Pharmaceutical inhalation dry-powder sampling device, method and uses thereof

Abstract

The present disclosure relates to a pharmaceutical inhalation dry-powder sampling device for a spray-drying apparatus, comprising a sampling inlet comprising an aerosol probe for receiving aerosol particles from the spray-drying apparatus, an aerosol disperser for deagglomerating and diluting the received aerosol particles, and an outlet for supplying the dispersed aerosol particles to an aerodynamic particle size sensor. Furthermore, the present disclosure also relates to a pharmaceutical inhalation dry- powder analysing device, a spray-drying apparatus and a method thereof, and a dry powder inhaler formulation development method.

Description

D E S C R I P T I O NPHARMACEUTICAL INHALATION DRY-POWDER SAMPLING DEVICE, METHOD AND USES THEREOFTECHNICAL FIELD

[0001] The present disclosure belongs to the technical field of pharmaceutical inhalation formulations of dry powders. More specifically, the present disclosure relates to a pharmaceutical inhalation dry-powder sampling device, a pharmaceutical inhalation dry-powder analysing device, a spray-drying apparatus and a method thereof, and a dry powder inhaler formulation development method. The device and method may be used to sample aerosolized dry powder during the spray-drying process, enabling precise particle aerodynamic size screening and monitoring and also ensuring the produced dry powder meets the desired specifications, namely particles' aerodynamic size.BACKGROUND

[0002] A Dry Powder Inhaler (DPI) product is comprised of an oral inhalation device and a dry powder formulation comprising at least one Active Pharmaceutical Ingredient (API). Upon actuation, the device generates an aerosol that is delivered to the lung. The dry powder can be released directly from the inhaler or from capsules that are punctured upon device actuation. This means that the powder can either be filled directly into the device's reservoir or filled into capsules that are then placed inside the inhaler.

[0003] The faster a new medicine can be developed and brought to market, the sooner patients can benefit from its potentially life-saving effects. Therefore, this development process must be quick and efficient. Additionally, urgent public health needs occasionally require a fast response, such as during a pandemic or an outbreak of a new disease. The rapid development of medicines can help to address these urgent health needs and prevent the further spread of illness. Besides time, materials use during the drug development process is also important as APIs are frequentlyunavailable or available only in small quantities. Thus, accelerated development of drug products using minimal API quantities is crucial.

[0004] The development of a DPI involves its aerodynamic characterization, typically carried out in vitro by cascade impaction. The impaction methods involve the use of cascade impactors, which are devices that separate particles based on their aerodynamic size. These instruments have been used extensively to measure particle size distributions by mass since the 1960s [William C. Hinds. Aerosol technology: properties, behavior and measurement of airborne particles [Internet], 2nd ed. Los Angeles: John Wiley & Sons, Inc.; 1999. Available from: http: / / www.tandfonline.com / doi / abs / 10.1080 / 17449200600935521],

[0005] Cascade impactors operate on the principle of inertial impaction. They consist of a series of stages, comprised of a plate with a specific nozzle arrangement and a collection surface. The aerosol is passed through a nozzle, and the output stream is directed against an impaction plate, that deflects the flow to form an abrupt 90° bend in the streamlines. Larger particles whose inertia exceeds a specific value cannot follow the streamlines and collide on the plate. Smaller particles can follow the streamlines and avoid the impaction plate. They remain airborne and flow out of the impactor. Thus, an impactor separates aerosol particles into two size ranges; particles larger than a certain aerodynamic particle size are removed from the airstream, and those smaller than that certain aerodynamic particle size remain in the aerosol and pass through the impactor. This allows the DPIs to be evaluated and ranked according to their Fine Particle Fraction (FPF), corresponding to the delivered mass percentage of particles with an aerodynamic below 5 micrometers.

[0006] Examples of impactors that can be used to determine the aerodynamic particle size distribution of DPIs include the Andersen Cascade Impactor (ACI), the Next Generation Impactor (NGI), Multi-Stage Liquid Impinger (MSLI) and Glass Twin Impinger (GTI), as described in U.S. Pharmacopeia, chapter 601 - Aerosols, nasal sprays, metered-dose inhalers, and dry powder inhalers.

[0007] The aerodynamic particle size distribution is characterized by two important parameters:MMAD (mass median aerodynamic diameter): diameter of the particles deposited in the impactor for which 50% w / w have a lower aerodynamic diameter and 50% w / w have a higher diameter;GSD (geometric standard deviation): expresses the particle size distribution around the MMAD value.

[0008] In a typical formulation development process for DPIs, several spray drying runs are carried out with different excipients and / or process conditions, with each run producing a dry, drug powder. Then, for each drug powder produced during a spray drying run, the capsule filling parameters are evaluated, resulting in tens of powders to be characterized by cascade impaction (which is performed at least in triplicate).

[0009] The impaction tests are time-consuming analyses that are performed at least in triplicate and can last up to a work day done by one person.

[0010] The extensive number of experiments, which involves conducting several spray drying trials and characterizing them through laser diffraction and cascade impaction methods, coupled with the time-intensive nature of the cascade impaction techniques, hinder the development and optimization of DPI formulations within acceptable timeframes for drug formulation development. This limitation not only results in significant R&D lead times but also incurs substantial costs during the drug development phase, particularly since APIs are rarely available during early clinical development.

[0011] Time-of-flight analyzers are capable of measuring the aerodynamic diameter of aerosol particles [Mitchell JP, Nagel MW. Time-of-flight aerodynamic particle size analyzers: Their use and limitations for the evaluation of medical aerosols. J Aerosol Med Depos Clear Eff Lung. 1999;12:217-40.] For example, the TSI® Aerodynamic Particle Size (TSI APS) 3321 Model provides real-time aerodynamic diameters of particles from 0.5 to 20 pm. It uses the time-of-flight principle to measure the aerodynamic particle size. It is commonly used in air quality monitoring, atmospheric research, and industrial hygiene applications to measure the concentration and size distribution of airborne particles such as dust, smoke, and aerosols [TSI Incorporated. AERODYNAMIC PARTICLE SIZER (APS) 3321 [Internet], Available from:spectrometers / aerodynamic particle sizer-aps- 33211. Inside the instrument, the aerosol and sheath flow are constricted through a nozzle, accelerating the airflow. Particles within the airflow are also accelerated. Longer times are associated with larger-sized particles due to the enhanced drag they experience in the accelerating flow field. Thus, it is possible to have a particle velocity related to its aerodynamic diameter. As particles exit the nozzle, the time of flight between the two laser beams is recorded and converted to aerodynamic diameter using a calibration curve. Each particle creates a single, continuous signal with two crests, recorded by a photodetector. The time between the two crests is the particle's time of flight. Particles with only one crest (phantom particles) or more than two crests (coincidence error) are not used in building size distribution calculations. The result is a count distribution which can then be converted to mass distribution using particle density.

[0012] For example the aerodynamic particle sizer model TSI APS 3321, has been extensively used in the pharmaceutical industry to measure the aPSD (aerodynamic Particle Size Distribution) of the powder delivered by the inhalation device and to establish correlations between the aPSD measured by time-of-flight and cascade impaction for MDIs (Metered Dose Inhalers) or between the aPSD measured by time- of-flight and the particle size distribution measured by laser diffraction.

