WO2024121032A1

WO2024121032A1 - Process for producing lactose crystals, inhalable formulation

Info

Publication number: WO2024121032A1
Application number: PCT/EP2023/084067
Authority: WO
Inventors: Laura Elisabeth FORSTER; Gunilla Ingmarsdotter PETERSSON; Amy Louise ROBERTSON; Claire Seonaid MACLEOD; Humera SIDDIQUE; Kenneth Baird Smith; Ian Nicholas Houson; Vishal RAVAL
Original assignee: Astrazeneca Ab
Priority date: 2022-12-05
Filing date: 2023-12-04
Publication date: 2024-06-13

Abstract

Provided herein are methods for preparing lactose crystals for use in pharmaceutical formulations. The methods allow for specific control over both the habit or shape of the crystals (single crystals versus agglomerated crystals), as well as crystal size and the span of the crystal size.

Description

PROCESS FOR PRODUCING LACTOSE CRYSTALS, INHALABLE FORMULATION

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This specification claims the benefit of priority to U.S. Provisional Patent Application No. 63/386,082 (filed December 5 2022). The entire text of the abovereferenced patent application is incorporated by reference into this specification.

FIELD OF THE DISCLOSURE

Provided herein are methods for preparing lactose crystals for use in pharmaceutical formulations. The methods allow for specific control over both the shape of the crystals (single crystals versus agglomerated crystals), as well as crystal size and the span of the crystal size.

BACKGROUND

For inhalation therapy using dry powder formulation, therapeutic drug particles having a particle size in the range of about 0.1 to 10 pm are often associated with excipient carrier particles, such as lactose, that have a significantly larger diameter (e.g., 40 to 200 pm). However, the ability to tightly control both the mass median diameter of lactose carrier particles, as well as the crystal habit or shape (single crystal vs. agglomerated crystals) allows the formulation to be tailored to the therapeutic drug and the inhalation device used which is highly desirable to ensure proper delivery of an active agent to a patient.

Lactose crystallization processes utilize various cooling processes and crystallizer devices to try and achieve single, or agglomerated crystals, having a specific particle size and a tight particle size distribution, or avoid agglomeration all together. However, most of these processes simply rely on trial and error to achieve the desired characteristics, or top-down milling or size classification approaches, and often cannot receive tight control of particle size. What is needed is a process that can reproducibly yield targeted particle size characteristics and crystal habit or shape for lactose crystals. The present disclosure fulfills these needs.

SUMMARY OF THE DISCLOSURE

In embodiments, the present disclosure provides a method for production of lactose agglomerated crystals, comprising introducing a feedstock solution comprising lactose monohydrate into a first module of a continuous oscillatory baffle crystallizer (COBC), passing the feedstock solution through the first module of the COBC, introducing a seed slurry comprising lactose agglomerated seeds to the feedstock solution following the passage through the first module of the COBC to create a crystallization slurry, continuously crystalizing the crystallization slurry through a second module, a third module, and a fourth module of the COBC, collecting a slurry of lactose agglomerated crystals following the fourth module of the COBC, filtering the lactose agglomerated crystals from the slurry of lactose agglomerated crystals; washing and drying the lactose agglomerated crystals. In embodiments, a temperature of the feedstock solution reduces from a first temperature of about 45°C to about 55°C to a lower, second temperature of about 37°C to about 49°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 37°C to about 49°C to a lower, third temperature of about 34°C to about 42°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 34°C to about 42°C to a lower, fourth temperature of about 25°C to about 34°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 25°C to about 34°C to a lower, fifth temperature of about 15°C to about 25°C during passage through the fourth module of the COBC, and suitably the lactose agglomerated crystals exhibit a particle size distribution span ((D9O-DIO)/DSO)) of less than about 2.0.

In additional embodiments, provided herein is a method for production of lactose single crystals, comprising introducing a feedstock solution comprising lactose monohydrate into a first module of a continuous oscillatory baffle crystallizer (COBC), passing the feedstock solution through the first module of the COBC, introducing a seed slurry comprising lactose single crystal seeds to the feedstock solution following the passage through the first module of the COBC to create a crystallization slurry, continuously crystalizing the crystallization slurry through a second module, a third module, and a fourth module of the COBC, collecting a slurry of lactose single crystals following the fourth module of the COBC, filtering the lactose single crystals from the slurry of lactose single crystals; washing and drying the lactose single crystals. In embodiments, a temperature of the feedstock solution reduces from a first temperature of about 45°C to about 55°C to a lower, second temperature of about 37°C to about 49°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 37°C to about 49°C to a lower, third temperature of about 34°C to about 42°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 34°C to about 42°C to a lower, fourth temperature of about 25 °C to about 34°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 25°C to about 34°C to a lower, fifth temperature of about 15°C to about 25°C during passage through the fourth module of the COBC. In embodiments, the lactose single crystals exhibit a particle size distribution span ((D90- Dio)/Dso)) of less than about 2.0.

Also provided herein is a method of formulating an inhalable drug molecule compound, comprising: providing lactose single crystals having a particle size of about 40 pm to about 55 pm (D50), and a particle size distribution span ((D9O-DIO)/DSO)) of less than about 1.5; and loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w).

Also provided herein is a method of formulating an inhalable drug molecule compound, comprising: providing lactose single crystals having a particle size of about 80 pm to about 130 pm (D50), and a particle size distribution span ((D9O-DIO)/DSO)) of less than about 1.5; and loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w).

In further embodiments, provided herein is a method of formulating an inhalable drug molecule compound, comprising: providing lactose single crystals having a particle size of about 140 pm to about 170 pm (D50), and a particle size distribution span ((D₉O-DIO)/D₅O)) of less than about 1.7; and loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w).

Also provided herein is a method of formulating an inhalable drug molecule compound, comprising: providing lactose agglomerated crystals having a particle size of about 40 pm to about 55 pm (D50), and a particle size distribution span ((D9O-DIO)/DSO)) of less than about 1.5; and loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w).

Also provided herein is a method of formulating an inhalable drug molecule compound, comprising: providing lactose agglomerated crystals having a particle size of about 80 pm to about 130pm (D50), and a particle size distribution span ((D9O-DIO)/DSO)) of less than about 1.5; and loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w).

In further embodiments, provided herein is a method of formulating an inhalable drug molecule compound, comprising providing lactose agglomerated crystals having a particle size of about 140 pm to about 170 pm (D50), and a particle size distribution span ((D9O-DIO)/DSO)) of less than about 1.7; and loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w). As provided herein is an inhalable formulation comprising lactose single crystals having a particle size of about 40-55 pm, and a particle size distribution span ((D₉O-DIO)/D₅O)) of less than about 1.5; and a drug molecule compound loaded onto the lactose single crystals.

In further embodiments, provided herein is an inhalable formulation comprising lactose single crystals having a particle size of about 80-130 pm, and a particle size distribution span ((Dgo-DioXDso)) of less than about 1.5; and a drug molecule compound loaded onto the lactose single crystals.

In still further embodiments, provided herein is an inhalable formulation comprising lactose single crystals having a particle size of about 140-170 pm, and a particle size distribution span ((D9O-DIO)/DSO)) of less than about 1.7; and a drug molecule compound loaded onto the lactose single crystals.

In additional embodiments, provided herein is an inhalable formulation comprising lactose agglomerated crystals having a particle size of about 40-55 pm, and a particle size distribution span ((D9O-DIO)/DSO)) of less than about 1.5; and a drug molecule compound loaded onto the lactose agglomerated crystals.

In still further embodiments, provided herein is an inhalable formulation comprising lactose agglomerated crystals having a particle size of about 80-130 pm, and a particle size distribution span ((D9O-DIO)/DSO)) of less than about 1.5; and a drug molecule compound loaded onto the lactose agglomerated crystals.

Also provided herein is an inhalable formulation comprising lactose agglomerated crystals having a particle size of about 140-170 pm, and a particle size distribution span ((D9O-DIO)/DSO)) of less than about 1.7; and a drug molecule compound loaded onto the lactose agglomerated crystals.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1A shows a scanning electron micrograph (SEM) of an exemplary lactose crystal formulation that comprises active agent and lactose crystals.

FIG. IB shows an SEM of lactose single crystals.

FIG. 1C shows an SEM of lactose agglomerated crystals.

FIG. 2A shows a diagram of a continuous oscillatory baffled crystallizer (COBC).

FIG. 2B shows a photograph of a COBC. FIG. 3 shows a scanning electron micrograph (SEM) of a tomahawk lactose crystal.

FIG. 4 shows the strategy for super saturation control in cooling crystallization.

FIG. 5 shows the effect of feed concentration and supersaturation on lactose crystal particle size and shape.

DETAILED DESCRIPTION

Definitions

Unless specifically defined otherwise, the technical terms, as used herein, have their normal meaning as understood in the art. The following terms are specifically defined for the sake of clarity.

The term “active agent” is used herein to include any agent, drug, compound, composition, or other substance that may be used on, or administered to, a human or animal for any purpose, including therapeutic, pharmaceutical, pharmacological, diagnostic, cosmetic, and prophylactic agents and immunomodulators. Active agent may be used interchangeably with the terms active ingredient, active pharmaceutical ingredient (API), drug, pharmaceutical, medicament, drug substance, or therapeutic. As used herein, active agent may also encompass natural or homeopathic products that are not generally considered therapeutic.

