WO2018073839A1

WO2018073839A1 - Amorphous osimertinib mesylate, processes for its preparation and solid amorphous dispersions thereof

Info

Publication number: WO2018073839A1
Application number: PCT/IN2017/050481
Authority: WO
Inventors: Ramakoteswara Rao Jetti; Hemant Malhari MANDE; Anjaneyaraju Indukuri; Aggi Ramireddy Bommareddy; Vinay Kumar Shukla; Prakash Bansode
Original assignee: Mylan Laboratories Limited
Priority date: 2016-10-18
Filing date: 2017-10-17
Publication date: 2018-04-26

Abstract

The present disclosure provides amorphous osimertinib mesylate, amorphous solid dispersions of osimertinib mesylate, and processes for the preparation thereof. Amorphous osimertinib mesylate and solid dispersions thereof may be used to prepare pharmaceutical dosage forms.

Description

AMORPHOUS OSIMERTINIB MESYLATE, PROCESSES FOR ITS PREPARATION AND SOLID AMORPHOUS DISPERSIONS THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Indian provisional patent application No. 201641035651 filed on October 18, 2016, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to generally to active pharmaceutical ingredients and more specifically to amorphous osimertinib mesylate, amorphous solid dispersions of osimertinib mesylate, and processes for the preparation thereof.

BACKGROUND OF THE INVENTION

Osimertinib mesylate, chemically known as N-(2-{2-dimethylaminoethyl-methylamino}-4- methoxy-5-{ [4-(l-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate salt (AZD9291) has the structure shown below as Formula I.

Formula I

Osimertinib mesylate is a kinase inhibitor and the active ingredient in TAGRISSO®, which is indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC).

PCT Patent Application Publication No. WO 2013014448 discloses processes for the preparation of osimertinib mesylate and its intermediates. PCT Patent Application Publication No. WO2013014448 discloses osimertinib mesylate salt crystalline polymorphs Form A and Form B, amorphous osimertinib free base as well as Form A, Form B, Form C, Form D, Form E, Form F, and Form K. The present invention provides amorphous osimertinib mesylate as well as solid dispersions of osimertinib mesylate and processes for the preparation thereof.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides amorphous osimertinib mesylate. In another aspect, the present invention provides a process for the preparation of amorphous osimertinib mesylate.

In one embodiment, amorphous osimertinib mesylate may be prepared by a process that includes the steps of:

1. dissolving osimertinib mesylate in a solvent; and

2. removing the solvent to isolate amorphous osimertinib mesylate.

Within the context of this embodiment, the solvent may be a polar solvent, for example, an alcohol solvent, a ketone solvent, a nitrile solvent, an ether solvent, water, or mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, 1-propanol, n-butanol, 2-butanol, isobutanol, t-butanol, 2-methoxy ethanol, 2- ethoxy ethanol, and mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof. Examples of suitable nitrile solvents include, but are not limited to, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, and mixtures thereof. Examples of suitable ether solvents include, but are not limited to, anisole, 1,2-dimethoxyethane, and mixtures thereof. In another aspect, the present invention provides an amorphous solid dispersion of osimertinib mesylate. In another aspect, the present invention provides a process for the preparation of an amorphous solid dispersion of osimertinib mesylate.

In one embodiment, an amorphous solid dispersion of osimertinib mesylate may be prepared by a process that includes the steps of: a) dissolving osimertinib mesylate and pharmaceutically acceptable excipient in a solvent; and

b) removing the solvent to isolate an amorphous solid dispersion of osimertinib mesylate.

Within the context of this embodiment, osimertinib mesylate and a pharmaceutically acceptable excipient may be dissolved in a solvent. This step may be optionally carried out in the presence of an acidic solubilizing agent.

Examples of suitable acidic solubilizing agents include, but are not limited to, tartaric acid, citric acid, lactic acid, fumaric acid, formic acid, hydrochloric acid, phosphoric acid, acetic acid, succinic acid, malic acid, propionic acid, oxalic acid, sulphuric acid, and mixtures thereof.

Within the context of this embodiment, the solvent may be a polar solvent, for example, an alcohol solvent, a ketone solvent, a nitrile solvent, water, or mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-l- butanol, 2-methyl-2-butanol, 2,2-dimethyl-l-butanol, 3-methyl-2-butanol, ethylene glycol 2,2- dimethyl-1 -propanol, and mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), and mixtures thereof. Examples of suitable nitrile solvents include, but are not limited to, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, and mixtures thereof. In particularly useful embodiments, the acidic solubilizing agent is citric acid or acetic acid and the solvent is water. Examples of suitable pharmaceutically acceptable excipient include, but are not limited to, polysaccharides, polyvinylpyrrolidones, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone- vinyl acetate copolymers, Ci-C₆ polyalkylene glycols, copolymers of polyethylene glycol and polypropylene glycol, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), croscarmellose, carboxymethyl cellulose (CMC), methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), a-cyclodextrin, optionally substituted a- cyclodextrins, β-cyclodextrin, optionally substituted β-cyclodextrins, γ-cyclodextrin optionally substituted γ-cyclodextrins, silica-based carriers, citric acid, sugar alcohols (for example, mannitol), and mixtures thereof.

In particularly useful embodiments, the pharmaceutically acceptable excipient is povidone with a K value of 30, a 60:40 linear random copolymer of N-vinyl-2-pyrrolidone and vinyl acetate copolymer sold under the brand name of PLASDONE S-630, HPMC, β-cyclodextrin, or hydroxypropyl- β-cyclodextrin, citric acid.

In particularly useful embodiments, the pharmaceutically acceptable excipient is mannitol, for example, mannitol sold under the tradename PEARLITOL® 160C.

Within the context of the present invention, the amorphous osimertinib mesylate or solid dispersions thereof may be formulated into a pharmaceutical dosage form comprising an amorphous solid dispersion of osimertinib mesylate.

In another embodiment, an amorphous solid dispersion of osimertinib mesylate may be prepared by a process that includes the steps of: a) dissolving osimertinib free base and pharmaceutically acceptable excipient in a solvent; and

Within the context of this embodiment, osimertinib free base and a pharmaceutically acceptable excipient may be dissolved in a solvent. This step may be carried out optionally in the presence of an acidic solubilizing agent. Examples of acidic solubilizing agents include, but are not limited to, tartaric acid, citric acid, lactic acid, fumaric acid, formic acid, hydrochloric acid, phosphoric acid, acetic acid, succinic acid, malic acid, propionic acid, oxalic acid, sulphuric acid, and mixtures thereof.

