U.S. patent application number 15/873779 was filed with the patent office on 2018-12-06 for methods and systems for conditioning of particulate crystalline materials.
The applicant listed for this patent is Pearl Therapeutics, Inc.. Invention is credited to Sarvajna Dwivedi, James Ivey, Ali Kazmi, David Lechuga-Ballesteros, Herman E. Snyder, Jason H. Speck, Reinhard Vehring.
Application Number | 20180344747 15/873779 |
Document ID | / |
Family ID | 50487199 |
Filed Date | 2018-12-06 |
United States Patent
Application |
20180344747 |
Kind Code |
A1 |
Kazmi; Ali ; et al. |
December 6, 2018 |
METHODS AND SYSTEMS FOR CONDITIONING OF PARTICULATE CRYSTALLINE
MATERIALS
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.
Inventors: |
Kazmi; Ali; (San Francisco,
CA) ; Lechuga-Ballesteros; David; (San Jose, CA)
; Snyder; Herman E.; (West Lafayette, IN) ; Ivey;
James; (Edmonton, CA) ; Vehring; Reinhard;
(Edmonton, CA) ; Speck; Jason H.; (Dublin, CA)
; Dwivedi; Sarvajna; (Redwood City, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Pearl Therapeutics, Inc. |
Redwood City |
CA |
US |
|
|
Family ID: |
50487199 |
Appl. No.: |
15/873779 |
Filed: |
January 17, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14213834 |
Mar 14, 2014 |
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15873779 |
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61799956 |
Mar 15, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/56 20130101;
A61K 9/14 20130101; A61K 31/58 20130101; A61K 31/537 20130101; B02C
19/06 20130101; A61P 11/00 20180101; A61K 31/7016 20130101; A61K
31/40 20130101 |
International
Class: |
A61K 31/56 20060101
A61K031/56; A61K 31/40 20060101 A61K031/40; A61K 9/14 20060101
A61K009/14; A61K 31/7016 20060101 A61K031/7016; B02C 19/06 20060101
B02C019/06; A61K 31/537 20060101 A61K031/537; A61K 31/58 20060101
A61K031/58 |
Claims
1. A method of conditioning a micronized crystalline material
comprising: aerosolizing micronized crystalline particles within a
delivery gas, wherein said micronized crystalline particles contain
one or both of an amorphous material and a residual solvent;
continuously mixing the micronized crystalline particles with a
conditioning gas comprising a carrier gas and a conditioning vapor
in a chamber; maintaining the aerosolized 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 one or both of reducing the
presence of the amorphous material or reduction in the amount of
residual solvent; and separating the micronized crystalline
particles from the conditioning gas.
2. The method of claim 1, wherein the micronized crystalline
material is mixed with the conditioning gas for between about 0.1
to 600 seconds before the micronized crystalline material exits the
conditioning zone.
3. (canceled)
4. (canceled)
5. The method of claim 1, wherein the micronized crystalline
material is water soluble, the solvent vapor included in the
conditioning gas is an aqueous solvent vapor, and the conditioning
gas is provided at a temperature ranging from 20.degree. C. to
100.degree. C. and at a relative humidity ranging from 0.05% to
95%.
6. The method of claim 1, wherein the micronized crystalline
material is 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 ranging from 20.degree. C. to
100.degree. C. and at a relative saturation of a non-aqueous
solvent in the range of 0.05% to 95%.
7. The method of claim 1, wherein the micronized crystalline
material is an admixture of water soluble and non-water soluble
materials, the solvent vapor included in the conditioning gas
comprises an aqueous solvent vapor and an organic solvent vapor,
and the conditioning gas is supplied at a temperature ranging from
10.degree. C. to 100.degree. C. and at a relative humidity of the
aqueous solvent in the range of 0.05% to 95% and a relative
saturation of the non-aqueous solvent in the range of 0.05% to
95%.
8. (canceled)
9. The method of claim 1, wherein the micronized crystalline
material is produced using a jet mill and is aerosolized in the jet
mill gas flow.
10. The method of claim 1, wherein the conditioning gas is mixed
with the aerosolized micronized crystalline material in a ratio of
1 to 10 parts conditioning gas with 1 part of the aerosolized
micronized crystalline material.
11. (canceled)
12. The method of claim 1, wherein the conditioning gas is supplied
at a flow rate ranging from about 25 standard cubic feet per minute
(SCFM) up to 300 SCFM while mixing with the micronized crystalline
material.
13. The method of claim 1, wherein the aerosolized micronized
crystalline material is supplied at a flow rate ranging from about
25 standard cubic feet per minute (SCFM) up to 200 SCFM while
mixing with the conditioning gas.
14. The method of claim 1, wherein the conditioning gas comprises
nitrogen gas.
15. The method of claim 1, wherein the micronized crystalline
material is mixed with the conditioning gas in a closed
chamber.
16. A system for in-process conditioning of a micronized
crystalline material comprising: a micronizing zone comprising a
device for micronizing at least one crystalline material; a mixing
zone in fluid communication with the micronizing zone, wherein the
at least one micronized crystalline material 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 providing the conditioning gas at a desired temperature and
solvent vapor concentration to the mixing zone to be mixed with the
at least one micronized crystalline material; a conditioning zone
in fluid communication with the mixing zone, wherein the mixture of
the at least one micronized crystalline material and the
conditioning gas is delivered and remains in the conditioning zone
for a desired residence time; a separation and collection zone,
wherein the conditioned micronized crystalline material is
separated from the conditioning gas and the conditioned active
agent is collected.
17. The system of claim 16, wherein the micronized crystalline
material is water soluble and the conditioning gas supply zone is
configured to provide the conditioning gas at a temperature ranging
from 20.degree. C. to 100.degree. C. and at a humidity ranging from
0.05% to 90% relative humidity.
18. The system of claim 16, wherein the micronized crystalline
material is not water soluble and the conditioning gas supply zone
is configured to provide the conditioning gas at a temperature
ranging from 20.degree. C. to 100.degree. C. and at a relative
saturation of a non-aqueous solvent in the range of 0.05% to 90% in
the flowing conditioning gas stream.
19. The system of claim 16, wherein the micronized crystalline
material 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
20.degree. C. to 30.degree. C. and at a relative humidity of 50 to
75% and a relative saturation of a non-aqueous solvent in the range
of 50% to 75% in the flowing conditioning gas stream.
20. The system of claim 16, wherein the conditioning gas supply
zone is configured to provide the conditioning gas at a temperature
of about 25.degree. C. and with a humidity of about 65% relative
humidity.
21. The system of claim 16, wherein the conditioning zone is
configured to maintain the mixture of the at least one micronized
crystalline material and the conditioning gas within the
conditioning zone for a residence time of between about 0.5 to 60
seconds.
22. The system of claim 16, wherein the conditioning zone is
configured to maintain the mixture of the at least one micronized
crystalline material and the conditioning gas within the
conditioning zone for a residence time of between about 1 to about
10 seconds.
23. The system of claim 16 wherein the conditioning zone is
configure to maintain the mixture of the at least one micronized
crystalline material and the conditioning gas within the
conditioning zone for a residence time of about 3 seconds.
24. The system of claim 16, wherein the micronizing zone comprises
a jet mill configured for micronizing the at least one crystalline
material.
25. The system of claim 16, wherein the conditioning gas supply
zone is configured to provide the conditioning gas to the mixing
zone at a flow rate ranging from 150 standard cubic feet per minute
(SCFM) up to 300 SCFM.
26. The system of claim 16, wherein the micronizing zone is
configured to deliver the at least one micronized crystalline
material as an aerosolized particulate material to the mixing zone
at a flow rate ranging from 35 standard cubic feet per minute
(SCFM) up to 200 SCFM.
27. The system of claim 16, wherein the mixing zone comprises a
dispersion head assembly, and wherein the conditioning gas and the
micronized crystalline material are mixed in the dispersion head
assembly.
28. The system of claim 27, wherein the dispersion head assembly
comprises a mixing head configured to control the mixing of the
conditioning gas and the at least one micronized crystalline
material.
29. The system of claim 28, wherein the mixing head comprises an
injection nozzle inlet configured to deliver the conditioning gas
to an injection nozzle, and wherein the mixing head comprises a
delivery gas inlet configured to deliver the micronized crystalline
material to the injection nozzle, and wherein the injection nozzle
is configured for mixing the conditioning gas with the at least one
micronized crystalline material.
