NZ711200B2

NZ711200B2 - Methods and systems for conditioning of particulate crystalline materials

Info

Publication number: NZ711200B2
Application number: NZ711200A
Authority: NZ
Inventors: Sarvajna Dwivedi; James Ivey; Ali Kazmi; David Lechuga; Herm Snyder; Jason H Speck; Reinhard Vehring
Original assignee: Pearl Therapeutics Inc
Priority date: 2013-03-15
Filing date: 2014-03-14
Publication date: 2021-01-06

Abstract

Methods and systems for the preparation of conditioned micronized active agents. Additionally, methods and systems for in-process conditioning of micronized active agent particles and compositions comprising conditioned micronized materials.

Description

METHODS AND SYSTEMS FOR CONDITIONING OF PARTICULATE CRYSTALLINE MATERIALS BACKGROUND Technical Field This disclosure relates generally to systems and methods for the preparation and stabilization of particulate materials. More specifically, this disclosure relates to systems and methods for conditioning particulate materials to improve the physicochemical stability of the materials as well as compositions orating such les.

Description of the Related Art Particulate crystalline materials, including micronized crystalline particulates, are useful in a variety of contexts. For example, certain industrially useful compounds are conveniently stored in bulk as dry, particulate powders.

Additionally, certain compounds can be better utilized or orated into commercial products when provided as micronized lline particulates. This can be seen with pharmaceutically active compounds that exhibit improved formulation, delivery, or therapeutic utes when ed in micronized crystalline form.

However, processes used to produce certain crystalline materials can result in material characteristics that introduce an undesired level of physiochemical ility. Techniques for micronization of crystalline material often e energy-intensive milling, grinding, shearing or particle-to-particle collisions to reduce le size. An example of one such technique is air jet milling, which uses high velocity air or gas to cause particle-to-particle collisions and to generate micronized material, including particles ranging from about 0.5 to about 30 pm in diameter. The exertion of thermal or mechanical energy during -intensive ization processes can cause the ion of non-crystalline, amorphous material that can lead to significant physicochemical instability of the resulting micronized particles. Such amorphous al may be present in the form of amorphous regions on otherwise crystalline particles or as substantially amorphous particles.

The presence of amorphous material within micronized crystalline material can result in a sity for the particles to fuse, aggregate, and/or agglomerate. In certain cases, the instability appears particularly acute when the ized material is exposed, even for very short periods of time, to an environment that includes a solvent e of solubilizing or plasticizing the amorphous material. In such instances, exposure of the micronized material often leads to recrystallization of amorphous material ned therein or sorbed, vapor-driven conversion of amorphous phase to crystalline phase, which can be accompanied by fusing and agglomeration of the ized particles. The fusing, aggregation and/or agglomeration of the micronized les can cause significant s in particle size and the overall particle size distribution of the micronized material, which is problematic for applications requiring the long-term physical stability of the micronized material.

In addition, processes used in the manufacture and purification of crystalline materials can leave undesired contaminants. For e, solvents, ing various organic solvents, play an important role in the manufacture of pharmaceutically active nds and ents used in the production of drug products. Solvents are often used during the synthesis of ceutically active compounds and drug product excipients to increase yields or aid in crystallization. In many manufacturing processes, the final purification step involves crystallization or re-crystallization of the desired compound, and the crystalline material formed in such processes can entrap solvent present in the solution from which the material is crystallized. Even after subjecting the material to a drying step, such as a freeze-drying or a high temperature drying process, solvent ped in a crystalline material is often difficult to completely remove, and some amount of residual solvent can remain.

The presence of residual solvent, even in small amount can have undesirable WO 44894 effects. Organic solvents, in ular, can present health and safety hazards and can influence product efficacy, safety and stability.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE GS Figure 1 is a diagram showing one ment of a system sed herein for in-process conditioning of micronized crystalline material.

Figure 2 is a diagram showing an embodiment of a system disclosed herein for in-process conditioning of micronized crystalline material.

Figure 3A is a drawing of one view of one embodiment of a sion head assembly as described in the present disclosure.

Figure 3B is a drawing of another view of one embodiment of a dispersion head assembly as described in the present sure.

Figure 3C is a drawing of a sectional view of one embodiment of a sion head assembly.

Figure 4A is a cross-sectional drawing of one embodiment of a mixing head as described in the present disclosure.

Figure 4B is a cross-sectional drawing of another embodiment of a mixing head as described in the present disclosure.

Figure 5 is a graph ing the unstable particle size distribution of a standard micronized glycopyrrolate sample as discussed in Example 1.

Figure 6A is an electron micrograph showing the amorphous morphology of a standard micronized glycopyrrolate sample as discussed in Example 1.

Figure 6B is an electron micrograph showing the fusing and eration of a standard micronized glycopyrrolate sample after exposure as discussed in Example 1.

Figure 7 is a graph depicting the stable particle size distribution of a conditioned micronized glycopyrrolate sample as discussed in Example 1.

Figure 8A is an electron micrograph showing the crystalline morphology of a conditioned micronized glycopyrrolate sample as discussed in Example 1.

Figure 8B is an electron micrograph showing the increased stability of a conditioned ized yrrolate sample after exposure as discussed in Example 1.

Figure 9 provides the ethanol vapor sorption isotherm at 250C for micronized budesonide materials prepared in Example 2.

Figure 10 includes SEM micrographs of micronized budesonide materials prepared in Example 2.

Figure 11 provides the ethanol vapor sorption isotherm at 250C for micronized fluticasone propionate materials prepared in Example 3.

Figure 12 es SEM micrographs of micronized fluticasone materials prepared in Example 3.

Figure 13 provides the water vapor sorption isotherm at 250C for micronized e materials prepared in e 4.

Figure 14 includes SEM micrographs of micronized sucrose materials prepared in Example 4.

Figure 15 provides a graph illustrating the particle size bution of micronized, conditioned sucrose material prepared in Example 4.

Figure 16 illustrates an exemplary plasticization curve, which shows the Tg of a given amorphous al as a function of solvent t.

Figure 17 illustrates an exemplary sorption isotherm, representing the amount of solvent in an amorphous material as a function of the solvent activity at a given temperature.

Figure 18 illustrates an exemplary stability diagram for glycopyrrolate.

Figure 19 is a diagram showing an embodiment of a system disclosed herein configured to tate multiple ioning steps.

Figure 20 is a diagram showing r embodiment of a system disclosed herein configured to facilitate multiple conditioning steps. 2014/029489 DETAILED DESCRIPTION Systems and methods for conditioning particulate crystalline material are described herein. ioning a particulate crystalline material according to the present description generally involves (i) providing a particulate material to be conditioned, (ii) delivering the material to be conditioned to a mixing zone where it is combined with a conditioning gas, (iii) maintaining the material in contact with the conditioning gas within a conditioning zone for a d residence time, (iv) separating the conditioned material from the conditioning gas, and (v) collecting the conditioned material. In carrying out a conditioning s according to the present description, the al to be conditioned is lly entrained or aerosolized within a delivery gas that is blended with the conditioning gas, and the particulate material remains entrained, suspended or aerosolized in the conditioning gas as it travels through the conditioning zone. The nature of the conditioning gas and the residence time of the particulate al within the conditioning zone are lled to accomplish annealing or phase transformation of the material.

In n embodiments, the systems and methods described herein may be adapted for conditioning a single crystalline al. In alternative embodiments, the systems and methods described herein may be adapted to simultaneously ion two or more crystalline materials. For example, where two or more materials are to be ioned simultaneously, the materials may be introduced into a conditioning zone as a blended material or as individual materials delivered via independent material inputs.

Additionally, the systems and methods described herein can be configured and adapted to provide one or more ioning steps. For example, in certain ments, systems and methods may be d to provide a conditioning gas and conditioning zone that subject the particulate material to annealing conditions whereby amorphous material is converted into a more stable crystalline structure, and the amorphous content of the of the crystalline material is measurably reduced or eliminated. In other embodiments, the systems and methods described herein may be adapted to anneal particulate crystalline material by reducing the ce of residual solvent(s). In such embodiments, the systems and methods may be adapted to provide a conditioning gas and conditioning zone that subject the particulate material to annealing conditions y residual solvent within the crystalline al is reduced, removed, or replaced by, for example, vaporization or by solvent exchange. In still other embodiments, the methods and systems described herein can be adapted to both reduce or ate amorphous content and reduce or eliminate the ce of residual t(s). In such embodiments, the different annealing ses may be conducted simultaneously (e.g., using a conditioning gas and conditioning zone that serves to reduce both amorphous content and the presence of one or more solvent within the crystalline material) or sequentially using primary and secondary conditioning environments.

Where the systems and methods described herein are adapted to reduce amorphous content, without being bound by a particular theory, it is presently believed that amorphous material present in the crystalline ulate material oes an amorphous to crystalline phase transformation preceded by the plasticization or zed dissolution followed by llization of the amorphous material. Annealing of particulate material, including micronized material, as described herein works to reduce the amount of amorphous al and preserve the desired particle size distribution of the particulate material by inhibiting fusing, aggregation, and/or agglomeration of the micronized particles as a result of the plasticization or localized dissolution that can occur in unannealed materials. In specific embodiments, the methods described herein provide a reduction in amorphous content relative to itioned material of at least 50%. For example, in such embodiments, the methods described herein provide a reduction in amorphous content ve to itioned material selected from of at least 75% and at least 90%.

The systems and methods described herein are suited to conditioning a wide variety of particulate crystalline materials that include, for example, amorphous material (e.g., particles formed of amorphous material or crystalline les that include one or more regions of amorphous material) and/or residual solvent. For example, the systems and methods described herein are suitable for application to materials exhibiting different al and chemical characteristics (e.g., water soluble als and materials soluble in c solvents), and the methods and systems described herein are applicable to materials prepared for and useful in a wide range of products and processes, including, for e, industrial chemicals and processes, food products and additives, cosmetic ts, nutritional products and formulations, such as ional supplement products, nutraceutical products and formulations, ceutically active agents, and pharmaceutical excipients. In the context of food additives and nutritional products, for example, among many others, the systems and methods described herein may be utilized to improve the physiochemical stability of one or more of the following: ame; cyclamate; rin; stevia; sucralose; amino acids; vitamins; minerals for nutritional supplements; creatine; and ascorbic acid.

Though not limited to such applications, for convenience of description and exemplification, the disclosure and experimental examples provided herein describe the present systems and methods in the context of micronized crystalline materials for use in pharmaceutical products.

Micronization of crystalline active agent and pharmaceutical excipient material is often employed and can be useful in formulation of pharmaceutical compositions for a variety of reasons. For example, for a given active agent or excipient, a crystalline morphology is the most physically and chemically stable morphology, yet it is often beneficial to reduce the particle size bution of crystalline materials to facilitate delivery (e.g., micronization to allow respiratory or pulmonary delivery or to provide improved formulation characteristics, delivery performance, dissolution performance, and/or bioavailability). Where micronized material is utilized, however, ving the physiochemical stability of micronized particulates is also lly important to maintaining the efficacy and shelf-life of pharmaceutical products incorporating such materials. Though they are described in the context of ized pharmaceutical materials, the systems and methods according to the present description can be utilized to condition a variety of crystalline materials ting any le size distribution that allows the al to be entrained, suspended, or aerosolized within a conditioning gas contained within a conditioning zone for a residence time sufficient to anneal the selected material.

Active agents that can be delivered or formulated as a lline material can be processed using the systems and methods described herein.

Systems and methods according to the present description are adaptable to water soluble active agents as well as to active agents soluble in organic solvents. Examples of active agents that may be sed according to the present methods include, but are not limited to, beta agonists, inic antagonists, corticosteroids, PDE4 inhibitors, anti-infectives, diuretics, beta blockers, statins, anti-inflammatories, including non-steroidal nflammatory actives, analgesics, and active agents exhibiting a combination of one or more of the preceding pharmacological effects (e.g., bi- or multifunctional molecules, such as, for example, a bi-functional muscarinic antagonist and beta agonist).

More specific examples of active agents le for processing using the systems and methods described herein include steroids, muscarinic antagonists, R-agonists, and bi-functional compounds ting, for example, muscarinic antagonist and R-agonists activity suited for respiratory or pulmonary delivery. Such actives include, for example, short-acting beta ts, e.g., bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline (isoproterenol), levosalbutamol, orciprenaline (metaproterenol), erol, procaterol, rimiterol, salbutamol (albuterol), terbutaline, terol, reproterol, ipratropium and hrine; long-acting P2 rgic receptor agonist, e.g., bambuterol, clenbuterol, formoterol, and salmeterol; ultra-long-acting P2 rgic receptor agonists, e.g., carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived P2 agonists; osteroids, e.g., beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone; anti-inflammatories, e.g., fluticasone propionate, beclomethasone dipropionate, WO 44894 flunisolide, budesonide, tripedane, cortisone, prednisone, prednisilone, dexamethasone, betamethasone, or triamcinolone acetonide; antitussives, e.g., noscapine; bronchodilators, e.g., ephedrine, adrenaline, fenoterol, formoterol, naline, metaproterenol, salbutamol, albuterol, salmeterol, terbutaline; and muscarinic antagonists, ing cting muscarinic antagonists, e.g., glycopyrronium, dexipirronium, scopolamine, tropicamide, epine, dimenhydrinate, tiotropium, darotropium, aclidinium, trospium, ipatropium, atropine, benzatropin, or oxitropium.

Where appropriate, the active agents conditioned using the systems and methods described herein may be provided as salts (e.g., alkali metal or amine salts or as acid addition salts), esters, solvates (hydrates), derivatives, or a free base. Additionally, the active agents may be in any isomeric form or e of isomeric forms, for example, as pure enantiomers, a mixture of enantiomers, as racemates or as mixtures thereof. In this regard, the form of the active agent may be selected to optimize the ty and/or stability.

