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Purpose: For locally-acting dry powder inhalers (DPIs), developing novel analytical tools that are able to evaluate the state of aggregation may provide a better understanding of the impact of material properties and processing parameters on the in vivo performance. This study explored the utility of the Morphologically-Directed Raman Spectroscopy (MDRS) and dissolution as orthogonal techniques to assess microstructural equivalence of the aerosolized dose of DPIs collected with an aerosol collection device., Methods: Commercial DPIs containing different strengths of Fluticasone Propionate (FP) and Salmeterol Xinafoate (SX) as monotherapy and combination products were sourced from different regions. These inhalers were compared with aerodynamic particle size distribution (APSD), dissolution, and MDRS studies., Results: APSD testing alone might not be able to explain differences reported elsewhere in in vivo studies of commercial FP/SX drug products with different Advair® strengths and/or batches. Dissolution studies demonstrated different dissolution rates between Seretide™ 100/50 and Advair® 100/50, whereas Flixotide™ 100 and Flovent® 100 had similar dissolution rates between each other. These differences in dissolution profiles were supported by MDRS results: the dissolution rate is increased if the fraction of FP associated with high soluble components is increased. Principle component analysis was used to identify the agglomerate classes that better discriminate different products., Conclusions: MDRS and dissolution studies of the aerosolized dose of DPIs were successfully used as orthogonal techniques. This study highlights the importance of further assessing in vitro tools that are able to provide a bridge between material attributes or process parameters and in vivo performance., (© 2024. The Author(s).)

Purpose: Asthma is a prevalent lung disorder that cause heavy burdens globally. Inhalation medicaments can relieve symptoms, improve lung function and, thus, the quality of life. However, it is well-documented that patients often do not get the prescribed dose out of an inhaler and the deposition of drug is suboptimal, due to incorrect handling of the device and wrong inhalation technique. This study aims to design and fabricate an acoustic dry powder inhaler (ADPI) for monitoring inhalation flow and related drug administration in order to evaluate whether the patient receives the complete dose out of the inhaler., Methods: The devices were fabricated using 3D printing and the impact of the acoustic element geometry and printing resolution on the acoustic signal was investigated. Commercial Foradil (formoterol fumarate) capsules were used to validate the availability of the ADPI for medication dose tracking. The acoustic signal was analysed with Partial-Least-Squares (PLS) regression., Results: Indicate that specific acoustic signals could be generated at different air flow rates using a passive acoustic element with specific design features. This acoustic signal could be correlated with the PLS model to the air flow rate. A more distinct sound spectra could be acquired at higher printing resolution. The sound spectra from the ADPI with no capsule, a full capsule and an empty capsule are different which could be used for medication tracking., Conclusions: This study shows that it is possible to evaluate the medication quality of inhaled medicaments by monitoring the acoustic signal generated during the inhalation process.

Purpose: This work investigated the effect of relative humidity (RH) on bipolar electrostatic charge profiles of dry powder inhaler aerosols using the Bipolar Charge Analyzer (BOLAR)., Methods: Two commercial products, Pulmicort® (400 μg, budesonide) and Bricanyl® (500 μg, terbutaline sulfate) Turbuhaler®, were used as model dry powder inhalers (DPIs) in this study. Three individual doses from each Turbuhaler® were sampled at 15, 40, 65 and 90% RH. Subsequently, charge and mass profiles were determined for each dispersion., Results: The aerosols from these two Turbuhaler® DPI were bipolarly charged, with larger particles carrying negative charge and smaller particles positive charge. Particles changed polarity around 2.60-4.17 μm and 0.95-2.60 μm for Pulmicort® and Bricanyl®, respectively. The effect of RH on particles differed between DPIs even though the mass output was not significantly affected. The net charge profiles of Pulmicort® were relatively independent of RH, whereas those of Bricanyl® showed a reduction in the charge magnitude with increasing RH. Both positive and negative charge profiles followed a similar trend with the change in RH and individually they had higher magnitudes than the measured net charge., Conclusions: This study showed drug-specific bipolar charging of the Turbuhaler® DPI aerosols at varied RHs. Bricanyl® was more susceptible to RH and showed decreased bipolar and net charge levels with increasing RH, in comparison to Pulmicort®.

