Performance Of Dry Powder Inhalers Research Articles

Co-spraying of carriers (mannitol-lactose) as a method to improve aerosolization performance of salbutamol sulfate dry powder inhaler

Although in dry powder inhaler (DPI) formulations a single carrier is used, a single carrier is not able to provide an excellent aerosolization performance when it is used in DPI formulations. Thereby, the aim of this study was to engineer a suitable ternary mixture of mannitol-lactose-leucine to be used in a DPI formulation with enhanced aerosolization performance. To this end, binary mixtures of mannitol:lactose containing a constant amount of leucine (5% w/w of carriers) were spray-dried as a single solution. Spray-dried samples were blended with salbutamol sulfate to determine the efficiency of their aerosolization performance. Interestingly, note that lactose was in its amorphous state stabilized by the presence of mannitol in the samples. Spray-dried mannitol without lactose showed a combination of the α- and β-polymorphic forms which was the case in all other ratios of mannitol:lactose. It was shown that the highest fine particle fraction (FPF) was 62.42 ± 4.21% which was obtained for the distinct binary mixtures (1:3 mannitol:lactose) compared to a single carrier. This study opens a new window to investigate further the implementation of binary mixtures of sugar carriers containing leucine in DPI formulations to overcome poor aerosolization performance the mentioned DPI formulations.

Investigation of Electrostatic Behavior of Dry Powder-Inhaled Model Formulations

The accumulation of electrostatic charge on drug particles and excipient powders arising from interparticulate collisions or contacts with other surfaces can lead to agglomeration and adhesion problems during the manufacturing process, filling, and delivery of dry powder inhaler (DPI) formulations. The objective of the study was to investigate the role of triboelectrification to better understand the influence of electrostatic charge on the performance of DPIs with 2 capsule-based dimensionally similar devices constructed with different materials. In addition, strategies to reduce electrostatic charge build up during the manufacturing process, and the processes involved in this phenomenon were investigated. Electrostatic charge measurements showed that there was a significant difference in electrostatic charge generated between tested formulations and devices. This affects particle detachment from carrier and thus significantly impacts aerosol performance. Conditioning fluticasone DPI capsules at defined temperature and humidity conditions reduced electrostatic charges acquired during manufacturing. Conditioning salmeterol DPI capsules at same conditions seemed disadvantageous for their aerosol performance because of increasing capillary forces and solid bridge formation caused by water absorption. Knowledge and understanding of the role of electrostatic forces in influencing DPI formulation performance was increased by these studies.

Tribo-Charging Behaviour of Inhalable Mannitol Blends with Salbutamol Sulphate

PurposeThe performance of carrier-based dry powder inhaler (DPI) formulations can be critically impacted by interfacial interactions driven by tribo-electrification. Therefore, the aim of the present work was to understand how distinct API particle characteristics affect the charging behaviour of blends intended for DPI delivery.MethodsSalbutamol sulphate (SBS) particles engineered via spray-drying and jet milling were used as model APIs. D-mannitol was selected as a model carrier. The materials were characterized concerning their different particle properties and their charge was analysed alone and in blends before and after flow over a stainless-steel pipe.ResultsThe spray-dried SBS (amorphous and spherical) charged positively and to a higher extent than jet milled SBS (crystalline and acicular) that charged negatively and to a lower extent. D-mannitol charged positively and to a higher extent than the APIs. All drug-excipient blends charged negatively and differences were found between the spray-dried and jet milled SBS blends at 2% and 5% drug loads.ConclusionsIt was demonstrated how distinct solid-states, particle shape, size and morphology as well as different water contents of the different materials can affect tribo-charging. For their binary blends, the amount and nature of fines seem to govern inter-particle contacts critically impacting charge evolution.

