# US 10,501,450 B2 · Anhydrate-free polymorphically pure micronized crystalline brexpiprazole di-hydrate for use in intramuscular injectable sustained release formulations

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- Number: US 10,501,450 B2
- Document ID: US10501450B2
- Status: Granted
- Kind: B2
- Application number: 16/073,366
- Filed: 2017-01-31
- Published: 2019-02-14
- Granted: 2019-12-10
- Earliest claimed: 2016-02-01
- Assignees: Hexal AG
- Applicants: Hexal AG
- Inventors: Max Born; Christoph Langes; Hannes Lengauer
- Web page: https://patentgrep.com/patent/US10501450B2

## CPC

- C07D 409/12: linked by a chain containing hetero atoms as chain links
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention relates to a brexpiprazole dihydrate crystalline form having a particle size distribution of d50 of at most 10 μm and less than 5% w/w of brexpiprazole anhydrate. The present invention also relates to a process for preparing this brexpiprazole dihydrate crystalline form and to pharmaceutical compositions thereof. The present invention also relates to a process for determining the absence of brexpiprazole anhydrate in this brexpiprazole dihydrate crystalline form. This brexpiprazole dihydrate crystalline form is used for the preparation of pharmaceutical compositions having delayed release properties upon intramuscular injection.

## Claims

### Claim 1

A process for preparing a batch of brexpiprazole dihydrate comprising less than 5% w/w of brexpiprazole anhydrate in relation to the total amount of brexpiprazole, which is suitable for pharmaceutical purposes, wherein the process comprises the steps of:
a. providing a batch of brexpiprazole dihydrate by
(i) providing brexpiprazole dihydrate in the form of crystalline material having a particle size distribution characterized by a d50 of at least 10 μm,
(ii) adding brexpiprazole dihydrate to an aqueous medium to form a suspension, and
(iii) subjecting the aqueous suspension of brexpiprazole dihydrate to a size reduction means to obtain brexpiprazole dihydrate in the form of crystalline material having a particle size distribution characterized by a d50 of at most 10 μm;
b. taking a batch sample and subjecting same to PXRD analysis; and
c. obtaining the batch as a pharmaceutical suitable batch, if reflections at 2-Theta angles of 10.0°+/−0.2° and 17.4°+/−0.2° are absent in the PXRD pattern.

### Claim 2 (depends on 1)

The process of claim 1, wherein the batch of brexpiprazole dihydrate contains an amount of at least 10 kg.

### Claim 3 (depends on 1)

A process for preparing a batch of pharmaceutical injectable delayed-release single unit or multiple unit preparations of brexpiprazole dihydrate, the process comprising formulating the batch obtained in claim 1 into pharmaceutical injectable delayed-release single unit or multiple unit preparations.