Within the context of this embodiment, the solvent may be a polar solvent, for example, an alcohol solvent, a ketone solvent, a nitrile solvent, water, or mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-l- butanol, 2-methyl-2-butanol, 2,2-dimethyl-l-butanol, 3-methyl-2-butanol, ethylene glycol 2,2- dimethyl-1 -propanol, and mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), and mixtures thereof. Examples of suitable nitrile solvents include, but are not limited to, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, and mixtures thereof.

In particularly useful embodiments, the acidic solubilizing agent is citric acid or acetic acid and the solvent is water. Examples of suitable pharmaceutically acceptable excipient include, but are not limited to, polysaccharides, polyvinylpyrrolidones, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone- vinyl acetate copolymers, Ci-C₆ polyalkylene glycols, copolymers of polyethylene glycol and polypropylene glycol, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), croscarmellose, carboxymethyl cellulose (CMC), methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), a-cyclodextrin, optionally substituted a- cyclodextrins, β-cyclodextrin, optionally substituted β-cyclodextrins, γ-cyclodextrin optionally substituted γ-cyclodextrins, silica-based carriers, citric acid, PEARLITOL 160 C (standard mannitol).and mixtures thereof. In particularly useful embodiments, the pharmaceutically acceptable excipient is PEARLITOL 160 C (standard mannitol). Within the context of the present invention, amorphous osimertinib mesylate and amorphous solid dispersions thereof may be incorporated into a pharmaceutical dosage form, for example, a tablet or capsule.

BRIEF DESCRIPTION OF THE DRAWINGS Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:

Figure 1 is a powder X-ray diffraction (PXRD) pattern of amorphous osimertinib mesylate; Figure 2 is a PXRD pattern of an amorphous solid dispersion of osimertinib mesylate with 50 % PLASDONE S-630 prepared per Example 3;

Figure 3 is a PXRD pattern of an amorphous solid dispersion of osimertinib mesylate with 50% w/w Povidone K30 prepared per Example 5;

Figure 4 is a PXRD pattern of an amorphous solid dispersion of osimertinib mesylate with 50% w/w β-cyclodextrin prepared per Example 7;

Figure 5 is a PXRD pattern of an amorphous solid dispersion of osimertinib mesylate with 50% w/w HPMC prepared per Example 9;

Figure 6 is a PXRD pattern of an amorphous solid dispersion of osimertinib mesylate with 50% w/w PEARLITOL 160 C prepared per Example 14; Figure 7 is a PXRD pattern of an amorphous solid dispersion of osimertinib mesylate with 27 % w/w Citric acid prepared per Example 11 ;

Figure 8 is a PXRD pattern of an amorphous solid dispersion of osimertinib mesylate with 50% w/w PLASDONE S-630 prepared per Example 19; Figure 9 is a PXRD pattern of an amorphous solid dispersion of osimertinib mesylate with 50% w/w PLASDONE S-630 prepared per Example 27; Figure 10 is a PXRD pattern of an amorphous solid dispersion of osimertinib mesylate with 25% w/w PLASDONE S-630 prepared per Example 28;

Figure 11 is a PXRD pattern of an amorphous solid dispersion of osimertinib mesylate with 24 % w/w Citric acid prepared per Example 15; and

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides amorphous osimertinib mesylate.

Amorphous osimertinib mesylate, prepared by methods disclosed herein, may be characterized by powder x-ray diffraction. Thus, samples of amorphous osimertinib mesylate were analyzed on a BRUKER D-8 Discover powder diffractometer equipped with a goniometer of Θ/2Θ configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.

In one embodiment, amorphous osimertinib mesylate may be characterized by the PXRD pattern as depicted in Figure 1.

In another aspect, the present invention provides a process for the preparation of amorphous osimertinib mesylate.

In one embodiment, osimertinib mesylate may be prepared by a process that includes the steps of:

a) dissolving osimertinib mesylate in a solvent; and b) removing the solvent to isolate amorphous osimertinib mesylate.

According to this embodiment, osimertinib mesylate may be dissolved in a solvent. Within the context of this embodiment, the osimertinib mesylate starting material may be any polymorphic form. Examples of suitable solvents include, but are not limited to, polar solvent. Examples of suitable polar solvents include, but are not limited to, alcohol solvents, ketone solvents, nitrile solvents, ether solvents, water, and mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, 1-propanol, n-butanol, 2-butanol, isobutanol, t-butanol, 2-methoxy ethanol, 2-ethoxy ethanol, and mixtures thereof. Examples of suitable ketone solvents include, but are not limited acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof. Examples of suitable nitrile solvents include, but are not limited to acetonitrile, propionitrile, butyronitrile, isobutyronitrile, and mixtures thereof. Examples of suitable ether solvents include, but are not limited to anisole, 1 ,2-dimethoxyethane, and mixtures thereof. In particularly useful embodiments, methanol or water is used as a solvent.

Next, the solvent may be removed to isolate amorphous osimertinib mesylate. This may be carried out by conventional methods including, but not limited to, distillation, lyophilization, spray drying, agitated thin film drying, or combinations thereof. In another aspect, the present invention provides an amorphous solid dispersion of osimertinib mesylate. Within the context of the present invention, the solid dispersion may contain osimertinib mesylate and one or more pharmaceutically acceptable excipients.

In some embodiments, a vinylpyrrolidone-vinyl acetate copolymer (e.g., a copolymer with a 40:60 ratio of N-vinyl-2-pyrrolidone to vinyl acetate) is the pharmaceutically acceptable excipient. In particularly useful embodiments, between about 10% to 50% w/w (which includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50%) of a copolymer with a 40:60 ratio of N- vinyl-2-pyrrolidone to vinyl acetate (e.g., PLASDONE S-630) is used. Figure 2 shows a representative PXRD of a sample of a solid dispersion of osimertinib mesylate with 50% w/w PLASDONE S-630. In some embodiments, PLASDONE S-630 is the pharmaceutically acceptable excipient. whereas citric acid is used as acidic solubilizing agent. In particularly useful embodiments, between about 10% to 50% w/w (which includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50%) of PLASDONE S-630 is used. Figure 8 and Figure 9 shows a representative PXRD of a sample of a solid dispersion of osimertinib mesylate with 50% w/w PLASDONE S-630. Figure 10 shows a representative PXRD of a sample of a solid dispersion of osimertinib mesylate with 25% w/w PLASDONE S-630.