Insights into the processability and performance of adhesive blends of inhalable jet-milled and spray dried salbutamol sulphate at different drug loads

The multi-factorial interplay between particle engineering, particle properties, their downstream processability and aerodynamic performance contributes to the overall dry powder inhaler (DPI) performance. Inhalable particles of salbutamol sulphate were prepared by jet-milling and spray drying, characterized, and blended with lactose at low and high drug loads. These were filled into capsules using different process parameters and tested for their in vitro aerosolization performance. Differences were found in the particle interactions of jet-milled and spray dried powders, affecting their downstream processability. Blends of the spray dried particles revealed to be more prone to detachment during processing, resulting in a poorer aerodynamic in vitro performance. A higher drug load further affected the drug interaction with the excipient resulting in weaker carrier attachment and a higher in vitro fine particle fraction. The mean fill weight and blend homogeneity of the filled capsules showed distinct effects in relation to the type of mixture being processed, resulting into variable aerosolization performance results depending on the compression ratio used. By investigating the impact of distinct API properties and drug loadings on all the downstream processability chain, critical parameters needed to be considered in product quality and performance of jet-milled and spray dried drug particles were derived.

Chitosan-based binary dry powder inhaler carrier with nanometer roughness for improving in vitro and in vivo aerosolization performance.

Suitable nanometer roughness favors interactions between drugs and carriers, and it is a promising approach to enhance the aerosolization performance of carrier-based dry powder inhalers (DPIs). In this study, by altering the molecular migration rates, chitosan-based binary carriers (CBBCs) with nanometer roughness were fabricated for DPIs. Comprehensive physicochemical characterizations were conducted to elucidate the formation mechanism of the CBBCs. It was hypothesized that different constituent ratios in the formulations would result in different assembling of the particles and diverse roughness scales. The fine particle fractions (FPF, approximately 40~60%) of nanometer roughness CBBC-based DPI formulations were satisfactory, demonstrating the enhancement of the in vitro aerodynamic performance. The positive correlation (R2 = 0.9883) between the nanometer roughness and FPF was revealed, and the surface roughness of 20nm might achieve the best aerosolization performance. CBBCs (optimal formulations) showed no difference in cytotoxicity on A549 and Calu-3 cells (p > 0.05). Additionally, the increased Cmax and AUC0-8h of the formulation with the nanometer roughness (p < 0.05) were observed in pharmacokinetic studies, which resulted from the improved in vivo aerosolization performance. In summary, the CBBCs were a prospective tool to improve the in vitro and in vivo aerosolization performance of DPIs. Graphical abstract ᅟ.

Towards quantitative prediction of the performance of dry powder inhalers by multi-scale simulations and experiments

This work demonstrates the use of multi-scale simulations coupled with experiments to build a quantitative prediction tool for the performance of adhesive mixtures in a dry powder inhaler (DPI). Using discrete element model (DEM), the behaviour of fine-carrier particle assemblies upon different mechanisms encountered during dose entrainment and dispersion can be described at the individual particle level. Combining these results with computational fluid dynamics (CFD) simulations, the complete dosing event from a DPI can be captured and key performance measures can be extracted. A concept of apparent surface energy, ASE, was introduced to overcome challenges associated with the complex particle properties, e.g. irregular particle shapes and surface roughness. This approach correctly predicts trends observed experimentally regarding API adhesivity, flow rate and device geometry. By incorporating the effects of drug load, critical adhesion and surface energy distributions to the simulation tool, the fine particle fraction could be predicted with good agreement to experiments for two different formulations in two different devices at two flow rates. It is concluded that multi-scale simulations provide a useful tool to support device and formulation development, as well as to gain further insight into the physical mechanisms governing dispersion from DPIs.

Characterizing the Surface Roughness Length Scales of Lactose Carrier Particles in Dry Powder Inhalers.

