EP4100125A1 - Polymorph of rucaparib mesylate - Google Patents

Polymorph of rucaparib mesylate

Info

Publication number
EP4100125A1
EP4100125A1 EP21702480.1A EP21702480A EP4100125A1 EP 4100125 A1 EP4100125 A1 EP 4100125A1 EP 21702480 A EP21702480 A EP 21702480A EP 4100125 A1 EP4100125 A1 EP 4100125A1
Authority
EP
European Patent Office
Prior art keywords
rucaparib
mesylate
crystalline form
composition
range
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21702480.1A
Other languages
German (de)
French (fr)
Inventor
Marijan STEFINOVIC
Ulrich Griesser
Stefan OBERPARLEITER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sandoz AG
Original Assignee
Sandoz AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sandoz AG filed Critical Sandoz AG
Publication of EP4100125A1 publication Critical patent/EP4100125A1/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an anhydrous crystalline form of rucaparib mesylate, preferably in polymorphically pure form and to a process for its preparation. Furthermore, the invention relates to a pharmaceutical composition comprising the anhydrous crystalline form of rucaparib mesylate, preferably in polymorphically pure form 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 cancer.
  • Rucaparib is an oral, small molecule inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes including PARP-1, PARP-2 and PARP-3, which play a role in DNA repair.
  • PARP inhibitors have been described to be useful as therapeutics in treatment of cancers and in the amelioration of the effects of stroke, head trauma and neurodegenerative disease.
  • Chemically designated as 8-fluoro-2-(4-methylaminomethyl-phenyl)-l,3,4,5-tetrahydro-azepino[5,4,3- cz/]indol-6-one, rucaparib may be represented by the chemical structure as depicted in Formula
  • Rucaparib has been first approved in the US as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies. It has received conditional marketing authorisation in the EU.
  • the active ingredient in the commercial product (Rubraca ® ) is the camsylate salt of rucaparib.
  • WO 00/42040 A1 discloses tricyclic PARP inhibiting agents and pharmaceutically acceptable salts thereof.
  • One of said PARP inhibitors is rucaparib, which was synthesized as the free base having a melting point of 154-155°C in example IIII of said application.
  • WO 2004/087713 Al discloses in example A the preparation of the mesylate salt of rucaparib, which was produced by first treating rucaparib free base with methane sulfonic acid in the presence of methanol. Then, after partial concentration of the methanol solution in vacuo , water was added followed by lyophilization, which yielded rucaparib mesylate as bright yellow solid.
  • the molecular formula provided in example A indicates that the obtained rucaparib mesylate contains about 2 mol equivalents of water per mol rucaparib mesylate.
  • Experimental repetition of example A yielded a hydrate (see reference example 1 hereinafter).
  • Example 39 of WO 2018/140377 Al rucaparib base was reacted with 2 mol equivalents of methanesulfonic acid in the presence of a THF/FhO mixture (2:1).
  • the obtained wet crystals which were designated as Form I, were dried in a vacuum oven at 50°C for 4 hours to obtain rucaparib mesylate as Form II.
  • Form A An anhydrous crystalline form of rucaparib mesylate designated as Form A is described in WO 2019/086509 Al.
  • 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-state forms.
  • a metastable polymorph can present a problem in pharmaceutical development.
  • serious pharmaceutical consequences arise if polymorphic transformation occurs in a dosage form, e.g. upon storage.
  • Such a polymorphic transformation can for example be triggered by temperature and/or moisture, certain excipients of the formulation or if polymorphic impurities are present. It is therefore desirable to use a polymorphically pure and thermodynamically stable polymorph e.g. a kinetically stable polymorph or preferably the thermodynamically most stable polymorph at ambient conditions for the preparation of a safe and efficacious drug product.
  • the inventors of the present invention surprisingly identified a polymorph of rucaparib mesylate, which is thermodynamically more stable at ambient conditions e.g. at a temperature in the range of 15 to 30°C compared to polymorph A of WO 2019/086509 A1 (see also Comparative Example 1 hereinafter). Furthermore, the polymorph of the present invention can be reliably obtained in polymorphically pure form. Hence, the polymorph of the present invention allows for the reliable production of a stable drug product containing rucaparib mesylate, which is safe and efficacious over the whole shelf-life.
  • rucaparib refers to the compound with the chemical name 8-fluoro- 2-(4-methyl ami nomethyl -phenyl)-! ,3,4,5-tetrahydro-azepino[5,4,3-c6 ]indol-6-one, which is represented by the chemical structure as depicted in Formula (I) above.
  • rucaparib indicates the free base form.
  • room temperature refers to a temperature in the range of from 20 to 30°C.
  • 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% relative humidity, preferably 30-50% relative humidity such as 40% relative humidity.
  • reflection with regards 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.
  • amorphous material does not display a definitive X-ray diffraction pattern with reflections.
  • 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 12.6° 2- Theta for example can appear between 12.4 and 12.8° 2-Theta, preferably between 12.5 and 12.7° 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.
  • the anhydrous crystalline form of rucaparib mesylate of the present invention may be referred to herein as being characterized by graphical data "as shown in" a figure.
  • graphical data include for example powder X-ray diffractograms.
  • 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 peak positions and intensities.
  • a comparison of the graphical data in the figures herein with the graphical data generated for another or an unknown solid-state 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.
  • Form A or “polymorph A” as used herein, when talking about a solid-state form of rucaparib mesylate refers to the anhydrous crystalline form of rucaparib mesylate, which is disclosed in WO 2019/086509 Al.
  • Said Form A of rucaparib mesylate can for example be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (9.9 ⁇ 0.2)°, (11.7 ⁇ 0.2)°, (12.2 ⁇ 0.2)°, (16.3 ⁇ 0.2)° and (22.5 ⁇ 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.
  • solid-state form refers to any crystalline or amorphous phase of a substance.
  • anhydrous refers 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.
  • an anhydrous form does not contain more than 2.0 w-%, preferably not more than 1.0 w-% of water, based on the weight of the crystalline form.
  • 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 /lew/hydrate or as a /wwohydrate depending on the water/compound stoichiometry.
  • the water content can be measured, for example, by Karl-Fischer-Coulometry.
  • a “predetermined amount” as used herein with regard to rucaparib mesylate refers to the initial amount of rucaparib mesylate used for the preparation of a pharmaceutical composition having a desired dosage strength of rucaparib.
  • the term “effective amount” as used herein with regard to rucaparib mesylate encompasses an amount of rucaparib mesylate, which provides the desired therapeutic and/or prophylactic effect.
  • pharmaceutically acceptable excipient 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. Excipients may take on the function of vehicle, diluent, release agent, disintegrating agent, dissolution modifying agent, absorption enhancer, stabilizer or a manufacturing aid among others. Excipients may include fillers (diluents), binders, disintegrants, lubricants and glidants.
  • filler or “diluent” as used herein refer to substances that are used to dilute the active pharmaceutical ingredient prior to delivery. Diluents and fillers can also serve as stabilizers.
  • binder refers to substances which bind the active pharmaceutical ingredient and pharmaceutically acceptable excipient together to maintain cohesive and discrete portions.
  • disintegrant refers to substances which, upon addition to a solid pharmaceutical composition, facilitate its break-up or disintegration after administration and permit the release of the active pharmaceutical ingredient as efficiently as possible to allow for its rapid dissolution.
  • lubricant refers to substances which are added to a powder blend to prevent the compacted powder mass from sticking to the equipment during tableting or encapsulation process. They aid the ejection of the tablet from the dies and can improve powder flow.
  • glidant refers to substances which are used for tablet and capsule formulations in order to improve flow properties during tablet compression and to produce an anti -caking effect.
  • the term “about” means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1% and most typically within 0.1% of the indicated value or range. Sometimes, such a range can lie within the experimental error, typical of standard methods used for the measurement and/or determination of a given value or range.
  • mother liquor refers to the solution remaining after crystallization of a solid.
  • Figure 1 illustrates a representative powder X-ray diffractogram of the crystalline form (Form B) of rucaparib mesylate according to 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.
