CROSS-REFERENCE TO PRIOR APPLICATIONS

[001] This application claims priority to U.S. Provisional Patent Application No. 62/561,974, filed September 22, 2017, which is hereby expressly incorporated by reference in its entirety.

FIELD

[002] The embodiments generally relate to improved methods for the manufacture of inhalation powders. More particularly, aspects of the disclosure relate to methods for characterizing the cohesiveness of a powder comprising a drug or active agent to determine its suitability for the manufacture of inhalation powder blends.

BACKGROUND

[003] Inhalation therapy is currently the best option for lung diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). Pulmonary delivery allows the use of smaller drug doses and reduced systemic side effects. Moreover, pulmonary delivery is attractive as a route for systemic administration due to fast absorption by the massive surface area of the alveolar region, the abundant vasculature and thin air-blood barrier, and the avoidance of first pass metabolism. (Ibrahim et al., Medical Devices: Evidence and Research, 2015, 8: 131- 139).

[004] Two widely used systems for the administration of drugs to the airways are dry powder inhalers (DPIs) comprising micronized drug particles as dry powder usually admixed with coarser excipient particles of pharmacologically inert materials such as lactose, and pressurized metered-dose inhalers (pMDIs) comprising a suspension of micronized drug particles in a propellant gas. DPI drug formulations have greater chemical stability than liquid formulations, but manufacturing powders with the appropriate characteristics for easy aerosolization and alveolar delivery is more complicated. The drug particles to be delivered must be sufficiently small so that the particles can be inhaled and penetrate into the deep lung. The aerodynamic diameter of the particles primarily influences this behavior, since deposition in the respiratory tract is controlled by a particle's aerodynamic size rather than its physical or geometric shape.

Lung deposition improves substantially for particles less than 5 microns in aerodynamic diameter and decreases substantially for particles with effective aerodynamic diameters of greater than 5 microns. A drug particle size between 1 and 5 pm is needed for entry into the deep lung by inhalation and particles of 1-2 pm are most suitable for reaching the small airways, an important target for the treatment of asthma and COPD.

[005] DPI drug formulations may be either fine powder drug blended with large carrier particles to prevent aggregation and increase powder flow prior to aerosolization, or may consist of drug alone. In all cases, the powder formulations travel along the airways to deposit in the targeted areas of the lung, and then dissolve to exert their pharmacological effect or are absorbed to reach systemic targets. Powder blends for DPIs typically consist of micronized drug particles blended with an inactive excipient (e.g., lactose, mannitol, trehalose, sucrose, sorbitol, glucose) of larger sizes. These components are usually blended together to form an“interactive mixture” wherein the finer drug particles are strongly adhered to the surface of the carrier particles.

Unoptimized powder blends can exhibit interparticulate cohesive forces that cause powder aggregates, making powder dispersion very difficult.

[006] Both cohesive (drug-drug) and adhesive (drug-excipient and drug-container) interactions have an effect on the aerosolization and dispersion of DPI formulations during inhalation. For example, adhesive forces need to be high enough to enable the successful preparation of the formulation and provide stability during storage, but not be low enough to hinder particle disaggregation upon inhalation. When the drug is mixed with carriers, it is expected that adhesion between the drug and the excipients will be higher than the cohesive forces between respective drug particles. Staniforth, et al ., W02001/078695 and its progeny, the disclosures of which are incorporated herein by reference in their entirety, discloses problems associated with the strong cohesive forces of micronized powders intended for inhalation.

[007] Manufacturing powder blends containing micronized APIs is a challenging process. Micronized drugs, especially drug particles having a diameter within the range of from about 1 pm to about 5 pm, have a high surface energy and substantial adhesive and cohesive properties. Some APIs used in dry powder inhalation products are particularly challenging to homogenize. For example, the cohesive nature of salmeterol xinafoate is well documented. It is possible to improve homogeneity of salmeterol xinafoate by increasing the blending energy, however, this adversely affects the aerodynamic particle size distribution (i.e., reduces the fine particle dose). [008] It is desirable to achieve homogeneous powder blends to ensure consistency in delivered dose and aerodynamic particle size distribution when the drug is administered to a patient. In order to evaluate both the cohesive and adhesive interactions between materials used in drug delivery, a number of research groups have used atomic forces microscopy (AFM). In particular, cohesive adhesive balance (CAB) measurements with colloidal probe AFM can establish whether a system is dominated by cohesive or adhesive forces, which affects the fluidization and dispersion properties of the powder. (Weiss et al ., International Journal of Pharmaceutics, 2015, 494: 393-407). However, AFM is not practical in its ability to discriminate batch to batch variations that may also impact blend homogeneity. Thus, an improved method is needed for screening batches of active pharmaceutical ingredients (APIs) to allow for the selection of batches that will mix under standardized conditions to achieve homogeneous blends.