Purpose: To investigate the applicability of Bipolar Charge Analyzer (BOLAR), a new commercial instrument developed by Dekati Ltd., in simultaneously characterizing the bipolar electrostatic charge profile and measuring the size distribution of commercial metered dose inhalers (MDIs)., Methods: Intal Forte(®) (sodium cromoglycate), Tilade(®) (nedocromil sodium), Ventolin(®) (salbutamol sulphate), and QVAR(®) (beclomethasone dipropionate) were used as model MDIs in this study. Three individual actuations of each MDI were introduced into the BOLAR at an air flow rate of 60 l/min. Charge and mass profiles for each actuation were determined., Results: The BOLAR was found to have better performance in collecting valid charge data (≥80%) than valid mass data (≥50%). In all tested products, both positively and negatively charged particles were found in five defined size fractions between zero and 11.6 μm, with the charge magnitude decreased with increasing particle size. The net charge profiles obtained from the BOLAR qualitatively agreed with the results reported previously. In all suspension type MDIs, negligible masses were detected in the smallest size fraction (<0.95 μm), for which the charge was most likely caused by the propellant and excipients. QVAR was the only solution MDI tested and the charge and mass profiles were significantly different from the suspension-type MDIs. Its mass profile was found to follow closely with the charge profile., Conclusions: Positively and negatively charged MDI particles of different size fractions and their corresponding charge-to-mass profiles were successfully characterized by the BOLAR.

Purpose: Properly charged particles can be used for effective lung targeting of pharmaceutical aerosols. The objective of this study was to characterize the performance of a new induction charger that operates with a mesh nebulizer for the production of highly charged submicrometer aerosols to bypass the mouth-throat and deliver clinically relevant doses of medications to the lungs., Methods: Variables of interest included combinations of model drug (albuterol sulfate) and charging excipient (NaCl) as well as strength of the charging field (1-5 kV/cm). Aerosol charge and size were measured using a modified electrical low pressure impactor system combined with high performance liquid chromatography., Results: At the approximate mass median aerodynamic diameter (MMAD) of the aerosol (~0.4 μm), the induction charge on the particles was an order of magnitude above the field and diffusion charge limit. The nebulization rate was 439.3 ± 42.9 μl/min, which with a 0.1% w/v solution delivered 419.5 ± 34.2 μg of medication per minute. A new correlation was developed to predict particle charge produced by the induction charger., Conclusions: The combination of the aerosol induction charger and predictive correlations will allow for the practical generation and control of charged submicrometer aerosols for targeting deposition within the lungs.

Purpose: To investigate the agglomeration behaviour of the fine (<5.0 μm) and coarse (>12.8 μm) particle fractions of salmeterol xinafoate (SX) and fluticasone propionate (FP) by isolating aerodynamic size fractions and characterising their physicochemical and re-dispersal properties., Methods: Aerodynamic fractionation was conducted using the Next Generation Impactor (NGI). Re-crystallized control particles, unfractionated and fractionated materials were characterized for particle size, morphology, crystallinity and surface energy. Re-dispersal of the particles was assessed using dry dispersion laser diffraction and NGI analysis., Results: Aerosolized SX and FP particles deposited in the NGI as agglomerates of consistent particle/agglomerate morphology. SX particles depositing on Stages 3 and 5 had higher total surface energy than unfractionated SX, with Stage 5 particles showing the greatest surface energy heterogeneity. FP fractions had comparable surface energy distributions and bulk crystallinity but differences in surface chemistry. SX fractions demonstrated higher bulk disorder than unfractionated and re-crystallized particles. Upon aerosolization, the fractions differed in their intrinsic emission and dispersion into a fine particle fraction (<5.0 μm)., Conclusions: Micronized powders consisted of sub-populations of particles displaying distinct physicochemical and powder dispersal properties compared to the unfractionated bulk material. This may have implications for the efficiency of inhaled drug delivery.