  • Figure 2 illustrates on the bottom a representative DSC curve and on the top a representative TGA curve of the crystalline form of rucaparib mesylate (form B) according to the present invention.
  • the x-axis shows the temperature in degree Celsius (°C).
  • the right y-axis shows the heat flow with endothermic peaks going up, the left y-axis shows the mass (loss) of the sample in weight percent (w-%).
  • the present invention provides a stable and polymorphically pure anhydrous crystalline form of rucaparib mesylate, herein also designated as “Form B” or “polymorph B”.
  • polymorph B of rucaparib mesylate of the present invention is thermodynamically more stable e.g. in the temperature range of 15 to 30°C compared to polymorph A of WO 2019/086509 A1 (see Comparative Example 1 hereinafter).
  • Rucaparib mesylate in particular polymorph B of rucaparib mesylate according to the present invention is characterized by the chemical structure as depicted in Formula (II)
  • rucaparib mesylate in particular polymorph B of rucaparib mesylate according to the present invention is characterized by a molar ratio of rucaparib and methanesulfonic acid in the range of from 1.0: 0.8 to 1.0: 1.2, preferably of from 1.0: 0.9 to 1.0: 1.1, more preferably of from 1.00: 0.95 to 1.00: 1.05 and most preferably the molar ratio is about 1.0: 1.0.
  • Polymorph B of rucaparib mesylate 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, DSC and TGA. It may be characterized by one of the aforementioned analytical methods or by combining them. In particular, polymorph B of rucaparib mesylate 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 present invention relates to an anhydrous crystalline form of rucaparib mesylate (Form B) characterized by having a PXRD comprising reflections at 2- Theta angles of:
  • the invention relates to an anhydrous crystalline form (Form B) of rucaparib mesylate characterized by having a PXRD comprising reflections at 2-Theta angles of (12.6 ⁇ 0.2)°, (13.7 ⁇ 0.2)°, (14.2 ⁇ 0.2)°, (16.8 ⁇ 0.2)°, (17.3 ⁇ 0.2)°, (18.3 ⁇ 0.2)°, (20.7 ⁇ 0.2)°, (22.3 ⁇ 0.2)°, (23.2 ⁇ 0.2)° and (24.5 ⁇ 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.
  • the present invention relates to an anhydrous crystalline form (Form B) of rucaparib mesylate characterized by having a PXRD comprising reflections at 2-Theta angles of:
  • the invention relates to an anhydrous crystalline form (Form B) of rucaparib mesylate characterized by having a PXRD comprising reflections at 2-Theta angles of (12.6 ⁇ 0.1)°, (13.7 ⁇ 0.1)°, (14.2 ⁇ 0.1)°, (16.8 ⁇ 0.1)°, (17.3 ⁇ 0.1)°, (18.3 ⁇ 0.1)°, (20.7 ⁇ 0.1)°, (22.3 ⁇ 0.1)°, (23.2 ⁇ 0.1)° and (24.5 ⁇ 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 rucaparib mesylate polymorph B of the present invention can be readily distinguished from the PXRD of rucaparib mesylate polymorph A of WO 2019/086509 Al.
  • Polymorph B for example shows characteristic reflections at (7.8 ⁇ 0.2)°, (12.6 ⁇ 0.2)°, (13.7 ⁇ 0.2)°, (16.8 ⁇ 0.2)° and (24.5 ⁇ 0.2)° 2-Theta, whereas polymorph A shows no reflections in the same ranges.
  • polymorph A shows characteristic reflections at (9.9 ⁇ 0.2)°, (11.7 ⁇ 0.2)°, (15.1 ⁇ 0.2)°, (16.3 ⁇ 0.2)° and (19.9 ⁇ 0.2)° 2-Theta, whereas polymorph B shows no reflections in the same ranges.
  • the present invention relates to a crystalline form (Form B) of rucaparib mesylate which can be characterized by having a PXRD as defined in any one of the above described embodiments, but comprising no reflections at 2-Theta angles of (9.9 ⁇ 0.2)°, (11.7 ⁇ 0.2)°, (15.1 ⁇ 0.2)°, (16.3 ⁇ 0.2)° and/or (19.9 ⁇ 0.2)°, preferably comprising no reflections at 2-Theta angles of (9.9 ⁇ 0.2)°, (11.7 ⁇ 0.2)°, (16.3 ⁇ 0.2)° and/or (19.9 ⁇ 0.2)°, more preferably comprising no reflections at 2-Theta angles of (11.7 ⁇ 0.2)°, (16.3 ⁇ 0.2)° and/or (19.9 ⁇ 0.2)° and most preferably comprising no reflections at 2-Theta angles of (11.7 ⁇ 0.2)° and/or (16.3 ⁇ 0.2)°, when
  • the present invention relates to an anhydrous crystalline form (Form B) of rucaparib mesylate 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.
  • the present invention relates to an anhydrous crystalline form (Form B) of rucaparib mesylate characterized by having a DSC curve showing an endothermic peak, preferably a sole endothermic peak, in the range of from 280 to 289°C, preferably of from 283 to 288°C, when measured at a heating rate of 10 K/min.
  • Form B anhydrous crystalline form of rucaparib mesylate characterized by having a DSC curve showing an endothermic peak, preferably a sole endothermic peak, in the range of from 280 to 289°C, preferably of from 283 to 288°C, when measured at a heating rate of 10 K/min.
  • the present invention relates to a crystalline form (Form B) of rucaparib mesylate characterized by having a DSC curve showing an endothermic peak, preferably a sole endothermic peak, with an onset at a temperature of (285 ⁇ 2)°C, preferably of (285 ⁇ 1)°C, when measured at a heating rate of 10 K/min.
  • the present invention relates to a crystalline form (Form B) of rucaparib mesylate characterized by having a DSC curve showing an endothermic peak, preferably a sole endothermic peak, with a peak maximum at a temperature of (287 ⁇ 2)°C, preferably of (287 ⁇ 1)°C, when measured at a heating rate of 10 K/min.
  • the endothermic peak is caused by the melting of the anhydrous crystalline form (Form B) of rucaparib mesylate of the present invention.
  • the present invention relates to an anhydrous crystalline form (Form B) of rucaparib mesylate characterized by having a TGA curve showing a mass loss of not more than 2.0 w-%, preferably of not more than 1.5 w-%, based on the weight of the crystalline form, when heated from 25 to 250°C at a rate of 10 K/min.
  • Form B anhydrous crystalline form of rucaparib mesylate characterized by having a TGA curve showing a mass loss of not more than 2.0 w-%, preferably of not more than 1.5 w-%, based on the weight of the crystalline form, when heated from 25 to 250°C at a rate of 10 K/min.
  • the present invention relates to a composition
  • a composition comprising the anhydrous crystalline form (Form B) of rucaparib mesylate of the present invention as defined in any one of the above described embodiments, said composition being essentially free of any other solid- state form of rucaparib mesylate.
  • a composition comprising the anhydrous crystalline form (Form B) of rucaparib mesylate of the present invention comprises at most 20 w-%, preferably at most 10 w-%, more preferably at most 5, 4, 3, 2 or 1 w-% of any other solid- state form of rucaparib mesylate, based on the weight of the composition.
  • the any other solid-state form of rucaparib mesylate is form A of WO 2019/086509 Al.
  • Form A of rucaparib mesylate exhibits a PXRD comprising amongst others characteristic reflections at 2- Theta angles of (9.9 ⁇ 0.2)°, (11.7 ⁇ 0.2)°, (15.1 ⁇ 0.2)°, (16.3 ⁇ 0.2)° and (19.9 ⁇ 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.
  • the present invention relates to a composition
  • a composition comprising the anhydrous crystalline form (Form B) of rucaparib mesylate of the present invention as defined in any one of the above described embodiments, said composition having a PXRD comprising no reflections at 2-Theta angles of (9.9 ⁇ 0.2)°, (11.7 ⁇ 0.2)°, (15.1 ⁇ 0.2)°, (16.3 ⁇ 0.2)° and (19.9 ⁇ 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.
  • the invention in another embodiment, relates to a composition
  • a composition comprising at least 90 w-%, including at least 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 w-%, and also including equal to about 100 w-% of the anhydrous crystalline form (Form B) of rucaparib mesylate of the present invention as defined in any one of the above described embodiments, based on the total weight of the composition.
  • the remaining material may comprise other solid-state form(s) of rucaparib mesylate, and/or reaction impurities and/or processing impurities arising from the preparation of the composition.
  • the invention relates to a process for the preparation of the anhydrous crystalline form (Form B) of rucaparib mesylate or the composition comprising the same as defined in any one of the above described aspects and their corresponding embodiments comprising:
  • the rucaparib free base starting material applied in step (a) may be prepared according to the process provided in example IIII of WO 00/42040 Al.
  • Rucaparib is treated with methanesulfonic acid in the presence of acetone, wherein the molar ratio of rucaparib and methanesulfonic acid applied is in the range of from about 1.0 (rucaparib): 0.8 to 1.2 (methanesulfonic acid), preferably from about 1.0 (rucaparib): 0.9 to 1.1 (methanesulfonic acid), more preferably form about 1.00 (rucaparib): 0.95 to 1.05 (methanesulfonic acid) and most preferably the molar ratio is about 1.0: 1.0.
  • the rucaparib mesylate concentration of the mixture provided in step (a) is in the range of from about 13 to 18 g/L acetone, such as about 16 g/L acetone.
  • the reaction is preferably carried out at a temperature in the range of from about 15 to 30°C, for example at about 20 to 25°C.
  • step (a) The mixture obtained in step (a) is stirred, wherein stirring may be performed for a period in the range of from about 5 minutes to 24 hours, preferably of from about 10 minutes to 12 hours, more preferably of from about 15 minutes to 6 hours. Stirring is conducted until Form B, preferably in polymorphically pure form is obtained, which can be monitored by taking samples and analyzing them by PXRD.