Surface roughness is well recognized as a critical physical property of particulate systems, particularly in relation to adhesion, friction, and flow. An example is the surface property of carrier particles in carrier-based dry powder inhaler (DPI) formulations. The numerical characterization of roughness remains rather unsatisfactory due to the lack of spatial (or length scale) information about surface features when a common amplitude parameter such as average roughness ( Ra) is used. An analysis of the roughness of lactose carrier particles at three different length scales, designed for specificity to the study of interactive mixtures in DPI, was explored in this study. Three Ra parameters were used to represent the microscale, intermediate scale, and macroscale roughness of six types of surface-modified carriers. Coating of micronized lactose fines on coarse carrier particles increased their microroughness from 389 to 639 nm while the macroroughness was not affected. Roller compaction at higher roll forces led to very effective surface roughening, particularly at longer length scales. Changes in Ra parameters corroborated the visual observations of particles under the scanning electron microscope. Roughness at the intermediate scale showed the best correlation with the fine particle fraction (FPF) of DPI formulations. From the range of 250 to 650 nm, every 100 nm increase in the intermediate roughness led to ∼8% increase in the FPF. However, the effect of surface roughness was greatly diminished when fine lactose (median size, 9 μm) of comparable amounts to the micronized drug were added to the formulation. The combination of roughness parameters at various length scales provided much discriminatory surface information, which then revealed the "quality" of roughness necessary for improving DPI performance.

Agglomerated novel spray-dried lactose-leucine tailored as a carrier to enhance the aerosolization performance of salbutamol sulfate from DPI formulations

Spray-drying allows to modify the physicochemical/mechanical properties of particles along with their morphology. In the present study, L-leucine with varying concentrations (0.1, 0.5, 1, 5, and 10% w/v) were incorporated into lactose monohydrate solution for spray-drying to enhance the aerosolization performance of dry powder inhalers containing spray-dried lactose-leucine and salbutamol sulfate. The prepared spray-dried lactose-leucine carriers were analyzed using laser diffraction (particle size), differential scanning calorimetry (thermal behavior), scanning electron microscopy (morphology), powder X-ray diffraction (crystallinity), Fourier transform infrared spectroscopy (interaction at molecular level), and in vitro aerosolization performance (deposition). The results showed that the efficacy of salbutamol sulfate’s aerosolization performance was, in part, due to the introduction of L-leucine in the carrier, prior to being spray-dried, accounting for an increase in the fine particle fraction (FPF) of salbutamol sulfate from spray-dried lactose-leucine (0.5% leucine) in comparison to all other carriers. It was shown that all of the spray-dried carriers were spherical in their morphology with some agglomerates and contained a mixture of amorphous, α-lactose, and β-lactose. It was also interesting to note that spray-dried lactose-leucine particles were agglomerated during the spray-drying process to make coarse particles (volume mean diameter of 79 to 87 μm) suitable as a carrier in DPI formulations.

An In Vitro Examination of the Effects of Altitude on Dry Powder Inhaler Performance.

The effects of altitude on dry powder inhaler (DPI) performance remain understudied. As existing standardized testing methodologies do not consider altitude, inhalation devices may be used in environments in which their performance has not been sufficiently characterized. Six DPIs spanning a range of device resistances were examined in vitro in an environmental chamber mimicking a high-altitude environment equivalent to an altitude of 4200 m, with controls established at an altitude of 700 m. Deposition and size distribution data were quantified by using an Alberta Idealized Throat coupled to a Next-Generation Impactor, operated by using a square inhalation profile. Controls were established for two cases, one with a standard pressure drop and the other with a minimal efficacious flowrate. Experiments at simulated altitude were performed first by using a matched volumetric flowrate and second with a matched pressure drop, corresponding to values obtained in the controls. In vitro results were input into a lung deposition model to examine the relationship between particle-size distributions, inhalation flowrates, and regional deposition in the respiratory tract. Simulated altitude caused statistically significant effects in some DPIs, but effects were variable, device dependent, and relatively minor. Medium-high resistance devices were more affected by the flowrate used to establish the control than by any effects of altitude. Patients able to generate sufficient inspiratory efforts can expect relatively consistent device performance at altitudes up to 4200 m for the devices examined here.

