WO2022162107A1 - Crystalline form of risdiplam - Google Patents
Crystalline form of risdiplam Download PDFInfo
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- WO2022162107A1 WO2022162107A1 PCT/EP2022/051976 EP2022051976W WO2022162107A1 WO 2022162107 A1 WO2022162107 A1 WO 2022162107A1 EP 2022051976 W EP2022051976 W EP 2022051976W WO 2022162107 A1 WO2022162107 A1 WO 2022162107A1
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- Prior art keywords
- risdiplam
- crystalline form
- pharmaceutical composition
- present
- range
- Prior art date
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- ASKZRYGFUPSJPN-UHFFFAOYSA-N 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound CC1=CN2N=C(C=C(C)C2=N1)C1=CC(=O)N2C=C(C=CC2=N1)N1CCNC2(CC2)C1 ASKZRYGFUPSJPN-UHFFFAOYSA-N 0.000 title claims abstract description 65
- 229940121322 risdiplam Drugs 0.000 title claims abstract description 58
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 208000002320 spinal muscular atrophy Diseases 0.000 claims abstract description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 239000013078 crystal Substances 0.000 claims description 18
- 230000005855 radiation Effects 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 10
- 229940086542 triethylamine Drugs 0.000 claims description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000796 flavoring agent Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- -1 acidifyer Substances 0.000 claims description 4
- 239000012452 mother liquor Substances 0.000 claims description 4
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 claims description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 230000003078 antioxidant effect Effects 0.000 claims description 3
- 235000006708 antioxidants Nutrition 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 235000013355 food flavoring agent Nutrition 0.000 claims description 3
- 235000003599 food sweetener Nutrition 0.000 claims description 3
- 239000000314 lubricant Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000003755 preservative agent Substances 0.000 claims description 3
- 230000002335 preservative effect Effects 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000003765 sweetening agent Substances 0.000 claims description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 3
- 229960000281 trometamol Drugs 0.000 claims description 3
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 235000016623 Fragaria vesca Nutrition 0.000 claims description 2
- 240000009088 Fragaria x ananassa Species 0.000 claims description 2
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 239000004376 Sucralose Substances 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 235000019634 flavors Nutrition 0.000 claims description 2
- 239000000905 isomalt Substances 0.000 claims description 2
- 235000010439 isomalt Nutrition 0.000 claims description 2
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229940059097 powder for oral solution Drugs 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 2
- 235000019408 sucralose Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 6
- 239000008186 active pharmaceutical agent Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000011343 solid material Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 102000047499 Survival of Motor Neuron 2 Human genes 0.000 description 2
- 108700024745 Survival of Motor Neuron 2 Proteins 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 229940100688 oral solution Drugs 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000009490 roller compaction Methods 0.000 description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 2
- 150000004684 trihydrates Chemical class 0.000 description 2
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000003869 coulometry Methods 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- XBRDBODLCHKXHI-UHFFFAOYSA-N epolamine Chemical compound OCCN1CCCC1 XBRDBODLCHKXHI-UHFFFAOYSA-N 0.000 description 1
- 229950008932 epolamine Drugs 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000008184 oral solid dosage form Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000004942 pyridazin-6-yl group Chemical group N1=NC=CC=C1* 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
Definitions
- the present invention relates to a crystalline form of risdiplam and to a process for its preparation. Furthermore, the invention relates to a pharmaceutical composition comprising the crystalline form of risdiplam of the present invention and at least one pharmaceutically acceptable excipient.
- the pharmaceutical composition of the present invention can be used as a medicament, in particular for the treatment of spinal muscular atrophy (SMA).
- WO 2020/079203 Al mentions various crystalline forms of risdiplam free base including Form A (anhydrous), Form B (metastable polymorph), Form C (monohydrate), Form D (trihydrate), Form E (trihydrate), Form F (hydrate) and Form G (metastable polymorph).
- Form A anhydrous
- Form B metalstable polymorph
- Form C monohydrate
- Form D trihydrate
- Form E trihydrate
- Form F hydrate
- Form G metalstable polymorph
- Risdiplam Form 1 of the present invention posesses one or more advantageous properties selected from the group consisting of chemical stability, physical stability, melting point, hygroscopicity, solubility, dissolution, morphology, crystallinity, flowability, bulk density, compactibility and wettability.
- the crystalline Form 1 of the present invention was only accessible by applying very specific crystallization conditions.
- the inventors of the present invention followed a different approach by treating risdiplam dihydrochloride salt with an amine base such as tri ethylamine in the presence of methanol, which unexpectedly yielded the novel Form 1 of risdiplam of the present invention.
- the term “measured at a temperature in the range of from 20 to 30°C” refers to a measurement under standard conditions.
- standard conditions mean a temperature in the range of from 20 to 30°C, i.e. at room temperature.
