Boris Y. Shekunov

Particle Engineering for Pulmonary Drug Delivery

With the rapidly growing popularity and sophistication of inhalation therapy, there is an increasing demand for tailor-made inhalable drug particles capable of affording the most efficient delivery to the lungs and the most optimal therapeutic outcomes. To cope with this formulation demand, a wide variety of novel particle technologies have emerged over the past decade. The present review is intended to provide a critical account of the current goals and technologies of particle engineering for the development of pulmonary drug delivery systems. These technologies cover traditional micronization and powder blending, controlled solvent crystallization, spray drying, spray freeze drying, particle formation from liquid dispersion systems, supercritical fluid processing and particle coating. The merits and limitations of these technologies are discussed with reference to their applications to specific drug and/or excipient materials. The regulatory requirements applicable to particulate inhalation products are also reviewed briefly.

Particle Size Analysis in Pharmaceutics: Principles, Methods and Applications

AbstractPhysicochemical and biopharmaceutical properties of drug substances and dosage forms can be highly affected by the particle size, a critical process parameter in pharmaceutical production. The fundamental issue with particle size analysis is the variety of equivalent particle diameters generated by different methods, which is largely ascribable to the particle shape and particle dispersion mechanism involved. Thus, to enable selection of the most appropriate or optimal sizing technique, cross-correlation between different techniques may be required. This review offers an in-depth discussion on particle size analysis pertaining to specific pharmaceutical applications and regulatory aspects, fundamental principles and terminology, instrumentation types, data presentation and interpretation, in-line and process analytical technology. For illustration purposes, special consideration is given to the analysis of aerosols using time-of-flight and cascade impactor measurements, which is supported by a computational analysis conducted for this review.

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.

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

AbstractPurpose. 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 60°C 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 (-ΔGA) of the three samples obtained at various temperatures follow this order: SX-II > MSX ≈ 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 (ΔHA) and a much less negative entropy of adsorption (ΔSA) than MSX and SX-I, suggesting that the high -ΔGA of SX-II is contributed by a considerably reduced entropy loss. The dispersive component of surface free energy (γsD) 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 (-ΔGASP) is higher for SX-II than for SX-I. That SX-II displays the highest -ΔGA for the NP but the lowest γsD of all the SX samples may be explained by the additional -ΔGA 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, KA and KD, that were derived from ΔHASP reveal significant differences in the relative acid and base properties among the samples. The calculated Hansen solubility parameters (δD, δP, and δH) 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.

Surface tension of ethanol in supercritical CO2

Abstract Laser interferometric microscopy, applied in this work, enabled simultaneous measurements of the droplet surface tension, σ, and the surface solvent composition. The data, obtained within the temperature interval 313.15–363.15 K and pressure range 60–135 bar, indicated a significantly lower dynamic surface tension compared to the equilibrium. The apparent mixture critical pressures (mcps), determined by zero-σ extrapolation of the equilibrium isotherms, were in an agreement with the theoretical predictions obtained from the Peng-Robinson EOS. A quantitative description of σ based on parachor method indicated the best fit scaling exponent ranging from 3.3 to 3.98 for different temperatures, with mean absolute deviations ±3%. The concentration gradient of ethanol in the droplet diffusion boundary layer accounted for the variation of σ and apparent mcp in the non-equilibrium case.

Refractive index of supercritical CO 2 -ethanol solvents

In-line analysis of refractive index is required for efficient design and monitoring of supercritical fluid extraction and precipitation processes. In the present work, a robust method has been developed based on measurements of laser beam deviation using an interferometer and image processing system. Data on refractive index of CO 2 -ethanol mixtures were obtained at pressures between 70 and 200 bar and temperatures between 308 and 363 K, for continuous flow of premixed solvents and, in addition, for equilibrium gas phase below the mixture critical pressure. The refractive index of a mixture is a linear function of ethanol mole fraction and can adequately describe mixing and phase behavior in the vessel. For pure CO 2 , refractive index was determined as a function of pressure and density and its Lorentz-Lorenz functions determined.