30. The system of claim 16, wherein the residence time in the
conditioning zone of the mixture of the micronized crystalline
material and the conditioning gas may be modified by adjusting the
geometry of the conditioning zone.
31. The system of claim 16, wherein the residence time in the
conditioning zone of the mixture of the micronized crystalline
material and the conditioning gas may be modified by adjusting the
rate at which the mixture of the micronized crystalline material
and the conditioning gas is delivered from the mixing zone to the
conditioning zone.
32. The system of claim 16, wherein the separation and collection
zone comprises a cyclone collector.
33. (canceled)
34. (canceled)
35. (canceled)
36. (canceled)
37. (canceled)
38. (canceled)
39. (canceled)
40. (canceled)
41. The method of claim 1, wherein the micronized crystalline
particles comprise glycopyrrolate.
42. The method of claim 1, wherein the micronized crystalline
particles comprise budesonide.
Description
BACKGROUND
Technical Field
[0001] 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 incorporating
such particles.
Description of the Related Art
[0002] 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 incorporated into commercial
products when provided as micronized crystalline particulates. This
can be seen with pharmaceutically active compounds that exhibit
improved formulation, delivery, or therapeutic attributes when
provided in micronized crystalline form.
[0003] However, processes used to produce certain crystalline
materials can result in material characteristics that introduce an
undesired level of physiochemical instability. Techniques for
micronization of crystalline material often utilize
energy-intensive milling, grinding, shearing or
particle-to-particle collisions to reduce particle 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 .mu.m in diameter. The exertion of thermal or mechanical
energy during energy-intensive micronization processes can cause
the formation of non-crystalline, amorphous material that can lead
to significant physicochemical instability of the resulting
micronized particles. Such amorphous material may be present in the
form of amorphous regions on otherwise crystalline particles or as
substantially amorphous particles.
[0004] The presence of amorphous material within micronized
crystalline material can result in a propensity for the particles
to fuse, aggregate, and/or agglomerate. In certain cases, the
instability appears particularly acute when the micronized material
is exposed, even for very short periods of time, to an environment
that includes a solvent capable of solubilizing or plasticizing the
amorphous material. In such instances, exposure of the micronized
material often leads to recrystallization of amorphous material
contained therein or sorbed, vapor-driven conversion of amorphous
phase to crystalline phase, which can be accompanied by fusing and
agglomeration of the micronized particles. The fusing, aggregation
and/or agglomeration of the micronized particles can cause
significant changes 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.
[0005] In addition, processes used in the manufacture and
purification of crystalline materials can leave undesired
contaminants. For example, solvents, including various organic
solvents, play an important role in the manufacture of
pharmaceutically active compounds and excipients used in the
production of drug products. Solvents are often used during the
synthesis of pharmaceutically 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 entrapped 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 effects. Organic solvents, in particular, can present
health and safety hazards and can influence product efficacy,
safety and stability.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0006] FIG. 1 is a diagram showing one embodiment of a system
disclosed herein for in-process conditioning of micronized
crystalline material.
[0007] FIG. 2 is a diagram showing an embodiment of a system
disclosed herein for in-process conditioning of micronized
crystalline material.
[0008] FIG. 3A is a drawing of one view of one embodiment of a
dispersion head assembly as described in the present
disclosure.
[0009] FIG. 3B is a drawing of another view of one embodiment of a
dispersion head assembly as described in the present
disclosure.
[0010] FIG. 3C is a drawing of a cross-sectional view of one
embodiment of a dispersion head assembly.
[0011] FIG. 4A is a cross-sectional drawing of one embodiment of a
mixing head as described in the present disclosure.
[0012] FIG. 4B is a cross-sectional drawing of another embodiment
of a mixing head as described in the present disclosure.
[0013] FIG. 5 is a graph depicting the unstable particle size
distribution of a standard micronized glycopyrrolate sample as
discussed in Example 1.
[0014] FIG. 6A is an electron micrograph showing the amorphous
morphology of a standard micronized glycopyrrolate sample as
discussed in Example 1.
[0015] FIG. 6B is an electron micrograph showing the fusing and
agglomeration of a standard micronized glycopyrrolate sample after
exposure as discussed in Example 1.
[0016] FIG. 7 is a graph depicting the stable particle size
distribution of a conditioned micronized glycopyrrolate sample as
discussed in Example 1.
[0017] FIG. 8A is an electron micrograph showing the crystalline
morphology of a conditioned micronized glycopyrrolate sample as
discussed in Example 1.
[0018] FIG. 8B is an electron micrograph showing the increased
stability of a conditioned micronized glycopyrrolate sample after
exposure as discussed in Example 1.
[0019] FIG. 9 provides the ethanol vapor sorption isotherm at
25.degree. C. for micronized budesonide materials prepared in
Example 2.
[0020] FIG. 10 includes SEM micrographs of micronized budesonide
materials prepared in Example 2.
[0021] FIG. 11 provides the ethanol vapor sorption isotherm at
25.degree. C. for micronized fluticasone propionate materials
prepared in Example 3.
[0022] FIG. 12 includes SEM micrographs of micronized fluticasone
materials prepared in Example 3.
[0023] FIG. 13 provides the water vapor sorption isotherm at
25.degree. C. for micronized sucrose materials prepared in Example
4.
[0024] FIG. 14 includes SEM micrographs of micronized sucrose
materials prepared in Example 4.
[0025] FIG. 15 provides a graph illustrating the particle size
distribution of micronized, conditioned sucrose material prepared
in Example 4.
[0026] FIG. 16 illustrates an exemplary plasticization curve, which
shows the Tg of a given amorphous material as a function of solvent
content.
[0027] FIG. 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.
[0028] FIG. 18 illustrates an exemplary stability diagram for
glycopyrrolate.
[0029] FIG. 19 is a diagram showing an embodiment of a system
disclosed herein configured to facilitate multiple conditioning
steps.
[0030] FIG. 20 is a diagram showing another embodiment of a system
disclosed herein configured to facilitate multiple conditioning
steps.
DETAILED DESCRIPTION
[0031] Systems and methods for conditioning particulate crystalline
material are described herein. Conditioning 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 desired residence time, (iv) separating the conditioned
material from the conditioning gas, and (v) collecting the
conditioned material. In carrying out a conditioning process
according to the present description, the material to be
conditioned is typically 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 material within the conditioning zone are controlled to
accomplish annealing or phase transformation of the material.
[0032] In certain embodiments, the systems and methods described
herein may be adapted for conditioning a single crystalline
material. In alternative embodiments, the systems and methods
described herein may be adapted to simultaneously condition two or
more crystalline materials. For example, where two or more
materials are to be conditioned simultaneously, the materials may
be introduced into a conditioning zone as a blended material or as
individual materials delivered via independent material inputs.
[0033] Additionally, the systems and methods described herein can
be configured and adapted to provide one or more conditioning
steps. For example, in certain embodiments, systems and methods may
be adapted 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 presence 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
whereby residual solvent within the crystalline material 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 eliminate
amorphous content and reduce or eliminate the presence of residual
solvent(s). In such embodiments, the different annealing processes
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.
[0034] 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 particulate material undergoes an amorphous to
crystalline phase transformation preceded by the plasticization or
localized dissolution followed by crystallization of the amorphous
material. Annealing of particulate material, including micronized
material, as described herein works to reduce the amount of
amorphous material 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 unconditioned material of at least 50%. For example, in such
embodiments, the methods described herein provide a reduction in
amorphous content relative to unconditioned material selected from
of at least 75% and at least 90%.
[0035] 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 particles 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 physical and
chemical characteristics (e.g., water soluble materials and
materials soluble in organic 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
example, industrial chemicals and processes, food products and
additives, cosmetic products, nutritional products and
formulations, such as nutritional supplement products,
nutraceutical products and formulations, pharmaceutically 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:
aspartame; cyclamate; saccharin; stevia; sucralose; amino acids;
vitamins; minerals for nutritional supplements; creatine; and
ascorbic acid.
[0036] 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
distribution 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, preserving the physiochemical
stability of micronized particulates is also generally important to
maintaining the efficacy and shelf-life of pharmaceutical products
incorporating such materials. Though they are described in the
context of micronized pharmaceutical materials, the systems and
methods according to the present description can be utilized to
condition a variety of crystalline materials exhibiting any
particle size distribution that allows the material 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.