SUMMARY OF THU INVENTION

[009] An aspect of the disclosure is to provide a method for characterizing the cohesiveness of a powder comprising a drug or active agent. The method may include (i) optionally conditioning the powder; (ii) determining the tapped density of the powder; (iii) determining the total flow energy of the powder; (iv) calculating an average tapped density and average total flow energy of the powder based on collected data for a plurality of units of the powder; (v) determining whether a correlation exists between the average tapped density and the average total flow energy of the powder; (vi) if a correlation exists, then determining the blend uniformity of the powder; (vii) correlating the blend uniformity with the tapped density and/or total flow energy; and (viii) determining a tapped density threshold and /or total flow energy threshold to achieve satisfactory blend uniformity. After carrying out the method, powder manufacturers can use the tapped density and /or total flow energy threshold values to select suitable powders.

[010] An additional aspect of the disclosure is to provide a method for determining the suitability of powders for manufacturing a powder blend. The method may include: (i) optionally conditioning the powder; (ii) determining the tapped density of the powder; (iii) determining the total flow energy of the powder; (iv) calculating an average tapped density and average total flow energy of the powder based on collected data for a plurality of units of the powder; (v) determining whether a correlation exists between the average tapped density and the average total flow energy of the powder; (vi) if a correlation exists, then determining the blend uniformity of the powder; (vii) correlating the blend uniformity with the tapped density and/or the total flow energy; (viii) determining a tapped density threshold and/or total flow energy threshold to achieve satisfactory blend uniformity; and selecting powders that do not exceed the tapped density threshold and/or total flow energy threshold.

[Oil] For batches having very good correlation between their average tapped density and average total flow energy, tapped density or total flow energy can be used as a surrogate for the cohesiveness of the API bulk batch to predict satisfactory blend uniformity. Thus, the embodiments disclosed herein can be used to screen batches of APIs to allow for the selection of batches that will mix under standardized conditions to achieve homogeneous blends. Other objects and features of the embodiments will be in part apparent and in part pointed out hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

[012] FIG. 1 shows a Split Vessel Assembly, in accordance with one or more embodiments.

[013] FIG. 2 shows the rotation of the FT4 blade in the conditioning step, in accordance with one or more embodiments.

[014] FIG. 3 shows the measurement of work done by downward traverse of the FT4 blade through the previously consolidated power bed, in accordance with one or more embodiments.

[015] FIG. 4 shows a graph depicting the correlation between total flow energy and tapped density for salmeterol xinafoate, in accordance with one or more embodiments.

[016] FIG. 5 shows a graph depicting the total flow energy of different salmeterol xinafoate batches, in accordance with one or more embodiments.

[017] FIG. 6 shows a graph depicting the tapped density of different salmeterol xinafoate batches, in accordance with one or more embodiments. DETAILED DESCRIPTION

[018] When describing features of aspects or preferred embodiment(s) thereof, the articles "a", "an", "the", and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there are additional elements other than the listed elements.

[019] Unless otherwise indicated, the terms "drug" or "active agent" include any agent, drug, composition of matter or mixture which provides a pharmacologic effect that can be

demonstrated in vivo or in vitro.

[020] The term "active pharmaceutical ingredient" as used herein means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. The term includes those components that may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect.

[021] The term "excipient" (also "inactive ingredient") as used herein means any component other than an active ingredient.

[022] The term "batch" as used herein means a specific quantity of a product that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during a same cycle of manufacture. Batch refers to the quantity of material and does not specify a mode of manufacture.

[023] "Dry powder" refers to a powder composition that typically contains less than about 20% moisture, preferably less than 10% moisture, more preferably contains less than about 5-6% moisture, and most preferably contains less than about 3% moisture, depending upon the particular formulation.

[024] A dry powder that is "suitable for pulmonary delivery" refers to a composition comprising solid (i.e., non-liquid) or partially solid particles that are capable of being (i) readily dispersed in/by an inhalation device and (ii) inhaled by a subject so that a portion of the particles reach the lungs to permit penetration into the alveoli . Such a powder is considered to be

"respirable". [025] "Flowability" is a bulk powder characteristic. The term "flowable" means an irreversible deformation of a powder to make it flow due to the application of external energy or force.

