CA3080657A1 - Crystalline salt of a tricyclic poly(adp-ribose) polymerase inhibitor - Google Patents
Crystalline salt of a tricyclic poly(adp-ribose) polymerase inhibitor Download PDFInfo
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- CA3080657A1 CA3080657A1 CA3080657A CA3080657A CA3080657A1 CA 3080657 A1 CA3080657 A1 CA 3080657A1 CA 3080657 A CA3080657 A CA 3080657A CA 3080657 A CA3080657 A CA 3080657A CA 3080657 A1 CA3080657 A1 CA 3080657A1
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- Prior art keywords
- rucaparib
- mesylate
- anhydrous crystalline
- crystalline
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- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 title description 5
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 title description 5
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 title description 5
- 229940123066 Polymerase inhibitor Drugs 0.000 title description 2
- 229950004707 rucaparib Drugs 0.000 claims abstract description 137
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- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 2
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- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
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- INBJJAFXHQQSRW-STOWLHSFSA-N rucaparib camsylate Chemical compound CC1(C)[C@@H]2CC[C@@]1(CS(O)(=O)=O)C(=O)C2.CNCc1ccc(cc1)-c1[nH]c2cc(F)cc3C(=O)NCCc1c23 INBJJAFXHQQSRW-STOWLHSFSA-N 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
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- 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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention relates to crystalline rucaparib mesylate salt and to a process for its preparation. Furthermore, the invention relates to a pharmaceutical composition comprising the crystalline rucaparib mesylate salt 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
CRYSTALLINE SALT OF A TRICYCLIC POLY(ADP-RIBOSE) POLYMERASE INHIBITOR
FIELD OF THE INVENTION
The present invention relates to crystalline rucaparib mesylate salt and to a process for its preparation. Furthermore, the invention relates to a pharmaceutical composition comprising the crystalline rucaparib mesylate salt 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-pheny1)- 1,3 ,4,5-tetrahydro-azepino [5,4,3-cd]indol-6-one, rucaparib may be represented by the chemical structure as depicted in formula I:
o F
HN /
/
NH
formula (I) Rucaparib is approved in the USA as a monotherapy for the treatment of patients with the BRCA mutation (germline and/or somatic), the mutation occuring in patients with advanced ovarian cancer who have been previously treated with two or more chemotherapeutic regimens.
The active ingredient in the commercial product (Rubraca ) is the camsylate salt of rucaparib.
FIELD OF THE INVENTION
The present invention relates to crystalline rucaparib mesylate salt and to a process for its preparation. Furthermore, the invention relates to a pharmaceutical composition comprising the crystalline rucaparib mesylate salt 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-pheny1)- 1,3 ,4,5-tetrahydro-azepino [5,4,3-cd]indol-6-one, rucaparib may be represented by the chemical structure as depicted in formula I:
o F
HN /
/
NH
formula (I) Rucaparib is approved in the USA as a monotherapy for the treatment of patients with the BRCA mutation (germline and/or somatic), the mutation occuring in patients with advanced ovarian cancer who have been previously treated with two or more chemotherapeutic regimens.
The active ingredient in the commercial product (Rubraca ) is the camsylate salt of rucaparib.
2 WO 00/42040 Al discloses tricyclic PARP inhibiting agents and pharmaceutically acceptable salts thereof. One of said PARP inhibitors is rucaparib, which was synthesized as the free base with a melting point of 154-155 C in example IIII of said application.
Various salts of rucaparib and different solid state modifications thereof are disclosed in applications WO 2004/087713 Al, WO 2006/033007 A2 and WO 2011/098971 Al.
Various salts of rucaparib and different solid state modifications thereof are disclosed in applications WO 2004/087713 Al, WO 2006/033007 A2 and WO 2011/098971 Al.
3 Al for instance discloses in example A the preparation of the mesylate salt of rucaparib, which was prepared by treating rucaparib free base with methane sulfonic acid in the presence of methanol. 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. The aqueous solubility of the prepared rucaparib mesylate was determined to be 15.5 mg/mL (see table "water solubilities of different salt forms", page 8 of WO 2004/087713 Al).