[0037] Active agents that can be delivered or formulated as a
crystalline 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 processed according to the present methods
include, but are not limited to, beta agonists, muscarinic
antagonists, corticosteroids, PDE4 inhibitors, anti-infectives,
diuretics, beta blockers, statins, anti-inflammatories, including
non-steroidal anti-inflammatory 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).
[0038] More specific examples of active agents suitable for
processing using the systems and methods described herein include
steroids, muscarinic antagonists, -agonists, and bi-functional
compounds exhibiting, for example, muscarinic antagonist and
-agonists activity suited for respiratory or pulmonary delivery.
Such actives include, for example, short-acting beta agonists,
e.g., bitolterol, carbuterol, fenoterol, hexoprenaline,
isoprenaline (isoproterenol), levosalbutamol, orciprenaline
(metaproterenol), pirbuterol, procaterol, rimiterol, salbutamol
(albuterol), terbutaline, tulobuterol, reproterol, ipratropium and
epinephrine; long-acting .beta..sub.2 adrenergic receptor agonist,
e.g., bambuterol, clenbuterol, formoterol, and salmeterol;
ultra-long-acting .beta..sub.2 adrenergic receptor agonists, e.g.,
carmoterol, milveterol, indacaterol, and saligenin- or
indole-containing and adamantyl-derived .beta..sub.2 agonists;
corticosteroids, e.g., beclomethasone, budesonide, ciclesonide,
flunisolide, fluticasone, methyl-prednisolone, mometasone,
prednisone and trimacinolone; anti-inflammatories, e.g.,
fluticasone propionate, beclomethasone dipropionate, flunisolide,
budesonide, tripedane, cortisone, prednisone, prednisilone,
dexamethasone, betamethasone, or triamcinolone acetonide;
antitussives, e.g., noscapine; bronchodilators, e.g., ephedrine,
adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol,
salbutamol, albuterol, salmeterol, terbutaline; and muscarinic
antagonists, including long-acting muscarinic antagonists, e.g.,
glycopyrronium, dexipirronium, scopolamine, tropicamide,
pirenzepine, dimenhydrinate, tiotropium, darotropium, aclidinium,
trospium, ipatropium, atropine, benzatropin, or oxitropium.
[0039] 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
mixture 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 activity and/or stability.
[0040] The systems and methods described herein are also applicable
to excipients, adjuvants, carriers, etc. used in pharmaceutical
formulations. Such materials can be processed according to the
methods described herein either individually or in mixtures
suitable for formulation. Though not limited to these specific
examples, the systems and methods described herein can be utilized
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.
[0041] 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
context of the present description, the term "micronized" refers to
materials exhibiting a median size as large as, for example, 500
microns, and "micronization" processes 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 factors, 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 example,
milling or grinding processes, including wet-milling and jet
milling processes, precipitation from supercritical or
near-supercritical solvents, high pressure homogenization, spray
drying, spray freeze drying, or lyophilization. Examples of patent
references teaching suitable methods for obtaining micronized
crystalline particles include, for example, in U.S. Pat. No.
6,063,138, U.S. Pat. No. 5,858,410, U.S. Pat. No. 5,851,453, U.S.
Pat. No. 5,833,891, U.S. Pat. No. 5,707,634, and International
Patent Publication No. WO 2007/009164, the contents of each of
which are incorporated herein by reference.
[0042] Though the median size of a micronized material may be as
large as 500 .mu.m, often where a micronized material is needed,
the particle size distribution of the material will be
significantly smaller. For example, in many contexts requiring
micronized material, the material will exhibit a median particle
size of 100 .mu.m or less. In the context of pharmaceutically
active agents or materials prepared for use in pharmaceutical
formulations, the median particle size of the micronized material
may be below 50 .mu.m or even 10 .mu.m. Where the micronized
material conditioned according to the methods described 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 distribution that facilitates pulmonary
delivery. In such embodiments, for example, 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 .mu.m or less. In other such embodiments, the micronized
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 10 .mu.m to about 1 .mu.m,
about 9 .mu.m to about 1 .mu.m, about 8 .mu.m to about 1 .mu.m,
about 7 .mu.m to about 1 .mu.m, about 5 .mu.m to about 2 .mu.m, and
about 3 .mu.m to about 2 .mu.m. 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 optical diameter selected from
10 .mu.m or less, 9 .mu.m or less, 8 .mu.m or less, 7 .mu.m or
less, 6 .mu.m or less, 5 .mu.m or less, 4 .mu.m or less, 3 .mu.m or
less, 2 .mu.m or less, or 1 .mu.m or less.
[0043] It will be readily understood that the embodiments, as
generally described 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 representative of various embodiments.
I. Definitions
[0044] Unless specifically defined otherwise, the terms used herein
have their normal meaning as understood in the art. The following
terms are specifically defined for the sake of clarity.
[0045] The term "active agent" as used herein includes any agent,
drug, compound, 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, pharmaceutical, pharmacological,
diagnostic, cosmetic, prophylactic agents and/or immunomodulating
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 encompass natural or homeopathic products that are not
generally considered therapeutic.
[0046] 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 crystalline particulate
material is reduced or eliminated by, for example, solvent
vaporization and/or exchange. In still further embodiments, the
methods and systems described herein may anneal a crystalline
particulate material by both reducing amorphous content and
reducing the presence of a residual solvent.
[0047] The term "conditioning," as used herein, generally refers to
methods and processes that may be used to improve the
physiochemical stability of a particulate crystalline material. In
specific embodiments, the term "conditioning" refers to methods
that cause a controlled annealing of the particulate material.
[0048] The term "phase transformation" refers to a change in the
bulk of the crystals present in a particulate crystalline material.
In particular embodiments, annealing of a material using the
conditioning systems or methods described herein results 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.
[0049] As used herein, "physiochemical" refers to one or both of
the physical and chemical stability of a material.
[0050] As used herein, the term "inhibit" refers to a reduction,
prevention, or slowing of any given process, event, or
characteristic.
[0051] When used to refer to the conditioned 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 stability may be
evaluated through exposing the particulate material to accelerated
degradation conditions, such as increased temperature and/or
humidity as described herein.
[0052] 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, Clausthal-Zellerfeld, Germany).
II. Systems for Conditioning Particulate Crystalline Material
[0053] FIG. 1 provides a schematic illustration of an embodiment of
a system for conditioning 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 delivered and prepared
for mixing with a conditioning gas. The system also includes a
conditioning gas supply zone 120. The conditioning gas is supplied
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 delivering the crystalline particulate material, and the
particulate material being conditioned remains entrained,
suspended, or aerosolized within the controlled atmosphere within
the conditioning chamber. The crystalline material undergoes an
annealing process within the conditioning zone 140 as it is
maintained within the conditioning zone 140 for a desired 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.
[0054] The nature of and extent to which annealing of the
particulate material takes place can be controlled by the residence
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 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.
[0055] The material to be conditioned may be provided to the
delivery zone 110 in a form that is appropriate for the chosen
material and the conditioning process. 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 suitable
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.
[0056] In certain embodiments, particulate material may be
subjected to a micronization process within the delivery zone 110.
In such embodiments, the delivery zone 110 may include 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 delivery zone 110 may incorporate any one
of a number of known devices or systems for micronization. For
example, the crystalline material may be micronized in the delivery
zone 110 using known milling or grinding processes, known
crystallization or recrystallization processes, or known
micronization processes utilizing precipitation from supercritical
or near-supercritical solvents, spray drying, spray freeze drying,
or lyophilization.
[0057] 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 systems 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 associated
with the annealing achieved by the conditioning 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
material.
[0058] The mixing zone 130 illustrated in FIG. 1 is shown as
separate from the conditioning zone 140. In such an embodiment, the
crystalline material to be conditioned (such as, e.g., micronized
material suspended or entrained 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 dispersion 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 accomplishes the mixing required for annealing of the
particulate material within the conditioning zone. In such
embodiments, the micronized material may be introduced into the
conditioning 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 delivery gas and the micronized material
disbursed therein upon entry into the conditioning zone 140.
[0059] 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 conditioning of one or more selected
particulate materials. In particular embodiments, the conditioning
gas is delivered at a specified rate and mixes with the delivery
gas at a selected 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 ranging
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 delivery gases are introduced into the
conditioning zone 140 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. 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 supplied 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 controlled 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.