- Standard conditions can mean a temperature of about 22°C.
- standard conditions can additionally mean a measurement under 20-60% RH, preferably 30-50% RH, more preferably 40% RH and most preferably 20 - 30% RH.
- reflection with regard to powder X-ray diffraction as used herein, means peaks in an X-ray diffractogram, which are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material, which are distributed in an ordered and repetitive pattern in a long-range positional order.
- a solid material is classified as crystalline material, whereas amorphous material is defined as solid material, which lacks long-range order and only displays short-range order, thus resulting in broad scattering.
- long-range order e.g.
- the term “essentially the same” with reference to powder X-ray diffraction means that variabilities in reflection positions and relative intensities of the reflections are to be taken into account.
- a typical precision of the 2-Theta values is in the range of ⁇ 0.2° 2-Theta, preferably in the range of ⁇ 0.1° 2-Theta.
- a reflection that usually appears at 7.5° 2-Theta for example can appear between 7.3° and 7.7° 2-Theta, preferably between 7.4° and 7.6° 2- Theta on most X-ray diffractometers under standard conditions.
- relative reflection intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, particle size, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.
- Crystalline Form 1 of risdiplam of the present invention may be referred to herein as being characterized by graphical data "as shown in" a figure.
- Such data include, for example, powder X-ray diffraction.
- factors such as variations in instrument type, response and variations in sample directionality, sample concentration and sample purity may lead to small variations for such data when presented in graphical form, for example variations relating to the exact reflection positions and intensities.
- a comparison of the graphical data in the figure herein with the graphical data generated for another or an unknown solid form and the confirmation that two sets of graphical data relate to the same crystal form is well within the knowledge of a person skilled in the art.
- amorphous refers to a solid-state form of a compound that is not crystalline. An amorphous compound possesses no long-range order and does not display a definitive X-ray diffraction pattern with reflections.
- anhydrous form or “anhydrate” as used herein refer to a crystalline solid where no water is cooperated in or accommodated by the crystal structure.
- Anhydrous forms may still contain residual water, which is not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal.
- hydrate refers to a crystalline solid where either water is cooperated in or accommodated by the crystal structure e.g. is part of the crystal structure or entrapped into the crystal (water inclusions). Thereby, water can be present in a stoichiometric or non- stoichiometric amount.
- the hydrate may be referred to by adding greek numeral prefixes.
- a hydrate may be referred to as a hemihydrate or as a monohydrate depending on the water/compound stoichiometry.
- the water content can be measured, for example, by Karl-Fischer-Coulometry.
- mother liquor refers to the solution remaining after crystallization of a solid from said solution.
- the present invention provides a crystalline form of risdiplam, herein also designated as “Form 1”.
- Crystalline Form 1 of risdiplam of the present invention may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to powder X-ray diffraction, FTIR spectroscopy, DSC; TGA and GMS.
- Risdiplam Form 1 of the present invention may be characterized by one of the aforementioned analytical methods or by combining two or more of them.
- Form 1 of risdiplam of the present invention may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.
- the invention relates to a crystalline form (Form 1) of risdiplam characterized by having a PXRD comprising reflections at 2-Theta angles of:
- the present invention relates to a crystalline form (Form 1) of risdiplam characterized by having a PXRD comprising reflections at 2-Theta angles of: (7.5 ⁇ 0.1)°, (13.1 ⁇ 0.1)° and (26.2 ⁇ 0.1)°; or
- the present invention relates to a crystalline form (Form 1) of risdiplam as defined in any one of the above described embodiments characterized by having a PXRD comprising no reflection at 2-Theta angles of or below (6.9 ⁇ 0.2)°, (6.8 ⁇ 0.2)°, (6.7 ⁇ 0.2)°, (6.6 ⁇ 0.2)°, (6.5 ⁇ 0.2)°, (6.4 ⁇ 0.2)°, (6.3 ⁇ 0.2)°, (6.2 ⁇ 0.2)°, (6.1 ⁇ 0.2)°, (6.0 ⁇ 0.2)°, (5.9 ⁇ 0.2)°, (5.8 ⁇ 0.2)°, (5.7 ⁇ 0.2)°, (5.6 ⁇ 0.2)°, (5.5 ⁇ 0.2)°, (5.4 ⁇ 0.2)°, (5.3 ⁇ 0.2)°, (5.2 ⁇ 0.2)°, (5.1 ⁇ 0.2)° and (5.0 ⁇ 0.2)°, when measured at a temperature in the range of from 20 to
- the present invention relates to a crystalline form (Form 1) of risdiplam characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (7.5 ⁇ 0.2)°, (13.1 ⁇ 0.2)° and (26.2 ⁇ 0.2)°, but comprising no reflection at 2-Theta angles of or below (7.0 ⁇ 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai, 2 radiation having a wavelength of 0.15419 nm.