[026] "Aerosolized" or "aerosolizable" particles are particles which, when dispensed into a gas stream by either a passive or an active inhalation device, remain suspended in the gas for an amount of time sufficient for at least a portion of the particles to be inhaled by the patient, so that a portion of the particles reaches the lungs.

[027] "Pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[028] "Pharmaceutically acceptable salt" refers to the relatively non-toxic, inorganic and organic, acid or base addition salts of compounds of disclosed herein. Representative salts include, for example, those listed in Berge etal, "Pharmaceutical Salts," J. Pharm Sci, Vol. 66, pp. 1-19, (1977). Pharmaceutically acceptable acid addition salts include, but are not limited to, those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, p- toluenesulphonic, benzenesulphonic, isethionic, and naphthalenecarboxylic, such as l-hydroxy-2-naphthalenecarboxylic (i.e., xinafoic) acids.

[029] The expression "Aerodynamic diameter" denotes the diameter of a sphere of unit density which behaves aerodynamically as the particle of the test substance. It is used to compare particles of different sizes, shapes and densities and to predict where in the respiratory tract such particles may be deposited. The term is used in contrast to volume equivalent, optical, measured or geometric diameters which are representations of actual diameters which in themselves cannot be related to deposition within the respiratory tract. The aerodynamic diameter, daer, can be calculated from the equation: where d _g is the geometric diameter, for example the Mass Median Aerodynamic Diameter" (MMAD), and p is the powder density. See, for example, U.S. Patent No. 9,539,211, the disclosure of which is incorporated herein by reference in its entirety.

(030] The "Mass Median Aerodynamic Diameter" (MMAD) is a statistically derived figure for a particle sample. For instance, an MMAD of 5 um means that 50% of the total sample mass will be present in particles having aerodynamic diameters less than 5 um.

[031] "Total flow energy" represents a powder' s resistance to being made to flow in a dynamic state. It can be calculated from measurements of rotational resistance (Torque) and vertical resistance (Force) experienced by a blade moving through a column of powder in a rheometer.

[032] The expression "blend uniformity" (BU) refers in general to a measure of the uniformity of a blend of powder. The FDA published a draft guidance document for analyzing blend uniformity in August 1999 (FDA, "Guidance for Industry; AND As: Blend Uniformity Analysis," August 3, 1999, available at The draft guidance document states that an "acceptable blend uniformity," which is defined herein with the same definition, is one in which 90.0 to 110.0 percent of the expected quantity of the active ingredient is recovered with a relative standard deviation (RSD) of no more than 5.0%. Standards for assessing blend uniformity must comply with regulations set forth in, for example, 21 CFR 211.110; 211.160; 211.165,

A final

FDA draft guidance document was published in 2003 (the "draft guidance document") that describes procedures for assessing blend uniformity and determining "acceptable blend uniformity." FDA, "Guidance for Industry; Powder Blends and Finished Dosage Units - Stratified In-Process Dosage Unit Sampling and Assessment," Oct. 2003, available at

[033] An aspect of the disclosure provides a method for the manufacture of drug inhalation powders, particularly powders for use in a dry powder inhaler (DPI). More specifically, embodiments include methods for characterizing the cohesiveness of powders comprising a drug or active agent to facilitate the manufacture of homogeneous dry powder blends. The methods are particularly useful for screening batches of micronized APIs to select batches that can be mixed under standardized conditions and still achieve blend uniformity. [034] In one embodiment, powder rheology is used for the measurement of inter-particulate forces in bulk powders and provides a measurement of the cohesiveness of individual batches of an active pharmaceutical ingredient (API). In an embodiment, the total flow energy can be measured on an FT4 Powder Rheometer® (commercially available from Freeman Technology, Gloucestershire, United Kingdom), which measures the energy required by a screw/blade to travel a fixed distance in a powder bed. Cohesive materials, which have strong inter-particulate forces, provide more resistance to the travel of the screw/blade and have higher total flow energy. It has been discovered that total flow energy correlates very well with the tapped density of the material, since a powder which is well packed requires more energy to overcome inter particulate forces and move the particles, which in turn may correlate with the cohesiveness between API particles which can have influence in achieving good blend uniformity of powder formulation, thereby providing a fast and effective method of determining powder suitability. This method allows for selection of suitable batches of API to be used in the manufacture of homogeneous powder blends.