[0060] The temperature of the conditioning gas may also be
controlled. Annealing of particulate material can be significantly
affected by temperature. In certain embodiments, the temperature of
the conditioning gas is selected from between about 10.degree. C.
and 100.degree. C. In specific examples of such embodiments, the
temperature of the conditioning gas may be selected from one of the
following ranges, between about 10.degree. C. and 70.degree. C.,
between about 20.degree. C. and 50.degree. C., between about
10.degree. C. and 50.degree. C., and between about 20.degree. C.
and 30.degree. C., depending on the nature of the particulate
material being processed.
[0061] 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 adapted to
reduce or eliminate the presence of residual solvent(s) by solvent
exchange.
[0062] 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 soluble, but exhibits solubility in one or more
organic solvents, the solvent vapor included in the conditioning
gas may simply include an organic solvent vapor, such as an alcohol
(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.) 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
solvent vapor. Examples of inert gases include, without 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 according 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 material includes solvent exchange, the solvent(s)
included in the conditioning gas may be selected to provide
improved safety and/or physiochemical stability of the particulate
material.
[0063] Where a solvent is included 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.
[0064] The relative concentration of solvent vapor included in a
conditioning gas can also be adjusted 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 specific 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 amorphous 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.
[0065] 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 amorphous solids, measurement and effects on stability. In
Progress in Amorphous Food and Pharmaceutical Systems, Levine, H.,
Ed. The Royal Society of Chemistry: London, 2002; pp 275-316).
Exposure of amorphous material to temperature in excess of the
glass transition can be achieved in the absence of any solvent by
exposing the amorphous material to a stream of hot air above its
glass transition temperature. However, the glass transition
temperature is also a function of the fraction of solvent present
in the amorphous material, an effect known as plasticization.
Plasticization is typically represented by a plasticization curve,
such as the one shown in FIG. 16, which shows the Tg of a given
amorphous material as a function of solvent (in this case water)
content.
[0066] 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 FIG. 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.
[0067] The glass transition plasticization curve and the sorption
isotherm can be combined to construct a stability diagram as the
one shown in FIG. 18 for the selected material. The stability
diagram shown in FIG. 18 is one created for glycopyrrolate. The
stability diagram can be used to choose operational conditions for
the systems and methods described herein that promote fast
annealing of the crystalline material selected for conditioning.
For example, as is illustrated in FIG. 18, in the case of
glycopyrrolate fast crystallization of amorphous material will
occur at RH>50% in the range of 20-40.degree. C., and at
60.degree. C. it would only require 10% RH to promote
annealing.
[0068] 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, relatively 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 delivery 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 particle 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
creates a more turbulent recirculating dispersion of the
gas(es).
[0069] 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
seconds. In certain such embodiments, the particulate material 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 seconds, 9 seconds, and 10 seconds.
[0070] After the particulate material has been annealed in the
conditioning zone 140, the conditioned material is separated from
the conditioning gas and collected in the separation and collection
zone 150. The micronized 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 materials, including
micronized materials, and separation of such materials from a
conditioning gas. Cyclone collectors are commercially available and
suitable for use as the collection zone 150 of the systems
described herein.
[0071] In addition to a collection device, such as a cyclone
collector, the collection zone 150 may be configured to facilitate
direct collection of the processed material. 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 collection 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 included in
the collection 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 conditioned 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. Depending 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.
[0072] In still other embodiments, the collection zone 150 may be
configured to allow further processing 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 processing of
the conditioned material. In such embodiments, the collector
included 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 include or be in operable
communication with a holding chamber as described and illustrated
herein, such as, for example, in association with the systems
illustrated in FIG. 19 and FIG. 20.
[0073] In some embodiments, the systems and methods described
herein may be utilized to simultaneously process and condition more
than one particulate material. For example, 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
conditioning zone as a particulate material including a combination
of two or more chemical entities. 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 solubility characteristics (e.g., each of the
different materials exhibit solubility in water or each of the
materials exhibit solubility in a given organic 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 exhibit
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).
[0074] 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 FIG. 2.
Because the delivery zone of the system illustrated in FIG. 2
includes a device configured for the micronization of the material
to be conditioned, the delivery zone of the system will be referred
to as a micronizing zone 210. As shown in FIG. 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 carried by a delivery gas 216 and supplied to
the mixing zone 230.
[0075] The micronized crystalline material is supplied to the
mixing zone 230 as a micronized material with a desired particle
size distribution. In certain embodiments, for example, at least
90% of the micronized particles by volume exhibit an optical
diameter of about 10 .mu.m 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 .mu.m to about 1
.mu.m, about 9 .mu.m to about 1 .mu.m, about 8 .mu.m to about 1
.mu.m, about 7 .mu.m to about 1 .mu.m, about 5 .mu.m to about 2
.mu.m, and about 3 .mu.m to about 2 .mu.m. In further embodiments,
at least 90% of the micronized crystalline particles by volume
exhibit an optical diameter selected from 10 .mu.m or less, 9 .mu.m
or less, 8 .mu.m or less, 7 .mu.m or less, 6 .mu.m or less, 5 .mu.m
or less, 4 .mu.m or less, 3 .mu.m or less, 2 .mu.m or less, or 1
.mu.m or less.
[0076] The micronizing zone 210 may be separated from an external
environment or contained within a safety barrier or enclosure (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 micronized material produced in the micronizing
zone 210. Where included in the systems described herein, a safety
barrier may be constructed of any suitable material such as metal,
glass, plastic, composites, etc., that are sufficient to contain
micronized particles.
[0077] With reference to FIG. 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 heating
chamber 221 comprises a heat source, such as an electric 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, including, for
example, compressed air, nitrogen, oxygen, and helium.
[0078] The conditioning gas supply zone 220 may further comprise a
liquid evaporation chamber 225. The solvent used to produce the
solvent vapor disbursed within the carrier gas 222 can be generated
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 desired relative humidity. In other embodiments,
particularly where the micronized crystalline material to be
conditioned is not water soluble, the solvent for use with the
systems disclosed herein may be a non-aqueous liquid, such as an
organic solvent described herein.
[0079] 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 atomizer 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 atomizer 223 can be selected
from, for example, pressure nozzles, pneumatic atomizers, impinging
jet atomizers. In one such embodiment, the carrier gas 222 is
heated in the heating chamber 221, a liquid atomizer 223 delivers
liquid solvent to the carrier gas within the conditioning gas
supply zone 220, and the carrier gas 222 and atomized liquid
solvent 224 are supplied to the liquid evaporation chamber 225. As
the carrier gas 222 and atomized liquid solvent 224 pass through
the liquid evaporation chamber, the liquid solvent vaporizes and
the carrier gas becomes a conditioning gas 226 having a desired
solvent vapor concentration.
[0080] 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.degree. C. to about
100.degree. C., 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.degree. C., 21.degree. C., 22.degree. C.,
23.degree. C., 24.degree. C., 25.degree. C., 26.degree. C.,
27.degree. C., 28.degree. C., 29.degree. C., and 30.degree. C. 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 embodiments, however, the temperature may be as high as
22.degree. C. and the relative humidity as low as 0.05%.
[0081] With continued reference to FIG. 2, the mixing zone 230 is
configured to mix incoming micronized crystalline material 235 with
the conditioning gas 226. In particular embodiments, the mixing
zone 230 is configured to mix a delivery gas flow 216 with a
conditioning gas 226. In some embodiments of the systems 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 FIGS. 3A, 3B, and 3C, a dispersion head assembly 330
suitable for use in the systems described herein may include a
housing 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
FIG. 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
exposing the micronized crystalline material to the conditioning
gas 326.
[0082] Where a mixing head is included in a system according to the
present description, as shown in FIG. 3, the mixing head may be
modifiable and interchangeable 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 adjusted 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 modified and
adjusted to control the mixing dynamics and the volume and/or rate
of mixed gases that exit the mixing head 340.
[0083] 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 mixture leaves the mixing zone 230
and is delivered to the conditioning zone 240. For example, FIGS.
4A and 4B provide further embodiments of different mixing heads
that may be used in the systems described herein. FIG. 4A shows
mixing head 420 comprising delivery gas inlet 450 and injection
nozzle inlet 425 located near the base of the injection nozzle 445.
FIG. 4B shows a mixing head 430 comprising a delivery gas inlet 450
and injection 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 be mixed in the injection nozzle 445
before the mixture leaves the mixing zone 230 and is delivered to
the conditioning zone 240.
[0084] 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 embodiments, 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 delivery 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.
[0085] With continued reference to FIG. 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 micronized 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 another. Alternatively, the mixing zone 230
and conditioning 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.