Void forming index: A new parameter for detecting microstructural transformation caused by powder agglomeration

As powder agglomeration during storage causes a decrease in the performance of dry powder inhalers (DPIs), it is important to understand the properties of powder agglomeration in developing DPIs. Generally, powder agglomeration is caused by capillary force and crystalline transformation in conditions of higher humidity. It is, however, difficult to correlate crystalline transformation and powder agglomeration, especially when the crystalline transformation is limited. In this study, we focused on the application of inverse gas chromatography (iGC) to detect powder agglomeration directly. There was a slight change between the powder state and lactose agglomerates using powder X-ray diffraction, and dynamic vapor sorption. On the other hand, a change in pressure drop was found during measurement of lactose using iGC. After measurement by iGC, powdered lactose agglomerated. This finding suggests that a pressure drop is related to powder agglomeration and can be employed to detect the onset of powder agglomeration. Based on these findings, we propose a novel index—the Void Forming Index (VFI)—which is related to the pressure drop with iGC. The VFI is a useful index in the evaluation of powder agglomeration, and will be especially useful during DPI development.

Dry powder inhaler performance of spray dried mannitol with tailored surface morphologies as carrier and salbutamol sulphate

Nowadays, dry powder inhalation as applied in the therapy of pulmonary diseases is known as a very effective route of drug delivery to the lungs. Here, the system of coarse carrier and fine drug particles attached to the carrier surface has successfully been applied to overcome the cohesiveness of small drug particles. Particle properties of both carrier and drug are known to affect drug dispersion as has widely been discussed for lactose monohydrate and various drugs. This study utilises particle-engineered mannitol as an alternative carrier to discover the effect of mannitol carrier particle properties like particle shape, surface roughness, flowability or particle size on aerodynamic performance during inhalation. Spray drying as a technique to accurately control those properties was chosen for the generation of carrier sizes between 50 and 80 μm and different morphologies and therefore various carrier flowabilities. A set of these carriers has then been blended with different spray dried and jet-milled qualities of salbutamol sulphate as model drug to examine the influence of carrier particle properties on aerodynamic behaviour and at the same time to cover the effect of drug particle properties on particle–particle interactions. This experimental setup allowed a general view on how drug and carrier properties affect the Fine Particle Fraction (FPF) as indicator for inhalation performance and gave the first study to distinguish between mannitol carrier particle shape and surface roughness. Further it was possible to relate carrier particle size and shape to drug accumulation and detachment mechanisms during inhalation as size and shape had the main influence on drug detachment. The addition of jet-milled mannitol fines provided an initial insight into the improving effect of ternary powder blends as has been intensively studied for lactose monohydrate but not for mannitol yet.

Nano- and Microstructured model carrier surfaces to alter dry powder inhaler performance

The present study investigates the effect of different carrier surface modifications on the aerosolisation performance and on the effective carrier payload of interactive blends for inhalation. Two different active pharmaceutical ingredients (APIs) were used: Formoterol fumarate dihydrate (FF) and budesonide (BUD). Blends were prepared with glass beads as model carriers which have been subjected to mechanical surface modifications in order to introduce surface roughness via treatment with hydrofluoric acid (HF) and/or milling with tungsten carbide (TC).As far as effective carrier payload, in this study expressed as true surface coverage (TSC), is concerned, surface modification had varying effects on blends containing BUD or FF.Aerodynamic characterisation in vitro showed a significant decrease in respirable fraction for glass beads treated with HF (40.2–50.1%), due to the presence of clefts and cavities, where drug particles were sheltered during inhalation. In contrast, grinding with TC leads to surface roughness on a nano scale, ultimately increasing aerodynamic performance up to 20.0–38.1%. These findings are true for both APIs, regardless of their chemical properties.

P152 Robust performance of a multidose dry powder inhaler with albuterol sulfate under various misuse scenarios

P152 Robust performance of a multidose dry powder inhaler with albuterol sulfate under various misuse scenarios

Dry-powder inhalers in patients with persistent airflow limitation: usability and preference.