Within the context of the invention, the term "about" when modifying an absolute measurement, such as time, mass, or volume, is meant to mean the recited value plus or minus 10% of that value.

In some embodiments, polyvinylpyrrolidone is the pharmaceutically acceptable excipient. In particularly useful embodiments, between about 10% to 50% w/w (which includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50%) of a polyvinylpyrrolidone with a K-value of 30 is used. Figure 3 shows a representative PXRD of a sample of a solid dispersion of osimertinib mesylate with 50% w/w Povidone K30.

In some embodiments, β-cyclodextrin is the pharmaceutically acceptable excipient. In particularly useful embodiments, between about 10% to 50% w/w (which includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and about 50%) β-cyclodextrin is used. Figure 4 shows a representative PXRD of a sample of a solid dispersion of osimertinib mesylate with 50% w/w β- cyclodextrin.

In some embodiments, a substituted β-cyclodextrins is the pharmaceutically acceptable excipient. In particularly useful embodiments, between about 10% to 50% w/w (which includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50%) of hydroxypropyl β-cyclodextrin is used.

In some embodiments, hydroxypropyl methylcellulose (HPMC) is the pharmaceutically acceptable excipient. In particularly useful embodiments, between about 10% to 50% w/w (which includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and about 50%) HPMC is used. Figure 5 shows a representative PXRD of a sample of a solid dispersion of osimertinib mesylate with 50% w/w HPMC. In some embodiments, PEARLITOL 160C is the pharmaceutically acceptable excipient. In particularly useful embodiments, between about 10% to 50% w/w (which includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50%) of PEARLITOL 160 C is used.

In some embodiments, PEARLITOL 160C is the pharmaceutically acceptable excipient. whereas citric acid is used as acidic solubilizing agent. In particularly useful embodiments, between about 10% to 50% w/w (which includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50%) of PEARLITOL 160C is used. Figure 6 shows a representative PXRD of a sample of a solid dispersion of osimertinib mesylate with 50% w/w PEARLITOL 160 C.

In some embodiments, citric acid is the pharmaceutically acceptable excipient. In particularly useful embodiments, between about 20% to 30% w/w (which includes 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% and 30%) of citrcic acid is used. Figure 7 shows a representative PXRD of a sample of a solid dispersion of osimertinib mesylate with 27% w/w citrcic acid. Figure 11 shows a representative PXRD of a sample of a solid dispersion of osimertinib mesylate with 24% w/w citrcic acid. In yet another aspect, the present invention provides a process for the preparation of an amorphous solid dispersion of osimertinib mesylate.

In one embodiment, an amorphous solid dispersion of osimertinib mesylate may be prepared by a process that includes the steps of: a) dissolving osimertinib mesylate and a pharmaceutically acceptable excipient in a solvent; and

Within the context of this embodiment, osimertinib mesylate and a pharmaceutically acceptable excipient are dissolved in a solvent. This step may be optionally carried out in the presence of an acidic solubilizing agent. Within the context of this embodiment, examples of acidic solubilizing agent include, but are not limited to citric acid, acetic acid, tartaric acid, lactic acid, fumaric acid, formic acid, hydrochloric acid, phosphoric acid, succinic acid, malic acid, propionic acid, oxalic acid, sulphuric acid, and mixtures thereof.

Within the context of this embodiment, the solvent may be a polar solvent. Examples of suitable polar solvents include, but are not limited to, alcohol solvents, ketone solvents, nitrile solvents, water, and mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, t-butanol, 1-pentanol, 2- pentanol, 3-pentanol, 2-methyl-l-butanol, 2-methyl-2-butanol, 2,2-dimethyl-l-butanol, 3- methyl-2-butanol, ethylene glycol 2,2-dimethyl-l -propanol, and mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), and mixtures thereof. Examples of suitable nitrile solvents include, but are not limited to, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, and mixtures thereof. In particularly useful embodiments, water, methanol, or a 1 :2 mixture of acetone:water is used.

Within the context of this embodiment, examples of suitable pharmaceutical excipients include, but are not limited to, polysaccharides, polyvinylpyrrolidones (povidones), polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers, Ci-C₆ polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), copolymers of polyethylene glycol and polypropylene glycol (e.g., the families of block copolymers based on ethylene oxide and propylene oxide sold under the PLURONIC® tradename), silica carriers (e.g., Aeroperl 300, Aerosil 200, Syloid AL-1 FP), citric acid, sugar alcohols (for example, mannitol), and mixtures thereof.

Suitable polysaccharides include, for example, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), croscarmellose, carboxymethyl cellulose (CMC) and salts thereof, methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), cyclodextrins and mixtures thereof.

Examples of suitable cyclodextrins include a-cyclodextrins, optionally substituted a- cyclodextrins, β-cyclodextrin, optionally substituted β-cyclodextrins (e.g., hydroxypropyl β- cyclodextrin), γ-cyclodextrin, optionally substituted γ-cyclodextrins (e.g., hydroxypropyl γ- cyclodextrin), and mixtures thereof. As used herein, the term "substituted" with respect to cyclodextrins means the addition of side chain groups, for example, hydroxyl, hydroxypropyl, Ci-C₆ alkyl, Ci-C₆ hydroxyalkyl, and combinations thereof. Within the context of this embodiment, the pharmaceutically acceptable excipient may be combined with osimertinib mesylate in an amount from about 1% w/w (pharmaceutically acceptable excipient total final composition mass) to about 80% w/w, which may be about 1% w/w, 2% w/w, 5% w/w, 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, 55% w/w, 60% w/w, 65% w/w, 70% w/w, 75% w/w, 80% w/w or between any of the aforementioned w/w percentages, including the ranges of about 1-80%, 1- 70%, 1-60%, 1-50%, 1-40%, 1-30%, 1-20%, 1-10%, 10-90%, 10-80%, 10-70%, 10-60%, 10- 50%, 10-40%, 10-30%, 10-20%, 20-90%, 20-80%, 20-70%, 20-60%, 20-50%, 20-40%, 20-30%, 30-90%, 30-80%, 30-70%, 30-60%, 30-50%, 30-40%, 40-90%, 40-80%, 40-70%, 40-60%, 40- 50%, 50-90%, 50-80%, 50-70%, 50-60%, 60-90%, 60-80%, 60-70%, 70-90%, 70-80%, and 80- 90%.