[0013] However, employing this time-of-flight sensor as a PAT tool is a recent application. Process Analytical Technology (PAT) is defined by the United States Food and Drug Administration as "a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality. [Ivey et al. [Ivey JW, Barona D, Gomez M, Kuan L, Mcallister R, Oberhagemann L, et al. Isokinetic In-line Sampling Enables Rapid Characterization of Atomizers and Cyclones for Spray Drying Process Development. RDD 2018. 2018. p. 551-6.] [Ivey JW. Particle Formation from Evaporating Microdroplets for Inhaled Drug Delivery. University of Alberta; 2018.] [Ivey JW, Vehring R. A Methodology for Efficient Pharmaceutical Spray Drying Process Development. AAPS Annu Meet Expo Novemb 13-17, 2016, Denver, CO, USA [Internet], 2016; Available from:https: / / www.researchgate.net / publication / 310753550_A_Methodology_for_Efficient_ Pharmaceutical_Spray_Drying_Process_Development] developed an isokinetic aerosol sampling system that enables real-time measurement of the aPSD during spray drying. Their setup was based on a custom-built spray drier and was used to characterize the performance of an atomizer and a cyclone supplied by BUCHL They claimed that the sampling could be done at the various points of the drying process, but the locations were not specified. This sampling system comprised a probe, a flow mixer and an aerodynamic particle sizer (APS, 3321, TSI, MN, USA).

[0014] From the same research group, Wang et al. [Wang Z, Wang H, Vehring R. Leucine enhances the dispersibility of trehalose-containing spray-dried powders on exposure to a high-humidity environment. Int J Pharm [Internet], 2021;601:120561. Available from: https: / / linkinghub.elsevier.com / retrieve / pii / S0378517321003665] sampled isokinetically in a custom-built spray-dryer and measured the aPSD using an aerodynamic particle sizer (APS, 3321, TSI, MN, USA) to control the monodispersity of the aPSD by adjusting the driving frequency of a microjet atomizer.

[0015] In another work [Wang H, Ordoubadi M, Connaughton P, Lachacz K, Carrigy N, Tavernini S, et al. Spray Dried Rugose Lipid Particle Platform for Respiratory Drug Delivery. Pharm Res [Internet], 2022;39:805-23. Available from: https: / / link.springer.com / 10.1007 / sll095-022-03242-w], the same research group measured in-process the aerodynamic particle size distributions of the dried particles using a combination of an isokinetic sampling probe, an aerosol diluter (3302A, TSI, MN, USA) and a time-of-flight aerodynamic particle sizer (APS, 3321, TSI, MN, USA) placed close to the outlet of the spray dryer. The TSI 3302A diluter samples isokinetically the aerosol, sends a portion through a capillary tube, filters the remaining aerosol and mixes them before sending it to TSI APS 3321. It dilutes aerosols in the ratios 20:1 and 100:1.

[0016] These facts are disclosed in order to illustrate the technical problem addressed by the present disclosure.GENERAL DESCRIPTION

[0017] The present disclosure pertains to the technical field of pharmaceutical inhalation formulations involving dry powders. Namely the present disclosure relates to a pharmaceutical inhalation dry-powder sampling device, for use with a spraydrying apparatus. The device and method of the present disclosure allow the sampling of aerosolized dry powder during the spray-drying process, enabling precise and continuous control and monitoring of the aerodynamic particle size and ensuring that the produced dry powder meets the desired specifications, in particularly in terms of aerodynamic particle size or diameter.

[0018] An aspect of the present disclosure relates to a pharmaceutical inhalation drypowder sampling device for a spray-drying apparatus, comprising: a sampling inlet comprising an aerosol probe for receiving aerosol particles from the spray-drying apparatus; an aerosol disperser for deagglomerating and diluting the received aerosol particles; and an outlet for supplying the dispersed aerosol particles to an aerodynamic particle size sensor.

[0019] The device of the present disclosure integrates a real-time monitoring mechanism within the spray-drying process, surprisingly allowing for continuous and precise adjustment of aerodynamic particle size distribution even with size inferior to 3 pm, which is not achievable with existing methods.

[0020] The innovative sampling device of the present disclosure allow the proper deagglomeration and dilution of the aerosol particles, allowing precise and reproducible analysis by the aerodynamic particle size sensor. In particular, it allows a proper control of the dilution of the aerosol particles, which is essential to obtain an accurate determination of the aerodynamic particle size by the aerodynamic particle size sensor, in particular for aerosol particles with aPSD ranging from 0.5- 3pm.

[0021] The device of the present disclosure enables rapid screening of formulation compositions and evaluation of existing formulations for inclusion of new APIs.Surprisingly, the device and method of the present disclosure provides a positive correlation between the aPSD measured during spray dry manufacturing (measured at the supplied aerosol particles) and the aPSD obtained using the DPI device.

[0022] The present disclosure provides a novel and innovative device and method, using an aerodynamic particle sizer, preferably a time-of-flight sensor, which may be used as a PAT tool to assess in real time (during processing) the aPSD (aerodynamic particle size) of the particles obtained in a spray drying process.

[0023] Of upmost importance, the apparatus and process of the present disclosure can be applied / coupled to commercially available spray drying apparatus.

[0024] Using the device and methodology of the present disclosure, only one spray drying trial per formulation composition is required, eliminating the need for timeconsuming optimization and iterations of the aerodynamic particle size distribution. This significantly reduces the number of experiments required by a factor of at least 5 to 10.

[0025] The present device and method enable the comparison of formulations at a given aerodynamic particle size during the initial stages of development. This approach decouples the primary aerodynamic diameter from the aerodynamic performance of a DPI, which depends both on the properties of the powder (including particle shape, density and surface properties) and the inhalation device.

[0026] For the first time in the field of DPI formulation development, the reliance on trial and error, which can yield false positives and negatives, can be eliminated. Without the need for extensive experimentation to mitigate confounding effects, the present disclosure provides a device and method which allow to eliminate these challenges from the outset. It represents a significant advancement in formulation evaluation and optimization, offering a practical and innovative solution to a longstanding problem.

[0027] The device and method of the present disclosure enable real-time monitoring of the drying process, allowing for adjustments to be made to the process parameters in real time, ensuring that the dry powder is obtained with the desired characteristics.

[0028] The device of the present disclosure also allows the real-time adjustment of the spray-drying process parameters based on the aerodynamic size of the aerosolized particles, ensuring that the produced powder meets the desired inhalation specifications.

[0029] In an embodiment for better results, the disperser comprises a secondary inlet for receiving a dilution gas to dilute the received aerosol particles.

[0030] In an embodiment for better results, the secondary inlet comprises a dilution gas flow regulator for regulating the dilution gas, in particular the dilution gas flow regulator comprises a rotameter.

[0031] In an embodiment for better results, the aerosol disperser is an eductor, a venturi tube or a nozzle, preferably a venturi tube.

[0032] In an embodiment for better results, the disperser is a disperser arranged to disperse the received aerosol particles by acceleration, shear flow, and / or collision.

[0033] In an embodiment for better results, the dispersed aerosol particles has a concentration ranging from 50-3000 particles / cm3; preferably 100-1000 particles / cm3.

[0034] Another aspect of the present disclosure relates to a pharmaceutical inhalation dry-powder analysing device for a spray-drying apparatus, comprising the sampling device herein described and the aerodynamic particle size sensor.

[0035] In an embodiment for better results, the analysing device further comprises a computer processor arranged to: acquire at least an aPSD, aerodynamic Particle Size Distribution, parameter of the supplied aerosol particles using the aerodynamic particle size sensor, obtain, from the acquired aPSD parameter, a corresponding inhalation device aPSD parameter, using a previously obtained correlation between aerodynamic particle size sensor aPSD parameter (of the supplied aerosol particles) and inhalation device aPSD parameter.

[0036] In an embodiment for better results, the aerodynamic particle size sensor is a TSI® APS.

[0037] In an embodiment for better results, the aPSD parameter of the supplied aerosol particles is MMAD, mass median aerodynamic diameter, in particular the MMAD of the supplied aerosol particles ranges from 0.5- 3pm.