The systems and methods described herein are also applicable to excipients, adjuvants, rs, etc. used in pharmaceutical formulations. Such materials can be processed according to the methods described herein either individually or in es suitable for formulation. Though not limited to these specific examples, the systems and methods described herein can be ed to improve the physiochemical stability of sucrose, a-lactose monohydrate, mannitol, citric acid, glucose, maltose, arabinose, xylose, ribose, fructose, mannose, galactose, sorbose, trehalose, sorbitol, xylitiol, maltodextrin, and isomaltol.

Where a micronized crystalline material is conditioned using the methods or systems described herein, the material can be prepared to exhibit a wide range of desired particle size distributions using any suitable micronization technique. In the t of the present description, the term "micronized" refers to materials exhibiting a median size as large as, for e, 500 microns, and "micron ization" ses refer to any suitable process by which a micronized crystalline material is produced. The desired particle size or size distribution of crystalline material conditioned according to the present description will depend on, among other s, the nature of the material and its desired use or application of the material. Techniques suitable for preparing and providing micronized crystalline material include, for e, milling or grinding processes, including wet-milling and jet milling processes, precipitation from supercritical or near-supercritical ts, high pressure homogenization, spray drying, spray freeze drying, or lyophilization. Examples of patent references teaching suitable s for obtaining micronized crystalline particles include, for example, in U.S. Pat. No. 6,063,138, U.S. Pat. No. ,858,410, U.S. Pat. No. 5,851,453, U.S. Pat. No. 5,833,891, U.S. Pat. No. 634, and International Patent Publication No. WO 2007/009164, the contents of each of which are incorporated herein by reference.

Though the median size of a micronized material may be as large as 500 pm, often where a micronized material is , the particle size distribution of the material will be significantly r. For e, in many contexts requiring micronized material, the material will exhibit a median particle size of 100 pm or less. In the t of pharmaceutically active agents or materials prepared for use in pharmaceutical formulations, the median particle size of the micronized material may be below 50 pm or even 10 pm.

Where the micronized material conditioned according to the methods bed herein is an excipient or active agent to be used in a pharmaceutical product for pulmonary delivery, the micronized material is prepared to exhibit a particle size bution that facilitates pulmonary delivery. In such embodiments, for e, the micronized material may exhibit a particle size distribution wherein at least 90% of the active agent particles by volume exhibit an optical diameter of about 10 pm or less. In other such embodiments, the ized material may exhibit a particle size distribution wherein at least 90% of the active agent particles by volume exhibit an optical diameter selected from a range of about pm to about 1 pm, about 9 pm to about 1 pm, about 8 pm to about 1 pm, about 7 pm to about 1 pm, about 5 pm to about 2 pm, and about 3 pm to about 2 pm. In still further embodiments where the micronized material is prepared for use in a pharmaceutical product for pulmonary delivery, the micronized material may exhibit a particle size distribution wherein at least 90% of the active agent particles by volume exhibit an l diameter selected from 10 pm or less, 9 pm or less, 8 pm or less, 7 pm or less, 6 pm or less, 5 pm or less, 4 pm or less, 3 pm or less, 2 pm or less, or 1 pm or less.

It will be readily understood that the embodiments, as generally bed herein, are exemplary. The more detailed description of the systems and methods provided herein is not intended to limit the scope of the present disclosure, but is merely entative of various embodiments.

I. Definitions Unless specifically defined ise, the terms used herein have their normal meaning as understood in the art. The following terms are specifically defined for the sake of y.

The term "active agent" as used herein includes any agent, drug, nd, composition or other substance that may be used on, or administered to a human or animal for any purpose, including any agent, drug, compound, composition or other substance that provides a nutritional, therapeutic, ceutical, pharmacological, diagnostic, cosmetic, prophylactic agents and/or modulating effect. The term "active agent" may be used interchangeably with the terms, "drug," "pharmaceutical," "medicament," "drug substance," "active pharmaceutical ingredient," "pharmaceutically active agent," or "therapeutic." As used herein the "active agent" may also ass natural or homeopathic ts that are not generally considered therapeutic.

The term "annealing" refers to a physiochemical change or phase transformation in a material that results in improved physiochemical stability. In certain embodiments, the term "annealing" refers to a process whereby amorphous content within a crystalline particulate material is reduced or eliminated. In other embodiments, the term "annealing" refers to a process whereby residual solvent contained within a lline particulate material is reduced or eliminated by, for example, solvent vaporization and/or ge. In still further embodiments, the methods and systems described herein may anneal a crystalline ulate material by both reducing amorphous content and reducing the presence of a residual solvent.

The term "conditioning," as used herein, lly refers to methods and processes that may be used to improve the physiochemical stability of a particulate crystalline material. In ic embodiments, the term "conditioning" refers to methods that cause a controlled annealing of the particulate material.

The term "phase transformation" refers to a change in the bulk of the crystals present in a particulate crystalline al. In particular embodiments, annealing of a material using the conditioning systems or methods described herein s in a phase transformation selected from, for example, removal of a solvent of crystallization, replacement of a solvent of crystallization, an amorphous to crystalline phase change, or a change in physical structure beyond just an amorphous to crystalline phase change.

As used herein, "physiochemical" refers to one or both of the physical and chemical stability of a al.

As used herein, the term it" refers to a reduction, prevention, or slowing of any given process, event, or teristic.

When used to refer to the ioned particulate material described herein, the terms "physical stability" and "physically stable" refer to a composition that is resistant to one or more of particle fusing, aggregation, agglomeration, and particle size changes. In certain embodiments, physical ity may be evaluated through exposing the particulate material to accelerated degradation conditions, such as increased temperature and/or ty as described herein.

When referred to herein, the term "optical diameter" indicates the size of a particle as measured using a laser diffraction particle size analyzer equipped with a dry powder dispenser (e.g., Sympatec GmbH, hal Zellerfeld, Germany).

WO 44894 11. Systems for Conditioninq Particulate Crystalline Material Figure 1 es a schematic illustration of an embodiment of a system for ioning particulate crystalline material according to the present description. The system 100 includes a delivery zone 110, wherein one or more crystalline materials (e.g., one or more pharmaceutically active agents or pharmaceutically acceptable excipients or adjuvants) may be red and prepared for mixing with a conditioning gas. The system also includes a conditioning gas supply zone 120. The conditioning gas is ed from the conditioning gas supply zone 120, and in certain embodiments, the conditioning gas is generated within the conditioning gas supply zone 120. The crystalline particulate material and the conditioning gas may be introduced into a mixing zone 130, after which they enter a conditioning zone 140. The conditioning zone 140 includes a controlled atmosphere contained and maintained within a conditioning chamber. The controlled atmosphere includes the conditioning gas and any delivery gas used for ring the crystalline particulate al, and the particulate material being conditioned s entrained, suspended, or lized within the controlled atmosphere within the ioning chamber. The crystalline material undergoes an annealing process within the conditioning zone 140 as it is maintained within the conditioning zone 140 for a d residence time. The micronized material may be separated from the conditioning gas and collected from the conditioning zone 140 in the separation and collection zone 150, which can include any of a number of well-known components suited to the collection of micronized material.

The nature of and extent to which annealing of the particulate material takes place can be controlled by the nce time of the material within the conditioning zone and by the properties of the conditioning gas, including, for example the presence and concentration of one or more solvents, and the temperature, flow rate, and direction or turbulence of flow of the conditioning gas. In some embodiments of the systems disclosed herein, the residence time of the micronized active agent particles in the conditioning zone 2014/029489 140 may be controlled by the geometry of the conditioning zone 140 or by the flow rate of the conditioning gas through the conditioning zone 140.

The material to be conditioned may be ed to the delivery zone 110 in a form that is appropriate for the chosen material and the ioning s. Where a particulate material exhibiting a desired particle size distribution is desired, the material may be prepared to exhibit the targeted particle size distribution prior to introduction into the delivery zone 110. In such an embodiment, the particulate material can be fed from the delivery zone 110 into the mixing zone 130 using any le device or system for controlled feeding of a powder or particulate material at a desired feed rate. Controlled feeding of the particulate material will typically include entraining the particulate material in a dispersion component, such as, for example a delivery gas suitable for dispersion and delivery of the particulate material into the mixing zone 130 and/or the conditioning zone 140.

In certain embodiments, particulate al may be subjected to a micronization process within the delivery zone 110. In such embodiments, the delivery zone 110 may e a device or system that processes the crystalline material to provide a micronized particulate material that exhibits a desired particle size distribution. Where the delivery zone 110 includes a device or system suitable for carrying out micronization of the selected crystalline material, the ry zone 110 may incorporate any one of a number of known devices or systems for micronization. For e, the crystalline material may be micronized in the delivery zone 110 using known milling or grinding processes, known crystallization or recrystallization processes, or known ization ses utilizing precipitation from supercritical or near ritical ts, spray drying, spray freeze drying, or lyophilization.

In embodiments where the delivery zone 110 includes a micronizer, the mixing zone 130 and/or conditioning zone 140 may be operably linked to the micronizer. In such embodiments, the crystalline material may be processed to exhibit the targeted particle size distribution within the delivery zone 110 and, prior to collection, immediately delivered to the mixing zone 130 while the particles remain airborne as they exit from the micronizer. Therefore, the s and methods described herein allow for conditioning of micronized material as a sequential but integrated step in a process of producing and collecting a micronized crystalline material. Such "in-line" or "in-process" conditioning of micronized crystalline material provides the benefits ated with the annealing achieved by the ioning process, while also eliminating the need to conduct a first process for producing micronized (or size comminuted) material followed by a second, separate conditioning process for annealing the micronized al.

The mixing zone 130 illustrated in Figure 1 is shown as separate from the conditioning zone 140. In such an embodiment, the lline material to be conditioned (such as, e.g., micronized material suspended or ned within a delivery gas) and the conditioning gas are delivered to the mixing zone 130 prior to their entry into the conditioning zone 140. The mixing zone 130 can be sized and configured as desired to achieve desired mixing of the particulate material and conditioning gas. In certain embodiments, the mixing zone 130 may include a sion head assembly into which both the particulate material and the conditioning gas are fed and directed into the conditioning zone 140. Alternatively, in other embodiments, the mixing zone 130 may be an area within the conditioning zone 140 where the particulate material and the conditioning gas are delivered into the conditioning zone in a manner that lishes the mixing ed for annealing of the particulate material within the conditioning zone. In such embodiments, the micronized material may be introduced into the ioning zone as a particulate material entrained or aerosolized within a delivery gas, and the conditioning gas may be introduced into the conditioning chamber such that the conditioning gas begins to mix with the ry gas and the micronized material disbursed therein upon entry into the ioning zone 140.

The conditioning zone 140 may be formed within a conditioning chamber, which can be provided by any structure, such as a column, tank, tube, funnel, coil, or the like, suitable for maintaining a controlled atmosphere and receiving the particulate material and conditioning gas. The characteristics of the controlled atmosphere within the conditioning zone 140 can be adjusted to achieve a desired ioning of one or more selected particulate materials.

In particular embodiments, the conditioning gas is red at a specified rate and mixes with the delivery gas at a ed ratio. For example, the conditioning gas may be supplied to the conditioning zone 140 (e.g., through a dispersion head assembly) at a targeted gas flow rate. The gas flow rate will depend on, among other factors, the amount of micronized material being processed and the angle at which the gas is introduced into the conditioning zone 140. In certain embodiments, the conditioning gas is introduced into the conditioning zone 140 at a rate g from about 20 SCFM up to about 500 SCFM, and the delivery gas having the particulate material to be conditioned entrained therein may be supplied at a gas flow rate ranging from about 20 SCFM up to about 75 SCFM. However, depending on the angle at which the conditioning and ry gases are introduced into the conditioning zone 140 and the nature of the material being processed, the gas flow rate of both the ioning gas and the delivery gas may be increased as high as 3,300 SCFM. In other embodiments, the conditioning gas may be supplied at a flow rate of 30 SCFM up to about 100 SCFM and the delivery gas containing the micronized material to be conditioned may be ed at a gas flow rate ranging from about 30 SCFM up to about 60 SCFM. In addition to, or as an alternative to, controlling the rate at which the conditioning gas is introduced into the lled atmosphere, the ratio of the conditioning gas to the delivery gas may be selected to facilitate conditioning of the micronized material. In particular embodiments, the conditioning gas is mixed with the delivery gas at a ratio selected from 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2.0:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3:1, 3.2:1, 3.4:1, 3.6:1, 3.8:1, and 4:1.

The ature of the conditioning gas may also be controlled.

Annealing of particulate material can be icantly affected by temperature.

In certain embodiments, the temperature of the conditioning gas is selected from between about 100 C and 1000 C. In specific examples of such embodiments, the temperature of the conditioning gas may be selected from one of the following ranges, between about 100 C and 700 C, between about 200 C and 500 C, between about 100 C and 500 C, and between about 200 C and 300 C, depending on the nature of the particulate material being processed.

The conditioning gas may also include one or more solvent vapors. In such embodiments, the conditioning gas includes a carrier gas having one or more solvent vapors dispersed therein. The inclusion of a solvent vapor within the conditioning gas can be particularly useful in conditioning processes adapted to reduce or eliminate amorphous content and to conditioning process d to reduce or eliminate the presence of residual solvent(s) by t ge.

Where a solvent is included in the conditioning gas, the solvent will typically be selected according to the material to be conditioned. For example, in embodiments where the material to be conditioned is water soluble, the conditioning gas may include water vapor carried within an inert gas. In certain embodiments, the solvent vapor may be a combination of water and water miscible organic solvents (e.g., alcohols, ketones, esters, etc.) Alternatively, in embodiments where the material to be conditioned is not water e, but exhibits solubility in one or more organic solvents, the t vapor ed in the conditioning gas may simply include an organic solvent vapor, such as an alcohol (e.g., l, methanol, isopropyl alcohol, etc.), ketone (e.g., acetone, methyl ketone, ethyl ketone, etc.), ester (e.g., ethyl e, etc.), tic alcohol (e.g., octanol, etc.), or alkane (e.g., octane, nonane, etc.) vapor, carried within an inert gas. As used herein, "inert" refers to a carrier gas that is non-reactive with the micronized material being conditioned and preferably the t vapor. Examples of inert gases include, t limitation, compressed dry air, nitrogen, inert gas (e.g., argon, helium, etc.), carbon dioxide, and the carrier gas included in the conditioning gas can be selected ing to the solvent vapor or combination of solvent vapors to be used in the conditioning gas or conditioning zone. In embodiments where the conditioning of the particulate al includes solvent exchange, the WO 44894 solvent(s) included in the conditioning gas may be selected to provide improved safety and/or physiochemical stability of the particulate material.