- Form 1 a crystalline form of risdiplam characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (7.5 ⁇ 0.2)°, (13.1 ⁇ 0.2)° and (26.2 ⁇ 0.2)°, but comprising no reflection at 2-Theta angles of or below (7.0 ⁇ 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai, 2 radiation
- the present invention relates to a crystalline form (Form 1) of risdiplam as defined in any one of the above described embodiments characterized by having a PXRD comprising no reflection at 2-Theta angles of or below (7.0 ⁇ 0.1)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
- the amine base in step (b) is selected from the group consisting of ammonia, benethamine, benzathine, tert-butylamine, diethanolamine, diethylamine, epolamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, glucamine, hydrabamine, imidazole, meglumine, morpholine, piperazine, pyrrolidine, triethanolamine, triethylamine and tromethamine.
- the amine base is selected from the group consisting of tert-butylamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, triethanolamine, triethylamine and tromethamine, most preferably the amine base is triethylamine.
- the amine base is used in an amount of from 1.5 to 5.0 mol equivalent, preferably of from 1.8 to 2.2 mol equivalent such as 2.0 mol equivalent, based on the amount of risdiplam dihydrochloride.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising the crystalline form of risdiplam (Form 1) of the present invention and at least one pharmaceutically acceptable excipient.
- the at least one pharmaceutically acceptable excipient which is comprised in the pharmaceutical composition of the present invention, is preferably selected from the group consisting of one or more diluent, acidifyer, preservative, antioxidant, stabilizer, lubricant, sweetener, flavoring agent and combinations thereof.
- the diluent is mannitol and/or isomalt.
- the acidifyer is tartaric acid.
- the preservative is sodium benzoate.
- the antioxidant is ascorbic acid.
- the lubricant is polyethylene glycol.
- the sweetener is sucralose.
- the flavoring agent is a strawberry flavour.
- the present invention relates to the crystalline form of risdiplam (Form 1) of the present invention or the pharmaceutical composition comprising the crystalline form of risdiplam (Form 1) of the present invention for use as a medicament.
- the present invention relates to the crystalline form of risdiplam (Form 1) of the present invention or the pharmaceutical composition comprising the crystalline form of risdiplam (Form 1) of the present invention for use in the treatment of spinal muscular atrophy (SMA).
- SMA spinal muscular atrophy
- the present invention relates to a method of treating spinal muscular atrophy (SMA) said method comprising administering an effective amount of the crystalline form of risdiplam (Form 1) of the present invention or the pharmaceutical composition comprising the crystalline form of risdiplam (Form 1) of the present invention to a patient in need of such a treatment.
- SMA spinal muscular atrophy
- Risdiplam dihydrochloride (5.00 g, prepared by treating either risdiplam free base or a Boc- protected precursor as described in Example 11 of WO 2019/057740 Al with hydrochloric acid in a solvent or solvent mixture) was suspended in methanol (70 mL) at room temperature. Triethylamine (4.3 mL, 3 mol eqivalents) was added and the suspension was stirred at room temperature for 4 hours. Subsequently, the crystals were collected by filtration and dried for 17 hours at 40°C under vacuum (5 mbar).
- Powder X-ray diffraction was performed with a PANalytical X’Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphai,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector.
- Diffractograms were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013° 2-theta with 40s per step (255 channels) in the angular range of 2° to 40° 2-Theta at ambient conditions.
- a typical precision of the 2-Theta values is in the range of ⁇ 0.2° 2-Theta, preferably of ⁇ 0.1° 2-Theta.
- Table 2 is used to constitute oral solutions with water to obtain 80 mL solution.
- Table 2 Powder blend comprising risdiplam Form 1 of the present invention
- Example 4 Powder blend for the preparation of an oral solution of risdiplam at a concentration of 0.75 mg/mL in a bottle containing 80 mL solution
- the formulation process comprises dry granulation by roller compaction.
- the composition of Table 3 is used to constitute oral solutions with water to obtain 80 mL solution.
Abstract
The present invention relates to a crystalline form of risdiplam and to a process for its preparation. Furthermore, the invention relates to a pharmaceutical composition comprising the crystalline form of risdiplam of the present invention and at least one pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be used as a medicament, in particular for the treatment of spinal muscular atrophy (SMA).
Description
CRYSTALLINE FORM OF RISDIPLAM
FIELD OF THE INVENTION
The present invention relates to a crystalline form of risdiplam and to a process for its preparation. Furthermore, the invention relates to a pharmaceutical composition comprising the crystalline form of risdiplam of the present invention and at least one pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be used as a medicament, in particular for the treatment of spinal muscular atrophy (SMA).