In some embodiments, a vinylpyrrolidone-vinyl acetate copolymer (e.g., a copolymer with a 40:60 ratio of N-vinyl-2-pyrrolidone to vinyl acetate) is used as the pharmaceutically acceptable excipient. In particularly useful embodiments, between about 10% to 50% w/w (which includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50%) of a copolymer with a 40:60 ratio of N- vinyl-2-pyrrolidone to vinyl acetate (e.g. PLASDONE S-630) is used.

In some embodiments, polyvinylpyrrolidone is used as the pharmaceutically acceptable excipient. In particularly useful embodiments, between about 10% to 50% w/w (which includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50%) of a polyvinylpyrrolidone with a K- value of 30 is used. In some embodiments, β-cyclodextrin is used as the pharmaceutically acceptable excipient. In particularly useful embodiments, between about 10% to 50% w/w (which includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and about 50%) β-cyclodextrin is used. In some embodiments, a substituted β-cyclodextrins is used as the pharmaceutically acceptable excipient. In particularly useful embodiments, between about 10% to 50% w/w (which includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50%) of hydroxypropyl β-cyclodextrin is used. In some embodiments, hydroxypropyl methylcellulose (HPMC) is used as the pharmaceutically acceptable excipient. In particularly useful embodiments, between about 10% to 50% w/w (which includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and about 50%) HPMC is used.

In some embodiments, citrcic acid is the pharmaceutically acceptable excipient. In particularly useful embodiments, between about 20% to 30% w/w (which includes 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% and 30%) of citrcic acid is used. Figure 7 shows a representative PXRD of a sample of a solid dispersion of osimertinib mesylate with 24% w/w citrcic acid.

In some embodiments, PEARLITOL 160C is used as the pharmaceutically acceptable excipient. In particularly useful embodiments, between about 10% to 50% w/w (which includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50%) of PEARLITOL 160 C is used.

Next, the solvent may be removed to isolate an amorphous solid dispersion of osimertinib mesylate. This may be carried out using conventional methods such as distillation, lyophilization, spray drying, agitated thin film drying, or any combination thereof. In another embodiment, an amorphous solid dispersion of osimertinib mesylate may be prepared by a process that includes the steps of: a) dissolving osimertinib free base and pharmaceutically acceptable excipient in a solvent; b) adding methane sulfonic acid; and

c) removing the solvent to isolate an amorphous solid dispersion of osimertinib mesylate. Within the context of this embodiment, osimertinib free base and a pharmaceutically acceptable excipient are dissolved in a solvent. This step may be optionally carried out in the presence of an acidic solubilizing agent. Within the context of this embodiment, examples of acidic solubilizing agent include, but are not limited to, citric acid, acetic acid, tartaric acid, lactic acid, fumaric acid, formic acid, hydrochloric acid, phosphoric acid, succinic acid, malic acid, propionic acid, oxalic acid, sulphuric acid, and mixtures thereof. Within the context of this embodiment, osimertinib free base together with one or more pharmaceutically acceptable excipients may be dissolved in a solvent.

The solvent may be a polar solvent, for example, an alcohol solvent, a ketone solvent, a nitrile solvent, water, or mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-l-butanol, 2-methyl-2-butanol, 2,2-dimethyl-l-butanol, 3- methyl-2-butanol, ethylene glycol 2,2-dimethyl-l -propanol, and mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), and mixtures thereof. Examples of suitable nitrile solvents include, but are not limited to, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, and mixtures thereof.

Examples of suitable pharmaceutically acceptable excipient include, but are not limited to, polysaccharides, polyvinylpyrrolidones, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone- vinyl acetate copolymers, Ci-C₆ polyalkylene glycols, copolymers of polyethylene glycol and polypropylene glycol, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), croscarmellose, carboxymethyl cellulose (CMC), methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), a-cyclodextrin, optionally substituted a- cyclodextrins, β-cyclodextrin, optionally substituted β-cyclodextrins, γ-cyclodextrin optionally substituted γ-cyclodextrins, silica-based carriers, citric acid, mannitol (e.g., mannitol sold under the brand name PEARLITOL 160 C), and mixtures thereof.

Within the context of this embodiment, the pharmaceutically acceptable excipient may be combined with osimertinib free base in an amount from about 1% w/w (pharmaceutically acceptable excipient/total final composition mass) to about 80% w/w, which may be about 1% w/w, 2% w/w, 5% w/w, 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, 55% w/w, 60% w/w, 65% w/w, 70% w/w, 75% w/w, 80% w/w or between any of the aforementioned w/w percentages, including the ranges of about 1-80%, 1- 70%, 1-60%, 1-50%, 1-40%, 1-30%, 1-20%, 1-10%, 10-90%, 10-80%, 10-70%, 10-60%, 10- 50%, 10-40%, 10-30%, 10-20%, 20-90%, 20-80%, 20-70%, 20-60%, 20-50%, 20-40%, 20-30%, 30-90%, 30-80%, 30-70%, 30-60%, 30-50%, 30-40%, 40-90%, 40-80%, 40-70%, 40-60%, 40- 50%, 50-90%, 50-80%, 50-70%, 50-60%, 60-90%, 60-80%, 60-70%, 70-90%, 70-80%, and 80- 90%.

In some embodiments, citrcic acid is the pharmaceutically acceptable excipient. In particularly useful embodiments, between about 20% to 30% w/w (which includes 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% and 30%) of citrcic acid is used. Figure 7 shows a representative PXRD of a sample of a solid dispersion of osimertinib mesylate with 27% w/w citrcic acid.

In some embodiments, PEARLITOL 160 C (standard mannitol) is used as the pharmaceutically acceptable excipient. In particularly useful embodiments, between about 10% to 50% w/w (which includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50%) of PEARLITOL 160 C is used.

In particularly useful embodiments, the dissolving step is carried out in the presence of acetic acid or citric acid and the solvent is water. Next, methane sulfonic acid may be added. In some embodiments, methane sulfonic acid is added drop wise.

Next, the solvent may be removed to isolate an amorphous solid dispersion of osimertinib mesylate. This may be carried by conventional methods, for example, but not limited to, distillation, lyophilization, spray drying, agitated thin film drying, or any combination thereof.