Where a solvent is ed in the conditioning gas, the conditioning gas can be prepared and maintained at a specified temperature or temperature range in order to maintain the solvent as a vapor. As already mentioned, controlling the temperature of the conditioning gas can also serve to facilitate the conditioning process, with the temperature being selected to facilitate a desired level of annealing over a selected residence time.

The relative concentration of solvent vapor included in a conditioning gas can also be ed to accomplish a desired level of conditioning for different material characteristics. For example, the concentration of solvent vapor within the conditioning gas may be adjusted based on the chemical or physical properties of the crystalline material to be processed. In ic embodiments, the relative humidity (RH) or relative saturation (RS) and temperature conditions of the conditioning gas are selected to provide RH or RS and temperature conditions that exceed the glass transition temperature (Tg) of the ous content of the material being processed. For example, for each of the solvents included within the conditioning gas, the vapor pressure of the solvent may be maintained at a vapor pressure of about 0.05 to 0.95 of the saturation vapor pressure for the solvent.

Crystallization of an amorphous phase typically occurs rapidly when the amorphous material is exposed to conditions that exceed its glass transition temperature, usually twenty degrees Celsius above the glass transition temperature (Lechuga-Ballesteros, D.; Miller, D. P.; Zhang, J., Residual water in ous solids, measurement and effects on stability. In Progress in Amorphous Food and ceutical Systems, , H., Ed.

The Royal Society of Chemistry: London, 2002; pp 275-316). re of amorphous material to temperature in excess of the glass transition can be ed in the absence of any solvent by exposing the amorphous al to a stream of hot air above its glass tion temperature. However, the glass tion temperature is also a on of the on of t present in the amorphous material, an effect known as cization. Plasticization is typically ented by a plasticization curve, such as the one shown in Figure 16, which shows the Tg of a given amorphous material as a on of solvent (in this case water) content.

In addition, the solvent content held in an amorphous material is a function of the vapor concentration of the solvent surrounding the amorphous solid. This can be illustrated by the sorption isotherm provided in Figure 17.

The sorption isotherm of a given material is a representation of the amount of solvent in the amorphous material as a function of the solvent activity (which is proportional to the solvent vapor pressure to saturation solvent vapor pressure ratio) at a given temperature.

The glass transition plasticization curve and the sorption isotherm can be ed to construct a stability diagram as the one shown in Figure 18 for the selected al. The stability diagram shown in Figure 18 is one created for glycopyrrolate. The stability diagram can be used to choose operational conditions for the systems and methods bed herein that promote fast annealing of the crystalline material selected for conditioning. For example, as is illustrated in Figure 18, in the case of glycopyrrolate fast llization of amorphous material will occur at RH>50% in the range of 20 400C, and at 600C it would only require 10%RH to promote annealing.

The nature and extent of annealing that takes place within the conditioning zone can also be adjusted by altering the residence time of the particulate material within the conditioning zone 140. The residence time is the average time particulate material spends within the conditioning zone 140. The residence time of the particulate material within the conditioning zone 140 can be adjusted by changes to one or more of a variety of process variables. For example, the volume and dimensions of the conditioning chamber can be altered, to provide longer or shorter residence times, with, for example, vely higher volume or larger physical dimensions generally resulting in relatively longer residence times. The flow rates and temperatures of one or both of the conditioning gas and the ry gas can also be adjusted to affect residence time. In addition, the manner by which the conditioning gas or delivery gas is introduced into the conditioning chamber can affect le residence time. As an example, introduction of the conditioning gas and/or delivery gas in a manner that creates a generally linear flow through the conditioning chamber may create a relatively shorter residence time compared to introduction of the same gas(es) in a manner that s a more turbulent recirculating sion of the gas(es).

In general, the residence time of the particulate material within the conditioning chamber can be selected from about 0.5 seconds to several minutes. In particular embodiments, the residence time may be up to about 10 minutes or 600 seconds. In particular embodiments, the residence time may be selected from about 0.5 to about 10 seconds, 0.5 to about 20 seconds, 0.5 to about 30 seconds, 0.5 to about 40 seconds, and 0.5 to about 50 s. In certain such embodiments, the particulate al may be conditioned by the conditioning gas for a residence time selected from about 0.5 seconds, 1 second, 1.5 seconds, 2 seconds, 2.5 seconds, 3 seconds, 3.5 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 s, 9 seconds, and 10 seconds.

After the particulate material has been annealed in the ioning zone 140, the conditioned al is separated from the conditioning gas and collected in the separation and collection zone 150. The ized material may be separated and collected from the conditioning gas using known particle collection techniques and equipment. In certain embodiments of the systems disclosed herein, the micronized material may continue to anneal while in the separation and collection zone 150. The collection zone 150 can be formed by or include a cyclone collector. Cyclone collectors for collection of particulate als, including micronized materials, and separation of such materials from a conditioning gas. e collectors are commercially available and suitable for use as the collection zone 150 of the systems described herein. 2014/029489 In addition to a collection device, such as a cyclone tor, the collection zone 150 may be configured to facilitate direct collection of the processed al. Where a collection zone 150 is configured to allow direct collection of the conditioned material, the collector included in the collection zone may simply deliver the conditioned product to a container from which the conditioned material can be collected or removed. Such a container may include a tion bag that can be removed from the collection device, as is often used in conjunction with a cyclone collector. The collection bag may be sealable and formed using a material that enables efficient collection of the conditioned material, while also being permeable to a gas used in the collection system. In another embodiment, the collector ed in the tion zone 150 may be configured as a holding chamber. In such an embodiment, the collector, such as a cyclone collector, may be used to separate the conditioned material from a conditioning gas and collect the conditioned material into a holding chamber where the ioned material can be maintained in a fluidized state for a desired period of time. Annealing of the crystalline material processed according to the present description is not always complete as the material exits the conditioning zone 140, and may continue as the material is collected. ing on the material being processed and the annealing conditions, it may be beneficial to maintain the conditioned material in a fluidized state within a collection chamber for a period of time sufficient to allow additional progress of the annealing process.

In still other embodiments, the collection zone 150 may be ured to allow further sing of the conditioned material. In such embodiments, the collection zone 150 may be operably linked to one or more additional systems, including an additional conditioning system as described herein, for further sing of the conditioned material. In such embodiments, the tor ed in the collection zone 150 may be configured to deliver the conditioned material directly for continued processing or the collection zone 150 may be configured to e or be in operable communication with a holding chamber as described and illustrated herein, WO 44894 such as, for e, in association with the systems illustrated in Figure 19 and Figure 20.

In some embodiments, the systems and methods described herein may be utilized to simultaneously process and condition more than one particulate material. For e, two or more micronized materials may be simultaneously introduced into a conditioning zone. The materials may be combined prior to introduction into the conditioning zone or they may be introduced independently into the conditioning zone. In some embodiments, the materials may be combined prior to micronization and introduced into the ioning zone as a particulate material including a combination of two or more chemical es. Even further, where two or more different particulate materials are introduced into the conditioning zone (whether as a combined product stream or as two or more independently introduced materials), the materials may exhibit similar lity characteristics (e.g., each of the different materials t solubility in water or each of the materials exhibit solubility in a given c solvent). However, the methods described herein are also suited to simultaneously conditioning two or more materials in the same conditioning zone where at least two of the two or more different materials t different solubility characteristics (e.g., at least one is water soluble, while another is soluble only in an organic solvent, or one is soluble in a first organic solvent, while a second is soluble in a second organic solvent).

Certain embodiments of a system for the in-process conditioning of a micronized material according to the present description can be represented by the system illustrated in Figure 2. Because the delivery zone of the system illustrated in Figure 2 includes a device configured for the micronization of the al to be ioned, the ry zone of the system will be referred to as a micronizing zone 210. As shown in Figure 2, the micronizing zone 210 may be configured to deliver aerosolized micronized particles directly into a mixing zone 230. In specific embodiments, the micronization zone 210 includes a jet mill 213 and the crystalline material 211 to be micronized is delivered to the jet mill 213 using a standard feeder 212.

After micronization, the micronized material 235 may be delivered through an outlet 214 as aerosolized particles d by a delivery gas 216 and supplied to the mixing zone 230.

The micronized crystalline material is ed to the mixing zone 230 as a micronized material with a d le size distribution. In certain embodiments, for example, at least 90% of the micronized particles by volume exhibit an optical diameter of about 10 pm or less. In other embodiments, at least 90% of the micronized crystalline particles by volume exhibit an optical diameter selected from a range of about 10 pm to about 1 pm, about 9 pm to about 1 pm, about 8 pm to about 1 pm, about 7 pm to about 1 pm, about 5 pm to about 2 pm, and about 3 pm to about 2 pm. In further embodiments, at least 90% of the micronized crystalline particles by volume t an optical diameter selected from 10 pm or less, 9 pm or less, 8 pm or less, 7 pm or less, 6 pm or less, 5 pm or less, 4 pm or less, 3 pm or less, 2 pm or less, or 1 pm or less.

The micronizing zone 210 may be separated from an external environment or contained within a safety barrier or ure (not shown).

Such a design can be particularly advantageous where the micronized material is an active agent or is otherwise biologically active. The safety barrier may be used in order to prevent unwanted contact with any ized material produced in the micronizing zone 210. Where included in the systems described herein, a safety r may be constructed of any suitable material such as metal, glass, plastic, composites, etc., that are sufficient to contain micronized particles.

With nce to Figure 2, in particular embodiments, the conditioning gas 226 utilized in an in-line conditioning system may be prepared within the conditioning gas supply zone 220. For example, the conditioning gas supply zone 220 may include a heating chamber 221 to which a carrier gas 222 may be provided for heating to a desired temperature. In one such embodiment, the g chamber 221 comprises a heat source, such as an ic heater or furnace, for heating the carrier gas 222. The carrier gas 222 provided for use in the systems disclosed herein may comprise one or more gases suitable for the methods described herein for conditioning a given micronized crystalline material. For example, the carrier gas 222 may comprise one or more inert gasses or atmospheric gasses such as those described herein, ing, for example, compressed air, nitrogen, oxygen, and helium.

The conditioning gas supply zone 220 may further comprise a liquid evaporation chamber 225. The t used to produce the solvent vapor disbursed within the r gas 222 can be ted within or provided from the evaporation chamber 225, and the evaporation chamber can be configured to provide the carrier gas 222 with a desired concentration of solvent vapor within the conditioning gas 226. Where the micronized crystalline material is water soluble, the solvent can be an aqueous solvent, such as purified or distilled water, and in such embodiments, the evaporation chamber 225 is configured to create a conditioning gas 226 having a d relative humidity.

In other embodiments, particularly where the micronized crystalline material to be conditioned is not water soluble, the solvent for use with the s disclosed herein may be a non-aqueous liquid, such as an organic solvent described herein.

A liquid atomizer 223 may be used to deliver liquid solvent to the carrier gas 222 in the form of atomized liquid droplets 224 suspended within the carrier gas 222. Atomization of the liquid solvent facilitates conversion of the liquid solvent into a solvent vapor within the evaporation chamber 225. In more specific embodiments, a liquid er used in the systems described herein provides control over the size of the atomized droplets delivered to the carrier gas 222 as well as the rate and volume of liquid solvent atomized. Where used, a liquid er 223 can be selected from, for example, pressure nozzles, tic atomizers, impinging jet atomizers. In one such embodiment, the r gas 222 is heated in the heating chamber 221, a liquid atomizer 223 delivers liquid t to the carrier gas within the conditioning gas supply zone 220, and the carrier gas 222 and atomized liquid solvent 224 are ed to the liquid evaporation chamber 225. As the carrier gas 222 and WO 44894 2014/029489 atomized liquid t 224 pass through the liquid evaporation r, the liquid solvent vaporizes and the carrier gas becomes a conditioning gas 226 having a desired solvent vapor concentration.

In certain embodiments, where the solvent vapor is formed from an aqueous solvent, the conditioning gas 226 may be supplied at a temperature ranging from about 20 0C to about 100 0C, and with a relative humidity ranging from about 0.05% to about 75%. In more specific embodiments where the solvent used to form the solvent vapor is an aqueous solvent, the conditioning gas 226 may be supplied having a temperature selected from at least about 20 C, 21 C, 22 C, 23 C, 24 C, 25 C, 26 C, 27 C, 28 C, 29 C, and 30 0C and having a relative humidity selected from at least about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74% and 75%. In particular ments, r, the temperature may be as high as 22 0C and the relative humidity as low as 0.05%.

With continued reference to Figure 2, the mixing zone 230 is configured to mix incoming micronized crystalline material 235 with the conditioning gas 226. In particular ments, the mixing zone 230 is configured to mix a delivery gas flow 216 with a conditioning gas 226. In some embodiments of the s disclosed herein for in-process conditioning of micronized active agents, the mixing zone 230 may comprise a dispersion head assembly configured to mix the delivery gas 216 with the conditioning gas 226.

With reference to Figures 3A, 3B, and 3C, a dispersion head ly 330 suitable for use in the systems described herein may include a g 335 and a mixing head 340, wherein a conditioning gas 326 and a delivery gas 316 may be mixed. The housing 335 comprises a conditioning gas inlet 324 and a gas outlet 325, wherein the conditioning gas 326 may be supplied to the dispersion head assembly 330 through the conditioning gas inlet 324. As shown in Figure 3C, the conditioning gas 326 may be delivered to the mixing head 340 where it can enter an injection nozzle 345 through an injection inlet 342. The mixing head 340 may also comprise a delivery gas inlet 350 through which the delivery gas 316, having the micronized material entrained therein, may enter the injection nozzle 345. As the delivery gas 316 and the conditioning gas 326 enter the injection nozzle 345 they are mixed together thereby ng the micronized crystalline material to the conditioning gas 326.

