Insights into Spray Development from Metered-Dose Inhalers Through Quantitative X-ray Radiography.

PURPOSE: Typical methods to study pMDI sprays employ particle sizing or visible light diagnostics, which suffer in regions of high spray density. X-ray techniques can be applied to pharmaceutical sprays to obtain information unattainable by conventional particle sizing and light-based techniques. METHODS: We present a technique for obtaining quantitative measurements of spray density in pMDI sprays. A monochromatic focused X-ray beam was used to perform quantitative radiography measurements in the near-nozzle region and plume of HFA-propelled sprays. RESULTS: Measurements were obtained with a temporal resolution of 0.184 ms and spatial resolution of 5 µm. Steady flow conditions were reached after around 30 ms for the formulations examined with the spray device used. Spray evolution was affected by the inclusion of ethanol in the formulation and unaffected by the inclusion of 0.1% drug by weight. Estimation of the nozzle exit density showed that vapour is likely to dominate the flow leaving the inhaler nozzle during steady flow. CONCLUSIONS: Quantitative measurements in pMDI sprays allow the determination of nozzle exit conditions that are difficult to obtain experimentally by other means. Measurements of these nozzle exit conditions can improve understanding of the atomization mechanisms responsible for pMDI spray droplet and particle formation.

Investigation of the potential for direct compaction of a fine ibuprofen powder dry-coated with magnesium stearate.

Intensive dry powder coating (mechanofusion) with tablet lubricants has previously been shown to give substantial powder flow improvement. This study explores whether the mechanofusion of magnesium stearate (MgSt), on a fine drug powder can substantially improve flow, without preventing the powder from being directly compacted into tablets. A fine ibuprofen powder, which is both cohesive and possesses a low-melting point, was dry coated via mechanofusion with between 0.1% and 5% (w/w) MgSt. Traditional low-shear blending was also employed as a comparison. No significant difference in particle size or shape was measured following mechanofusion. For the low-shear blended powders, only marginal improvement in flowability was obtained. However, after mechanofusion, substantial improvements in the flow properties were demonstrated. Both XPS and ToF-SIMS demonstrated high degrees of a nano-scale coating coverage of MgSt on the particle surfaces from optimized mechanofusion. The study showed that robust tablets were produced from the selected mechanofused powders, at high-dose concentration and tablet tensile strength was further optimized via addition of a Polyvinylpyrrolidone (PVP) binder (10% w/w). The tablets with the mechanofused powder (with or without PVP) also exhibited significantly lower ejection stress than those made of the raw powder, demonstrating good lubrication. Surprisingly, the release rate of drug from the tablets made with the mechanofused powder was not retarded. This is the first study to demonstrate such a single-step dry coating of model drug with MgSt, with promising flow improvement, flow-aid and lubrication effects, tabletability and also non-inhibited dissolution rate.

A novel high-speed imaging technique to predict the macroscopic spray characteristics of solution based pressurised metered dose inhalers.

PURPOSE: Non-volatile agents such as glycerol are being introduced into solution-based pMDI formulations in order to control mean precipitant droplet size. To assess their biopharmaceutical efficacy, both microscopic and macroscopic characteristics of the plume must be known, including the effects of external factors such as the flow generated by the patient's inhalation. We test the hypothesis that the macroscopic properties (e.g. spray geometry) of a pMDI spray can be predicted using a self-similarity model, avoiding the need for repeated testing. METHODS: Glycerol-containing and glycerol-free pMDI formulations with matched mass median aerodynamic diameters are investigated. High-speed schlieren imaging is used to extract time-resolved velocity, penetration and spreading angle measurements of the pMDI spray plume. The experimental data are used to validate the analytical model. RESULTS: The pMDI spray develops in a manner characteristic of a fully-developed steady turbulent jet, supporting the hypothesis. Equivalent glycerol-containing and non glycerol-containing formulations exhibit similar non-dimensional growth rates and follow a self-similar scaling behaviour over a range of physiologically relevant co-flow rates. CONCLUSIONS: Using the proposed model, the mean leading edge penetration, velocity and spreading rate of a pMDI spray may be estimated a priori for any co-flow conditions. The effects of different formulations are captured in two scaling constants. This allows formulators to predict the effects of variation between pMDIs without the need for repeated testing. Ultimately, this approach will allow pharmaceutical scientists to rapidly test a number of variables during pMDI development.