BACKGROUND OF THE INVENTION
Risdiplam is a survival of motor neuron 2 (SMN2) gene splicing modifier indicated for the treatment of spinal muscular atrophy (SMA). The chemical name of risdiplam is 7-(4,7- diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)pyrido-4Z7-[l,2- a]pyrimidin-4-one. Risdiplam can be represented by the following chemical structure according to Formula (A)
Formula (A).
Risdiplam and its preparation are disclosed in WO 2015/173181 Al. In Example 20 the product is obtained as light yellow solid after purification by column chromatography.
In Examples 14 and 15 of WO 2019/057740 Al risdiplam is obtained as yellow crystals, respectively.
WO 2020/079203 Al mentions various crystalline forms of risdiplam free base including Form A (anhydrous), Form B (metastable polymorph), Form C (monohydrate), Form D (trihydrate), Form E (trihydrate), Form F (hydrate) and Form G (metastable polymorph).
Several anhydrous and hydrated forms of risdiplam are also mentioned in WO 2021/021775 Al, which are therein denominated as Form 1, Form 2, Form 3, Form 4 and Form 5.
Different solid-state forms of an active pharmaceutical ingredient often possess different properties. Differences in physicochemical properties of solid-state forms can play a crucial role for the improvement of pharmaceutical compositions, for example, pharmaceutical formulations with improved dissolution profile and bioavailability or with improved stability or shelf-life can become accessible due to an improved solid-state form of an active pharmaceutical ingredient. Also processing or handling of the active pharmaceutical ingredient during the formulation process may be improved. New solid-state forms of an active pharmaceutical ingredient can thus have desirable processing properties. They can be easier to handle, better suited for storage, and/or allow for better purification, compared to previously known solid forms.
There is thus a need for the provision of solid-state forms of risdiplam having improved physicochemical properties.
SUMMARY OF THE INVENTION
The present invention provides a crystalline form of risdiplam, which is hereinafter also designated as “Form 1”.
Risdiplam Form 1 of the present invention posesses one or more advantageous properties selected from the group consisting of chemical stability, physical stability, melting point, hygroscopicity, solubility, dissolution, morphology, crystallinity, flowability, bulk density, compactibility and wettability.
It is noteworthy, that the crystalline Form 1 of the present invention was only accessible by applying very specific crystallization conditions. In contrast to the teaching of the prior art (e.g. WO 2020/079203 Al and WO 2021/021775 Al), which uses ridsiplam free base as starting material for the preparation of the various forms, the inventors of the present invention followed a different approach by treating risdiplam dihydrochloride salt with an amine base such as tri ethylamine in the presence of methanol, which unexpectedly yielded the novel Form 1 of risdiplam of the present invention.
Abbreviations
PXRD powder X-ray diffractogram
FTIR Fourier transform infrared
DSC differential scanning calorimetry
TGA thermogravimetric analysis
GMS gravimetric moisture sorption
Boc tert-butyloxycarbonyl
RH relative humidity
EDTA ethylenediaminetetraacetic acid
PEG polyethylne glycol
Definitions
In the context of the present invention the following definitions have the indicated meaning, unless explicitly stated otherwise:
As used herein, the term “measured at a temperature in the range of from 20 to 30°C” refers to a measurement under standard conditions. Typically, standard conditions mean a temperature in the range of from 20 to 30°C, i.e. at room temperature. Standard conditions can mean a temperature of about 22°C. Typically, standard conditions can additionally mean a measurement under 20-60% RH, preferably 30-50% RH, more preferably 40% RH and most preferably 20 - 30% RH.
The term “reflection” with regard to powder X-ray diffraction as used herein, means peaks in an X-ray diffractogram, which are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material, which are distributed in an ordered and repetitive pattern in a long-range positional order. Such a solid material is classified as crystalline material, whereas amorphous material is defined as solid material, which lacks long-range order and only displays short-range order, thus resulting in broad scattering. According to literature, long-range order e.g. extends over approximately 100 to 1000 atoms, whereas short-range order is over a few atoms only (see “Fundamentals of Powder Diffraction and Structural Characterization of Materials ” by Vitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers, 2003, page 3).
The term “essentially the same” with reference to powder X-ray diffraction means that variabilities in reflection positions and relative intensities of the reflections are to be taken into account. For example, a typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably in the range of ± 0.1° 2-Theta. Thus, a reflection that usually appears at 7.5° 2-Theta for example can appear between 7.3° and 7.7° 2-Theta, preferably between 7.4° and 7.6° 2-
Theta on most X-ray diffractometers under standard conditions. Furthermore, one skilled in the art will appreciate that relative reflection intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, particle size, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.
