of the single-solute L-arginine solution resulted in cake-structure solids composed of its anhydrous crystal. Thermal and powder X-ray diffraction (PXRD) analysis suggested slow crystal nucleation of L-arginine dihydrate in the frozen solutions. Characterization of the frozen solutions and freeze-dried solids should enable rational formulation design and process control of amino acid-containing lyophilized pharmaceuticals.

A microcalorimetric method for measurement of the dissolution rate of sodium chloride was presented. The method applied the deconvolution theory to heat conduction microcalorimetry. When a calorimetric curve for the heat of dilution was regarded as the response for a unit impulse input (heat conduction profile), a calorimetric curve for the heat of solution was considered to be the convolution of dissolution profile and heat conduction profile. Thus, the dissolution profile was calculated from the calorimetric curves for the heat of dilution and for the heat of solution by a numerical deconvolution. Dissolution rate determined by the calorimetric method coincided well with that obtained by a titration method.

The purpose of this study was to elucidate the effect of solute miscibility in frozen solutions on their micro- and macroscopic structural integrity during freeze-drying. Thermal analysis of frozen solutions containing poly(vinylpyrrolidone) (PVP) and dextran showed single or multiple thermal transitions (T'g: glass transition temperature of maximally freeze-concentrated solutes) depending on their composition, which indicated varied miscibility of the concentrated noncrystalline polymers. Freeze-drying of the miscible solute systems (e.g., PVP 10,000 and dextran 1060, single T'g induced physical collapse during primary drying above the transition temperatures T'g). Phase-separating PVP 29,000 and dextran 35,000 mixtures (two T'g s) maintained their cylindrical structure following freeze-drying below both of the T'g s (-24 °C). Primary drying of the dextran-rich systems at temperatures between the two T'g s (-20 to -14 °C) resulted in microscopically disordered "microcollapsed" cake-structure solids. Freeze-drying microscopy (FDM) analysis of the microcollapsing polymer system showed locally disordered solid region at temperatures between the collapse onset (T(c1)) and severe structural change (T(c2)). The rigid dextran-rich matrix phase should allow microscopic structural change of the higher fluidity PVP-rich phase without loss of the macroscopic cake structure at the temperature range. The results indicated the relevance of physical characterization and process control for appropriate freeze-drying of multicomponent formulations.

Magnetic resonance imaging (MRI) was used to assess in situ swelling behaviors of spray-dried chitosan acetate (CSA) in 0.1 N HCl, pH 6.8 and pH 5.0 Tris–HCl buffers. The in vitro drug releases from CSA matrix tablets containing the model drugs, diclofenac sodium and theophylline were investigated in all media using USP-4 apparatus. The effect of chitosan molecular weight, especially in pH 6.8 Tris–HCl, was also studied. In 0.1 N HCl, the drug release from the matrix tablets was the lowest in relation to the highest swelling of CSA. The swelling kinetics in Tris–HCl buffers are Fickian diffusion according to their best fit to Higuchi’s model as well as the drug release kinetics in all the media. The high swelling rate ( k s ′ ) was found to delay the drug release rate (k′). The linear relationship between the swelling and fractions of drug release in Tris–HCl buffers was observed, indicating an important role of the swelling on controlling the drug release mechanism. Additionally, CSA of 200 and 800 kDa chitosan did not swell in pH 6.8 Tris–HCl but disintegrated into fractions, and the drug release from the matrix tablets was the highest.

A heat conduction microcalorimeter was used to evaluate the isothermal transition in water from anhydrate to monohydrate at 298 K. Sulfaguanidine (SGN) anhydrate was used as a model compound for the measurement of hydration kinetics in water. It is the well-known that SGN is very slightly soluble in water and capable of existing as the anhydrate or monohydrate form in the solid state. The transition rates of SGN anhydrate to monohydrate in tablets and granules were investigated. The hydration kinetics of tablets with controlled surface areas, obtained by coating the side with paraffin in aqueous solution, followed an apparent zero-order mechanism. On the other hand, the transition mechanism of the granules involved a phase boundary-controlled contracting interface reaction.