Effect of surface coating with magnesium stearate via mechanical dry powder coating approach on the aerosol performance of micronized drug powders from dry powder inhalers.

The objective of this study was to investigate the effect of particle surface coating with magnesium stearate on the aerosolization of dry powder inhaler formulations. Micronized salbutamol sulphate as a model drug was dry coated with magnesium stearate using a mechanofusion technique. The coating quality was characterized by X-ray photoelectron spectroscopy. Powder bulk and flow properties were assessed by bulk densities and shear cell measurements. The aerosol performance was studied by laser diffraction and supported by a twin-stage impinger. High degrees of coating coverage were achieved after mechanofusion, as measured by X-ray photoelectron spectroscopy. Concomitant significant increases occurred in powder bulk densities and in aerosol performance after coating. The apparent optimum performance corresponded with using 2% w/w magnesium stearate. In contrast, traditional blending resulted in no significant changes in either bulk or aerosolization behaviour compared to the untreated sample. It is believed that conventional low-shear blending provides insufficient energy levels to expose host micronized particle surfaces from agglomerates and to distribute guest coating material effectively for coating. A simple ultra-high-shear mechanical dry powder coating step was shown as highly effective in producing ultra-thin coatings on micronized powders and to substantially improve the powder aerosolization efficiency.

Powder strength distributions for understanding de-agglomeration of lactose powders.

PURPOSE: The purpose was to calculate distributions of powder strength of a cohesive bed to explain the de-agglomeration of lactose. METHODS: De-agglomeration profiles of Lactohale 300(®) (L300) and micronized lactose (ML) were constructed by particle sizing aerosolised plumes dispersed at air flow rates of 30-180 l/min. The work of cohesion distribution was determined by inverse gas chromatography. The primary particle size and tapped density distributions were determined. Powder strength distributions were calculated by Monte Carlo simulations from distributions of particle size, work of cohesion and tapped density measurements. RESULTS: The powder strength distribution of L300 was broader than that of ML. Up to 85th percentile, powder strength of L300 was lower than ML which was consistent with the better de-agglomeration of L300 at low flow rates. However, ~15% of L300 particles had higher powder strength than ML which likely to cause lower de-agglomeration for L300 at high air flow rates. CONCLUSION: Cohesive lactose powders formed matrices of non-homogenous powder strength. De-agglomeration of cohesive powders has been shown to be related to powder strength. This study provided new insights into powder de-agglomeration by a new approach for calculating powder strength distributions to better understand complex de-agglomeration behaviour.

Determination of the polar and total surface energy distributions of particulates by inverse gas chromatography.

This Letter reports a technique of measuring polar surface energy distributions of lactose using inverse gas chromatography (IGC). The significance of this study is that the total surface energy distributions can now be characterized by combining the already known dispersive surface energy distribution with polar surface energy distribution determined in this study. The polar surface energy was calculated from the specific free energies for surface interactions with a monopolar basic probe, ethyl acetate, and a monopolar acidic probe, dichloromethane.

The effect of mechanical dry coating with magnesium stearate on flowability and compactibility of plastically deforming microcrystalline cellulose powders.

Mechanofusion is a dry coating method that can be used to improve the flowability of cohesive powder by coating host particles with a lubricant, for example magnesium stearate (MgSt). It has been shown previously that fragmenting material can under some circumstances be mechanofused with MgSt without impairing compactibility of the powder and without reducing the dissolution rate of the resulting tablets. However, the effects on material with viscoelastic behaviour, known to be sensitive for the negative effects of MgSt, is not known. Therefore, mechanofusion of microcrystalline cellulose (MCC) with MgSt was investigated in this study. Four MCC grades were mechanofused with different MgSt concentrations and process parameters, and the resulting flowability and compactibility were studied. Starting materials and low-shear blended binary mixtures were studied as a reference. Mechanofusion improved the flow properties of small particle size MCC powders (d50 < 78 µm) substantially, but increasing the MgSt content consequently resulted in weaker tablets. Larger particle size MCC grades, however, fractured under the shear forces during the mechanofusion process and hence their flow properties were decreased. Improvement of the flow properties but also the negative effects on compactibility of small particle size grades were observed even at relatively mild mechanofusion parameters and low lubricant concentrations.