Purpose: This study aimed to characterize inherent charge generated by micron-sized drug-only formulations of amorphous and crystalline salbutamol sulfate (SS)., Methods: Amorphous SS was produced by spray-drying whilst crystalline SS was produced by conditioning spray-dried SS with supercritical CO2 and menthol. Electrostatic charge of the powders was characterized in two ways. Firstly, the charge profile of the aerosols dispersed from an Aerolizer® was measured using a modified Electrostatic Low Pressure Impactor (ELPI™). Secondly, the net charge of the bulk powders generated from tumbling in containers composed of different materials (polyethylene, polyvinyl chloride, Teflon, nylon and stainless steel) was measured by a Faraday pail., Results: Following aerosolization, crystalline SS appeared to show more consistent charging and mass deposition than amorphous SS. In the tumbling experiment crystalline SS had a significant correlation between net charge and work function, which was absent in amorphous SS. This may be due to the long-range crystal packing which was reflected as more predictable charging. In addition, the polarity of charging was attributed to the arrangement of SS molecules in the crystal lattice., Conclusions: The effect of crystallinity on the electrostatic charge behavior of inhalable micron-sized spherical drug particles with well-defined particle size distribution was investigated for the first time. The knowledge gained may assist in the development of optimized inhaled pharmaceutical products.

Purpose: To demonstrate two sequential solid-state reactions in intact tablets: dehydration of active pharmaceutical ingredient (API), and cocrystal formation between the anhydrous API and a second formulation component mediated by the released water. To evaluate the implication of this in situ phase transformation on the tablet dissolution behavior., Methods: Tablets containing theophylline monohydrate (TPM) and anhydrous citric acid (CA) were stored at 40°C in sealed polyester pouches and the relative humidity in the headspace above the tablet was continuously measured. Dehydration to anhydrous theophylline (TPA) and the product appearance (TPA-CA cocrystal) were simultaneously monitored by powder X-ray diffractometry. Carbamazepine dihydrate and nicotinamide formed the second model system., Results: The water of crystallization released by TPM dehydration was followed first by deliquescence of citric acid, evident from the headspace relative humidity (~ 68%; 40°C), and then the formation of TPA-CA cocrystal in intact tablets. The noncovalent synthesis resulted in a pronounced decrease in the dissolution rate of theophylline from the tablets. Similarly, the water released by dehydration of carbamazepine dihydrate caused the cocrystallization reaction between anhydrous carbamazepine and nicotinamide., Conclusions: The water released by API dehydration mediated cocrystal formation in intact tablets and affected dissolution behavior.

Purpose: To study the effect of the size of the surface-coated polycaprolactone (PCL) microparticle carriers on the aerosolization and dispersion of Salbutamol Sulfate (SS) from Dry Powder Inhaler (DPI) formulations., Methods: The microparticles were fabricated using an emulsion technique in four different sizes (25, 48, 104 and 150 μm) and later coated with Magnesium stearate (MgSt) and leucine. They were characterized by laser diffraction and SEM. The Fine Particle Fraction (FPF) of SS from powder mixtures was determined by a Twin Stage Impinger (TSI)., Results: As the carrier size increased from 25 μm to 150 μm, the FPF of the SS delivered by the coated PCL particles increased approximately four fold. A linear relationship was found between the FPF and Volume mean Diameter (VMD) of the particles over this range., Conclusions: The dispersion behaviour of SS from PCL carriers was dependent on the inherent size of the carriers and the increased FPF of SS with increased carrier size probably reflects the higher mechanical forces produced due to the carrier-carrier collisions or collisions between the carrier particles and the internal walls of the inhaler during aerosolization.