[0038] Another aspect of the present disclosure relates to a spray-drying apparatus for obtaining a pharmaceutical inhalation dry-powder, comprising a sampling device as herein described, wherein said spray-drying apparatus comprises a drying chamber supplying a cyclone, and said cyclone comprises a cyclone discharge and a powder collection container.

[0039] In an embodiment for better results, the spray-drying apparatus comprises a computer processor arranged to: acquire at least an aPSD, aerodynamic Particle Size Distribution, parameter of the supplied aerosol particles using the aerodynamic particle size sensor; obtain, from the acquired aPSD parameter, a corresponding inhalation device aPSD parameter, using a previously obtained correlation between aerodynamic particle size sensor aPSD parameter (of the supplied aerosol particles) and inhalation device aPSD parameter; and adjust one or more parameters of the spray-drying apparatus using the obtained corresponding inhalation device aPSD parameter, in particular to optimize the aPSD parameter of said aerosol particles.

[0040] In an embodiment for better results, the one or more parameters of the spraydrying apparatus are selected from: gas flow rate, liquid flow rate, temperature, pressure; in particular gas atomization flow rate, liquid feed flow rate, outlet temperature, inlet temperature, drying gas flow rate, among others.

[0041] In an embodiment, the aerosol probe is located after the drying chamber and before the cyclone. In an embodiment for better results, the aerosol probe is a collection tube parallel to the direction of particle flow.

[0042] In an embodiment, the aerosol probe is located at the cyclone, in particular between the cyclone discharge (output of the cyclone) and the (input of the) powder collection container. In an embodiment for better results, the aerosol probe is a flute probe perpendicular to the direction of particle collection at the cyclone.

[0043] Another aspect of the present disclosure relates to a pharmaceutical inhalation dry-powder sampling method for a spray-drying apparatus, comprising: receiving aerosol particles from the spray-drying apparatus using a sampling inlet comprising an aerosol probe; deagglomerating and diluting the received aerosol particles using an aerosol disperser; and supplying the dispersed aerosol particles to an aerodynamic particle size sensor.

[0044] In an embodiment for better results, the method further comprises receiving a dilution gas to dilute the received aerosol particles using a secondary inlet at the disperser.

[0045] In an embodiment for better results, the method further comprises regulating the dilution gas, using a dilution gas flow regulator, in particular using a dilution gas flow regulator comprising a rotameter.

[0046] In an embodiment for better results, the aerosol disperser is an eductor, a Venturi tube or a nozzle, preferably a Venturi tube.

[0047] In an embodiment for better results, the disperser is a disperser arranged to disperse the received aerosol particles by acceleration, shear flow, and / or collision.

[0048] In an embodiment for better results, the dispersed aerosol particles has a concentration ranging from 50-3000 particles / cm3; preferably 100-1000 particles / cm3.

[0049] Another aspect of the present disclosure relates to a pharmaceutical inhalation dry-powder analysing method for a spray-drying method, comprising the sampling method herein described and acquiring at least an aPSD, aerodynamic particle size distribution, parameter of the supplied aerosol particles using the aerodynamic particle size sensor.

[0050] In an embodiment for better results, the pharmaceutical inhalation dry-powder analysing method further comprises using a computer processor to: acquire at least an aPSD, aerodynamic Particle Size Distribution, parameter of the supplied aerosol particles using the aerodynamic particle size sensor,obtain, from the acquired aPSD parameter, a corresponding inhalation device aPSD parameter, using a previously obtained correlation between aerodynamic particle size sensor aPSD parameter and inhalation device aPSD parameter.

[0051] In an embodiment for better results, the aerodynamic particle size sensor is a TSI® APS

[0052] In an embodiment for better results, the aPSD parameter of the supplied aerosol particles is MMAD, mass median aerodynamic diameter, in particular the MMAD of the supplied aerosol particles ranges from 0.5- 3pm.

[0053] Another aspect of the present disclosure relates to a spray drying method for obtaining a pharmaceutical inhalation dry-powder, comprising using a method as herein described, wherein said spray-drying method comprises using a spray-drying apparatus comprising a drying chamber supplying a cyclone.

[0054] In an embodiment for better results, said spray drying method further comprises using a computer processor to: acquire at least an aPSD, aerodynamic Particle Size Distribution, parameter of the of the supplied aerosol particles using the aerodynamic particle size sensor; obtain, from the acquired aPSD parameter, a corresponding inhalation device aPSD parameter, using a previously obtained correlation between aerodynamic particle size sensor aPSD parameter and inhalation device aPSD parameter; and adjust one or more parameters of the spray-drying apparatus using the obtained corresponding inhalation device aPSD parameter.

[0055] In an embodiment for better results, the one or more parameters of the spray drying method are selected from: gas flow rate, liquid flow rate, temperature, pressure.

[0056] In an embodiment for better results, the one or more parameters of the spraydrying apparatus are selected from: gas flow rate, liquid flow rate, temperature, pressure; in particular gas atomization flow rate, liquid feed flow rate, outlet temperature, inlet temperature, drying gas flow rate, among others.

[0057] Another aspect of the present disclosure relates to a DPI (Dry Powder Inhaler) formulation development method (formulation screening method) using the spray drying apparatus herein described comprising the steps of:- obtaining a first set of aerosol particles and a second set of aerosol particles; deagglomerating and diluting the first of aerosol particles and deagglomerating and diluting the second set of aerosol particles through an aerosol disperser to obtain a first set of dispersed aerosol particles and a second set of dispersed aerosol particles- determining, using an aerodynamic particle size sensor, an aPSD parameter of the first set of dispersed aerosol particles and an aPSD parameter of the second set of dispersed aerosol particles;- determining, using a cascade impactor, an aPSD parameter of the first set of aerosol particles and an aPSD parameter of the second set of aerosol particles;- correlating the aPSD parameter of each set of dispersed aerosol particles with the aPSD parameter of the corresponding set of aerosol particles, for determining the Fine Particle Fraction parameter of each set of aerosol particles;- selecting the best set of aerosol particles in terms of Fine Particle Fraction (FPF), in particular selecting the set of aerosol particles with highest FPF.

[0058] The DPI (Dry Powder Inhaler) formulation development method of the present disclosure provides the first correlation between the aPSD measured during spray dry manufacturing and the aPSD obtained using the DPI device.

[0059] In an embodiment for better results, the concentration of the dispersed aerosol particles in the step of determining the aPSD parameter using the aerodynamic particle size sensor ranges from 100-1000 particles / cm3; preferably said aPSD parameter is acquired for at least 20s.

[0060] In an embodiment for better results, the aPSD parameter of the dispersed aerosol particles ranges from 0.5 to 3 pm (size range for adequate lung delivery).

[0061] In an embodiment for better results, the selected set of aerosol particles has a Fine Particle Fraction of at least 40%.

[0062] In an embodiment for better results, the dry powder inhaler formulation development method further comprises using a computer processor to adjust one or more of the formulation parameters using the correlating between the aPSD parameter of each set of dispersed aerosol particles with the aPSD parameter of the corresponding set of aerosol particles.

[0063] In an embodiment for better results, the one or more parameters of the formulation parameters are selected from: feedstock solids concentration, solvents and solvent ratio, excipients, API(s).

[0064] An aspect of the present disclosure relates to a spray drying apparatus set up comprising: a spray dryer, an aerosol probe for sampling aerosol particles, an aerosol disperser for deagglomerating and diluting the sampled aerosol particles, and an aerodynamic particle size sensor for determination of the primary aerodynamic particle size distribution of the sampled aerosol particles.

[0065] In an embodiment for better results, the aerosol disperser is an eductor, venturi, or nozzle.

[0066] In an embodiment for better results, the aerosol disperser is a venturi

[0067] In an embodiment for better results, the aerosol disperser deagglomerates sampled aerosol particles, by breaking up agglomerates into primary particles by acceleration and / or shear flow, and collisions with other particles and device walls

[0068] In an embodiment for better results, the aerosol probe is located at the spray dryer outlet.

