Agglomerate strength and dispersion of pharmaceutical powders

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik e.V, 2012

Due to their small size, the respirable drug particles tend to form agglomerates which prevent flowing and aerosolisation. A carrier is used to be mixed with drug in one hand to facilitate the powder flow during manufacturing, in other hand to help the fluidisation upon patient inhalation. Depending on drug concentration, drug agglomerates can be formed in the mixture. The aim of this work was to study the agglomeration behaviour of fluticasone propionate (FP) within interactive mixtures for inhalation. The agglomerate phenomenon of fluticasone propionate after mixing with different fractions of lactose without fine particles of lactose (smaller than 32 μm) was demonstrated by the optical microscopy observation. A technique measuring the FP size in the mixture was developed, based on laser diffraction method. The FP agglomerate sizes were found to be in a linear correlation with the pore size of the carrier powder bed (R2 = 0.9382). The latter depends on the particle size distribution of carrier. This founding can explain the role of carrier size in de-agglomeration of drug particles in the mixture. Furthermore, it gives more structural information of interactive mixture for inhalation that can be used in the investigation of aerosolisation mechanism of powder. According to the manufacturing history, different batches of FP show different agglomeration intensities which can be detected by Spraytec®, a new laser diffraction method for measuring aerodynamic size. After mixing with a carrier, Lactohale LH200, the most cohesive batch of FP, generates a lower fine particle fraction. It can be explained by the fact that agglomerates of fluticasone propionate with very large size was detected in the mixtures. By using silica–gel beads as ball-milling agent during the mixing process, the FP agglomerate size decreases accordingly to the quantity of mixing aid. The homogeneity and the aerodynamic performance of the mixtures are improved. The mixing aid based on ball-milling effect could be used to ameliorate the quality of inhalation mixture of cohesive drug, such as fluticasone propionate. However, there is a threshold where an optimal amount of mixing aids should be used. Not only the drug des-aggregation reaches its peak but the increase in drug–carrier adhesion due to high energy input should balance the de-agglomeration capacity of mixing process. This approach provides a potential alternative in DPI formulation processing.Mixing process is a critical operation in the manufacturing of DPI formulations. FPF improvement depends on the amount of mixing aid. This is in relation with the FP agglomerate size that decreases gradually when increasing the quantity of mixing aid.

Pharmaceutical Research, 2000

To investigate the influence of the cohesive-adhesive balances on dry powder formulation aerosolization and delivery characteristics. Methods. De-agglomeration properties of pharmaceutical powders were investigated using an Aerosizer at various shear forces. Aerosol drug deposition properties of drug-only formulations and carrierbased formulations were investigated using a low-resistance device (Rotahaler) and a high-resistance device (Turbuhaler) via a twinstage impinger. Results. A paradoxical relationship between particle cohesive strength and de-agglomeration efficiencies of drug-only formulations was observed, where an increase in cohesive strength led to a higher fine particle fraction. A possible explanation for the variation in the fluidization and aerosolization properties between low and high cohesive particles was modeled on the relationship between cohesion, metastable agglomerate size, and the resulting aerodynamic drag force acting on the fluidized agglomerates. The addition of a fine particle lactose carrier influenced the drug deposition patterns in different ways depending on the relative cohesive and adhesive force balances within the formulation. Conclusions. The use of the colloid Atomic Force Microscrope (AFM) technique in combination with the cohesive-adhesive balance (CAB) system provides a novel preformulation tool for investigating the likely behavior of a dry powder formulation and a possible means of interpreting the possible de-aggregation and dispersion mechanisms of carrier-based formulations.

2011

Background: Nanosized dry powder inhalers provide higher stability for poorly water-soluble drugs as compared with liquid formulations. However, the respirable particles must have a diameter of 1-5 µm in order to deposit in the lungs. Controlled agglomeration of the nanoparticles increases their geometric particle size so they can deposit easily in the lungs. In the lungs, they fall apart to reform nanoparticles, thus enhancing the dissolution rate of the drugs. Theophylline is a bronchodilator with poor solubility in water. Methods: Nanosized theophylline colloids were formed using an amphiphilic surfactant and destabilized using dilute sodium chloride solutions to form the agglomerates. Results: The theophylline nanoparticles thus obtained had an average particle size of 290 nm and a zeta potential of −39.5 mV, whereas the agglomerates were 2.47 µm in size with a zeta potential of −28.9 mV. The release profile was found to follow first-order kinetics (r 2. 0.96). The aerodynamic characteristics of the agglomerated nanoparticles were determined using a cascade impactor. The behavior of the agglomerate was significantly better than unprocessed raw theophylline powder. In addition, the nanoparticles and agglomerates resulted in a significant improvement in the dissolution of theophylline. Conclusion: The results obtained lend support to the hypothesis that controlled agglomeration strategies provide an efficient approach for the delivery of poorly water-soluble drugs into the lungs.