  • the obtained rucaparib mesylate Form B crystals are separated from the mother liquor by any conventional method such as filtration or centrifugation, most preferably by filtration.
  • the isolated Form B crystals are additionally washed with acetone.
  • the rucaparib mesylate Form B crystals are dried at a temperature in the range of from about 20 to 80°C, preferably of from about 20 to 60°C, more preferably of from about 20 to 40°C, for example at room temperature. Drying may be performed for a period in the range of from about 1 to 72 hours, preferably of from about 2 to 48 hours, more preferably of from about 4 to 24 hours and most preferably of from about 6 to 18 hours. Drying may be performed at ambient pressure and/or under vacuum preferably at about 100 mbar or less, more preferably at about 50 mbar or less and most preferably at about 30 mbar or less, for example at about 20 mbar or less.
  • the invention relates to the use of the anhydrous crystalline form (Form B) of rucaparib mesylate as defined in any one of the above described embodiments for the preparation of a pharmaceutical composition.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the anhydrous crystalline form (Form B) of rucaparib mesylate or the composition comprising the same as defined in anyone of the above described aspects and their corresponding embodiments, preferably in an effective and/or predetermined amount and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the present invention is an oral solid dosage form such as a tablet or a capsule. More preferably, the pharmaceutical composition of the present invention is a tablet, even more preferably a film-coated tablet and most preferably the pharmaceutical composition of the present invention is an immediate- release film-coated tablet.
  • the at least one pharmaceutically acceptable excipient is preferably selected from the group consisting of fillers, binders, disintegrants, lubricants and glidants. More preferably, the at least one pharmaceutically acceptable excipient is selected from the group consisting of microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate. In a preferred embodiment, all of these excipients are comprised in the pharmaceutical composition of the present invention.
  • a preferred film-coated tablet of the present invention invention consists of a tablet core comprising the anhydrous crystalline form (Form B) of rucaparib mesylate or the composition comprising the same as defined in anyone of the above described aspects and their corresponding embodiments, preferably in an effective and/or predetermined amount, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate and a film-coating comprising a colorant, polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol and talc.
  • Form B anhydrous crystalline form of rucaparib mesylate or the composition comprising the same as defined in anyone of the above described aspects and their corresponding embodiments, preferably in an effective and/or predetermined amount, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate and a film-coating comprising a colorant, polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol and talc.
  • the present invention relates to a pharmaceutical composition as defined in any one of the above described embodiments, wherein the predetermined and/or effective amount of the anhydrous crystalline form (Form B) of rucaparib mesylate of the present invention is selected from the group consisting of 200 mg, 250 mg and 300 mg, calculated as rucaparib free base.
  • the pharmaceutical composition of the present invention as defined in any one of the above described embodiments may be prepared by a standard manufacturing process well known to the skilled person.
  • the manufacturing process may comprise standard procedures including blending, sieving, roller compaction or wet granulation, compression, film-coating and packaging.
  • the pharmaceutical composition as defined in any one of the above described embodiments may be administered twice daily such that a daily dose selected from the group consisting of 600 mg, 800 mg, 1000 mg and 1200 mg, calculated as rucaparib free base is administered to a patient in need of such a treatment.
  • the present invention relates to the pharmaceutical composition as defined in any one of the above described embodiments, wherein the pharmaceutical composition is stored at a temperature in the range of from 15 to 30°C, preferably of from 20 to 25°C.
  • the present invention relates to the anhydrous crystalline form (Form B) of rucaparib mesylate, the composition comprising the anhydrous crystalline form (Form B) of rucaparib mesylate or the pharmaceutical composition comprising the same as defined in any one of the above described aspects and their corresponding embodiments for use as a medicament.
  • the invention relates to the anhydrous crystalline form (Form B) of rucaparib mesylate, the composition comprising the anhydrous crystalline form (Form B) of rucaparib mesylate or the pharmaceutical composition comprising the same as defined in any one of the above described aspects and their corresponding embodiments for the treatment of cancer, in particular for the treatment of cancer with BRCA mutation.
  • the cancer is selected from the group consisting of ovarian cancer, breast cancer, prostate cancer and pancreatic cancer.
  • the invention relates to the anhydrous crystalline form (Form B) of rucaparib mesylate, the composition comprising the anhydrous crystalline form (Form B) of rucaparib mesylate or the pharmaceutical composition comprising the same as defined in any one of the above described aspects and their corresponding embodiments for the treatment of solid tumors.
  • Example 1 Preparation of rucaparib mesylate Form B
  • rucaparib free base 250.0 mg, e.g. prepared according to the procedure disclosed in example IIII of WO 00/42040 Al
  • acetone 15 mL
  • methanesulfonic acid 74.3 mg, 1.0 mol equivalent
  • acetone 5 mL
  • the reaction mixture was stirred at room temperature for 15 minutes before the crystals were isolated by filtration and washed with acetone (3x 5 mL).
  • the obtained crystals were dried in a vacuum oven (30 mbar) for 16 hours to obtain rucaparib mesylate form B (320 mg).
  • the PXRD was obtained with an X’Pert PRO diffractometer (PANalytical, Almelo, The Netherlands) equipped with a theta/theta coupled goniometer in transmission geometry, programmable XYZ stage with well plate holder, Cu-Kal,2 radiation source (wavelength 0.15419 nm) with a focussing mirror, a 0.5° divergence slit, a 0.02° sober slit collimator and a 0.5° anti -scattering slit on the incident beam side, a 2 mm anti-scattering slit, a 0.02° sober slit collimator, aNi-filter and a solid state PIXcel detector on the diffracted beam side.
  • the patterns were recorded at a tube voltage of 40 kV, tube current of 40 mA, applying a stepsize of 0.013° 2-Theta with 80s per step in the angular range of 2° to 40° 2-Theta.
  • Table 1 PXRD reflection positions of rucaparib mesylate polymorph B of the present invention in the range of from 2 to 40° 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 Thermoanalysis Differential scanning calorimetry DSC was performed with a DSC 7 instrument (PerkinElmer, Norwalk, Ct, USA) controlled by the Pyris 2.0 software. The sample (4.00 mg) was weighed into an aluminum pan and sealed with a cover, which was perforated by a needle. Dry nitrogen was used as purge gas (sample purge: 20 mL/min, balance purge: 40 mL/min).
  • the DSC curve shows no thermal event until an endothermic peak having an onset temperature of about 285 °C and a peak temperature of about 287 °C occurs, which is due to the melting of the sample.
  • a representative DSC curve of rucaparib mesylate Form B of the present invention is displayed in Figure 2 herein.
  • Thermogravimetric analysis TGA was performed using a TGA 7 instrument (PerkinElmer, Norwalk, Ct., USA) controlled by the Pyris 2.0 software. The sample was heated to 300 °C at a rate of 10 K/min and dry nitrogen was used as the purge gas (sample purge: 20 mL/min, balance purge: 40 mL/min).
  • the crystalline form of rucaparib mesylate (form B) of the present invention showed a mass loss of only about 1.4 weight%, based on the initial weight of the sample up to a temperature of about 250 °C indicating the presence of an anhydrous and solvent free form.
  • a mixture (1 : 1 weight ratio) of rucaparib mesylate polymorph A of WO 2019/086509 A1 (prepared according to Example 2 of WO 2019/086509 Al) and polymorph B of the present invention (prepared according to Example 1 hereinabove) were suspended in acetonitrile and stirred at a temperature in the range of 15 to 30°C using a magnetic stir bar. After 2 weeks of stirring the solid was analyzed by PXRD and confirmed the formation of phase pure polymorph B. Hence, it can be concluded that in the temperature range of 15 to 30°C polymorph B is thermodynamically more stable than polymorph A.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to an anhydrous crystalline form of rucaparib mesylate, preferably in polymorphically pure form and to a process for its preparation. Furthermore, the invention relates to a pharmaceutical composition comprising the anhydrous crystalline form of rucaparib mesylate, preferably in polymorphically pure form 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 cancer.

