WO2023277172A1 - Process for preparing pharmaceutical salts of pyrimidine derivatives - Google Patents

Abstract

The present disclosure relates to compositions of Compound 1 and processes for preparing compositions of Compound 1.

Description

PROCESS FOR PREPARING PHARMACEUTICAL SALTS OF PYRIMIDINE DERIVATIVES

CROSS-REFERENCES TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 63/216,934, filed on June 30, 2021. The entire contents of the aforementioned application are incorporated herein by reference in their entireties.

TECHNICAL FIELD
The present disclosure relates to compositions comprising Compound 1. The present disclosure further relates to processes for the preparation of Compound 1.

BACKGROUND
Lung cancer is composed of non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), and neuroendocrine tumors. Approximately 10% of patients with NSCLC in the US (10,000 cases/year) and 35% in East Asia are reported to have tumor-associated epidermal growth factor receptor (EGFR) mutations. New England J. Med. 2004; 350(21):2129-39.

EGFR (alternatively named ErbB1 or HER1) is part of the ErbB family of transmembrane receptor tyrosine kinases involved in signal transduction pathways that regulate proliferation and apoptosis. Inhibitors of the EGFR have emerged as effective therapies for some patients and represent an important target for therapeutic intervention in oncology. The development and clinical application of inhibitors that target EGFR provide important insights for new lung cancer therapies, as well as for the broader field of targeted cancer therapies. Nature Review Cancer 2007; 7, 169-181 (March 2007).

A primary concern for the manufacture of pharmaceutical compounds is the stability of an active substance. An active substance ideally has a stable crystalline morphology to ensure consistent processing parameters and pharmaceutical quality. Unstable active substances may affect the reproducibility of the manufacturing process and thus lead to final formulations which do not meet the high quality and stringent requirements imposed on formulations of pharmaceutical compositions.

Thus, there is a continuing need for new EGFR inhibitors, additional stable forms of EGFR inhibitors, and improved manufacturing processes for preparing EGFR inhibitors.
Further, there is a need for additional development of pharmaceutical compositions and methods of treatment, including developing dosages and dosing regimens.

New England J. Med. 2004; 350(21):2129-39 Nature Review Cancer 2007; 7, 169-181 (March 2007)

SUMMARY
In one embodiment, the present disclosure provides a composition comprising

wherein Compound 1 has a bulk density of from about 0.18 g/mL to about 0.55 g/mL, and/or a tapped density of from about 0.32 g/mL to about 0.61 g/mL.

In some embodiments, Compound 1 comprises particles having a d₁₀ of about 10 μm to about 54 μm, a d₅₀ of from about 31 μm to about 137 μm, and/or a d₉₀ of from about 76 μm to about 353 μm.

In some embodiments, the present disclosure provides a milled form of Compound 1.

In another embodiment, the present disclosure provides a pharmaceutical composition comprising Compound 1. In some embodiments, the pharmaceutical composition is in a capsule. In some embodiments, the capsule comprises Compound 1 that is equivalent to 40 mg of Compound (A). In some embodiments, the capsule does not contain pharmaceutical excipients.

In another embodiment, the present disclosure provides a composition of Compound 1 prepared by a process comprising the steps of: (i) mixing Compound (A) with succinic acid in the presence of a solvent; (ii) heating the mixture of step (i); (iii) adding a seeding material to the mixture of step (ii); (iv) thermal cycling the mixture at a temperature of between about 45 °C-75 °C; (v) repeating the (iv) thermal cycling step; (vi) performing a cool-heat step at a temperature of between about 15 °C-45 °C; (vii) collecting solids to provide Compound 1; and (viii) optionally, milling the solids obtained in step (vii) to provide a milled form of Compound 1.

In some embodiments, the seeding material is in an amount of about 0.5% to about 1.5% by weight of Compound (A).

In some embodiments, the process comprises the optional milling step (viii). In some embodiments, the milling is pin-milling.

Specifically, the present invention comprises the following.
(Item 1) A composition comprising Compound 1

wherein Compound 1 has
a) a bulk density of from about 0.18 g/mL to about 0.55 g/mL, and/or
b) a tapped density of from about 0.32 g/mL to about 0.61 g/mL.
(Item 2) The composition of any one of the preceding items, wherein Compound 1 has a bulk density higher than 0.22 g/mL and less than 0.55 g/mL.
(Item 3) The composition of any one of the preceding items, wherein Compound 1 has a bulk density higher than 0.30 g/mL and less than 0.40 g/mL.
(Item 4) The composition of any one of the preceding items, wherein Compound 1 has a tapped density of from about 0.32 g/mL to 0.51 g/mL.
(Item 5) The composition of any one of the preceding items, wherein Compound 1 has a tapped density of from about 0.33 g/mL to 0.44 g/mL.
(Item 6) The composition of any one of the preceding items, wherein Compound 1 is in a milled form.
(Item 7) The composition of any one of the preceding items, wherein the milled form is pin-milled.
(Item 8) The composition of any one of the preceding items, wherein Compound 1 comprises particles having a d₁₀ of about 10 μm to about 54 μm.
(Item 9) The composition of any one of the preceding items, wherein Compound 1 comprises particles having a d₅₀ of from about 31 μm to about 137 μm.
(Item 10) The composition of any one of the preceding items, wherein Compound 1 comprises particles having a d₉₀ of from about 76 μm to about 353 μm.
(Item 11) A pharmaceutical composition comprising the composition of any one of the preceding items.
(Item 12) The pharmaceutical composition of any one of the preceding items, wherein the pharmaceutical composition is in a capsule.
(Item 13) The pharmaceutical composition of any one of the preceding items, wherein the capsule comprises Compound 1 that is equivalent to 40 mg of Compound (A).
(Item 14) The pharmaceutical composition of any one of the preceding items, wherein the capsule does not contain pharmaceutical excipients.
(Item 15) A composition of Compound 1

prepared by a process comprising the steps of:
(i) mixing Compound (A) with succinic acid in the presence of a solvent

(ii) heating the mixture of step (i),
(iii) adding a seeding material to the mixture of step (ii),
(iv) thermal cycling the mixture at a temperature of between about 45 °C-75 °C,
(v) repeating the (iv) thermal cycling step,
(vi) performing a cool-heat step at a temperature of between about 15 °C-45 °C,
(vii) collecting solids to provide Compound 1, and
(viii) optionally, milling the solids obtained in step (vii) to provide a milled form of Compound 1.
(Item 16) The compound of any one of the preceding items, wherein after step (ii) and before step (iii), the process further comprises a clarifying filtration step, an ethanol rinse step, and a distillation to a target volume step.
(Item 17) The composition of any one of the preceding items, wherein the seeding material is a crystalline succinate salt suspended in an organic solvent.
(Item 18) The composition of any one of the preceding items, wherein the organic solvent is ethanol.
(Item 19) The composition of any one of the preceding items, wherein the seeding material is in an amount of about 0.5% to about 1.5% by weight of Compound (A).
(Item 20) The composition of any one of the preceding items, wherein the seeding material is in an amount of about 1.0% by weight of Compound (A).
(Item 21) The composition of any one of the preceding items, wherein after the addition of the seeding material, the mixture is kept at a temperature of about 70 °C for about 30 to 60 minutes prior to proceeding to step (iv).
(Item 22) The composition of any one of the preceding items, wherein each thermal cycle of step (iv) has a duration of about 160 minutes to about 280 minutes.
(Item 23) The composition of any one of the preceding items, wherein each thermal cycle has a duration of about 200 minutes to about 250 minutes.
(Item 24) The composition of any one of the preceding items, wherein each thermal cycle has a duration of about 200 minutes.
(Item 25) The composition of any one of the preceding items, wherein the process comprises 3 thermal cycles.
(Item 26) The composition of any one of the preceding items, wherein the cool-heat cycle of step (vi) comprises:
(vi.1) slow-cooling the mixture to between about 15 °C and about 25 °C,
(vi.2) holding the temperature for about 15-75 minutes,
(vi.3) slow-heating the mixture to between about 35 °C and about 45 °C,
(vi.4) holding the temperature for about 15-75 minutes, and
(vi.5) cooling the mixture to between about 10 °C to about 20 °C.
(Item 27) The composition of any one of the preceding items, comprising the optional milling step (viii).
(Item 28) The composition of any one of the preceding items, wherein the milling occurs at a speed of 2700 rotations per minute (RPM) to 4700 RPM.
(Item 29) The composition of any one of the preceding items, wherein the milling occurs at 2700 RPM.
(Item 30) The composition of any one of the preceding items, wherein the milling is pin-milling.
(Item 31) The composition of any one of the preceding items, wherein Compound 1 has a bulk density of 0.18 g/mL to 0.55 g/mL.
(Item 32) The composition of any one of the preceding items, wherein Compound 1 has a bulk density higher than 0.22 g/mL and less than 0.55 g/mL.
(Item 33) The composition of any one of the preceding items, wherein Compound 1 has a bulk density of higher than 0.30 g/mL and less than 0.40 g/mL.
(Item 34) The composition of any one of the preceding items, wherein Compound 1 has a tapped density of from 0.32 g/mL to 0.61 g/mL.
(Item 35) The composition of any one of the preceding items, wherein Compound 1 has a tapped density of from 0.32 g/mL to 0.51 g/mL.
(Item 36) The composition of any one of the preceding items, wherein Compound 1 has a tapped density of from 0.33 g/mL to 0.44 g/mL.
(Item 37) The composition of any one of the preceding items, wherein Compound 1 comprises particles having a d₁₀ of from about 10 μm to about 54 μm.
(Item 38) The composition of any one of the preceding items, wherein Compound 1 comprises particles having a d₅₀ of from about 31 μm to about 137 μm.
(Item 39) The composition of any one of the preceding items, wherein Compound 1 comprises particles having a d₉₀ of from about 76 μm to about 353 μm.
(Item 40) A process for preparing Compound 1