Crystalline Form 1 of risdiplam of the present invention may be referred to herein as being characterized by graphical data "as shown in" a figure. Such data include, for example, powder X-ray diffraction. The person skilled in the art understands that factors such as variations in instrument type, response and variations in sample directionality, sample concentration and sample purity may lead to small variations for such data when presented in graphical form, for example variations relating to the exact reflection positions and intensities. However, a comparison of the graphical data in the figure herein with the graphical data generated for another or an unknown solid form and the confirmation that two sets of graphical data relate to the same crystal form is well within the knowledge of a person skilled in the art.
The term“solid-state form” as used herein refers to any crystalline and/or amorphous phase of a compound.
As used herein, the term “amorphous” refers to a solid-state form of a compound that is not crystalline. An amorphous compound possesses no long-range order and does not display a definitive X-ray diffraction pattern with reflections.
The terms “anhydrous form” or “anhydrate” as used herein refer to a crystalline solid where no water is cooperated in or accommodated by the crystal structure. Anhydrous forms may still contain residual water, which is not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal.
The term “hydrate” as used herein, refers to a crystalline solid where either water is cooperated in or accommodated by the crystal structure e.g. is part of the crystal structure or entrapped into the crystal (water inclusions). Thereby, water can be present in a stoichiometric or non- stoichiometric amount. When water is present in stoichiometric amount, the hydrate may be referred to by adding greek numeral prefixes. For example, a hydrate may be referred to as a hemihydrate or as a monohydrate depending on the water/compound stoichiometry. The water content can be measured, for example, by Karl-Fischer-Coulometry.
As used herein, the term “mother liquor” refers to the solution remaining after crystallization of a solid from said solution.
The term “pharmaceutically acceptable excipient” as used herein refers to substances, which do not show a significant pharmacological activity at the given dose and that are added to a pharmaceutical composition in addition to the active pharmaceutical ingredient.
BRIEF DESCRIPTION OF THE FIGURE
Figure 1: illustrates a representative PXRD of Form 1 of risdiplam of the present invention. The x-axis shows the scattering angle in °2-Theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a crystalline form of risdiplam, herein also designated as “Form 1”.
Crystalline Form 1 of risdiplam of the present invention may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to powder X-ray diffraction, FTIR spectroscopy, DSC; TGA and GMS. Risdiplam Form 1 of the present invention may be characterized by one of the aforementioned analytical methods or by combining two or more of them. In particular, Form 1 of risdiplam of the present invention may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.
In one embodiment the invention relates to a crystalline form (Form 1) of risdiplam characterized by having a PXRD comprising reflections at 2-Theta angles of:
(7.5 ± 0.2)°, (13.1 ± 0.2)° and (26.2 ± 0.2)°; or
(7.5 ± 0.2)°, (12.3 ± 0.2)°, (13.1 ± 0.2)° and (26.2 ± 0.2)°; or
(7.5 ± 0.2)°, (12.3 ± 0.2)°, (13.1 ± 0.2)°, (14.5 ± 0.2)° and (26.2 ± 0.2)°; or
(7.5 ± 0.2)°, (12.3 ± 0.2)°, (13.1 ± 0.2)°, (14.5 ± 0.2)°, (21.5 ± 0.2)° and (26.2 ± 0.2)°; or
(7.5 ± 0.2)°, (12.3 ± 0.2)°, (13.1 ± 0.2)°, (14.5 ± 0.2)°, (15.1 ± 0.2)°, (21.5 ± 0.2)° and (26.2 ±
0.2)°; or