Different solid form modifications of a compound can possess different physicochemical properties such as but not limited to melting point, physical and chemical stability, hygroscopicity, solubility, flowability, wettability and compressibility. Most drug products are administered as oral solid dosage forms, but not every solid form modification of a compound is suitable for being formulated e.g. as a tablet or capsule, because some have unfavorable physicochemical properties. For example, the rucaparib mesylate salt disclosed in WO
2004/087713 Al has a significant water content and shows only limited water solubility, both properties not being ideal for the formulation of pharmaceutical drug products.
It is thus an objective of the present invention to provide an improved rucaparib mesylate salt form, e.g. a form of rucaparib mesylate which has a low water content, is non-hygroscopic, shows increased aqueous solubility and/or which is chemically and physically stable.
SUMMARY OF THE INVENTION
The invention solves one or more of the above defined problems by providing crystalline rucaparib mesylate in anhydrous form. The crystalline rucaparib mesylate of the present invention possesses one or more improved physicochemical properties selected from solubility, dissolution rate, hygroscopicity, chemical stability, physical stability, morphology, flowability, bulk density and compressibility. In particular, the crystalline rucaparib mesylate of the present invention is non-hygroscopic and physically stable upon moisture contact. In addition, it was found that the crystalline rucaparib mesylate of the present invention shows increased water solubility and requires fewer production steps compared to the mesylate salt disclosed in WO
2004/087713 Al.
Definitions The term "rucaparib" as used herein refers to the compound with the chemical name 8-fluoro-2-(4-methylaminomethyl-pheny1)-1,3,4,5-tetrahydro-azepino[5,4,3-cd] indo1-6-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 20-75% relative humidity, preferably 30-70% relative humidity, more preferably 40-60% relative humidity and most preferably 50% 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.
Thus, a reflection that usually appears at 22.5 2-Theta for example can appear between 22.3 and 22.7 2-Theta on most X-ray diffractometers under standard conditions.
Furthermore, one
The molecular formula provided in example A indicates that the obtained rucaparib mesylate contains about 2 mol equivalents of water per mol rucaparib mesylate. The aqueous solubility of the prepared rucaparib mesylate was determined to be 15.5 mg/mL (see table "water solubilities of different salt forms", page 8 of WO 2004/087713 Al).
Different solid form modifications of a compound can possess different physicochemical properties such as but not limited to melting point, physical and chemical stability, hygroscopicity, solubility, flowability, wettability and compressibility. Most drug products are administered as oral solid dosage forms, but not every solid form modification of a compound is suitable for being formulated e.g. as a tablet or capsule, because some have unfavorable physicochemical properties. For example, the rucaparib mesylate salt disclosed in WO
2004/087713 Al has a significant water content and shows only limited water solubility, both properties not being ideal for the formulation of pharmaceutical drug products.
It is thus an objective of the present invention to provide an improved rucaparib mesylate salt form, e.g. a form of rucaparib mesylate which has a low water content, is non-hygroscopic, shows increased aqueous solubility and/or which is chemically and physically stable.
SUMMARY OF THE INVENTION
The invention solves one or more of the above defined problems by providing crystalline rucaparib mesylate in anhydrous form. The crystalline rucaparib mesylate of the present invention possesses one or more improved physicochemical properties selected from solubility, dissolution rate, hygroscopicity, chemical stability, physical stability, morphology, flowability, bulk density and compressibility. In particular, the crystalline rucaparib mesylate of the present invention is non-hygroscopic and physically stable upon moisture contact. In addition, it was found that the crystalline rucaparib mesylate of the present invention shows increased water solubility and requires fewer production steps compared to the mesylate salt disclosed in WO
2004/087713 Al.
Definitions The term "rucaparib" as used herein refers to the compound with the chemical name 8-fluoro-2-(4-methylaminomethyl-pheny1)-1,3,4,5-tetrahydro-azepino[5,4,3-cd] indo1-6-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 20-75% relative humidity, preferably 30-70% relative humidity, more preferably 40-60% relative humidity and most preferably 50% 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.