Enhancement of the dissolution of indomethacin in interactive mixtures using added fine lactose.

The objective of the study was to investigate the effect of fine lactose on the in vitro dissolution of indomethacin in interactive mixtures containing spray-dried lactose and lactose monohydrate (106-250 microm). Dissolution of the indomethacin was measured using an automated dissolution apparatus following the USP paddle method at 100 rpm. The particle size distributions of indomethacin mixtures were measured using a Mastersizer S under non-sink conditions. Data fitted bi-exponential or tri-exponential dissolution models, representing dissolution from dispersed and agglomerated particle distributions. The addition of fine lactose (VMD 3.8+/-0.4 microm) to 20% indomethacin-coarse lactose mixtures resulted in significantly increased rates of dissolution caused by increases in the estimated dissolution rate constants for dispersed particles (Kd) and by de-agglomeration. Agglomerates in the mixture showed little tendency to comminute under shear pressure. De-agglomeration in the dissolution medium was attributed to increased porosity of agglomerates, caused by dissolution of water soluble fine lactose in the agglomerate structure. The median particle size (D50) of the dispersed particle distribution decreased with increasing concentrations of added fine lactose, indicating increasing extents of de-agglomeration, and a good correlation between Kd and (D50)2 resulted for the coarse lactose-based mixtures (R2>0.984).

Adhesion and redistribution of salmeterol xinafoate particles in sugar-based mixtures for inhalation.

The aim of this study was to evaluate coarse and fine sugars as potential alternative excipients in dry powder inhalation formulations and to develop a greater understanding of the key interactions between the particulate species in these mixtures. Interactive mixtures composed of salmeterol xinafoate (SX) and different type of sugars (lactose, glucose, mannitol and sorbitol) were prepared using validated laboratory scale mixing. The sugars and SX were characterised by laser diffraction, scanning electron microscopy, atomic force microscopy and loss on drying method. Deposition of SX was measured using a twin-stage impinger and analysed using validated HPLC method (r(2)=1.0, CV=0.4-1.0%). Good correlation existed between the fine particle fraction (FPF) of SX and both the adhesion force and the moisture content. The addition of 10% fine sugars to produce ternary mixtures (i.e. SX, coarse and fine sugars) generally increased dispersion, with the addition of fine glucose>fine mannitol>fine lactose>fine sorbitol. The dispersion of SX showed a reciprocal relationship with the moisture content of the sugars with glucose showing the greatest and sorbitol showing the lowest extent of SX dispersion. The study clearly demonstrated that strong SX adhesion to coarse sugars reduced the extent of dispersion and that surface detachment of the SX and fine sugar from the coarse sugar carrier was important in the dispersion process.

Single-step Coprocessing of Cohesive Powder via Mechanical Dry Coating for Direct Tablet Compression.

This study aims at testing the feasibility of a single-step coating process to produce a powder formulation of active and inactive ingredients for direct compression. A cohesive ibuprofen powder was coprocessed with a coating material, a binder (polyvinylpyrrolidone K25), and a superdisintegrant (crospovidone). Magnesium stearate (MgSt), l-leucine, and silica were selected as coating materials (1% w/w). A coprocessed powder without any coating material was employed as a control. Coating with MgSt, l-leucine, or silica produced significantly improved powder flow in comparison to the control batch. Robust tablets were produced from the processed powders for each coating material. The tablets compacted using the coated powders with MgSt or l-leucine also exhibited significantly lower tablet ejection forces than the control batch, demonstrating their lubrication effect. Furthermore, the disintegration time and dissolution rates of these tablets made of the formulations coprocessed with lubricants were enhanced, even for those coated with the hydrophobic material such as MgSt that has been previously reported to inhibit dissolution. However, the tablets made with silica-coated powders would not disintegrate. This study indicated the feasibility of a single-step dry coating process to produce powders with both flow-aid and lubrication effects, which are suitable for direct compression.