[035] Some of the analytical techniques used herein can be carried out using conventional apparatus used to measure tapped density and total flow energy.

[036] The embodiments may optionally include first conditioning a powder. Powders have memory, in that their behavior and flowability can be influenced by their previous packing state. Powders are complex materials that primarily contain three distinct phases: (1) solids in the form of particles; (2) gases in the form of air between the particles; and (3) often liquids in the form of water either on the surface of the particles or within its structure. The behavior of powders, such as flowability, compressibility, adhesivity, permeability, hydrophobicity, etc., is difficult to model and predict from first principles. Powder behavior is a function not only of the physical and chemical properties of the particles, but external variables such as packing, moisture levels, electrostatic charge, etc. If a powder has been consolidated, a proportion of this stress will be retained after the consolidating load has been removed. Conversely, if the powder has previously been aerated, then excess air may exist within the powder. In both cases, the flow properties of the powder can be influenced by the previous packing state. [037] It therefore can be desirable to carry out a conditioning process prior to measuring certain physical properties of the powder to prepare the powder in a homogeneous fashion, creating a uniform, low-stress packing throughout the powder sample, thereby removing stress history or excess air prior to measuring the physical characteristics of the powder. Any conditioning process can be used in accordance with the embodiments. Conditioning is a simple, but effective mechanical process designed to prepare the sample for the following measurement. The conditioning process involves gentle displacement of the whole sample in order to loosen and slightly aerate the powder. The aim is to disturb and gently drop each particle in order to construct a homogenously packed powder bed, removing any pre-compaction or excess air and ensuring the results from the following test are independent of how the operator handles the powder and places it into the testing vessel.

[038] In a preferred aspect of the disclosure, a bulk API powder can be conditioned by downward traverse of a rheometer blade and then upward traverse to establish a low stress, homogeneous packing state, free of localized stress and any excess air, as shown in Figure 2. As shown therein, the downward traverse uses a 5° positive helix where the blade action is more slicing than compacting; the upward traverse uses a 5° negative helix that gently lifts the powder and drops it over the blade with each particle coming to rest behind the blade. A particularly preferred apparatus used to condition powders is the FT4 Powder Rheometer®, commercially available from Freeman Technology, Gloucestershire, United Kingdom.

[039] The embodiments described herein may include determining the tapped density of a powder, which is the ratio of the mass of the powder to the volume occupied by the powder after it has been tapped for a defined period of time. The tapped density of a powder represents its random dense packing. Tapped density can be calculated using the following equation (Eq. 1), where M = mass in grams and Vf = the tapped volume in milliliters.

[040] The tapped density of a powder may be measured by first gently introducing a known mass of a sample powder into a vessel (e.g., a graduated cylinder) and carefully leveling the powder without compacting it. The cylinder is then mechanically tapped by raising the cylinder and allowing it to drop under its own weight using a mechanical tapped density tester that provides a suitable fixed drop distance and nominal drop weight. Volume or weight readings are taken until little further volume or weight change is observed. Alternatively, the tapped density of a powder may be measured by first gently introducing an excess known mass of a sample powder into a vessel with a known volume (e.g., FT4 split vessel assembly or cylinder or equivalent) and conditioning the powder. The cylinder is then mechanically tapped by raising the cylinder and allowing it to drop under its own weight using a mechanical tapped density tester that provides a suitable fixed drop distance and drop weight. After tapping remove excess weight from the cylinder with known volume. Weight readings are taken until little further weight change is observed.

[041] Tapped density is distinguished from bulk density, which is the mass per unit volume of a loose (untapped) powder bed. Methods for the determination of bulk density and tap density are provided in the United States Pharmacopeia Convention, 2014, Chapter 616, "Bulk Density and Tapped Density of Powders." Any apparatus can be used to measure the tapped density, including the use of a single platform tapped density tester (Varian Inc., North Carolina, USA), or a split vessel assembly used in an FT4 Powder Rheometer® (Freeman Technology,

Gloucestershire, United Kingdom).