comprising:
(i) mixing Compound (A) with succinic acid in the presence of a solvent

(ii) heating the mixture of step (i),
(iii) adding a seeding material to the mixture of step (ii),
(iv) thermal cycling the mixture at a temperature of between about 45 °C-75 °C,
(v) repeating the (iv) thermal cycling step,
(vi) performing a cool-heat step at a temperature of between about 15 °C-45 °C,
(vii) collecting solids to provide Compound 1, and
(viii) optionally, milling the solids obtained in step (vii) to provide a milled form of Compound 1.
(Item 41) The process of any one of the preceding items, wherein after step (ii) and before step (iii), the process further comprises a clarifying filtration step, an ethanol rinse step, and a distillation to a target volume step.
(Item 42) The process of any one of the preceding items, wherein the seeding material is a jet-milled seed.
(Item 43) The process of any one of the preceding items, wherein the seeding material is a crystalline succinate salt suspended in an organic solvent.
(Item 44) The process of any one of the preceding items, wherein the organic solvent is ethanol.
(Item 45) The process of any one of the preceding items, wherein the seeding material is in an amount of about 0.5% to 1.5% by weight Compound (A).
(Item 46) The process of any one of the preceding items, wherein after the addition of the seeding material, the mixture is kept at a temperature of about 70 °C for about 30 to 60 minutes prior to proceeding to step (iv).
(Item 47) The process of any one of the preceding items, wherein each thermal cycle of step (iv) has a duration of about 160 minutes to about 280 minutes.
(Item 48) The process of any one of the preceding items, wherein each thermal cycle has a duration of about 200 minutes to about 250 minutes.
(Item 49) The process of any one of the preceding items, wherein each thermal cycle has a duration of about 200 minutes.
(Item 50) The process of any one of the preceding items, wherein the process comprises 3 (iv) thermal cycles.
(Item 51) The process of any one of the preceding items, wherein the cool-heat cycle of step (vi) comprises:
(vi.1) slow-cooling the mixture to between about 15 °C and about 25 °C,
(vi.2) holding the temperature for about 15-75 minutes,
(vi.3) slow-heating the mixture to between about 35 °C and about 45 °C,
(vi.4) holding the temperature for about 15-75 minutes, and
(vi.5) cooling the mixture to between about 10 °C to about 20 °C.
(Item 52) The process of any one of the preceding items, comprising the optional milling step (viii).
(Item 53) The process of any one of the preceding items, wherein the milling occurs at a speed of 2700 rotations per minute (RPM) to 4700 RPM.
(Item 54) The process of any one of the preceding items, wherein the milling occurs at 2700 RPM.
(Item 55) The process of any one of the preceding items, wherein the milling is pin-milling.
(Item 56) The process of any one of the preceding items, wherein Compound 1 has a bulk density of 0.18 g/mL to 0.55 g/mL.
(Item 57) The process of any one of the preceding items, wherein Compound 1 has a bulk density higher than 0.22 g/mL and less than 0.55 g/mL.
(Item 58) The process of any one of the preceding items, wherein Compound 1 has a bulk density higher than 0.30 g/mL and less than 0.40 g/mL.
(Item 59) The process of any one of the preceding items, wherein Compound 1 has a tapped density of 0.32 g/mL to 0.61 g/mL.
(Item 60) The process of any one of the preceding items, wherein Compound 1 has a tapped density of from about 0.32 g/mL to 0.51 g/mL.
(Item 61) The process of any one of the preceding items, wherein Compound 1 has a tapped density of about 0.33 g/mL to about 0.44 g/mL.
(Item 62) The process of any one of the preceding items, wherein Compound 1 comprises particles having a d₁₀ particle size of from about 10 μm to about 54 μm.
(Item 63) The process of any one of the preceding items, wherein Compound 1 comprises particles having a d₅₀ particle size of from about 31 μm to about 137 μm.
(Item 64) The process of any one of the preceding items, wherein Compound 1 comprises particles having a d₉₀ particle size from about 76 μm to about 353 μm.

FIG. 1 is an exemplified process workflow for the process of Example 1. FIG. 2 is an exemplified process workflow for the process of Example 2.

FIG. 3 is an exemplified process workflow for the process of Example 5.

FIG. 4 is microscopy and particle size distribution (PSD) data for particles of Compound 1 produced by different processes of the present invention.

FIG. 5 is microscopy and PSD data for particles of Compound 1 produced by a 1 wt% seeded process of Example 6.

FIG. 6A-B are microscopy and PSD data for particles of Compound 1 produced by a 1 wt% seeded process of Example 6 with (A) heat cycling between 60-70 °C and (B) heat cycling between 50-70 °C.

FIG. 7 is a bar graph showing the variance analysis of distribution for d₁₀.

FIG. 8 is a bar graph showing the variance analysis of distribution for d₅₀.

FIG. 9 is a bar graph showing the variance analysis of distribution for d₉₀.

FIG. 10 is a bar graph showing the variance analysis of distribution for bulk density.

FIG. 11 is a bar graph showing the variance analysis of distribution for tapped density.

FIG. 12 is a bar graph showing the variance analysis of distribution for yield.

DETAILED DESCRIPTION
Definitions
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Accordingly, the following terms are intended to have the following meanings:

As used in the specification and claims, the singular form "a", "an" and "the" includes plural references unless the context clearly dictates otherwise.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The pharmaceutically acceptable carrier or excipient does not destroy the pharmacological activity of the disclosed compound and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions as disclosed herein is contemplated. Non-limiting examples of pharmaceutically acceptable carriers and excipients include sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as polyethylene glycol and propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; releasing agents; coating agents; sweetening, flavoring and perfuming agents; preservatives; antioxidants; ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS) such as d-atocopherol polyethyleneglycol 1000 succinate; surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices; serum proteins such as human serum albumin; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based substances; polyacrylates; waxes; and polyethylene-polyoxypropylene-block polymers. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein.

The term “crystalline” refers to a solid in which the constituent atoms, molecules, or ions are packed in a regularly ordered, repeating three-dimensional pattern having a highly regular chemical structure. In particular, a crystalline compound or salt might be produced as one or more crystalline forms. For the purposes of this application, the terms “polymorphic form”, “polymorph” or “crystalline form” are synonymous.

The term “solution” refers to a solvent containing a substance(s) that is at least partially dissolved; and which may contain undissolved substance(s).

The terms "room temperature" and "ambient temperature" are used interchangeably herein. These terms refer to the temperature of the surrounding environment.

The term “seeding” or “seeding material” refers to the addition of a small amount of a crystalline material to a solution or mixture to initiate crystallization.
Compound 1
Compound 1 has the following structure:

Compound 1 is a succinate salt of propan-2-yl 2-[5-(acryloylamino)-4-{[2-(dimethylamino)ethyl](methyl)amino}-2-methoxyanilino]-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate.