The terms “associate,” “associate with,” or “association” refer to an interaction or relationship between a chemical entity, composition, or structure in a condition of proximity of a surface, such as the surface of another chemical entity, composition, or structure. Association includes, for example, adsorption, adhesion, covalent bonding, hydrogen bonding, ionic bonding and electrostatic attraction, Lifshitz - van der Waals interactions, and polar interactions. The terms “adhere” or “adhesion” refer to a form of association, and are used a generic terms for all forces tending to cause a particle or mass to be attracted to a surface. Adhere also refers to bringing and keeping particles in contact with each other, such that there is substantially no visible separation between particles under normal conditions. In one embodiment, a particle that attaches to or binds to a surface is encompassed by the term adhere. As described herein, active particles may associate with carrier particles to form an ordered mixture or adhesive mixture, where there is substantially no visible separation between the carrier particles and the active agent particles.

A “patient” refers to an animal in which the one or more active agents as described herein will have a therapeutic effect. In some embodiments, the patient is a human being.

A “therapeutically effective amount” is the amount of compound which achieves a therapeutic effect by inhibiting a disease or disorder in a patient or by prophylactically inhibiting or preventing the onset of a disease or disorder. A therapeutically effective amount may be an amount which relieves to some extent one or more symptoms of a disease or disorder in a patient; returns to normal either partially or completely one or more physiological or biochemical parameters associated with or causative of the disease or disorder; and/or reduces the likelihood of the onset of the disease or disorder.

Methods of Production of Lactose Crystals

The methods described herein relate to the production of lactose crystals for use in the pharmaceutical industry, including for use in inhalable formulations. FIG. 1A shows an exemplary lactose crystal formulation 100 in which active agent molecules 102 are associated with lactose crystals 104, as the carrier.

Lactose, a disaccharide comprised of glucose and galactose, is the main constituent of milk whey. Lactose production starts by the removal of cheese and whey cream from milk. The remaining whey is evaporated to concentrate lactose. Lactose crystals are formed in crystallization tanks by holding the slurry over a carefully controlled time and temperature profiles. After crystallization, the solid is washed, dried and optionally milled or sieved before packing. Additional processes also involve antisolvent crystallization.

Crystallization, including the habit or shape and size of crystals produced, along with the size span of the crystals, directly impacts formulation quality. Crystallization, usually including nucleation and crystal growth, is a complex physicochemical phenomenon of phase transition. Many factors including concentration, temperature, viscosity of solution, agitation intensity, residence time or crystallization time etc., have an impact on crystallization. To efficiently obtain high quality lactose, crystallization must be optimally controlled.

The methods described herein provide highly controlled methods that allow for the specific control of crystal habit or shape, size, and particle size span. In embodiments, methods are provided for the production of lactose agglomerated crystals. In other embodiments, methods are provided for the production of lactose single crystals.

As used herein, the term “lactose single crystals” or “lactose individual crystals” or “single crystal” or “individual crystal” refers to a crystal habit or shape that comprises one crystal of lactose, not associated with another crystal of lactose. FIG. IB shows lactose single crystals 110, where each crystal is separate from each other and there are no associations or crystals bridges between the crystals.

As used herein, the term “lactose agglomerated crystals” or “agglomerated crystals” or “agglomerates” refers to a crystal habit or shape that comprises two or more crystals of lactose associated together to habit or shape a structure where individual crystals are not easily separable, and in many instances, a crystalline bridge forms between individual crystals during crystallization. Agglomerated lactose crystals 120 are shown in FIG. 1C.

Lactose single crystals and agglomerated crystals are referred to as different “morphologies,” “habits,” “shapes,” or “structures” of lactose crystals.

In embodiments, provided herein is a method for production of lactose agglomerated crystals, utilizing a continuous oscillatory baffled crystallizer (COBC). FIG. 2A shows a diagram of a COBC, and FIG. 2B shows a photograph of a COBC. The COBC 200 is a tubular crystallizer containing periodically spaced orifice baffles with oscillatory motion superimposed on the net flow. (See, e.g., WO 2011/051728, the disclosure of which is incorporated by reference herein in its entirety). FIG. 2A shows the feed solution 202, which provides the desired concentration of lactose in water (a feedstock), at a desired temperature and flow rate, to the first of four (204, 206, 208 and 210) modules, followed by a collection reservoir 220. Introduction of a seed slurry 212 suitably occurs after the first COBC module 204 and prior to the second COBC module 206. The COBC modules can be monitored via various focused beam reflectance measurement (FBRM) particle analysis probes (214 and 216) as well as infrared sensor probes (218). Mixing in the COBC is provided by the generation and cessation of eddies when flow interacts with baffles (see 222 of FIG. 2A).

In embodiments, lactose agglomerated crystals are produced by introducing a feedstock solution (e.g., 202) comprising lactose monohydrate into a first module (204) of a continuous oscillatory baffle crystallizer (COBC) (200). As used herein “module” refers to the individual, connected crystallizers, of the COBC. The feedstock solution is passed through the first module 204 of the COBC. In the first module feed solution temperature is reduced to create the driving force for crystallization. Then, a seed slurry (e.g., 212) comprising lactose agglomerated seeds is introduced following passage through the first module to create a crystallization slurry. As used herein “seed slurry” means a saturated solution that promotes crystallization, suitably itself including either lactose agglomerated seeds, lactose single crystal seeds, or a combination thereof. A “seed” refers to an agglomerated crystal or single crystal of lactose that promotes crystallization when added to a feedstock solution of lactose. A “crystallization slurry” refers to a mixture of a lactose feedstock saturated solution and a seed (or seed slurry) that is undergoing crystallization, or will undergo crystallization, when under appropriate conditions. Suitably for agglomerated crystals agglomerated seeds are used. These may be preprepared from other continuous experiments or may be micronised seeds.

The crystallization slurry is then crystallized through the second module 206, the third module 208 and the fourth module 210 of the COBC 200. The slurry of lactose agglomerated crystals is then collected, for example in collection reservoir 220. The lactose agglomerated crystals are then filtered from the solution, washed and then dried.

As described herein, various temperature profiles can be utilized with the COBC to generate lactose crystals (both agglomerated and single crystals) having desired sizes and particle size distributions.

As used herein, the particle size of a lactose crystal (whether single or agglomerated) refers to the diameter (D50) of lactose crystals within a crystal population, such that 50% of the total volume of crystals are below the stated diameter, and 50% of the total volume of lactose crystals are above the stated diameter (i.e., D50).

In embodiments, a temperature of the feedstock solution (202) reduces from a first temperature of about 45°C to about 55°C, or about 39°C to about 55°C to a lower, second temperature of about 37°C to about 49°C, or about 33°C to about 49°C, during passage through the first module 204 of the COBC. That is, when the feedstock solution 202 is introduced to the first module 204 of the COBC, it will generally be introduced at a temperature of about 40°C to about 60°C, more suitably a temperature of about 45°C to about 55°C, about 45°C to about 50°C, about 50°C to about 55°C, or about 45°C, about 50°C, or about 55°C. As the feedstock passes through the first module 204, it cools from this first, introductory temperature, to a lower, second temperature. In embodiments, the lower, second temperature is about 35°C to about 50°C, for example, about 37°C to about 49°C, about 37°C to about 48°C, about 38°C to about 47°C, about 39°C to about 46°C, about 40°C to about 45°C, or about 37°C, about 38°C, about 39°C, about 40°C, about 41°C, about 42°C, about 43°C, about 44°C, about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, or about 50°C, including values and ranges within these ranges.

The methods of production further include reducing the temperature of the crystallization slurry (i.e., the feedstock solution with added seed slurry) from the second temperature of about 37°C to about 49°C to a lower, third temperature of about 34°C to about 42°C during passage through the second module 206 of the COBC. In embodiments, the lower, third temperature is about 32°C to about 45°C, for example, about 32°C to about 42°C, about 34°C to about 42°C, about 34°C to about 40°C, about 37°C to about 42°C, about 35°C to about 40°C, or about 34°C, about 35°C, about 36°C, about 37°C, about 38°C, about 39°C, about 40°C, about 41°C, or about 42°C, including values and ranges within these ranges.

The methods of production further include reducing the temperature of the crystallization slurry from the third temperature of about 34°C to about 42°C to a lower, fourth temperature of about 25°C to about 34°C during passage through the third module 208 of the COBC. In embodiments, the lower, fourth temperature is about 20°C to about 35°C, for example, about 22°C to about 34°C, about 25°C to about 34°C, about 22°C to about 30°C, about 28°C to about 34°C, about 26°C to about 32°C, or about 25°C, about 26°C, about 27°C, about 28°C, about 29°C, about 30°C, about 31 °C, about 32°C, about 33°C, or about 34°C, including values and ranges within these ranges.