Dielectric Analysis of Phosphorylcholine Head Group Mobility in Egg Lecithin Liposomes

AbstractPurpose. A knowledge of the interfacial properties of lecithin underpins our understanding of many of the physicochemical characteristics of drug delivery systems such as liposomes and lecithin stabilized microemulsions. In order to further this understanding, a high frequency dielectric study of the interfacial properties of egg lecithin liposomes was undertaken. Methods. The effect of temperature, lecithin concentration and probe sonication on the interfacial dielectric properties of liposomal suspensions was investigated by high frequency dielectric relaxation spectroscopy between 0.2–6 GHz. Results. The frequency dependent permittivity of each suspension exhibited a dielectric dispersion centred around 100 MHz, corresponding to the relaxation of zwitterionic head groups. The activation energy for head group reorientation was estimated as ΔH = 6.3 kJ mol−1. There was an increase in extent of inter-head group interactions on increasing the liposome volume fraction, whereas the effect of probe sonication showed that: (i) head groups in both the outer and inner lamellae contribute to the dielectric response; (ii) the head groups may be less restricted in liposomes of high surface curvature with few lamellae; (iii) the high frequency permittivity of the suspension increased on sonication, as a result of a reduction in the amount of (depolarized) interlamellar water following a reduction in the number of lamellae per liposome. Conclusions. Dielectric analysis of the zwitterionic head groups of lecithin therefore provides a means for investigating the surface of lecithin liposomes, and may be used to investigate the effect of drugs and other solutes on membranes.

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

Abstract 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.

Determination of solubility of paracetamol in supercritical carbon dioxide

Solubility is a critical parameter influencing all particle formation processes which involve precipitation using supercritical fluids. SEDS, (solution enhanced dispersion by supercritical fluids, York & Hanna 1996) has been developed in our laboratory to achieve a rapid expansion/precipitation process in a highly turbulent flow of solvent modified supercritical carbon dioxide (SF-C02). The substance is rapidly dispersed within the fluid as the carrier solvent is simultaneously extracted. The present work is researching analytical techniques to optimise process crystallisation conditions based upon SF-CO2 solubility behaviour. Temperatures between 40 and 8OOC and pressures between 80 and 300 bar were investigated using the model compound paracetamol. Both pure SF-CO2 or SFC02 modified with ethanol have been investigated. The equilibrium (static) solubility is measured using a closed system. SF-CO2 at defined temperature and pressure is continuously passed over a bed of drug substance coated onto glass beads using a magnetic recirculation pump. Samples of the equilibrated mixture are quantified using HPLC. When estimating the SEDS effluent (non-equilibrium) solubility the fluid exiting from the particle formation vessel containing the drug is trapped using cooled ethanol and then analysed off-line by HPLC. The total C 0 2 effluent mass is determined using a digital flow meter enabling calculation of the solubility of paracetamol in the effluent SF-CO2. In addition an extraction method has been devised to analyse the dissolution kinetics of paracetamol. A bed of drug substance coated onto glass beads is packed into a high pressure vessel. The extractant fluid is pumped through the vessel and is then analysed using an on-line HPLC UV detector equipped with a high pressure flow cell. Cooled ethanol is also used to trap the effluent from the detector before it passes through a digital flow meter. The on-line detector response is calibrated using standard solutions of paracetamol in ethanol. This technique was also validated by off-line HPLC analysis of the trap contents, the results agreeing well with the on-line analysis. By elevating the temperature from 40 to 80°C at 245 bar the equilibrium solubility of paracetamol increased from 5.75~10-6 to 1.51~10-5 (mole fraction) in pure SF-CO2. At 40°C and 245 bar, the equilibrium solubility was enhanced to 8.42~10-6 in ethanol-modified SF-CO2 (0.85% mole percent). At 80°C and 245 bar the solubility also increased to 1.71~10-5 (mole fraction) in ethanol modified SF-CO2. These findings were confirmed by the effluent analysis. Furthermore, increasing the velocity of turbulent SF-CO2 under identical process conditions significantly reduced the residual concentration of paracetamol in the SEDS effluent. At 40°C and 200 bar increasing the solution flow (and hence the level of ethanol modification) also enhanced the residual concentration of paracetamol into the effluent, which is in agreement with the equilibrium solubility data. The extraction analysis correlated well with data obtained from both the equilibrium and effluent analyses and provides a rapid and reliable determination of the solubility behaviour of paracetamol.