Where a mixing head is ed in a system according to the present description, as shown in Figure 3, the mixing head may be able and hangeable such that the mixing head 340 may be removed from the dispersion head assembly 330 and modified or exchanged for a different mixing head. The design of the mixing head 340, such as the size, shape, number, and location of one or more injection nozzle inlets 342, may be modified and ed to control the mixing dynamics, volume, and/or rate at which the delivery gas and conditioning gas exit the mixing head 340 and are delivered to the conditioning zone 240. In specific embodiments, the design of the mixing head 340, including the size, shape, and location of the delivery gas inlet 350, may be ed and adjusted to control the mixing cs and the volume and/or rate of mixed gases that exit the mixing head 340.

In certain embodiments, the dispersion head assembly and/or mixing head may be configured to mix the conditioning gas and the micronized crystalline material upon entry into the conditioning zone 240. Alternatively, the dispersion head assembly and/or mixing head may be configured to mix the conditioning gas and micronized crystalline material before the e leaves the mixing zone 230 and is delivered to the conditioning zone 240. For example, Figures 4A and 4B provide further embodiments of ent mixing heads that may be used in the systems described herein. Figure 4A shows mixing head 420 comprising delivery gas inlet 450 and injection nozzle inlet 425 located near the base of the injection nozzle 445. Figure 4B shows a mixing head 430 comprising a delivery gas inlet 450 and ion nozzle inlet 435 located near the edge of the injection nozzle 445. In further embodiments, the mixing heads disclosed herein may include one or more injection nozzle inlets located at desired positions within or around the injection nozzle 445. In other embodiments, the conditioning gas and the micronized crystalline material may WO 44894 be mixed in the injection nozzle 445 before the mixture leaves the mixing zone 230 and is delivered to the conditioning zone 240.

The systems disclosed herein can include a mixing zone 230 configured to mix the conditioning gas 226 with the delivery gas 216 in a desired ratio, such as a ratio of gas volumes (volume/volume) or a mass flow rate ratio (SCFM/SCFM). For example, in particular ments, the mixing zone, including, for example, a dispersion head assembly, may be configured to mix the conditioning gas 226 and delivery gas 216 in a ratio of about 1 to 4 parts conditioning gas 226 with about 1 part of the delivery gas 216. In certain such embodiments, the conditioning gas 226 may be mixed with the ry gas 216 in a ratio selected from any of about 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2.0:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3:1, 3.2:1, 3.4:1, 3.6:1, 3.8:1, and 4:1.

With ued reference to Figure 2, the conditioning zone 240 (also referred to herein as a "conditioning chamber") included in the systems described herein is configured to contain and maintain a controlled atmosphere tailored to the conditioning of a desired ized material and to receive the delivery gas 216 and conditioning gas 226 from the mixing zone 230. As noted above, in some embodiments, the conditioning chamber 240 and mixing zone 230 may be provided as separate subsystems placed in fluid communication one with r. atively, the mixing zone 230 and ioning chamber 240 may be integrated such that two different subsystems are not required.

Where, provided as separate subsystems, the mixing zone 230 and conditioning chamber 240 are configured such that the mixed delivery gas 216 and conditioning gas 226 are delivered into the conditioning chamber 240 from the mixing zone 230.

In certain ments, after the conditioning gas 226 and the delivery gas 216, comprising micronized active agent particles, are mixed together in the mixing zone 230, the micronized les 235 enter the conditioning chamber 240 together with the conditioning gas 226. While in the conditioning chamber 240, the micronized particles 235 are exposed for a desired time period to the conditioning gas 226, and during their residence time 2014/029489 within the ioning chamber 240, the amorphous material included in the micronized particles 235 anneals. The residence time of the micronized particles 235 in the conditioning chamber 240 may be controlled by one or more of the following: the dimension and geometry of the conditioning r 240; the rate at which the mixture of the conditioning gas 226 and the delivery gas 216 are delivered into the conditioning chamber 240; the flow pattern of the mixture of the conditioning gas 226 and the delivery gas 216 within the conditioning chamber 240; the amount of micronized material carried by the e of delivery gas 216 and conditioning gas 226; and the system used for collection of the conditioned micronized material. In particular embodiments, the residence time of the micronized active agent particles 235 within the conditioning chamber 240 may be for a period of time ranging from about 0.5 to seconds. In certain such embodiments, the nce time of the ized particles 235 within the conditioning chamber 240 may be selected from one the nce times detailed herein.

A conditioning chamber 240 suitable for use in the systems described may be configured as for e, a tank, a column, a funnel, a tube, or other appropriate s or structures. In further ments, the conditioning chamber 240 may further include heaters, inlets, outlets, and other means and devices for controlling the conditions and gas flow within the conditioning chamber 240. The geometry of the ioning chamber 240 may be modified by adjusting, for example, the length, width, height, volume, and shape of the conditioning chamber 240.

Conditioned micronized active agent particles 246 are separated from the ioning gas 226 in a separating zone 250. The separating zone 250 may comprise elements or devices designed to separate ioned micronized active agent particles 246 from the carrier gas 216 and conditioning gas 226, such as, for example, a cyclone separator, bag collector or other separation equipment, as known by those of skill in the art. In particular embodiments, the separating zone 250 may comprise an exhaust outlet 255 whereby, for example, the exhaust gas and other materials may exit from the separating zone 250. Though micronized material will have been conditioned within the conditioning zone 240, in certain embodiments, the process of annealing is does not end immediately upon collection of the micronized material from the ioning zone 240. For example, in n embodiments, although the controlled atmosphere of the conditioning zone 240 initiates or even substantially tes the annealing process, annealing of amorphous material continues as the ized material exits the conditioning zone 240 and is separated and collected. In addition to a system or device of separating the conditioned micronized material from the delivery and conditioning gases, the separating zone 250 may further included one or more filters and collectors.

Filters may be placed, for example, at the exhaust outlet 255 to e or prevent unwanted escape of fines. Additionally, a collector 260 is included within the separating zone 250 to facilitate capture and containment of the conditioned material. Once collected the, conditioned crystalline material can be stored or further processed, as d.

Though Figure 1 and Figure 2 illustrate conditioning systems having a single conditioning zone, s according to the present description may also e multiple conditioning zones. In such embodiments, the different conditioning zones may expose the crystalline particulate al to different annealing conditions. Such s, therefore, can be configured to provide multiple in-process conditioning steps. Figure 19 and Figure 20 provide schematic illustrations of two embodiments of conditioning systems that e two conditioning zones, thereby facilitating multiple annealing steps within a single system.

As shown in Figure 19, a conditioning system 600 as described herein may include a ry zone 610, a conditioning gas supply zone 620, a mixing zone 630, a conditioning zone 640, and a collection zone 650, as described herein. In addition, the system may include a product holding chamber 660 that is separated from the collection zone 650 by, for example, a cut-off valve 670. In such an embodiment, the ioning system can be configured as described in relation to the systems illustrated in Figure 1 and Figure 2, and the system can be adapted for annealing a wide range of materials using any suitable process conditions described herein. As conditioned product is collected in the collection zone 650, the cut-off valve 670 remains open and conditioned t is delivered to the product holding chamber 660. The product holding chamber 660 can be configured to maintain the conditioning product in a uously fluidized state. The cut-off valve 670 can be any valve mechanism suited to use in this context, that can be cycled between open and closed states, and when closed provides a physical barrier capable of separating the ioned material from collection zone 650. In certain embodiments, the cut-off valve 670 seals the product holding r 660 from the collection zone 650 such that, once closed, the conditioned product will not regress into the collection zone 650 and process gases (e.g., delivery gas or conditioning gas) do not pass between the collection zone 650 and the product holding chamber 660.

Once delivered to the product g chamber 660, the conditioned product may be maintained in a fluidized state and the cut-off valve 670 closed. At that point, the system can re-equilibrate to supply a ary conditioning gas. In such an embodiment, the upstream components of the conditioning system 600 (e.g., the delivery zone 610, ioning gas supply zone 620, mixing zone 630, conditioning zone 640, and collection zone 650) may be purged of the primary conditioning gas used to condition the material present in the product g r 660, and a secondary conditioning gas can be supplied from and/or generated in the gas supply zone 620. Once the system is re-equilibrated with the secondary conditioning gas, the cut-off valve 670 may be opened to expose the conditioned product contained within the product holding chamber 660 to the secondary ioning gas. The product can be maintained in a continuously fluidized state within the product holding r 660 as it is exposed to the secondary conditioning gas for a period of time sufficient to accomplish a secondary annealing. The nature and content of the secondary conditioning gas, including the ce and concentration of one or more solvents, and the temperature, flow rate, and direction or turbulence of flow of the secondary ioning gas may be adjusted to accomplish a desired secondary annealing for a wide range of selected materials using process conditions bed . By adjusting the characteristics of the ary conditioning gas and the residence time of the particulate material within the product holding chamber 660, the system illustrated in Figure 19 can be utilized to provide multiple conditioning steps using a single system.

The residence time of the conditioned t within the holding chamber 660 can be easily adjusted based on the al itself, the conditioning gas(es), and the nature or extent of annealing desired. For example, as is true of particles conditioned within a conditioning zone, the residence time of a conditioned product within a holding chamber 660 may be a matter of seconds or minutes. For example the residence time of the conditioned material within the holding chamber 660 may be selected from those residence times detailed above in relation to the conditioning zone.

However, the conditioned product can also be maintained within the holding chamber 660 indefinitely. In certain embodiments, the conditioned product is maintained within a holding chamber 660 for a time selected from up to 5 minutes, up to 10 minutes, up to 30 minutes, up to 1 hour, up to 1.5 hours, up to 2 hours, up to 5 hours, up to 10 hours, up to 12 hours, up to 18 hours, and up to 24 hours. Such ility enables the conditioned product to be exposed to a secondary conditioning gas for any amount of time needed to accomplish secondary conditioning. A relatively longer residence time affords exposure to a secondary conditioning gas over a long period of time and may be particularly useful for a secondary conditioning process that requires more time than might be practically achieved within a given system's conditioning zone.

Figure 20 illustrates a conditioning system 700 that es two ioning tems, a primary conditioning system 701 and secondary conditioning system 801. The primary conditioning system 701, includes a ry zone 710, a primary conditioning gas supply zone 720, a primary mixing zone 730, a primary conditioning zone 740, and a y collection zone 750. The primary conditioning system 701 and the secondary conditioning system 801 may be separated by, for example, a y holding chamber 760 and one or more cut-off valve 770 (only a single cut-off valve is shown). The primary holding chamber 760 may be configured for maintaining ioned product received from the primary conditioning system 701 in a continuously fluidized state, and the cut-off valve 770 can be any valve mechanism suited to use in this context, that can be cycled between open and closed states, and when closed es a physical barrier capable of isolating the y and secondary conditioning systems 701, 801. In n embodiments, the cut-off valve 770 seals the primary holding chamber 760 from the secondary conditioning system 801 such that, when closed, product collected from the primary conditioning system 701 will not pass into the secondary conditioning system 801, material transferred to the secondary conditioning system 801 will not regress into the primary conditioning system 701, and process gases (e.g., ry gas or conditioning gas) do not pass between the primary and secondary conditioning systems 701, 801. In some embodiments, a second cut-off valve (not shown) can be positioned between the primary holding r 760 and the primary collection zone 750. Such a configuration may be particularly advantageous where communication of process gases between the primary and secondary conditioning systems 701, 801 must be minimized.

As shown in Figure 20, the secondary conditioning system 801 may include a secondary conditioning gas supply zone 820, a secondary mixing zone 830, a secondary conditioning zone 840, and a secondary collection zone 850. In the embodiment illustrated in Figure 20, the primary and secondary conditioning systems 701, 801 can be configured as described in relation to the systems illustrated in Figure 1 and Figure 2, and the systems can be adapted for conditioning a wide range of materials using any process conditions described .

As al is processed in the y conditioning system 701 a primary annealing of the material takes place and the primary annealed material is collected in the primary collection zone 750 and red to the primary holding chamber 760. While the product is processed in the primary conditioning system 701 and collected in the y holding chamber 760, the cut-off valve 770 will typically remain closed. Once the first conditioning process is complete and the primary annealed al is collected in the primary holding r 760, the cut-off valve 770 may be opened and the primary ed material delivered into the secondary mixing zone 830. The primary annealed material may be dispersed within a delivery gas as it is delivered to or within the secondary mixing zone 830. The delivery gas can be any suitable delivery gas as described herein, and by dispersing the primary annealed product in a delivery gas, the primary annealed product is suspended or entrained within the delivery gas. A secondary ioning gas is delivered and/or generated within the secondary conditioning gas supply zone 820, and the secondary conditioning gas is mixed with the primary annealed product (and any delivery gas used to se the primary annealed product) in the secondary mixing zone 830.

The primary annealed product remains entrained, suspended or aerosolized in the secondary conditioning gas within the secondary ioning zone 840. The primary ed product is maintained within the secondary conditioning zone 840 for a period of time sufficient to accomplish a secondary annealing. As is true of the conditioning gas utilized in each embodiment of the systems bed herein, the nature and content of the secondary conditioning gas, ing the ce and concentration of one or more ts, and the temperature, flow rate, and direction or turbulence of flow of the secondary conditioning gas may be adjusted to accomplish a desired secondary ing for a wide range of selected materials using process conditions described herein. By adjusting the characteristics of the secondary conditioning gas and the residence time of the particulate material within the secondary conditioning zone 840, the system illustrated in Figure 20 can be utilized to provide multiple conditioning steps using a single system.

