Evidence for the existence of powder sub-populations in micronized materials : Aerodynamic size-fractions of aerosolized powders possess distinct physicochemical properties

This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.Purpose: To investigate the agglomeration behaviour of the fine ( 12.8 µm) particle fractions of salmeterol xinafoate (SX) and fluticasone propionate (FP) by isolating aerodynamic size fractions and characterising their physicochemical and re-dispersal properties. Methods: Aerodynamic fractionation was conducted using the Next Generation Impactor (NGI). Re-crystallized control particles, unfractionated and fractionated materials were characterized for particle size, morphology, crystallinity and surface energy. Re-dispersal of the particles was assessed using dry dispersion laser diffraction and NGI analysis. Results: Aerosolized SX and FP particles deposited in the NGI as agglomerates of consistent particle/agglomerate morphology. SX particles depositing on Stages 3 and 5 had higher total surface energy than unfractionated SX, with Stage 5 particles showing the greatest surface energy heterogeneity. FP fractions had comparable surface energy distributions and bulk crystallinity but differences in surface chemistry. SX fractions demonstrated higher bulk disorder than unfractionated and re-crystallized particles. Upon aerosolization, the fractions differed in their intrinsic emission and dispersion into a fine particle fraction (< 5.0 µm). Conclusions: Micronized powders consisted of sub-populations of particles displaying distinct physicochemical and powder dispersal properties compared to the unfractionated bulk material. This may have implications for the efficiency of inhaled drug deliveryPeer reviewe

Controlled Crystallization of the Lipophilic Drug Fenofibrate During Freeze-Drying: Elucidation of the Mechanism by In-Line Raman Spectroscopy

We developed a novel process, “controlled crystallization during freeze-drying” to produce drug nanocrystals of poorly water-soluble drugs. This process involves freeze-drying at a relatively high temperature of a drug and a matrix material from a mixture of tertiary butyl alcohol and water, resulting in drug nanocrystals incorporated in a matrix. The aim of this study was to elucidate the mechanisms that determine the size of the drug crystals. Fenofibrate was used as a model lipophilic drug. To monitor the crystallization during freeze-drying, a Raman probe was placed just above the sample in the freeze-dryer. These in-line Raman spectroscopy measurements clearly revealed when the different components crystallized during freeze-drying. The solvents crystallized only during the freezing step, while the solutes only crystallized after the temperature was increased, but before drying started. Although the solutes crystallized only after the freezing step, both the freezing rate and the shelf temperature were critical parameters that determined the final crystal size. At a higher freezing rate, smaller interstitial spaces containing the freeze-concentrated fraction were formed, resulting in smaller drug crystals (based on dissolution data). On the other hand, when the solutes crystallized at a lower shelf temperature, the degree of supersaturation is higher, resulting in a higher nucleation rate and consequently more and therefore smaller crystals. In conclusion, for the model drug fenofibrate, a high freezing rate and a relatively low crystallization temperature resulted in the smallest crystals and therefore the highest dissolution rate

Predicting the aerosol performance of dry powder inhalation formulations by interparticulate interaction analysis using inverse gas chromatography

Previous studies have demonstrated the utility of inverse gas chromatography (IGC) in discriminating the differences in surface energy between salmeterol xinafoate (SX) powders prepared by conventional sequential batch crystallization and micronization and by supercritical fluid crystallization. In the present study, solubility parameters derived from IGC analysis at infinite dilution (zero coverage) were further utilized to evaluate the influence of solid-solid interactions on the in vitro aerosol performance of these SX samples, with or without the inclusion of a lactose carrier. To this end, the strength of cohesive SX-SX interactions and that of adhesive SX-lactose interactions were computed for the samples from the corresponding solubility parameters, and their fine particle fractions determined using a multi-stage liquid impinger. It was found that the aerosol performance of SX could be substantially improved by the addition of lactose carrier only if the adhesive SX-lactose interactions were stronger than the cohesive SX-SX interactions. The difference in strength between these two forms of interactions also displayed a significant correlation with the increase in fine particle fraction after the addition of lactose carrier. These results suggest that IGC-based interparticulate interaction measurements may serve as a useful means for predicting the aerosol performance of dry powder inhalation formulations. (c) 2005 Wiley-Liss, Inc

Influence of polymorphism on the surface energetics of salmeterol xinafoate crystallized from supercritical fluids