The amorphous osimertinib mesylate and particular embodiments of amorphous solid dispersions thereof prepared by methods disclosed herein may exhibit physical stability. The stability of samples of amorphous solid dispersions of osimertinib mesylate with 50% w/w of PLASDONE S-630, 50% w/w povidone K-30, 50% w/w HPMC, 50% w/w β-cyclodextrin (BCD), and 50% hydroxypropyl- β-cyclodextrin (ΗΡ-β-CD) was tested by storing the samples at 40 °C/75% relative humidity (RH) and at 25 °C/60% relative humidity (RH) for 6 months. Samples were analyzed by PXRD for retention polymorph integrity (i.e., samples remained amorphous).

As used herein, the term "molecular weight" means the weight-average molecular weight (MW).

Stability tests revealed that amorphous osimertinib mesylate prepared by methods disclosed herein shows no significant no change in PXRD pattern when stored for 6 months at 40 °C/75% relative humidity (RH) and at 25 °C/60% RH conditions. These data are shown below in Table 1.

Stability tests revealed that amorphous solid dispersions of osimertinib mesylate with 50% w/w PLASDONE S-630 show no significant change in PXRD pattern when stored for 6 months at 40 °C/75% RH and at 25 °C/60% RH conditions. These data are shown below in Table 1.

Stability tests revealed that amorphous solid dispersions of osimertinib mesylate with 50% w/w Povidone K-30 show no significant change in PXRD pattern when stored for 6 months at 40 °C/75% RH and at 25 °C/60% RH conditions. These data are shown below in Table 1. Stability tests revealed that amorphous solid dispersions of osimertinib mesylate with 50% w/w hydroxypropyl methylcellulose show no significant change in PXRD pattern when stored for 6 months at 40 °C/75% RH and at 25 °C/60% RH conditions. These data are shown below in Table 1. Stability tests revealed that amorphous solid dispersions of osimertinib mesylate with 50% w/w β-cyclodextrin show no significant change in PXRD pattern when stored for 6 months at 40 °C/75% RH and at 25 °C/60% RH conditions. These data are shown below in Table 1.

Stability tests revealed that amorphous solid dispersions of osimertinib mesylate with 50% w/w hydroxypropyl- β-cyclodextrin show no significant change in PXRD pattern when stored for 6 months at 40 °C/75% RH and at 25 °C/60% RH conditions. These data are shown below in Table 1.

Table 1

Within the context of the present invention, the amorphous osimertinib mesylate and solid dispersions thereof disclosed herein may be useful in the formulation of a pharmaceutical dosage form as well as useful in the treatment of patients with metastatic epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer, particularly in those who have progressed on or after EGFR tyrosine kinase inhibitor therapy. Particularly useful dosage forms include oral dosage forms, for example, a tablet or capsule. Tablets or capsules may contain one or more inactive ingredients, including, for example, mannitol, microcrystalline cellulose, low- substituted hydroxypropyl cellulose, sodium stearyl fumarate, and mixtures thereof. The tablet or capsule, in some embodiments, may be coated with a film that includes polyvinyl alcohol, titanium dioxide, polyethylene glycol (e.g., macrogol 3350), talc, and artificial colorings such as those based on ferric oxides (e.g., red, yellow, black).

The following examples are provided to illustrate the process of the present invention. They are, however, not intended to limit the scope of the present invention in any way. Examples

Example 1: Preparation of amorphous osimertinib mesylate

Osimertinib mesylate (1 g) was dissolved in methanol (30 mL) at 60-70 °C. The clear solution was filtered through Hyflo to remove any undissolved particulate. The clear filtrate was then distilled-out completely using a rotary evaporator at 70 °C to yield an amorphous osimertinib mesylate.

Example 2: Preparation of amorphous osimertinib mesylate

Osimertinib mesylate (6 g) was dissolved in water (50 mL) at 60-70 °C. The clear solution was filtered through Hyflo to remove any undissolved particulate. The clear filtrate was then subjected to lyophilization to yield an amorphous osimertinib mesylate.

Example 3: Preparation of an amorphous solid dispersions of osimertinib mesylate with 50% w/w PLASDONE S-630

Osimertinib mesylate (1 g) and PLASDONE-S630 (1 g) were dissolved in methanol (50 mL) at 60-70 °C. The clear solution was filtered through Hyflo to remove any undissolved particulate. The clear filtrate was then distilled-out completely using a rotary evaporator at 70 °C to yield an amorphous solid dispersion of osimertinib mesylate with PLASDONE S-630.

Example 4: Preparation of an amorphous solid dispersion of osimertinib mesylate with 50% w/w PLASDONE S-630

Osimertinib mesylate (5.0 g) and PLASDONE-S630 (5.0 g) were dissolved in methanol (250 mL) at 65 °C. The clear solution was filtered through Hyflo to remove any undissolved particulate. The clear filtrate was subjected to spray-drying in a laboratory Spray Dryer (Model Buchi-290) with a solution feed rate of 10 mL/min and inlet temperature of 70 °C with 100% aspiration to yield an amorphous solid dispersion of osimertinib mesylate with PLASDONE S- 630. Example 5: Preparation of amorphous solid dispersion of osimertinib mesylate with 50% w/w Povidone K30

Osimertinib mesylate (1 g) and Povidone K30 (1 g) were dissolved in methanol (50 mL) at 60- 70 °C. The clear solution was filtered through Hyflo to remove any undissolved particulate. The clear filtrate was then distilled-out completely using a rotary evaporator at 70 °C to yield an amorphous solid dispersion of osimertinib mesylate with Povidone K30.

Example 6: Preparation of an amorphous solid dispersion of osimertinib mesylate with 50% w/w Povidone K30

Osimertinib mesylate (5.0 g) and Povidone K30 (5.0 g) were dissolved in methanol (250 mL) at 65 °C. The clear solution was filtered through Hyflo to remove any undissolved particulate. The clear filtrate was subjected to spray-drying in a laboratory Spray Dryer (Model Buchi-290) with a solution feed rate 10 mL/min and inlet temperature of 70 °C with 100% aspiration to yield an amorphous solid dispersion of osimertinib mesylate with Povidone K30.