[0086] In certain embodiments, 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 particles
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 within
the conditioning 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 chamber 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 mixture 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 10 seconds. In certain such embodiments, the
residence time of the micronized particles 235 within the
conditioning chamber 240 may be selected from one the residence
times detailed herein.
[0087] A conditioning chamber 240 suitable for use in the systems
described may be configured as for example, a tank, a column, a
funnel, a tube, or other appropriate devices or structures. In
further embodiments, 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 conditioning chamber 240 may be
modified by adjusting, for example, the length, width, height,
volume, and shape of the conditioning chamber 240.
[0088] Conditioned micronized active agent particles 246 are
separated from the conditioning gas 226 in a separating zone 250.
The separating zone 250 may comprise elements or devices designed
to separate conditioned 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 conditioning
zone 240. For example, in certain embodiments, although the
controlled atmosphere of the conditioning zone 240 initiates or
even substantially completes the annealing process, annealing of
amorphous material continues as the micronized 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
capture 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 desired.
[0089] Though FIG. 1 and FIG. 2 illustrate conditioning systems
having a single conditioning zone, systems according to the present
description may also include multiple conditioning zones. In such
embodiments, the different conditioning zones may expose the
crystalline particulate material to different annealing conditions.
Such systems, therefore, can be configured to provide multiple
in-process conditioning steps. FIG. 19 and FIG. 20 provide
schematic illustrations of two embodiments of conditioning systems
that provide two conditioning zones, thereby facilitating multiple
annealing steps within a single system.
[0090] As shown in FIG. 19, a conditioning system 600 as described
herein may include a delivery 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 conditioning system can be configured as
described in relation to the systems illustrated in FIG. 1 and FIG.
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 product is delivered
to the product holding chamber 660. The product holding chamber 660
can be configured to maintain the conditioning product in a
continuously 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 conditioned material from
collection zone 650. In certain embodiments, the cut-off valve 670
seals the product holding chamber 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.
[0091] Once delivered to the product holding 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 secondary conditioning gas. In such an
embodiment, the upstream components of the conditioning system 600
(e.g., the delivery zone 610, conditioning 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 holding chamber 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 conditioning gas. The product
can be maintained in a continuously fluidized state within the
product holding chamber 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 presence and concentration of one
or more solvents, and the temperature, flow rate, and direction or
turbulence of flow of the secondary conditioning gas may be
adjusted to accomplish a desired secondary annealing 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 product holding chamber 660, the system illustrated in
FIG. 19 can be utilized to provide multiple conditioning steps
using a single system.
[0092] The residence time of the conditioned product within the
holding chamber 660 can be easily adjusted based on the material
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
flexibility 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.
[0093] FIG. 20 illustrates a conditioning system 700 that includes
two conditioning subsystems, a primary conditioning system 701 and
secondary conditioning system 801. The primary conditioning system
701, includes a delivery zone 710, a primary conditioning gas
supply zone 720, a primary mixing zone 730, a primary conditioning
zone 740, and a primary collection zone 750. The primary
conditioning system 701 and the secondary conditioning system 801
may be separated by, for example, a primary 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 conditioned 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 provides a physical barrier capable of isolating the
primary and secondary conditioning systems 701, 801. In certain
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., delivery 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 chamber 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.
[0094] As shown in FIG. 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
FIG. 20, the primary and secondary conditioning systems 701, 801
can be configured as described in relation to the systems
illustrated in FIG. 1 and FIG. 2, and the systems can be adapted
for conditioning a wide range of materials using any process
conditions described herein.
[0095] As material is processed in the primary 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 delivered to the primary holding chamber 760. While the product
is processed in the primary conditioning system 701 and collected
in the primary holding chamber 760, the cut-off valve 770 will
typically remain closed. Once the first conditioning process is
complete and the primary annealed material is collected in the
primary holding chamber 760, the cut-off valve 770 may be opened
and the primary annealed 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 conditioning 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 disperse
the primary annealed product) in the secondary mixing zone 830.
[0096] The primary annealed product remains entrained, suspended or
aerosolized in the secondary conditioning gas within the secondary
conditioning zone 840. The primary annealed 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
described herein, the nature and content of the secondary
conditioning gas, including the presence and concentration of one
or more solvents, and the temperature, flow rate, and direction or
turbulence of flow of the secondary conditioning gas may be
adjusted to accomplish a desired secondary annealing 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 FIG. 20 can be utilized to provide multiple conditioning steps
using a single system.
[0097] Though described in relation to embodiments illustrated in
the figures provided herein, conditioning systems according to the
present description are not limited to the specific, illustrated
embodiments. The systems for conditioning crystalline particulate
materials described herein are scalable and adaptable for areas of
various size. In particular embodiments, the systems 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., according the desired output rate
and the available 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
well-suited for efficient production of conditioned, micronized
particulates. For example, the systems as disclosed here may be
incorporated into commercial milling and micronization processes 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 embodiments, 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 Particulate Crystalline Material
[0098] Methods for conditioning particulate crystalline material
are also provided herein. Methods according to the present
description can be carried out using the conditioning systems
provided herein. In general, the methods described herein include:
(1) generating and/or providing a crystalline 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 typically 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 material within the conditioning zone are controlled to
accomplish annealing of the material.
[0099] In specific embodiments, the methods include a continuous
process for micronizing, conditioning, and collecting a crystalline
material. In such embodiments, generating the crystalline material
includes subjecting the material to a micronization process 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 conditioning of micronized material
(or, more generally, any size comminuted material), the particulate
material may be blended with a conditioning gas and retained within
a conditioning zone to anneal the particulate prior to particle
collection.
[0100] In other embodiments, methods according to the present
description include primary and secondary conditioning steps. In
such embodiments, the crystalline particulate material can be
introduced into (e.g., entrained, suspended, or aerosolized within)
a first conditioning gas to carry out a primary annealing and
subsequently introduced 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
annealing are carried out using a single conditioning gas, the
conditioning gas may anneal the particulate material through both
reduction of amorphous content and removal of an undesired residual
solvent by vaporization or solvent replacement.
[0101] The methods provided can be tailored to specific materials
to be processed. 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 particular 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, citrate, tartrate, malate, maleate,
succinate, benzoate, p-chlorobenzoate, diphenyl-acetate or
triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate,
1-hydroxynaphthalene-2-carboxylate,
3-hydroxynaphthalene-2-carboxylate, methanesulfonate and
benzenesulfonate. In particular embodiments of the methods
described herein, the bromide salt of glycopyrronium is used,
namely (3-[(cyclopentylhydroxyphenylacetyl)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.
[0102] Where crystalline glycopyrronium, such as crystalline
glycopyrrolate, is the material processed by the methods described
herein, the glycopyrronium material can be micronized to exhibit
particle size characteristics as described herein, such as, for
example, a particle size distribution suitable for pulmonary
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 embodiment, the
glycopyrronium is micronized 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.
[0103] In specific embodiments, the bromide salt of glycopyrronium
(glycopyrrolate) may be processed 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 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.
[0104] When conditioning glycopyrrolate, the conditioning gas may
be delivered at a temperature ranging from about 20.degree. C. to
about 30.degree. C. and include water vapor as a solvent. In
particular embodiments of methods for conditioning glycopyrrolate,
the temperature of the conditioning gas may be selected from at
least 20.degree. C., 21.degree. C., 22.degree. C., 23.degree. C.,
24.degree. C., 25.degree. C., 26.degree. C., 27.degree. C.,
28.degree. C., 29.degree. C., and 30.degree. C. Moreover, where
included in the conditioning gas for annealing glycopyrrolate
according 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
micronized 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 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
reduction of amorphous content.
[0105] In other embodiments, the methods provided can be tailored
to for the annealing of materials soluble in organic solvents. For
example, the methods described herein can be tailored to the
conditioning of corticosteroid active agents soluble in organic
solvents. In certain such embodiments, the methods described 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
example, in U.S. Pat. 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. Pat. No. 3,929,768, the contents of
which are incorporated herein by reference.
[0106] Micronization of crystalline corticosteroids, such as
budesonide and fluticasone, can lead to a micronized material that
includes significant amorphous content, and in particular
embodiments, the present methods can be adapted to reduce or
eliminate amorphous material from particulate crystalline
corticosteroid 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 solvate (hydrates).
[0107] 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 corticosteroid 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 micronized via a jet mill and the
delivery gas may be typical gas flow exiting the jet mill, which
would include aerosolized, micronized particles of the
corticosteroid.