The influence of lung surfactant liquid crystalline nanostructures on respiratory drug delivery.

The respiratory route increasingly has been used for both local and systemic drug delivery. Although drug is absorbed rapidly after respiratory delivery, the role of lung surfactant in drug delivery is not well understood. The human lung contains only around 15mL of surface lining fluid spread over ∼100m2 surface. The fluid contains lung surfactant at a concentration of 8-24mg/kg/body weight; the lung surfactant which is lipo-protein in nature can form different liquid crystalline nanostructures. After a brief overview of the anatomy of respiratory system, the review has focused on the current understanding of lung surface lining fluid, lung surfactants and their composition and possible self-assembled nanostructures. The role of lung surfactant in drug delivery and drug dissolution has been briefly considered. Lung surfactant may form different liquid crystalline phases which can have an active role in drug delivery. The hypotheses developed in this review focuses on the potential roles of surface epithelial fluid containing liquid crystalline nanostructures in defining the dissolution mechanism and rate. The hypotheses also focus an understanding how liquid crystalline nanostructures can be used to control dissolution rate and how the nanostructures might be changed to influence delivery and induce toxicity.

Understanding agglomeration of indomethacin during the dissolution of micronised indomethacin mixtures through dissolution and de-agglomeration modeling approaches.

The purpose of this research was to correlate the state of agglomeration determined by the modeling of dissolution and de-agglomeration profiles, using mixtures of micronised indomethacin designed to have different dissolution rates and extents of particle agglomeration in dissolution media. Dissolution profiles were determined using the USP paddle method. De-agglomeration profiles were obtained from laser diffraction particle sizing of mixtures of indomethacin in dissolution media under non-sink conditions. Data were modeled and key parameters estimated using a non-linear least squares estimation algorithm. The key parameters of initial apparent volume concentrations as dispersed and agglomerated particles, and dissolution rate constants (for dissolution modeling), and the apparent volume concentrations of dispersible and non-dispersible agglomerates and the de-agglomeration rate constant (for de-agglomeration modeling) were related to indomethacin and sodium lauryl sulphate concentrations in the lactose-povidone mixtures. Micronised sodium lauryl sulphate added to the mixture was more effective in de-agglomeration than equivalent concentrations in the dissolution media. An excellent correlation existed between the total initial apparent volume concentration of agglomerates determined by dissolution and de-agglomeration (P=0.98). The use of key parameters estimated from the modeling of dissolution and de-agglomeration profiles provides a useful tool in dosage form development of formulations of poorly water soluble drugs.

Surface Energy Determined by Inverse Gas Chromatography as a Tool to Investigate Particulate Interactions in Dry Powder Inhalers.

Dry powder inhalers (DPIs) usually contain drug particles <6 µm which agglomerate and/ or adhere on the surfaces of large carriers particles. The detachment of drug particles from carriers and de-agglomeration of drug particles into primary particles is essential for drug deposition in the deep lung. These processes are influenced by the surface energy of particles. Inverse gas chromatography (IGC) has been used to determine the surface energy of powder particles used in DPI to characterize materials and to understand aerosolization behaviour. Early studies used an infinite dilution technique to determine nonpolar surface energy and free energy of adsorption for polar interactions separately. Although some correlations were observed with the change in nonpolar surface energy before and after micronization, milling and storage, a lack of consistency in the change of free energy of adsorption was common. Moreover, a consistent relationship between complex de-agglomeration behaviour and surface energy has not been established and there are even some examples of negative correlation. In fact, nonpolar surface energy at infinite dilution is an incomplete representation of powder surface characteristics. The techniques for measuring polar surface energy, total surface energy and surface energy distribution have provided more revealing information about surface energetics of powders. Surface energy distributions determined by IGC or surface energy analyser have been successfully used to understand energetic heterogeneity of surfaces, characterize different polymorphs and understand changes due to micronization, structural relaxation, dry coating and storage. Efforts have been made to utilize surface energy distribution data to calculate powder strength distribution and to explain complex de-agglomeration behaviour of DPI formulations.

Influence of coating material on the flowability and dissolution of dry-coated fine ibuprofen powders.