[042] For different APIs or the same APIs processed differently, the tapping frequency and number of taps can be different as long as the combination of both parameters results in constant tapped density as per compendial requirements. Generally, the tapping drop height is between 3 ± 2 mm to 20 ± 2 mm, the tapping frequency is about 200 to about 400 taps per minute with about 250 to about 2500 total taps. Preferably, the tapping frequency is about 225 to about 350 taps per minute with about 250 to about 2500 total taps. More preferably, the tapping frequency is about 250 to about 300 taps per minute, with about 500 to about 2500 total taps. In one embodiment, the tapping frequency is about 300 taps per minute for a total of about 400 taps. In accordance with the guidelines provided herein, those skilled in the art will be capable of determining the appropriate tapping frequency and total taps depending on the API, such that the combination of tapping frequency and total taps produces a substantially constant tapped density as per compendial requirements.

[043] The fixed drop distance used to determine tapped density can also be varied according to the API. Generally, the tap density tester is set to a drop height of from about 3 ± 2 mm to about 20 ± 2 mm, preferably from about 6 ± 2 mm to about 20 ± 2 mm, and more preferably from about 9 ± 2 mm to about 20 ± 2 mm. In one embodiment of the invention, the tap density tester is set to a drop height of from about 10 ± 2 mm to about 20 ± 2 mm. In a preferred embodiment, the tap density tester is set to a drop height of from about 10 ± 2 mm to about 14 ± 2 mm.

[044] The embodiments described herein may also include determining the total flow energy of a powder, which can be done for example, using an FT4 Powder Rheometer® (Freeman

Technology, Gloucestershire, United Kingdom). The FT4 Powder Rheometer was designed to characterize the rheoiogy, or flow properties, of powders. To measure total flow energy, a blade can be rotated and moved downward through a powder to establish a precise flow pattern. The more difficult it is to move the blade, the more the particles resist motion and the harder it is to get the powder to flow. As the blade rotates and moves vertically, it will experience a resistance to rotation and a resistance to vertical movement. The FT4 Powder Rheometer measures both rotational and vertical resistance in the form of Torque and Force, respectively. The composite of these two signals quantifies the powder's total resistance to flow. Using the calculation of Work Done it is possible to represent both resistances as a total energy, the energy required to move the blade from the top to the bottom of the powder column.

[045] Typically, the rheometer blades are configured to move downward through the powder in a helical path defined by the helix angle and blade tip speed. The parameters for helix angle and tip speed can be modified and optimized, depending on the material used, and those skilled in the art will be capable of optimizing these parameters using the guidelines provided herein.

Generally, the blades traverse downward through the powder in a counter-clockwise helical path at a helix angle of from about 3° to about 7°. The blade tip speed is from about SO to about 300 mm/sec, preferably from about 100 to about 300 mm/sec, and more preferably from about 200 to about 300 mm/sec. In one embodiment, the blades traverse downward through the powder at a helix angle of 5° positive at a tip speed of about 100 mm/sec.

[046] The embodiments further may include determining whether a correlation exists between the tapped density and total flow energy of the powder, preferably a linear correlation.

Determining whether a correlation exists between tapped density and total flow energy can be determined by plotting the respective product characteristics and assessing whether a correlation between the characteristics exists (see, e.g., Figure 4). If no or little correlation exists, then it can be assumed that tapped density of the powder would not be an appropriate indicator for the final product characteristics, if it is determined that a correlation exists, then the embodiments may include further determining the API cohesiveness and blend uniformity of the powder. (047] The blend uniformity of the powder can be determined using any known method, including for example, those disclosed in the draft guidance document. The blend uniformity for the powder then can be correlated with the tapped density and/or the total flow energy. If a correlation exists between acceptable blend uniformity and tapped density, the embodiments include establishing a threshold tapped density to achieve acceptable blend uniformity - i.e., one in which 90.0 to 110.0 percent of the expected quantity of the active ingredient is recovered with a relative standard deviation (RSD) of no more than 5.0%. The threshold tapped density then can be used as a simple test to assess the material quality to achieve adequate blend uniformity. Similarly, if a correlation exists between acceptable blend uniformity and total flow energy, the embodiments include establishing a threshold total flow energy to achieve an acceptable blend uniformity.

[048] In accordance with the embodiments, various powders can be analyzed to determine whether correlations exist between tapped density, total flow energy, and blend uniformity. If a correlation exists, then product manufacturers can simply use the determined threshold tapped density and/or threshold total flow energy as an API and/or product quality control determinant.