The methods of production then further include reducing the temperature of the crystallization slurry from the fourth temperature of about 25°C to about 34°C to a lower, fifth temperature of about 15°C to about 25°C during passage through the fourth module 210 of the COBC. In embodiments the lower, fourth temperature is about 14°C to about 30°C, for example, about 15 °C to about 28 °C, about 15 °C to about 22°C, about 18 °C to about 25°C, about 16°C to about 24°C, about 17°C to about 23°C, or about 15°C, about 16°C, about 17°C, about 18°C, about 19°C, about 20°C, about 21°C, about 22°C, about 23 °C, about 24°C, or about 25 °C, including values and ranges within these ranges.

As described herein, it has surprisingly been found that the methods provided allow for the production of lactose crystals having a specific size (diameter) as well as a narrow particle size distribution. As used herein “particle size distribution” refers to a series of values, a histogram or a mathematical function indicating what sizes of particles, in what counts or proportions, are present in the lactose crystal system. As used herein, the mathematical function defining particle size distribution span is: span of the particle size distribution

where D90 is used to indicate that 90% of the total particle volume of the lactose crystals have a diameter smaller than D90, Dio is used to indicate that 10% of the total particle volume of the lactose crystals have a diameter smaller than Dio, and D50 is the median diameter of the lactose crystals, as defined herein.

As described herein, the term ‘D50’ refers to the median diameter from a volume weighted particle size distribution as measured using a laser diffraction particle sizing instrument such as, for example, the Malvern Mastersizer 3000 or the Sympatec Helos. ‘D50’ means the diameter for which 50% of the total particle volume consists of particles with a smaller diameter and 50% consists of particles with a larger diameter.

In suitable embodiments, the lactose agglomerated crystals prepared by the methods described herein exhibit a particle size distribution span of less than about 2.5, less than about 2.4, less than about 2.3, less than about 2.2, less than about 2.1, less than about 2.0, less than about 1.9, less than about 1.8, less than about 1.7, less than about 1.6, less than about 1.5, or about 1.0 to about 2.5, about 1.1 to about 2.4, about 1.2 to about 2.3, about 1.2 to about 2.1, about 1.2 to about 2.0, about 1.2 to about 1.9, about 1.2 to about 1.8, about 1.2 to about 1.7, about 1.2 to about 1.6, about 1.2 to about 1.5, about 1.2 to about 1.4, about 1.3 to about 1.7, about 1.3 to about 1.6, or about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0.

In further embodiments, methods for production of lactose single crystals are provide herein. The methods comprise introducing a feedstock solution comprising lactose monohydrate into a first module of a continuous oscillatory baffle crystallizer (COBC). The crystallization solution is then passed through the first module of the COBC, after which a seed slurry comprising lactose single crystal seeds is introduced to the crystallization solution following the passage through the second module of the COBC to create a crystallization slurry. As discussed herein, it has been surprisingly found that the choice of the type of seed selected (e.g., single crystals) produce single crystals following the production process. The crystallization slurry is continuously crystallized through a second module, a third module, and a fourth module of the COBC. Then, a slurry of lactose single crystals is collected following the fourth module of the COBC. The lactose single crystals are then filtered from the slurry of lactose single crystals, washed and then dried.

As described herein, in embodiments, a temperature of the feedstock solution (202) reduces from a first temperature of about 45 °C to about 55 °C to a lower, second temperature of about 37°C to about 49°C during passage through the first module 204 of the COBC. That is, when the feedstock solution 202 is introduced to the first module 204 of the COBC, it will generally be introduced at a temperature of about 40°C to about 60°C, in some embodiments a temperature of about 45 °C to about 55 °C, about 45 °C to about 50°C, about 50°C to about 55°C, or about 45°C, about 50°C, or about 55°C. As the feedstock passes through the first module 204, it cools from this first, introductory temperature, to a lower, second temperature. In embodiments, the lower, second temperature is about 35°C to about 50°C, for example, about 37°C to about 49°C, about 37°C to about 48°C, about 38°C to about 47°C, about 39°C to about 46°C, about 40°C to about 45°C, or about 37°C, about 38°C, about 39°C, about 40°C, about 41°C, about 42°C, about 43°C, about 44°C, about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, or about 50°C, including values and ranges within these ranges.

The methods of production further include reducing the temperature of the crystallization slurry (i.e., the feedstock solution with added seed slurry) from the second temperature of about 37°C to about 49°C to a lower, third temperature of about 34°C to about 42°C during passage through the second module 206 of the COBC. In embodiments, the lower, third temperature is about 32°C to about 45°C, for example, about 32°C to about 42°C, about 34°C to about 42°C, about 34°C to about 40°C, about 37 °C to about 42°C, about 35°C to about 40°C, or about 34°C, about 35°C, about 36°C, about 37°C, about 38°C, about 39°C, about 40°C, about 41°C, or about 42°C, including values and ranges within these ranges.

The methods of production further include reducing the temperature of the crystallization slurry from the third temperature of about 34°C to about 42°C to a lower, fourth temperature of about 25°C to about 34°C during passage through the third module 208 of the COBC. In embodiments, the lower, fourth temperature is about 20°C to about 35°C, for example, about 22°C to about 34°C, about 25°C to about 34°C, about 22°C to about 30°C, about 28°C to about 34°C, about 26°C to about 32°C, or about 25°C, about 26°C, about 27°C, about 28°C, about 29°C, about 30°C, about 31 °C, about 32°C, about 33°C, or about 34°C, including values and ranges within these ranges. The methods of production then further include reducing the temperature of the crystallization slurry from the fourth temperature of about 25°C to about 34°C to a lower, fifth temperature of about 15°C to about 25°C during passage through the fourth module 210 of the COBC. In embodiments, the lower, fourth temperature is about 14°C to about 30°C, for example, about 15 °C to about 28 °C, about 15 °C to about 22°C, about 18 °C to about 25°C, about 16°C to about 24°C, about 17°C to about 23°C, or about 15°C, about 16°C, about 17°C, about 18°C, about 19°C, about 20°C, about 21°C, about 22°C, about 23 °C, about 24°C, or about 25 °C, including values and ranges within these ranges.

As described herein, the methods provided not only allow for selection of a desired particle size for the lactose single crystals, but the lactose single crystals exhibit a particle size distribution span ((D9O-DIO)/DSO)) of less than about 2.0.

Table 1 below shows exemplary parameters that have been determined to provide the desired particle size and particle size distribution span.

Table 1: Parameter Boundaries to Select Particle Size and Span

For the methods described herein, the seed slurry that is utilized suitably comprises seeds (either lactose agglomerated seeds or lactose single crystal seeds) have a size of about 2 m to about 100 pm, depending on the desired final crystal size. As described throughout, it has been surprisingly found that selecting a specific seed crystal size, and crystal habit or shape (single or agglomerated) provides specific control over the final product size, span and crystal habit or shape. For example, seed size can be about 2 pm to about 10 pm, about 2 pm to about 8 pm, about 3 pm to about 7 pm, about 3 pm to about 6 pm, about 3 pm to about 5 pm, or about 4 pm to produce lactose crystals having a particle size of about 40-60 pm. In other embodiments, seed size can be about 30 pm to about 60 pm, about 35 pm to about 60 pm, about 40 pm to about 60 pm, about 40 pm to about 55 pm, about 45 pm to about 55 pm, or about 50 pm to produce lactose crystals having a particle size of about 80-140 pm. In further embodiments, seed size can be about 50 pm to about 80 pm, about 50 pm to about 75 pm, about 55 pm to about 75 pm, about 60 pm to about 75 pm, about 70 pm to about 75 pm, or about 70 pm to produce lactose crystals having a particle size of about 130-180 pm.

In exemplary methods provided herein, a seed slurry comprises lactose agglomerated seeds having a size of about 3 pm to about 5 pm, and the lactose agglomerated crystals produced by the method exhibit a particle size of about 40 pm to about 55 pm (D50) and a particle size distribution span of 1.1-1.5. In such embodiments, the temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55°C to the lower, second temperature of about 37°C to about 39°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 37°C to about 39°C to the lower, third temperature of about 34°C to about 35°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 34°C to about 35°C to the lower, fourth temperature of about 25°C to about 27°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 25°C to about 27°C to the lower, fifth temperature of about 15°C to about 20°C during passage through the fourth module of the COBC.

In additional embodiments, the seed slurry comprises lactose single crystal seeds having a size of about 3 pm to about 5 pm, and the lactose single crystals exhibit a particle size of about 40 pm to about 55 pm (D50) and a particle size distribution span of 1.1-1.5. In such embodiments, the temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55 °C to the lower, second temperature of about 37°C to about 39°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 37°C to about 39°C to the lower, third temperature of about 34°C to about 35°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 34°C to about 35°C to the lower, fourth temperature of about 25°C to about 27°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 25°C to about 27°C to the lower, fifth temperature of about 15°C to about 20°C during passage through the fourth module of the COBC.