Description

POLYMORPH OF RUCAPARIB MESYLATE
FIELD OF THE INVENTION
The present invention relates to an anhydrous crystalline form of rucaparib mesylate, preferably in polymorphically pure form and to a process for its preparation. Furthermore, the invention relates to a pharmaceutical composition comprising the anhydrous crystalline form of rucaparib mesylate, preferably in polymorphically pure form 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 cancer.
BACKGROUND OF THE INVENTION Rucaparib is an oral, small molecule inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes including PARP-1, PARP-2 and PARP-3, which play a role in DNA repair. PARP inhibitors have been described to be useful as therapeutics in treatment of cancers and in the amelioration of the effects of stroke, head trauma and neurodegenerative disease. Chemically designated as 8-fluoro-2-(4-methylaminomethyl-phenyl)-l,3,4,5-tetrahydro-azepino[5,4,3- cz/]indol-6-one, rucaparib may be represented by the chemical structure as depicted in Formula
(I)
Formula (I).
Rucaparib has been first approved in the US as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies. It has received conditional marketing authorisation in the EU. The active ingredient in the commercial product (Rubraca®) is the camsylate salt of rucaparib.
WO 00/42040 A1 discloses tricyclic PARP inhibiting agents and pharmaceutically acceptable salts thereof. One of said PARP inhibitors is rucaparib, which was synthesized as the free base having a melting point of 154-155°C in example IIII of said application.
Several salts of rucaparib including various crystalline forms are disclosed in applications WO 2004/087713 Al, WO 2006/033007 A2, WO 2011/098971 Al, WO 2018/140377 A1 and WO 2019/086509 Al.
In particular, various solid-state forms of the rucaparib mesylate salt are disclosed in WO 2004/087713 Al, WO 2018/140377 Al and WO 2019/086509 Al.
WO 2004/087713 Al for instance discloses in example A the preparation of the mesylate salt of rucaparib, which was produced by first treating rucaparib free base with methane sulfonic acid in the presence of methanol. Then, after partial concentration of the methanol solution in vacuo , water was added followed by lyophilization, which yielded rucaparib mesylate as bright yellow solid. The molecular formula provided in example A indicates that the obtained rucaparib mesylate contains about 2 mol equivalents of water per mol rucaparib mesylate. Experimental repetition of example A yielded a hydrate (see reference example 1 hereinafter).
In Example 39 of WO 2018/140377 Al rucaparib base was reacted with 2 mol equivalents of methanesulfonic acid in the presence of a THF/FhO mixture (2:1). The obtained wet crystals, which were designated as Form I, were dried in a vacuum oven at 50°C for 4 hours to obtain rucaparib mesylate as Form II.
An anhydrous crystalline form of rucaparib mesylate designated as Form A is described in WO 2019/086509 Al.
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-state forms.
Furthermore, the sudden appearance or disappearance of a metastable polymorph can present a problem in pharmaceutical development. Similarly, serious pharmaceutical consequences arise if polymorphic transformation occurs in a dosage form, e.g. upon storage. Such a polymorphic transformation can for example be triggered by temperature and/or moisture, certain excipients of the formulation or if polymorphic impurities are present. It is therefore desirable to use a polymorphically pure and thermodynamically stable polymorph e.g. a kinetically stable polymorph or preferably the thermodynamically most stable polymorph at ambient conditions for the preparation of a safe and efficacious drug product.
SUMMARY OF THE INVENTION
The inventors of the present invention surprisingly identified a polymorph of rucaparib mesylate, which is thermodynamically more stable at ambient conditions e.g. at a temperature in the range of 15 to 30°C compared to polymorph A of WO 2019/086509 A1 (see also Comparative Example 1 hereinafter). Furthermore, the polymorph of the present invention can be reliably obtained in polymorphically pure form. Hence, the polymorph of the present invention allows for the reliable production of a stable drug product containing rucaparib mesylate, which is safe and efficacious over the whole shelf-life.
Abbreviations
PXRD powder X-ray diffractogram
DSC differential scanning calorimetry
TGA thermogravimetric analysis
RT room temperature w-% weight percent
THF tetrahydrofuran
Definitions
The term “rucaparib” as used herein refers to the compound with the chemical name 8-fluoro- 2-(4-methyl ami nomethyl -phenyl)-! ,3,4,5-tetrahydro-azepino[5,4,3-c6 ]indol-6-one, which is represented by the chemical structure as depicted in Formula (I) above. The term “rucaparib” indicates the free base form. As used herein the term “room temperature” refers to a temperature in the range of from 20 to 30°C.
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% relative humidity, preferably 30-50% relative humidity such as 40% relative humidity.
The term “reflection” with regards 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. Hence, amorphous material does not display a definitive X-ray diffraction pattern with reflections. According to literature, long-range order e.g. extends over at least 103 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 12.6° 2- Theta for example can appear between 12.4 and 12.8° 2-Theta, preferably between 12.5 and 12.7° 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.
The anhydrous crystalline form of rucaparib mesylate 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 diffractograms. 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 peak positions and intensities. However, a comparison of the graphical data in the figures herein with the graphical data generated for another or an unknown solid-state 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 “Form A” or “polymorph A” as used herein, when talking about a solid-state form of rucaparib mesylate refers to the anhydrous crystalline form of rucaparib mesylate, which is disclosed in WO 2019/086509 Al. Said Form A of rucaparib mesylate can for example be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (9.9 ± 0.2)°, (11.7 ± 0.2)°, (12.2 ± 0.2)°, (16.3 ± 0.2)° and (22.5 ± 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.
The term “solid-state form” as used herein refers to any crystalline or amorphous phase of a substance.
The term “anhydrous” as used herein refers 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. Typically, an anhydrous form does not contain more than 2.0 w-%, preferably not more than 1.0 w-% of water, based on the weight of the crystalline form.
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 /lew/hydrate or as a /wwohydrate depending on the water/compound stoichiometry. The water content can be measured, for example, by Karl-Fischer-Coulometry.
A “predetermined amount” as used herein with regard to rucaparib mesylate refers to the initial amount of rucaparib mesylate used for the preparation of a pharmaceutical composition having a desired dosage strength of rucaparib. The term “effective amount” as used herein with regard to rucaparib mesylate encompasses an amount of rucaparib mesylate, which provides the desired therapeutic and/or prophylactic effect.
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. Excipients may take on the function of vehicle, diluent, release agent, disintegrating agent, dissolution modifying agent, absorption enhancer, stabilizer or a manufacturing aid among others. Excipients may include fillers (diluents), binders, disintegrants, lubricants and glidants.
