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04 Development and Aerodynamic Particle Sizing of DPI Formulations _________________________________________________________________ Write-up 1. Below are two scanning electron micrographs (SEMs) of the same active pharmaceutical ingredient (API). The SEM on the left (A) is of the API processed by micronisation (fluid energy milling) while the SEM on the right is the product obtained by spray drying a solution of the API. Provide a brief explanation of why the two different processes result in particles of the morphologies shown. A B Answer: 1|Page 04 Development and Aerodynamic Particle Sizing of DPI Formulations _________________________________________________________________ 2. The two SEMs below show micronized salbutamol sulphate immediately post processing (SEM A) and after storage for two weeks (SEM B). SEM B shows particle agglomeration. Provide a short explanation as to why such agglomeration might be observed. How could such agglomeration be avoided or controlled? A B Answer: 2|Page 04 Development and Aerodynamic Particle Sizing of DPI Formulations _________________________________________________________________ 3. The data sets shown in the table below are the NGI in vitro deposition data at 30 L/min flow rate for two different batches of the same DPI powder formulation. Using a commercial software package (available from Copley Scientific Ltd.) the Mass Median Aerodynamic Diameter (MMAD) and the Geometric Standard Deviation (GSD) were determined for both data sets. Results are shown in red text in the table below. (i) Data set 1 Impactor Stage Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 Stage 6 Stage 7 Filter (MOC) MMAD = GSD = Drug Collected (mg) 10.5 26.8 44.3 37.8 13.5 5.45 0.55 0.04 Data set 2 Impactor Stage Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 Stage 6 Stage 7 Filter (MOC) Drug Collected (mg) 12.9 42.7 36.6 27.2 13.5 5.80 0.56 0.03 4.52 μm 1.76 MMAD = GSD = 5.35 μm 2.02 Comment on the significance of the results and possible reasons for the difference in the results obtained for the two sets of data. Answer: 3|Page 04 Development and Aerodynamic Particle Sizing of DPI Formulations _________________________________________________________________ (ii) Would you expect a change in air flow rate through the NGI to have an impact on the results? If so, how? Explain you answer. Answer: 4|Page 04 Development and Aerodynamic Particle Sizing of DPI Formulations _________________________________________________________________ Title: Development and aerodynamic particle size characterisation of dry powder inhaler formulations This practical consists of two parts: Part 1: Demonstration of instrumentation used to generate micronized material suitable for inclusion in dry powder inhaler formulations 1.1 Demonstration of fluid energy mill/jet mill/microniser 1.2 Demonstration of spray dryer To support the demonstration provided in the lab, students should view the Panopto recording in Blackboard and may also wish to view the YouTube clips provided here: Fluid energy milling/jet milling: https://www.youtube.com/watch?v=t4O20uwV1II https://www.jetpulverizer.com/how-jet-mills-work/ https://www.youtube.com/watch?v=dNWP8zquhz4 Spray drying: https://www.youtube.com/watch?v=auo-6aNsFoQ https://www.youtube.com/watch?v=O_fiKH2Zd7c Students should also review the relevant lectures from Prof. Healy that were delivered last year in PHU22104. 1|Page 04 Development and Aerodynamic Particle Sizing of DPI Formulations _________________________________________________________________ Part 2: Demonstration of in vitro characterisation of aerosol particles Aerodynamic Particle Size Distribution (APSD) To support the demonstration provided in the lab, students should view the Panopto recording in Blackboard and may also wish to view the YouTube/Vimeo clips provided here: https://www.youtube.com/watch?v=thiKRrXzp6o https://vimeo.com/174810678 The Aerodynamic Particle Size Distribution (APSD) is a Critical Quality Attribute (CQA) in measuring the therapeutic efficacy of orally inhaled products. Evaluation of Aerodynamic Particle Size Distribution (APSD) The aerodynamic size distribution of an aerosol cloud defines where the particles in that cloud are likely to deposit following inhalation. It is generally accepted, for example, that to be therapeutically effective the particles should be in the range of 1 to 5 microns in order to deposit in the lungs. The particle mass below 5 microns is normally described as the fine particle mass or fine particle dose. Particles having an aerodynamic size in excess of 5 microns (5 μm) will generally impact in the oropharynx and be swallowed whereas below 1 micron the possibility exists that the particles will remain entrained in the air stream and be exhaled. Mass-weighted APSD is a key attribute for pharmaceutical products developed to deliver drugs to or through the lungs. In development and quality control, APSD is primarily determined using multistage cascade impactors and the impactor is the instrument of choice for regulators and manufacturers for the measurement of the aerodynamic size distribution (particle size) of inhaled products. 