[0069] In an embodiment for better results, the aerosol probe is located at the cyclone.

[0070] In an embodiment for better results, the aerosol probe for sampling particles is a flute probe.

[0071] In an embodiment for better results, the set up further comprises a dilution gas flow regulator.

[0072] In an embodiment for better results, the dilution gas flow regulator is a rotameter.

[0073] Another aspect of the present disclosure relates to a DPI formulation development method using the spray drying apparatus set up herein described comprising the steps of: producing, during one run of the spray dryer, more than one powder with each powder having a unique primary aPSD; sampling aerosol particles of each powder; deagglomerating and diluting the sampled aerosol particles of each powder; measuring, during steady state operation of the spray dryer, the primary aPSD of each powder; determining by cascade impaction the aPSD of each powder; correlating the primary aPSD of each powder measured in step (c) with the aPSD of each powder determined in step (d); selecting the best candidate in terms of Fine Particle Fraction (FPF).

[0074] In an embodiment for better results, the particle concentration suitable for the sensor measurement (e.g. 100-1000 # / cm3) and acquired for at least 20s.

[0075] In an embodiment for better results, the primary aPSD by spray drying is between 0.5 and 3 pm, size range for adequate lung delivery.

[0076] In an embodiment for better results, the selected candidates have a Fine Particle Fraction of at least 40%.BRIEF DESCRIPTION OF THE DRAWINGS

[0077] The following figures provide preferred embodiments for illustrating the disclosure and should not be seen as limiting the scope of invention.

[0078] Figure 1: Scheme of a spray-drying apparatus for obtaining a pharmaceutical inhalation dry-powder, comprising the analysing device of the present disclosure, wherein the aerosol probe is located after the drying chamber and before the cyclone. (1- spray drying chamber; 2- aerosol probe; 3-dilution gas; 4- aerosol disperser; 5- aerodynamic particle size sensor (TSI® APS™); 6- cyclone).

[0079] Figure 2: Scheme of a spray-drying apparatus for obtaining a pharmaceutical inhalation dry-powder, comprising the analysing device of the present disclosure,wherein the aerosol probe is located at the cyclone. (1- spray drying chamber; 2- aerosol probe; 3-dilution gas; 4- aerosol disperser; 5- aerodynamic particle size sensor (TSI® APS™); 6- cyclone; 7- cyclone discharge; 8- powder collection container).

[0080] Figure 3A-3B: A) Event data recorded in a measurement without aerosol dilution before aPSD measurement. B) Event data recorded in a measurement with aerosol dilution before measurement.

[0081] Figure 4A-4C. aPSDs measured in different sampling points of the spray-drying process: A) smaller particles; B) intermediate particles; C) larger particles. The error bars represent the standard deviation (n=3).

[0082] Figure 5: Correlation between the MMAD of dispersed aerosol particles sampled with the device of the present disclosure (sampled after the drying chamber and before the cyclone), analysed by an aerodynamic particle size sensor (TSI APS) and the ACI (Andersen Cascade Impactor) of the dry powder in the dry powder inhaler RS01 model 7 DPI device, for the placebo formulations.

[0083] Figure 6: Correlation between the MMAD of dispersed aerosol particles sampled with the device of the present disclosure (sampled after the drying chamber and before the cyclone), analysed by an aerodynamic particle size sensor (TSI APS) and the ACI (Andersen Cascade Impactor) of the dry powder in the dry powder inhaler RS01 model 7 DPI device, for the placebo formulations, in the inhalable range.

[0084] Figure 7: Correlation between the MMAD of dispersed aerosol particles sampled with the device of the present disclosure (sampled after the drying chamber and before the cyclone), analysed by an aerodynamic particle size sensor (TSI APS) and the ACI (Andersen Cascade Impactor) of the dry powder in the dry powder inhaler RS01 model 7 DPI device, for the tobramycin formulations.

[0085] Figure 8: Correlation between the MMAD of dispersed aerosol particles sampled with the device of the present disclosure (sampled after the drying chamber and before the cyclone), analysed by an aerodynamic particle size sensor (TSI APS) and the ACI (Andersen Cascade Impactor) of the dry powder in the dry powder inhaler RS01 model 7 DPI device, for the tobramycin formulations, in the inhalable range.

[0086] Figure 9: Correlation between MMAD of dispersed aerosol particles sampled with the device of the present disclosure (sampled after the drying chamber and before the cyclone), analysed by an aerodynamic particle size sensor (TSI APS) and the ACI (Andersen Cascade Impactor) of the dry powder in the dry powder inhaler TwinMax device for the placebo formulations.

[0087] Figure 1 - Correlation between MMAD of TSI APS and ACI for the tobramycin formulations with a TwinMax device.DETAILED DESCRI PTION

[0088] The present disclosure relates to a pharmaceutical inhalation dry-powder sampling device for a spray-drying apparatus, comprising a sampling inlet comprising an aerosol probe for receiving aerosol particles from the spray-drying apparatus, an aerosol disperser for deagglomerating and diluting the received aerosol particles, and an outlet for supplying the dispersed aerosol particles to an aerodynamic particle size sensor. Furthermore, the present disclosure also relates to a pharmaceutical inhalation dry-powder analysing device, a spray-drying apparatus and a method thereof, and a dry powder inhaler formulation development method.

[0089] The present disclosure also relates to a pharmaceutical inhalation dry-powder sampling device for a spray-drying apparatus, comprising: a sampling inlet comprising an aerosol probe for receiving aerosol particles from the spray-drying apparatus; an aerosol disperser for deagglomerating and diluting the received aerosol particles; and an outlet for supplying the dispersed aerosol particles to an aerodynamic particle size sensor.

[0090] The present disclosure proposes a novel device and method for DPI development to expedite formulation and particle engineering process development that includes the use of a setup for measuring the aPSD during the spray drying manufacturing process. This setup includes a device that ensures the aerosol containsits primary particles in a suitable concentration before measurement of the in-process aPSD.

[0091] The present disclosure addresses the challenges associated with testing and optimizing prototypes in DPI development. This methodology provides a practical solution to the common pitfalls encountered in the industry. It introduces a paradigmshifting approach to formulation in DPI development. By eliminating the need for extensive testing and optimization of prototypes, this method enables the early identification of candidates with suitable aerodynamic particle size diameter, streamlining the entire development process. Unlike traditional methods that often result in discovering formulation inadequacies only at the later stages of performance evaluation, the device and method of the present disclosure allows early identification of suitable candidates and online optimization, saving valuable time and resources.

[0092] In DPI process development, multiple iterations and revisions are commonly required to achieve formulations within the desired inhalable range. These iterative cycles result in significant time and material expenses, burdening the project timeline.

[0093] Process Analytical Technology (PAT) is defined by the United States Food and Drug Administration as "a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality.

[0094] The device and method of the present invention allow for particle sampling in different locations of the spray-drying process / apparatus. and is comprised of a sampling inlet, an aerosol disperser and an outlet for supplying the dispersed aerosol particles to an aerodynamic particle size sensor (for example, the TSI® APS 3321 model). The aerosol dispersor may further comprise a dilution gas flow regulator (preferably a rotameter).

[0095] The aerosol disperser that simultaneously dilutes the aerosol can be any device in which a secondary inlet with dilution gas enters the process. The disperser can be an eductor, venturi, nozzle, or any other device that breaks up agglomerates into primary particles by acceleration and / or shear flow, and collisions with other particles anddevice walls. Preferably, the disperser is a venturi. The disperser is carefully designed to not disturb the pressure inside the spray dryer.