In still further embodiments, the seed slurry comprises lactose agglomerated seeds having a size of about 45 pm to about 55 pm, and the lactose agglomerated crystals exhibit a particle size of about 80 pm to about 130 pm (D50) and a particle size distribution span of 1.2- 1.5. In such embodiments, the temperature of the feedstock solution reduces from the first temperature of about 45°C to about 55°C to the lower, second temperature of about 45°C to about 47°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 45°C to about 47°C to the lower, third temperature of about 38°C to about 40°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 38 °C to about 40°C to the lower, fourth temperature of about 30°C to about 31 °C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 30°C to about 31 °C to the lower, fifth temperature of about 19°C to about 21 °C during passage through the fourth module of the COBC.

In still further embodiments, the seed slurry comprises lactose single crystal seeds having a size of about 45 pm to about 55 pm, and the lactose single crystals exhibit a particle size of about 80 pm to about 130 pm (D50) and a particle size distribution span of 1.2-1.5. In such embodiments, the temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55 °C to the lower, second temperature of about 45°C to about 47°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 45°C to about 47°C to the lower, third temperature of about 38°C to about 40°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 38 °C to about 40°C to the lower, fourth temperature of about 30°C to about 31 °C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 30°C to about 31 °C to the lower, fifth temperature of about 19°C to about 21 °C during passage through the fourth module of the COBC.

In further embodiments, the seed slurry comprises lactose agglomerated seeds having a size of about 60 pm to about 75 pm, and the lactose agglomerated crystals exhibit a particle size of about 140 pm to about 170 pm (D50) and a particle size distribution span of 1.3- 1.7. In such embodiments, the temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55 °C to the lower, second temperature of about 47°C to about 49°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 47°C to about 49°C to the lower, third temperature of about 40°C to about 42°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 40°C to about 42°C to the lower, fourth temperature of about 31 °C to about 34°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 31 °C to about 34°C to the lower, fifth temperature of about 20°C to about 25°C during passage through the fourth module of the COBC.

In additional embodiments, the seed slurry comprises lactose singly crystal seeds having a size of about 60 pm to about 75 pm, and the lactose singly crystals exhibit a particle size of about 140 pm to about 170 pm (D50) and a particle size distribution span of 1.3-1.7. In such embodiments, temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55 °C to the lower, second temperature of about 47 °C to about 49°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 47°C to about 49°C to the lower, third temperature of about 40°C to about 42°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 40°C to about 42°C to the lower, fourth temperature of about 31 °C to about 34°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 31 °C to about 34°C to the lower, fifth temperature of about 20°C to about 25°C during passage through the fourth module of the COBC.

As described herein, the residence time and cooling profiles utilized in the COBC are controlled to provide the desired particle size and particle size distribution characteristics. In suitable embodiments, the total residence time within the COBC is about 2 hours to about 6 hours, more suitably about 3 hours to about 6 hours, or about 4 hours to about 5 hours, including about 3 hours, about 4 hours, about 5 hours or about 6 hours. The cooling profiles described throughout are suitably carried out using a quadratic cooling profile, whether slow (e.g., about 5-6 hours) or fast (about 3-4 hours).

In suitable embodiments, the methods described herein are performed such that the COBC is operated in plug flow with low shear mixing. Such conditions are unique to the COBC and are generally not achievable using a batch crystallizer. Plug flow refers to flow through a tubular reactor, such as in the COBC utilized herein, and low shear mixing refers to mixing that occurs with a shear rate of less than 20 s’¹.

The rate at which the feedstock solution 202 is provided (inlet feedstock solution flow rate) to the first module 204 can be controlled, as desired by the process, and is suitably about 30-100 g/min, more suitably about 40-80 g/min, about 40-70 g/min, about 40-60 g/min, about 40-50 g/min, or about 40 g/min or about 50 g/min. The oscillation of the feedstock solution can also be controlled at the inlet to first module, such that an oscillation of about 1-10 Hz is utilized, more suitably about 2-8 Hz, about 3-6Hz, or an oscillation of about 3-5Hz, suitably 2-4 Hz, is utilized.

The ratio of lactose monohydrate and water in the feedstock solution 202 can also be controlled as desired. In embodiments, the feedstock solution 202 comprises lactose monohydrate and water at a ratio of about 20 g lactose: 100 g water (gram lactose:gram water), to about 100 g lactose: 100 g water (i.e., a ratio of 1:5 to about 1:1 by weight). In further embodiments, the ratio can be about 20 g lactose: 100 g water to about 80 g lactose: 100 g water, or about 20 g lactose: 100 g water to about 70 g lactose: 100 g water, or about 30 g lactose: 100 g water to about 60 g lactose: 100 g water, or about 30 g lactose: 100 g water, about 40 g lactose: 100 g water, about 50 g lactose: 100 g water or about 60 g lactose: 100 g water.

The rate at which the seed slurry (whether agglomerated or single lactose crystal seeds) is introduced at 212, can also be controlled as desired in the production process. For example, the seed slurry can be introduced at a rate of about 1.0 g to about 10 g of seed slurry/min, including at a rate of about 1.0 g to about 8.0 g of seed slurry/min, about 1.0 g to about 7.0 g of seed slurry/min, about 1.0 g to about 6.0 g of seed slurry/min, about 2.0 g to about 6.0 g of seed slurry/min, about 3.0 g to about 6.0 g of seed slurry/min, or about 3.0 g of seed slurry/min, about 4.0 g of seed slurry/min, about 5.0 g of seed slurry/min, or about 6.0 g of seed slurry/min. In embodiments, the crystal load in the saturated solution was about 5% to about 20%, suitably about 10% (100 g seed/ 1000 g of saturated solution) and held constant. The process for washing the lactose agglomerated or single crystals produced by the methods described herein suitably utilizes a wash with a solution of organic solvent and water, followed by a wash with an organic solvent. In embodiments, the organic solvent is an alcohol. In embodiments, the organic solvent is ethanol. The washing process suitably occurs following the filtering, but prior to the drying of the crystals, and is utilized to preserve the crystals following the production process by removing fine material from the surface of the crystals and residual crystallization solvent entrapped between crystals. In embodiments the crystals are washed at least two-times with a solution of ethanokwater (70:30) followed by washing at least two-times with ethanol.

In addition to providing control over the particle size and particle size distribution of the lactose crystals, the methods provided herein also have been found to produce a “tomahawk crystal morphology” desirable in the pharmaceutical industry. An exemplary tomahawk crystal morphology is shown in FIG. 3. The crystal morphology is produced in both single and agglomerate lactose crystals, in the processes described herein.

Methods of Formulating Inhalables and Inhalable Formulations

In further embodiments, provided herein are methods of formulating an inhalable drug molecule compound utilizing the lactose crystals having the characteristics described herein, including those prepared using the methods described herein.

For example, methods of formulating an inhalable drug molecule compound suitably comprise providing lactose single crystals having a particle size of about 140 pm to about 170 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.7; and loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30% (w/w), etc. In suitable embodiments, the drug molecule compound can be loaded onto the lactose single crystals at a weight percentage of at least about 30%, at least about 40%, at least about 50%, at least about 60%, or about 20% to about 60%, about 30% to about 60%, about 30% to about 50%, or about 20% to about 40% (w/w). Loading an active agent onto lactose carrier particles as described herein refers to adhering the active onto the carrier through a process such as, for example, dry mixing/blending. As used here, weight percent “% (w/w)” refers to the weight of drug molecule /(weight of drug molecule + weight of lactose crystals), where the lactose crystals may be lactose agglomerated crystals and/or lactose single crystals.

In further embodiments, the methods of formulating an inhalable drug molecule, such as a drug molecule compound can comprise loading a drug molecule compound onto lactose single crystals having a particle size of about 40 pm to about 55 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; or a particle size of about 80 pm to about 130 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0.

In further embodiments, methods of formulating an inhalable drug molecule compound can comprise loading a drug molecule compound onto a lactose agglomerated crystal having a particle size of about 40 pm to about 55 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; or onto lactose agglomerated crystals having a particle size of about 80 pm to about 130 pm (D50), and a particle size distribution ((D₉O-DIO)/D₅O)) of less than about 1.5; or onto lactose agglomerated crystals having a particle size of about 140 pm to about 170 pm (D50), and a particle size distribution ((D90- Dio)/Dso)) of less than about 1.7.

In further embodiments, the methods of formulating an inhalable drug molecule, such as a drug molecule compound can comprise loading a drug molecule compound onto a mixture of (a) a lactose single crystals having a particle size of about 40 pm to about 55 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0, and (b) a lactose agglomerated crystal having a particle size of about 40 pm to about 55 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; or a lactose agglomerated crystals having a particle size of about 80 pm to about 130 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; or a lactose agglomerated crystals having a particle size of about 140 pm to about 170 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.7. In further embodiments, the methods of formulating an inhalable drug molecule, such as a drug molecule compound can comprise loading a drug molecule compound onto a mixture of (a) a lactose single crystals having a particle size of about 80 pm to about 130 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0, and (b) a lactose agglomerated crystal having a particle size of about 40 pm to about 55 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; or a lactose agglomerated crystals having a particle size of about 80 pm to about 130 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; or a lactose agglomerated crystals having a particle size of about 140 pm to about 170 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.7.