Compound (A) is the freebase of propan-2-yl 2-[5-(acryloylamino)-4-{[2-(dimethylamino)ethyl](methyl)amino}-2-methoxyanilino]-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate. Compound (A) has the following structure:

In some embodiments, Compound 1 is provided as a polymorphic form of the succinate salt of Compound 1.

In some embodiments, Compound 1 is provided as a pharmaceutically acceptable form, e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, or prodrugs.

Compound 1 and Compound (A) or pharmaceutically acceptable salts, hydrates, solvates, isomers, or prodrugs thereof, may be produced according to the methods described in WO2015/195228 and/or WO2019/222093, each of which is incorporated herein by reference in its entirety.

In some embodiments, Compound 1 is provided in a composition as a solid form.

As used herein, “solid form” refers to a drug substance having the physical properties (e.g., bulk density, tap density, particle size distribution, and/or compressibility) described herein.

In some embodiments, Compound 1 has a bulk density of from about 0.18 g/mL to about 0.55 g/mL. In some embodiments, Compound 1 has a bulk density of from about 0.22 g/mL to about 0.55 g/mL. In some embodiments, Compound 1 has a bulk density of from about 0.30 g/mL to about 0.40 g/mL. In some embodiments, Compound 1 has a bulk density of from about 0.18 g/mL to about 0.33 g/mL.

“Bulk density” is the ratio of the mass of a bulk solid to its volume, and it determines the space occupied by a given amount of material.

In some embodiments, Compound 1 has a tapped density of from about 0.32 g/mL to about 0.61 g/mL. In some embodiments, Compound 1 has a tapped density of from about 0.32 g/mL to about 0.51 g/mL. In some embodiments, Compound 1 has a tapped density of from about 0.33 g/mL to about 0.44g/mL.

“Tap density” and “tapped density” are used interchangeably. Tapped density is the ratio of the mass of a compound to its volume (measured in a container) after the container has been tapped for a defined period of time. The tapped density represents its random dense packing.

In some embodiments, Compound 1 has a bulk density of from about 0.18 g/mL to about 0.55 g/mL, and/or a tapped density of from about 0.32 g/mL to about 0.61 g/mL. In some embodiments, Compound 1 has a bulk density of from about 0.18 g/mL to about 0.55 g/mL, or a tapped density of from about 0.32 g/mL to about 0.61 g/mL. In some embodiments, Compound 1 has a bulk density of from about 0.18 g/mL to about 0.55 g/mL, and a tapped density of from about 0.32 g/mL to about 0.61 g/mL.

In some embodiments, Compound 1 is in a milled form. In some embodiments, Compound 1 is in a pin-milled form.

In some embodiments, the compositions described herein comprise particles of Compound 1. In some embodiments, the particles comprise an un-milled form of Compound 1.

In some embodiments, the particles comprise a milled form of Compound 1. In some embodiments, the particles comprise a pin-milled form of Compound 1.

“Particles” as used herein are solid forms of Compound 1 having a measurable particle size distribution (PSD). The PSD can be calculated by the measuring instrument software and is generally reported in d₁₀, d₅₀, and d₉₀.

The terms D10, D50 and D90 and d₁₀, d₅₀ and d₉₀ are used interchangeably and are commonly used to represent the particle size distribution of a given sample. “D10” is the value in which 10% of the particles are equal to or smaller than a defined measurement, for example a particle diameter. “D50” is the value in which 50% of the particles are equal to or smaller than a defined measurement, for example a particle diameter. “D60” is the value in which 60% of the particles are equal to or smaller than a defined measurement, for example a particle diameter. “D70” is the value in which 70% of the particles are equal to or smaller than a defined measurement. “D80” is the value in which 80% of the particles are equal to or smaller than a defined measurement, for example a particle diameter. “D90” is the value in which 90% of the particles are equal to or smaller than a defined measurement, for example a particle diameter.

The particle size distribution is generally measured via laser diffraction and the PSD is determined by application of the Mie Theory. Mie Theory uses an optical scattering model based on refractive indices of the particle and dispersion medium and particle absorption values to calculate particle size distribution.

In some embodiments, the particles have a D10 from about 5 μm to about 54 μm. In some embodiments, the particles have a D10 from about 8.5 μm to about 30 μm. In some embodiments, the particles have a D10 from about 6.6 μm to about 30.5 μm. In some embodiments, the particles have a D10 from about 5 μm to about 16 μm. In some embodiments, the particles have a D50 from about 15 μm to about 137 μm. In some embodiments, the particles have a D50 from about 28 μm to about 74 μm. In some embodiments, the particles have a D50 from about 23 μm to about 81.1 μm. In some embodiments, the particles have a D50 from about 18 μm to about 29 μm. In some embodiments, the particles have a D50 from about 15 μm to about 48 μm. In some embodiments, the particles have a D90 from about 32 μm to about 353 μm. In some embodiments, the particles have a D90 from about 70 μm to about 142 μm. In some embodiments, the particles have a D90 from about 54.6 μm to about 156.4 μm. In some embodiments the particles have a D90 from about 38 μm to about 57 μm. In some embodiments, the particles have a D90 from about 45 μm to about 55 μm. In some embodiments, the particles have a D90 from about 32 μm to about 95 μm.

In some embodiments, the particles have a D10 from about 5 μm to about 16 μm, a D50 from about 15 μm to about 48 μm, and a D90 from about 32 μm to about 95 μm. In some embodiments, the particles have a D10 from about 6.6 μm to about 30.5 μm, a D50 from about 23 μm to about 81.1 μm, and a D90 from about 54.6 μm to about 156.4 μm.

In some embodiments, the particles comprise an un-milled form of Compound 1. In some embodiments, the particles comprise an un-milled form of Compound 1 and said particles have a D10 from about 8.5 μm to about 30 μm. In some embodiments, the particles comprise an un-milled form of Compound 1 and said particles have a D50 from about 28 μm to about 74 μm. In some embodiments, the particles comprise an un-milled form of Compound 1 and said particles have a D90 from about 69 μm to about 142 μm.

In some embodiments, the particles comprise a milled form of Compound 1. In some embodiments, the particles comprise a milled form of Compound 1 and said particles have a D10 from about 5 μm to about 10 μm. In some embodiments, the particles comprise a milled form of Compound 1 and said particles have a D50 from about 18 μm to about 29 μm. In some embodiments, the particles comprise a milled form of Compound 1 and said particles have a D90 from about 38 μm to about 57 μm.

In some embodiments, the density at 15kPa, also referred to as “compressibility,” of Compound 1 is measured. In some embodiments, Compound 1 has a compressibility of from about 0.55 g/mL to about 0.65 g/mL. In some embodiments, Compound 1 has a compressibility of from about 0.56 g/mL to about 0.62 g/mL.
Pharmaceutical Compositions

In certain embodiments, Compound 1 can be formulated as pharmaceutical compositions for administration in solid or liquid form, including those adapted for the following: oral administration, for example, tablets, capsules, boluses, powders, granules, or pastes; intravaginally or intrarectally, for example, as a pessary, cream, stent or foam; sublingually; ocularly; pulmonarily; local delivery by catheter or stent; intrathecally, or nasally.

In some embodiments, Compound 1 is formulated as pharmaceutical composition for administration in the form of a capsule.

In some embodiments, pharmaceutical compositions comprise Compound 1, and optionally one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. In some embodiments, a pharmaceutical composition described herein includes a second active agent such as an additional therapeutic agent, (e.g., a chemotherapeutic).

In some embodiments, the compositions comprise Compound 1 together with a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.

In some embodiments, the compositions comprise Compound 1 filled in a capsule without any excipients. For example, Compound 1 may be filled directly into hard gelatin capsules, with no excipients.

In some embodiments, the compositions may be formulated as a drug-in-capsule without excipients.

In certain embodiments, the drug-in-capsule composition comprises Compound 1 that is equivalent to 20 mg of Compound (A).

In certain embodiments, the drug-in-capsule composition comprises Compound 1 that is equivalent to 40 mg of Compound (A).

Examples of suitable aqueous and nonaqueous carriers which can be employed in pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, lubricants, and/or antioxidants. Prevention of the action of microorganisms upon Compound 1 can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It can also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

Methods of preparing these formulations or compositions include the step of bringing into association Compound 1 and/or the chemotherapeutic with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association Compound 1 with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington’s Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.
Processes for Preparing Compound 1

In certain embodiments, the present disclosure provides processes for preparing Compound 1. Exemplary processes, as described herein, for preparing Compound 1 are shown in FIG. 1 and FIG. 2.