The terms “filler” or “diluent” as used herein refer to substances that are used to dilute the active pharmaceutical ingredient prior to delivery. Diluents and fillers can also serve as stabilizers.
As used herein the term “binder” refers to substances which bind the active pharmaceutical ingredient and pharmaceutically acceptable excipient together to maintain cohesive and discrete portions.
The term “disintegrant” as used herein refers to substances which, upon addition to a solid pharmaceutical composition, facilitate its break-up or disintegration after administration and permit the release of the active pharmaceutical ingredient as efficiently as possible to allow for its rapid dissolution.
The term “lubricant” as used herein refers to substances which are added to a powder blend to prevent the compacted powder mass from sticking to the equipment during tableting or encapsulation process. They aid the ejection of the tablet from the dies and can improve powder flow.
The term “glidant” as used herein refers to substances which are used for tablet and capsule formulations in order to improve flow properties during tablet compression and to produce an anti -caking effect.
As used herein, the term “about” means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1% and most typically within 0.1% of the indicated value or range. Sometimes, such a range can lie within the experimental error, typical of standard methods used for the measurement and/or determination of a given value or range. As used herein, the term “mother liquor” refers to the solution remaining after crystallization of a solid.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: illustrates a representative powder X-ray diffractogram of the crystalline form (Form B) of rucaparib mesylate according to 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.
Figure 2: illustrates on the bottom a representative DSC curve and on the top a representative TGA curve of the crystalline form of rucaparib mesylate (form B) according to the present invention. The x-axis shows the temperature in degree Celsius (°C). The right y-axis shows the heat flow with endothermic peaks going up, the left y-axis shows the mass (loss) of the sample in weight percent (w-%).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a stable and polymorphically pure anhydrous crystalline form of rucaparib mesylate, herein also designated as “Form B” or “polymorph B”.
The present inventors have surprisingly found that polymorph B of rucaparib mesylate of the present invention is thermodynamically more stable e.g. in the temperature range of 15 to 30°C compared to polymorph A of WO 2019/086509 A1 (see Comparative Example 1 hereinafter).
Rucaparib mesylate, in particular polymorph B of rucaparib mesylate according to the present invention is characterized by the chemical structure as depicted in Formula (II)
Formula (II). Preferably, rucaparib mesylate, in particular polymorph B of rucaparib mesylate according to the present invention is characterized by a molar ratio of rucaparib and methanesulfonic acid in the range of from 1.0: 0.8 to 1.0: 1.2, preferably of from 1.0: 0.9 to 1.0: 1.1, more preferably of from 1.00: 0.95 to 1.00: 1.05 and most preferably the molar ratio is about 1.0: 1.0.
Polymorph B of rucaparib mesylate 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, DSC and TGA. It may be characterized by one of the aforementioned analytical methods or by combining them. In particular, polymorph B of rucaparib mesylate of the present invention may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.
Hence, in a first embodiment the present invention relates to an anhydrous crystalline form of rucaparib mesylate (Form B) characterized by having a PXRD comprising reflections at 2- Theta angles of:
(7.8 ± 0.2)°, (12.6 ± 0.2)° and (24.5 ± 0.2)°; or
(7.8 ± 0.2)°, (12.6 ± 0.2)°, (13.7 ± 0.2)° and (24.5 ± 0.2)°; or
(7.8 ± 0.2)°, (12.6 ± 0.2)°, (13.7 ± 0.2)°, (14.2 ± 0.2)° and (24.5 ± 0.2)°; or
(7.8 ± 0.2)°, (12.6 ± 0.2)°, (13.7 ± 0.2)°, (14.2 ± 0.2)°, (17.3 ± 0.2)° and (24.5 ± 0.2)°; or
(7.8 ± 0.2)°, (12.6 ± 0.2)°, (13.7 ± 0.2)°, (14.2 ± 0.2)°, (16.8 ± 0.2)°, (17.3 ± 0.2)° and (24.5 ±
0.2)°; or
(7.8 ± 0.2)°, (12.6 ± 0.2)°, (13.7 ± 0.2)°, (14.2 ± 0.2)°, (16.8 ± 0.2)°, (17.3 ± 0.2)°, (18.3 ± 0.2)° and (24.5 ± 0.2)°; or
(7.8 ± 0.2)°, (12.6 ± 0.2)°, (13.7 ± 0.2)°, (14.2 ± 0.2)°, (16.8 ± 0.2)°, (17.3 ± 0.2)°, (18.3 ± 0.2)° (20.7 ± 0.2)° and (24.5 ± 0.2)°; or
(7.8 ± 0.2)°, (12.6 ± 0.2)°, (13.7 ± 0.2)°, (14.2 ± 0.2)°, (16.8 ± 0.2)°, (17.3 ± 0.2)°, (18.3 ± 0.2)° (20.7 ± 0.2)°, (23.2 ± 0.2)° and (24.5 ± 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.
In another embodiment, the invention relates to an anhydrous crystalline form (Form B) of rucaparib mesylate characterized by having a PXRD comprising reflections at 2-Theta angles of (12.6 ± 0.2)°, (13.7 ± 0.2)°, (14.2 ± 0.2)°, (16.8 ± 0.2)°, (17.3 ± 0.2)°, (18.3 ± 0.2)°, (20.7 ± 0.2)°, (22.3 ± 0.2)°, (23.2 ± 0.2)° and (24.5 ± 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. In a further embodiment, the present invention relates to an anhydrous crystalline form (Form B) of rucaparib mesylate characterized by having a PXRD comprising reflections at 2-Theta angles of:
(7.8 ± 0.1)°, (12.6 ± 0.1)° and (24.5 ± 0.1)°; or
(7.8 ± 0.1)°, (12.6 ± 0.1)°, (13.7 ± 0.1)° and (24.5 ± 0.1)°; or
(7.8 ± 0.1)°, (12.6 ± 0.1)°, (13.7 ± 0.1)°, (14.2 ± 0.1)° and (24.5 ± 0.1)°; or
(7.8 ± 0.1)°, (12.6 ± 0.1)°, (13.7 ± 0.1)°, (14.2 ± 0.1)°, (17.3 ± 0.1)° and (24.5 ± 0.1)°; or
(7.8 ± 0.1)°, (12.6 ± 0.1)°, (13.7 ± 0.1)°, (14.2 ± 0.1)°, (16.8 ± 0.1)°, (17.3 ± 0.1)° and (24.5 ±
0.1)°; or
(7.8 ± 0.1)°, (12.6 ± 0.1)°, (13.7 ± 0.1)°, (14.2 ± 0.1)°, (16.8 ± 0.1)°, (17.3 ± 0.1)°, (18.3 ± 0.1)° and (24.5 ± 0.1)°; or
(7.8 ± 0.1)°, (12.6 ± 0.1)°, (13.7 ± 0.1)°, (14.2 ± 0.1)°, (16.8 ± 0.1)°, (17.3 ± 0.1)°, (18.3 ± 0.1)° (20.7 ± 0.1)° and (24.5 ± 0.1)°; or
(7.8 ± 0.1)°, (12.6 ± 0.1)°, (13.7 ± 0.1)°, (14.2 ± 0.1)°, (16.8 ± 0.1)°, (17.3 ± 0.1)°, (18.3 ± 0.1)° (20.7 ± 0.1)°, (23.2 ± 0.1)° and (24.5 ± 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 an anhydrous crystalline form (Form B) of rucaparib mesylate characterized by having a PXRD comprising reflections at 2-Theta angles of (12.6 ± 0.1)°, (13.7 ± 0.1)°, (14.2 ± 0.1)°, (16.8 ± 0.1)°, (17.3 ± 0.1)°, (18.3 ± 0.1)°, (20.7 ± 0.1)°, (22.3 ± 0.1)°, (23.2 ± 0.1)° and (24.5 ± 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 rucaparib mesylate polymorph B of the present invention can be readily distinguished from the PXRD of rucaparib mesylate polymorph A of WO 2019/086509 Al. Polymorph B for example shows characteristic reflections at (7.8 ± 0.2)°, (12.6 ± 0.2)°, (13.7 ± 0.2)°, (16.8 ± 0.2)° and (24.5 ± 0.2)° 2-Theta, whereas polymorph A shows no reflections in the same ranges. On the other hand polymorph A shows characteristic reflections at (9.9 ± 0.2)°, (11.7 ± 0.2)°, (15.1 ± 0.2)°, (16.3 ± 0.2)° and (19.9 ± 0.2)° 2-Theta, whereas polymorph B shows no reflections in the same ranges.