The lactose crystals described herein are suitably useful in formulating inhalable drug molecules, such as drug molecule compounds such as bronchodilators. Exemplary small molecule compounds that can be formulated with the lactose crystals described herein include, but are not limited to, short-acting beta agonists (SABA), e.g., bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline (isoproterenol), levosalbutamol, orciprenaline (metapro terenol), pirbuterol, procaterol, rimiterol, salbutamol (albuterol), terbutaline, tulobuterol, reproterol, ipratropium and epinephrine; long-acting P2 adrenergic receptor agonist (“LABA”), e.g., bambuterol, clenbuterol, formoterol, vilanterol, and salmeterol; ultra long-acting P2 adrenergic receptor agonists, e.g., carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived P2 agonists; corticosteroids, e.g., beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone, fluticasone furoate, and triamcinolone,; 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 (“LAMA”), e.g., glycopyrrolate, dexpirronium, scopolamine, tropicamide, pirenzepine, dimenhydrinate, tiotropium, darotropium, aclidinium, trospium, ipatropium, atropine, benzatropin, umeclidinium, or oxitropium.

Also provided herein are inhalable formulations comprising the lactose crystals described herein, suitably prepared according to the disclosed methods, and a drug molecule compound loaded onto the lactose crystals (including single crystals and agglomerated crystals). In embodiments, the lactose single crystals can have a particle size of about 40-55 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; or a particle size of about 80-130 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; or a particle size of about 140-170 pm, and a particle size distribution ((D₉O-DIO)/D₅O)) of less than about 1.7. Lactose agglomerated crystals for use in the inhalable formulations can have a particle size of about 40-55 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; or a particle size of about 80-130 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; or a particle size of about 140-170 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.7; and

Exemplary drug molecules for use in the inhalable formulations are described herein and also known in the art.

In additional embodiments, methods of treating a patient suffering from a disease or disorder are provided herein, comprising administering any of the inhalable formulations described throughout. In embodiments the methods are for treating a pulmonary disease or disorder, including asthma or chronic obstructive pulmonary disease (COPD).

In additional embodiments, there is provided any of the inhalable formulations described throughout for use in treatment of a disease or disorder. In embodiments, the disease of disorder is a pulmonary disease or disorder. In embodiments, the pulmonary disease is asthma or chronic obstructive pulmonary disease (COPD).

In additional embodiments, there is provided the use of any of the inhalable formulations described throughout in the manufacture of a medicament for the treatment of a pulmonary disease. In embodiments, the pulmonary disease is asthma or chronic obstructive pulmonary disease (COPD).

The specific examples included herein are for illustrative purposes only and are not to be considered as limiting to this disclosure. Moreover, the compositions, systems and methods disclosed herein have been described in relation to certain embodiments thereof, and many details have been set forth for purposes of illustration, it will be apparent to those skilled in the art that the disclosure is susceptible to additional embodiments and that certain of the details described herein may be varied without departing from the basic principles of the disclosure. Any active agents and reagents used in the following examples are either commercially available or, with the benefit of the teachings provided herein, can be prepared according to standard literature procedures by those skilled in the art. The entire contents of all publications, patents, and patent applications referenced herein are hereby incorporated herein by reference.

EXAMPLES

Example 1 - Lactose Crystallization Protocols

Commonly in the pharmaceutical industry, trial-and-error is used to experimentally determine an operating profile that lies within the metastable zone and gives acceptable crystals. However, a more efficient approach is direct design, which uses a feedback control scheme to follow the desired super saturation curve profile in the metastable zone. Though technically referred to as concentration control (C-control), such a scheme is commonly called supersaturation control, since the solute concentration is kept on the super saturation curve profile through the action of feedback control.

A closed-loop control strategy as shown in FIG. 4, was utilized to optimize the crystallization processes described herein. The scheme, implemented through PharmaMV advanced process control (APC) system, consists of a calibration model, super saturation model predictive control (MPC) and the reactor temperature MPC controller. As shown in FIG. 4, the APC system measures the IR spectra, pre-processes it, and the calibration model then uses this data (along with temperature measurements) to predict the Lactose concentration in real-time. By comparing this Lactose concentration with its desired value, the super saturation controller prescribes a temperature rate-of-change setpoint (as a solution to an optimization problem in real-time). Finally, based on this rate- of-change, the reactor temperature MPC controller manipulates the jacket temperature, pump speeds and flows utilized in the COBC to maintain the solution on the supersaturation curve during the crystallization process.

Process parameters from Table 1 above, were utilized and the results are provided in FIG. 5. As indicated, the desired particle size and particle size distribution span were readily controlled so that a specific size and span could be “dialed-in” as described herein. The particle size distributions were measured using a laser diffraction particle sizing instrument after filtering, washing and drying of the lactose crystals. Wet dispersion measurements were done by redispersing dried lactose crystals in standard saturated lactose solution or ethanol. Desired crystal morphology was also achieved, as shown in FIG. 3, with the tomahawk crystal shape.

Table 2 shows the cooling profiles utilized to maintain the system under controlled supersaturation.

Table 2: Cooling Profiles

Slow cooling profiles allow for control over supersaturation and secondary nucleation. Residence time has an inverse effect on particle span, but can readily be controlled, as described herein. Conclusions

Selection of seed material provides a high level of control over the desired product quality and morphology. Seed morphology combined with process parameters dictates the habit or shape of final product. Agglomerated seeds lead to agglomerated product and single crystal seeds leads to single crystal.

In addition, starting concentration and supersaturation also provide control over crystallization profiles. The growth rate of lactose is highly dependent on the concentration and supersaturation in the system. Below 25°C is the region where growth is minimal and the secondary nucleation boundary is quite narrow. As long as a process is designed to avoid going into that region, secondary nucleation can be minimized.

Seed loading and cooling profiles are established based on supersaturation control experiments. In these experiments cooling profile is extracted by keeping crystallization within controlled supersaturation, hence making growth the dominant process and avoiding secondary nucleation. Seed loading is generally kept between 2-3% and seed slurry density is 10% throughout. Cooling profile is generally parabolic extracted from supersaturation-controlled experiments.

EMBODIMENTS

In Embodiment 1, provided herein is a method for production of lactose agglomerated crystals, comprising: introducing a feedstock solution comprising lactose monohydrate into a first module of a continuous oscillatory baffle crystallizer (COBC); passing the feedstock solution through the first module of the COBC; introducing a seed slurry comprising lactose agglomerated seeds to the feedstock solution following the passage through the first module of the COBC to create a crystallization slurry; continuously crystalizing the crystallization slurry through a second module, a third module, and a fourth module of the COBC; collecting a slurry of lactose agglomerated crystals following the fourth module of the COBC; filtering the lactose agglomerated crystals from the slurry of lactose agglomerated crystals; washing and drying the lactose agglomerated crystals, wherein a temperature of the feedstock solution reduces from a first temperature of about 45 °C to about 55 °C to a lower, second temperature of about 37 °C to about 49°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 37°C to about 49°C to a lower, third temperature of about 34°C to about 42°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 34°C to about 42°C to a lower, fourth temperature of about 25 °C to about 34°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 25°C to about 34°C to a lower, fifth temperature of about 15°C to about 25°C during passage through the fourth module of the COBC, and wherein the lactose agglomerated crystals exhibit a particle size distribution span ((D₉O-DIO)/D₅O)) of less than about 2.0.

Embodiment 2 is a method for production of lactose single crystals, comprising: introducing a feedstock solution comprising lactose monohydrate into a first module of a continuous oscillatory baffle crystallizer (COBC); passing the feedstock solution through the first module of the COBC; introducing a seed slurry comprising lactose single crystal seeds to the feedstock solution following the passage through the first module of the COBC to create a crystallization slurry; continuously crystalizing the crystallization slurry through a second module, a third module, and a fourth module of the COBC; collecting a slurry of lactose single crystals following the fourth module of the COBC; filtering the lactose single crystals from the slurry of lactose single crystals; washing and drying the lactose single crystals, wherein a temperature of the feedstock solution reduces from a first temperature of about 45 °C to about 55 °C to a lower, second temperature of about 37°C to about 49°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 37°C to about 49°C to a lower, third temperature of about 34°C to about 42°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 34°C to about 42°C to a lower, fourth temperature of about 25°C to about 34°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 25°C to about 34°C to a lower, fifth temperature of about 15°C to about 25°C during passage through the fourth module of the COBC, and wherein the lactose single crystals exhibit a particle size distribution span ((D9O-DIO)/DSO)) of less than about 2.0.

Embodiment 3 includes the method of Embodiment 1, wherein: the seed slurry comprises lactose agglomerated seeds having a size of about 3 pm to about 5 pm; and the lactose agglomerated crystals exhibit a particle size of about 40 pm to about 55 pm (D50) and a particle size distribution span of 1.1 -1.5, and wherein the temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55 °C to the lower, second temperature of about 37°C to about 39°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 37°C to about 39°C to the lower, third temperature of about 34°C to about 35°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 34°C to about 35°C to the lower, fourth temperature of about 25°C to about 27°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 25 °C to about 27 °C to the lower, fifth temperature of about 15 °C to about 20°C during passage through the fourth module of the COBC.