In certain embodiments, the process for the preparation of Compound 1 comprises:
(i) mixing Compound (A) with succinic acid in the presence of a solvent

(ii) heating the mixture of step (i),
(iii) adding a seeding material to the mixture of step (ii),
(iv) thermal cycling the mixture at a temperature of between about 45 °C-75 °C
(v) repeating the (iv) thermal cycling step,
(vi) performing a cool-heat step at a temperature of between about 20 °C-40 °C,
(vii) collecting solids to provide Compound 1, and
(viii) optionally, milling the solids obtained in step (vii) to provide a milled form of Compound 1.

In certain embodiments, the solvent in step (i) is acetone, acetone/water (3:1), acetonitrile, anisole, methanol, ethanol, propanol, 1-butanol, dimethylacetamide, dimethylformamide, dimethylsulfoxide, 1,4-dixoane, ethyl acetate, a mixture of methanol and water (3:1), 2-methoxyethanol, methyltetrahydrofuran, tetrahydrofuran, a mixture of tetrahydrofuran and water (3:1), a mixture of methyltetrahydrofuran and water (96:4), methyl acetate, methylethyl ketone, methyl isobutyl ketone, N-methyl-2-pyrrolidone, or a mixture thereof.

In certain embodiments, the solvent in step (i) is an alcohol, such as methanol, ethanol, propanol, or 1-butanol.

In certain embodiments, the solvent in step (i) is ethanol.

In certain embodiments, the temperature of step (ii) is from about 73°C to about 83 °C. In some embodiments, the temperature of step (ii) is about 78°C. In some embodiments, the temperature of step (ii) has a 5 °C variation. In some embodiments, the temperature of step (ii) is 78±5 °C.

In certain embodiments, the amount of solvent in step (i) ranges from about 28.5 liters of solvent per kilogram of Compound (A) to about 31.5 liters of solvent per kilogram of Compound (A).

In certain embodiments, after step (ii), an optional clarifying filtration step is performed on the resulting mixture of, followed by a solvent rinse. In some embodiments, the solvent rinse is between about 1.9 liters of solvent per kilogram of Compound (A) and about 2.1 liters of solvent per kilogram of Compound (A). In certain embodiments, the temperature of the clarifying filtration step is from about 73°C to about 83 °C. In some embodiments, the temperature the clarifying filtration step about 78°C. In some embodiments, the temperature the clarifying filtration step has a 5 °C variation. In some embodiments, the temperature of the clarifying filtration step is 78±5 °C.

The mixture after step (ii) or after the optional clarifying filtration is distilled to a target volume. In some embodiments, the target volume is about 11 liters of solvent per kilogram of Compound (A) to about 15 liters of solvent per kilogram of Compound (A). In some embodiments, the target volume is about 12 liters of solvent per kilogram of Compound (A) to about 14 liters of solvent per kilogram of Compound (A). In some embodiments, the target volume is about 13 liters of solvent per kilogram of Compound (A).

After distillation, the mixture is cooled to a temperature of about 73°C to about 77 °C, and held until the temperature is stabilized. In some embodiments, the mixture is cooled down to a temperature of about 75°C.

In certain embodiments, a seeding material is added to the mixture of step (ii). In some embodiments, about 0.5%, about 0.75%, about 1.0%, about 1.25%, or about 1.5% by weight of seeding material is added to the mixture. In some embodiments, about 0.75%, about 1.0%, or about 1.25% by weight of seeding material is added to the mixture. In some embodiments, about 1.0% by weight of seeding material is added to the mixture.

In some embodiments, the seeding material is Compound 1 in milled form. In some embodiments, the seeding material is Compound 1 in jet-milled form. In some embodiments, Compound 1 is suspended in an organic solvent. In some embodiments, the organic solvent in which Compound 1 is suspended in is an alcohol, such as methanol, ethanol, propanol, or 1-butanol. In some embodiments, the organic solvent in which Compound 1 is suspended in is ethanol. In some embodiments, the seeding material is a jet-milled form of Compound 1 suspended in ethanol.

In some embodiments, the seeding material has a particle size distribution defined by a D90. In some embodiments, the D90 of the seeding material is about 3 μm (micron) to about 8 μm (micron). In some embodiments, the seeding material has a particle size distribution defined by surface area. In some embodiments, the seed surface area of the seeding material is between about 3 m²/g and about 11 m²/g. In some embodiments, the seed surface area of the seeding material is between about 4 m²/g and about 7 m²/g.

The addition of the seeding material to the mixture, results in a slurry. In some embodiments, the resulting slurry is held at a stable temperature for a period of about 15 min to about 60 minutes. In some embodiments, the resulting slurry is held at a stable temperature for about 30 min. In some embodiments, the resulting slurry is held at a stable temperature for about 60 min.

In certain embodiments, the resulting mixture is placed under “thermal cycling” at a temperature of between about 45 °C-75 °C.

As used herein, the term “thermal cycling” refers to the process of cooling the mixture to a low temperature point of the cycle over a fixed period of time, holding the mixture at that low temperature for a fixed period of time, heating the mixture to the high temperature point of the cycle over a fixed period of time, and holding the mixture at that high temperature for a fixed period of time. In certain embodiments, the temperature cycling is conducted, meaning that the temperature is increased or decreased depending on the point of the cycle, at a rate of from about 0.05 to about 0.5 °C per minute. In certain embodiments, thermal cycling is conducted at a rate of from about 0.1 to about 0.3 °C per minute. In certain embodiments, thermal cycling is conducted at a rate of about 0.1 °C per minute.

In certain embodiments, during the thermal cycle, the mixture is slow-cooled to about 45 °C to about 55 °C. In certain embodiments, during the thermal cycle, the mixture is slow-cooled to about 48 °C to about 52 °C. In certain embodiments, during the thermal cycle, the mixture is slow-cooled to about 50 °C. In certain embodiments, the slow-cooling is conducted at a rate of from about 0.1 to about 0.5 °C per minute. In certain embodiments, the slow-cooling period is between about 200 and about 350 minutes. In certain embodiments, the slow-cooling period is between about 250 and about 300 minutes. In certain embodiments, the slow-cooling period is about 250 minutes. In certain embodiments, the slow-cooling period is about 200 minutes. In certain embodiments, the resulting mixture is slow-cooled to about 50 °C over a period of about 250 minutes. In certain embodiments, the resulting mixture is slow-cooled to about 50 °C over a period of about 200 minutes.

In certain embodiments, the mixture is held at the low temperature of the cycle. In certain embodiments, following the slow-cooling, the mixture is held for a period of about 15 minutes to about 75 minutes. In certain embodiments, following the slow-cooling, the mixture is held for a period of about 30 minutes to about 60 minutes. In certain embodiments, following the slow-cooling, the mixture is held for a period of about 30 minutes.

In certain embodiments, during the thermal cycle, the mixture is slow-heated to about 65 °C to about 75 °C. In certain embodiments, during the temperature cycle, the mixture is slow-heated to about 68 °C to about 72 °C. In certain embodiments, during the temperature cycle, the resulting mixture is slow-heated to about 70 °C. In certain embodiments, the slow-heating period is between about 160 and about 280 minutes. In certain embodiments, the slow-heating period is between about 200 and about 250 minutes. In certain embodiments, the slow-heating period is about 200 minutes. In certain embodiments, the resulting mixture is slow-heated to about 70 °C over a period of at least 200 minutes.

In certain embodiments, the mixture is held at the high temperature of the cycle. In certain embodiments, following the slow-heating, the mixture is held for a period of about 15 minutes to about 75 minutes. In certain embodiments, following the slow-heating, the mixture is held for a period of about 30 minutes to about 60 minutes. In certain embodiments, following the slow-heating, the mixture is held for a period of about 30 minutes.

In certain embodiments, the thermal cycling step is repeated one to three times. In certain embodiments, the thermal cycling step is repeated once for a total of two cycles. In certain embodiments, the thermal cycling step is repeated twice for a total of three cycles. In certain embodiments, the thermal cycling step is repeated three times for a total of four cycles.

After completion of the thermal cycling (i.e., steps (iv) and (v)), the temperature being at between 65 °C and 75 °C, a (vi) cool-heat step is performed at a temperature of between about 15 °C-45 °C.