Example 7: Preparation of an amorphous solid dispersion of osimertinib mesylate with 50 % w/w β-cyclodextrin

Osimertinib mesylate (3 g) and β-cyclodextrin (3 g) were dissolved in water (90 mL) at 70- 80 °C. The clear solution was filtered through Hyflo to remove any undissolved particulate. The clear filtrate was then subjected to lyophilization to yield an amorphous solid dispersion of osimertinib mesylate with β-cyclodextrin. Yield: 5.6 g Example 8: Preparation of amorphous solid dispersions of osimertinib mesylate with 50 % w/w hydroxypropyl-P-cyclodextrin

Osimertinib mesylate (3 g) and hydroxypropyl-P-cyclodextrin (3 g) were dissolved in water (90 mL) at 70-80 °C. The clear solution was filtered through Hyflo to remove any undissolved particulate. The clear filtrate was then subjected to lyophilization to yield an amorphous solid dispersion of osimertinib mesylate with hydroxypropyl-P-cyclodextrin. Yield: 5.45 g Example 9: Preparation of an amorphous solid dispersion of osimertinib mesylate with 50% w/w HPMC

Osimertinib mesylate (3 g) and hydroxypropyl methylcellulose (3 g) were dissolved in a mixture of 1:2 acetone: water (90 mL) at 50-60 °C. The clear solution was filtered through Hyflo to remove any undissolved particulate. The clear filtrate was then subjected to lyophilization to yield an amorphous solid dispersion of osimertinib mesylate with hydroxypropyl methylcellulose. Yield: 5.7 g

Example 10: Preparation of amorphous osimertinib mesylate

Osimertinib mesylate (3.0 g) was dissolved in methanol (100 mL) at 65 °C. The clear solution was filtered through Hyflo to remove any undissolved particulate. The clear filtrate was subjected to spray-drying in a laboratory Spray Dryer (Model Buchi-290) with a solution feed rate of 10 mL/min and inlet temperature of 70 °C with 100% aspiration to yield an amorphous osimertinib mesylate.

Example 11: Preparation of an amorphous solid dispersion of osimertinib mesylate Citric acid (77 mg) was dissolved in water (8 mL) and cooled to 0-5 °C. Osimertinib base (200 mg) was added to the above mixture and stirred for 15 minutes at 0-5 °C to get a clear solution. A solution of methane sulfonic acid (36.5 mg) in water (2 mL) was added dropwise at 0-5 °C over the course of 15 minutes. The resulting clear solution was filtered through Hyflo to remove any undissolved particulates and the filtrate was lyophilized using a Labocon lyophilizer (Model LFD-BT-104) to yield an amorphous solid dispersion of osimertinib mesylate.

Example 12: Preparation of an amorphous solid dispersion of osimertinib mesylate with 50% w/w PEARLITOL 160 C

Acetic acid (60 mg) was dissolved in water (16 mL) and cooled to 0-5 °C. Osimertinib base (0.5 g) was added to the above solution and stirred for 15 minutes at 0-5 °C to get a clear solution. A solution of methane sulfonic acid (92 mg) in water (4 mL) was added dropwise at 0- 5 °C over the course of 15 minutes. PEARLITOL 160 C (0.5 g) in water (3 mL) was added to the clear solution at 25-30 °C. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and lyophilized using a Labocon lyophilizer (Model: LFD-BT-104) to yield an amorphous solid dispersion of osimertinib mesylate.

Example 13: Preparation of amorphous solid dispersion of osimertinib mesylate with 50% w/w PEARLITOL 160 C

PEARLITOL 160 C (1 g) was dissolved in water (30 mL) after which acetic acid (120 mg) was added. The solution was cooled to 0-5 °C. Osimertinib base (1 g) was added and the mixture was stirred for 15 minutes at 0-5 °C. A solution of methane sulfonic acid (183 mg) in water (10 mL) was added dropwise at 0-5 °C over the course of 15 minutes. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and lyophilized using a Labocon lyophilizer (Model: LFD-BT-104) to yield an amorphous solid dispersion of osimertinib mesylate.

Example 14: Preparation of amorphous solid dispersion of osimertinib mesylate with 50% w/w PEARLITOL 160 C

PEARLITOL 160 C (1 g) and citric acid (384.5 mg) were dissolved in water (30 mL) and cooled to 0-5 °C. Osimertinib base (1 g) was added to the above solution and stirred for 15 minutes at 0-5 °C to get a clear solution. Then, a solution of methane sulfonic acid (183 mg) in water (10 mL) was added drop wise at 0-5 °C over the course of 15 minutes. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and lyophilized using a Labocon lyophilizer (Model: LFD-BT-104) to yield an amorphous solid dispersion of osimertinib mesylate

Example 15: Preparation of amorphous solid dispersion of osimertinib mesylate

Citric acid (64.5 mg) was dissolved in water (8 mL) and cooled to 0-5 °C. Osimertinib mesylate (200 mg) was added to the above solution and stirred for 15 minutes at 25 °C to get a clear solution. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and lyophilized using a Labocon lyophilizer (Model: LFD-BT-104) to yield an amorphous solid dispersion of osimertinib mesylate.

Example 16: Preparation of amorphous solid dispersion of osimertinib mesylate with 50% w/w PEARLITOL 160 C PEARLITOL 160 C (200 mg) was dissolved in water (8 mL). Acetic acid (60 mg) was added and the solution was cooled to 0-5 °C. Osimertinib mesylate (200 mg) was added to the above mixture and stirred for 15 minutes at 0-5 °C to get a clear solution. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and lyophilized using a Labocon lyophilizer (Model: LFD-BT-104) to yield an amorphous solid dispersion of osimertinib mesylate.

Example 17: Preparation of amorphous solid dispersion of osimertinib mesylate with 50% w/w PEARLITOL 160 C

Citric acid (64.5 mg) and PEARLITOL 160 C (200 mg) were dissolved in water (8 mL) and cooled to 0-5 °C. Osimertinib mesylate (200 mg) was added to the above mixture and stirred for 15 minutes at 0-5 °C to get a clear solution. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and lyophilized using a Labocon lyophilizer (Model: LFD-BT-104) to yield an amorphous solid dispersion of osimertinib mesylate.

Example 18: Preparation of amorphous solid dispersion of osimertinib mesylate with 50% w/w PEARLITOL 160 C PEARLITOL 160 C (1 g) and citric acid (322.5 mg) were dissolved in water (45 mL) at 0-5 °C. Osimertinib mesylate (1 g) was added to the above mixture and stirred for 15 minutes to get a clear solution at 0-5 °C. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and subjected to using a Labocon lyophilizer (Model: LFD-BT-104) to yield an amorphous solid dispersion of osimertinib mesylate.