Embodiment 4 includes the method of Embodiment 2, wherein: the seed slurry comprises lactose single crystal seeds having a size of about 3 pm to about 5 pm; and the lactose single crystals exhibit a particle size of about 40 pm to about 55 pm (D50) and a particle size distribution span of 1.1 -1.5, and wherein the temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55 °C to the lower, second temperature of about 37°C to about 39°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 37°C to about 39°C to the lower, third temperature of about 34°C to about 35°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 34°C to about 35°C to the lower, fourth temperature of about 25°C to about 27°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 25 °C to about 27 °C to the lower, fifth temperature of about 15 °C to about 20°C during passage through the fourth module of the COBC.

Embodiment 5 includes the method Embodiment 1, wherein: the seed slurry comprises lactose agglomerated seeds having a size of about 45 pm to about 55 pm; and the lactose agglomerated crystals exhibit a particle size of about 80 pm to about 130 pm (D50) and a particle size distribution span of 1.2- 1.5, and wherein the temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55 °C to the lower, second temperature of about 45°C to about 47°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 45 °C to about 47 °C to the lower, third temperature of about 38 °C to about 40°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 38°C to about 40°C to the lower, fourth temperature of about 30°C to about 31 °C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 30°C to about 31 °C to the lower, fifth temperature of about 19°C to about 21 °C during passage through the fourth module of the COBC.

Embodiment 6 includes the method of Embodiment 2, wherein: the seed slurry comprises lactose single crystal seeds having a size of about 45 pm to about 55 pm; and the lactose single crystals exhibit a particle size of about 80 pm to about 130 pm (D50) and a particle size distribution span of 1.2- 1.5, and wherein the temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55 °C to the lower, second temperature of about 45°C to about 47°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 45 °C to about 47 °C to the lower, third temperature of about 38 °C to about 40°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 38°C to about 40°C to the lower, fourth temperature of about 30°C to about 31 °C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 30°C to about 31 °C to the lower, fifth temperature of about 19°C to about 21 °C during passage through the fourth module of the COBC.

Embodiment 7 includes the method of Embodiment 1, wherein: the seed slurry comprises lactose agglomerated seeds having a size of about 60 pm to about 75 pm; and the lactose agglomerated crystals exhibit a particle size of about 140 pm to about 170 pm (D50) and a particle size distribution span of 1.3-1.7, and wherein the temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55 °C to the lower, second temperature of about 47°C to about 49°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 47°C to about 49°C to the lower, third temperature of about 40°C to about 42°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 40°C to about 42°C to the lower, fourth temperature of about 31 °C to about 34°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 31 °C to about 34°C to the lower, fifth temperature of about 20°C to about 25°C during passage through the fourth module of the COBC.

Embodiment 8 includes the method of Embodiment 2, wherein: the seed slurry comprises lactose single crystal seeds having a size of about 60 pm to about 75 pm; and the lactose single crystals exhibit a particle size of about 140 pm to about 170 pm (D50) and a particle size distribution span of 1.3-1.7, and wherein the temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55 °C to the lower, second temperature of about 47°C to about 49°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 47°C to about 49°C to the lower, third temperature of about 40°C to about 42°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 40°C to about 42°C to the lower, fourth temperature of about 31 °C to about 34°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 31 °C to about 34°C to the lower, fifth temperature of about 20°C to about 25°C during passage through the fourth module of the COBC.

Embodiment 9 includes the method of any of Embodiments 1-8, wherein the COBC is operated in plug flow with low shear mixing.

Embodiment 10 includes the method of any of Embodiments 1-9, wherein an inlet feedstock rate of the first module is about 40-50 g/min, with an oscillation of about 2-5Hz.

Embodiment 11 includes the method of any of Embodiments 1-10, wherein the feedstock solution comprises lactose monohydrate and water at a ratio of about 30 g lactose: 100g water to about 60 g lactose: 100g water.

Embodiment 12 includes the method of any of Embodiments 1-11, wherein the introducing the seed slurry occurs at a rate of about 1.0 g to about 6.0 g of seed slurry /min.

Embodiment 13 includes the method Embodiment 12, wherein the rate is about 3.0 g to about 6.0 g of seed slurry/min.

Embodiment 14 includes the method of any of Embodiments 1-13, wherein the lactose agglomerated crystals or the lactose single crystals are washed following the filtering, but before the drying, at least two-times with a solution of organic solvent:water mixture followed by washing at least two-times with organic solvent.

Embodiment 15 includes the method of any of Embodiments 1-14, wherein the lactose agglomerated crystals or the lactose single crystals have a tomahawk crystal morphology.

Embodiment 16 is a method of formulating an inhalable drug molecule compound, comprising: providing lactose single crystals having a particle size of about 40 pm to about 55 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; and loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w).

Embodiment 17 is a method of formulating an inhalable drug molecule compound, comprising: providing lactose single crystals having a particle size of about 80 pm to about 130 pm (D50), and a particle size distribution ((Dgo-DioVDso)) of less than about 1.5; and loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w).

Embodiment 18 is a method of formulating an inhalable drug molecule compound, comprising: providing lactose single crystals having a particle size of about 140 pm to about 170 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.7; and loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w).

Embodiment 19 is a method of formulating an inhalable drug molecule compound, comprising: providing lactose agglomerated crystals having a particle size of about 40 pm to about 55 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; and loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w).

Embodiment 20 is a method of formulating an inhalable drug molecule compound, comprising: providing lactose agglomerated crystals having a particle size of about 80 pm to about 130 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; and loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w).

Embodiment 21 is a method of formulating an inhalable drug molecule compound, comprising: providing lactose agglomerated crystals having a particle size of about 140 pm to about 170 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.7; and loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w).

Embodiment 22 is a method of formulating an inhalable drug molecule compound, comprising: a. providing lactose agglomerated crystals having a particle size of about 40 pm to about 55 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; b. providing lactose single crystals having a particle size of about 40 pm to about 55 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; c. mixing the lactose agglomerated crystals and the lactose single crystals; and d. loading a drug molecule compound onto the mixture of lactose agglomerated crystals and lactose single crystals at a weight percentage of at least about 0.5% (w/w).

Embodiment 23 is a method of formulating an inhalable drug molecule compound, comprising: a. providing lactose agglomerated crystals having a particle size of about 80 pm to about 130 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; b. providing lactose single crystals having a particle size of about 80 pm to about 130 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; c. mixing the lactose agglomerated crystals and the lactose single crystals; and d. loading a drug molecule compound onto the mixture of lactose agglomerated crystals and lactose single crystals at a weight percentage of at least about 0.5% (w/w).

Embodiment 24 is a method of formulating an inhalable drug molecule compound, comprising: a. providing lactose agglomerated crystals having a particle size of about 140 pm to about 170 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.7; d. providing lactose single crystals having a particle size of about 140 pm to about 170 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.7; c. mixing the lactose agglomerated crystals and the lactose single crystals; and d. loading a drug molecule compound onto the mixture of lactose agglomerated crystals and lactose single crystals at a weight percentage of at least about 0.5% (w/w).

Embodiment 25 is a method of formulating an inhalable drug molecule compound, comprising: providing lactose agglomerated crystals having a particle size of about 40 pm to about 55 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; and loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w), wherein the lactose agglomerated crystals are prepared according to the method of any one of Embodiments 1, 3, 5, 7 or 9 to 15. Embodiment 26 is a method of formulating an inhalable drug molecule compound, comprising: providing lactose agglomerated crystals having a particle size of about 80 pm to about 130 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; and loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w), wherein the lactose agglomerated crystals are prepared according to the method of any one of Embodiments 1, 3, 5, 7 or 9 to 15.

Embodiment 27 is a method of formulating an inhalable drug molecule compound, comprising: providing lactose agglomerated crystals having a particle size of about 140 pm to about 170 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; and loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w), wherein the lactose agglomerated crystals are prepared according to the method of any one of Embodiments 1, 3, 5, 7 or 9 to 15.

Embodiment 28 is a method of formulating an inhalable drug molecule compound, comprising: providing lactose single crystals having a particle size of about 40 pm to about 55 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; and loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w), wherein the lactose single crystals are prepared according to the method of any one of Embodiments 2, 4, 6 or 8 to 15.

Embodiment 29 is a method of formulating an inhalable drug molecule compound, comprising: providing lactose single crystals having a particle size of about 80 pm to about 130 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; and loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w), wherein the lactose single crystals are prepared according to the method of any one of Embodiments 2, 4, 6 or 8 to 15.

Embodiment 30 is a method of formulating an inhalable drug molecule compound, comprising: providing lactose single crystals having a particle size of about 140 pm to about 170 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; and loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w), wherein the lactose single crystals are prepared according to the method of any one of Embodiments 2, 4, 6 or 8 to 15.

Embodiment 31 is a method of formulating an inhalable drug molecule compound, comprising: a. providing lactose agglomerated crystals prepared according to the method of any one of Embodiments 1, 3 5, 7 or 9 to 15; b. loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w).

Embodiment 32 is a method of formulating an inhalable drug molecule compound, comprising: a. providing lactose single crystals prepared according to the method of any one of Embodiments 2, 4, 6 or 8 to 15; b. loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w).