Purpose: Deposition characteristics of MDI and DPI aerosols were compared throughout the conducting airways for the first time using a combination of in vitro experiments and a newly developed stochastic individual path (SIP) model for different inhalation profiles., Methods: In vitro experiments were used to determine initial particle distribution profiles and to validate computational fluid dynamics (CFD) model results for a MDI and DPI delivering the same dose of drug in a geometry of the mouth-throat and tracheobronchial airways. The validated CFD model was then used to predict the transport and deposition of the drug using correct and incorrect inhalation profiles for each inhaler., Results: The MDI delivered approximately two times more drug to the tracheobronchial region compared with the DPI for both correct and incorrect inhalation profiles. Errors in inhalation reduced the deposited tracheobronchial dose by approximately 30% for both inhalers. The DPI delivered the largest dose to the mouth-throat (~70%) and the MDI delivered the largest dose to the alveolar airways (~50%)., Conclusions: The developed in silico model provides new insights into the lung delivery of pharmaceutical aerosols and can be applied in future studies in combination with pharmacokinetic analysis to establish bioequivalence between devices.

Purpose: To measure aerosol performance of a lactose carrier/salbutamol sulphate powder blend and identify contributions of non-formulation and formulation components on the resulting aerosol charge., Methods: A 67.5:1 (%w/w) blend of 63-90 microm lactose with salbutamol sulphate, and lactose alone (with and without the blending process), was dispersed from a Cyclohaler into the electrical Next Generation Impactor at 30, 60 and 90 L/min. Mass and charge profiles were measured from each dispersion, as a function of impactor stage. The charge profile from an empty capsule in the Cyclohaler was also studied., Results: Lactose deposition from the blend was significantly greater, and net charge/mass ratios were smaller, in the pre-separator compared to formulations without drug. Fine particle fraction of salbutamol sulphate increased with flow rate (9.2 +/- 2.5% to 14.7 +/- 2.7%), but there was no change in net charge/mass ratio. The empty capsule produced a cycle of alternating net positive and negative discharges ( approximately 200 pC to 4 nC)., Conclusions: Capsule charge can ionize surrounding air and influence net charge measurements. Detachment of fine drug during aerosolisation may reduce net specific charge and lead to increased lactose deposition in the pre-separator. Increase in FPF may be due to increased force of detachment rather than electrostatic forces.

Purpose: Study objectives were to develop, characterize, and evaluate a novel excipient for dry powder inhalation formulations in a canine model with a model compound., Methods: Dry powder inhalation formulations of albuterol sulphate were developed and compared to a commercially available nebulizer albuterol solution formulation. In vitro analysis indicated a high fine-particle fraction (FPF, >70%) and a respirable particle size ( approximately 2.5 microm MMAD). Each inhalation formulation, including controls, was delivered targeting a deposited lung dose of 10 microg/kg albuterol. Active formulations were evaluated for pharmacokinetic (PK) profile and bronchodilatory effects in a ragweed-sensitized dog model of allergic airway responses., Results: In vitro, the dextran spray-dried formulated materials showed that aerosol performance, including FPF, MMAD, glass transition temperature, and amorphous characteristics, were all largely unaffected by amount of drug loaded. Both the commercial and the dry powder formulations attenuated the ragweed-induced bronchoconstriction by 91.59 +/- 3.60 and 81.28 +/- 9.29%, respectively. The PK profiles for both albuterol formulations were similar, as were the corresponding T(max), C(max) and T(1/2)., Conclusions: Results indicate that dextran 10 has promise as a novel excipient for dry powder inhalation drug delivery, in a preclinical setting, over a wide range of drug loadings.

Purpose: Engineering of inhalation particles incorporating, in each individual particle, a combination of a long-acting beta-agonist and a glucocorticosteroid in a pre-determined and constant ratio for delivery via a dry powder inhaler (DPI)., Methods: Individual crystalline particles containing both the glucocorticosteroid fluticasone propionate (FP) and long-acting beta-agonist salmeterol (SX) were prepared, in a ratio of 10:1, using the solution atomization and crystallization by sonication (SAX) process. Combination drug particles were characterized by particle size, morphology, crystallinity and aerosolisation efficiency using inertial impaction., Results: Combination drug particles were spherical and crystalline, with a median diameter of 4.68 +/- 0.01 microm. Aerosolisation of formulations containing combination drug particles resulted in greater uniformity in delivery ratios of both actives across all stages of the impactor before and after storage., Conclusions: Actives in a pre-determined dose ratio can be crystallised in a single particle using the SAX process.