In certain embodiments, the cool-heat step comprises a (vi.1) slow-cooling step, (vi.2) a hold time at a low temperature, a (vi.3) heating step, (vi.4) a hold time at high temperature, and a (vi.5) final cooling step.

In certain embodiments, the (vi) cool-heat step comprises the steps of:
(vi.1) slow-cooling the mixture to a temperature between about 15 °C and about 25 °C over a period of about 400 to about 700 minutes,
(vi.2) holding the temperature for about 15 minutes to about 75 minutes
(vi.3) slow-heating the mixture to a temperature between about 35 °C and about 45 °C over a period of about 150 to about 250 minutes
(vi.4) holding the temperature for about 15 minutes to about 75 minutes, and
(vi.5) cooling the mixture to a temperature between about 10 °C and about 20 °C over a period of about 160 to about 280 minutes.

In certain embodiments, step (vi.1) comprises slow-cooling the mixture between a temperature of about 18 °C and about 22 °C. In certain embodiments, step (vi.1) comprises slow-cooling the mixture to about 20 °C. In certain embodiments, step (vi.1) comprises slow-cooling the mixture over a period of about 500 to about 600 minutes. In certain embodiments, step (vi.1) comprises slow-cooling the mixture over a period of about 500 minutes.

In certain embodiments, step (vi.2) comprises holding the mixture at about 15 °C and about 25 °C for about 30 minutes to about 60 minutes. In certain embodiments, step (vi.2) comprises holding the mixture at about 15 °C and about 25 °C for about 30 minutes.

In certain embodiments, step (vi.3) comprises slow-heating the mixture to a temperature between about 38 °C and about 42 °C. In certain embodiments, step (vi.3) comprises slow-heating the mixture to about 40 °C. In certain embodiments, step (vi.3) comprises slow-heating the mixture over a period of about 200 to about 250 minutes. In certain embodiments, step (vi.3) comprises slow-cooling the mixture over a period of about 200 minutes.

In certain embodiments, step (vi.4) comprises holding the mixture at a temperature between about 35 °C and about 45 °C for about 30 minutes to about 60 minutes. In certain embodiments, step (vi.4) comprises holding the mixture at about 15 °C and about 25 °C for about 30 minutes.

In certain embodiments, step (vi.5) comprises cooling the mixture to a temperature between about 18 °C and about 22 °C. In certain embodiments, step (vi.5) comprises cooling the mixture to about 20 °C. In certain embodiments, step (vi.5) comprises cooling the mixture over a period of about 200 to about 250 minutes. In certain embodiments, step (vi.5) comprises cooling the mixture over a period of about 200 minutes

Upon completion of the (vi) cool-heat step, the resulting mixture is held at the final temperature for a period of about 1 hour to about 48 hours. In certain embodiments, the resulting mixture is held for a period of about 3 hours to about 24 hours. In certain embodiments, the resulting mixture is held for a period of about 3 hours

As used herein, holding a mixture for a period of time is sometimes referred to as “aging” the mixture. Accordingly, these two terms are used interchangeably.

After aging the mixture, solids of Compound 1 are collected by filtration. The solids are washed with a solvent and dried under vacuum. In certain embodiments, the solvent is an alcohol, such as methanol, ethanol, propanol, or 1-butanol. In some embodiments, the solvent is ethanol.

In certain embodiments, the process comprises an optional (viii) milling step. An exemplary process comprising this step is shown in FIG. 2.

In some embodiments, milling occurs at a speed of 2700 rotations per minute (RPM) to 4700 RPM. In some embodiments, milling occurs at a speed of 2700 RPM. In some embodiments, the milling is pin-milling.

In some embodiments, Compound 1 is made by the process shown in FIG. 1.

In some embodiments, Compound 1 is made by:
(i) mixing Compound (A) with succinic acid in the presence of a solvent

(ii) heating the mixture of step (i) to 78±5 °C in solvent at a concentration of about 30 liters of solvent per kg of Compound (A),
(iii) performing a clarifying filtration,
(iv) distilling the mixture to a concentration of about 13 liters of solvent per kg of Compound (A),
(v) cooling the mixture to 75 ±2 °C,
(vi) adding 1 wt% of a seeding material to the mixture,
(vii) aging the mixture for 30-60 minutes,
(viii) cooling the mixture to 50±5 °C at a rate of 0.1 °C/min,
(ix) aging the mixture for 30-60 minutes,
(x) thermal cycling the mixture at a temperature of between 50 ±5 °C and 70 ±5 °C,
(xi) aging the mixture for 30 minutes each time the temperature reaches 50 ±5 °C and 70 ±5 °C,
(xii) repeating the thermal cycling step two more times,
(xiii) slow-cooling the mixture to 20 ±5 °C,
(xiv) heating the mixture to 40 ±2 °C,
(xv) cooling the mixture to 20 ±5 °C.
(xvi) aging the mixture for 1-24 hours,
(xvii) collecting solids to provide Compound 1,
(xviii) washing the solids with ethanol, and
(xix) drying under vacuum at 65±5 °C.

In some embodiments, Compound 1 is made by the process shown in FIG. 2.

In some embodiments, Compound 1 is prepared by a process comprising:
(i) mixing Compound (A) with succinic acid in the presence of a solvent

(ii) heating the mixture of step (i) to 78±5 °C in solvent at a concentration of about 30 liters of solvent per kg of Compound (A),
(iii) performing a clarifying filtration,
(iv) distilling the mixture to a concentration of about 13 liters of solvent per kg of Compound (A),
(v) cooling the mixture to 75±2 °C,
(vi) adding 1 wt% of a seeding material to the mixture,
(vii) aging the mixture for 30-60 minutes,
(viii) cooling the mixture to 50±5 °C at a rate of 0.1 °C/min,
(ix) aging the mixture for 30-60 minutes,
(x) thermal cycling the mixture at a temperature of between 50±5 °C and 70±5 °C,
(xi) aging the mixture for 30 minutes each time the temperature reaches 50 ±5 °C and 70±5 °C,
(xii) repeating the thermal cycling step two more times,
(xiii) slow-cooling the mixture to 20±5 °C,
(xiv) heating the mixture to 40±2 °C,
(xv) cooling the mixture to 20±5 °C.
(xvi) aging the mixture for 1-24 hours,
(xvii) collecting solids to provide Compound 1,
(xviii) washing the solids with ethanol,
(xix) drying under vacuum at 65±5 °C, and
(xx) pin-milling the solids to provide a milled form of Compound 1.
Polymorphic Forms

In certain embodiments, Compound 1 obtained by the processes described herein is in a substantially crystalline form.

The term “substantially crystalline form” refers to at least a particular percentage by weight of Compound 1 that is crystalline. Particular weight percentages include at least about 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% and 99.9%.

Bulk and Tap Density
Bulk and Tap Analysis is performed using a Copley Tap Density Analyzer. First, the bulk density is assessed using a 25ml graduated cylinder. A graduated cylinder is placed on a balance and tared. The cylinder is then held horizontally, and sample is scooped from the powder container directly into the graduated cylinder. Powder is added into the graduated cylinder, with care being taken to avoid tapping or jostling the cylinder to prevent consolidation. When the cylinder is almost full, the cylinder is carefully rotated to the vertical position, and a volume reading is taken. If the powder is unevenly distributed at the top of the cylinder, an average line can be used between the peaks and troughs to estimate the total volume.

After the bulk volume is recorded, the sample is placed on the balance and the net weight of powder is recorded. The sample is then placed on the Tap Density Analyzer, under a protective ring. The cylinder is then automatically tapped a total of 2000 times. After tapping is complete, the protective rings are removed and the volume of the powder in the cylinder is recorded.