Though bed in relation to embodiments illustrated in the figures provided herein, conditioning systems according to the present ption are not limited to the ic, illustrated embodiments. The systems for conditioning crystalline particulate materials bed herein are scalable and adaptable for areas of various size. In particular embodiments, the s disclosed herein may be scaled-up or scaled-down with regard to, for example, gas flow rates, active agent mass, material output, desired particle residence time, etc., ing the desired output rate and the ble space and equipment. In certain embodiments, the systems disclosed herein may be assembled as a modular unit and incorporated or built into established processes and systems for the manufacture of conditioned particulate material, and are uited for efficient production of conditioned, micronized particulates. For example, the systems as disclosed here may be incorporated into commercial milling and micronization ses or a built into a spray drying system. In further embodiments, the systems described herein may be operated as part of a batch process where one or more micronized materials are conditioned and then collected in separate batches. In alternative ments, the systems described herein may be operated as part of a continuous feed process whereby one or more micronized materials are continuously delivered to the system and continuously conditioned and collected.

III. Methods for conditioning ulate crystalline material Methods for conditioning particulate crystalline al are also provided herein. Methods according to the present description can be carried out using the conditioning systems provided . In general, the methods described herein include: (1) generating and/or providing a lline particulate material; (2) introducing the particulate material in an atmosphere where it is blended with a conditioning gas; (3) maintaining the particulate material in contact with the conditioning gas for a desired residence time; and (4) collecting the conditioned particulate material. In specific embodiments, the particulate material is a micronized crystalline material. Examples of materials that may be conditioned using the methods described herein include those materials already described. In particular embodiments of methods according to the present description, the material to be conditioned is lly entrained or aerosolized within a delivery gas that is blended with the conditioning gas, and the particulate material remains entrained, suspended or aerosolized in the conditioning gas as it travels through the conditioning zone. The nature of the conditioning gas and the residence time of the ulate material within the ioning zone are controlled to accomplish annealing of the material.

In specific embodiments, the methods include a continuous process for micronizing, conditioning, and collecting a crystalline material. In such embodiments, generating the crystalline al includes subjecting the al to a micronization s and conditioning of the micronized material may be conducted in-line with particle collection. Where, the methods described herein provide in-line or in-process ioning of micronized material (or, more generally, any size comminuted material), the particulate material may be blended with a ioning gas and retained within a conditioning zone to anneal the particulate prior to particle collection.

In other embodiments, methods according to the present description include primary and secondary conditioning steps. In such embodiments, the crystalline particulate al can be introduced into (e.g., entrained, suspended, or aerosolized within) a first conditioning gas to carry out a primary annealing and subsequently uced into (e.g., entrained, suspended, or aerosolized within)a second conditioning gas to carry out a secondary annealing. Alternatively, for certain materials, a conditioning gas may be selected that provides substantially simultaneous primary and secondary annealing of the particulate material. For example, in methods where primary and secondary ing are d out using a single ioning gas, the conditioning gas may anneal the ulate material through both reduction of amorphous content and removal of an undesired al solvent by vaporization or t replacement.

The methods provided can be tailored to ic materials to be sed. For example, glycopyrronium is an active agent that can be conditioning using the systems and methods described herein. Micronization of crystalline glycopyrronium can lead to a micronized material that includes significant amorphous content, and in ular embodiments, the present methods can be adapted to reduce or eliminate amorphous material from crystalline glycopyrronium particulates. Glycopyrronium conditioned according to the present description may be in any crystalline form, isomeric form or mixture of isomeric forms. In this regard, the form of glycopyrronium may be selected to optimize the activity and/or stability of glycopyrronium. Where appropriate, glycopyrronium may be provided as a salt (e.g. alkali metal or amine salts, or as acid addition salts), esters or solvate (hydrates). Suitable counter ions include, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, e, tartrate, , maleate, succinate, te, p chlorobenzoate, diphenyl-acetate or triphenylacetate, o-hydroxybenzoate, p hydroxybenzoate, oxynaphthalenecarboxylate, 3-hydroxynaphthalene 2-carboxylate, methanesulfonate and benzenesulfonate. In particular embodiments of the methods described , the bromide salt of glycopyrronium is used, namely yclopentylhydroxyphenylacetyl)oxy]-1, 1 dimethyl-, bromide). The bromide salt of glycopyrronium is commonly referred to as glycopyrrolate. Glycopyrrolate is commercially available and can be prepared according to the procedures set out in U.S. Pat. No. 2,956,062, the contents of which are incorporated herein by reference.

Where crystalline glycopyrronium, such as crystalline glycopyrrolate, is the material sed by the methods described herein, the glycopyrronium material can be ized to exhibit particle size teristics as described herein, such as, for example, a particle size distribution le for ary delivery. Moreover, the micronized glycopyrronium can be prepared and provided using any suitable micronization technique and delivered into the conditioning chamber via a delivery gas suitable to the chosen micronization technique. In one such ment, the glycopyrronium is ized via a jet mill and the delivery gas may be typical gas flow exiting the jet mill, which would include aerosolized, micronized particles of glycopyrronium.

In specific embodiments, the bromide salt of glycopyrronium (glycopyrrolate) may be sed according to the present methods. Where glycopyrrolate is the material being conditioned, a conditioning gas may be mixed with a delivery gas (e.g., a jet mill gas flow) in a ratio of about 1 to 4 parts conditioning gas flow with about 1 part of the delivery gas. In certain such embodiments, the conditioning gas flow may be mixed with the jet mill gas flow in a ratio selected from about 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2.0:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3:1, 3.2:1, 3.4:1, 3.6:1, 3.8:1, and 4:1. In specific embodiments, the conditioning gas may be supplied at a gas flow rate ranging from about 150 SCFM up to about 500 SCFM, and the delivery gas may be supplied at a gas flow rate of g from about 20 SCFM up to about 75 SCFM. However, in some embodiments, depending on the desired conditions for the conditioning zone and the nature of the material being processed, the gas flow rate of both the conditioning gas and the delivery gas may be increased as high as 3,300 SCFM.

When conditioning glycopyrrolate, the conditioning gas may be delivered at a temperature ranging from about 20 0C to about 30 0C and include water vapor as a t. In particular embodiments of methods for conditioning yrrolate, the temperature of the conditioning gas may be selected from at least 20 0C, 21 C, 22 C, 23 C, 24 C, 25 C, 26 C, 27 C, 28 C, 29 C, and 30 C. Moreover, where ed in the conditioning gas for ing glycopyrrolate ing to the methods described herein, water vapor may be provided at a concentration that results in a relative humidity ranging from about 50% to about 80%. In particular embodiments of methods for conditioning glycopyrrolate, the conditioning gas may be supplied at a temperature described herein with a relative humidity selected from at least about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74% and 75%. At the temperatures and relative humidity described herein, the residence time of the ized glycopyrrolate material within the conditioning chamber may be from about 0.5 to about 10 seconds. In certain such embodiments, the micronized glycopyrrolate material is present within the conditioning chamber for a residence time selected from about 0.5 seconds, about 1 second, about 1.5 seconds, about 2 seconds, about 2.5 seconds, about 3 seconds, about 3.5 seconds, about 4 s, about 5 seconds, about 6 seconds, about 7 seconds, about 8 seconds, about 9 seconds, and about 10 seconds.

However, the residence time can be ed as needed to achieve the desired reduction of ous content.

In other embodiments, the s provided can be tailored to for the annealing of materials soluble in organic solvents. For example, the methods bed herein can be tailored to the conditioning of corticosteroid active agents soluble in organic solvents. In certain such embodiments, the methods bed herein can be tailored for the conditioning of a corticosteroid selected from fluticasone and budesonide. Fluticasone, pharmaceutically acceptable salts of fluticasone, such as fluticasone propionate, and preparation of such materials are known, and described, for e, in U.S. Patent Nos. 4,335,121, 4,187,301, and U.S. Patent Publication No. US2008/125407, the contents of which are incorporated herein by reference. Budesonide is also well known and described, for example, in U.S. Patent No. 3,929,768, the contents of which are incorporated herein by reference.

Micronization of crystalline osteroids, such as budesonide and fluticasone, can lead to a micronized material that includes significant amorphous content, and in particular ments, the present methods can be adapted to reduce or eliminate amorphous material from particulate crystalline osteroid material. A corticosteroid conditioned according to the present description may be in any crystalline form, isomeric form or mixture of isomeric forms. In this regard, the form of the corticosteroid may be selected to optimize the activity and/or stability of corticosteroid. Where appropriate, the corticosteroid may be provided as a salt (e.g. alkali metal or amine salts, or as acid addition salts), esters or e (hydrates).

Where a crystalline corticosteroid material, such as crystalline fluticasone or budesonide, is the material processed by the methods described herein, the corticosteroid material can be micronized to exhibit particle size characteristics as described herein, such as a particle size distribution suitable for pulmonary delivery. Moreover, the micronized osteroid can be prepared and provided using any suitable micronization technique and delivered into the conditioning chamber via a delivery gas suitable to the chosen micronization technique. In one such embodiment, the selected corticosteroid is ized via a jet mill and the delivery gas may be l gas flow exiting the jet mill, which would include lized, micronized particles of the osteroid.

In ic embodiments, the osteroid to be processed according to the present methods is selected from fluticasone propionate and budesonide. In such embodiments, a conditioning gas may be mixed with a delivery gas (e.g., a jet mill gas flow) in a ratio of about 1 to 4 parts conditioning gas flow with about 1 part of the delivery gas. In certain such embodiments, the conditioning gas flow may be mixed with the jet mill gas flow in a ratio selected from about 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2.0:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3:1, 3.2:1, 3.4:1, 3.6:1, 3.8:1, and 4:1. In specific embodiments, the conditioning gas may be supplied at a gas flow rate ranging from about 150 SCFM up to about 500 SCFM and the delivery gas may be supplied at a gas flow rate of ranging from about 20 SCFM up to about 75 SCFM. However, in some embodiments, depending on the desired conditions for the conditioning zone and the nature of the material being processed, the gas flow rate of both the conditioning gas and the delivery gas may be increased as high as 3,300 SCFM.

When conditioning a corticosteroid exhibiting solubility in an c solvent, such as fluticasone propionate or budesonide, the conditioning gas may be delivered at a temperature ranging from about 20 OC to about 30 0C and include an organic solvent vapor as a solvent. In particular embodiments of methods for conditioning a corticosteroid, ing a corticosteroid selected from fluticasone propionate and budesonide, the temperature of the conditioning gas may be selected from at least 20 0C, 21 C, 22 C, 23 C, 24 C, 25 C, 26 C, 27 C, 28 C, 29 C, and 30 C.

Moreover, where included in the conditioning gas, the organic solvent vapor may be provided within the ioning gas to provide a relative saturation of the solvent in the conditioning zone ranging from about 10% to about 95%. Suitable organic solvents include an l (e.g., ethanol, methanol, isopropyl alcohol, etc.), ketone (e.g., acetone, methyl ketone, ethyl ketone, etc.), ester (e.g., ethyl acetate, etc.), aliphatic alcohol (e.g., octanol, etc.), or alkane (e.g., octane, nonane, etc.). In specific embodiments for the conditioning of corticosteroid materials, including corticosteroids ed from fluticasone propionate and budesonide, the c solvent vapor may be provided within the conditioning gas to e a relative saturation of the solvent in the conditioning zone ranging from about 50% to about 80%. For example, in ments of methods for conditioning corticosteroid materials, including corticosteroids selected from asone propionate and budesonide, the conditioning gas may be supplied at a temperature described herein with a relative solvent saturation ed from at least about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74% and 75%. At the temperatures and relative solvent saturation described herein, the residence time of the micronized corticosteroid material within the conditioning chamber may be from about 0.5 to about 10 seconds. In certain such embodiments, the micronized corticosteroid material is present within the conditioning chamber for a residence time selected from about 0.5 seconds, about 1 second, about 1.5 seconds, about 2 seconds, about 2.5 seconds, about 3 seconds, about 3.5 seconds, about 4 seconds, about 5 seconds, about 6 seconds, about 7 seconds, about 8 seconds, about 9 seconds, and about 10 seconds.

However, the residence time can be adjusted as needed to achieve the desired ioning.

As is further evidenced by the experimental examples that , methods according to the present description can be adapted to accomplish conditioning of varying materials exhibiting divergent physical and chemical properties.

IV. Exemplary Embodiments In specific ments, methods for conditioning a particulate crystalline material (e.g., micronized crystalline material) according to the present description include: providing aerosolized micronized crystalline particles, wherein said micronized crystalline particles contain one or both of an amorphous material and a residual solvent; continuously mixing the micronized lline particles with a conditioning gas comprising a r gas and a conditioning vapor in a chamber connected directly to the exit of a micronization apparatus; maintaining the micronized crystalline particles in contact with the conditioning gas for sufficient time to result in annealing of said micronized crystalline particles, wherein said annealing results in a phase transformation; and separating the micronized crystalline particles from the conditioning gas.

As detailed herein, such a phase transformation refers to a change in the bulk of the crystals present in a particulate crystalline material. In such embodiments, the phase transformation may be selected from removal of a solvent of crystallization, ement of a solvent of crystallization, an amorphous to crystalline phase , or a change in physical structure beyond just an amorphous to crystalline phase change.

The al (e.g., micronized crystalline material) processed according to any method described herein may be mixed with the conditioning gas for between about 0.1 to 600 seconds before the micronized lline material exits the conditioning zone.

The al (e.g., micronized crystalline al) sed ing to any method described herein may be mixed with the conditioning gas for between about 2 to 6 seconds before the material exits the conditioning zone.

The material (e.g., micronized crystalline material) processed according to any method described herein may be mixed with the conditioning gas for about 3 seconds before the micronized crystalline al exits the conditioning zone.

The material (e.g., micronized crystalline material) processed according to methods described herein may be water soluble. Where the material to be processed according to a method described herein is water soluble, the conditioning gas may include a solvent vapor that is an aqueous solvent vapor, and the conditioning gas may be provided at a temperature ranging from about 20 0C to 100 0C and at a relative humidity g from about 0.05% to 95%.

The material (e.g., micronized crystalline material) processed according methods bed herein may not be water soluble (e.g., soluble in one or more organic solvents). Where the al to be sed according to a method described herein is not water soluble the conditioning gas may include a solvent vapor that is an organic solvent vapor, and the conditioning gas may be provided at a temperature ranging from about 20 0C to 100 0C and at a vapor pressure of a non-aqueous solvent in the range of about 0.05% to 95%.

