Henry H.Y. Tong

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.

Spray freeze drying with polyvinylpyrrolidone and sodium caprate for improved dissolution and oral bioavailability of oleanolic acid, a BCS Class IV compound

Spray-freeze-drying (SFD) of oleanolic acid (OA), a BCS Class IV compound, with polyvinylpyrrolidone-40 (PVP-40) as stabilizer and sodium caprate (SC) as wetting agent and penetration enhancer produced kinetically stable, amorphous solid dispersion systems with superior in vitro dissolution performance, and better and more uniform absorption in comparison with commercial OA tablet. Relative to the SC-free formulation, the presence of SC in the formulation resulted in a significant increase in the in vivo absorption rate of OA while exerting no apparent impact on the extent of OA absorption. The SFD-processed OA formulations and commercial OA tablet generally exhibited large inter-animal variability in oral bioavailability, consistent with the absorption characteristics of BCS Class IV compounds. Inclusion of SC coupled with the replacement of OA with its sodium salt (OA-Na) in the formulation was shown to substantially decrease the observed absorption variability. Above results suggested that increases in both dissolution rate and intestinal permeability of BCS Class IV compounds, as exemplified by the SFD-processed dispersion system containing both OA-Na and SC, are critical to reducing the large inter-individual absorption variability commonly observed with this class of drugs.

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.

Anti-hygroscopic effect of dextrans in herbal formulations

Equilibrium moisture sorptions of two dried aqueous herbal extracts and their mixtures with dextrans of various molecular weights were investigated as a function of relative humidity at ambient temperature, and the data were analyzed by both the Guggenheim-Anderson-deBoer (GAB) and Brunauer-Emmett-Teller (BET) equations. Glass transition temperatures (T(g)) of the samples were measured by differential scanning calorimetry, and their dependence on the moisture contents of the extracts was analyzed by the linear, Fox and expanded Gordon-Taylor mathematical models. All dextran-extract mixtures exhibited single T(g) values, indicating that they existed as single homogeneous phases. The BET equation was found adequate for description of the moisture sorption isotherms for all samples. The dextrans appeared to reduce the hygroscopicity of the herbal extracts solely by a dilution effect. The observed increase in T(g) and accompanying decrease in tackiness of the herbal extracts in the presence of dextrans may be explained by the ability of dextrans to restrict the molecular mobility of simple sugars and to counteract the plasticizing effect of water in the extracts. The expanded Gordon-Taylor equation has proved useful in predicting the T(g) of hygroscopic amorphous herbal mixtures.

Physical characterization of oleanolic acid nonsolvate and solvates prepared by solvent recrystallization.

Oleanolic acid is a naturally occurring compound used clinically in China for the treatment of hepatitis B. The solid-state chemistry of oleanolic acid recrystallized from a variety of solvents was investigated. Glassy materials were prepared from dichloromethane and chloroform solvents. The oleanolic acid non-solvate prepared from acetone (OA-acetone), and the two oleanolic acid solvates prepared from methanol (OA-methanol) and ethanol (OA-ethanol) were physicochemically characterized. Upon desolvation, both the methanol and ethanol solvates were found to undergo phase transformation to a crystalline phase similar to OA-acetone around 190-195 degrees C. The PXRD patterns of commercial pharmaceutical grade OA and the OA-methanol were similar, so the commercial form is probably desolvated oleanolic acid methanol solvate.

Process‐Induced Phase Transformation of Berberine Chloride Hydrates

Berberine is a natural quaternary ammonium alkaloid used clinically in the chloride salt form for the treatment of diarrhea in many Asian countries. Although the hydrate formation of berberine chloride (BCl) is well documented, the associated mechanism and implications in pharmaceutical formulation have not been studied in detail. In this study, pure BCl dihydrate and BCl tetrahydrate were recrystallized from water and their phase transformation behaviors under defined conditions were investigated. Additionally, pharmacopoeial grade BCl material consisting predominantly of the dihydrate form was examined for potential phase changes when being subjected to a conventional wet granulation procedure for tablet production. Results from solubility measurements, thermal analysis, variable temperature-powder X-ray diffraction (VT-PXRD), and variable temperature-Fourier transform infrared spectroscopy (VT-FTIR) confirmed the solid-state interconversions between the tetrahydrate and dihydrate at 30-49 degrees C and between the dihydrate and anhydrate at 70-87 degrees C. Consistent with the observed phase changes of the two pure hydrates, wet massing of the pharmacopoeial grade BCl sample led to a thermodynamics-driven transition to the tetrahydrate form at room temperature while subsequent tray drying at 50 degrees C caused a reversion back to the dihydrate form. The rate and extent of such hydrate conversion depended largely on the water activity of the granulated powder matrix, which in turn was governed by the particular excipients employed. The present findings have important implications in the regulation of the hydrate forms of BCl in the finished products using specific excipients.

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.

Resveratrol cocrystals with enhanced solubility and tabletability

Two new 1:1 cocrystals of resveratrol (RES) with 4-aminobenzamide (RES-4ABZ) and isoniazid (RES-ISN) were synthesized by liquid assisted grinding (LAG) and rapid solvent removal (RSR) methods using ethanol as solvent. Their physiochemical properties were characterized using PXRD, DSC, solid state and solution NMR, FT-IR, and HPLC. Pharmaceutically relevant properties, including tabletability, solubility, intrinsic dissolution rate, and hygroscopicity, were evaluated. Temperature-composition phase diagram for RES-ISN cocrystal system was constructed from DSC data. Both cocrystals show higher solubility than resveratrol over a broad range of pH. They are phase stable and non-hygroscopic even under high humidity conditions. Importantly, both cocrystals exhibit improved solubility and tabletability compared with RES, which make them more suitable candidates for tablet formulation development.