[0096] The probe to sample the aerosol after the drying chamber and before the cyclone comprises a tube aligned with the gas flow, placed in its opposite direction, as represented in Figure 1.

[0097] The probe to collect the aerosol in the cyclone comprises a flute probe perpendicular to the direction of particle collection, as represented in Figure 2.

[0098] The rotameter controls the dilution gas flow rate and should measure up to 10 L / min. The aerosol disperser allows proper dilution and deagglomeration of the aerosol to be measured.

[0099] Contrary to the previous works, the device and method of the present disclosure ensures that the aerosol is properly deagglomerated and diluted before the measurement. Additionally, it does not require any TSI accessories, such as dilutors and / or impactors. The device and method herein described is versatile and can me usedin commercially available spray dryer apparatus and can also be applied to other manufacturing process scales.

[0100] The device and method of the present disclosure may be used for measuring the aerodynamic particle size distribution of several formulation candidates during development. Each formulation should be sampled from the spray-drying process using the device of the present disclosure, which provides proper dilution and dispersion of the sample The measurement should be carried out for at least 20 s, and the particle's concentration within the dispersed aerosol particles should be maintained between 100 and 1000 #.cnr3, preferably between 500 and 1000 tf.crrr3(particles per cubic centimeter) by adjusting the dilution gas. The spray-dried powder candidates are selected based on having a measured primary aerodynamic particle size between 0.5 and 3 pm (inhalable range). Then, the respective MMADs can be correlated with the MMADs obtained by cascade impaction for the same device. Based on this, only the formulations displaying the best Fine Particle Fractions (FPFs) are tested by cascade impaction. Formulations with higher FPFs are preferred, startingfrom 40%. Only the formulations with primary aerodynamic particle size in the range 0.5 and 3 pm will be used to optimize the capsule / device filling parameters.

[0101] The device / method of the present disclosure may be implemented on a lab scale to aid formulation development bringing the processes quicker to the manufacturing plant. But it can also be integrated into the production process as a PAT sensor to monitor the aerodynamic particle size distribution - a strategy for controlling the product critical attribute aerodynamic diameter.

[0102] Furthermore, the knowledge of the primary aerodynamic particle size distribution of aerosols can be used to aid the development of new inhalation devices.

[0103] The formulations that can benefit from the present invention include the ones prepared by spray drying suspensions or solutions containing excipients and / or APIs. The APIs can be small molecules or biologies.ExamplesExample 1: Aerosol concentration study

[0104] This example illustrates the importance of the inclusion of the aerosol disperser in the pharmaceutical inhalation dry-powder sampling device to produce dispersed (and diluted) aerosol particles suitable for a correct aerodynamic particle size measurement.

[0105] Solutions with a concentration of 3% wt solids were prepared by dissolving a,a-Trehalose Dihydrate and L-leucine in a 80:20% wt ratio using a 87.5:12.5%wt mixture of deionized water and ethanol 96%.

[0106] The dry powder formulations were produced in a Mini Spray Drier B-290, (BUCHI, Switzerland) equipped with a two-fluid external mixing nozzle with a 0.7 mm orifice and 1.5 mm cap, with a high-efficiency cyclone used as powder collector. The unit was operated in open cycle mode, with nitrogen at a drying flow rate of 20 kg / h and an atomization flow rate of 1.15 kg / h. The solution feeding rate was set at 3 gmin-1. The inlet temperature was adjusted to maintain the outlet temperature at 80°C.

[0107] The aerosol was sampled (through the aerosol probe) at the spray dryer chamber outlet (after the drying chamber and before the cyclone) and sent to theaerosol disperser operated with nitrogen before entering the TSI APS 3321. The aPSDs were acquired three times during 60 s after 10 minutes of the start-up so that the measurement was done in steady state. The collected mass distributions and their respective moments, MMAD and GSD were retrieved from Aerosol Instrument Manager® Software V. 9.0.0.0, assuming a particle density of 1 gem-3.

[0108] A diluted aerosol measurement using the disperser and a non-diluted aerosol (that went directly from the spray dryer to the TSI APS 3321) measurement were measured using the setup.

[0109] An offline measurement of the collected powder was carried out by laser diffraction (SYMPATEC, Sympatec Inc., Pennington, NJ, USA). The instrument is equipped with a dispensing unit RODOS / Mand a laser diffraction sensor HELOS (Helium-Neon Laser Optical System). Dry powders were measured directly with a dispersing pressure of 5 bar at a feed velocity of 25 mm / s and a laser measuring range of 0.1 pm to 35 pm, R1 lens. The measurements were performed in triplicate.

[0110] Table 1 - aPSD moments of measurements of a diluted aerosol and a nondiluted aerosol.

[0111] Table 2 - Offline particle size measurement by laser diffraction.

[0112] Only events 1 and 2 are included in the particle size distribution results. Event 1 occurs when the signal for a small particle cannot stay above the threshold and only one crest is detected. Therefore, this type of event corresponds to fines. Event 2 represents a valid particle measurement. The signal stays above the threshold and two crests are detected. The time-of-flight between the two crests is recorded. Event 3 iscaused by coincidence. Although the signal remains above the threshold, three or more crests are detected. In event 4, the signal remains above the threshold until it moves outside the timer range, and only one crest is detected. It is usually caused by large or recirculating particles. Figure 3 displays the increase in 53% of valid measurements (event type 2) when the aerosol is diluted with the disperser and the corresponding decrease in coincidence (event type 3).

[0113] Without using the disperser, a higher MMAD is observed, corresponding to an aerosol with particles outside the inhalable range size. When measured using the disperser, the MMAD lowers to an inhalable size value, corroborated by the laser diffraction result (Table 2). Similarly to the aerosol measured with the disperser, the laser diffraction equipment measures the primary size of the particles after powder dispersion.

[0114] A high aerosol concentration in the TSI APS 3321 is not desired due to the errors introduced in the measurement, e.g. coincidence errors and clogging of the system (nozzle and filters), as per Table 1 and Figure 3. Therefore, it was surprisingly found that including the disperser allowed a proper measurement of the concentrated aerosol collected from the spray drying process.Example 2: Different sampling locations

[0115] This example aims at showing that the aerosol can be measured at several points of the process and that the same distribution is obtained regardless of the sampling technique employed.

[0116] Solutions with a concentration of 3% wt solids were prepared by dissolving a,a-Trehalose Dihydrate and L-leucine in a 80:20% wt ratio using a 87.5:12.5%wt mixture of deionized water and ethanol 96%.

[0117] The dry powder formulations were produced in a Mini Spray Drier B-290, (BUCHI, Switzerland) equipped with a two-fluid external mixing nozzle with a 0.7 mm orifice and 1.5 mm cap, with a high-efficiency cyclone used as powder collector. The unit was operated in open cycle mode, with nitrogen at a drying flow rate of 20 kg / h. Three different particle sizes were generated, covering the inhalation range, in orderto compare the sampling locations. The spray drying conditions correspondent to each particle size are presented in Table 3

[0118] Online aPSD was measured during the spray-drying process using the device of the present disclosure, using a TSI APS 3321 (TSI, USA) as aerodynamic particle size sensor, at two different locations: chamber outlet (after the drying chamber and before the cyclone) and cyclone. For the standard measurement, the aerosol was sampled at the spray drying chamber outlet and sent to a disperser operated with nitrogen before entering the aerodynamic particle size sensor (TSI APS 3321). The aPSDs were acquired three times during 60 s after 10 minutes of the start-up so that the measurement was done in steady state. The collected mass distributions were retrieved from Aerosol Instrument Manager® Software V. 9.0.0.0. The mass distributions were calculated by the software from the number distribution assuming a particle's density of 1 gcm-3.

[0119] Table 3 - Spray drying operation conditions.Tout: spray drying outlet temperature;Ffeed: spray drying feed flow rate;Fatom: atomization flow rate.Csolids: solids concentration in the feedstock.