[049] The method can be used with any powder pharmaceutical agent. In one embodiment, the powder active pharmaceutical ingredient (API) can be a bronchodilator. The bronchodilator can be a Short-Acting Beta Adrenoceptor Agonist (SABA), such as albuterol, bitolterol, fenoterol, isoproterenol, levalbuterol, metaproterenol, pirbuterol or procaterol, a Long Acting Beta

Adrenoceptor Agonist (LABA) such as arformoterol, bambuterol, clenbuterol, formoterol or salmeterol, or an Ultra Long Acting Beta Adrenoceptor Agonist (Ultra-LABA), such as abediterol, carmoterol, indacaterol, olodaterol or vilanterol. In another embodiment, the API may be an anticholinergic agent that blocks the activity of the muscarinic acetylcholine receptor, including a Short-Acting Muscarinic Antagonist (SAMA) such as ipratropium, or a Long-Acting Muscarinic Agent (LAMA), such as aclidinium, glycopyrronium, tiotropium, and umeclidinium. In another embodiment, the API may be an inhaled corticosteroid (ICS) such as, for example, budesonide, ciclesonide, flunisolide, beclomethasone, fluticasone, mometasone or triamcinolone. In other embodiments, the API is a pharmaceutically acceptable salt of any of the above- mentioned APIs. In another embodiment, the API is another powder API known in the art or later discovered, or mixtures of one or more of any of the above-mentioned APIs.

|050| The powder formulations can be utilized with any type of DPIs known in the art. DPIs can be divided into two basic types: (i) single dose inhalers, for the administration of pre- subdivided single doses of the active compound; and (ii) multidose dry powder inhalers (MDPIs), either with pre-subdivided single doses or pre-loaded with quantities of active ingredient sufficient for multiple doses. DPIs can be further classified on the basis of the required inspiratory flow rates (L/min), which in turn depend on their design and mechanical features. Thus, DPIs can be classified as: (i) low-resistance devices (> 90 L/min); (ii) medium-resistance devices (about 60 L/min); and (iii) high-resistance devices (about 30 L/min).

[051] Having described the invention in detail, it will be apparent that modifications and variations are possible without departing from the scope of the invention defined in the appended claims.

EXAMPLES

[052] The following non-limiting examples are provided to further illustrate the present invention.

Test Equipment - 25 mm x 25 mL Split Vessel Assembly

[053] The equipment used to measure the tapped density and total flow energy of the Active Pharmaceutical Ingredient (API) was a 25 mm x 25 mL Split Vessel Assembly shown in FIG. 1. This assembly may be included as part of an FT4 Powder Rheometer® (commercially available from Freeman Technology, Gloucestershire, United Kingdom). The assembly was constructed using the following procedure.

[054] (1) The vessel was inverted and the clamp ring loosely fit thereon; (2) The clamp ring was positioned approximately 1 mm from the end of the vessel; (3) The clamp ring was secured with a hex driver or other suitable tooling; (4) The standard base was positioned into the bottom of the vessel; (4) The levelling assembly was opened and placed on top of the vessel; (6) The vessel and level assembly were inverted and placed on the edge of a flat surface. Then, pressure was applied by pushing down on both the vessel and the levelling assembly to ensure they become flush with the flat surface. After that, the levelling assembly was tightened with a hex driver or other suitable tooling; (7) The vessel was held to ensure that the vessel and split mechanism were flush by running your finger around the top; (8) The levelling assembly was closed, the 25 mm x 25 mL extension vessel was placed into the top half of the levelling assembly gently rotated to ensure it was in contact with the vessel below, and then gently tightened with a hex driver or other suitable tooling; and (9) The funnel was placed on top. The Split Vessel Assembly is shown in Figure 1.

Test Method for Characterization of Powder Sample

[055] A powder sample of API was conditioned to loosen and remove any pre-compaction, slightly aerate the powder and construct a homogenously packed powder bed. The conditioned powder was consolidated by tapping, and its tap density measured. The flowability of the consolidated powder was measured using an FT4 Powder Rheometer® (Freeman Technology, Ltd., Gloucestershire, UK). The testing procedure was repeated with additional samples of the same powder and then the data used to correlate the tap density (g/mL) and total flow energy (mJ) for the powder.

Conditioning the Powder

[056] A powder sample of API was prepared for both tapped density and total flow energy measurements according to the following procedure: (i) The 25mm X 25 mL split vessel assembly with a feeding funnel discussed above was attached to an FT4 Powder Rheometer instrument table, supplied by Freeman Technology); (ii) The empty vessel was tared to the nearest 0.01 g; (iii) Approximately 8 ± 0.50 g of micronized Active Pharmaceutical Ingredient (API) was charged into the vessel assembly via the feeding funnel and allowing powder excess using a stainless steel spatula; (iv) The bulk API was conditioned by downward traverse of the FT4 Rheometer blade and then upward traverse to establish a low stress, homogeneous packing state, free of localized stress and any excess air. The downward traverse used a 5° positive helix where the blade action is more slicing than compacting; the upward traverse used a 5° negative helix that gently lifts the powder and drops it over the blade with each particle coming to rest behind the blade. The downward traverse and upward traverse of the FT4 Rheometer blade in the conditioning step is shown in Figure 2.