Purpose: The crystallization and structural integrity of micron-sized inhalable salbutamol sulphate particles coated with L-leucine by different methods are investigated at different humidities. The influence of the L-leucine coating on the crystallization of salbutamol sulphate beneath the coating layer is explored., Methods: The coated particles are prepared by an aerosol flow reactor method, the formation of the L-leucine coating being controlled by the saturation conditions of the L-leucine. The coating is formed by solute diffusion within a droplet and/or by vapour deposition of L-leucine. The powders are humidified at 0%, 44%, 65% and 75% of relative humidity and the changes in physical properties of the powders are investigated with dynamic vapour sorption analysis (DVS), a differential scanning calorimeter (DSC), and a scanning electron microscope (SEM)., Results: Visual observation show that all the coated particles preserve their structural integrity whereas uncoated salbutamol sulphate particles are unstable at 65% of relative humidity. The coating layer formed by diffusion performs best in terms of its physical stability against moisture and moisture-induced crystallization. The degree of crystallization of salbutamol in the as-prepared powders is within the range 24-35%. The maximum degree of crystallization after drying ranges from 55 to 73% when the salbutamol crystallizes with the aid of moisture. In addition to providing protection against moisture, the L-leucine coating also stabilizes the particle structure against heat at temperatures up to 250 degrees C., Conclusion: In order to preserve good flowability together with good physical stability, the best coating would contain two L-leucine layers, the inner layer being formed by diffusion (physical stability) and the outer layer by vapour deposition (flowability).

Purpose: To investigate the aerosolization and behaviour of microparticles of salmeterol xinafoate (SX) and fluticasone propionate (FP) suspended in hydrofluoroalkane (HFA) propellant., Methods: Microcrystals of SX and FP were produced from poly(ethylene glycol) by antisolvent crystallization. The suspension behaviour and aerosolization of the microcrystals when formulated as metered dose inhalers (MDIs) in HFA 134a propellant was compared with that of microparticles produced by micronization (mSX and mFP) using a glass twin stage impinger and by laser light diffraction using a pressurized cell., Results: FP microparticles underwent non-reversible aggregation in suspension as seen by a doubling in the volume median diameter compared to the raw material. The degree of aggregation of SX particles in suspension was found to decrease as the particle size of the original particles increased. However, because the SX aggregate size was lowest for the particles with the smallest initial size (mSX), the highest fine particle fraction (FPF) of SX was obtained from a suspension of mSX. The FPFs following aerosolization of FP suspensions were similar although the FPF was lowest for particles with the largest original size., Conclusions: The size of the aggregates in the HFA suspensions was found to correlate directly with the FPFs determined by impaction.

Purpose: To investigate the role of in situ generated fine excipient particles on the fluidization and aerosolization properties of dry powder inhaler (DPI) formulations., Materials and Methods: Carrier 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., Results: High 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., Conclusions: The 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.

Purpose: A novel aerosol flow reactor method for the combined gas phase synthesis and coating of particles for drug delivery has been developed., Materials and Methods: As an example, micron-sized salbutamol sulfate particles were produced via droplet-to-particle conversion and in-situ coated by the physical vapor deposition (PVD) of L-leucine vapor., Results: During the deposition, L-leucine vapor crystallized on the surfaces of amorphous salbutamol particles. The size of L-leucine crystallites increased with increasing vapor concentration of L-leucine. The salbutamol particles with rough L-leucine surfaces exhibited good flowability enabling to them to be dispersed into air flow without the delivery aid of coarse lactose carriers., Conclusions: The fraction of particles smaller than 5 micrometers varied between 0.35 and 0.48 when dispersed into 60 l/min air flow having a jet Reynolds number of 30700. When the coated fine particles were blended with lactose carriers, the fine particle fraction was as high as 90%. The L-leucine coating also improved the stability of salbutamol particles when stored at 45% relative humidity atmosphere.