Using the mass measurement, the bulk density is calculated by dividing the mass by the pre-tap volume, while the tap density is calculated by dividing the mass by the post-tap volume.
Compressibility

Compressibility begins by measuring condition bulk density first. Before each test is run, the powder is first conditioned. This is to standardize the powder packing of each sample as the process removes any compaction or excess air, it also removes variability introduced by the operator during loading of the sample. A conditioning cycle comprises a traverse of the blade downward and then a traverse upward. This is repeated 3 times. For the compressibility test, the sample is then split such that the top, excess portion of the sample is removed. Since the volume and weight of the sample is then known, the conditioned bulk density can then be calculated. After the conditioning steps, the stirrer blade is replaced with a piston that then applies force to the sample. A standardized method incrementally applies forces of 0.5, 1, 2, 4, 6, 8, 10, 12, 15kPa on a 50mm vessel. Other methods may be used to measure compressibility, such as varying the applied force.
Pin-Milling

Un-milled Compound 1 is poured into a hopper and then conveyed to the pin-mill via a vibratory feeder at a set feed rate (center-point 3.6 kg/hr). The mill is run at a set speed (center-point 3700 RPM), and the milled product is collected in a bag. An intermediate process control (IPC) sample is removed from the product, and the particle size of the product is tested against the d₉₀ target size range. If necessary, the milling speed is then adjusted to achieve the desired particle size.
Particle Size Distribution

Particle size distribution is measured via laser diffraction. Specifically, the particle size distribution may be measured via laser diffraction using the Malvern Mastersizer 3000 optical bench equipped with a Hydro MV wet dispersion unit. The particle size distribution is determined by application of the Mie Theory. Mie theory uses an optical scattering model based on refractive indices of the particle and dispersion medium and particle absorption values to calculate particle size distribution.

Sample measurement: (a) Gently rotate and invert the sample container to ensure the sample is homogenous. (b) Weigh approximately 100 mg of sample into a 20 mL scintillation vial. (c) Add approximately 20 mL of toluene to the vial. Gently swirl and invert the vial to mix. (d) Vortex the vial for 15 seconds. (e) Align the instrument laser and measure the background. (f) Immediately prior to analysis, aspirate the sample with a plastic transfer pipette to ensure a uniformly-dispersed suspension. (g) Add the sample suspension drop-wise to the sample well until the obscuration is within the range, making sure to continue aspiration of the sample suspension so as to not allow for sedimentation in the pipette tip. (h) After the obscuration has stabilized, allow the sample to circulate for at least 1 minute and then initiate the measurement. (i) Between sample preparations, empty and rinse the sample well at least three times with toluene until the light energy is less than 100 for all detectors.

Calculations: The particle size distribution for the samples is calculated by the instrument software using the "General Purpose" calculation model, normal sensitivity, and non-spherical particle shape settings. D10, D50, and D90 are reported.

Example 1
Preparation of isopropyl 2-((5-acrylamido-4-((2-(dimethylamino)ethyl) (methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate succinate (Compound 1).

FIG. 1 is a graphic representation of the process described below.

A clean and dry reactor is charged with Compound (A) (1.0 eq), succinic acid (1.02 eq) and ethanol (30.0 L/kg). The resultant slurry is agitated and heated to 78 °C, at which point a clear solution is obtained. A clarifying filtration is performed, followed by a 2.0 L/kg ethanol vessel rinse. The solution is distilled down to 13 volumes (13L/kg). The solution is cooled to 75 °C and held until the temperature is stable. A slurry of 1 wt% Compound 1 jet-milled seed in ethanol is charged to the reactor and the slurry is held for 30 minutes to ensure the seeds hold. The batch is subjected to 3 heating and cooling cycles between 50 °C and 70 °C at a rate of 0.1 °C/min with 30 minute holds each time the temperature reaches both 50 °C and 70 °C. Once the third thermal-cycle is completed, the temperature of the batch is reduced to 20 °C at approximately 0.1 °C/min. After reaching 20 °C, the solution is held for 30 minutes, followed by heating the batch to 40 °C at approximately 0.1 °C/min, held for 30 minutes, then cooled to 20 °C at 0.1 °C/min. The batch is held for 3-24 hours. The solids are collected by filtration, washed with ethanol (2 x 3 L/Kg) and dried under vacuum at 55-65 °C.

Using the general method above, an 8-factor fractional factorial design of experiments (DoE) was performed on the process to determine which crystallization parameters were most impactful on the product. The factors selected can be seen in Table 1.

Table 1 Factors for DoE

Due to the high number of parameters in the process, multiple parameters were linked together rather than assessing them independently. The high-end of all the thermal cycles were lumped together into a single parameter and were not controlled independently. The low-end of all the thermal cycles were also lumped together into a single parameter and were not controlled independently. All the hold times between the thermal cycles were lumped together into a single parameter. Finally, the heating/cooling times were lumped together and adjusted by the same percentage. Though this parameter lumping results in losing the ability to assess the impact each individual heat cycle, lumping the parameters in this fashion was the only feasible path to evaluating the entire crystallization space.

The values for the factors were selected based on the typical settings in the manufacturing settings. Seed surface area from production ranged from 4 to 7 m²/g, so a wider range of seed surface area was chosen. Variation of the seed loading at production is ± 0.003 wt%, but due to the scale, this was deemed infeasible to accurately charge, so the range was increased to ± 0.5 wt%. Distillation accuracy is ± 1 volume, a double range was selected. For temperature, the process has a ± 2 °C tolerance, so this was doubled to roughly ± 4 °C. The high-end and low-end of the thermocycling have a ±2°C tolerance but a ±5 °C tolerance was selected. A ±15-minute range hold time was used. The tolerance for time of the temperature adjustments used was a non-linear range of -20% and +40%.

A total of 16 experiments plus 3 center-point experiments were performed in this DoE Example. The experiments were executed on a 32-gram scale (Compound (A)). The full design can be seen in Table 2.

Table 2 DoE Design

Though several in-process samples were analyzed throughout the course of the DoE, the primary responses from the DoE were the particle size d₁₀, d₅₀, and d₉₀. Additional responses were yield, bulk density, and tapped density.

Physical property responses to this DoE Example are captured in Table 3. From the results, there is a significant variation in the physical properties across the experimental design. The PSD range showed nearly a 5x range across the design for the d₁₀, d₅₀, and d₉₀. The bulk density varied from 0.14 to 0.33 g/mL, and the tapped density varies from 0.26 to 0.47 g/mL. The yield ranged from 77.3% up to 92.0% across the design.

Table 3 Physical Property Responses for the DoE

Analysis of variance plots for the various DoE were measured. The d₁₀ varied across the DoE design space from 9.8 to 53.6 μm, with a median of 22.3 μm (FIG. 7). The d₅₀ varied across the DoE design space from 30.9 to 136.7 μm, with a median of 67.5 μm (FIG. 8). The d₉₀ varied across the DoE design space from 76.9 to 352.6 μm, with a median of 152.1 μm (FIG. 9). The bulk density varied across the DoE design space from 0.14 to 0.33 g/mL, with a median of 0.22 g/mL (FIG. 10). The tapped density varied across the DoE design space from 0.26 to 0.47 g/mL, with a median of 0.36 g/mL (FIG. 11). The yield varied across the DoE design space from 77.3 to 92.0%, with a median of 84.8% (FIG. 12).

As noted above, the DoE ranges were set to be significantly wider than the typical tolerance during routine manufacturing. The results of the maximization and minimization of the PSD parameters can be seen in Table 4. In addition, a calculation was made assuming that the PSD would be reduced by 50% after going through an agitated filter dryer. From these more reasonable ranges for the factors, and assuming a 50% reduction of the PSD, the d₁₀ now ranges from 8.2 to 20.2 μm, the d₅₀ ranges from 26.1 to 53.9 μm, and the d₉₀ ranges from 65.5 to 124.3 μm.

Table 4 Optimization Parameters

Example 2
Preparation of isopropyl 2-((5-acrylamido-4-((2-(dimethylamino)ethyl) (methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate succinate (Compound 1).

For example, Compound 1 can be made by a process where Compound (A) (25.6 kg), Succinic Acid (1.02 eq, approx.. 5.3 kg), and Ethanol (approx. 607 kg), are charged to a reactor and are heated to reflux until dissolution is achieved. The contents of the reactor are transferred to a second reactor by passing the solution through a filter. Additional EtOH (approximately 41 kg) is added to the first reactor to rinse it of residue, and the rinsate is filtered and charged to the second reactor. The reaction mixture is heated to reflux and distilled to approximately 333 L. Upon completion of the distillation, the temperature is adjusted to 75°C. A seed slurry is prepared in a suitable container by mixing micronized Compound 1 (approx. 0.26 kg) and filtered EtOH (approx. 2.6 kg). The seed slurry is then charged to the reactor and the mixture undergoes three temperature cycles between 50°C and 70°C. Once the third heating cycle is complete, the mixture is cooled to 20°C, warmed to 40°C, and cooled one final time 20°C. The mixture is aged while maintaining a target temperature of 20°C. The slurry is filtered, and the collected solids are washed twice with filtered EtOH (approx. 61 kg each). The resulting filter cake is dried at 60°C. The expected yield of Compound 1 is 84 to 91%. The dried Compound 1 is pin-milled to the target particle size distribution (d₉₀ = 45-55 μm) and is packaged in the final container closure.