[0120] As expected, the spray drying conditions generated particles with distinct particle size distributions. Figure 4A - 4C shows a non-inhalable formulation, with particles larger than 5 micrometers. The fact that similar distributions are obtained in both sampling points, as showed in Figures A-C, supports the measurement quality of the device and method of the present invention.Example 3: Correlation placebo

[0121] This example intends to show the relation between the primary particle size measured during the spray-drying process and the one measured offline by a cascade impaction technique using a generic device for a placebo formulation.

[0122] Solutions with concentrations (1, 3, 5 and 8% wt solids) were prepared by dissolving a,a-Trehalose Dihydrate and L-leucine in a 80:20% wt ratio in a mixture of deionized water and ethanol 96% at different proportions (0, 12.5 and 25% wt of ethanol).

[0123] The dry powder formulations were produced in a Mini Spray Drier B-290, (BUCHI, Switzerland) equipped with a two-fluid external mixing nozzle with a 0.7 mm orifice and 1.5 mm cap, with a high-efficiency cyclone used as powder collector. The unit was operated in open cycle mode, with nitrogen at a drying flow rate of 20 kg / h and different atomization flow rates (0.27, 0.32, 0.39, 0.49, 0.73, 1.15 and 1.68 kg / h), feeding rates (1, 3 and 5 g / min) and temperatures (75, 80 and 85°C) so that formulations with different aerodynamic particle sizes would be obtained.

[0124] The aerosol was sampled at the spray drying chamber outlet (after the drying chamber and before the cyclone) and sent to the disperser operated with nitrogen before entering the aerodynamic particle size sensor (TSI APS 3321). The aPSDs were acquired three times during 60 s after 10 minutes of the start-up so that the measurement was done in steady state. The collected mass distributions were retrieved from Aerosol Instrument Manager® Software V. 9.0.0.0, assuming a particle's density of 1 gcm-3. MMAD is defined as the mid-point of the cumulative mass plot (particle size at which 50% of the mass of particles is smaller than this value) and was determined by linear interpolation of the correspondent bins.

[0125] Offline aPSD of the DPI formulations was determined by ACL HPMC (HydroxyPropyl MethylCellulose) size 3 capsules were manually filled with 30±5 mg of each formulation and, using a High resistance RS01 model 7 DPI device (a Dry Powder Inhaler), their aerodynamic performance was evaluated using an eight-stage Andersen Cascade Impactor in modified configuration at 60 Lmin-1, with a pressure drop of 4 kPa and the actuation time adjusted to correspond to a sampling volume of 4 L. The powder mass remaining in the capsule and in each of the ACI plates and in the filter was gravimetrically determined. The MMAD was calculated analogously to themethodology described above and data generated from the online measurement. The analysis was performed in triplicate.

[0126] According to Figure 5 and Figure 6, it was surprisingly found that the MMAD obtained from the dispersed aerosol particles sampled with the device of the present disclosure (sampled after the drying chamber and before the cyclone) and analysed by the aerodynamic particle size sensor TSI APS, and ACI methods (of the dry powder in the dry powder inhaler )correlate positively. Of upmost importance, in the range of inhalable particle sizes - Figure 6 - the slope gets closer to 1. Therefore, in the inhalable range, it is showed that this relation is appropriate for selecting adequate DPI formulation candidates based on an appropriate sampling and appropriate aerodynamic particle size distribution and, consequently, avoid further iterations. In Figure 5, for the higher particle sizes, significant differences in particle shape and density are observed, which can affect the results, since spherical particles and a density of 1 g / cm3 are assumed. Additionally, the first cut-off size of the ACI is 8.6 pm. The last points in Figure 6 represent particles around this size that may not be correctly discriminated.

[0127] A slope of 1 would mean the perfect formulation and inhaler. Therefore, this correlation can be applied to inhalation device development. Additionally, the slope of this correlation was not expected to be 1 as the MMAD obtained in the ACI depends also on the powder's cohesiveness and on the inhaler device used in the ACI test. The online measurement corresponds to the primary particles while the ACI gives the dispersed particle size distribution.Example 4: Correlation tobramycin

[0128] In this example, the relation between the primary particle size measured during the spray-drying process and the one measured offline by a cascade impaction technique using a generic device for an API formulation is studied.

[0129] Solutions with concentrations (1, 3, 5 and 8% wt solids) were prepared by dissolving tobramycin free base (USP grade), a,a-Trehalose Dihydrate, and L-leucine in a 25:55:20% wt ratio, respectively, in a mixture of deionized water and ethanol 96% at different proportions (0, 12.5, 25% wt of ethanol).

[0130] The dry powder formulations were produced in a Mini Spray Drier B-290, (BUCHI, Switzerland) equipped with a two-fluid external mixing nozzle with a 0.7 mm orifice and 1.5 mm cap, with a high-efficiency cyclone used as powder collector. The unit was operated in open cycle mode, with nitrogen at a drying flow rate of 20 kg / h and different atomization flow rates (0.27, 0.32, 0.39, 0.49, 0.73, 1.15 and 1.68 kg / h), feeding rates (1, 3 ,5 g / min) and temperatures (75, 80 and 85°C) so that formulations with different aerodynamic particle sizes would be obtained.

[0131] The aerosol was sampled at the spray dryer chamber outlet (after the drying chamber and before the cyclone) and sent to a disperser operated with nitrogen before entering the aerodynamic particle size sensor (TSI APS 3321). The aPSDs were acquired three times during 60 s after 10 minutes of the start-up so that the measurement was done in steady state. The collected mass distributions were retrieved from Aerosol Instrument Manager® Software V. 9.0.0.0, assuming a particle's density of 1 gcm-3. MMAD is defined as the mid-point of the cumulative mass plot (particle size at which 50% of the mass of particles is smaller than this value) and was determined by linear interpolation of the correspondent bins.

[0132] Offline aPSD of the DPI formulations was determined by ACL HPMC size 3 capsules were manually filled with 30±5 mg of each formulation and, using a High resistance RS01 model 7 DPI device (a dry powder inhaler), their aerodynamic performance was evaluated using an eight-stage Andersen Cascade Impactor in modified configuration at 60 Lmin-1, with a pressure drop of 4 kPa and the actuation time adjusted to correspond to a sampling volume of 4 L. The powder mass remaining in the capsule and in each of the ACI plates and in the filter was gravimetrically determined. The MMAD was calculated analogously to the methodology described above and data generated from the online measurement. The analysis was performed in triplicate.

[0133] Figure 7 and Figure 8 lead to the same conclusions as Figure 5 andFigure 6, even though the line parameters are different. In fact, the slope is higher for the tobramycin containing formulations than for the placebo, reflecting the influence of the presence of the API on the MMADs.Example 5: Correlation different inhaler - Placebo

[0134] This example aims at showing the relation between the particle size measured during the spray-drying process, using the sampling device of the present disclosure, and the one measured offline by a cascade impaction technique with the TwinMax device (a dry powder inhaler) for a placebo and API containing formulation.

[0135] Solutions with different concentrations (1 and 3% wt solids) were prepared by dissolving a,a-Trehalose Dihydrate in a 80:20% wt ratio in a mixture of deionized water and ethanol 96% at different proportions (0 and 25% wt of ethanol).

[0136] The dry powder formulations were produced in a Mini Spray Drier B-290, (BUCHI, Switzerland) equipped with a two-fluid external mixing nozzle with a 0.7 mm orifice and 1.5 mm cap, with a high-efficiency cyclone used as powder collector. The unit was operated in open cycle mode, with nitrogen at a drying flow rate of 20 kg / h and different atomization flow rates (0.39, 0.49, 0.73, 1.15, 1.68 kg / h), feeding rates (3 and 5 g / min) and temperatures (75 and 80°C) so that formulations with different aerodynamic particle sizes would be obtained.