Determining the Tap Density of the Powder

[057] After conditioning the API powder sample as described in Step 1, the tapped density of powder sample was measured with a standard tap density tester (e.g., VanKel® Tap Density Tester, Varian Inc., Cary, North Carolina) according to the following procedure: (i) The split vessel assembly containing the conditioned API was transferred to the holder on top of the tapped density tester and the vessel secured; (ii) The Tapped Density Tester was set at 5 taps per second for a total of 400 taps with a drop height at 14 ± 2 mm, and Tester was started to begin mechanical tapping; (iii) Excess powder was split from the split vessel assembly and the final powder weight was measured after tapping. The final powder weight was used to calculate the tap density using the formula in Equation 1 : Tapped density (g/mL) = IU/VF, where m is the mass of the tapped powder and VF is the final tapped volume of the powder in the split vessel assembly.

[058] Alternatively, the FT4 instrument can calculate the tapped density based on the calculated / weighted mass of the tapped powder and fixed volume of the split vessel assembly.

Determining the Total Flow Energy of the Powder

[059] After consolidating the API powder sample as described in Step 2, the total flow energy (i.e., flowability) of the consolidated powder was directly measured as follows: (i) The Split Vessel Assembly containing tapped API was transferred to the FT4 instrument table and secured;

(ii) The Levelling Assembly was rotated to split and remove excess powder as described above and excess powder was transferred into a plastic weighing boat. If applicable, the side of the Levelling Assembly was gently tapped with a stainless steel spatula to completely remove any retained powders stuck on the inner surface of the Levelling Assembly and the feeding funnel;

(iii) The flowability of the consolidated powder was directly measured by measuring the work done in moving the FT4 blade through the powder from the top of the vessel to the bottom in a counter-clockwise motion, i.e. during the downward motion at 100 mm/s tip speed (Figure 3). Work done in moving the blade was calculated using the FT4 Powder Rheometer system, and reported as the flow energy (mJ).

Calculating the Averaged Tapped Density and the Average Total Flow Energy of the Powder

[060] After measuring the flowability of the powder as described in Step 3, additional samples (i.e., units of the powder) were tested in order to calculate average values for tapped density and total flow energy. The procedure was as follows: (i) The standard base was gently pulled out of the Split Vessel Assembly to transfer all the powder from the sample tested into a stainless steel waste container with the aid of stainless steel spatula and the cleaning brush; (ii) The standard base was placed back over the Split Vessel Assembly; (iii) Steps 1-3 were repeated once or twice with fresh sample of the same powder in order to determine the tapped density and total flow energy of additional powder samples; (iv) The average tapped density (g/mL) and average total flow energy (mJ) was calculated for the powder based on collected data for a plurality of units of the powder.

Example 3: Correlating Average Tapped Density and Average Total Flow Energy

[061] Using the equipment described in Example 1 and the test method described in Example 2, twenty batches of salmeterol xinafoate were tested. A graph of the average tapped density vs. average total flow energy for each batch shows a very good correlation (Figure 4). This data establishes the use of average tapped density and /or average total flow energy as a surrogate for the cohesiveness of the bulk material from individual batches of salmeterol.

[062] Consolidating the bulk powder (i.e., tapping to produce the tapped density) appears to facilitate the cohesiveness between the API particles and allows for more discrimination between different batches of API with different bulk densities. With the enhanced discrimination via tapping, it also allows the total flow energy technique to be more discriminatory because higher energy is required to move the consolidated powder. Therefore, good correlation between tapped density and total flow energy in the consolidated powder is observed.

[063] The average total flow energy and average tapped density calculated from different batches of salmeterol xinafoate raw material are provided in Figure 5 and Figure 6, respectively. The bars on the graph represent the data spread obtained from the duplicate or triplicate measurements for each batch, indicating that the technique is reproducible. As can be seen in Figures 5 and 6, there was considerable batch to batch fluctuation for both tapped density and total flow energy. For example, Batch 10 (SXI0513012) was found to have an average flow energy of 1108 mJ, whereas Batch 7 (SXI1112025) was found to have an average flow energy of 2998 mJ, almost 3x as high. Similarly, Batch 10 was found to have an average tapped density of 0.24 g/mL, whereas Batch 7 was found to have a significantly higher average tap density of 0.31 g/mL.

