Zhen Xu

Particle Interactions in Dry Powder Inhaler Unit Processes: A Review

Recent development and methods of designing and optimizing dry powder formulations have extended the therapeutic potential of inhaled dosage forms. Successful drug delivery as indicated by a high and reproducible fine particle fraction, required to achieve the desired therapeutic effect while minimizing potential toxicity, depends on an understanding of the physico-chemical properties of powder blends, their performance and availability of adequate tools to screen and predict their behavior. The scope of this review includes three important perspectives for inhaled drug delivery: (1) Fundamental aspects of interparticulate interactions of pharmaceutical dry powder aerosols at rest and in resuspension; (2) The influences of pharmaceutical processing including milling, mixing, filling and storage, and their influence on powder dispersion; (3) Current strategies for formulation optimization and methods for in vitro aerosolization performance prediction.

Dry Powder Aerosols Generated by Standardized Entrainment Tubes From Drug Blends With Lactose Monohydrate: 2. Ipratropium Bromide Monohydrate and Fluticasone Propionate

The objectives of this study were: systematic investigation of dry powder aerosol performance using standardized entrainment tubes (SETs) and lactose-based formulations with two model drugs; mechanistic evaluation of performance data by powder aerosol deaggregation equation (PADE). The drugs (IPB and FP) were prepared in sieved and milled lactose carriers (2% w/w). Aerosol studies were performed using SETs (shear stresses tau(s) = 0.624-13.143 N/m(2)) by twin-stage liquid impinger, operated at 60 L/min. PADE was applied for formulation screening. Excellent correlation was observed when PADE was adopted correlating FPF to tau(s). Higher tau(s) corresponded to higher FPF values followed by a plateau representing invariance of FPF with increasing tau(s). The R(2) values for PADE linear regression were 0.9905-0.9999. Performance described in terms of the maximum FPF (FPF(max): 15.0-37.6%) resulted in a rank order of ML-B/IPB > ML-A/IPB > SV-A/IPB > SV-B/IPB > ML-B/FP > ML-A/FP > SV-B/FP > SV-A/FP. The performance of IPB was superior to FP in all formulations. The difference in lactose monohydrate carriers was less pronounced for the FPF in IPB than in FP formulations. The novel PADE offers a robust method for evaluating aerodynamic performance of dry powder formulations within a defined tau(s) range.

Dry Powder Aerosols Generated by Standardized Entrainment Tubes from Alternative Sugar Blends: 3. Trehalose Dihydrate and d-Mannitol Carriers

The relationship between physicochemical properties of drug/carrier blends and aerosol drug powder delivery was evaluated. Four pulmonary drugs each representing the major pulmonary therapeutic classes and with a different pharmacological action were employed. Specifically, the four pulmonary drugs were albuterol sulfate, ipratropium bromide monohydrate, disodium cromoglycate, and fluticasone propionate. The two carrier sugars, each representing a different sugar class, were D-mannitol and trehalose dihydrate. Dry powder aerosols (2%, w/w, drug in carrier) delivered using standardized entrainment tubes (SETs) were characterized by twin-stage liquid impinger. The fine particle fraction (FPF) was correlated with SET shear stress, tau(s), and the maximum fine particle fraction (FPF(max)) was correlated with a deaggregation constant, k(d), by using a powder aerosol deaggregation equation (PADE) by nonlinear and linear regression analyses applied to pharmaceutical inhalation aerosol systems in the solid state. For the four pulmonary drugs representing the major pulmonary therapeutic classes and two chemically distinct pulmonary sugar carriers (non-lactose types) aerosolized with SETs having well-defined shear stress values, excellent correlation and predictive relationships were demonstrated for the novel and rigorous application of PADE for dry powder inhalation aerosol dispersion within a well-defined shear stress range, in the context of pulmonary drug/sugar carrier physicochemical and interfacial properties.

Dry Powder Aerosols Generated by Standardized Entrainment Tubes From Drug Blends With Lactose Monohydrate: 1. Albuterol Sulfate and Disodium Cromoglycate:

The major objective of this study was: discriminatory assessment of dry powder aerosol performance using standardized entrainment tubes (SETs) and lactose-based formulations with two model drugs. Drug/lactose interactive physical mixtures (2%w/w) were prepared. Their properties were measured: solid-state characterization of phase behavior and molecular interactions by differential scanning calorimetry and X-ray powder diffraction; particle morphology and size by scanning electron microscopy and laser diffraction; aerosol generation by SETs and characterization by twin-stage liquid impinger and Andersen cascade impactor operated at 60 L/min. The fine particle fraction (FPF) was correlated with SET shear stress (tau(s)), using a novel powder aerosol deaggregation equation (PADE). Drug particles were <5 microm in volume diameter with narrow unimodal distribution (Span <1). The lowest shear SET (tau(s) = 0.624 N/m(2)) gave a higher emitted dose (ED approximately 84-93%) and lower FPF (FPF(6.4) approximately 7-25%). In contrast, the highest shear SET (tau(s) = 13.143 N/m(2)) gave a lower ED (ED approximately 75-89%) and higher FPF (FPF(6.4) approximately 15-46%). The performance of disodium cromoglycate was superior to albuterol sulfate at given tau(s), as was milled with respect to sieved lactose monohydrate. Excellent correlation was observed (R(2) approximately 0.9804-0.9998) when pulmonary drug particle release from the surface of lactose carriers was interpreted by PADE linear regression for dry powder formulation evaluation and performance prediction.

Heterogeneous Particle Deaggregation and Its Implication for Therapeutic Aerosol Performance

Aerosolization performance of dry powder blends of drugs for the treatment of asthma or chronic obstructive pulmonary diseases have been reported in three previous articles. In vitro aerosolization was performed at defined shear stresses (0.624-13.143 N/m(2)). Formulations were characterized aerodynamically and powder aerosol deaggregation equations (PADE) and corresponding linear regression analyses for pharmaceutical aerosolization were applied. Particle deaggregation is the result of overcoming fundamental forces acting at the particle interface. A new method, PADE, describing dry powder formulation performance in a shear stress range has been developed which may allow a fundamental understanding of interparticulate and surface forces. The application of PADE predicts performance efficiency and reproducibility and supports rational design of dry powder formulations. The analogy of aerosol performance with surface molecular adsorption has important implications. Expressions describing surface adsorption were intended to allow elucidation of mechanisms involving surface heterogeneity, lateral interaction, and multilayer adsorption of a variety of materials. By using a similar expression for drug aerosolization performance, it is conceivable that an analogous mechanistic approach to the evaluation of particulate systems would be possible.