Jagdeep Shur

The Role of Fines in the Modification of the Fluidization and Dispersion Mechanism Within Dry Powder Inhaler Formulations

PurposeTo investigate the role of in situ generated fine excipient particles on the fluidization and aerosolization properties of dry powder inhaler (DPI) formulations.Materials and MethodsCarrier based DPI formulations were prepared under low and high shear blending. Powder rheometery was utilized to measure bulk powder properties in a consolidated and aerated state. Powder fluidization and aerosolization characteristics were related to bulk powder properties using high speed imaging and inertial impaction measurements.ResultsHigh shear blending of formulations resulted in the in situ generation of excipient fines, which corresponded to an increase in aerosolization efficiency. The generation of fines were shown to increase the tensile strength and free volume of the carrier, which resulted in a characteristic change in the fluidization properties, as observed by high speed imaging. The increase in minimum fluidization velocity and aerodynamic drag forces required to aerate the powder may provide the source of energy for the increase in fine particle re-suspension.ConclusionsThe in situ generation of excipient fines affect bulk powder properties of DPI formulations, which directly affects fluidization and aerosolization behaviour of DPI formulations. The study suggests an alternative mode of action by which fines increase DPI formulation performance.

An investigation into the relationship between carrier-based dry powder inhalation performance and formulation cohesive-adhesive force balances.

The inclusion of different carrier materials in a dry powder inhaler (DPI) system can alter formulation performance, which might be attributable to variation in the adhesion between drug and carrier particles. The aim of this study was, therefore, to further examine the relationship between drug-carrier adhesion and performance, by comparing data relating to many different drug-carrier combinations. Four drugs and four carriers were employed, giving a total of 16 combinations. The relative magnitude of the drug-carrier adhesion for each combination was quantified using the cohesion-adhesion balance (CAB) approach to colloidal probe atomic force microscopy. The in vitro inhalation performance of the 16 formulations (1.5% w/w drug) was investigated and found to vary significantly. Plots of fine particle dose against drug-carrier CAB ratio revealed that performance was optimised when the drug-carrier CAB ratio was slightly cohesive. This trend was found to fit with those from similar previous studies, although due to the smaller number of formulations investigated previously, the full extent of this relationship had not been revealed. It was concluded, therefore, that when developing a carrier-based DPI, the selection of a drug-carrier combination with a slightly cohesive CAB ratio might result in optimal performance.

The Role of Force Control Agents in High-Dose Dry Powder Inhaler Formulations

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.

Cospray-dried unfractionated heparin with L-leucine as a dry powder inhaler mucolytic for cystic fibrosis therapy

Accumulation of inspissated secretions that are difficult to clear and congest the airways is a feature of lung disease in patients with cystic fibrosis (CF). These secretions restrict airflow, harbour infection and limit the delivery of inhaled drugs including gene therapy vectors to the underlying target cells. Unfractionated heparin (UFH) has mucolytic properties suggesting that it may be a useful therapeutic agent for lung disease in these patients. For the pulmonary delivery of UFH to patients with CF, the dry powder inhaler has potential advantages over systems using nebulised suspensions. However, spray-dried particles in the appropriate size range (1-5 microm) may absorb atmospheric moisture, causing aggregation. UFH has been cospray-dried with L-leucine (1%, w/w) to produce particles that are less cohesive than UFH alone and show good aerosolisation performance. Rheological analysis has shown that spray-dried UFH and UFH cospray-dried with L-leucine significantly (p < 0.05) reduce the elasticity and yield stress of CF sputum. The superior physical properties of UFH/L-leucine indicate this is the preferred formulation for development as an inhaled mucolytic.

Characterisation and functionality of inhalation anhydrous lactose.

The relationships between the physicochemical properties and functionality in dry powder inhaler (DPI) performance was investigated for inhalation grade anhydrous lactose and compared to monohydrate grades. The excipients were characterised using a range of techniques including particle size analysis, moisture sorption and powder rheometry. The inhalation anhydrous lactose grades were readily characterisable. The aerosolisation performance of capsule based DPI formulations containing budesonide (200microg) and different grades of lactose evaluated using inertial impaction measurements produced fine particle doses of budesonide ranging from 24 to 49microg. There were no apparent relationships between aerosolisation performance and excipient characteristics, such as particle size and powder density. However, formulations containing lactose grades which exhibit higher powder fluidisation energy values resulted in higher fine particle doses of budesonide.