[0137] The aerosol was sampled at the spray dryer chamber outlet (after the drying chamber and before the cyclone) and sent to a disperser operated with nitrogen (dilution gas) before entering the aerodynamic particle size sensor TSI APS 3321. The aPSDs were acquired three times during 60 s after 10 minutes of the start-up so that the measurement was done in steady state. The collected mass distributions were retrieved from Aerosol Instrument Manager® Software V. 9.0.0.0, assuming a particle's density of 1 gem-3. MMAD is defined as the mid-point of the cumulative mass plot (particle size at which 50% of the mass of particles is smaller than this value) and was determined by linear interpolation of the correspondent bins.

[0138] Offline aPSD of the DPI formulations was determined by ACI. HPMC size 3 capsules were manually filled with 30±5 mg of each formulation and, using a TwinMax device (a dry powder inhaler) (15 mg per cavity), their aerodynamic performance was evaluated using an eight-stage Andersen Cascade Impactor in the standard configuration, with a pressure drop of 4 kPa and the actuation time adjusted to correspond to a sampling volume of 4 L. The powder mass remaining in the capsuleand in each of the ACi plates and in the filter was gravimetrically determined. The MMAD was calculated analogously to the methodology described above and data generated from the online measurement. The analysis was performed in triplicate.

[0139] Figure 9 shows that, as expected, higher MMADs are observed in the ACI using an inhaler with higher resistance, when compared to the results of Example 3. Again, a positive correlation between the MMADs is observed.Example 6: Correlation different inhaler - Tobramycin

[0140] Solutions with concentrations (1, 3, 5% wt solids) were prepared by dissolving tobramycin free base (USP grade), a,a-Trehalose Dihydrate, and L-leucine in a 25:55:20% wt ratio, respectively, in a mixture of deionized water and ethanol 96% at different proportions (0, 12.5, 25% wt of ethanol).

[0141] The dry powder formulations were produced in a Mini Spray Drier B-290, (BUCHI, Switzerland) equipped with a two-fluid external mixing nozzle with a 0.7 mm orifice and 1.5 mm cap, with a high-efficiency cyclone used as powder collector. The unit was operated in open cycle mode, with nitrogen at a drying flow rate of 20 kg / h and different atomization flow rates (0.39, 0.49, 0.73, 1.15, 1.68 kg / h), feeding rates (3 and 5 g / min) and temperatures (75 and 80°C) so that formulations with different aerodynamic particle sizes would be obtained.

[0142] The aerosol was sampled at the spray dryer chamber outlet (after the drying chamber and before the cyclone) and sent to each disperser operated with nitrogen (dilution gas) before entering the aerodynamic particle size sensor (TSI APS 3321). The aPSDs were acquired three times during 60 s after 10 minutes of the start-up so that the measurement was done in steady state. The collected mass distributions were retrieved from Aerosol Instrument Manager® Software V. 9.0.0.0, assuming a particle's density of 1 gcm-3. MMAD is defined as the mid-point of the cumulative mass plot (particle size at which 50% of the mass of particles is smaller than this value) and was determined by linear interpolation of the correspondent bins.

[0143] Offline aPSD of the DPI formulations was determined by ACI. HPMC size 3 capsules were manually filled with 30±5 mg of each formulation and, using a TwinMax device (a dry powder inhaler) (15 mg per cavity), their aerodynamic performance wasevaluated using an eight-stage Andersen Cascade Impactor in the standard configuration, with a pressure drop of 4 kPa and the actuation time adjusted to correspond to a sampling volume of 4 L. The powder mass remaining in the capsule and in each of the ACI plates and in the filter was gravimetrically determined. The MMAD was calculated analogously to the methodology described above and data generated from the online measurement. The analysis was performed in triplicate.

[0144] Again, Figure 10 shows that, despite using a different inhaler, the correlation of the tobramycin-containing formulation has a higher slope than the placebo, similarly to Example 5, showing the robustness of the correlation between MMAD of dispersed aerosol particles sampled with the device of the present disclosure at the spray drying apparatus and the ACI (Andersen Cascade Impactor) of the dry powder in the dry powder inhaler.

[0145] The term "comprising" whenever used in this document is intended to indicate the presence of stated features, integers, steps, components, but not to preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

[0146] The disclosure should not be seen in any way restricted to the embodiments described and a person with ordinary skill in the art will foresee many possibilities to modifications thereof. The above-described embodiments are combinable.

[0147] The following dependent claims further set out particular embodiments of the disclosure.References1. William C. Hinds. Aerosol technology: properties, behavior and measurement of airborne particles [Internet]. 2nd ed. Los Angeles: John Wiley & Sons, Inc.; 1999. Available from: http: / / www.tandfonline.com / doi / abs / 10.1080 / 174492006009355212. Mitchell JP, Nagel MW. Time-of-flight aerodynamic particle size analyzers: Their use and limitations for the evaluation of medical aerosols. J Aerosol Med Depos Clear Eff Lung. 1999;12:217-40.3. TSI Incorporated. AERODYNAMIC PARTICLE SIZER (APS) 3321 [Internet]. Available from: https: / / tsi.com / products / particle-sizers / supermicron-capable-particle-sizer- spectrometers / aerodynamic-particle-sizer-(aps)-3321 / Ivey et al. [Ivey JW, Barona D, Gomez M, Kuan L, Mcallister R, Oberhagemann L, et al. Isokinetic In-line Sampling Enables Rapid Characterization of Atomizers and Cyclones for Spray Drying Process Development. RDD 2018. 2018. p. 551-6.Ivey JW. Particle Formation from Evaporating Microdroplets for Inhaled Drug Delivery. University of Alberta; 2018.Ivey JW, Vehring R. A Methodology for Efficient Pharmaceutical Spray Drying Process Development. AAPS Annu Meet Expo Novemb 13-17, 2016, Denver, CO, USA [Internet]. 2016; Available from: https: / / www.researchgate.net / publication / 310753550_A_Methodology_for_Efficient_Pharmaceutical_ Spray_Drying_Process_DevelopmentWang Z, Wang H, Vehring R. Leucine enhances the dispersibility of trehalose-containing spray-dried powders on exposure to a high-humidity environment. Int J Pharm [Internet]. 2021;601:120561. Available from: https: / / linkinghub.elsevier.com / retrieve / pii / S0378517321003665Wang H, Ordoubadi M, Connaughton P, Lachacz K, Carrigy N, Tavernini S, et al. Spray Dried Rugose Lipid Particle Platform for Respiratory Drug Delivery. Pharm Res [Internet]. 2022;39:805-23. Available from: https: / / link.springer.com / 10.1007 / sll095-022-03242-w

Claims

C L A I M S1. Pharmaceutical inhalation dry-powder sampling device for a spray-drying apparatus, comprising: a sampling inlet comprising an aerosol probe for receiving aerosol particles from the spray-drying apparatus; an aerosol disperser for deagglomerating and diluting the received aerosol particles; and an outlet for supplying the dispersed aerosol particles to an aerodynamic particle size sensor.

2. Sampling device according to the previous claim wherein the disperser comprises a secondary inlet for receiving a dilution gas to dilute the received aerosol particles.

3. Sampling device according to any of the previous claims wherein the secondary inlet comprises a dilution gas flow regulator for regulating the dilution gas, in particular the dilution gas flow regulator comprises a rotameter.

4. Sampling device according to any of the previous claims wherein the aerosol disperser is an eductor, a venturi tube or a nozzle, preferably a venturi tube.

5. Sampling device according to any of the previous claims wherein the disperser is a disperser arranged to disperse the received aerosol particles by acceleration, shear flow, and / or collision.