Particle-tailoring technique requires significant improvement for wide use of pulmonary route for systemic drug delivery. In this study, the spray-dry method was used to prepare particles using maltose as a model component, with focus on interpretation of the dynamic process during the spray-drying. High-speed camera observation proved that the time required for particle formation was assumed to be on the millisecond scale. The surface tension at 10ms was found to correlate well with both the size of the droplet produced from the spray nozzle and that of the solid particles. The surfactant molecules accumulated spontaneously on the particle surface to improve surface characteristics, including dispersity and hygroscopicity. Addition of polymer molecules made the particle surface rough, which significantly improved particle dispersity. Good correlation was found between the surface roughness and the aerodynamic performance of the particles, which was determined by a cascade impactor. The particle morphology was interpreted in terms of the mass transport of each component during the drying process. This excipient approach seems to be a promising method to prepare fine drug particles of high dispersity for achieving an efficient pulmonary drug delivery.

A fast disintegrating compressed tablet was formulated using amino acids, such as L-lysine HCl, L-alanine, glycine and L-tyrosine as disintegration accelerator. The tablets having the hardness of about 4 kgf were prepared and the effect of amino acids on the wetting time and disintegration time in the oral cavity of tablets was examined on the basis of surface free energy of amino acids. The wetting time of the tablets increased in the order of L-lysine HCl, L-alanine, glycine and L-tyrosine, whereas the disintegration time in the oral cavity of the tablets increased in the order of L-alanine, glycine, L-lysine HCl and L-tyrosine. These behaviors were well analyzed by the introduction of surface free energy. When the polar component of amino acid was large value or the dispersion component was small value, faster wetting of tablet was observed. When the dispersion component of amino acid was large value or the dispersion component was small value, faster disintegration of tablet was observed, expect of L-tyrosine tablet. The fast disintegration of tablets was explained by the theory presented by Matsumaru.

The Eudragit RS and polyethylene glycol 400 (PEG 400) blend polymer (EPG) membranes were prepared by the solvent casting method to pioneer a novel application of Eudragit RS to a thermo-sensitive material. The EPG membranes containing 2.5-10% PEG 400 (2.5-10% EPG) showed the glass transition temperatures (Tgs) around the body temperature (32-42 degrees C). Drug permeation studies through the EPG membranes were carried out using acetaminophen (AAP) and aminopyrine (AMP) as the model drugs. The permeability of AAP and AMP through the EPG membranes has been shown to be a discontinuous function of temperature, that is, their permeability increased steeply above the Tg of the membranes. The amount of AMP permeated at 42 degrees C was nearly eight times as much as that at 36 degrees C. Arrhenius plots of the steady-state permeability coefficient (P) of AAP indicated two straight lines that intersect at the Tg of the 10% EPG membrane. In the water uptake study for the 10% EPG membrane, the degree of the swelling for the membrane tended to increase with increasing temperature above the Tg of the membrane. The thermo-sensitive permeation mechanism for the EPG membranes might be based on the structure change of the membranes caused by the glass transition, so that the membranes could absorb more water. Considering the high biological safety of Eudragit RS and PEG 400, the EPG membranes might be used to develop a novel thermo-sensitive drug delivery system.

Sulfacetamide reacted with phthalic anhydride in the solid state and was gradually converted into phthalylsulfacetamide with mechanical grinding. Formation of phthalylsulfacetamide was confirmed by high pressure liquid chromatography and Fourier transform infrated spectroscopy. The X-ray diffraction pattern of ground powder of sulfacetamide and phthalic anhydride mixture (1 : 1 by molar ratio) gradually became a halo with the formation of phthalylsulfacetamide, indicating that amorphous phthalylsulfacetamide was obtained by the solid-state reaction with mechanical grinding. The solid-state reaction between sulfacetamide and phthalic anhydride also occurred when a mixture of the two was heated. Crystalline phthalylsulfacetamide was formed by the solid-state reaction with heating.

We have proposed a theory indicating the correlation between the dissolution rate and the heat of solution of drug substances. The initial dissolution rates of the drug substances containing amorphous were predicted accurately from their heats of solution. In this report, the possibility for the theory to estimate the dissolution rates of hydrate and polymorphs was examined using thermal analysis. The initial dissolution rates of carbamazepine dihydrate and polymorphs (forms I, II, and III) were measured by the rotating disk method. The heats of solution and the heats of fusion of samples were measured by microcalorimetry and Differential Scanning Calorimetry (DSC), respectively. The logarithm of the initial dissolution rate of the sample was correlated linearly with the heat of fusion as well as the heat of solution. The obtained correlation would be applicable for the quality control of the drug substances that contained hydrate and/or polymorphic forms.