This study investigates the effects of a variety of coating materials on the flowability and dissolution of dry-coated cohesive ibuprofen powders, with the ultimate aim to use these in oral dosage forms. A mechanofusion approach was employed to apply a 1% (w/w) dry coating onto ibuprofen powder with coating materials including magnesium stearate (MgSt), L-leucine, sodium stearyl fumarate (SSF) and silica-R972. No significant difference in particle size or shape was measured following mechanofusion with any material. Powder flow behaviours characterised by the Freeman FT4 system indicated coatings of MgSt, L-leucine and silica-R972 produced a notable surface modification and substantially improved flow compared to the unprocessed and SSF-mechanofused powders. ToF-SIMS provided a qualitative measure of coating extent, and indicated a near-complete layer on the drug particle surface after dry coating with MgSt or silica-R972. Of particular note, the dissolution rates of all mechanofused powders were enhanced even with a coating of a highly hydrophobic material such as magnesium stearate. This surprising increase in dissolution rate of the mechanofused powders was attributed to the lower cohesion and the reduced agglomeration after mechanical coating.

Titanium Imido Complexes Supported by Amidinate Ligands: Synthesis, Solution Dynamics, and Solid State Structures.

Reaction of Li[PhC(NSiMe(3))(2)] with the complexes [Ti(NR)Cl(2)(py)(3)] affords the corresponding (N,N'-bis(trimethylsilyl)benzamidinato)titanium imido derivatives [Ti(NR){PhC(NSiMe(3))(2)}Cl(py)(2)] [R = Bu(t) (1), 2,6-C(6)H(3)Me(2) (2), 2,6-C(6)H(3)Pr(i)(2) (3)], which, in solution, exist in temperature-dependent, dynamic equilibrium with their mono(pyridine) homologues [Ti(NR){PhC(NSiMe(3))(2)}Cl(py)] and free pyridine. Kinetic and thermodynamic data for these processes are reported, and the relative contributions of the DeltaH and DeltaS terms associated with all three equilibria are identified. The arylimido complexes 2 and 3 may also be prepared by treating 1 with the appropriate arylamine. Reaction of Li[MeC(NC(6)H(11))(2)] with [Ti(NBu(t))Cl(2)(py)(3)] gives the binuclear N,N'-bis(cyclohexyl)acetamidinato derivative [Ti(2)(&mgr;-NBu(t))(2){MeC(NC(6)H(11))(2)}(2)Cl(2)] (4). The X-ray structures of 2 and 4 have been determined. Crystal data for 2: triclinic, P&onemacr;, a = 11.219(5) Å, b = 12.131(6) Å, c = 13.208(7) Å, alpha = 80.34(5) degrees, beta = 87.41(4) degrees, gamma = 75.13(3) degrees, V = 1722.1(15) Å(3), Z = 2, R = 0.054, R(w) = 0.056. Crystal data for 4: triclinic, P&onemacr;, a = 10.455(3) Å, b = 10.637(5) Å, c = 11.024(3) Å, alpha = 90.52(4) degrees, beta = 112.62(3) degrees, gamma = 114.10(3) degrees, V = 1012.8(10) Å(3), Z = 1, R = 0.0453, R(w) = 0.0495.

Modeling the deagglomeration of micronized benzodiazepines from powder mixtures added to dissolution media.

The objective of this research was to model benzodiazepine deagglomeration profiles of percent agglomerated versus time when interactive mixtures containing micronized benzodiazepines were added to water. Micronized diazepam, nitrazepam, oxazepam, and, for ternary mixtures, micronized sodium lauryl sulfate were mixed with lactose-povidone granules (250-355 microm). After rapid dissolution of the lactose granules, bimodal particle size distributions of benzodiazepines, determined by laser diffraction particle sizing, represented dispersed and agglomerated distributions. The concentrations of agglomerated particle decreased with time and approached constant values. Deagglomeration profiles were determined and best modeled by a three-parameter single-exponential decay equation. A nonlinear least-squares approach was used to estimate the concentration of dispersible (C(0)) and nondispersible agglomerates (C(0a)) and the deagglomeration rate constant (K(a)). Increasing benzodiazepine and sodium lauryl sulphate concentrations in the lactose-povidone mixtures increased both dispersible and nondispersible agglomerate concentrations. Deagglomeration rate was relatively fast with half-lives around 15 min. The estimated parameters of C(0a) and K(a) may provide useful information in optimizing the design of formulations of poorly water soluble, micronized drugs to maximize their dispersion.