Embodiment 33 is a method of formulating an inhalable drug molecule compound, comprising: a. providing lactose agglomerated crystals prepared according to the method of any one of Embodiments 1, 3 5, 7 or 9 to 15; b. providing lactose single crystals prepared according to the method of any one of Embodiments 2, 4, 6 or 8 to 15; c. mixing the lactose agglomerated crystals and lactose single crystals; d. loading a drug molecule compound onto the mixture of lactose agglomerated crystals and lactose single crystals at a weight percentage of at least about 0.5% (w/w).

Embodiment 34 is a method of formulating an inhalable drug molecule compound, comprising: a. providing lactose agglomerated crystals having a particle size of about 40 pm to about 55 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; b. providing lactose single crystals having a particle size of about 40 pm to about 55 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; c. mixing the lactose agglomerated crystals and lactose single crystals; and d. loading a drug molecule compound onto the mixture of lactose agglomerated crystals and lactose single crystals at a weight percentage of at least about 0.5% (w/w), wherein the lactose agglomerated crystals are prepared according to the method of any one of Embodiments 1, 3 or 9 to 15, and the lactose single crystals are prepared according to the method of any one of Embodiments 2, 4, or 9 to 15.

Embodiment 35 is a method of formulating an inhalable drug molecule compound, comprising: a. providing lactose agglomerated crystals having a particle size of about 80 pm to about 130 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; b. providing lactose single crystals having a particle size of about 80 pm to about 130 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; c. mixing the lactose agglomerated crystals and lactose single crystals; and d. loading a drug molecule compound onto the mixture of lactose agglomerated crystals and lactose single crystals at a weight percentage of at least about 0.5% (w/w), wherein the lactose agglomerated crystals are prepared according to the method of any one of Embodiments 1, 5 or 9 to 15, and the lactose single crystals are prepared according to the method of any one of Embodiments 2, 6 or 9 to 15.

Embodiment 36 is a method of formulating an inhalable drug molecule compound, comprising: a. providing lactose agglomerated crystals having a particle size of about 140 pm to about 170 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; b. providing lactose single crystals having a particle size of about 140 pm to about 170 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; c. mixing the lactose agglomerated crystals and lactose single crystals; and d. loading a drug molecule compound onto the mixture of lactose agglomerated crystals and lactose single crystals at a weight percentage of at least about 0.5% (w/w), wherein the lactose agglomerated crystals are prepared according to the method of any one of Embodiments 1, 7 or 9 to 15, and the lactose single crystals are prepared according to the method of any one of Embodiments 2 or 8 to 15.

Embodiment 37 is a method of any one of Embodiments 16-36, wherein the drug molecule compound is a bronchodilator.

Embodiment 38 is an inhalable formulation comprising: lactose single crystals having a particle size of about 40-55 pm, and a particle size distribution ((D90- Dio)/Dso)) of less than about 1.5; and a drug molecule compound loaded onto the lactose single crystals.

Embodiment 39 is an inhalable formulation comprising: lactose single crystals having a particle size of about 80-130 pm, and a particle size distribution ((D90- Dio)/Dso)) of less than about 1.5; and a drug molecule compound loaded onto the lactose single crystals.

Embodiment 40 is an inhalable formulation comprising: lactose single crystals having a particle size of about 140-170 pm, and a particle size distribution ((D90- Dio)/Dso)) of less than about 1.7; and a drug molecule compound loaded onto the lactose single crystals.

Embodiment 41 is an inhalable formulation comprising: lactose agglomerated crystals having a particle size of about 40-55 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; and a drug molecule compound loaded onto the lactose agglomerated crystals.

Embodiment 42 is an inhalable formulation comprising: lactose agglomerated crystals having a particle size of about 80-130 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; and a drug molecule compound loaded onto the lactose agglomerated crystals.

Embodiment 43 is an inhalable formulation comprising: lactose agglomerated crystals having a particle size of about 140-170 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.7; and a drug molecule compound loaded onto the lactose agglomerated crystals. Embodiment 44 is an inhalable formulation comprising: a. lactose agglomerated crystals having a particle size of about 40-55 mm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; b. lactose single crystals having a particle size of about 40-55 mm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; and c. a drug molecule compound loaded onto the lactose agglomerated crystals and lactose single crystals.

Embodiment 45 is an inhalable formulation comprising: a. lactose agglomerated crystals having a particle size of about 80-130 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; b. lactose single crystals having a particle size of about 80-130 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; and c. a drug molecule compound loaded onto the lactose agglomerated crystals and lactose single crystals.

Embodiment 46 is an inhalable formulation comprising: a. lactose agglomerated crystals having a particle size of about 140-170 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.7; b. lactose single crystals having a particle size of about 140-170 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.7; and c. a drug molecule compound loaded onto the lactose agglomerated crystals and lactose single crystals.

Embodiment 47 includes the inhalable formulation of any one of Embodiments 38-46, wherein the drug molecule compound is a bronchodilator.

Embodiment 48 is a method of treating a patient suffering from a disease or disorder comprising administering the inhalable formulation of any one of Embodiments 39-47 to the patient.

Embodiment 49 includes the method of Embodiment 48, wherein the disease is a pulmonary disease or disorder. Embodiment 50 includes the method of Embodiment 49, wherein the pulmonary disease or disorder is asthma or COPD.

Embodiment 51 includes the inhalable formulation of any one of Embodiments 38-46, for use in the treatment of a pulmonary disease or disorder. Embodiment 52 includes the inhalable formulation of any one of

Embodiments 38-46, for use in the treatment of asthma or COPD.

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 are incorporated herein by reference, in their entirety, unless specified otherwise herein. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.

These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method for production of lactose agglomerated crystals, comprising: a. introducing a feedstock solution comprising lactose monohydrate into a first module of a continuous oscillatory baffle crystallizer (COBC); b. passing the feedstock solution through the first module of the COBC; c. introducing a seed slurry comprising lactose agglomerated seeds to the feedstock solution following the passage through the first module of the COBC to create a crystallization slurry; d. continuously crystalizing the crystallization slurry through a second module, a third module, and a fourth module of the COBC; e. collecting a slurry of lactose agglomerated crystals following the fourth module of the COBC; f. filtering the lactose agglomerated crystals from the slurry of lactose crystals; g. washing and drying the lactose agglomerated crystals, wherein a temperature of the feedstock solution reduces from a first temperature of about 45 °C to about 55 °C to a lower, second temperature of about 37 °C to about 49°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 37 °C to about 49 °C to a lower, third temperature of about 34°C to about 42°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 34°C to about 42°C to a lower, fourth temperature of about 25°C to about 34°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 25°C to about 34°C to a lower, fifth temperature of about 15°C to about 25°C during passage through the fourth module of the COBC, and wherein the lactose agglomerated crystals exhibit a particle size distribution span ((D90- Dio)/Dso)) of less than about 2.0. A method for production of lactose single crystals, comprising: a. introducing a feedstock solution comprising lactose monohydrate into a first module of a continuous oscillatory baffle crystallizer (COBC); b. passing the feedstock solution through the first module of the COBC; c. introducing a seed slurry comprising lactose single crystal seeds to the feedstock solution following the passage through the first module of the COBC to create a crystallization slurry; d. continuously crystalizing the crystallization slurry through a second module, a third module, and a fourth module of the COBC; e. collecting a slurry of lactose single crystals following the fourth module of the COBC; f. filtering the lactose single crystals from the slurry of lactose single crystals; g. washing and drying the lactose single crystals, wherein a temperature of the feedstock solution reduces from a first temperature of about 45 °C to about 55 °C to a lower, second temperature of about 37 °C to about 49°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 37°C to about 49°C to a lower, third temperature of about 34°C to about 42°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 34°C to about 42°C to a lower, fourth temperature of about 25 °C to about 34°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 25°C to about 34°C to a lower, fifth temperature of about 15°C to about 25°C during passage through the fourth module of the COBC, and wherein the lactose single crystals exhibit a particle size distribution span ((D90- Dio)/Dso)) of less than about 2.0. The method of claim 1, wherein: the seed slurry comprises lactose agglomerated seeds having a size of about 3 pm to about 5 pm; and the lactose agglomerated crystals exhibit a particle size of about 40 pm to about 55 pm (D50) and a particle size distribution span of 1.1 -1.5, and wherein the temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55 °C to the lower, second temperature of about 37°C to about 39°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 37°C to about 39°C to the lower, third temperature of about 34°C to about 35°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 34°C to about 35°C to the lower, fourth temperature of about 25°C to about 27°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 25°C to about 27°C to the lower, fifth temperature of about 15°C to about 20°C during passage through the fourth module of the COBC. The method of claim 2, wherein: the seed slurry comprises lactose single crystal seeds having a size of about 3 pm to about 5 pm; and the lactose single crystals exhibit a particle size of about 40 pm to about 55 pm (D50) and a particle size distribution span of 1.1 -1.5, and wherein the temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55 °C to the lower, second temperature of about 37°C to about 39°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 37°C to about 39°C to the lower, third temperature of about 34°C to about 35°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 34°C to about 35°C to the lower, fourth temperature of about 25°C to about 27°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 25°C to about