Purpose. To characterize the surface thermodynamic properties of two polymorphic forms (I and II) of salmeterol xinafoate (SX) prepared from supercritical fluids and a commercial micronized SX (form I) sample (MSX). Methods. Inverse gas chromatographic analysis was conducted on the SX samples at 30, 40, 50, and 60degreesC using the following probes at infinite dilution: nonpolar probes (NPs; alkane C5-C9 series); and polar probes (PPs; i.e., dichloromethane, chloroform, acetone, ethyl acetate, diethyl ether, and tetrahydrofuran). Surface thermodynamic parameters of adsorption and Hansen solubility parameters were calculated from the retention times of the probes. Results. The free energies of adsorption (-DeltaG(A)) of the three samples obtained at various temperatures follow this order: SX-II > MSX approximate to SX-I for the NPs; and SX-II > MSX > SX-I for the PPs. For both NPs and PPs, SX-II exhibits a less negative enthalpy of adsorption (DeltaH(A)) and a much less negative entropy of adsorption (DeltaS(A)) than MSX and SX-I, suggesting that the high -DeltaG(A) of SX-II is contributed by a considerably reduced entropy loss. The dispersive component of surface free energy (gamma(s)(D)) is the highest for MSX but the lowest for SX-II at all temperatures studied, whereas the specific component of surface free energy of adsorption (-DeltaG(A)(S)P) is higher for SX-II than for SX-I. That SX-II displays the highest -DeltaG(A) for the NP but the lowest gamma(s)(D) of all the SX samples may be explained by the additional -DeltaG(A) change associated with an increased mobility of the probe molecules on the less stable and more disordered SX-II surface. The acid and base parameters, K-A and K-D, that were derived from DeltaH(A)(S)P reveal significant differences in the relative acid and base properties among the samples. The calculated Hansen solubility parameters (delta(D), delta(P), and delta(H)) indicate that the surface of SX-II is the most polar and most energetic of all the three samples in terms of specific interactions (mostly hydrogen bonding). Conclusions. The metastable SX-II polymorph possesses a higher surface free energy, higher surface entropy, and a more polar surface than the stable SX-I polymorph

Characterization of two polymorphs of salmeterol xinafoate crystallized from supercritical fluids

Purpose. To characterize two polymorphs of salmeterol xinafoate (SX-I and SX-II) produced by supercritical fluid crystallization. Methods. SX-I and SX-II were crystallized as fine powders using Solution Enhanced Dispersion by Supercritical Fluids (SEDS). The two polymorphs and a reference micronized SX sample (MSX) were characterized using powder X-ray diffractometry (PXRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), aqueous solubility (and dissolution) determination at 5-40 degreesC, BET adsorption analysis, and inverse gas chromatography (IGC). Results. Compared with SX-T, SX-II exhibited a lower enthalpy of fusion, a higher equilibrium solubility, a higher intrinsic dissolution rate, a lower enthalpy of solution (based on van't Hoff solubility plots), and a different FTIR spectrum (reflecting differences in intermolecular hydrogen bonding). Solubility ratio plot yielded a transition temperature (similar to 99 degreesC) below the melting points of both polymorphs. MSX showed essentially the same crystal form as SX-T (confirmed by PXRD and FTIR), but a distinctly different thermal behaviour. Mild trituration of SX-I afforded a similar DSC profile to MSX while prolonged grinding of SX-I gave rise to an endotherm at similar to 109 degreesC, corresponding to solid-solid transition of SX-I to SX-II Surface analysis of MSX, SX-I, and SX-LI by IGC revealed significant differences in surface free energy in terms of both dispersive (nonpolar) interactions and specific (polar) acid-base properties. Conclusions. The SEDS-processed SX-I and SX-II display high polymorphic purity and distinctly different physical and surface properties. The: polymorphs are related enantiotropically with SX-T being the thermodynamically stable form at room temperature

Aerosolisation behaviour of micronised and supercritically-processed powders

Comparative analysis of salmeterol xinafoate (SX) powders was carried out to define the aerodynamic properties and mechanism of particle dispersion relevant to the use of these materials in dry powder inhalation drug delivery. Particle sizing methodology was evaluated using laser diffraction, time-of-flight and Andersen cascade impactor measurements combined with electron microscopy and surface area determination. Particle interactions, assessed on the basis of powder bulk density and inverse gas chromatography surface energy measurements, were compared with the aerodynamic forces generated by a dry-powder dispersion device. The supercritically produced material showed by a factor of seven reduced tensile strength of the aggregates and indicated a two-fold increase of fine particle fraction deposited in a cascade impactor when blended with lactose. This effect was explained by the reduced particle aggregation at low differential air pressures and flow rates. A relatively small value of aerodynamic stress required to disperse supercritically produced particles in comparison to micronized material comes from: (a) lower bulk density (loose aggregate structure), (b) larger volume mean diameter, (c) larger aerodynamic shape factor and (d) smaller specific free energy of S-SX particles, in this order of priority. It is shown that aggregation between primary drug particles is important for SX/lactose formulations because such aggregates survive the pre-separation impactor stage. (C) 2003 Elsevier Science Ltd. All rights reserved

An improved thermoanalytical approach to quantifying trace levels of polymorphic impurity in drug powders

Accurate quantification of impurities existing as separate crystalline phases at trace levels in drug materials is an important issue in the pharmaceutical industry. In the present study, a thermoanalytical approach previously developed for quantifying trace levels of polymorphic impurity (form II metastable nuclei) in commercial salmeterol xinafoate powders has been successfully applied with slight modifications to ribavirin, an antiviral drug exhibiting roughly similar polymorph-dependent crystallization kinetics in melts to that of salmeterol xinafoate. Essentially, the approach involved modeling of the crystallization kinetics of both tested and reference drug materials in melts using the Avrami-Erofe'ev (AE) rate expression, derivation of a mathematical equation for relating the AE kinetic constant to the composition of reference polymorph mixtures, and the use of this derived equation (in the form of a calibration curve) to calculate the impurity contents of the tested samples from their computed AE constants. For ribavirin, modification of the latter equation by incorporation of an empirical exponent was found necessary to account for the composition-dependent changes in crystallization kinetics of the reference mixtures. Such modification has made possible the determination of polymorphic impurity content of as low as 0.004% (w/w) in ribavirin samples induced by different forms of grinding treatment. &COPY; 2005 Elsevier B.V. All rights reserved