Hence, in a particularly preferred embodiment the present invention relates to a crystalline form (Form B) of rucaparib mesylate which can be characterized by having a PXRD as defined in any one of the above described embodiments, but comprising no reflections at 2-Theta angles of (9.9 ± 0.2)°, (11.7 ± 0.2)°, (15.1 ± 0.2)°, (16.3 ± 0.2)° and/or (19.9 ± 0.2)°, preferably comprising no reflections at 2-Theta angles of (9.9 ± 0.2)°, (11.7 ± 0.2)°, (16.3 ± 0.2)° and/or (19.9 ± 0.2)°, more preferably comprising no reflections at 2-Theta angles of (11.7 ± 0.2)°, (16.3 ± 0.2)° and/or (19.9 ± 0.2)° and most preferably comprising no reflections at 2-Theta angles of (11.7 ± 0.2)° and/or (16.3 ± 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 yet another embodiment, the present invention relates to an anhydrous crystalline form (Form B) of rucaparib mesylate 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 a further embodiment, the present invention relates to an anhydrous crystalline form (Form B) of rucaparib mesylate characterized by having a DSC curve showing an endothermic peak, preferably a sole endothermic peak, in the range of from 280 to 289°C, preferably of from 283 to 288°C, when measured at a heating rate of 10 K/min.
In yet a further embodiment, the present invention relates to a crystalline form (Form B) of rucaparib mesylate characterized by having a DSC curve showing an endothermic peak, preferably a sole endothermic peak, with an onset at a temperature of (285 ± 2)°C, preferably of (285 ± 1)°C, when measured at a heating rate of 10 K/min.
In still a further embodiment, the present invention relates to a crystalline form (Form B) of rucaparib mesylate characterized by having a DSC curve showing an endothermic peak, preferably a sole endothermic peak, with a peak maximum at a temperature of (287 ± 2)°C, preferably of (287 ± 1)°C, when measured at a heating rate of 10 K/min.
Preferably, the endothermic peak, more preferably the sole endothermic peak, is caused by the melting of the anhydrous crystalline form (Form B) of rucaparib mesylate of the present invention.
In another embodiment, the present invention relates to an anhydrous crystalline form (Form B) of rucaparib mesylate characterized by having a TGA curve showing a mass loss of not more than 2.0 w-%, preferably of not more than 1.5 w-%, based on the weight of the crystalline form, when heated from 25 to 250°C at a rate of 10 K/min.
In another aspect, the present invention relates to a composition comprising the anhydrous crystalline form (Form B) of rucaparib mesylate of the present invention as defined in any one of the above described embodiments, said composition being essentially free of any other solid- state form of rucaparib mesylate. For example, a composition comprising the anhydrous crystalline form (Form B) of rucaparib mesylate of the present invention comprises at most 20 w-%, preferably at most 10 w-%, more preferably at most 5, 4, 3, 2 or 1 w-% of any other solid- state form of rucaparib mesylate, based on the weight of the composition. Preferably, the any other solid-state form of rucaparib mesylate is form A of WO 2019/086509 Al. Form A of rucaparib mesylate exhibits a PXRD comprising amongst others characteristic reflections at 2- Theta angles of (9.9 ± 0.2)°, (11.7 ± 0.2)°, (15.1 ± 0.2)°, (16.3 ± 0.2)° and (19.9 ± 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. Therefore, the absence of reflections at 2-Theta angles of (9.9 ± 0.2)°, (11.7 ± 0.2)°, (15.1 ± 0.2)°, (16.3 ± 0.2)° and (19.9 ± 0.2)° in the PXRD confirms the absence of form A of rucaparib mesylate in the composition.
Hence, in a preferred embodiment, the present invention relates to a composition comprising the anhydrous crystalline form (Form B) of rucaparib mesylate of the present invention as defined in any one of the above described embodiments, said composition having a PXRD comprising no reflections at 2-Theta angles of (9.9 ± 0.2)°, (11.7 ± 0.2)°, (15.1 ± 0.2)°, (16.3 ± 0.2)° and (19.9 ± 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 composition comprising at least 90 w-%, including at least 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 w-%, and also including equal to about 100 w-% of the anhydrous crystalline form (Form B) of rucaparib mesylate of the present invention as defined in any one of the above described embodiments, based on the total weight of the composition. The remaining material may comprise other solid-state form(s) of rucaparib mesylate, and/or reaction impurities and/or processing impurities arising from the preparation of the composition.
In a further aspect, the invention relates to a process for the preparation of the anhydrous crystalline form (Form B) of rucaparib mesylate or the composition comprising the same as defined in any one of the above described aspects and their corresponding embodiments comprising:
(a) reacting rucaparib free base with methanesulfonic acid in the presence of acetone, wherein the rucaparib mesylate concentration of the mixture is in the range of from about 13 to 18 g/L acetone;
(b) stirring the suspension obtained in (a) in order to obtain the anhydrous crystalline form (Form B) of rucaparib mesylate of the present invention; (c) separating at least a part of the crystals obtained in step (b) from the mother liquor;
(d) optionally washing the crystals obtained in (c);
(e) drying the crystals obtained in (c) or (d);
The rucaparib free base starting material applied in step (a) may be prepared according to the process provided in example IIII of WO 00/42040 Al. Rucaparib is treated with methanesulfonic acid in the presence of acetone, wherein the molar ratio of rucaparib and methanesulfonic acid applied is in the range of from about 1.0 (rucaparib): 0.8 to 1.2 (methanesulfonic acid), preferably from about 1.0 (rucaparib): 0.9 to 1.1 (methanesulfonic acid), more preferably form about 1.00 (rucaparib): 0.95 to 1.05 (methanesulfonic acid) and most preferably the molar ratio is about 1.0: 1.0. Importantly, the rucaparib mesylate concentration of the mixture provided in step (a) is in the range of from about 13 to 18 g/L acetone, such as about 16 g/L acetone. The reaction is preferably carried out at a temperature in the range of from about 15 to 30°C, for example at about 20 to 25°C.
The mixture obtained in step (a) is stirred, wherein stirring may be performed for a period in the range of from about 5 minutes to 24 hours, preferably of from about 10 minutes to 12 hours, more preferably of from about 15 minutes to 6 hours. Stirring is conducted until Form B, preferably in polymorphically pure form is obtained, which can be monitored by taking samples and analyzing them by PXRD.
Then at least a part, preferably all of the obtained rucaparib mesylate Form B crystals are separated from the mother liquor by any conventional method such as filtration or centrifugation, most preferably by filtration. Optionally, the isolated Form B crystals are additionally washed with acetone.
Finally, the rucaparib mesylate Form B crystals are dried at a temperature in the range of from about 20 to 80°C, preferably of from about 20 to 60°C, more preferably of from about 20 to 40°C, for example at room temperature. Drying may be performed for a period in the range of from about 1 to 72 hours, preferably of from about 2 to 48 hours, more preferably of from about 4 to 24 hours and most preferably of from about 6 to 18 hours. Drying may be performed at ambient pressure and/or under vacuum preferably at about 100 mbar or less, more preferably at about 50 mbar or less and most preferably at about 30 mbar or less, for example at about 20 mbar or less. In another aspect, the invention relates to the use of the anhydrous crystalline form (Form B) of rucaparib mesylate as defined in any one of the above described embodiments for the preparation of a pharmaceutical composition.
In a further aspect the invention relates to a pharmaceutical composition comprising the anhydrous crystalline form (Form B) of rucaparib mesylate or the composition comprising the same as defined in anyone of the above described aspects and their corresponding embodiments, preferably in an effective and/or predetermined amount and at least one pharmaceutically acceptable excipient.
