Pexidartinib, New Patent, WO 2017215521, Crystal Pharmatech Co Ltd

Pexidartinib, New Patent, WO, 2017215521, Crystal Pharmatech Co Ltd
(WO2017215521) PLX3397 HYDROCHLORIDE CRYSTAL FORM, PREPARATION METHOD THEREFOR AND USE THEREOF
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017215521
CRYSTAL PHARMACEUTICAL (SUZHOU) CO., LTD
INVENTORS
CHEN, Minhua; (CN).
ZHANG, Yanfeng; (CN).
ZOU, Po; (CN).
ZHANG, Xiaoyu; (CN)
Novel crystalline forms of PLX3397 hydrochloride (designated as Forms CS2 and CS3), processes for their preparation and compositions comprising them are claimed. Also claim is their use for treating giant cell tumor of the tendon sheath.
The present invention relates to a PLX3397 hydrochloride crystal form, a preparation method therefor and use thereof. The PLX3397 hydrochloride crystal form has higher solubility, larger particle size, and good stability, especially better mechanical stability, is favorable for separation of products in subsequent production, provides a better choice for preparing PLX3397-containing pharmaceutical preparations, and is very important to medicinal development.

Pexidartinib (PLX3397) is a new drug used to treat tenosynovial giant cell tumor (TGCT). Tenoid sheath giant cell tumor is a rare type of tendon sheath cancer. At present, the disease is usually treated surgically by surgical resection, and the surgical treatment of the disease may lead to the deterioration of dysfunction and serious complications. And since TGCTs have multiple types, which typically occur at bone tissue and joints, the advent of new interventional therapies is urgently needed in the clinic. The PLX3397 is currently in Phase III clinical trials and has received the FDA's breakthrough drug therapy certification. The structural formula of PLX3397 is shown in formula (I).

 

Example 1 Preparation of monohydrochloride form CS2

[0112]

Weigh 101.6 mg of PLX3397 solids in a 5 mL glass vial and add 2 mL of n-heptane at 5 ° C. Under magnetic stirring, 440 μL of 0.6 mol / L diluted hydrochloric acid was added and the reaction was carried out for 40 min. The mixture was filtered and dried to obtain an off-white solid.

[0113]

Upon testing, the solid obtained in this example is the monohydrochloride form CS2. The XRPD pattern is shown in Figure 1, and the XRPD data is shown in Table 1. The resulting solid was monohydrochloride salt of PLX3397 as determined by ion chromatography. ¹ H NMR is shown in FIG. 4.

[0114]

When differential scanning calorimetry was used, the endothermic peak began to form when heated to about 72 ° C. When heated to around 227 ° C, the endothermic peak started to appear. The DSC is shown in FIG. 2.

[0115]

When subjected to thermogravimetric analysis, crystalline form CS2 has a mass loss gradient of about 8.3% when heated to 137 ° C, the TGA of which is shown in FIG. 3. Form CS2 is hydrate.

[Figure 0009]   
Fig. ¹ H NMR chart of crystalline form CS3 in Example 3. Fig
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