To investigate the influence of storage relative humidity (RH) on the aerosolisation efficiency and tribo-electrification of carrier based dry powder inhaler (DPI) formulations using the next generation impactor (NGI) in vitro methodology and the electrostatic low pressure impactor (ELPI). Micronised salbutamol (d (0.5) 1.48 +/- 0.03 microm) was blended with 63-90 microm sieve fractioned alpha-lactose monohydrate carrier and stored at a range of humidities (0-84% RH). The aerosolisation efficiency after storage for 24 h periods was investigated using the NGI. The same experiment was conducted using the ELPI, with corona charger switched off, to measure the net charge vs. mass deposition profile. Significant variations in the aerosolisation efficiency of the formulation were observed with respect to storage RH. In general, the fine particle fraction aerosol performance measured by NGI and ELPI (fraction with mass median aerodynamic diameter <4.46 and 4.04 microm, respectively) followed a positive parabola with aerosol performance increasing over the range 0-60% RH before decreasing >60% RH. Analysis of the ELPI charge data suggested that the micronised salbutamol sulphate had an electronegative charge when aerosolised from lactose based carriers, which was most electronegative at low RH. Increased storage RH resulted in a reduction in net charge to mass ratio with the greatest reduction at RH >60%. The aerosol performance of this binary system is dependent on both electrostatic and capillary forces. The use of the ELPI allows a degree of insight into how these forces affect formulation performances after storage at different RH.

Purpose: To determine a relationship between adhesive and cohesive inter-particulate forces of interactions and in vitro performance in pressurised metered dose inhalers (pMDIs) suspension formulations., Methods: Interparticulate forces of salbutamol sulphate (SS), budesonide (BUD) and formoterol fumarate dihydrate (FFD) were investigated by in situ atomic force microscopy (AFM) in a model propellant 2H, 3H perfluoropentane (HPFP). Experimental data were analysed using the recently developed cohesive/adhesive analysis method (CAB) and compared with in vitro deposition performances in pMDIs systems using Andersen cascade impactor (ACI)., Results: The in vitro investigation suggested that the micronised drug materials had significantly different aerosolisation profiles when manufactured as single or combination formulations. In general, the greatest significant differences were observed between SS single drug and SS-BUD and SS-FFD combinations. Analysis of the in vitro performance for the SS only formulation suggested that the cohesive nature of SS (as predicted by the CAB and observed with AFM) led to tightly bound flocs that did not fully deaggregate upon aerosolisation., Conclusions: It is suggested that the relationship between interparticulate interactions and in vitro performance of pMDIs suspension systems, when compared to direct measurement of the adhesion/cohesion forces, indicated good correlation. This approach may be useful in expediting the development of pMDI formulation and predicting performance.

Purpose: To assess the physicochemical characteristics and aerosol properties of suspensions of lipid-coated budesonide microcrystals dispersed in HFA-134a., Methods: Lipid-coated budesonide microcrystals were prepared by spray-drying an emulsion-based feedstock. Physicochemical characteristics of spray-dried particles were assessed by electron microscopy, laser diffraction, and differential scanning calorimetry. Purity and content were determined by reverse-phase HPLC. Particle aggregation and suspension stability were assessed visually, and aerosol performance was assessed by Andersen cascade impaction and dose content uniformity., Results: Spray-drying of micronized budesonide microcrystals in the presence of phospholipid-coated emulsion droplets results in the production of low-density lipid-coated microcrystals with low surface energy. These spray-dried particles form stable suspensions in HFA-134a. This translates into good uniformity in the metered dose across the contents of the inhaler and acceptable aerodynamic particle size distributions (MMAD = 3.2 to 3.4 microm). The formulation was observed to maintain its performance over 6 months at 40 degrees C/75% RH and 16 months at 25 degrees C/60% RH. No effect of storage orientation was observed on the content of first sprays following storage (i.e., no Cyr effect). The fine particle dose was found to be linear out to suspension concentrations of about 2% wt/vol, and FPD(4.7 microm) values approaching 400 microg can be delivered in a single inhalation., Conclusions: Engineered particles comprised of lipid-coated microcrystals may provide an acceptable alternative formulation technology for metered dose inhalers in the new hydrofluoroalkane propellants.