[0108] In specific embodiments, the corticosteroid 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.
[0109] When conditioning a corticosteroid exhibiting solubility in
an organic solvent, such as fluticasone propionate or budesonide,
the conditioning gas may be delivered at a temperature ranging from
about 20.degree. C. to about 30.degree. C. and include an organic
solvent vapor as a solvent. In particular embodiments of methods
for conditioning a corticosteroid, including a corticosteroid
selected from fluticasone propionate and budesonide, the
temperature of the conditioning gas may be selected from at least
20.degree. C., 21.degree. C., 22.degree. C., 23.degree. C.,
24.degree. C., 25.degree. C., 26.degree. C., 27.degree. C.,
28.degree. C., 29.degree. C., and 30.degree. C.
[0110] Moreover, where included in the conditioning gas, the
organic solvent vapor may be provided within the conditioning 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 alcohol (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 selected from fluticasone propionate and
budesonide, the organic solvent vapor may be provided within the
conditioning gas to provide a relative saturation of the solvent in
the conditioning zone ranging from about 50% to about 80%. For
example, in embodiments of methods for conditioning corticosteroid
materials, including corticosteroids selected from fluticasone
propionate and budesonide, the conditioning gas may be supplied at
a temperature described herein with a relative solvent saturation
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
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
conditioning.
[0111] As is further evidenced by the experimental examples that
follow, methods according to the present description can be adapted
to accomplish conditioning of varying materials exhibiting
divergent physical and chemical properties.
IV. Exemplary Embodiments
[0112] In specific embodiments, 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 crystalline particles with a conditioning gas comprising
a carrier 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, 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.
[0113] The material (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 crystalline material exits the conditioning
zone.
[0114] The material (e.g., micronized crystalline material)
processed according 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.
[0115] 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 material exits the conditioning zone.
[0116] 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.degree. C. to 100.degree. C. and at a relative humidity
ranging from about 0.05% to 95%.
[0117] The material (e.g., micronized crystalline material)
processed according methods described herein may not be water
soluble (e.g., soluble in one or more organic solvents). Where the
material to be processed 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.degree. C. to
100.degree. C. and at a vapor pressure of a non-aqueous solvent in
the range of about 0.05% to 95%.
[0118] The material (e.g., micronized crystalline material)
processed according to methods described 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 solvent vapor, and
the conditioning gas may be supplied at a temperature ranging from
about 10.degree. C. to 100.degree. C. and at a relative humidity of
the aqueous solvent in the range of about 0.05% to 95% and a vapor
pressure of the non-aqueous solvent in the range of about 0.05% to
95%.
[0119] In any of the methods described herein, the material (e.g.,
micronized crystalline material) 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
produced using a jet mill and aerosolized in the jet mill gas
flow.
[0120] In any of the embodiments of the methods and systems
described herein, 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 crystalline material. In
such embodiments, the aerosolized micronized crystalline material
may be entrained, suspended or aerosolized within a delivery
gas.
[0121] 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 25 standard cubic feet per minute (SCFM) up
to about 300 SCFM while mixing with the particulate crystalline
material.
[0122] In any of the embodiments of the systems and methods
described herein, the particulate material (e.g., micronized
crystalline material) may be entrained, suspended or aerosolized
within a delivery 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
conditioning gas.
[0123] In any of the embodiments of the systems and methods
described herein, the conditioning gas may comprise nitrogen
gas.
[0124] In any of the embodiments of the systems and methods
described herein, the particulate material (e.g., micronized
crystalline material) may be mixed with the conditioning gas in a
closed chamber.
[0125] In any of the embodiments of the systems and methods
described herein, the particulate material (e.g., micronized
crystalline material) 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.
[0126] In specific embodiments, systems for conditioning a
particulate crystalline material (e.g., micronized crystalline
material) according to the present description include: a delivery
zone for delivering the particulate material; a mixing zone in
fluid communication with the delivery zone, wherein the particulate
crystalline material 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 providing 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 material 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 conditioned material is
collected. In certain such embodiments, the delivery zone may be a
micronizing zone comprising a device for micronizing the
particulate crystalline material.
[0127] In particular embodiments, the systems described herein are
configured to process a particulate crystalline material (e.g.,
micronized crystalline 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.degree. C. to 100.degree. C. and at a
humidity ranging from about 0.05% to 90% relative humidity.
[0128] 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.degree. C. to 100.degree. C. and at a vapor pressure of a
non-aqueous solvent in the range of about 0.05% to 90%.
[0129] 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.degree. C. to 30.degree. C. and
at a relative humidity of 50 to 75% and vapor pressure of a
non-aqueous solvent in the range of about 50% to 75%.
[0130] In any of the embodiments described herein, the system for
conditioning particulate material may include a conditioning gas
supply zone configured to provide a conditioning gas at a
temperature of about 25.degree. C. and with a humidity of about 65%
relative humidity
[0131] In any of the embodiments described herein, the system for
conditioning particulate 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 between about
0.5 to 60 seconds. For example, the systems for conditioning
particulate material described herein may include a conditioning
zone configured to maintain a mixture of the particulate
crystalline material 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
conditioning 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.
[0132] In any of the embodiments described herein including a
delivery zone that comprises 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.
[0133] In any of the embodiments described herein, the systems for
conditioning a particulate material may be configured for
conditioning a material selected from a particulate crystalline
material (e.g., micronized crystalline material) selected 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,
including fluticasone propionate, budesonide, mometasone,
ciclesonide, and Compound A.
[0134] In particular embodiments of the systems described herein,
the systems may be configured for conditioning a particulate
glycopyrrolate material using any of the process conditions
detailed herein. In certain such embodiments, the systems described
herein can be configured for micronizing a crystalline
glycopyrrolate material. In such embodiments, the systems may
include a micronizing zone with a jet mill for micronizing
glycopyrrolate. In certain such embodiments, 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.
[0135] In any of the embodiments described herein, the systems for
conditioning a particulate crystalline material (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.
[0136] In any of the embodiments described herein, the systems 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
systems 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.
[0137] In any of the embodiments described herein, the systems for
conditioning a particulate crystalline material (e.g., micronized
crystalline material) may be configured 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 configured 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.
[0138] In any of the embodiments described herein, the systems for
conditioning a particulate crystalline material (e.g., micronized
crystalline material) the collection zone may include a cyclone
collector.
[0139] In any of the embodiments described herein, the systems for
conditioning a particulate crystalline material (e.g., micronized
crystalline material), the system may be configured to process
micronized crystalline material having a particle size ranging from
about 0.1 .mu.m to about 10 .mu.m.
[0140] In any of the embodiments described herein, the systems for
conditioning a particulate crystalline material (e.g., micronized
crystalline material), the system may include a holding chamber for
collecting the conditioned particles. In certain such embodiments,
the system may be configured to prepare and/or deliver a secondary
conditioning gas to the holding chamber and mix the secondary
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 crystalline particles. Alternatively,
in embodiments of a system for conditioning a particulate
crystalline material that include 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 holding chamber may be
configured to maintain the conditioned material in a continuously
fluidized state.
EXPERIMENTAL EXAMPLES
Example 1
[0141] Glycopyrrolate (3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,
1-dimethyl-, bromide) was received 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.
[0142] 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 through a droplet evaporation
chamber after which it was directed to a mixing zone. In the mixing
zone, the conditioning gas was mixed with the jet-milled 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 particles were
separated from the gas phase and transported to a collection
vessel. Upon completion of the batch processing, the collector was
disengaged and transferred to a glove box for sampling. The
sampling occurred in a <5% relative humidity environment.
Samples were then analyzed for particle size distribution and
amorphous content.
[0143] The particle size distribution of the standard jet milled
micronized GP particles and the micronized GP particles after
in-process 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 micronized GP particles.
TABLE-US-00001 TABLE 1 Comparison of micronized GP particle size
distributions Particle Size Distribution of Micronized GP X10 X50
X90 Span Process (.mu.m) (.mu.m) (.mu.m) ((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
[0144] Experimental batches of micronized GP particles were
prepared according to the in-process conditioning 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 conditioned 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-US-00002 TABLE 2 Micronized GP in-process conditioning
parameters Conditioning Parameters Jet Milling Parameters Approx.