The material (e.g., micronized crystalline material) processed according to methods bed herein may be an admixture of water soluble and non-water soluble materials. In such instances, the conditioning gas may include a solvent vapor that includes an aqueous solvent vapor and an organic t vapor, and the conditioning gas may be supplied at a temperature ranging from about 10 0C to 100 0C and at a relative ty of the aqueous solvent in the range of about 0.05% to 95% and a vapor re of the non aqueous solvent in the range of about 0.05% to 95%.

In any of the methods described herein, the material (e.g., micronized lline al) to be processed may be entrained, suspended, or aerosolized within a delivery gas before mixing with a conditioning gas. In such embodiments, the material may be ed using a jet mill and aerosolized in the jet mill gas flow.

In any of the embodiments of the methods and systems described , the conditioning gas may be mixed with the particulate material (e.g., an aerosolized micronized crystalline material) in a ratio of about 1 to 10 parts conditioning gas with about 1 part of the aerosolized micronized lline material. In such embodiments, the aerosolized micronized crystalline material may be ned, suspended or aerosolized within a delivery gas.

In any of the embodiments of the systems and methods described herein, the conditioning gas may be supplied at a flow rate ranging from about standard cubic feet per minute (SCFM) up to about 300 SCFM while mixing with the particulate crystalline material.

In any of the embodiments of the systems and methods described herein, the particulate material (e.g., micronized crystalline material) may be entrained, ded or lized within a ry gas and the aerosolized particulate material supplied at a flow rate ranging from about 25 standard cubic feet per minute (SCFM) up to about 200 SCFM while mixing with a ioning gas.

In any of the embodiments of the systems and s described herein, the conditioning gas may comprise nitrogen gas.

In any of the embodiments of the systems and methods described herein, the particulate material (e.g., micronized lline material) may be mixed with the conditioning gas in a closed chamber.

In any of the embodiments of the systems and methods described herein, the particulate material (e.g., micronized crystalline al) may be one of glycopyrronium, including glycopyrrolate, dexipirronium, scopolamine, tropicamide, pirenzepine, dimenhydrinate, tiotropium, darotropium, aclidinium, umeclidinium, trospium, ipatropium, atropine, benzatropin, oxitropium, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, salbutamol, albuterol, salmeterol, terbutaline, fluticasone, including fluticasone propionate, budesonide, mometasone, ciclesonide, and Compound A.

In specific embodiments, systems for conditioning a particulate crystalline material (e.g., ized crystalline al) according to the t description include: a ry zone for delivering the particulate material; a mixing zone in fluid communication with the ry zone, wherein the particulate crystalline al is delivered from the micronizing zone to the mixing zone and therein mixed with a conditioning gas; a conditioning gas supply zone in fluid communication with the mixing zone, the conditioning gas supply zone ing the conditioning gas at a desired temperature and solvent vapor concentration to the mixing zone to be mixed with the particulate crystalline material; a conditioning zone in fluid communication with the mixing zone, wherein the mixture of the particulate crystalline al and the conditioning gas is delivered and remains in the conditioning zone for a desired residence time; and a separation and collection zone, wherein the conditioned particulate crystalline material is separated from the conditioning gas and the ioned material is collected. In certain such embodiments, the delivery zone may be a micronizing zone comprising a device for micronizing the particulate crystalline material.

In particular embodiments, the systems described herein are configured to process a particulate crystalline material (e.g., micronized lline material) that is water soluble and the conditioning gas supply zone is configured to provide a conditioning gas that includes a water vapor at a temperature ranging from about 20 0C to 100 0C and at a humidity g from about 0.05% to 90% relative humidity.

In particular embodiments, the systems described herein are configured to process a particulate crystalline material (e.g., micronized crystalline material) that is not water soluble and the conditioning gas supply zone is configured to provide a conditioning gas that includes an non-aqueous (e.g. an organic solvent as described herein) vapor at a temperature ranging from about 20 0C to 100 0C and at a vapor pressure of a ueous solvent in the range of about 0.05% to 90%.

In particular embodiments, the systems described herein are configured to process a particulate crystalline material (e.g., micronized crystalline material) that is an admixture of water soluble and non-water soluble materials, and the conditioning gas supply zone is configured to provide the conditioning gas at a temperature ranging from about 20 0C to 30 0C and at a relative humidity of 50 to 75% and vapor re of a non-aqueous solvent in the range of about 50% to 75%.

In any of the ments described herein, the system for conditioning particulate material may include a conditioning gas supply zone configured to e a conditioning gas at a temperature of about 25 0C and with a humidity of about 65% relative humidity In any of the embodiments described herein, the system for ioning ulate material may include a conditioning zone configured to maintain the mixture of the particulate material (e.g., micronized crystalline material) and the conditioning gas within the conditioning zone for a residence time of n about 0.5 to 60 seconds. For e, the systems for conditioning particulate material described herein may include a conditioning zone configured to maintain a mixture of the particulate crystalline al and the conditioning gas within the conditioning zone for a residence time of between about 1 to about 10 seconds. In even more specific embodiments, the systems for conditioning particulate material described herein may include a ioning zone configured to maintain a mixture of the particulate crystalline material and the conditioning gas within the conditioning zone for a residence time of about 3 seconds.

In any of the embodiments described herein including a delivery zone that ses a device for micronizing the particulate crystalline material (i.e., a micronizing zone), the device for micronizing the particulate crystalline material may be a jet mill or any other suitable system or device as described herein.

In any of the embodiments described herein, the systems for conditioning a particulate material may be configured for ioning a material selected from a particulate crystalline material (e.g., micronized crystalline material) ed from at least one of glycopyrronium, including glycopyrrolate, dexipirronium, scopolamine, tropicamide, pirenzepine, dimenhydrinate, tiotropium, darotropium, aclidinium, umeclidinium, trospium, ipatropium, atropine, benzatropin, oxitropium, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, salbutamol, albuterol, salmeterol, terbutaline, fluticasone, ing fluticasone propionate, budesonide, mometasone, ciclesonide, and Compound A.

In particular embodiments of the systems described , the systems may be configured for conditioning a particulate glycopyrrolate material using any of the process conditions detailed herein. In certain such embodiments, the s described herein can be configured for micronizing a crystalline glycopyrrolate material. In such embodiments, the systems may e a micronizing zone with a jet mill for micronizing glycopyrrolate. In certain such ments, the jet mill gas may be a delivery gas and mixed with a conditioning gas within the mixing zone at a ratio of from about 1 to 4 parts conditioning gas mixed with about 1 part of the jet mill gas.

In any of the embodiments described herein, the systems for conditioning a particulate lline al (e.g., micronized crystalline material) may include a conditioning gas supply zone configured to provide the conditioning gas to the mixing zone at a flow rate ranging from about 150 standard cubic feet per minute (SCFM) up to about 300 SCFM.

In any of the embodiments described herein, the s for conditioning a particulate crystalline material (e.g., micronized crystalline material) may be configured to entrain, suspend, or aerosolize the particulate material within a delivery gas before the material is introduced to a mixing zone or blended with a conditioning gas. In any of the embodiments described herein, the s for conditioning a particulate crystalline material (e.g., micronized crystalline material) may be configured to deliver the particulate material in a delivery gas at a flow rate ranging from about 35 standard cubic feet per minute (SCFM) up to about 200 SCFM.

In any of the embodiments described , the systems for conditioning a particulate crystalline material (e.g., micronized crystalline material) may be ured to include a mixing zone that comprises a dispersion head assembly wherein the conditioning gas and the micronized crystalline material are mixed. In such embodiments, the dispersion head assembly may include a mixing head configured to control the mixing of the conditioning gas and the particulate crystalline material. Where a system as described herein includes a mixing head, the mixing head may be configured to include an injection nozzle inlet ured to deliver the conditioning gas to an injection nozzle and a delivery gas inlet configured to deliver the micronized crystalline material to the injection nozzle.

In any of the embodiments described herein, the systems for conditioning a particulate crystalline material (e.g., ized crystalline material) the collection zone may e a cyclone collector.

In any of the embodiments described herein, the systems for conditioning a particulate crystalline material (e.g., micronized crystalline al), the system may be ured to process ized crystalline material having a particle size ranging from about 0.1 pm to about 10 pm.

In any of the embodiments described herein, the systems for conditioning a ulate crystalline material (e.g., micronized crystalline material), the system may include a holding chamber for collecting the conditioned particles. In n such embodiments, the system may be configured to prepare and/or deliver a secondary conditioning gas to the holding chamber and mix the ary conditioning gas with the conditioned crystalline particles within in the holding chamber for a period of time sufficient to provide a secondary conditioning of the lline particles. Alternatively, in embodiments of a system for conditioning a particulate crystalline material that e a holding chamber, the holding chamber may be configured simply to receive the conditioned material or to facilitate transition of the conditioned material from a primary conditioning system to a secondary conditioning system. In any of the embodiments of the systems described herein that include a holding chamber, the g chamber may be ured to maintain the conditioned material in a continuously fluidized state.

EXPERIMENTAL EXAMPLES EXAMPLE 1 Glycopyrrolate yclopentylhydroxyphenylacetyl)oxy]-1, 1 dimethyl-, bromide) was ed as coarse crystalline active agent from the manufacturer (Boehringer Ingelheim Chemicals, Inc., Petersburg, VA 23805).

The glycopyrrolate (GP) was then micronized by jet milling to achieve a reduction in particle size distribution.

A portion of the micronized GP was also conditioned using an in process conditioning system wherein nitrogen conditioning gas was supplied to the in-process conditioning system and was controlled for flow rate, temperature and humidity. The conditioning gas was humidified h a droplet ation chamber after which it was directed to a mixing zone. In the mixing zone, the conditioning gas was mixed with the lled aerosol comprising the micronized GP. The aerosol then entered a conditioning zone where annealing of the micronized GP occurred. The particle residence time through the conditioning zone was adjusted by means of the conditioning zone chamber geometry and/or the gas flow rate through the conditioning zone chamber. After passing through the conditioning zone, the micronized GP particles reached the cyclone-collection zone where the solid les were separated from the gas phase and transported to a collection vessel. Upon completion of the batch processing, the collector was aged and transferred to a glove box for sampling. The sampling occurred in a <5% relative ty environment. Samples were then analyzed for particle size distribution and ous content.

The particle size distribution of the standard jet milled micronized GP particles and the micronized GP particles after cess conditioning were sampled and are shown in Table 1. The particle size distributions in Table 1 reflect the GP particle sizes sampled immediately after processing. As is shown in Table 1, the in-process conditioning does not affect the particle size distribution of the ized GP particles. 2014/029489 Table 1: Comparison of micronized GP le size distributions Particle Size Distribution of Micronized GP Process X10 X50 X90 Span (pm) (pm) (pm) ((X90-X10)/X50) Standard Jet Milling 0.5 1.4 3.0 1.7 In-Process 0.6 1.5 3.1 1.7 Conditioning Experimental batches of micronized GP les were ed according to the in-process ioning system as described herein. The jet milling parameters and the conditioning parameters used for the in-process conditioning for each of the experimental batches are shown in Table 2. Batch 1A was a control batch of standard micronized GP and was not ioned but was processed using dry nitrogen gas at ambient temperature. The powder feed rate for all batches were set nominally at 66 g/hr.

Table 2: Micronized GP in-process conditioning parameters Jet Milling ters Conditioning Parameters Conditioning Batch # Gas Temp Feed Grind Jet Mill Conditioning Approx. (0C/%RH) Pressure Pressure Gas Flow Gas Flow CMR Residence (psi) (psi) L in) (std L/min) Time (sec) 1A Ambient /0 82 75 122 265 2.2:1 2.9 2B 250/35 82 75 122 265 2.2:1 2.9 2C 250/65 82 75 122 265 2.2:1 2.9 2D 250/65 82 75 122 166 1.4:1 3.8 2E 26/51 82 75 122 265 2.2:1 2.9 2F 280/67 82 75 122 265 2.2:1 2.9 2G 240/64 82 75 122 166 1.4:1 3.8 Table 3 lists the particle size distribution for the experimental batches as was determined by laser diffraction immediately after processing and again after 1-day of exposure to 250C and 60% relative humidity. 2014/029489 Table 3: le size distributions initial and post-exposure % Particle Size Distribution Particle Size Distribution Batch # Amorphous Initial Post-exposure al Content X10 X50 X90 Span X10 X50 X90 Span Stability Initial (pm) (pm) (pm) (pm) (pm) (pm) (pm) (pm) 1A 17.9% 0.6 1.5 3.1 1.7 0.9 3.4 13.3 3.6 Unstable, Unstable, 2B 5.3% 0.6 1.6 3.1 1.6 0.7 2.0 3.6 1.4 lly fused 2C 0.9% 0.6 1.5 2.8 1.5 0.6 1.6 2.9 1.5 , I I no fusing 2D 0.9% 0.6 1.5 2.7 1.4 0.6 1.5 2.8 1.5 Stable, no fusing 2E 2.6% 0.5 1.3 2.6 1.6 0.5 1.4 2.7 1.5 Stable, Ino fusing 2F 0.9% 0.6 1.5 2.8 1.5 0.6 1.6 2.9 1.5 Stable, no fusing 2G 2.3% 0.5 1.4 2.7 1.6 0.6 1.5 2.9 1.5 Stable, 2G_________________ 2.3%___0.5_1__4_2__7_ no fusing 1 As shown in Figure 5, analysis of the particle size distribution of the 1A control batch confirms the instability of the standard micronized GP as evidenced by the significant increase in particle size distribution of the micronized GP particles after 1-day re.

Figure 6A is an electron micrograph of the 1A control sample before exposure showing an amorphous logy with rough surfaces and edges and increased shape variability. Figure 6B is an electron micrograph of the 1A control sample after exposure showing that the unstable amorphous micronized GP material leads to fusing and agglomeration of the micronized GP particles.