International Journal of Pharmaceutics, 2011

Purpose: The purpose of the current investigation is to understand the kinetics of de-agglomeration (k d ) of micronised salbutamol sulphate (SS) and lactohale 300 (LH300) under varying air flow rates (30-180 l min −1 ) from three dry powder inhaler devices (DPIs), Rotahaler ® (RH), Monodose Inhaler ® (MI) and Handihaler ® (HH). Results: Cumulative fine particle mass vs. time profiles were obtained from the powder concentration, emitted mass and volume percent <5.4 m, embedded in the particle size distributions of the aerosol at specific times. The rate of de-agglomeration (k d ), estimated from non-linear least squares modelling, increased with increasing air flow rates. The k d vs. air flow rate profiles of SS and LH300 were significantly different at high air flow rates. The k d was highest from RH and lowest from MI. Differences in k d between the devices were related to device mode of operation while the differences between the materials were due to the powder bed structure. Conclusion: This approach provided a methodology to measure the rate constant for cohesive powder de-agglomeration following aerosolisation from commercial devices and an initial understanding of the influence of device, air flow rate and material on these rate constants.

AIP Conference Proceedings, 2013

Journal of Controlled Release, 2001

The objective of this study was to determine the effects of formulation excipients and physical characteristics of inhalation particles on their in vitro aerosolization performance, and thereby to maximize their respirable fraction. Dry powders were produced by spray-drying using excipients that are FDA-approved for inhalation as lactose, materials that are endogenous to the lungs as albumin and dipalmitoylphosphatidylcholine (DPPC); and / or protein stabilizers as trehalose or mannitol. Dry powders suitable for deep lung deposition, i.e. with an aerodynamic diameter of individual particles ,3 mm, were prepared. 3 They presented 0.04-0.25 g / cm bulk tap densities, 3-5 mm geometric particle sizes, up to 90% emitted doses and 50% respirable fractions in the Andersen cascade impactor using a SpinhalerE inhaler device. The incorporation of lactose, albumin and DPPC in the formulation all improved the aerosolization properties, in contrast to trehalose and the mannitol which decreased powder flowability. The relative proportion of the excipients affected aerosol performance as well. The lower the bulk powder tap density, the higher the respirable fraction. Optimization of in vitro aerosolization properties of inhalation dry powders can be achieved by appropriately selecting composition and physical characteristics of the particles.

Crystal Growth & Design, 2012

This study provides, for the first time, an evaluation of the physicochemical properties of batch cooling crystallized mannitol particles combined with how these properties correlated with the inhalation performance from a dry powder inhaler (Aerolizer). The results showed that the type of polymorph changed from β-form (commercial mannitol) to mixtures of β-+δ-mannitol (cooling crystallized mannitol crystals). In comparison to mannitol particles, crystallized at a higher supersaturation degree, a lower degree of supersaturation favored the formation of mannitol crystals with a more regular and elongated habit, smoother surface, higher specific surface area, higher fine particle content, higher bulk density, and higher tap density. Cooling crystallized mannitol particles demonstrated considerably lower salbutamol sulfate−mannitol adhesion in comparison to commercial mannitol, with a linear reduction as surface roughness decreased and fines content increased. Also, mannitol crystals with smoother surfaces demonstrated a reduction in salbutamol sulfate content uniformity (expressed as %CV) within salbutamol sulfate−mannitol formulations. Despite the different physical properties, all mannitol products showed similar flow properties and similar emission of salbutamol sulfate upon inhalation. However, mannitol crystals grown from lower supersaturation (reduced roughness and increased fines) generated a finer aerodynamic size distribution and consequently deposited higher amounts of salbutamol sulfate on lower stages of the impactor. Regression analysis indicated linear relationships showing higher fine particle fraction of salbutamol sulfate in the case of mannitol particles having a more elongated shape, higher fines content, higher specific surface area, higher bulk density, and higher tap density. In conclusion, a cooling crystallization technique could be controlled to produce mannitol particles with controlled physical properties that could be used to influence aerosolization performance of a dry powder inhaler product.