FIG. 2 is a graphic representation of Example 2, wherein Compound 1 is pin-milled to the d₉₀ target size range of 45-55 μm.
Example 3
Milling and Bulk Density.

Comparing an unmilled batch to the same batch milled to two different particle size distributions shows little effect on bulk density or tapped density as shown in Table 5 below.

Table 5. Comparison of Unmilled and Milled particles.

Example 4
Milling and Capsule Preparation.

Table 6 shows various process parameters and sample properties of Compound 1 produced by the processes described above with the modifications shown in Table 6.

Table 6. Process parameters and properties of Compound 1 produced by processes of Example 4.

For each experiment, particle size distribution data was collected to understand its variation across the process design space, but manufacturability of the drug product was considered the primary response. Each batch of drug substance generated from the milling experiments was subjected to encapsulation using a commercial encapsulation apparatus. The success or failure of a set of pin-milling conditions was primarily assessed by capsule fill weight achieved upon its formulation. The parameters of pin-milling are shown in Table 7. The parameters of pin-milling and properties of resultant Compound 1 are shown in Table 8.
Table 7 Parameters and Limits used for the Pin-Milling

Table 8 Milling parameters and Compound 1 properties.

As can be seen on Table 8, with a target fill weight of 48.0 ± 2.4 mg, all of the additional 10 samples were able to be filled to the desired target fill weight. Thus, the entire milling design space generated product that was manufacturable.

An initial assessment of the pin-milling experiments revealed substantial variation in particle size distribution across all experiments as judged by laser diffraction with d₁₀ values ranging from 5.3 μm to 14.5 μm, d₅₀ values ranging from 18.3 μm to 43.5 μm and d₉₀ values ranging from 36.8 μm to 86.1 μm. Evaluation of individual process parameters demonstrated a strong correlation between the milled Compound 1 drug substance particle size and the input un-milled Compound 1 particle size, and a strong inverse correlation between milled Compound 1 drug substance particle size and the rotation speed of the mill. Feed rate of the un-milled Compound 1 into the mill was not an impactful parameter to the milling process.

Each of the batches of Compound 1 drug substance generated were subjected to encapsulation using the commercial encapsulation equipment. Despite the broad variation in particle sizes across the design space, all batches produced were effectively encapsulated to the desired target fill weight.

The results herein demonstrate that control of the Compound 1 drug product capsule strength can be maintained by the parameters established for the pin-mill rotation speed and the un-milled Compound 1 particle size distribution as defined by the milling experiments in addition to any in-process controls utilized during the encapsulation process.

Additional experiments were performed to fine-tune the milling and encapsulation process.

Example 5
Preparation of isopropyl 2-((5-acrylamido-4-((2-(dimethylamino)ethyl) (methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate succinate (Compound 1).

FIG. 3 is a graphic representation of Example 5.

Compound (A) (95 g) was charged to a 2 L glass reactor and treated with a solution of succinic acid in ethanol (1.02 eq. dissolved at 37 °C in EtOH 980 mL). Additional EtOH was used to rinse the flask and the filter, and the rinse was added to the reaction mixture. The reaction mixture was heated to 40 °C, clarified, heated to 70-80 °C, and then cooled to 10 °C over 5 h followed by aging at 0-5°C. The product was isolated by filtration, washed with EtOH, dried to give the title compound (96% yield).

This process produced undesirable material. The crystallization was uncontrolled without any seeding or set cooling ramp rates. There was no clarification of the entire process stream. Because there was no clarification step, a re-work procedure in the event of an out of specification batch was not possible. Finally, the resulting product from this process typically had a bulk density of 0.1 g/mL. The bulk density was too low to fill a 40 mg DiC Size 0 capsule.

This process produced product with low bulk density. Microscopy of the resulting product can be seen in FIG. 4, Example 5. The particle size distribution was wide and bi-modal as well (See FIG. 4, Example 5).

Example 6
Preparation of isopropyl 2-((5-acrylamido-4-((2-(dimethylamino)ethyl) (methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate succinate (Compound 1).

In order to improve Example 5, various process parameters were modified as indicated below.

Seeding

To control the crystallization, 1 wt% seeds were added after dissolution of the starting material. Microscopy and particle size distribution (PSD) of the resulting product can be seen in FIG. 5. The resultant compound grew as long needles, but the shape of the PSD did not improve, nor did the bulk density.

Seeds were generated using 3 different configurations (coarse, medium and fine) having particle size distributions shown in Table 9.

Table 9 PSD data for wet-milled seeds

The 3 lots of product were used as seed input to crystallizations at both 1 and 5 wt% loadings. The resulting physical properties from the crystallizations can be seen in Table 10. In addition to the 3 lots of wet-milled seeds, un-milled seeds were used as input as well. As seen in the Table 10, bulk density and d₉₀ particle size did not have a direct correlation with the seed input size. Because of the shape of the size distributions, the inconsistency and bi-modality of the size distributions likely resulted in material that could not pack together well, resulting in the poor bulk density. In addition, it was possible that the coarse, medium, and un-milled seeds did not provide sufficient surface area for only growth to occur during the crystallization process, resulting in bulk nucleation. The conditions that gave the highest bulk density of product was a 5 wt% loading of fine material. While the 5 wt% fine material loading provided a reasonable bulk density, seeding alone was insufficient to produce a reasonable bulk density.

Table 10. Properties of Samples 1-8 produced by Example 6.

Heat-cycling

Another attempt to increase the size of the crystals (and thus the bulk density) was through the use of heat-cycling. Two experiments were run that included heat cycling between 60-70 °C and between 50-70 °C 3 times before cooling to 20 °C to isolate the product. Microscopy and PSD data for these products can be seen in FIG. 6A and 6B. The distributions shifted towards a more mono-modal distribution, but the shapes were still irregular and the bulk densities did not improve.

A number of different heat-cycling parameters were assessed, including single pass cooling crystallization with micronized seed, thermal cycling with stepped down temperature ranges (i.e., 50-70 °C, followed by 40-60 °C), thermal cycling with lower temperature ranges to decrease the amount of material dissolved per cycle, and modifying the temperature ramp rate with extended holds at each temperature. A summary of the experiments performed for the optimization, key changes in each experiment, and overall conclusions can be seen in Table 10. Of these experiments, only decreasing the heating/cooling ramp rate to 0.1 °C/min and implementing 30 minute holds at each temperature increased the bulk properties. In most cases, changing the crystallization parameters resulted in lower bulk density.

Table 11. Heat-cycling experiments of Samples 9-16 of Example 6.

Seed Surface Area

Because using wet-milled seed crystals used in the seeding study may be impractical at large scale and 5 wt% seed loading may be higher than ideal for long term manufacturing, jet-milled seeds having a range of specific surface areas were evaluated. The process developed during the heat-cycling study was used: heat cycling at 50-70 °C 3 times with a heating and cooling rates of 0.1 °C/min with 30 minute holds before cooling to 20 °C to isolate the product. The impact of the seed size and seed loading on the bulk properties of the crystallization product were assessed and the results are summarized in Table 12.

Table 12 Seed response curve results

From the data in Table 12, the seed loading and seed properties did not have a significant impact on the bulk density of the isolated product.

The learnings from the seeding, heat cycling, and seed surface area studies were applied to produce the process in Example 1. The batch was seeded with 1 wt% medium sized seed and the thermalcycling was performed between 50-70 °C with a heating/cooling rate of 0.1 °C/min. Additionally, each time the crystallization reached 50 and 70 °C, a 30 minute hold was implemented. A final thermal cycle between 20 and 40 °C was also implemented.