In contrast, analysis of the 2D batch that was conditioned according to the cess conditioning parameters as listed in Table 2, showed particle size stability. As shown in Figure 7, the particle size distribution was essentially identical for the initial sampling and after the 1-day exposure at 250C and 60% relative humidity. Similar s were observed for the stability of the particle size distribution for the 2C, 2E, 2F, and the 2G samples (not shown).

WO 44894 Electron micrographs of the cess conditioned sample 2E show improved stability of conditioned micronized GP particles. As shown in Figure 8A, the conditioned micronized GP particles show a crystalline morphology with smooth surfaces and distinct edges. As seen in Figure 8B, the ioned micronized GP particles show improved stability with no fusing and agglomeration even after exposure to heat and humidity. Accordingly, the in process conditioning system disclosed herein improves micronized GP particle stability and prevents particle fusing and agglomeration.

EXAMPLES 2 & 3 Examples 2 and 3 provide examples of in-process conditioning of water ble les using a conditioning gas containing a vaporized c solvent (ethanol) to promote annealing. Budesonide and fluticasone propionate were selected as representative compounds. The ing conditions were determined by selecting conditions that would promote crystallization of the ous fraction under an ethanol atmosphere by determining the corresponding ethanol sorption isotherms.

Budesonide (16,17-(butylidenebis(oxy))-11,21-dihydroxy-, (11 p,16-a)-pregna-1,4-diene-3,20-dionel6,17-(butylidenebis(oxy))-11,21 dihydroxy-, (11-6,16-a)-pregna-1,4-diene-3,20-dione) was micronized using a laboratory scale jet mill set at 75 psig grinding re and 80 psig injection pressure. The lline budesonide was fed into the jet mill at a powder feed rate of approximately 25 ± 10% g/hr. Two batches of micronized budesonide were produced. One was not subjected to further processing, while the second was conditioned to remove amorphous content according to the present description.

Batch 1 (unannealed/not conditioned) did not undergo any thermal or vapor conditioning. The nitrogen gas was supplied dry to the system (i.e., no organic solvents were used), and the micronized material was collected under at ambient temperature. Batch 1 was collected and transferred into a purged isolator for sampling.

Batch 2 (annealed/conditioned) was conditioned according to the present description using a conditioning gas that included an ethanol vapor, with a target of 75% relative saturation in the conditioning zone. To form the conditioning gas, ethanol (95% w/w) was ed in nitrogen gas using a 0.21" atomizer nozzle with a set atomizer gas flow rate of 30 std. L/min (SLPM) and a liquid flow rate of 32 g/min. The conditioning gas flow rate was set to 205 SLPM with a humidifier inlet temperature of 1850C and conditioning zone outlet of 300C. The jet mill grind pressure was delivered at 75 psig with an injection pressure of 80 psig, resulting in a nominal micronizer gas flow rate of 122 SLPM, along with a total conditioning gas flow rate (including the atomizer gas flow) of 235 SLPM. The conditioning gas to izing gas (also ed to as a ry gas) ratio (CMR) for this process configuration was 1.9:1, with a nominal total system gas flow rate of 357 SLPM. Batch 2 was collected in a 0.5L stainless steel collector, transferred to a purged (<5% RH) isolator and sampled for analysis.

Both batches of micronized budesonide were analyzed for particle size distribution by Sympatec laser diffraction, with the results provided in Table 4. As can be seen in Table 4, Batch 2 (annealed) demonstrated good physical stability after micronization, whereas Batch 1 (unannealed) demonstrated potential agglomeration marked by a significant shift in size distribution.

Table 4: le Size Distribution of Micronized nide.

D10 D50 D90 Micronized Budesonide (pm) (pm) (pm) Span Batch 1 (unannealed) 0.6 2.3 5.4 2.1 Batch 2 (annealed) 0.5 1.2 2.5 1.7 The amorphous content by vapor sorption and particle morphology for both batches were also assessed. Figure 9 provides the l vapor sorption isotherm at 250C for both batches of micronized budesonide. As can be seen in Figure 9, Batch 1 (unannealed, top) remained substantially amorphous (weight loss at 60% p/po), while Batch 2 (annealed, bottom) was stable and showed no crystallization event. Figure 10 provides SEM imaging of the material from Batch 1 and Batch 2, and as can be seen by reference to Figure 10, the annealed material of Batch 2 (right) presented smoother surfaces and more rounded edges than the unannealed material of Batch 1 (left).

EXAMPLE 3 Fluticasone propionate (S-(fluoromethyl)-6a,9-difluoro-11p, 17 oxy-16a-methyloxoandrosta-1, 4-diene-17p-carbothioate, 17 propanoate) was micronized using a laboratory scale jet mill set at 65 psig grinding pressure and 74 psig injection re. The crystalline fluticasone was fed into the jet mill at a powder feed rate of approximately 25 ± 10% g/hr.

Two s of micronized fluticasone were ed. One was not subjected to further processing, while the second was ioned to remove amorphous t according to the present description.

Batch 1 (unannealed/not conditioned) did not undergo any thermal or vapor conditioning. The nitrogen gas was supplied dry to the system (i.e., no organic solvents were used), and the micronized material was collected under at ambient temperature. Batch 1 was collected and erred into a purged isolator for sampling.

Batch 2 (annealed/conditioned) was conditioned according to the present description using a conditioning gas that included an ethanol vapor, with a target of 75% ve saturation in the conditioning zone. To form the conditioning gas, ethanol (95% w/w) was atomized in nitrogen gas using a 0.21" atomizer nozzle with a set atomizer gas flow rate of 30 std. L/min (SLPM) and a liquid flow rate of 32 g/min. The conditioning gas flow rate was set to 205 SLPM with a humidifier inlet temperature of 1850C and conditioning zone outlet of 300C. At the given grind and ion pressures red to the system, the resulting micronizer gas flow was nominally 108 SLPM , along with a total WO 44894 conditioning gas flow rate (including the atomizer gas flow) of 235 SLPM. The ioning gas to micronizing gas (also referred to as a delivery gas) ratio (CMR) for this process was 2.2:1, with a total gas flow of 343 SLPM. Batch 2 was collected in a 0.5L stainless steel collector, transferred to a purged (<5% RH) isolator and sampled for analysis.

Both batches of micronized fluticasone were analyzed for particle size distribution by Sympatec laser diffraction, with the results provided in Table . As can be seen in Table 5, Batch 2 (annealed) trated good physical stability after micronization, whereas Batch 1 (unannealed) demonstrated agglomeration marked by a shift in size distribution.

Table 5: Particle Size Distribution of Micronized Fluticasone Propionate.

D10 D50 D90 Micronized Fluticasone propionate (pm) (pm) (pm) Span Batch 1 (unannealed) 0.5 1.5 3.4 2.0 Batch 2 (annealed) 0.5 1.4 3.1 1.9 The amorphous content by vapor sorption and particle morphology for both batches were also assessed. Figure 11 provides the ethanol vapor sorption isotherm at 250C for both batches of micronized fluticasone. As can be seen in Figure 11, Batch 1 (unannealed, top) remained substantially amorphous (weight loss at 60% p/po), while Batch 2 (annealed, bottom) was stable and showed no crystallization event. Figure 12 provides SEM g of the material from Batch 1 and Batch 2, and as can be seen by nce to Figure 10, the annealed al of Batch 2 (right) presented smoother surfaces and more rounded edges than the unannealed material of Batch 1 (left).

EXAMPLE 4 Three up batches of micronized glycopyrrolate (GP) were produced via a large-scale in-process micronization and conditioning system according to the present description that utilized a llector process at approximately 1 kg per batch. The first two lots were manufactured using a single, raw crystalline API lot, while the third used a different lot from the same vendor. All batches were produced on different dates using the same process configuration that utilized the same 4" jet mill, and the same conditioning environment (i.e., a target of 55% RH at 400C conditioning zone outlet temperature).

The system was brought to steady-state equilibrium, with the jet mill ing at 68 psig injection pressure and 48 psig grind pressure for a micronizer gas flow of approximately 36 SCFM. Again, the micronizer gas also served as the delivery gas for the ized material. The conditioning gas flow rate was supplied at approximately 78 SCFM with a humidifier outlet temperature of 570C. Water was red to the 0.21" atomizer nozzle at a liquid flow rate of 75.1 ml/min. The ioning to micronization gas ratio (CMR) was set at 2.2:1. Product was collected in 8L stainless steel collectors, which were heated using a thermal jacket to prevent the collector environment from falling below the dew-point temperature.

Once the system reached steady-state, powder was fed into the jet mill at a nominal rate of 1 kg/hr. A collector -out was performed half way through each run with a collector purging step before each change-out to obviate the risk of any post-process affects due to residual vapor. The collectors were transferred to a purged isolator (<5% RH) for ng and packaging to prevent any post-process affects due to ambient moisture.

All batches were analyzed for le size distribution by Sympatec laser ction, with the results provided in Table 6. n=3 replicates per collector were assessed (mean values are shown). As can be seen in Table 6, the le size distribution achieved in each batch exhibited good batch to batch reproducibility.

Table 6: Particle Size Distribution of Micron ized/Annealed GP Micronized/Annealed D10 D50 D90 Glycopyrrolate (pm) (pm) (pm) Span Batch A - Collector 1 0.52 1.48 3.02 1.68 Batch A - Collector 2 0.52 1.47 2.99 1.69 Batch B - Collector 1 0.52 1.47 3.02 1.70 Batch B - Collector 2 0.52 1.46 2.99 1.70 Batch C - tor 1 0.52 1.47 3.03 1.70 Batch C - Collector 2 0.51 1.45 2.96 1.69 All batches were also analyzed for amorphous content by dynamic vapor sorption using n=2 ates per collector. The results are provided in Table 7, which reflects that the amorphous t achieved in each batch also exhibited good batch to batch reproducibility.

Table 7: Amorphous Content of Conditioned GP Calculated Calculated Micronized/Annealed Amorphous t, Amorphous Content, GP Collector 1 Collector 2 Batch A 2.65% 2.35% Batch B 2.65% 2.40% Batch C 2.65% 2.45% EXAMPLE 5 Sucrose (saccharose; a-D-glucopyranosyl-(1 -D furanoside) was micronized and conditioned using the large scale micronization/annealing system utilized in e 4. Particulate sucrose was delivered to the 4" jet mill at a nominal powder feed rate of 0.5 kg/hr. Two batches of micronized sucrose were produced. For the first, the 4" jet mill was set at an 80 psig injection pressure and a grind pressure of 70 psig. For the second, the 4" jet mill was set at an 80 psig injection pressure and a grind pressure of 76 psig. Identical lots of the raw input material were used for dispensing both batches. Process conditions for each batch are provided in Table 8. e A (unannealed/not conditioned) did not undergo any thermal or vapor conditioning. The nitrogen gas was supplied dry to the system, and the system was run at ambient temperature. The jet mill was operated at 80 psig injection pressure and 70 psig grind pressure for a nominal micronizer gas flow of approximately 45.0 SCFM. The conditioning gas flow rate (ambient WO 44894 temperature, 0 %RH) was supplied at approximately 61.0 SCFM. The conditioning to micronizing gas Ratio (CMR) was set at 1.4:1. Product was collected in 8L stainless steel collectors, without the use of a thermal jacket.

Powder was fed into the jet mill at a nominal feed rate of 0.5 kg/hr.

A collector change-out was performed half way through each run. The collectors were transferred to a purged isolator (<5% RH) for sampling and packaging to t any post-process affects due to ambient moisture.

Sucrose B (annealed/conditioned) was conditioned at a target 55% ve humidity at 400C conditioning zone outlet temperature. The system was t to steady-state equilibrium, with the jet mill operating at 80 psig injection pressure and 76 psig grind pressure for a nominal micronizer gas flow of approximately 49.4 SCFM. The conditioning gas flow rate was supplied at imately 61.8 SCFM with a humidifier outlet temperature of 157.20C.

Water was delivered to a 0.21" atomizer nozzle at a liquid flow rate of 76.2 . The conditioning to izing gas Ratio (CMR) was set at 1.4:1.

Product was collected in 8L stainless steel collectors, which were heated using a thermal jacket to prevent the collector environment from falling below the dew-point temperature.

Once the system reached steady state, powder was fed into the jet mill at a rate of 0.5 kg/hr. A collector change-out was performed half way through each run, including a system purge-out step prior to each change-out to obviate the risk of any post-process s due to residual vapor. The tors were erred to a purged isolator (<5% RH) for sampling and packaging to prevent any post-process affects due to ambient moisture.

Table 8: Process Conditions for Production of Micronized Sucrose Batches.

Nominal Approx.

Powder Jet Mill Jet Mill Nominal Nominal Liquid Feed Grind Injection Micronizer Conditioning Flow Target Batch Rate Pressure Pressure Flow Rate CMR Gas Flow Rate Rate Conditioning # kg/hr psi psi SCFM - SCFM ml/min 'C/%RH Sucrose A 0.5 70 80 45.2 1.4 61.0 N/A 18/0 Sucrose B 0.5 76 80 49.4 1.4 61.8 76.2 40/55 WO 44894 Both micronized sucrose batches were analyzed for particle size distribution by Sympatec laser diffraction. The results of the analysis are provided in Table 9 and Figure 15. Sucrose A was not tested after exposure, however fusing of the material on ity was med by visual observation, demonstrating an unstable powder. Sucrose B was exposed to a 250C/60% RH environment and showed good stability even post-exposure. Figure 15 shows the particle size distribution ed in Sucrose B after it was freshly made and then after exposed to a 250C/60%RH environment.

Table 9: Particle Size Distribution of ized Sucrose Particle Size Distribution Particle Size Distribution Initial T=1 day at 250C/60%RH Physical Batch #___RH Pyia X10 X50 X90 Span X10 X50 X90 Span ity (pm) (pm) (pm) (pm) (pm) (pm) (pm) (pm) Sucrose 1 0.5 1.7 4.5 2.4 NT NT NT NT Unstable, Sucrose 2 0.6 2.2 4.9 1.9 0.7 2.5 5.2 1.9 Stable, ____ ____no____ __ _ ___ fusing The amorphous content by vapor sorption and particle morphology for both batches of micronized sucrose were also assessed.

