Investigation into the Influence of Primary Crystallization Conditions on the Mechanical Properties and Secondary Processing Behaviour of Fluticasone Propionate for Carrier Based Dry Powder Inhaler Formulations

Kubavat, Harshal A.; Shur, Jagdeep; Ruecroft, Graham; Hipkiss, David; Price, Robert

doi:10.1007/s11095-011-0640-1

Cited by 23 publications

(17 citation statements)

References 25 publications

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“…6) appeared to be sensitive to shift in the balance of forces between FP and SX upon FP lagering. As has been indicated in a number of studies, the greater the adhesive tendency between FP and SX, the more significant is the improvement in aerosolization performance of SX (1,16,19). These studies proposed that higher deaggregation efficiency of the SX occurred as a result of the greater propensity of FP and SX to form fine particle agglomerates during blending.…”

Section: In Vitro Aerosolization Performance Of Binary Dpi Formulationsmentioning

confidence: 89%

“…al. (1). They also showed that different solvent and anti-solvent conditions during primary crystallization conditions could directly affect the interfacial surface chemistry of the secondary processed FP.…”

Section: Post-micronization Conditioning Effects On Interfacial Forcesmentioning

confidence: 98%

“…Particle size reduction of active pharmaceutical ingredients (APIs) for delivery to the lungs requires secondary processing of primary crystals using highly energetic comminution techniques, such as air-jet micronization (1). For brittle materials, particle-particle and particle-wall collisions within a micronizer often lead to the formation of short-lived defects formed along existing flaws within a crystalline lattice that can lead to crystal fracture (2,3).…”

Section: Introductionmentioning

confidence: 99%

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The Influence of Secondary Processing on the Structural Relaxation Dynamics of Fluticasone Propionate

et al. 2014

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ABSTRACT. This study investigated the structural relaxation of micronized fluticasone propionate (FP) under different lagering conditions and its influence on aerodynamic particle size distribution (APSD) of binary and tertiary carrier-based dry powder inhaler (DPI) formulations. Micronized FP was lagered under low humidity (LH 25 C, 33% RH [relative humidity]), high humidity (HH 25°C, 75% RH) for 30, 60, and 90 days, respectively, and high temperature (HT 60°C, 44% RH) for 14 days. Physicochemical, surface interfacial properties via cohesive-adhesive balance (CAB) measurements and amorphous disorder levels of the FP samples were characterized. Particle size, surface area, and rugosity suggested minimal morphological changes of the lagered FP samples, with the exception of the 90-day HH (HH90) sample. HH90 FP samples appeared to undergo surface reconstruction with a reduction in surface rugosity. LH and HH lagering reduced the levels of amorphous content over 90-day exposure, which influenced the CAB measurements with lactose monohydrate and salmeterol xinafoate (SX). CAB analysis suggested that LH and HH lagering led to different interfacial interactions with lactose monohydrate but an increasing adhesive affinity with SX. HT lagering led to no detectable levels of the amorphous disorder, resulting in an increase in the adhesive interaction with lactose monohydrate. APSD analysis suggested that the fine particle mass of FP and SX was affected by the lagering of the FP. In conclusion, environmental conditions during the lagering of FP may have a profound effect on physicochemical and interfacial properties as well as product performance of binary and tertiary carrier-based DPI formulations.

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Section: In Vitro Aerosolization Performance Of Binary Dpi Formulationsmentioning

confidence: 89%

Section: Post-micronization Conditioning Effects On Interfacial Forcesmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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The Influence of Secondary Processing on the Structural Relaxation Dynamics of Fluticasone Propionate

et al. 2014

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“…These data highlight the challenges faced during generic drug product development, particularly as in most cases, the API and excipient are procured through third-party channels. Our previous work has suggested that variation in particle size and interfacial properties may be related to the process history of the API (23). In particular, the elastic properties of primary FP crystals that are secondarily processed by air-jet micronization results in material that does not always meet particle size specification and has variable surface interfacial properties.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, the elastic properties of primary FP crystals that are secondarily processed by air-jet micronization results in material that does not always meet particle size specification and has variable surface interfacial properties. This has been shown to impact finished drug product performance in both binary and combination DPI formulations (23). In order to understand the impact of the surface interfacial forces of the API on in vitro drug deposition, all batches of API were formulated with either milled or sieved lactose for further formulation investigation with the MOD MH 2 test device.…”

Section: Discussionmentioning

confidence: 99%

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

Shur

Saluja

Lee

et al. 2015

AAPS J

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Abstract. 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.KEY WORDS: aerosolization; computational fluid dynamics; device design; dry powder inhaler; in vitro comparability; in vitro performance.

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Applications of Scanning Probe Microscopy and Nanomechanical Analysis in Pharmaceutical Development

Lamm

2013

Scanning Probe Microscopy in Industrial Applications

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Investigation into the Influence of Primary Crystallization Conditions on the Mechanical Properties and Secondary Processing Behaviour of Fluticasone Propionate for Carrier Based Dry Powder Inhaler Formulations

Abstract: Crystallisation conditions may affect the mechanical properties of FP, and therefore secondary processing of the material and their interfacial properties and product performance in carrier based DPI formulations.

Cited by 23 publications

References 25 publications

The Influence of Secondary Processing on the Structural Relaxation Dynamics of Fluticasone Propionate

The Influence of Secondary Processing on the Structural Relaxation Dynamics of Fluticasone Propionate

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

Applications of Scanning Probe Microscopy and Nanomechanical Analysis in Pharmaceutical Development

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