Claims (64)

1. A composition comprising Compound 1
   

   

   wherein Compound 1 has
   a) a bulk density of from about 0.18 g/mL to about 0.55 g/mL, and/or
   b) a tapped density of from about 0.32 g/mL to about 0.61 g/mL.
2. The composition of claim 1, wherein Compound 1 has a bulk density higher than 0.22 g/mL and less than 0.55 g/mL.
3. The composition of claim 1, wherein Compound 1 has a bulk density higher than 0.30 g/mL and less than 0.40 g/mL.
4. The composition of claim 1, wherein Compound 1 has a tapped density of from about 0.32 g/mL to 0.51 g/mL.
5. The composition of claim 1, wherein Compound 1 has a tapped density of from about 0.33 g/mL to 0.44 g/mL.
6. The composition of claim 1, wherein Compound 1 is in a milled form.
7. The composition of claim 6, wherein the milled form is pin-milled.
8. The composition of claim 1, wherein Compound 1 comprises particles having a d₁₀ of about 10 μm to about 54 μm.
9. The composition of claim 1, wherein Compound 1 comprises particles having a d₅₀ of from about 31 μm to about 137 μm.
10. The composition of claim 1, wherein Compound 1 comprises particles having a d₉₀ of from about 76 μm to about 353 μm.
11. A pharmaceutical composition comprising the composition of claim 1.
12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is in a capsule.
13. The pharmaceutical composition of claim 12, wherein the capsule comprises Compound 1 that is equivalent to 40 mg of Compound (A).
14. The pharmaceutical composition of claim 13, wherein the capsule does not contain pharmaceutical excipients.
15. A composition of Compound 1
    

    

    prepared by a process comprising the steps of:
    (i) mixing Compound (A) with succinic acid in the presence of a solvent
    

    

    (ii) heating the mixture of step (i),
    (iii) adding a seeding material to the mixture of step (ii),
    (iv) thermal cycling the mixture at a temperature of between about 45 °C-75 °C,
    (v) repeating the (iv) thermal cycling step,
    (vi) performing a cool-heat step at a temperature of between about 15 °C-45 °C,
    (vii) collecting solids to provide Compound 1, and
    (viii) optionally, milling the solids obtained in step (vii) to provide a milled form of Compound 1.
16. The compound of claim 15, wherein after step (ii) and before step (iii), the process further comprises a clarifying filtration step, an ethanol rinse step, and a distillation to a target volume step.
17. The composition of claim 15, wherein the seeding material is a crystalline succinate salt suspended in an organic solvent.
18. The composition of claim 17, wherein the organic solvent is ethanol.
19. The composition of claim 15, wherein the seeding material is in an amount of about 0.5% to about 1.5% by weight of Compound (A).
20. The composition of claim 15, wherein the seeding material is in an amount of about 1.0% by weight of Compound (A).
21. The composition of claim 15, wherein after the addition of the seeding material, the mixture is kept at a temperature of about 70 °C for about 30 to 60 minutes prior to proceeding to step (iv).
22. The composition of claim 15, wherein each thermal cycle of step (iv) has a duration of about 160 minutes to about 280 minutes.
23. The composition of claim 22, wherein each thermal cycle has a duration of about 200 minutes to about 250 minutes.
24. The composition of claim 22, wherein each thermal cycle has a duration of about 200 minutes.
25. The composition of claim 15, wherein the process comprises 3 thermal cycles.
26. The composition of claim 15, wherein the cool-heat cycle of step (vi) comprises:
    (vi.1) slow-cooling the mixture to between about 15 °C and about 25 °C,
    (vi.2) holding the temperature for about 15-75 minutes,
    (vi.3) slow-heating the mixture to between about 35 °C and about 45 °C,
    (vi.4) holding the temperature for about 15-75 minutes, and
    (vi.5) cooling the mixture to between about 10 °C to about 20 °C.
27. The composition of claim 15, comprising the optional milling step (viii).
28. The composition of claim 27, wherein the milling occurs at a speed of 2700 rotations per minute (RPM) to 4700 RPM.
29. The composition of claim 28, wherein the milling occurs at 2700 RPM.
30. The composition of claim 27, wherein the milling is pin-milling.
31. The composition of claim 15, wherein Compound 1 has a bulk density of 0.18 g/mL to 0.55 g/mL.
32. The composition of claim 15, wherein Compound 1 has a bulk density higher than 0.22 g/mL and less than 0.55 g/mL.
33. The composition of claim 15, wherein Compound 1 has a bulk density of higher than 0.30 g/mL and less than 0.40 g/mL.
34. The composition of claim 15, wherein Compound 1 has a tapped density of from 0.32 g/mL to 0.61 g/mL.
35. The composition of claim 15, wherein Compound 1 has a tapped density of from 0.32 g/mL to 0.51 g/mL.
36. The composition of claim 15, wherein Compound 1 has a tapped density of from 0.33 g/mL to 0.44 g/mL.
37. The composition of claim 15, wherein Compound 1 comprises particles having a d₁₀ of from about 10 μm to about 54 μm.
38. The composition of claim 15, wherein Compound 1 comprises particles having a d₅₀ of from about 31 μm to about 137 μm.
39. The composition of claim 15, wherein Compound 1 comprises particles having a d₉₀ of from about 76 μm to about 353 μm.
40. A process for preparing Compound 1
    

    

    comprising:
    (i) mixing Compound (A) with succinic acid in the presence of a solvent
    

    

    (ii) heating the mixture of step (i),
    (iii) adding a seeding material to the mixture of step (ii),
    (iv) thermal cycling the mixture at a temperature of between about 45 °C-75 °C,
    (v) repeating the (iv) thermal cycling step,
    (vi) performing a cool-heat step at a temperature of between about 15 °C-45 °C,
    (vii) collecting solids to provide Compound 1, and
    (viii) optionally, milling the solids obtained in step (vii) to provide a milled form of Compound 1.
41. The process of claim 40, wherein after step (ii) and before step (iii), the process further comprises a clarifying filtration step, an ethanol rinse step, and a distillation to a target volume step.
42. The process of claim 40, wherein the seeding material is a jet-milled seed.
43. The process of claim 40, wherein the seeding material is a crystalline succinate salt suspended in an organic solvent.
44. The process of claim 43, wherein the organic solvent is ethanol.
45. The process of claim 40, wherein the seeding material is in an amount of about 0.5% to 1.5% by weight Compound (A).
46. The process of claim 40, wherein after the addition of the seeding material, the mixture is kept at a temperature of about 70 °C for about 30 to 60 minutes prior to proceeding to step (iv).
47. The process of claim 40, wherein each thermal cycle of step (iv) has a duration of about 160 minutes to about 280 minutes.
48. The process of claim 47, wherein each thermal cycle has a duration of about 200 minutes to about 250 minutes.
49. The process of claim 48, wherein each thermal cycle has a duration of about 200 minutes.
50. The process of claim 40, wherein the process comprises 3 (iv) thermal cycles.
51. The process of claim 40, wherein the cool-heat cycle of step (vi) comprises:
    (vi.1) slow-cooling the mixture to between about 15 °C and about 25 °C,
    (vi.2) holding the temperature for about 15-75 minutes,
    (vi.3) slow-heating the mixture to between about 35 °C and about 45 °C,
    (vi.4) holding the temperature for about 15-75 minutes, and
    (vi.5) cooling the mixture to between about 10 °C to about 20 °C.
52. The process of claim 40, comprising the optional milling step (viii).
53. The process of claim 52, wherein the milling occurs at a speed of 2700 rotations per minute (RPM) to 4700 RPM.
54. The process of claim 53, wherein the milling occurs at 2700 RPM.
55. The process of claim 52, wherein the milling is pin-milling.
56. The process of claim 40, wherein Compound 1 has a bulk density of 0.18 g/mL to 0.55 g/mL.
57. The process of claim 40, wherein Compound 1 has a bulk density higher than 0.22 g/mL and less than 0.55 g/mL.
58. The process of claim 40, wherein Compound 1 has a bulk density higher than 0.30 g/mL and less than 0.40 g/mL.
59. The process of claim 40, wherein Compound 1 has a tapped density of 0.32 g/mL to 0.61 g/mL.
60. The process of claim 40, wherein Compound 1 has a tapped density of from about 0.32 g/mL to 0.51 g/mL.
61. The process of claim 40, wherein Compound 1 has a tapped density of about 0.33 g/mL to about 0.44 g/mL.
62. The process of claim 40, wherein Compound 1 comprises particles having a d₁₀ particle size of from about 10 μm to about 54 μm.
63. The process of claim 40, wherein Compound 1 comprises particles having a d₅₀ particle size of from about 31 μm to about 137 μm.
64. The process of claim 40, wherein Compound 1 comprises particles having a d₉₀ particle size from about 76 μm to about 353 μm.

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