Conditioning Feed Grind Jet Mill Conditioning Residence Gas Temp
Pressure Pressure Gas Flow Gas Flow Time Batch # (.degree. C./% RH)
(psi) (psi) (std L/min) (std L/min) CMR (sec) 1A Ambient/0 82 75
122 265 2.2:1 2.9 2B 25.degree./35 82 75 122 265 2.2:1 2.9 2C
25.degree./65 82 75 122 265 2.2:1 2.9 2D 25.degree./65 82 75 122
166 1.4:1 3.8 2E 26.degree./51 82 75 122 265 2.2:1 2.9 2F
28.degree./67 82 75 122 265 2.2:1 2.9 2G 24.degree./64 82 75 122
166 1.4:1 3.8
[0145] 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
25.degree. C. and 60% relative humidity.
TABLE-US-00003 TABLE 3 Particle size distributions initial and
post-exposure % Particle Size Distribution Particle Size
Distribution Amorphous Initial Post-exposure Content X10 X50 X90
Span X10 X50 X90 Span Physical Batch # Initial (.mu.m) (.mu.m)
(.mu.m) (.mu.m) (.mu.m) (.mu.m) (.mu.m) (.mu.m) Stability 1A 17.9%
0.6 1.5 3.1 1.7 0.9 3.4 13.3 3.6 Unstable, fused 2B 5.3% 0.6 1.6
3.1 1.6 0.7 2.0 3.6 1.4 Unstable, partially fused 2C 0.9% 0.6 1.5
2.8 1.5 0.6 1.6 2.9 1.5 Stable, 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, no 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,
no fusing
[0146] As shown in FIG. 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 exposure.
[0147] FIG. 6A is an electron micrograph of the 1A control sample
before exposure showing an amorphous morphology with rough surfaces
and edges and increased shape variability. FIG. 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.
[0148] In contrast, analysis of the 2D batch that was conditioned
according to the in-process conditioning parameters as listed in
Table 2, showed particle size stability. As shown in FIG. 7, the
particle size distribution was essentially identical for the
initial sampling and after the 1-day exposure at 25.degree. C. and
60% relative humidity. Similar results were observed for the
stability of the particle size distribution for the 2C, 2E, 2F, and
the 2G samples (not shown).
[0149] Electron micrographs of the in-process conditioned sample 2E
show improved stability of conditioned micronized GP particles. As
shown in FIG. 8A, the conditioned micronized GP particles show a
crystalline morphology with smooth surfaces and distinct edges. As
seen in FIG. 8B, the conditioned 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
[0150] Examples 2 and 3 provide examples of in-process conditioning
of water insoluble molecules using a conditioning gas containing a
vaporized organic solvent (ethanol) to promote annealing.
Budesonide and fluticasone propionate were selected as
representative compounds. The annealing conditions were determined
by selecting conditions that would promote crystallization of the
amorphous fraction under an ethanol atmosphere by determining the
corresponding ethanol sorption isotherms.
Example 2
[0151] Budesonide (16,17-(butylidenebis(oxy))-11,21-dihydroxy-,
(11-.beta., 16-.alpha.)-pregna-1,4-diene-3,20-dione16,
17-(butylidenebis(oxy))-11,21-dihydroxy-, (11-.beta.,
16-.alpha.)-pregna-1,4-diene-3,20-dione) was micronized using a
laboratory scale jet mill set at 75 psig grinding pressure and 80
psig injection pressure. The crystalline 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.
[0152] 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.
[0153] 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 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 185.degree. C. and
conditioning zone outlet of 30.degree. C. 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 micronizing
gas (also referred to as a delivery 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 0.5 L stainless
steel collector, transferred to a purged (<5% RH) isolator and
sampled for analysis.
[0154] 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-US-00004 TABLE 4 Particle Size Distribution of Micronized
Budesonide. D10 D50 D90 Micronized Budesonide (.mu.m) (.mu.m)
(.mu.m) Span Batch 1 (unannealed) 0.6 2.3 5.4 2.1 Batch 2
(annealed) 0.5 1.2 2.5 1.7
[0155] The amorphous content by vapor sorption and particle
morphology for both batches were also assessed. FIG. 9 provides the
ethanol vapor sorption isotherm at 25.degree. C. for both batches
of micronized budesonide. As can be seen in FIG. 9, Batch 1
(unannealed, top) remained substantially amorphous (weight loss at
60% p/p.sub.o), while Batch 2 (annealed, bottom) was stable and
showed no crystallization event. FIG. 10 provides SEM imaging of
the material from Batch 1 and Batch 2, and as can be seen by
reference to FIG. 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
[0156] Fluticasone propionate
(S-(fluoromethyl)-6.alpha.,9-difluoro-11.beta.,
17-dihydroxy-16.alpha.-methyl-3-oxoandrosta-1,
4-diene-17.beta.-carbothioate, 17-propanoate) was micronized using
a laboratory scale jet mill set at 65 psig grinding pressure and 74
psig injection pressure. The crystalline fluticasone was fed into
the jet mill at a powder feed rate of approximately 25.+-.10% g/hr.
Two batches of micronized fluticasone were produced. One was not
subjected to further processing, while the second was conditioned
to remove amorphous content according to the present
description.
[0157] 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.
[0158] 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 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 185.degree. C. and
conditioning zone outlet of 30.degree. C. At the given grind and
injection pressures delivered to the system, the resulting
micronizer gas flow was nominally 108 SLPM, along with a total
conditioning gas flow rate (including the atomizer gas flow) of 235
SLPM. The conditioning 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 0.5 L
stainless steel collector, transferred to a purged (<5% RH)
isolator and sampled for analysis.
[0159] Both batches of micronized fluticasone were analyzed for
particle size distribution by Sympatec laser diffraction, with the
results provided in Table 5. As can be seen in Table 5, Batch 2
(annealed) demonstrated good physical stability after
micronization, whereas Batch 1 (unannealed) demonstrated
agglomeration marked by a shift in size distribution.
TABLE-US-00005 TABLE 5 Particle Size Distribution of Micronized
Fluticasone Propionate. Micronized Fluticasone D10 D50 D90
propionate (.mu.m) (.mu.m) (.mu.m) Span Batch 1 (unannealed) 0.5
1.5 3.4 2.0 Batch 2 (annealed) 0.5 1.4 3.1 1.9
[0160] The amorphous content by vapor sorption and particle
morphology for both batches were also assessed. FIG. 11 provides
the ethanol vapor sorption isotherm at 25.degree. C. for both
batches of micronized fluticasone. As can be seen in FIG. 11, Batch
1 (unannealed, top) remained substantially amorphous (weight loss
at 60% p/p.sub.o), while Batch 2 (annealed, bottom) was stable and
showed no crystallization event. FIG. 12 provides SEM imaging of
the material from Batch 1 and Batch 2, and as can be seen by
reference to FIG. 10, the annealed material of Batch 2 (right)
presented smoother surfaces and more rounded edges than the
unannealed material of Batch 1 (left).
Example 4
[0161] Three scale-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 two-collector 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
40.degree. C. conditioning zone outlet temperature).
[0162] The system was brought to steady-state equilibrium, with the
jet mill operating 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
micronized material. The conditioning gas flow rate was supplied at
approximately 78 SCFM with a humidifier outlet temperature of
57.degree. C. Water was delivered to the 0.21'' atomizer nozzle at
a liquid flow rate of 75.1 ml/min. The conditioning to
micronization gas ratio (CMR) was set at 2.2:1. Product was
collected in 8 L stainless steel collectors, which were heated
using a thermal jacket to prevent the collector environment from
falling below the dew-point temperature.
[0163] Once the system reached steady-state, powder was fed into
the jet mill at a nominal rate of 1 kg/hr. A collector change-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 sampling and packaging to prevent
any post-process affects due to ambient moisture.
[0164] All batches were analyzed for particle size distribution by
Sympatec laser diffraction, 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 particle size distribution achieved
in each batch exhibited good batch to batch reproducibility.
TABLE-US-00006 TABLE 6 Particle Size Distribution of
Micronized/Annealed GP Micronized/Annealed D10 D50 D90
Glycopyrrolate (.mu.m) (.mu.m) (.mu.m) 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 - Collector 1 0.52 1.47 3.03 1.70 Batch C -
Collector 2 0.51 1.45 2.96 1.69
[0165] All batches were also analyzed for amorphous content by
dynamic vapor sorption using n=2 replicates per collector. The
results are provided in Table 7, which reflects that the amorphous
content achieved in each batch also exhibited good batch to batch
reproducibility.