In a preferred embodiment, the pharmaceutical composition of the present invention is an oral solid dosage form such as a tablet or a capsule. More preferably, the pharmaceutical composition of the present invention is a tablet, even more preferably a film-coated tablet and most preferably the pharmaceutical composition of the present invention is an immediate- release film-coated tablet.
The at least one pharmaceutically acceptable excipient is preferably selected from the group consisting of fillers, binders, disintegrants, lubricants and glidants. More preferably, the at least one pharmaceutically acceptable excipient is selected from the group consisting of microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate. In a preferred embodiment, all of these excipients are comprised in the pharmaceutical composition of the present invention.
A preferred film-coated tablet of the present invention invention consists of a tablet core comprising the anhydrous crystalline form (Form B) of rucaparib mesylate or the composition comprising the same as defined in anyone of the above described aspects and their corresponding embodiments, preferably in an effective and/or predetermined amount, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate and a film-coating comprising a colorant, polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol and talc.
Preferably, the present invention relates to a pharmaceutical composition as defined in any one of the above described embodiments, wherein the predetermined and/or effective amount of the anhydrous crystalline form (Form B) of rucaparib mesylate of the present invention is selected from the group consisting of 200 mg, 250 mg and 300 mg, calculated as rucaparib free base. The pharmaceutical composition of the present invention as defined in any one of the above described embodiments may be prepared by a standard manufacturing process well known to the skilled person. For example, the manufacturing process may comprise standard procedures including blending, sieving, roller compaction or wet granulation, compression, film-coating and packaging.
The pharmaceutical composition as defined in any one of the above described embodiments may be administered twice daily such that a daily dose selected from the group consisting of 600 mg, 800 mg, 1000 mg and 1200 mg, calculated as rucaparib free base is administered to a patient in need of such a treatment.
In another embodiment, the present invention relates to the pharmaceutical composition as defined in any one of the above described embodiments, wherein the pharmaceutical composition is stored at a temperature in the range of from 15 to 30°C, preferably of from 20 to 25°C.
In another aspect, the present invention relates to the anhydrous crystalline form (Form B) of rucaparib mesylate, the composition comprising the anhydrous crystalline form (Form B) of rucaparib mesylate or the pharmaceutical composition comprising the same as defined in any one of the above described aspects and their corresponding embodiments for use as a medicament.
In still another aspect, the invention relates to the anhydrous crystalline form (Form B) of rucaparib mesylate, the composition comprising the anhydrous crystalline form (Form B) of rucaparib mesylate or the pharmaceutical composition comprising the same as defined in any one of the above described aspects and their corresponding embodiments for the treatment of cancer, in particular for the treatment of cancer with BRCA mutation. Preferably, the cancer is selected from the group consisting of ovarian cancer, breast cancer, prostate cancer and pancreatic cancer. In a further preferred embodiment the invention relates to the anhydrous crystalline form (Form B) of rucaparib mesylate, the composition comprising the anhydrous crystalline form (Form B) of rucaparib mesylate or the pharmaceutical composition comprising the same as defined in any one of the above described aspects and their corresponding embodiments for the treatment of solid tumors. EXAMPLES
The following non-limiting examples and analytical methods which have been applied for the generation of analytical data 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 rucaparib mesylate Form B
To a suspension of rucaparib free base (250.0 mg, e.g. prepared according to the procedure disclosed in example IIII of WO 00/42040 Al) in acetone (15 mL), a solution of methanesulfonic acid (74.3 mg, 1.0 mol equivalent) in acetone (5 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 15 minutes before the crystals were isolated by filtration and washed with acetone (3x 5 mL). The obtained crystals were dried in a vacuum oven (30 mbar) for 16 hours to obtain rucaparib mesylate form B (320 mg).
Example 2: Powder X-ray diffraction
The PXRD was obtained with an X’Pert PRO diffractometer (PANalytical, Almelo, The Netherlands) equipped with a theta/theta coupled goniometer in transmission geometry, programmable XYZ stage with well plate holder, Cu-Kal,2 radiation source (wavelength 0.15419 nm) with a focussing mirror, a 0.5° divergence slit, a 0.02° sober slit collimator and a 0.5° anti -scattering slit on the incident beam side, a 2 mm anti-scattering slit, a 0.02° sober slit collimator, aNi-filter and a solid state PIXcel detector on the diffracted beam side. The patterns were recorded at a tube voltage of 40 kV, tube current of 40 mA, applying a stepsize of 0.013° 2-Theta with 80s per step in the angular range of 2° to 40° 2-Theta. Table 1: PXRD reflection positions of rucaparib mesylate polymorph B of the present invention in the range of from 2 to 40° 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: Thermoanalysis Differential scanning calorimetry DSC was performed with a DSC 7 instrument (PerkinElmer, Norwalk, Ct, USA) controlled by the Pyris 2.0 software. The sample (4.00 mg) was weighed into an aluminum pan and sealed with a cover, which was perforated by a needle. Dry nitrogen was used as purge gas (sample purge: 20 mL/min, balance purge: 40 mL/min).
The DSC curve shows no thermal event until an endothermic peak having an onset temperature of about 285 °C and a peak temperature of about 287 °C occurs, which is due to the melting of the sample. A representative DSC curve of rucaparib mesylate Form B of the present invention is displayed in Figure 2 herein.
Thermogravimetric analysis TGA was performed using a TGA 7 instrument (PerkinElmer, Norwalk, Ct., USA) controlled by the Pyris 2.0 software. The sample was heated to 300 °C at a rate of 10 K/min and dry nitrogen was used as the purge gas (sample purge: 20 mL/min, balance purge: 40 mL/min).
The crystalline form of rucaparib mesylate (form B) of the present invention showed a mass loss of only about 1.4 weight%, based on the initial weight of the sample up to a temperature of about 250 °C indicating the presence of an anhydrous and solvent free form.
Example 1: Competitive slurry experiment
A mixture (1 : 1 weight ratio) of rucaparib mesylate polymorph A of WO 2019/086509 A1 (prepared according to Example 2 of WO 2019/086509 Al) and polymorph B of the present invention (prepared according to Example 1 hereinabove) were suspended in acetonitrile and stirred at a temperature in the range of 15 to 30°C using a magnetic stir bar. After 2 weeks of stirring the solid was analyzed by PXRD and confirmed the formation of phase pure polymorph B. Hence, it can be concluded that in the temperature range of 15 to 30°C polymorph B is thermodynamically more stable than polymorph A.