6. Sampling device according to any of the previous claims wherein the dispersed aerosol particles in the outlet flow of the aerosol disperser has a concentration ranging from 50-3000 particles / cm3; preferably 100-1000 particles / cm3; more preferably 500 and 1000 particles / cm3.

7. Pharmaceutical inhalation dry-powder analysing device for a spray-drying apparatus, comprising a sampling device according to any of the previous claims and the aerodynamic particle size sensor.

8. Analysing device according to the previous claim comprising a computer processor arranged to: acquire at least an aPSD, aerodynamic Particle Size Distribution, parameter of the supplied aerosol particles using the aerodynamic particle size sensor, obtain, from the acquired aPSD parameter, a corresponding inhalation device aPSD parameter, using a previously obtained correlation between aerodynamic particle size sensor aPSD parameter (of the supplied aerosol particles) and inhalation device aPSD parameter.

9. Analysing device according to the any of the claims 7-8 wherein the aerodynamic particle size sensor is a TSI® APS™.

10. Analysing device according to any of the previous claims 7-9 wherein the aPSD parameter of the supplied aerosol particles is MMAD, mass median aerodynamic diameter, in particular the MMAD of the supplied aerosol particles ranges from 0.5- 3pm.

11. Spray-drying apparatus for obtaining a pharmaceutical inhalation dry-powder, comprising a device according to any of the previous claims, wherein said spraydrying apparatus comprises a drying chamber supplying a cyclone.

12. Spray-drying apparatus according to the previous claim, comprising a computer processor arranged to: acquire at least an aPSD, aerodynamic Particle Size Distribution, parameter of the supplied aerosol particles using the aerodynamic particle size sensor; obtain, from the acquired aPSD parameter, a corresponding inhalation device aPSD parameter, using a previously obtained correlation between aerodynamic particle size sensor aPSD parameter (of the supplied aerosol particles) and inhalation device aPSD parameter; and adjust one or more parameters of thespray-drying apparatus using the obtained corresponding inhalation device aPSD parameter.

13. Spray-drying apparatus according to the previous claim, wherein the one or more parameters of the spray-drying apparatus are selected from: gas flow rate, liquid flow rate, temperature, pressure; in particular gas atomization flow rate, liquid feed flow rate, outlet temperature, inlet temperature, drying gas flow rate, among others.

14. Spray-drying apparatus according to any of the claims 11-13, wherein the aerosol probe is located after the drying chamber and before the cyclone.

15. Spray-drying apparatus according to the previous claim, wherein the aerosol probe is a collection tube parallel to the direction of particle flow.

16. Spray-drying apparatus according to any of the claims 11-15, wherein the aerosol probe is located at the cyclone, in particular between the cyclone discharge and the powder collection container.

17. Spray-drying apparatus according to the previous claim, wherein the aerosol probe is a flute probe perpendicular to the direction of particle collection at the cyclone.

18. Pharmaceutical inhalation dry-powder sampling method for a spray-drying apparatus, comprising: receiving aerosol particles from the spray-drying apparatus using a sampling inlet comprising an aerosol probe; deagglomerating and diluting the received aerosol particles using an aerosol disperser; and supplying the dispersed aerosol particles to an aerodynamic particle size sensor.

19. Sampling method according to the previous claim comprising receiving a dilution gas to dilute the received aerosol particles using a secondary inlet at the disperser.

20. Sampling method according to any of the previous claims 18-19 comprising regulating the dilution gas, using a dilution gas flow regulator, in particular using a dilution gas flow regulator comprising a rotameter.

21. Sampling method according to any of the previous claims 18-20 wherein the aerosol disperser is an eductor, a Venturi tube or a nozzle, preferably a Venturi tube.

22. Sampling method according to any of the previous claims 18-21 wherein the disperser is a disperser arranged to disperse the received aerosol particles by acceleration, shear flow, and / or collision.

23. Pharmaceutical inhalation dry-powder analysing method for a spray-drying method, comprising the sampling method according to any of the previous claims 18-22 and acquiring at least an aPSD, aerodynamic particle size distribution, parameter of the supplied aerosol particles using the aerodynamic particle size sensor.

24. Analysing method according to the previous claim comprising using a computer processor to: acquire at least an aPSD, aerodynamic Particle Size Distribution, parameter of the supplied aerosol particles using the aerodynamic particle size sensor, obtain, from the acquired aPSD parameter, a corresponding inhalation device aPSD parameter, using a previously obtained correlation between aerodynamic particle size sensor aPSD parameter and inhalation device aPSD parameter.

25. Analysing method according to the previous claims 23-25 wherein the aerodynamic particle size sensor is a TSI® APS.

26. Spray-drying method for obtaining a pharmaceutical inhalation dry-powder, comprising using a method according to any of the previous claims 18-25, wherein said spray-drying method comprises using a spray-drying apparatus comprising a drying chamber supplying a cyclone.

27. Spray-drying method according to the previous claim, comprising using a computer processor to: acquire at least an aPSD, aerodynamic Particle Size Distribution, parameter of the of the supplied aerosol particles using the aerodynamic particle size sensor; obtain, from the acquired aPSD parameter, a corresponding inhalation device aPSD parameter, using a previously obtained correlation between aerodynamic particle size sensor aPSD parameter and inhalation device aPSD parameter; and adjust one or more parameters of the spray-drying method using the obtained corresponding inhalation device aPSD parameter.

28. Spray-drying method according to the previous claim, wherein the one or more parameters of the spray-drying method are selected from: gas flow rate, liquid flow rate, temperature, pressure; in particular gas atomization flow rate, liquid feed flow rate, outlet temperature, inlet temperature, drying gas flow rate, among others.

29. Dry powder inhaler formulation development method using the spray drying apparatus according to any of the previous claims 11-17 comprising the steps of: obtaining a first set of aerosol particles and a second set of aerosol particles; deagglomerating and diluting the first set of aerosol particles and deagglomerating and diluting the second set of aerosol particles through an aerosol disperser to obtain a first set of dispersed aerosol particles and a second set of dispersed aerosol particles determining, using an aerodynamic particle size sensor, an aPSD parameter of the first set of dispersed aerosol particles and an aPSD parameter of the second set of dispersed aerosol particles; determining, using a cascade impactor, an aPSD parameter of the first set of aerosol particles and an aPSD parameter of the second set of aerosol particles; correlating the aPSD parameter of each set of dispersed aerosol particles with the aPSD parameter of the corresponding set of aerosol particles, for determining the Fine Particle Fraction parameter of each set of aerosol particles;selecting the best set of aerosol particles in terms of Fine Particle Fraction (FPF), in particular selecting the set of aerosol particles with highest FPF.

30. Method according to the previous claim wherein the concentration of the dispersed aerosol particles in the step of determining the aPSD parameter using the aerodynamic particle size sensor ranges from 100-1000 particles / cm3; preferably said aPSD parameter is acquired for at least 20s.

31. Method according to any of the previous claims 30-31 wherein the aPSD parameter of the dispersed aerosol particles ranges from 0.5 to 3 pm.

32. Method according to any of the previous claims 30-32 wherein the selected set of aerosol particles has a Fine Particle Fraction of at least 40%.

33. Dry powder inhaler formulation development method according to any of the previous claims 30-33 further comprising using a computer processor to adjust one or more of the formulation parameters using the correlating between the aPSD parameter of each set of dispersed aerosol particles with the aPSD parameter of the corresponding set of aerosol particles.

34. Dry powder inhaler formulation development method according to the previous claim wherein the one or more parameters of the formulation parameters are selected from: gas flow rate, liquid flow rate, temperature, pressure; in particular gas atomization flow rate, liquid feed flow rate, outlet temperature, inlet temperature, drying gas flow rate, among others.

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