Thus, a reflection that usually appears at 22.5 2-Theta for example can appear between 22.3 and 22.7 2-Theta on most X-ray diffractometers under standard conditions.
Furthermore, one
4 skilled in the art will appreciate that relative intensities of the reflections will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.
The crystalline 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.
The term "solid form", "solid form modification" or "physical form" as used herein refers to any crystalline or amorphous phase of a substance.
The terms "anhydrous" or "anhydrate" as used herein refer to a crystalline solid where no water is incorporated 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 weight%, preferably not more than 1.5 weight% and most preferably not more than 1.0 weight% of water, based on the weight of the crystalline form. The water content is to be determined by Karl-Fischer Coulometry of a sample that has been equilibrated with an atmosphere of 25 C and 40% relative humidity.
The term "non-hygroscopic" as used herein refers to a compound which shows a water uptake of at most 2.0 weight-%, preferably of at most 1.5 weight-%, such as at most 1.0 weight %, in the sorption cycle when measured with gravimetric moisture sorption at a relative humidity in the range of from 0 to 90% and a temperature of 25.0 0.1 C, based on the weight of the compound.
The term "non-solvated" as used herein, when talking about a crystalline solid indicates that no organic solvent is incorporated in or accommodated by the crystal structure.
Non-solvated forms may still contain residual organic solvents, which are not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal. Typically, a non-solvated form does not contain more than 1.0 weight%, preferably not more than 0.5 weight%, and most preferably not more than 0.3 weight%, 0.2 weight% or 0.1 weight% of organic solvents, based on the weight of the crystalline form. The organic solvent content can be determined by 1H-NMR.
A "predetermined amount" as used herein with regard to the crystalline rucaparib mesylate of the present invention refers to the initial amount of the crystalline rucaparib mesylate of the
The crystalline 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.
The term "solid form", "solid form modification" or "physical form" as used herein refers to any crystalline or amorphous phase of a substance.
The terms "anhydrous" or "anhydrate" as used herein refer to a crystalline solid where no water is incorporated 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 weight%, preferably not more than 1.5 weight% and most preferably not more than 1.0 weight% of water, based on the weight of the crystalline form. The water content is to be determined by Karl-Fischer Coulometry of a sample that has been equilibrated with an atmosphere of 25 C and 40% relative humidity.
The term "non-hygroscopic" as used herein refers to a compound which shows a water uptake of at most 2.0 weight-%, preferably of at most 1.5 weight-%, such as at most 1.0 weight %, in the sorption cycle when measured with gravimetric moisture sorption at a relative humidity in the range of from 0 to 90% and a temperature of 25.0 0.1 C, based on the weight of the compound.
The term "non-solvated" as used herein, when talking about a crystalline solid indicates that no organic solvent is incorporated in or accommodated by the crystal structure.
Non-solvated forms may still contain residual organic solvents, which are not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal. Typically, a non-solvated form does not contain more than 1.0 weight%, preferably not more than 0.5 weight%, and most preferably not more than 0.3 weight%, 0.2 weight% or 0.1 weight% of organic solvents, based on the weight of the crystalline form. The organic solvent content can be determined by 1H-NMR.
A "predetermined amount" as used herein with regard to the crystalline rucaparib mesylate of the present invention refers to the initial amount of the crystalline rucaparib mesylate of the
5 present invention 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 the crystalline rucaparib mesylate of the present invention encompasses an amount of the crystalline rucaparib mesylate of the present invention, 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 terms "disintegrant" or "disintegrating agent" as used herein refers to substances which, upon addition to a solid pharmaceutical composition, facilitate its break-up or disintegration after administration and permits 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 "effective amount" as used herein with regard to the crystalline rucaparib mesylate of the present invention encompasses an amount of the crystalline rucaparib mesylate of the present invention, 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 terms "disintegrant" or "disintegrating agent" as used herein refers to substances which, upon addition to a solid pharmaceutical composition, facilitate its break-up or disintegration after administration and permits 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.