The Influence of Crystal Habit on the Prediction of Dry Powder Inhalation Formulation Performance Using the Cohesive-Adhesive Force Balance Approach

The aim of this investigation was to study the influence of crystalline habit of active pharmaceutical ingredients on the cohesive–adhesive force balance within model dry powder inhaler (DPI) formulations and the corresponding affect on DPI formulation performance. The cohesive–adhesive balance (CAB) approach to colloid probe atomic force microscopy (AFM) was employed to determine the cohesive and adhesive interactions of micronized budesonide particles against the {102} and {002} faces of budesonide single crystals and crystalline substrates of different sugars (cyclodextrin, lactose, trehalose, raffinose, and xylitol), respectively. These data were used to measure the relative level of cohesion and adhesion via CAB and the possible influence on in vitro performance of a carrier-based DPI formulation. Varying the crystal habit of the drug had a significant effect on the cohesive measurement of micronized budesonide probes, with the cohesive values on the {102} faces being approximately twice that on the {002} crystal faces. However, although different CAB values were measured with the sugars with respect to the crystal faces chosen for the cohesive-based measurement, the overall influence on the rank order of the CAB values was not directly influenced. For these data sets, the CAB gradient indicated that a decrease in the dominance of the adhesive forces led to a concomitant increase in fine particle delivery, reaching a plateau as the cohesive forces became dominant. The study suggested that crystal habit of the primary drug crystals influences the cohesive interactions and the resulting force balance measurements of colloid probe CAB analysis.

Factors Affecting Defining the Quality and Functionality of Excipients Used in the Manufacture of Dry Powder Inhaler Products

The successful manufacture of a regulatory approved dry powder inhaler (DPI) product is only achievable by applying robust control systems to all aspects of analytical, engineering, and material based processes. Whilst many aspects of DPI drug product manufacturing can be adequately controlled, it is often the control of materials, that is, drug substance and excipients, which can lead to variation in the quality of the final drug product. This article gives an overview of DPI excipients and highlights the challenges of defining and, importantly, understanding the relationships between quality and functionality for excipient components in DPI formulations.

Advanced microscopy techniques to assess solid-state properties of inhalation medicines.

Efficient control and characterisation of the physico-chemical properties of active pharmaceutical ingredients (APIs) and excipients for orally inhaled drug products (OIDPs) are critical to successful product development. Control and reduction of risk require the introduction of a material science based approach to product development and the use of advanced analytical tools in understanding how the solid-state properties of the input materials influence structure and product functionality. The key issues to be addressed, at a microscopic scale, are understanding how the critical quality attributes of input materials influence surface, interfacial and particulate interactions within OIDPs. This review offers an in-depth discussion on the use of advanced microscopy techniques in characterising of the solid-state properties of particulate materials for OIDPs. The review covers the fundamental principles of the techniques, instrumentation types, data interpretation and specific applications in relation to the product development of OIDPs.

Influence of primary crystallisation conditions on the mechanical and interfacial properties of micronised budesonide for dry powder inhalation

Investigate the influence of primary crystallisation conditions on the mechanical properties and secondary processing behaviour of budesonide for dry powder inhaler (DPI) formulations. Youngs modulus of two batches of budesonide crystals (samples A and B) produced using different anti-solvents was determined using nanoindentation. Physicochemical and surface interfacial properties via the cohesive-adhesive balance (CAB) approach to colloid probe atomic force microscopy (AFM) of air-jet micronised budesonide crystals were also investigated. These data were correlated to in vitro aerosolization performance of carrier-based DPI formulations containing either budesonide samples A or B and lactose monohydrate. Youngs modulus of budesonide samples A and B crystals was 0.95 and 4.04 GPa, respectively. Sample A crystals with low Youngs modulus exhibited poorer micronisation efficiency than sample B. CAB analysis of micronised budesonide samples A and B, suggest that sample B budesonide had a greater adhesion to lactose than sample A. These data correlated with in vitro aerosolisation studies, which showed that the fine particle delivery of budesonide sample A was higher than that of sample B. In conclusion, crystallisation conditions may affect the mechanical properties of budesonide, and therefore secondary processing of the material and their interfacial properties and product performance in carrier based DPI formulations.

Effect of Device Design and Formulation on the In Vitro Comparability for Multi-Unit Dose Dry Powder Inhalers

The focus of this investigation was to understand the design space to achieve comparable in vitro performance of two multi-unit dose dry powder inhalers (DPIs)—Flixotide® Accuhaler® (reference product) and MultiHaler® (test product). Flow field, pressure drop and particle trajectories within the test and reference DPI devices were modelled via computational fluid dynamics (CFD). Micronized fluticasone propionate (FP) was characterized to determine particle size distribution (PSD), specific surface area (SSA) and surface interfacial properties using cohesive-adhesive balance (CAB). CFD simulations suggested that the pressure drop and airflow velocity in the MultiHaler® were greater than Accuhaler®. Two modified test devices (MOD MH 1 and MOD MH 2) were manufactured with the introduction of by-pass channels in the airflow path, which achieved comparable specific resistance and airflow path between the test and reference devices. Assessment of reference product formulation in modified test devices suggested that MOD MH 2 achieved comparable in vitro performance to the reference product. CAB analysis suggested that adhesion of all FP batches to lactose was different, with batch D showing greatest and batch A least adhesion to lactose. Test DPI formulations were manufactured using four different batches of FP with milled or sieved lactose, and showed that batch A FP formulated with sieved lactose in MOD MH 2 device demonstrated the highest degree of similarity to the Accuhaler® in vitro deposition. Application of CFD modelling and material characterization of formulation raw materials enabled the modification of device and formulation critical material attributes to create an in vitro comparable device/formulation system to the reference product.