[064] Interestingly, all batches of salmeterol xinafoate presented in Figures 5 and 6 were obtained from the same supplier, although they may not have been manufactured in exactly the same way or handled in the same manner post micronization. For example, one batch of material may have been exposed to the environment for a longer period of time than another. Prolonged exposure to the environment, especially at elevated relative humidity may increase the tapped density and total flow energy of the batch due to adsorbed moisture. This is not desirable for powders in DPIs because it could mean an increase in the cohesiveness of the API. The considerable fluctuation for tapped density and total flow energy from batch to batch of API from the same supplier further highlights the desirability of having a fast, simple, and effective method that can be used to assess powder suitability for producing satisfactory blend uniformity, thereby increasing production efficiency and reducing waste.

[065] Some of the materials characterized in the abovementioned batches were used to manufacture binary powder blends containing fluticasone propionate API (Fp) and salmeterol xinafoate API (Sx) at different concentrations. The binary powder blends were manufactured using a blending process with low energy input, as shown in Table 1.

Table 1: Blending Process Parameters for FS MDPI Products

[066] Blend uniformity was determined according to the FDA,“Guidance for Industry; Powder Blends and Finished Dosage Units - Stratified In-Process Dosage Unit Sampling and

Assessment;’ Oct. 2003, available at https://www.fda.gov/ohrms/dockets/98fr/03d-0493- gdl000l.pdf Accordingly, blend uniformity was assessed by collecting and assaying 10 samples from 10 sampling locations in the blender and/or intermediate bulk containers. The mean and relative standard deviations (RSD) of all individual results were then calculated. To meet Tier 1 criteria, the RSD of all individual results is < 5.0% and all individual results are within 10.0% (absolute) of the mean of the results. In the event of not meeting Tier 1 acceptance criteria, an additional 2 samples from each of the 10 locations were sampled and assayed according to Tier 2 criteria.

[067] The blend uniformity (BU) results of several binary powder blends containing the APIs fluticasone propionate and salmeterol xinafoate are presented in Table 2. A direct correlation can be seen between the average total flow energy of salmeterol xinafoate API and the blend uniformity results. Similarly, a direct correlation can be seen between the average tapped density of salmeterol xinafoate API and the blend uniformity results.

Table 2: Blend Uniformity Results for Fluticasone Propionate/Salmeterol Xinafoate

Powder Blends using Different Batches of Salmeterol Xinafoate

[068] As shown in Table 2, salmeterol xinafoate batches with high average tapped density such as 0.31 g/mL for SXI1112025 (Batch 7), 0.32 g/mL for SXI0113001 (Batch 8) and 0.30 g/mL for SXI0516024 (Batch 17), have a high tendency to result in blend uniformity failure. In contrast, salmeterol xinafoate raw material batches with lower average tapped density values are generally suitable for manufacturing fluticasone propionate / salmeterol xinafoate inhalation powder blends. Similarly, salmeterol xinafoate batches with high total flow energy have a greater tendency to result in blend uniformity failure and batches with low total flow energy are generally suitable for binary blends with fluticasone propionate.

[069] Accordingly, the total flow energy and tapped density as determined by the inventive method is useful for distinguishing the quality of salmeterol xinafoate raw material that is suitable for manufacturing inhalation powder blends. For example, the inventive methods have demonstrated utility for the manufacture of binary blends of salmeterol xinafoate with fluticasone propionate, a combination useful for the management of asthma and chronic obstructive pulmonary disease. Further, once a threshold tapped density or threshold total flow energy for salmeterol xinafoate has been established for the Fp + Sx combination, the inventive method can be applied to other powder blends containing Sx. The method may need to be repeated because, for some powders, it cannot be assumed that a threshold tapped density or threshold total flow energy for one API suitable for a particular powder blend extends to other blends with the same API.

[070] The inventive methods are broadly applicable to APIs other than salmeterol xinafoate used in inhalation powder blends. Suitable APIs include, but are not limited to, short acting beta agonists (SABA), long acting beta agonists (LAB A), inhaled corticosteroids (ICS), short acting muscarinic antagonists (SAMA), and long acting muscarinic antagonists (LAMA).