Purpose: To characterize two polymorphs of salmeterol xinafoate (SX-I and SX-II) produced by supercritical fluid crystallization., Methods: SX-I and SX-II were crystallized as fine powders using Solution Enhanced Dispersion by Supercritical Fluids (SEDS). The two polymorphs and a reference micronized SX sample (MSX) were characterized using powder X-ray diffractometry (PXRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), aqueous solubility (and dissolution) determination at 5-40 degrees C, BET adsorption analysis, and inverse gas chromatography (IGC)., Results: Compared with SX-I, SX-II exhibited a lower enthalpy of fusion, a higher equilibrium solubility, a higher intrinsic dissolution rate, a lower enthalpy of solution (based on van't Hoff solubility plots), and a different FTIR spectrum (reflecting differences in intermolecular hydrogen bonding). Solubility ratio plot yielded a transition temperature (-99 degrees C) below the melting points of both polymorphs. MSX showed essentially the same crystal form as SX-I (confirmed by PXRD and FTIR), but a distinctly different thermal behaviour. Mild trituration of SX-I afforded a similar DSC profile to MSX while prolonged grinding of SX-I gave rise to an endotherm at -109 degrees C, corresponding to solid-solid transition of SX-I to SX-II. Surface analysis of MSX, SX-I, and SX-II by IGC revealed significant differences in surface free energy in terms of both dispersive (nonpolar) interactions and specific (polar) acid-base properties., Conclusions: The SEDS-processed SX-I and SX-II display high polymorphic purity and distinctly different physical and surface properties. The polymorphs are related enantiotropically with SX-I being the thermodynamically stable form at room temperature.

Purpose: Efficient dispersion of bulk solids is critical for dry powder aerosol production which can be viewed as a sequence of events from stationary through dilated, flowing and finally dispersed particulates. The purpose of this study was to test the hypothesis that numerical descriptors of powder flow properties predict aerosol dispersion and pharmacodynamic effect., Methods: Drug and excipient particles were prepared in size ranges suitable for inhalation drug delivery, and their physico-chemical properties were evaluated. Novel techniques (chaos analysis of dynamic angle of repose and impact force separation) were developed and utilized to measure and characterize powder flow and particle detachment from solid surfaces, respectively. Dry powder aerosol dispersion was evaluated using inertial impaction. Pharmacodynamic evaluations of bronchodilation were performed in guinea pigs, for selected formulations., Results: We observed a direct correlation of powder flow with ease of particle separation (r2=0.9912) and aerosol dispersion (r2= 0.9741). In vivo evaluations indicated that formulations exhibiting a higher in vitro dose delivery resulted in a greater reduction in pulmonary inflation pressure., Conclusions: These results integrate powder behavior at various levels and indicate that numerical descriptors of powder flow accurately predict dry powder aerosol dispersion. A proportionality between aerosol dispersion and pharmacodynamic effect was observed in preliminary in vivo evaluations, which demonstrates the potential of these techniques for correlation studies between in vitro powder properties and in vivo effect.

Purpose: The purpose of this study is to investigate the effect of drug load, the coating of impactor stages, and the design of cascade impactors on albuterol MDIs particle size distribution measurements. The results of the investigation will be used to explain the "loading effect" recently reported., Methods: Particle size distribution parameters of a commercial albuterol MDI were measured using both Andersen (AI) and Marple-Miller (MMI) Cascade Impactors, where plates were either left uncoated or coated with silicone or glycerin. A previously validated HPLC-EC method was used for the assay of albuterol collected by the impactor and in single spray content determinations., Results: Coating impactor collection plates had an impact on measured MMAD and GSD values for single puff measurements but very little or no effect for the multi puff measurements. Due to particle bounce, the percent of albuterol fine particles deposited in the filter and impactor finer stages (< 1.10 microns in AI and < 1.25 microns in MMI) in uncoated single puff experiments was much higher in comparison to either coated single puff or multi-puff (coated and uncoated) measurements., Conclusions: Evaluation of drug load and plate coating are necessary to determine whether observed particle size distributions are representative of the generated aerosol or are the result of particle bounce and reentrainment. In order to minimize particle bounce, especially for single puff determinations, it may be useful to apply a thin layer of a sticky coating agent to the surfaces of impactor plates.