Claims

1) Anhydrous crystalline form (Form B) of 8-fluoro-2-(4-methylaminomethyl-phenyl)- l,3,4,5-tetrahydro-azepino[5,4,3-ci/]indol-6-one mesylate (rucaparib mesylate) according to the chemical structure as depicted in formula (II) formula (II), characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (7.8 ± 0.2)°, (12.6 ± 0.2)° and (24.5 ± 0.2)° and comprising no reflections at 2-Theta angles of (11.7 ± 0.2)° and/or (16.3 ± 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 rucaparib mesylate of claim 1 characterized by having a powder X-ray diffractogram comprising additional reflections at 2-Theta angles of (13.7 ± 0.2)° and/or (14.2 ± 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.
3) The crystalline form of rucaparib mesylate as defined in any one of the preceding claims, characterized by having a differential scanning calorimetric curve showing an endothermic peak in the range of from 283 to 288°C, when measured at a heating rate of 10 K/min.
4) The crystalline form of rucaparib mesylate as defined in claim 3, wherein the endothermic peak is the sole endothermic peak in the differential scanning calorimetric curve.
5) A composition comprising the crystalline form as defined in any one of the preceding claims and at most 20 weight-%, 10 weight-%, 5 weight-%, 4 weight-%, 3 weight-%, 2 weight-% or 1 weight-% of any other solid-state form of rucaparib mesylate, based on the weight of the composition.
6) The composition according to claim 5, wherein the any other solid-state form of rucaparib mesylate is Form A characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (9.9 ± 0.2)°, (11.7 ± 0.2)°, (12.2 ± 0.2)°, (16.3 ± 0.2)° and (22.5 ± 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.
7) The composition as defined in claim 5 or 6, characterized by having a powder X-ray diffractogram comprising no reflections at 2-Theta angles of (9.9 ± 0.2)°, (11.7 ± 0.2)°, (15.1 ± 0.2)°, (16.3 ± 0.2)° and (19.9 ± 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.
8) Use of the crystalline form of rucaparib mesylate as defined in any one of claims 1 to 4 or the composition as defined in any one of claims 5 to 7 for the preparation of a pharmaceutical composition.
9) A pharmaceutical composition comprising the crystalline form of rucaparib mesylate as defined in any one of claims 1 to 4 or the composition as defined in any one of claims 5 to 7 and at least one pharmaceutically acceptable excipient.
10) The pharmaceutical composition of claim 9, which is an oral dosage form.
11) The pharmaceutical composition of claim 9 or 10 comprising 200 mg, 250 mg or 300 mg of the crystalline form of rucaparib mesylate as defined in any one of claims 1 to 4 or the composition as defined in any one of claims 5 to 7, calculated as rucaparib free base.
12) The crystalline form as defined in any one of claims 1 to 4, the composition as defined in any one of claims 5 to 7 or the pharmaceutical composition as defined in any one of claims 9 to 11 for use as a medicament.
13) The crystalline form as defined in any one of claims 1 to 4, the composition as defined in any one of claims 5 to 7 or the pharmaceutical composition as defined in any one of claims 9 to 11 for use in the treatment and/or prophylaxis of cancer.
14) The use according to claim 13, wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, prostate cancer and pancreatic cancer.
EP21702480.1A 2020-02-03 2021-01-28 Polymorph of rucaparib mesylate Pending EP4100125A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP20155091 2020-02-03
PCT/EP2021/052029 WO2021156140A1 (en) 2020-02-03 2021-01-28 Polymorph of rucaparib mesylate

Publications (1)

Publication Number Publication Date
EP4100125A1 true EP4100125A1 (en) 2022-12-14

Family

ID=69467383

Family Applications (1)

Application Number Title Priority Date Filing Date
EP21702480.1A Pending EP4100125A1 (en) 2020-02-03 2021-01-28 Polymorph of rucaparib mesylate

Country Status (2)

Country Link
EP (1) EP4100125A1 (en)
WO (1) WO2021156140A1 (en)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1140936E (en) 1999-01-11 2004-06-30 Agouron Pharma TRICYLIC POLYMER INHIBITORS (ADP-RIBOSE) POLYMERASES
EP1611137A1 (en) 2003-03-31 2006-01-04 Pfizer Inc. Salts of tricyclic inhibitors of poly(adp-ribose) polymerases
NZ554659A (en) 2004-09-22 2010-08-27 Pfizer Polymorphic and amorphous forms of the phosphate salt of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one
CA3024216C (en) 2010-02-12 2021-03-30 Pfizer Inc. Salts and polymorphs of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6h-azepino[5,4,3-cd]indol-6-one
EP3573990B1 (en) 2017-01-24 2024-07-10 Assia Chemical Industries Ltd. Solid state forms of rucaparib and of rucaparib salts
MX2020004545A (en) 2017-11-03 2020-08-03 Sandoz Ag Crystalline salt of a tricyclic poly(adp-ribose) polymerase inhibitor.

Also Published As

Publication number Publication date
WO2021156140A1 (en) 2021-08-12

Similar Documents

Publication Publication Date Title
EP3808742A1 (en) Polymorph of selinexor
US20220056010A1 (en) Crystalline fumarate salt of (s)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone
US20240010621A1 (en) Crystalline solid forms of salts of n-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-n'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, processes for making, and methods of use
US11603363B2 (en) Crystalline form of LNP023
WO2022189599A1 (en) Crystalline forms of mavacamten for the treatment of hcm
EP3728261B1 (en) Co-crystal of an orally available janus kinase inhibitor
WO2019042641A1 (en) Co-crystal of an orally available hif prolyl hydroxylase inhibitor
EP3997090A1 (en) Crystalline forms of an orally available, selective kit and pdgfr kinase inhibitor
JP2018039807A (en) (s)-4-amino-n-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7h-pyrrolo[2,3-d]-pyrimidine-4-yl)piperidine-4-carboxamide in crystal form
WO2024110853A1 (en) Solid forms of a fused pyridine for the treamtent of cancer
US20240287066A1 (en) Crystalline Form of Sotorasib
JP2018111718A (en) SOLID SALT OF α-6-MPEG6-O-HYDROXYCODONE AS OPIOID AGONISTS AND USES THEREOF
WO2022069357A1 (en) Crystalline form of selpercatinib
KR20180008511A (en) Pharmaceutical composition
EP4100125A1 (en) Polymorph of rucaparib mesylate
US11236066B2 (en) Crystalline forms of niraparib tosylate
WO2021259732A1 (en) Multi-component compounds comprising zanubrutinib and a benzoic acid derivative
EP3887356B1 (en) Multi-component crystals of an orally available hif prolyl hydroxylase inhibitor
WO2019086509A1 (en) Crystalline salt of a tricyclic poly(adp-ribose) polymerase inhibitor
EP4227305A1 (en) Crystalline form of sotorasib
EP3587421A1 (en) Crystalline forms of (s)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-alpha]pyrazin-1-yl-n-(pyridin-2-yl)benzamide
WO2019166385A1 (en) Crystalline form ii of darolutamide
EP3888750A1 (en) Crystalline form of voxelotor
EP4126237B1 (en) Dimaleate form of 1-((2r,4r)-2-(1h-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea
WO2021069571A1 (en) Polymorph of lorlatinib

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20220715

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20230728