(7.5 ± 0.2)°, (12.3± 0.2)°, (13.1 ± 0.2)°, (13.7 ± 0.2)°, (14.5 ± 0.2)°, (15.1 ± 0.2)°, (21.5 ± 0.2)° and (26.2 ± 0.2)°; or
(7.5 ± 0.2)°, (12.3 ± 0.2)°, (13.1 ± 0.2)°, (13.7 ± 0.2)°, (14.5 ± 0.2)°, (15.1 ± 0.2)°, (19.4 ± 0.2)°, (21.5 ± 0.2)° and (26.2 ± 0.2)°; or
(7.5 ± 0.2)°, (12.3 ± 0.2)°, (13.1 ± 0.2)°, (13.7 ± 0.2)°, (14.5 ± 0.2)°, (15.1 ± 0.2)°, (16.4 ± 0.2)°, (19.4 ± 0.2)°, (21.5± 0.2)° and (26.2 ± 0.2)°; when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
In another embodiment, the invention relates to a crystalline form (Form 1) of risdiplam characterized by having a PXRD comprising reflections at 2-Theta angles of (7.5 ± 0.2)°, (12.3 ± 0.2)°, (13.1 ± 0.2)°, (14.5 ± 0.2)°, (16.4 ± 0.2)°, (17.0 ± 0.2)°, (18.5 ± 0.2)°, (19.4 ± 0.2)°, (19.8 ± 0.2)° and (26.2 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
In a further embodiment, the present invention relates to a crystalline form (Form 1) of risdiplam characterized by having a PXRD comprising reflections at 2-Theta angles of: (7.5 ± 0.1)°, (13.1 ± 0.1)° and (26.2 ± 0.1)°; or
(7.5 ± 0.1)°, (12.3 ± 0.1)°, (13.1 ± 0.1)° and (26.2 ± 0.1)°; or
(7.5 ± 0.1)°, (12.3 ± 0.1)°, (13.1 ± 0.1)°, (14.5 ± 0.1)° and (26.2 ± 0.1)°; or
(7.5 ± 0.1)°, (12.3 ± 0.1)°, (13.1 ± 0.1)°, (14.5 ± 0.1)°, (21.5 ± 0.1)° and (26.2 ± 0.1)°; or
(7.5 ± 0.1)°, (12.3 ± 0.1)°, (13.1 ± 0.1)°, (14.5 ± 0.1)°, (15.1 ± 0.1)°, (21.5 ± 0.1)° and (26.2 ±
0.1)°; or
(7.5 ± 0.1)°, (12.3± 0.1)°, (13.1 ± 0.1)°, (13.7 ± 0.1)°, (14.5 ± 0.1)°, (15.1 ± 0.1)°, (21.5 ± 0.1)° and (26.2 ± 0.1)°; or
(7.5 ± 0.1)°, (12.3 ± 0.1)°, (13.1 ± 0.1)°, (13.7 ± 0.1)°, (14.5 ± 0.1)°, (15.1 ± 0.1)°, (19.4 ± 0.1)°, (21.5 ± 0.1)° and (26.2 ± 0.1)°; or
(7.5 ± 0.1)°, (12.3 ± 0.1)°, (13.1 ± 0.1)°, (13.7 ± 0.1)°, (14.5 ± 0.1)°, (15.1 ± 0.1)°, (16.4 ± 0.1)°, (19.4 ± 0.1)°, (21.5± 0.1)° and (26.2 ± 0.1)°; when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
In yet another embodiment, the invention relates to a crystalline form (Form 1) of risdiplam characterized by having a PXRD comprising reflections at 2-Theta angles of (7.5 ± 0.1)°, (12.3 ± 0.1)°, (13.1 ± 0.1)°, (14.5 ± 0.1)°, (16.4 ± 0.1)°, (17.0 ± 0.1)°, (18.5 ± 0.1)°, (19.4 ± 0.1)°, (19.8 ± 0.1)° and (26.2 ± 0.1)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
The PXRD of risdiplam Form 1 of the present invention can be readily distinguished from the PXRDs of risdiplam Form A, Form B, Form C, Form D, Form E, Form F and Form G of
WO 2019/075108 Al, since in contrast to Forms A to G, the PXRD of Form 1 shows no reflections at or below (7.0 ± 0.2)° 2-Theta.
Hence, in one embodiment the present invention relates to a crystalline form (Form 1) of risdiplam as defined in any one of the above described embodiments characterized by having a PXRD comprising no reflection at 2-Theta angles of or below (7.0 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
For example, the present invention relates to a crystalline form (Form 1) of risdiplam as defined in any one of the above described embodiments characterized by having a PXRD comprising no reflection at 2-Theta angles of or below (6.9 ± 0.2)°, (6.8 ± 0.2)°, (6.7 ± 0.2)°, (6.6 ± 0.2)°, (6.5 ± 0.2)°, (6.4 ± 0.2)°, (6.3 ± 0.2)°, (6.2 ± 0.2)°, (6.1 ± 0.2)°, (6.0 ± 0.2)°, (5.9 ± 0.2)°, (5.8 ± 0.2)°, (5.7 ± 0.2)°, (5.6 ± 0.2)°, (5.5 ± 0.2)°, (5.4 ± 0.2)°, (5.3 ± 0.2)°, (5.2 ± 0.2)°, (5.1 ± 0.2)° and (5.0 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
In a particular preferred embodiment, the present invention relates to a crystalline form (Form 1) of risdiplam characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (7.5 ± 0.2)°, (13.1 ± 0.2)° and (26.2 ± 0.2)°, but comprising no reflection at 2-Theta angles of or below (7.0 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai, 2 radiation having a wavelength of 0.15419 nm.