Example 19: Preparation of amorphous solid dispersion of osimertinib mesylate with 50% w/w PLASDONE S-630 PLASDONE S-630 (0.5 g) and citric acid (192mg) were dissolved in water (15 mL) and cooled to 0-5 °C. Osimertinib base (0.5 g) was added to the above reaction mixture and stirred for 15 minutes at 0-5 °C to get a clear solution. A solution of methane sulfonic acid (92 mg) in water (5 mL) was added dropwise at 0-5 °C over the course of 15 minutes. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and lyophilized using a Labocon lyophilizer (Model: LFD-BT-104) to yield an amorphous solid dispersion of osimertinib mesylate.

Example 20: Preparation of amorphous solid dispersion of osimertinib mesylate with 50% w/w povidone K-30

Povidone K-30 (0.5 g) and citric acid (192 mg) were dissolved in water (15 mL) and cooled to 0- 5 °C. Osimertinib base (0.5 g) was added to the above mixture and stirred for 15 minutes at 0- 5 °C to get a clear solution. A solution of methane sulfonic acid (183 mg) in water (10 mL) was added dropwise at 0-5 °C over the course of 15 minutes. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and lyophilized using a Labocon lyophilizer (Model: LFD-BT-104) to yield an amorphous solid dispersion of osimertinib mesylate.

Example 21: Preparation of amorphous solid dispersion of osimertinib mesylate with 50% w/w PEARLITOL 160 C

PEARLITOL 160 C (200 mg) was dissolved in water (8.6 mL) and cooled to 0-5 °C. Osimertinib base (200 mg) was added and stirred for 15 minutes at 0-5 °C to get a clear solution. A solution of methane sulfonic acid (36.5 mg) in water (2.4 mL) was added dropwise at 0-5 °C over the course of 15 minutes. Citric acid (77 mg) was added and stirred at 0-5 °C for 15 minutes. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and lyophilized using a Labocon lyophilizer (Model: LFD-BT-104) to yield an amorphous solid dispersion of osimertinib mesylate.

Example 22: Preparation of amorphous solid dispersion of osimertinib mesylate with 25 % w/w PEARLITOL 160 C PEARLITOL 160 C (1.66 g) and citric acid (0.56 g) were dissolved in water (150 mL) at 25- 30 °C. The solution was cooled to 0-5 °C and osimertinib free base (5 g) was added at 0-5 °C. A solution of methane sulfonic acid (0.913 g) in water (50 mL) was added dropwise at 0-5 °C over the course of 15 minutes. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and lyophilized using a Labocon lyophilizer (Model: LFD-BT-104) yielded an amorphous solid dispersion of osimertinib mesylate.

Example 23: Preparation of amorphous solid dispersion of osimertinib mesylate with 25 % w/w PEARLITOL 160 C PEARLITOL 160 C (1.66 g) and citric acid (0.813 g) were dissolved in water (150 mL) at 25- 30 °C. The mixture was cooled to 0-5 °C and osimertinib free base (5 g) was added at 0-5 °C. A solution of methane sulfonic acid (0.913 g) in water (50 mL) was added dropwise at 0-5 °C over the course of 15 minutes. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and lyophilized using a Labocon lyophilizer (Model: LFD-BT-104) yielded an amorphous solid dispersion of osimertinib mesylate.

Example 24: Preparation of amorphous solid dispersion of osimertinib mesylate with 50 % w/w PEARLITOL 160 C

PEARLITOL 160 C (5 g) and citric acid (0.56 g) were dissolved in water (150 mL) at 25-30 °C. The mixture was cooled to 0-5 °C and osimertinib free base (5 g) was added at 0-5 °C. A solution of methane sulfonic acid (0.913 g) in water (50 mL) was added dropwise at 0-5 °C over the course of 15 minutes. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and lyophilized using a Labocon lyophilizer (Model: LFD-BT-104) yielded an amorphous solid dispersion of osimertinib mesylate.

Example 25: Preparation of amorphous solid dispersion of osimertinib mesylate with 50 % w/w PEARLITOL 160 C

PEARLITOL 160 C (5 g) and citric acid (0.813 g) were dissolved in water (150 mL) at 25- 30 °C. The mixture was cooled to 0-5 °C and osimertinib free base (5 g) was added at 0-5 °C. A solution of methane sulfonic acid (0.913 g) in water (50 mL) was added dropwise at 0-5 °C over the course of 15 minutes. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and lyophilized using a Labocon lyophilizer (Model: LFD-BT-104) yielded an amorphous solid dispersion of osimertinib mesylate.

Example 26: Preparation of amorphous solid dispersion of osimertinib mesylate with 50 % w/w PEARLITOL 160 C

PEARLITOL 160 C (5 g) and citric acid (1.93 g) were dissolved in water (150 mL) at 25-30 °C. The mixture was cooled to 0-5 °C and osimertinib free base (5 g) was added at 0-5 °C. A solution of methane sulfonic acid (0.913 g) in water (50 mL) was added dropwise at 0-5 °C over the course of 15 minutes. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and lyophilized using a Labocon lyophilizer (Model: LFD-BT-104) yielded an amorphous solid dispersion of osimertinib mesylate.

Example 27: Preparation of amorphous solid dispersion of osimertinib mesylate with 50% w/w Plasdone S-630

Plasdone S-630 (5g) and citric acid (0.813g) were dissolved in water (150mL) and cooled to 0- 5°C and added Osimertinib (5g) at 0-5°C. Then added dropwise methane sulfonic acid (0.913g) solution in water (50mL) at 0-5°C for 15min. The resulting clear solution was filtered through hyflo to remove any undissolved particulate and subjected to Lyophilisation using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous solid dispersion of Osimertinib Mesylate.

Example 28: Preparation of amorphous solid dispersion of osimertinib mesylate with 25% w/w Plasdone S-630

Plasdone S-630 (1.66g) and citric acid (0.813g) were dissolved in water (150mL) and cooled to 0-5°C and added Osimertinib (5g) at 0-5°C. Then added dropwise methane sulfonic acid (0.913g) solution in water (50 mL) at 0-5 °C for 15min. The resulting clear solution was filtered through hyflo to remove any undissolved particulate and subjected to Lyophilisation using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous solid dispersion of Osimertinib Mesylate.