BackgroundInhalation devices represent per sé critical factors because they can affect the therapeutic outcomes independently of the drug used. The role of patients’ usability and preference (PUP) for Dry Powder Inhalers (DPIs) is high indeed because they can influence the extent of the adherence to treatment and the therapeutic outcomes.Aim of the study was to assess and compare the PUP of three different DPIs in out-patients with persistent airflow limitation due to asthma or COPD.MethodsThe PUP of three different DPIs (Breezhaler; Genuair; Handihaler) were investigated by means of the Handling Questionnaire in out-patients with persistent airflow limitation needing an inhalation therapy. Patients had to report their preference before and after the nurse’s instruction on the handling of each device. The nurse had also to note the critical steps during the patient’s procedure for actuation; to count the number of attempts needed for actuating the device properly, and to measure the time (in sec.) required for these procedures. Data were collected up to three attempts per device.Statistics: Welch test was used for normal distributed variables, while the Wilcoxon test for not normal distributed variables. The χ2 test and the ANOVA test were also used. Univariate and multivariate regressions were also performed in order to investigate the effect of patients’ characteristics and of technical differences of each device on their proper use.ResultsThree hundred thirty-three consecutive out-patients (age range 55–58 years, and well matched for gender), with persistent airway limitation of different severity were investigated, suffering from bronchial asthma (n = 175) or from chronic obstructive pulmonary disease (COPD) (n = 158). In particular, 127 patients (38 %) tested the three DPIs, while 110 (33 %) tested Breezhaler and Genuair, and 96 (29 %) Breezhaler and Handihaler. More than 50 % of patients who tested all devices preferred the Genuair and perceived this device as the easiest to use. The nurse’s judgement confirmed their opinion. When compared to the other two DPIs, Genuair proved the least problematic either according to the patients’ judgement and to the nurse’s opinion. Mean number of attempts aimed to achieving the first proper actuation was lower with Genuair than with Breezhaler and Handihaler (1.5 vs 2.5–2.6, p < 0.0001). Finally, Genuair also proved the easiest to use and the least problematic according to the nurse judgement (0.0001), the most easily learned (0.0001), and that one with a successful rate of more than 56 % at the first attempt. Breezhaler and Handihaler needed an average of about one additional attempt to be used properly (p < 0.0001), and their usability proved significantly more difficult (OR of successful rate between 0.15 and 0.17, p < 0.001). In general, older patients needed more attempts to perform their first proper inhalation; their successful rate was lower, and they needed more time to learn how to use devices properly: with Genuair these differences were minimized.ConclusionsThe possibility of grading objectively the performance of different DPIs in terms of their usability and therapeutic convenience in daily life represents a crucial operational opportunity to pursue. To note that a substantial discrepancy exists between the patients’ belief “at glance” and the patients’ effective usability with can be registered with some devices. From a general point of view, devices requiring less manual actions for their actuation confirmed their better usability and proper handling after less attempts. In particular, Genuair came out as the most preferred DPI also when several different aspects of preference and usability are assessed objectively and compared.

Dry-powder inhalers in patients with persistent airflow limitation: usability and preference