AAPS PharmSciTech, 2017

The potential of fine excipient materials to improve the performance of carrier-based dry powder inhalation mixtures is well acknowledged. The mechanisms underlying this potential are, however, open to question till date. Elaborate understanding of these mechanisms is a requisite for rational rather than empirical development of ternary dry powder inhalation mixtures. While effects of fine excipient materials on drug adhesion to and detachment from surfaces of carrier particle have been extensively investigated, effects on other processes, such as carrier-drug mixing, capsule/blister/device filling, or aerosolization in inhaler devices, have received little attention. We investigated the influence of fine excipient materials on the outcome of the carrier-drug mixing process. We studied the dispersibility of micronized fluticasone propionate particles after mixing with α-lactose monohydrate blends comprising different fine particle concentrations. Increasing the fine (D &lt; 10.0 μm)...

Journal of Pharmaceutical Sciences, 2009

The aim of this study was to determine the aerosolisation and aerodynamic properties of model inhalation particles (salbutamol sulphate and budesonide) upon coprocessing with force control agents (FCAs)-leucine, lecithin and magnesium stearate. Coprocessing of the drug particles with FCAs (5%, w/w) was conducted using mechanofusion-a novel dry mechanical fusion process. The influence of mechanofused FCAs on the entrainment and deaggregation behaviour of the drug-only formulations was investigated using a next generation impactor (NGI) and an in-line Spraytec laser diffraction particle sizer. In vitro measurements of salbutamol sulphate coprocessed with FCAs indicated a significant (p < 0.001) improvement of the fine particle fraction (FPF). The coprocessing of salbutamol sulphate with magnesium stearate produced the highest FPF, with an increase from 29.18% to 79.42% of the emitted dose. Coprocessing of budesonide particles only led to a small increase in fine particle delivery but a greater reduction in device retention. Aerosolisation analysis of the aerosolised powders indicated more effective aerosolisation and a considerable time reduction in powder bed fluidisation and entrainment upon coprocessing of the APIs with FCAs. From these data, it can be postulated that processing of drug actives with FCAs using mechanofusion is an effective means of improving the deagglomeration and aerosolisation properties of cohesive powders in DPI systems.

Journal of Aerosol Medicine and Pulmonary Drug Delivery, 2012

Background: The performance of dry powder aerosol delivery systems depends not only on the powder formulation but also on the dry powder inhalers (DPIs). Effects of turbulence, grid, mouthpiece, inlet size, air flow, and capsule on the DPIs performance have been investigated previously. Considering powder dispersion in DPIs is a time-dependent process, the powder residence time in DPIs is supposed to have a great impact on DPIs efficiency. This study sought to investigate the effect of powder residence time on the performance of a commercial DPI Aerolizer Ò. Methods: A standard Aerolizer Ò (SD) and five modified devices (MD1, MD2, MD3, MD4, and MD5) were employed for this research. Computational fluid dynamics analysis was used to calculate the flow field and the powder residence time in these devices. Recombinant human interleukin-2 inhalation powders and a twin impinger were used for the deposition experiment. Results: The powder mean residence time in the secondary atomization zone of the devices was increased from 0 ms for SD to 0.33, 0.96, 1.42, 1.76, and 2.14 ms for MD1, MD2, MD3, MD4, and MD5, respectively. At a flow rate of 60 L/min, with an increase in the powder residence time in these devices, a significant gradual and increasing trend in the powder respirable fraction was observed from 29.1%-1.1% (MD1) to 32.6%-2.2% (MD2), 37.1%-1.1% (MD3), and 43.7%-2.1% (MD4). There was no significant difference in the powder respirable fraction between SD and MD1 or between MD4 and MD5. Conclusions: Within a certain range, increasing the powder residence time could improve the performance of Aerolizer Ò by increasing the powder-air interaction time (the main reason) and increasing the powder-device compaction (the secondary reason). Combination of high turbulence level and sufficient powder residence time could further improve the device performance.