2|Page 04 Development and Aerodynamic Particle Sizing of DPI Formulations _________________________________________________________________ Methods and instruments for measuring aerodynamic particle size Instrument 1: Twin Stage Impinger (TSI) Note: this instrument does not provide a particle size distribution – it simply splits the delivered dose into two fractions – the respirable dose and non-respirable dose. The Glass Twin Impinger or Twin Stage Impinger (TSI) operates on the principle of liquid impingement to divide the dose emitted from the inhaler into respirable and nonrespirable fractions. The non-respirable dose impacts on the oropharynx and is subsequently swallowed. This is considered as the back of the glass throat and the upper impingement chamber (collectively described as Stage 1). The remaining respirable dose penetrating the lungs is collected in the lower impingement chamber (Stage 2). Prior to testing, 7 mL of solvent is typically dispensed into the upper impingement chamber and 30 mL to the lower impingement chamber. After the test is complete, the active drug collected in the lower impingement chamber is assayed and expressed as a respirable fraction (or percentage) of the delivered dose. The upper impingement chamber is designed such that at a flow rate of 60 L/min through the impinger, the particle cut-off is 6.4 micron. Particles smaller than 6.4 micron pass into the lower impingement chamber. [Note: in this early-designed instrument an aerodynamic diameter of 6.4 micron was considered close enough to 5 micron to enable differentiation between respirable and non-respirable particles]. The value of the Glass Twin Impinger, particularly with respect to routine quality control, is recognised by its retention as Apparatus A in Ph.Eur. 2.9.18. It is relatively easy to use and assemble/disassemble. Its usage is restricted to the assessment of nebulisers, MDIs and such DPIs where it can be demonstrated that a flow rate of 60 (+/-5) L/min is suitable. Figure 1: Glass Impinger/Twin Stage Impinger 3|Page 04 Development and Aerodynamic Particle Sizing of DPI Formulations _________________________________________________________________ Multi-stage Cascade Impactor Systems Cascade impactors measure aerodynamic particle size which is a function of the density of the particles and velocity of the air, as well as the physical dimensions and shape of the particles concerned. This is important since it helps to explain how particles behave in a moving air stream as opposed to their “geometric” size. In its simplest form, an inhaler particle sizing system comprises the following components: • Mouthpiece Adapter • Induction Port (Throat) • Cascade Impactor • Vacuum Pump The impactor itself consists of a number of stages normally arranged in the form of a stack or series. These separate the particles entrained in the aerosol stream passing through them into a series of size bands or fractions, broadly corresponding to their likely deposition sites in the respiratory tract. The instruments operate on the principle of inertial impaction. Each stage of the impactor comprises a single or series of nozzles or jets through which the sample laden air is drawn, directing any airborne particles towards the surface of the collection plate for that particular stage. Whether a particular particle impacts on that stage is dependent on its aerodynamic diameter. Particles having sufficient inertia will impact on that particular stage collection plate, whilst smaller particles with insufficient inertia will remain entrained in the airstream and will move to the following stage where the process is repeated. The stages are normally assembled in a stack in order of decreasing particle size. As the jets get smaller, the air velocity increases and finer particles are collected. Any remaining particles are collected on an after-filter (or by a Micro-Orifice Collector). At the end of the test, the particle mass relating to each stage collection plate is recovered using a suitable solvent and then analysed, usually using HPLC, to determine the amount of drug (i.e. mass) present on each stage. By analysing the amount of drug deposited on the various stages in this manner, it is then possible to calculate the Fine Particle Dose (FPD) and Fine Particle Fraction (FPF) and, following further manipulation, the Mass Median Aerodynamic Distribution (MMAD) and Geometric Standard Deviation (GSD). 4|Page 04 Development and Aerodynamic Particle Sizing of DPI Formulations _________________________________________________________________ There are two cascade impactors that are in common use in the pharmaceutical industry – the Andersen Cascade Impactor (ACI) and the Next Generation Impactor (NGI) Instrument 2: Andersen Cascade Impactor (ACI) The 8-stage ACI was originally developed as a bacteriological air sampler and then adopted by the pharmaceutical industry for inhaler testing. Figure 2: Experimental Set Up for Andersen Cascade Impactor The standard Andersen Cascade Impactor is designed for use at 28.3 L/min (which is equivalent to 1 cubic foot/min) and the particle size cut-off values for each stage are shown below. However in many cases (particularly with low resistance DPIs), it is necessary to operate at flow rates greater than 28.3 L/min, if a pressure drop over the inhaler of 4 kPa is to be achieved (and as is required by the pharmacopeial test methods). In order to help address these problems, two modified