Background: Inhalation devices represent per sé critical factors because they can affect the therapeutic outcomes independently of the drug used. The role of patients’ usability and preference (PUP) for Dry Powder Inhalers (DPIs) is high indeed because they can influence the extent of the adherence to treatment and the therapeutic outcomes. Aim of the study was to assess and compare the PUP of three different DPIs in out-patients with persistent airflow limitation due to asthma or COPD. Methods: The PUP of three different DPIs (Breezhaler; Genuair; Handihaler) were investigated by means of the Handling Questionnaire in out-patients with persistent airflow limitation needing an inhalation therapy. Patients had to report their preference before and after the nurse’s instruction on the handling of each device. The nurse had also to note the critical steps during the patient’s procedure for actuation; to count the number of attempts needed for actuating the device properly, and to measure the time (in sec.) required for these procedures. Data were collected up to three attempts per device. Statistics: Welch test was used for normal distributed variables, while the Wilcoxon test for not normal distributed variables. The χ2 test and the ANOVA test were also used. Univariate and multivariate regressions were also performed in order to investigate the effect of patients’ characteristics and of technical differences of each device on their proper use. Results: Three hundred thirty-three consecutive out-patients (age range 55–58 years, and well matched for gender), with persistent airway limitation of different severity were investigated, suffering from bronchial asthma (n = 175) or from chronic obstructive pulmonary disease (COPD) (n = 158). In particular, 127 patients (38 %) tested the three DPIs, while 110 (33 %) tested Breezhaler and Genuair, and 96 (29 %) Breezhaler and Handihaler. More than 50 % of patients who tested all devices preferred the Genuair and perceived this device as the easiest to use. The nurse’s judgement confirmed their opinion. When compared to the other two DPIs, Genuair proved the least problematic either according to the patients’ judgement and to the nurse’s opinion. Mean number of attempts aimed to achieving the first proper actuation was lower with Genuair than with Breezhaler and Handihaler (1.5 vs 2.5–2.6, p &lt; 0.0001). Finally, Genuair also proved the easiest to use and the least problematic according to the nurse judgement (0.0001), the most easily learned (0.0001), and that one with a successful rate of more than 56 % at the first attempt. Breezhaler and Handihaler needed an average of about one additional attempt to be used properly (p &lt; 0.0001), and their usability proved significantly more difficult (OR of successful rate between 0.15 and 0.17, p &lt; 0.001). In general, older patients needed more attempts to perform their first proper inhalation; their successful rate was lower, and they needed more time to learn how to use devices properly: with Genuair these differences were minimized. Conclusions: The possibility of grading objectively the performance of different DPIs in terms of their usability and therapeutic convenience in daily life represents a crucial operational opportunity to pursue. To note that a substantial discrepancy exists between the patients’ belief “at glance” and the patients’ effective usability with can be registered with some devices. From a general point of view, devices requiring less manual actions for their actuation confirmed their better usability and proper handling after less attempts. In particular, Genuair came out as the most preferred DPI also when several different aspects of preference and usability are assessed objectively and compared.

Multivariate data analysis to assess dry powder inhalers performance from powder properties

The study aimed at investigating the correlations among the physical and bulk properties of carrier based dry powder inhaler formulations and the performance of the powder inhaler device estimated by in-vitro tests for a specific active pharmaceutical ingredient (API), and at obtaining predictive models for the in-vitro performance. Samples from scale-up process batches having different formulations, process settings and bulk size, were characterized by rheological, density and particle size tests. In vitro performance was evaluated by several parameters obtained by a dosage unit sampling apparatus (DUSA) and a next generation impactor (NGI). Correlations between powder properties and performance properties were established using partial least square (PLS) regression analysis. Variable importance in projection (VIP) was used in order to assess the most influential powder characterization variables to estimate the analytical ones. Particle size, density and rate of flowability are significant for modeling the Delivered Dose of the API and the total quantity of powder related to each dose. Powder characterization variables, describing the degree of cohesiveness and the flow properties of powder, are related to the total amount of the active ingredient for different formulations. DUSA test variables were satisfactory predicted on the basis of powder characterization variables, while NGI performance variables were predicted with higher error.