TABLE-US-00007 TABLE 7 Amorphous Content of Conditioned GP
Calculated Calculated Micronized/Annealed Amorphous Content,
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
[0166] Sucrose (saccharose;
.alpha.-D-glucopyranosyl-(1.fwdarw.2)-.beta.-D-fructofuranoside)
was micronized and conditioned using the large scale
micronization/annealing system utilized in Example 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.
[0167] Sucrose 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 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 8 L stainless steel collectors, without the use of a thermal
jacket.
[0168] 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 prevent any post-process
affects due to ambient moisture.
[0169] Sucrose B (annealed/conditioned) was conditioned at a target
55% relative humidity at 40.degree. C. conditioning zone outlet
temperature. The system was brought 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 approximately 61.8 SCFM with a humidifier outlet
temperature of 157.2.degree. C. Water was delivered to a 0.21''
atomizer nozzle at a liquid flow rate of 76.2 ml/min. The
conditioning to micronizing gas Ratio (CMR) was set at 1.4:1.
Product was collected in 8 L stainless steel collectors, which were
heated using a thermal jacket to prevent the collector environment
from falling below the dew-point temperature.
[0170] 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 affects due to residual vapor. The collectors were
transferred to a purged isolator (<5% RH) for sampling and
packaging to prevent any post-process affects due to ambient
moisture.
TABLE-US-00008 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
.degree. 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
[0171] 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 FIG. 15. Sucrose A was not
tested after exposure, however fusing of the material on stability
was confirmed by visual observation, demonstrating an unstable
powder. Sucrose B was exposed to a 25.degree. C./60% RH environment
and showed good stability even post-exposure. FIG. 15 shows the
particle size distribution observed in Sucrose B after it was
freshly made and then after exposed to a 25.degree. C./60% RH
environment.
TABLE-US-00009 TABLE 9 Particle Size Distribution of Micronized
Sucrose Particle Size Distribution Particle Size Distribution
Initial T = 1 day at 25.degree. C./60% RH X10 X50 X90 Span X10 X50
X90 Span Physical Batch # (.mu.m) (.mu.m) (.mu.m) (.mu.m) (.mu.m)
(.mu.m) (.mu.m) (.mu.m) Stability Sucrose 1 0.5 1.7 4.5 2.4 NT NT
NT NT Unstable, fused Sucrose 2 0.6 2.2 4.9 1.9 0.7 2.5 5.2 1.9
Stable, no fusing
[0172] The amorphous content by vapor sorption and particle
morphology for both batches of micronized sucrose were also
assessed. FIG. 13 provides the water vapor sorption isotherm at
25.degree. C. for both batches of micronized sucrose. As can be
seen in FIG. 13, Sucrose A (unannealed, top) remained substantially
amorphous (weight loss at 30% p/p.sub.o), while Sucrose B
(annealed, bottom) was stable and showed no crystallization event.
FIG. 14 provides SEM imaging of the material from Sucrose A and
Sucrose B, and as can be seen by reference to FIG. 14, the annealed
material of Sucrose B (right) presented smoother surfaces and more
rounded edges than the unannealed material of Sucrose A (left).
Example 6
[0173] Compound A, a novel bi-functional muscarinic antagonist and
beta2 agonist (IUPAC:
7-[(1R)-2-[2-[2-fluoro-5-[[4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-d-
iazaspiro[5.5]undecan-9-yl]methyl]phenyl]ethylamino]-1-hydroxy-ethyl]-4-hy-
droxy-3H-1,3-benzothiazol-2-one;
di[[(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonic acid]
salt), was selected for micronization and subsequent solvent
removal using primary and secondary conditioning steps. Compound A
retained .about.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 isopropyl
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 material were used for dispensing
all three batches.
TABLE-US-00010 TABLE 10 Nominal Jet Mill Jet Mill % Batch Powder
Grind Injection Relative Batch Description Feed rate Pressure
Pressure Temp Sat. Yields -- g/hr psi psi .degree. C. % RS % No
Conditioning 25 .+-. 2 70 80 21 0 49% 29.degree. C./69% RH 25 .+-.
2 70 80 29 69 62% 30.degree. C./53% RS 25 .+-. 2 70 80 30 53 53%
(ethanol)
[0174] 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 solvent vapor was
used). The total conditioning gas flow rate was 255 SLPM. The
micronization gas flow rate was about 110 SLPM at the given milling
pressures, giving a conditioning 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.
[0175] Batch 2 (conditioned with water vapor at 29.degree. C./69%
RH) was conditioned using a conditioning gas that provided water
vapor at 69% relative humidity (RH) in the conditioning zone. The
conditioning gas was formed by atomizing water 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 7 g/min. The
conditioning gas flow rate was set to 220 SLPM with a humidifier
inlet temperature of 100.degree. C. and conditioning zone outlet of
29.degree. C. 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 conditioning to
micronization gas Ratio (CMR) of 2.3:1 and total gas flow of 365
SLPM. Batch 2 was collected in a 0.5 L stainless steel collector,
transferred to a purged (<5% RH) isolator and sampled for
analysis.
[0176] Batch 3 (primary conditioning with ethanol at 30.degree.
C./53% RS; secondary conditioning with water at 30.degree. C./67%
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 ethanol (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 150.degree. C. and
conditioning zone outlet of 30.degree. C. The micronization gas
flow rate was about 110 SLPM at the given milling 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 100.degree. C. 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 30.degree. C. The material
was secondarily conditioned in the collector with a conditioning
gas containing water vapor at 67% RH. Batch 3 was collected in a
0.5 L stainless steel collector, transferred to a purged (<5%
RH) isolator and sampled for analysis.
[0177] All three batches were analyzed for particle size
distribution by Sympatec laser diffraction, with the results shown
in Table 11. Particle Size Distribution of conditioned Compound A
demonstrates good reproducibility, and the particle size
distribution of the conditioned Compound A is consistent with the
unannealed micronized material.
TABLE-US-00011 TABLE 11 D10 D50 D90 Compound A, PSD (.mu.m) (.mu.m)
(.mu.m) Raw (Un-milled) 1.1 3.7 16.3 Unannealed 0.6 1.6 3.1
30.degree. C./70% RH 0.6 1.6 3.1 30.degree. C./55% RS (ethanol);
30.degree. C./70% RH 0.6 1.7 3.2 (water)
[0178] 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 removed using primary (ethanol) and
secondary (water) conditioning. Material that was treated using a
secondary conditioning process exhibited increased replacement of
the IPA.
TABLE-US-00012 TABLE 12 % IPA % EtOH % Compound A Batches (w/w)
(w/w) Water Raw (un-milled) 4.7% 0.0% 3.1% Unannealed 3.9% 0.2%
3.0% 30.degree. C./70% RH 3.6% 0.1% 3.4% 30.degree. C./55% RS;
30.degree. C./70% RH 2.1% 1.2% 3.4%
Example 7
[0179] Compound A (IUPAC:
7-[(1R)-2-[2-[2-fluoro-5-[[4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-d-
iazaspiro[5.5]undecan-9-yl]methyl]phenyl]ethylamino]-1-hydroxy-ethyl]-4-hy-
droxy-3H-1,3-benzothiazol-2-one;
di[[(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonic acid]
salt) was received with a 3.8% ethanol residual content. This
material had been previously micronized and conditioned according
to the present description to reduce the presence of isopropyl
(IPA) and ethanol (EtOH) by solvent exchange/removal. The material
was exposed to another conditioning gas that included water vapor,
and was mixed with the conditioning gas in a conditioning zone for
approximately 1.5 hours. As shown in Table 13, residual IPA and
EtOH was nearly completely removed and water content of the
material increased.
TABLE-US-00013 TABLE 13 Micronized Compound A % IPA % EtOH % Batch
(w/w) (w/w) Water As Received 0.1% 3.8% 3.1% 30.degree. C./70% RH
(water) 0.0% 0.1% 3.6%
[0180] The various embodiments described above can be combined to
provide further embodiments. All of the U.S. patents, U.S. patent
application publications, U.S. patent applications, foreign
patents, foreign patent applications and non-patent publications
referred to in this specification and/or listed in the Application
Data Sheet, including but not limited to U.S. Provisional
Application No. 61/799,956, filed Mar. 15, 2013, are incorporated
herein by reference, in their entirety. Aspects of the embodiments
can be modified, if necessary to employ concepts of the various
patents, applications and publications to provide yet further
embodiments.
* * * * *