configurations of ACI are available for operating at flow rates of 60 and 90 L/min. In the 60 L/min version, stages 0 and 7 are removed and replaced with two additional stages, -0 and -1. Similarly, in the 90 L/min version, stages 0, 6 and 7 are removed and replaced with three additional stages, -0, -1 and -2. Table 1: Cut-off Points for Varying Flow Rates using ACI 5|Page 04 Development and Aerodynamic Particle Sizing of DPI Formulations _________________________________________________________________ Instrument 3: Next Generation Impactor (NGI) The Copley Next Generation Impactor (NGI) was launched in 2000 and was subsequently accepted into the European Pharmacopoeia as Apparatus E and into the United States Pharmacopeia as Apparatus 5 and 6. Figure 3: External Assembly of the Copley NGI Figure 4: Internal Assembly of the Copley NGI The air flow passes through the impactor in a saw tooth pattern. Particle separation and sizing is achieved by successively increasing the velocity of the airstream as it 6|Page 04 Development and Aerodynamic Particle Sizing of DPI Formulations _________________________________________________________________ passes through each stage by forcing it through a series of nozzles containing progressively reducing jet diameters. Figure 5: Schematic of Cup Arrangement Copley NGI The NGI requires the use of a preseparator when used with DPIs in order to catch any powder boluses and large non-inhalable particles (e.g. lactose carrier particles). The NGI Preseparator is a high capacity, high efficiency, two-stage preseparator with a sharp and reproducible cut-off point of between 10 and 15 microns depending on flow rate. Using the NGI at a volumetric flow rate of 60 L/min, the cut-off points for Stages 1 to 7 are 8.06, 4.46, 2.82, 1.66, 0.94, 0.55 and 0.34 microns respectively. Whilst not a particle classifying stage in its own right, the Micro Orifice Collector (MOC) has an 80% collection efficiency of 0.3 microns (at 30 L/min) thus, in most cases, eliminating the need for a final additional filter paper (internal or external to the NGI itself). In practice, its flexibility of use and high productivity and the ability to automate much of the sampling procedure are making the NGI the new “workhorse” within many inhaler research laboratories. References and Additional Resources 1. European Pharmacopoeia 10.0: Chapter 2.9.18. Preparations for inhalation: Aerodynamic assessment of fine particles. 2. United States Pharmacopoeia: General Chapter < 601 > Aerosols, nasal sprays, metered dose inhalers and dry powder inhalers. USP-NF 2021. 3. United States Pharmacopoeia: General Chapter < 1151 > Pharmaceutical Dosage Forms (Aerosols – Inhalations). USP-NF 2021. 4. Copley Scientific. (2015). “Quality Solutions for Inhaler Testing”. 2015 Edition http://www.copleyscientific.com/files/ww/brochures/Inhaler%20Testing%20Brochure%202 015_Rev4_Low%20Res.pdf 7|Page 04 Development and Aerodynamic Particle Sizing of DPI Formulations _________________________________________________________________ Write-up 1. Below are two scanning electron micrographs (SEMs) of the same active pharmaceutical ingredient (API). The SEM on the left (A) is of the API processed by micronisation (fluid energy milling) while the SEM on the right is the product obtained by spray drying a solution of the API. Provide a brief explanation of why the two different processes result in particles of the morphologies shown. A B Answer: 8|Page 04 Development and Aerodynamic Particle Sizing of DPI Formulations _________________________________________________________________ 2. The two SEMs below show micronized salbutamol sulphate immediately post processing (SEM A) and after storage for two weeks (SEM B). SEM B shows particle agglomeration. Provide a short explanation as to why such agglomeration might be observed. How could such agglomeration be avoided or controlled? A B Answer: 9|Page 04 Development and Aerodynamic Particle Sizing of DPI Formulations _________________________________________________________________ 3. The data sets shown in the table below are the NGI in vitro deposition data at 30 L/min flow rate for two different batches of the same DPI powder formulation. Using a commercial software package (available from Copley Scientific Ltd.) the Mass Median Aerodynamic Diameter (MMAD) and the Geometric Standard Deviation (GSD) were determined for both data sets. Results are shown in red text in the table below. (i) Data set 1 Impactor Stage Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 Stage 6 Stage 7 Filter (MOC) MMAD = GSD = Drug Collected (mg) 10.5 26.8 44.3 37.8 13.5 5.45 0.55 0.04 Data set 2 Impactor Stage Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 Stage 6 Stage 7 Filter (MOC) Drug Collected (mg) 12.9 42.7 36.6 27.2 13.5 5.80 0.56 0.03 4.52 μm 1.76 MMAD = GSD = 5.35 μm 2.02 Comment on the significance of the results and possible reasons for the difference in the results obtained for the two sets of data. Answer: 10 | P a g e 04 Development and Aerodynamic Particle Sizing of DPI Formulations _________________________________________________________________ (ii) Would you expect a change in air flow rate through the NGI to have an impact on the results? If so, how? Explain you answer. Answer: 11 | P a g e
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