Yasuo Yoshihashi

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.

Quantitative Correlation Between Initial Dissolution Rate and Heat of Solution of Drug

AbstractPurpose. 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. Methods. Polymorphic forms and quenched glass ofindomethacin, and some different crystallinity samples of terfenadine wereused. The heats of solution of samples were measured by isothermalmicrocalorimetry. The initial dissolution rates of samples were measured byrotating disk method at 25°C. Results. Each drug showed a linear correlation between theheats of solution and the logarithms of initial dissolution rate,irrespective of their different crystal structure, such as polymorphic formsand crystallinity. The logarithms of initial dissolution rates were wellcorrelated with the degree of crystallinity obtained by the isothermalmicro-calorimetry. Conclusions. The initial dissolution rates of drugsubstances could be estimated quantitatively from the heats of solution asestimated from the present theory. Isothermal microcalorimetry was extremelyuseful for the estimation of the initial dissolution rates of polymorphs andof partially crystalline samples.

Investigation of the dynamic process during spray-drying to improve aerodynamic performance of inhalation particles

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.

Correlation between Glass-Forming Ability and Fragility of Pharmaceutical Compounds

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.

Relationship between crystallization tendencies during cooling from melt and isothermal storage: toward a general understanding of physical stability of pharmaceutical glasses.

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.

An Investigation of Nifedipine Miscibility in Solid Dispersions Using Raman Spectroscopy

PurposeRaman 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.MethodsSolid 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.ResultsThe 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.ConclusionsRaman 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.

Quantitative correlation between initial dissolution rate and heat of fusion of drug substance.

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.

Estimation of initial dissolution rate of drug substance by thermal analysis: application for carbamazepine hydrate.

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.

Competition of Thermodynamic and Dynamic Factors During Formation of Multicomponent Particles via Spray Drying

As psicose cannot be spray dried because of its low glass transition temperature (T(g)), 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 T(g) 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 T(g) 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 T(g). 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.

Physicochemical and crystal structure analysis of pranlukast pseudo-polymorphs II: Solvate and cocrystal

Pranlukast (PRS) is a leukotriene receptor antagonist for the treatment of bronchial asthma. In this study, six new solvates and one new cocrystal of PRS were characterized by PXRD, TG-DTA, DSC, vapor sorption analysis and the dissolution test. In addition, the crystal structures were determined by single crystal X-ray structure analysis. PRS was found to be a rare example of a promiscuous multicomponent crystal former. The crystal packing patterns of these crystals can be categorized into the sheet-like and channel-like patterns. The ethanol solvate (PRS/ethanol) and urea cocrystal (PRS/urea) were more stable than the others under humid conditions. PRS/ethanol showed an improved dissolution profile compared to PRS HH and PRS/urea.