27°C to the lower, fifth temperature of about 15°C to about 20°C during passage through the fourth module of the COBC. The method of claim 1, wherein: the seed slurry comprises lactose agglomerated seeds having a size of about 45 pm to about 55 pm; and the lactose agglomerated crystals exhibit a particle size of about 80 pm to about 130 pm (D50) and a particle size distribution span of 1.2- 1.5, and wherein the temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55 °C to the lower, second temperature of about 45°C to about 47°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 45 °C to about 47 °C to the lower, third temperature of about 38 °C to about 40°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 38 °C to about 40°C to the lower, fourth temperature of about 30°C to about 31 °C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 30°C to about

31 °C to the lower, fifth temperature of about 19°C to about 21 °C during passage through the fourth module of the COBC. The method of claim 2, wherein: the seed slurry comprises lactose single crystal seeds having a size of about 45 pm to about 55 pm; and the lactose single crystals exhibit a particle size of about 80 pm to about 130 pm (D50) and a particle size distribution span of 1.2- 1.5, and wherein the temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55 °C to the lower, second temperature of about 45°C to about 47°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 45 °C to about 47 °C to the lower, third temperature of about 38 °C to about 40°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 38 °C to about 40°C to the lower, fourth temperature of about 30°C to about 31 °C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 30°C to about

31 °C to the lower, fifth temperature of about 19°C to about 21 °C during passage through the fourth module of the COBC. The method of claim 1, wherein: the seed slurry comprises lactose agglomerated seeds having a size of about 60 pm to about 75 pm; and the lactose agglomerated crystals exhibit a particle size of about 140 pm to about 170 pm (D50) and a particle size distribution span of 1.3-1.7, and wherein the temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55 °C to the lower, second temperature of about 47°C to about 49°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 47 °C to about 49 °C to the lower, third temperature of about 40°C to about 42°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 40°C to about 42°C to the lower, fourth temperature of about 31 °C to about 34°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 31 °C to about 34°C to the lower, fifth temperature of about 20°C to about 25°C during passage through the fourth module of the COBC. The method of claim 2, wherein: the seed slurry comprises lactose single crystal seeds having a size of about 60 m to about 75 pm; and the lactose single crystals exhibit a particle size of about 140 pm to about 170 pm (D50) and a particle size distribution span of 1.3- 1.7, and wherein the temperature of the feedstock solution reduces from the first temperature of about 45 °C to about 55 °C to the lower, second temperature of about 47°C to about 49°C during passage through the first module of the COBC, the temperature of the crystallization slurry reduces from the second temperature of about 47°C to about 49°C to the lower, third temperature of about 40°C to about 42°C during passage through the second module of the COBC, the temperature of the crystallization slurry reduces from the third temperature of about 40°C to about 42°C to the lower, fourth temperature of about 31 °C to about 34°C during passage through the third module of the COBC, and the temperature of the crystallization slurry reduces from about 31 °C to about

34°C to the lower, fifth temperature of about 20°C to about 25°C during passage through the fourth module of the COBC. The method of any one of claims 1-8, wherein the COBC is operated in plug flow with low shear mixing. The method of any one of claims 1-9, wherein an inlet feedstock rate of the first module is about 40-50 g/min, with an oscillation of about 2-5Hz. The method of any one of claims 1-10, wherein the feedstock solution comprises lactose monohydrate and water at a ratio of about 30 g lactose: 100g water to about 60 g lactose: 100g water. The method of any one of claims 1-11, wherein the introducing the seed slurry occurs at a rate of about 1.0 g to about 6.0 g of seed slurry /min. The method of claim 12, wherein the rate is about 3.0 g to about 6.0 g of seed slurry/min. The method of any one of claims 1-13, wherein the lactose agglomerated crystals or the lactose single crystals are washed following the filtering, but before the drying, at least two-times with a solution of organic solvent: water mixture followed by washing at least two-times with organic solvent. The method of any one of claims 1-14, wherein the lactose agglomerated crystals or the lactose single crystals have a tomahawk crystal morphology. A method of formulating an inhalable drug molecule compound, comprising: a. providing lactose single crystals having a particle size of about 40 pm to about 55 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; and b. loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w). ethod of formulating an inhalable drug molecule compound, comprising: a. providing lactose single crystals having a particle size of about 80 pm to about 130 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; and b. loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w). ethod of formulating an inhalable drug molecule compound, comprising: a. providing lactose single crystals having a particle size of about 140 pm to about 170 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.7; and b. loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w). ethod of formulating an inhalable drug molecule compound, comprising: a. providing lactose agglomerated crystals having a particle size of about 40 pm to about 55 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; and b. loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w). A method of formulating an inhalable drug molecule compound, comprising: a. providing lactose agglomerated crystals having a particle size of about 80 pm to about 130 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; and b. loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w). A method of formulating an inhalable drug molecule compound, comprising: a. providing lactose agglomerated crystals having a particle size of about 140 pm to about 170 pm (D50), and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.7; and b. loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w). A method of formulating an inhalable drug molecule compound, comprising: providing lactose agglomerated crystals having a particle size of about 40 pm to about 55 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; and loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w), wherein the lactose agglomerated crystals are prepared according to the method of any one of claims 1, 3 or 9 to 15. A method of formulating an inhalable drug molecule compound, comprising: providing lactose agglomerated crystals having a particle size of about 80 pm to about

130 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; and loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w), wherein the lactose agglomerated crystals are prepared according to the method of any one of claims 1, 5 or 9 to 15. A method of formulating an inhalable drug molecule compound, comprising: providing lactose agglomerated crystals having a particle size of about 140 pm to about

170 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; and loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w), wherein the lactose single agglomerated are prepared according to the method of any one of claims 1, 7 or 9 to 15. A method of formulating an inhalable drug molecule compound, comprising: providing lactose single crystals having a particle size of about 40 pm to about 55 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; and loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w), wherein the lactose single crystals are prepared according to the method of any one of claims 2, 4 or 9 to 15. A method of formulating an inhalable drug molecule compound, comprising: providing lactose single crystals having a particle size of about 80 pm to about 130 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; and loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w), wherein the lactose single crystals are prepared according to the method of any one of claims 2, 6 or 9 to 15. A method of formulating an inhalable drug molecule compound, comprising: providing lactose single crystals having a particle size of about 140 pm to about 170 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 2.0; and loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w), wherein the lactose single crystals are prepared according to the method of any one of claims 2 or 8 to 15. A method of formulating an inhalable drug molecule compound, comprising: a. providing lactose agglomerated crystals prepared according to the method of any one of claims 1, 3 5, 7 or 9 to 15; b. loading a drug molecule compound onto the lactose agglomerated crystals at a weight percentage of at least about 0.5% (w/w). A method of formulating an inhalable drug molecule compound, comprising: a. providing lactose single crystals prepared according to the method of any one of claims 2, 4, 6 or 8 to 15; b. loading a drug molecule compound onto the lactose single crystals at a weight percentage of at least about 0.5% (w/w). A method of formulating an inhalable drug molecule compound, comprising: a. providing lactose agglomerated crystals prepared according to the method of any one of claims 1, 3 5, 7 or 9 to 15; b. providing lactose single crystals prepared according to the method of any one of claims 2, 4, 6 or 8 to 15; c. mixing the lactose agglomerated crystals and lactose single crystals; d. loading a drug molecule compound onto the mixture of lactose agglomerated crystals and lactose single crystals at a weight percentage of at least about 0.5% (w/w). The method of any one of claims 16-30, wherein the drug molecule compound is a bronchodilator. An inhalable formulation comprising: a. lactose single crystals having a particle size of about 40-55 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; and b. a drug molecule compound loaded onto the lactose single crystals. An inhalable formulation comprising: a. lactose single crystals having a particle size of about 80-130 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; and b. a drug molecule compound loaded onto the lactose single crystals. An inhalable formulation comprising: a. lactose single crystals having a particle size of about 140-170 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.7; and b. a drug molecule compound loaded onto the lactose single crystals. An inhalable formulation comprising: a. lactose agglomerated crystals having a particle size of about 40-55 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; and b. a drug molecule compound loaded onto the lactose agglomerated crystals. An inhalable formulation comprising: a. lactose agglomerated crystals having a particle size of about 80-130 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.5; and b. a drug molecule compound loaded onto the lactose agglomerated crystals. An inhalable formulation comprising: a. lactose agglomerated crystals having a particle size of about 140-170 pm, and a particle size distribution ((D9O-DIO)/DSO)) of less than about 1.7; and b. a drug molecule compound loaded onto the lactose agglomerated crystals. The inhalable formulation of any one of claims 32-37, wherein the drug molecule compound is a bronchodilator. A method of treating a patient suffering from a disease or disorder comprising administering the inhalable formulation of any one of claims 32-38 to the patient. The method of claim 39, wherein the disease is a pulmonary disease or disorder. The method of claim 40, wherein the pulmonary disease or disorder is asthma or COPD. The inhalable formulation of any one of claims 32-38, for use in the treatment of a pulmonary disease or disorder. The inhalable formulation of any one of claims 32-38, for use in the treatment of asthma or COPD.