Comparison of the cohesion-adhesion balance approach to colloidal probe atomic force microscopy and the measurement of Hansen partial solubility parameters by inverse gas chromatography for the prediction of dry powder inhalation performance

The abilities of the cohesive-adhesive balance approach to atomic force microscopy (AFM) and the measurement of Hansen partial solubility parameters by inverse gas chromatography (IGC) to predict the performance of carrier-based dry powder inhaler (DPI) formulations were compared. Five model drugs (beclometasone dipropionate, budesonide, salbutamol sulphate, terbutaline sulphate and triamcinolone acetonide) and three model carriers (erythritol, α-lactose monohydrate and d-mannitol) were chosen, giving fifteen drug-carrier combinations. Comparison of the AFM and IGC interparticulate adhesion data suggested that they did not produce equivalent results. Comparison of the AFM data with the in vitro fine particle delivery of appropriate DPI formulations normalised to account for particle size differences revealed a previously observed pattern for the AFM measurements, with a slightly cohesive AFM CAB ratio being associated with the highest fine particle fraction. However, no consistent relationship between formulation performance and the IGC data was observed. The results as a whole highlight the complexity of the many interacting variables that can affect the behaviour of DPIs and suggest that the prediction of their performance from a single measurement is unlikely to be successful in every case.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 26 Edinburgh International Conference Centre Edinburgh, Scotland, UK December 9-11, 2015.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 26 Edinburgh International Conference Centre Edinburgh, Scotland, UK December 9-11, 2015.

Improving Dry Powder Inhaler Performance by Surface Roughening of Lactose Carrier Particles.

This study investigated the impact of macro-scale carrier surface roughness on the performance of dry powder inhaler (DPI) formulations. Fluid-bed processing and roller compaction were explored as processing methods to increase the surface roughness (Ra) of lactose carrier particles. DPI formulations containing either (a) different concentrations of fine lactose at a fixed concentration of micronized drug (isoniazid) or (b) various concentrations of drug in the absence of fine lactose were prepared. The fine particle fraction (FPF) and aerodynamic particle size of micronized drug of all formulations were determined using the Next Generation Impactor. Fluid-bed processing resulted in a modest increase in the Ra from 562 to 907nm while roller compaction led to significant increases in Ra > 1300nm. The roller compacted carriers exhibited FPF > 35%, which were twice that of the smoothest carriers. The addition of up to 5%, w/w of fine lactose improved the FPF of smoother carriers by 60-200% whereas only < 30% increase was observed in the rough carriers. Analysis of the FPF in tandem with shifts in the mass median aerodynamic diameter of dispersed drug suggested that the finest drug particles were entrapped on rougher surfaces while larger drug particles were dispersed in the air. The results showed that the processing of lactose carrier particles by roller compaction was immensely beneficial to improving DPI performance, primarily due to increased surface roughness at the macro-scale.

Quantitative determination of micronization-induced changes in the solid state of lactose

Lactose, in particular α-lactose monohydrate, is the most used carrier for inhalation. Its surface and solid-state properties play a key role in determining Dry Powder Inhalers (DPIs) performance. Techniques such as X-Ray Powder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC), which are commonly used for the characterization of lactose, are not always capable of explaining the solid-state changes induced by processing, such as micronization. In the present work, the evaluation of the effect of the micronization process on the solid-state properties of lactose was carried out by XRPD and DSC and a satisfactory, although not unequivocal, interpretation of the thermal behaviour of lactose was obtained. Thus, a new gravimetric method correlating in a quantitative manner the weight change in specific sections of the Dynamic Vapour Sorption (DVS) profile and the amount of different forms of α-lactose (hygroscopic anhydrous, stable anhydrous and amorphous) simultaneously present in a given sample was developed and validated. The method is very simple and provides acceptable accuracy in phase quantitation (LOD=1.6, 2.4 and 2.7%, LOQ=5.4, 8.0 and 8.9% for hygroscopic anhydrous, stable anhydrous and amorphous α-lactose, respectively). The application of this method to a sample of micronized lactose led to results in agreement with those obtained by DSC and evidenced that hygroscopic anhydrous α-lactose, rather than amorphous lactose, can be generated in the micronization process.The proposed method may find a more general application for the quantification of polymorphs of compounds different than lactose, provided that the various solid phases afford different weight variations in specific regions of the DVS profile.