Figure 13 provides the water vapor sorption isotherm at 250C for both batches of ized sucrose. As can be seen in Figure 13, Sucrose A (unannealed, top) remained substantially amorphous (weight loss at 30% p/po), while Sucrose B (annealed, bottom) was stable and showed no crystallization event. Figure 14 provides SEM imaging of the material from Sucrose A and Sucrose B, and as can be seen by reference to Figure 14, the annealed material of Sucrose B (right) presented er surfaces and more rounded edges than the unannealed al of Sucrose A (left).

EXAMPLE 6 nd A, a novel bi-functional muscarinic antagonist and beta2 agonist (IUPAC: 7-[(1 R)[2-[2-fluoro[[4-(2-isopropylthiazole-4 carbonyl)-1 -oxa-4,9-diazaspiro[5.5]undecanyl]methyl]phenyl]ethylamino]-1 hydroxy-ethyl]hydroxy-3H-1,3-benzothiazolone; di[[(1S,4R)-7,7-dimethyl 2-oxo-norbornanyl]methanesulfonic acid] salt), was selected for micronization and subsequent solvent removal using primary and secondary conditioning steps. Compound A retained -5% residual isopropyl alcohol solvent after manufacture. Compound A was micronized and conditioned using an in-process conditioning system according to the present description that included a 1" jet mill. Process conditions were selected to promote solvent exchange to reduce or remove residual pyl alcohol and replace the isopropyl alcohol either directly with water or with ethanol and secondarily with water. Three batches of micronized Compound A were produced as described in Table 10 below. Identical lots of the raw input al were used for dispensing all three batches.

Table 10 Nominal Jet Mill Jet Mill % Powder Grind Injection Relative Batch Batch Description Feed rate Pressure Pressure Temp Sat. Yields -g/hr psi psi C % RS % No Conditioning 25 ± 2 70 80 21 0 49% 29'C/69% RH 25 ±2 70 80 29 69 62% 30C/53% RS (ethanol) 25 ± 2 70 80 30 53 53% Batch 1 (unannealed) did not undergo any thermal or vapor conditioning. The nitrogen gas was supplied dry to the system and ran at ambient temperature (i.e., no heat or t vapor was used). The total ioning gas flow rate was 255 SLPM. The micronization gas flow rate was about 110 SLPM at the given milling res, giving a ioning to micronization gas Ratio (CMR) of 2.3:1 and total gas flow of 365 SLPM. Batch 1 was collected and transferred into a purged isolator for sampling.

Batch 2 (conditioned with water vapor at 29 0C/69%RH) was conditioned using a conditioning gas that provided water vapor at 69% relative humidity (RH) in the ioning zone. The conditioning gas was formed by ing water in nitrogen gas using a 0.21" atomizer nozzle, with a set er gas flow rate of 35 std. L/min (SLPM) and a liquid flow rate of 7 g/min.

The conditioning gas flow rate was set to 220 SLPM with a humidifier inlet temperature of 1000C and conditioning zone outlet of 290C. The total conditioning gas flow rate including the atomizer was 255 SLPM. The micronization gas flow rate was about 110 SLPM at the given milling pressures, giving a ioning to micronization gas Ratio (CMR) of 2.3:1 and total gas flow of 365 SLPM. Batch 2 was collected in a 0.5L stainless steel collector, transferred to a purged (<5% RH) isolator and sampled for analysis.

Batch 3 (primary conditioning with l at 300C/53%RS; secondary conditioning with water at 7%RH) was conditioned using a conditioning gas including ethanol vapor, with a target of 75% relative saturation in the conditioning zone. The conditioning gas was formed by atomizing l (95% w/w) in nitrogen gas using a 0.21" atomizer nozzle, with a set atomizer gas flow rate of 35 std. L/min (SLPM) and a liquid flow rate of 28 g/min. The conditioning gas flow rate was set to 220 SLPM with a humidifier inlet temperature of 1500C and ioning zone outlet of 300C. The micronization gas flow rate was about 110 SLPM at the given g pressures, giving a conditioning to micronization gas Ratio (CMR) of 2.3:1 and total gas flow of 365 SLPM. Upon completion of conditioning with ethanol, ethanol liquid flow was stopped, and the process was adjusted to provide a conditioning gas containing water vapor. The humidifier inlet temperature of 1000C was set and water was then fed into the system at a flow rate of 7 g/min at a CZ outlet temperature and collector temperature of 300C. The material was secondarily conditioned in the collector with a conditioning gas ning water vapor at 67 %RH. Batch 3 was collected in a 0.5L stainless steel collector, transferred to a purged (<5% RH) isolator and sampled for analysis.

All three batches were analyzed for particle size distribution by ec laser diffraction, with the results shown in Table 11. Particle Size Distribution of conditioned Compound A demonstrates good reproducibility, and the particle size bution of the conditioned Compound A is consistent with the unannealed micronized material.

Table 11 D10 D50 D90 Compound A, PSD (pm) (Pm) (pm) Raw (Un-milled) 1.1 3.7 16.3 Unannealed 0.6 1.6 3.1 300C/70%RH 0.6 1.6 3.1 300C/55%RS (ethanol); 300C/70%RH (water) 0.6 1.7 3.2 Residual solvent content of the material from different batches was also analyzed. Table 12 shows the residual solvent content of materials from each batch as assessed by GC analysis. Residual solvent is partially d using primary (ethanol) and secondary (water) conditioning. Material that was treated using a secondary conditioning s exhibited increased replacement of the IPA.

Table 12 Compound A Batches % IPA (w/w) % EtOH (w/w) % Water Raw (un-milled) 4.7% 0.0% 3.1% Unannealed 3.9% 0.2% 3.0% 300C/70%RH 3.6% 0.1% 3.4% 30C/55%RS; 300C/70%RH 2.1% 1.2% 3.4% EXAMPLE 7 Compound A (IUPAC: 7-[(1 R)[2-[2-fluoro[[4-(2 isopropylthiazolecarbonyl)-1 -oxa-4,9-diazaspiro[5.5]undecan-9 yl]methyl]phenyl]ethylamino]-1 xy-ethyl]hydroxy-3H-1,3-benzothiazol-2 one; S,4R)-7,7-dimethyloxo-norbornanyl]methanesulfonic acid] salt) was received with a 3.8% ethanol residual t. This material had been previously micronized and conditioned according to the present description to reduce the ce of isopropyl (IPA) and ethanol (EtOH) by solvent exchange/removal. The material was d to another conditioning gas that included water vapor, and was mixed with the conditioning gas in a conditioning zone for imately 1.5 hours. As shown in Table 13, residual IPA and EtOH was nearly completely removed and water content of the material increased.

Table 13 Micronized Compound A Batch % IPA (w/w) % EtOH (w/w) % Water As Received 0.1% 3.8% 3.1% 300C/70%RH (water) 0.0% 0.1% 3.6%

Claims

1. A method of conditioning micronized crystalline les comprising: aerosolizing micronized lline particles within a delivery gas, wherein said micronized crystalline particles contain one or both of an amorphous material and a al solvent; continuously mixing the micronized crystalline particles with a conditioning gas comprising a carrier gas and a solvent vapor in a chamber; maintaining the aerosolized micronized crystalline particles in contact with the conditioning gas in a conditioning zone for sufficient time to result in annealing of said micronized crystalline particles, wherein said annealing results in one or both of reducing the presence of the amorphous material or reduction in the amount of residual solvent; and separating the micronized lline particles from the conditioning gas.

2. The method of claim 1, wherein the micronized crystalline particles are mixed with the conditioning gas for between about 0.1 to 600 seconds before they exit the ioning zone.

3. The method of claim 1, wherein the micronized lline particles are water soluble, the solvent vapor included in the ioning gas is an s solvent vapor, and the conditioning gas is provided at a temperature ranging from about 20 °C to 100 °C and at a relative humidity ranging from about 0.05% to 95%.

4. The method of claim 1, wherein ized crystalline particles are not water soluble, the solvent vapor included in the conditioning gas is an organic solvent vapor, and the conditioning gas is provided at a temperature g from about 20 °C to 100 °C and at a relative saturation of a non-aqueous solvent in the range of about 0.05% to 95%.

5. The method of claim 1, wherein micronized crystalline particles are an admixture of water soluble and non-water soluble materials, the t vapor included in the conditioning gas ses an aqueous solvent vapor and an organic solvent vapor, and the conditioning gas is supplied at a temperature ranging from about 10 °C to 100 °C and at a relative humidity of the aqueous solvent in the range of about 0.05% to 95% and relative saturation of the non-aqueous solvent in the range of about 0.05% to 95%.

6. The method of any one of the preceding claims, n the micronized crystalline particles are produced using a jet mill and are aerosolized in the jet mill gas flow.

7. The method of any one of the preceding claims, wherein the conditioning gas is mixed with the aerosolized micronized crystalline particles in a ratio of about 1 to 10 parts conditioning gas with about 1 part of the aerosolized micronized crystalline particles (volume/volume).

8. The method of any one of the preceding claims, wherein the conditioning gas is supplied at a flow rate ranging from about 25 rd cubic feet per minute (SCFM) up to about 300 SCFM while mixing with the micronized crystalline particles.

9. The method of any one of the preceding claims, wherein the aerosolized micronized crystalline particles is supplied at a flow rate ranging from about 25 standard cubic feet per minute (SCFM) up to about 200 SCFM while mixing with the conditioning gas.

10. The method of any one of the preceding claims, wherein the conditioning gas ses nitrogen gas.

11. The method of any one of the preceding claims, wherein the micronized crystalline les are mixed with the conditioning gas in a closed chamber.

12. The method of any one of the preceding claims, n the micronized crystalline particles comprise glycopyrrolate.

13. The method of any one of the preceding claims, wherein the micronized crystalline particles comprise budesonide.

14. A system for in-process conditioning of micronized crystalline particles comprising: a micronizing zone comprising a device for izing at least one crystalline material to form micronized crystalline particles; a mixing zone in fluid communication with the micronizing zone, n the micronized crystalline les are delivered from the micronizing zone to the mixing zone and n mixed with a conditioning gas; a ioning gas supply zone in fluid communication with the mixing zone, the conditioning gas supply zone providing the conditioning gas at a desired temperature and solvent vapor tration to the mixing zone to be mixed with the micronized crystalline particles; a conditioning zone in fluid communication with the mixing zone, wherein the mixture of the micronized crystalline particles and the conditioning gas is delivered and remains in the ioning zone for a desired residence time; and a separation and collection zone, wherein the conditioned micronized crystalline particles are separated from the conditioning gas and the conditioned ized crystalline particles are collected.

15. The system of claim 14, n the micronized crystalline particles are water soluble and the conditioning gas supply zone is configured to provide the conditioning gas at a temperature ranging from about 20 °C to 100 °C an d at a humidity ranging from about 0.05% to 90% relative humidity.

16. The system of claim 14, wherein the ized crystalline particles are not water soluble and the conditioning gas supply zone is configured to provide the conditioning gas at a temperature ranging from about 20 °C to 10 0 °C and at a relative saturation of a non-aqueous solvent in the range of about 0.05% to 90% in the flowing conditioning gas stream.

17. The system of claim 14, wherein the micronized crystalline particles are an admixture of water soluble and non-water soluble materials, and the ioning gas supply zone is configured to provide the conditioning gas at a temperature ranging from about 20 °C to 30 °C and at a relative humidity of 50 to 75% and a relative saturation of a nonaqueous solvent in the range of about 50% to 75% in the flowing conditioning gas stream.

18. The system of claim 14, wherein the conditioning gas supply zone is configured to provide the conditioning gas at a temperature of about 25 °C and with a humidity of about 65% relative humidity.

19. The system of claim 14, wherein the conditioning zone is configured to maintain the mixture of the micronized lline particles and the conditioning gas within the conditioning zone for a residence time of between about 0.5 to 60 seconds.

20. The system of claim 14, wherein the conditioning zone is configured to maintain the e of the micronized lline particles and the conditioning gas within the ioning zone for a residence time of between about 1 to about 10 seconds.

21. The system of claim 14 wherein the conditioning zone is configured to maintain the e of the ized crystalline particles and the conditioning gas within the conditioning zone for a residence time of about 3 seconds.

22. The system of claim 14, wherein the micronizing zone comprises a jet mill configured for izing the at least one lline material.

23. The system of claim 14, n the conditioning gas supply zone is configured to e the conditioning gas to the mixing zone at a flow rate ranging from about 150 standard cubic feet per minute (SCFM) up to about 300 SCFM.

24. The system of claim 14, wherein the micronizing zone is configured to deliver the micronized crystalline particles as an aerosolized particulate material to the mixing zone at a flow rate ranging from about 35 rd cubic feet per minute (SCFM) up to about 200 SCFM.

25. The system of claim 14, wherein the mixing zone comprises a sion head assembly, and wherein the conditioning gas and the micronized crystalline particles are mixed in the dispersion head assembly.

26. The system of claim 25, wherein the sion head assembly comprises a mixing head configured to control the mixing of the conditioning gas and the micronized crystalline particles.

27. The system of claim 26, wherein the mixing head comprises an injection nozzle inlet configured to deliver the conditioning gas to an injection , and wherein the mixing head comprises a delivery gas inlet configured to deliver the micronized crystalline particles to the injection nozzle, and wherein the injection nozzle is configured for mixing the conditioning gas with the micronized crystalline particles.

28. The system of claim 14, wherein the nce time in the conditioning zone of the mixture of the micronized crystalline particles and the conditioning gas is modified by ing the geometry of the conditioning zone.

29. The system of claim 14, n the residence time in the conditioning zone of the mixture of the micronized crystalline particles and the conditioning gas is modified by adjusting the rate at which the mixture of the micronized crystalline particles and the conditioning gas is delivered from the mixing zone to the conditioning zone.

30. The system of claim 14, wherein the separation and collection zone ses a cyclone collector. W0