Influence of physico-chemical carrier properties on the in vitro aerosol deposition from interactive mixtures.

Interactive mixtures were prepared containing 5% (w/w) salbutamol sulfate using various lactose carrier systems, including sieved fractions and blended mixtures of coarse and fine particles. The solid state and powder properties of the lactose carriers were examined by laser diffraction, differential scanning calorimetry, thermogravimetric analysis, powder X-ray diffraction, vapor sorption gravimetry, rotating drum and atomic force microscopy. The in vitro aerosol deposition was determined using a twin-stage impinger with a Rotahaler at an airflow rate of 60l/min. The fine particle fraction (FPF) of salbutamol sulfate was determined using a validated HPLC assay. All samples were highly crystalline with minimal moisture sorption and the major phase in all samples was alpha-lactose monohydrate. Significant differences in FPF were observed using the various carrier systems. FPF increased with decreasing carrier d(50%) (r(2)=0.919) and increasing proportion of fine carrier particles (below 5 microm) (r(2)=0.841). Carriers consisting of very large proportions of fine particles showed low FPF and did not fit the correlation. The presence of coarse carrier particle fractions was essential to achieve maximum FPF, which occurred when about 10% of fine carrier particles were present in the mixture. Dispersion characteristics may be related to the degree of drug aggregation on the carrier surface.

The influence of aggregate microenvironment on the dissolution of oxazepam in ternary surfactant interactive mixtures.

The purpose of this research was to test the hypothesis that the dissolution rate of oxazepam in interactive mixtures was dependent on the influence of surfactant within the microenvironment of mixed oxazepam-surfactant aggegrates produced during dissolution. The studies utilised both powder and intrinsic dissolution methodology; spectrophotometric assays were developed and validated and dissolution data were modelled using multi-exponential equations and dissolution rate constants estimated using non-linear least squares algorithms. For a series of water-soluble ternary additives to the oxazepam interactive mixture, sodium lauryl sulfate and cetrimide were shown not only to decrease aggregation through enhanced dispersion, but also to increase the dissolution rate constant. Such an increase in dissolution rate constant was observed in the intrinsic dissolution studies when surfactant concentrations exceeded the critical micelle concentration and the oxazepam solubility increased. Laser diffraction particle sizing during the dissolution process confirmed the presence of dispersed particles and aggregates and demonstrated that the presence of surfactant improved the state of dispersion. The results of studies using different rotational speeds produced unexpected increases in aggregation and decreases in dissolution rate constants at about 150 rev min(-1), consistent with the transient formation of loose aggregates containing dissolved surfactant.

De-agglomeration of micronized benzodiazepines in dissolution media measured by laser diffraction particle sizing.

The objective of this research was to develop a method to characterize the degree of particle agglomeration using laser diffraction particle sizing, following the addition of benzodiazepine interactive mixtures to water. Interactive mixtures of diazepam, nitrazepam and oxazepam (up to 20% w/w) were prepared by mixing micronized benzodiazepines with lactose granules (250-355 microm). Micronized sodium lauryl sulfate and cetrimide (up to 5% w/w) were added to the benzodiazepine-lactose interactive mixes to produce ternary mixtures. Particle size distributions of benzodiazepines, after addition of the interactive mixtures to water, were determined using laser diffraction particle sizing. Bimodal distributions representing dispersed particles and agglomerates were observed initially after lactose carrier dissolution. Partial agglomerate to dispersed particle transition occurred during a 60-min observation period for all mixtures, reaching a constant level of agglomeration after this time. Interactive mixtures with higher benzodiazepine concentrations displayed transition profiles with higher levels of agglomeration. The presence of surfactant in interactive mixtures dramatically decreased agglomeration. Sodium lauryl sulfate was more effective than cetrimide in dispersing agglomerates. The shape of the transition curves during de-agglomeration demonstrated the presence of stable agglomerates that remained after the initial transition; these may be important in explaining dissolution and absorption rates.