Claims

We claim:

1. Amorphous osimertinib mesylate.

2. A process for the preparation of amorphous form of osimertinib mesylate comprising the steps of:

a) dissolving osimertinib mesylate in a solvent; and

b) removing the solvent to isolate amorphous osimertinib mesylate.

3. The process according to claim 2, wherein the solvent is a polar solvent.

4. The process according to claim 3, wherein the polar solvent is selected from the group consisting of an alcohol solvent, a ketone solvent, a nitrile solvent, an ether solvent, water, and mixtures thereof.

5. The process according to claim 4, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, n-butanol, 2-butanol, isobutanol, t-butanol, 2-methoxy ethanol, 2-ethoxy ethanol, and mixtures thereof.

6. The process according to claim 4, wherein the ketone solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.

7. The process according to claim 4, wherein the nitrile solvent is selected from the group consisting of acetonitrile, propionitrile, butyronitrile, isobutyronitrile, and mixtures thereof.

8. The process according to claim 4, wherein the ether solvent is selected from the group consisting of anisole, 1,2-dimethoxyethane, and mixtures thereof.

9. An amorphous solid dispersion of osimertinib mesylate.

10. The process for the preparation of an amorphous solid dispersion of osimertinib mesylate comprising the steps of:

a) dissolving osimertinib mesylate and pharmaceutically acceptable excipient in a solvent; and

11. The process according to claim 10, where in step a) dissolution of osimertinib mesylate is carried out in presence of acidic solubilizing agent.

12. The process according to claim 10, wherein the pharmaceutically acceptable excipient is selected from the group consisting of polysaccharides, polyvinylpyrrolidones, polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers, Ci-C₆ polyalkylene glycols, copolymers of polyethylene glycol and polypropylene glycol, microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, a-cyclodextrin, optionally substituted a-cyclodextrins, β-cyclodextrin, optionally substituted β-cyclodextrins, γ-cyclodextrin optionally substituted γ- cyclodextrins, silica-based carriers, citric acid, sugar alcohols, and mixtures thereof.

13. The process according to claim 10, wherein the pharmaceutically acceptable excipient is povidone with a K value of 30, a 60:40 linear random copolymer of N-vinyl-2-pyrrolidone and vinyl acetate copolymer sold under the brand name of PLASDONE S-630, hydroxypropyl methylcellulose, β-cyclodextrin, hydroxypropyl-P-cyclodextrin, mannitol sold under the brand name PEARLITOL 160 C, or mixtures thereof.

14. The process according to claim 10, wherein the solvent is a polar solvent.

15. The process according to claim 14, wherein the polar solvent is selected from the group consisting of an alcohol solvent, a ketone solvent, a nitrile solvent, water, and mixtures thereof.

16. The process according to claim 14, wherein the alcohol solvent is selected the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, t-butanol, 1- pentanol, 2-pentanol, 3-pentanol, 2-methyl-l-butanol, 2-methyl-2-butanol, 2,2-dimethyl-l- butanol, 3-methyl-2-butanol, ethylene glycol 2,2-dimethyl-l -propanol, and mixtures thereof.

17. The process according to claim 14, wherein the ketone solvent is selected from the group consisting of acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), and mixtures thereof.

18. The process according to claim 14, wherein the nitrile solvent is selected from the group consisting of acetonitrile, propionitrile, butyronitrile, isobutyronitrile, and mixtures thereof.

19. The process according to claim 11, acidic solubilizing agent is selected from citric acid, acetic acid, tartaric acid, lactic acid, fumaric acid, formic acid, hydrochloric acid, phosphoric acid, succinic acid, malic acid, propionic acid, oxalic acid, sulphuric acid.

20. The process for the preparation of an amorphous solid dispersion of osimertinib mesylate comprising the steps of:

a) dissolving osimertinib base and pharmaceutically acceptable excipient in a solvent b) adding methane sulfonic acid; and

c) removing the solvent to isolate an amorphous solid dispersion of osimertinib mesylate.

21. The process according to claim 20, where in step a) dissolution of osimertinib base is carried out in presence of acidic solubilizing agent.

22. The process according to claim 20, wherein the pharmaceutically acceptable excipient is selected from the group consisting of polysaccharides, polyvinylpyrrolidones, polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers, Ci-C₆ polyalkylene glycols, copolymers of polyethylene glycol and polypropylene glycol, microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, a-cyclodextrin, optionally substituted a-cyclodextrins, β-cyclodextrin, optionally substituted β-cyclodextrins, γ-cyclodextrin optionally substituted γ- cyclodextrins, silica-based carriers, citric acid, sugar alcohols, and mixtures thereof.

23. The process according to claim 22, wherein the pharmaceutically acceptable excipient is povidone with a K value of 30, a 60:40 linear random copolymer of N-vinyl-2-pyrrolidone and vinyl acetate copolymer sold under the brand name of PLASDONE S-630, hydroxypropyl methylcellulose, β-cyclodextrin, hydroxypropyl-P-cyclodextrin, citric acid, mannitol sold under the brandname PEARLITOL 160 C, or mixtures thereof.

24. The process according to claim 20, wherein the solvent is a polar solvent.

25. The process according to claim 24, wherein the polar solvent is selected from the group consisting of an alcohol solvent, a ketone solvent, a nitrile solvent, water, and mixtures thereof.

26. The process according to claim 24, wherein the alcohol solvent is selected the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, t-butanol, 1- pentanol, 2-pentanol, 3-pentanol, 2-methyl-l-butanol, 2-methyl-2-butanol, 2,2-dimethyl-l- butanol, 3-methyl-2-butanol, ethylene glycol 2,2-dimethyl-l -propanol, and mixtures thereof.

27. The process according to claim 24, wherein the ketone solvent is selected from the group consisting of acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), and mixtures thereof.

28. The process according to claim 24, wherein the nitrile solvent is selected from the group consisting of acetonitrile, propionitrile, butyronitrile, isobutyronitrile, and mixtures thereof.

29. The process according to claim 21, acidic solubilizing agent is selected from citric acid, acetic acid, tartaric acid, lactic acid, fumaric acid, formic acid, hydrochloric acid, phosphoric acid, succinic acid, malic acid, propionic acid, oxalic acid, sulphuric acid.

30. A pharmaceutical dosage form comprising an amorphous solid dispersion of osimertinib mesylate.