In another embodiment the present invention relates to a crystalline form (Form 1) of risdiplam as defined in any one of the above described embodiments characterized by having a PXRD comprising no reflection at 2-Theta angles of or below (7.0 ± 0.1)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
For example, the present invention relates to a crystalline form (Form 1) of risdiplam as defined in any one of the above described embodiments characterized by having a PXRD comprising no reflection at 2-Theta angles of or below (6.9 ± 0.1)°, (6.8 ± 0.1)°, (6.7 ± 0.1)°, (6.6 ± 0.1)°, (6.5 ± 0.1)°, (6.4 ± 0.1)°, (6.3 ± 0.1)°, (6.2 ± 0.1)°, (6.1 ± 0.1)°, (6.0 ± 0.1)°, (5.9 ± 0.1)°, (5.8 ± 0.1)°, (5.7 ± 0.1)°, (5.6 ± 0.1)°, (5.5 ± 0.1)°, (5.4 ± 0.1)°, (5.3 ± 0.1)°, (5.2 ± 0.1)°, (5.1 ± 0.1)° and (5.0 ± 0.1)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
In a preferred embodiment, the present invention relates to a crystalline form (Form 1) of risdiplam characterized by having a powder X-ray diffractogram comprising reflections at 2- Theta angles of (7.5 ± 0.1)°, (13.1 ± 0.1)° and (26.2 ± 0.1)°, but comprising no reflection at 2- Theta angles of or below (7.0 ± 0.1)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai, 2 radiation having a wavelength of 0.15419 nm.
In yet another embodiment, the present invention relates to a crystalline form (Form 1) of risdiplam characterized by having a PXRD essentially the same as shown in Figure 1 of the present invention, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm.
In another aspect, the present invention relates to a process for the preparation of the crystalline form of risdiplam (Form 1) of the present invention as defined in the above described aspect and its corresponding embodiments comprising:
(a) providing risdiplam dihydrochloride;
(b) treating the risdiplam dihydrochloride provided in (a) with an amine base in the presence of a solvent comprising methanol;
(c) crystallizing risdiplam from the mixture obtained in (b);
(d) separating at least a part of the crystals obtained in (c) from the mother liquor;
(e) optionally, washing the isolated crystals obtained in (d); and
(f) drying the crystals obtained in (d) or (e);
In one embodiment, the amine base in step (b) is selected from the group consisting of ammonia, benethamine, benzathine, tert-butylamine, diethanolamine, diethylamine, epolamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, glucamine, hydrabamine, imidazole, meglumine, morpholine, piperazine, pyrrolidine, triethanolamine, triethylamine and tromethamine. In a preferred embodiment the amine base is selected from the group consisting of tert-butylamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, triethanolamine, triethylamine and tromethamine, most preferably the amine base is triethylamine. In another embodiment, the amine base is used in an amount of from 1.5 to 5.0 mol equivalent, preferably of from 1.8 to 2.2 mol equivalent such as 2.0 mol equivalent, based on the amount of risdiplam dihydrochloride.
In a further embodiment, the crystals are separated in step (d) from their mother liquor by any conventional method such as filtration, centrifugation, solvent evaporation or decantation, more preferably by filtration or centrifugation and most preferably by filtration.
In still another embodiment, the crystals are dried in step (f) at a temperature of about 60°C or less, preferably of about 40°C or less.
In a further aspect, the present invention relates to the use of the crystalline form of risdiplam (Form 1) of the present invention as defined in the above described aspect and its corresponding embodiments for the preparation of a pharmaceutical composition.
Furthermore, the present invention relates to a pharmaceutical composition comprising the crystalline form of risdiplam (Form 1) of the present invention and at least one pharmaceutically acceptable excipient.
The at least one pharmaceutically acceptable excipient, which is comprised in the pharmaceutical composition of the present invention, is preferably selected from the group consisting of one or more diluent, acidifyer, preservative, antioxidant, stabilizer, lubricant, sweetener, flavoring agent and combinations thereof.
In one embodiment, the diluent is mannitol and/or isomalt. In another embodiment, the acidifyer is tartaric acid. In still another embodiment, the preservative is sodium benzoate. In a further embodiment the antioxidant is ascorbic acid. In an additional embodiment, the lubricant is polyethylene glycol. In another embodiment, the sweetener is sucralose. In a further embodiment the flavoring agent is a strawberry flavour.
Preferably, the pharmaceutical composition of the present invention as defined in any one of the above described embodiments is an oral solid dosage form, more preferably a powder for oral solution.
In a further aspect, the present invention relates to the crystalline form of risdiplam (Form 1) of the present invention or the pharmaceutical composition comprising the crystalline form of risdiplam (Form 1) of the present invention for use as a medicament.
In still a further aspect, the present invention relates to the crystalline form of risdiplam (Form 1) of the present invention or the pharmaceutical composition comprising the crystalline form of risdiplam (Form 1) of the present invention for use in the treatment of spinal muscular atrophy (SMA).
In another aspect, the present invention relates to a method of treating spinal muscular atrophy (SMA) said method comprising administering an effective amount of the crystalline form of risdiplam (Form 1) of the present invention or the pharmaceutical composition comprising the
crystalline form of risdiplam (Form 1) of the present invention to a patient in need of such a treatment.
EXAMPLES
The following non-limiting examples are illustrative for the disclosure and are not to be construed as to be in any way limiting for the scope of the invention.
Example 1: Preparation of risdiplam Form 1
Risdiplam dihydrochloride (5.00 g, prepared by treating either risdiplam free base or a Boc- protected precursor as described in Example 11 of WO 2019/057740 Al with hydrochloric acid in a solvent or solvent mixture) was suspended in methanol (70 mL) at room temperature. Triethylamine (4.3 mL, 3 mol eqivalents) was added and the suspension was stirred at room temperature for 4 hours. Subsequently, the crystals were collected by filtration and dried for 17 hours at 40°C under vacuum (5 mbar).
Yield: 3.86 g (91% of theory)
Example 2: Powder X-ray diffraction
Powder X-ray diffraction was performed with a PANalytical X’Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphai,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector. Diffractograms were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013° 2-theta with 40s per step (255 channels) in the angular range of 2° to 40° 2-Theta at ambient conditions. A typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta.
The reflection list of crystalline Form 1 of risdiplam of the present invention is provided in Table 1 below.
Table 1: Reflection positions of crystalline Form 1 of risdiplam in the range of from 2 to 30° 2-Theta; a typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0. 1° 2-Theta.
Example 3: Powder blend for the preparation of an oral solution of risdiplam at a concentration of 0.75 mg/mL in a bottle containing 80 mL solution The formulation process comprises dry granulation by roller compaction. The composition of
Table 2 is used to constitute oral solutions with water to obtain 80 mL solution.
Table 2: Powder blend comprising risdiplam Form 1 of the present invention
Example 4: Powder blend for the preparation of an oral solution of risdiplam at a concentration of 0.75 mg/mL in a bottle containing 80 mL solution The formulation process comprises dry granulation by roller compaction. The composition of Table 3 is used to constitute oral solutions with water to obtain 80 mL solution.
Table 3: Powder blend comprising risdiplam Form 1 of the present invention
Claims
1) A crystalline form of risdiplam (Form 1) according to the chemical structure as depicted in Formula (A)
Formula (A), characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (7.5 ± 0.2)°, (13.1 ± 0.2)° and (26.2 ± 0.2)°, but comprising no reflection at 2- Theta angles of or below (7.0 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
2) The crystalline form of claim 1 characterized by having a powder X-ray diffractogram comprising additional reflections at 2-Theta angles of (12.3 ± 0.2)° and/or (14.5 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
3) A process for the preparation of the crystalline form as defined in claim 1 or 2 comprising:
(a) providing risdiplam dihydrochloride;
(b) treating the risdiplam dihydrochloride provided in (a) with an amine base in the presence of a solvent comprising methanol;
(c) crystallizing risdiplam from the mixture obtained in (b);
(d) separating at least a part of the crystals obtained in (c) from the mother liquor;
(e) optionally, washing the isolated crystals obtained in (d); and
(f) drying the crystals obtained in (d) or (e);
4) The process of claim 3, wherein the amine base in (b) is selected from the group consisting of Zc/V-butylamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, triethanolamine, triethylamine and tromethamine.
5) The process of claim 4, wherein the amine base is tri ethylamine.
) The process as defined in any one of claims 3 to 5, wherein the amount of amine base in (b) is in the range of from 1.5 to 5.0 mol equivalents, based on the amount of risdiplam dihydrochloride. ) The process of claim 6, wherein the amount of amine base is in the range of from 1.8 to 2.2 mol equivalents, based on the amound of risdiplam dihydrochloride. ) The process as defined in any one of claims 3 to 7, wherein in (f) the crystals are dried at a temperature of about 60°C or less. ) Use of the crystalline form as defined in claim 1 or 2 for the preparation of a pharmaceutical composition. 0) A pharmaceutical composition comprising the crystalline form as defined in claim 1 or 2 and at least one pharmaceutically acceptable excipient. 1) The pharmaceutical composition of claim 10, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of one or more diluent, acidifyer, preservative, antioxidant, stabilizer, lubricant, sweetener, flavoring agent and combinations thereof. 2) The pharmaceutical composition of claim 10, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of mannitol, isomalt, tartaric acid, sodium benzoate, ascorbic acid, polyethylene glycol, sucralose and strawberry flavour. 3) The pharmaceutical composition according to any one of claims 10 to 12, which is a powder for oral solution. 4) The crystalline form as defined in claims 1 or 2 or the pharmaceutical composition as defined in any one of claims 10 to 13 for use as a medicament. 5) The crystalline form as defined in claims 1 or 2 or the pharmaceutical composition as defined in any one of claims 10 to 13 for use in the treatment of spinal muscular atrophy (SMA).
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| VITALIJ K. PECHARSKYPETER Y. ZAVALIJ: "Fundamentals of Powder Diffraction and Structural Characterization of Materials", 2003, KLUWER ACADEMIC PUBLISHERS, pages: 3 |
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