6 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 of rucaparib mesylate (form A) 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 a representative differential scanning calorimetry curve of the crystalline form of rucaparib mesylate (form A) according to the present invention. The x-axis shows the temperature in degree Celsius ( C), the y-axis shows the heat flow in Joule per gram (J/g) with endothermic peaks going up.
Figure 3: illustrates gravimetric moisture sorption and desorption curves of the crystalline form of rucaparib mesylate (form A) of the present invention. The x-axis shows the relative humidity the y-axis shows the mass change each in percent (%).
Figure 4: illustrates a powder X-ray diffractogram of a composition comprising the crystalline form of rucaparib mesylate (form A) 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.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have surprisingly found that anhydrous crystalline rucaparib mesylate of the present invention posseses advantageous physicochemical properties making it particularly useful for the preparation of a pharmaceutical drug product. While the rucaparib mesylate salt of WO 2004/087713 Al has certain drawbacks associated with its usability for the preparation of solid dosage forms such as significant water content and limited aqueous solubility, the
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 of rucaparib mesylate (form A) 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 a representative differential scanning calorimetry curve of the crystalline form of rucaparib mesylate (form A) according to the present invention. The x-axis shows the temperature in degree Celsius ( C), the y-axis shows the heat flow in Joule per gram (J/g) with endothermic peaks going up.
Figure 3: illustrates gravimetric moisture sorption and desorption curves of the crystalline form of rucaparib mesylate (form A) of the present invention. The x-axis shows the relative humidity the y-axis shows the mass change each in percent (%).
Figure 4: illustrates a powder X-ray diffractogram of a composition comprising the crystalline form of rucaparib mesylate (form A) 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.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have surprisingly found that anhydrous crystalline rucaparib mesylate of the present invention posseses advantageous physicochemical properties making it particularly useful for the preparation of a pharmaceutical drug product. While the rucaparib mesylate salt of WO 2004/087713 Al has certain drawbacks associated with its usability for the preparation of solid dosage forms such as significant water content and limited aqueous solubility, the
7 crystalline meslyate salt form of the present invention, hereinafter also designated as form A, was found to be non-hygroscopic and physically stable upon moisture stress. In addition, it was found that the crystalline rucaparib mesylate of the present invention shows increased water solubility compared to the mesylate salt disclosed in WO 2004/087713 Al. The latter property may not only translate into higher bioavailability for oral drug products but also allow for the preparation of more customized liquid formulations. Besides, the crystalline rucaparib mesylate form of the present invention can be prepared in fewer steps than the mesylate salt of WO
2004/087713 Al. A shorter process, with controlled crystallization conditions, is advantageous for the production of rucaparib mesylate, for example with regard to quality and overall cost.
Different aspects of the invention are described below in further detail by embodiments, without being limited thereto. Each aspect of the invention may be described by one embodiment or by combining two or more of the embodiments.
In a first aspect, the present invention relates to anhydrous crystalline rucaparib mesylate.
More preferably, the anhydrous crystalline rucaparib mesylate of the present invention is characterized by the chemical structure according to formula (II) HN /
/S'CH3 /
NH2+
formula (II).
Preferably, the anhydrous crystalline rucaparib mesylate of the present invention as defined in any one of the embodiments described above 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 and most preferably the molar ratio is about 1.0: 1Ø
2004/087713 Al. A shorter process, with controlled crystallization conditions, is advantageous for the production of rucaparib mesylate, for example with regard to quality and overall cost.
Different aspects of the invention are described below in further detail by embodiments, without being limited thereto. Each aspect of the invention may be described by one embodiment or by combining two or more of the embodiments.
In a first aspect, the present invention relates to anhydrous crystalline rucaparib mesylate.
More preferably, the anhydrous crystalline rucaparib mesylate of the present invention is characterized by the chemical structure according to formula (II) HN /
/S'CH3 /
NH2+
formula (II).
Preferably, the anhydrous crystalline rucaparib mesylate of the present invention as defined in any one of the embodiments described above 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 and most preferably the molar ratio is about 1.0: 1Ø
8 The anhydrous crystalline 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, differential scanning calorimetry, thermogravimetric analysis and gravimetric moisture sorption. It may be characterized by one of the aforementioned analytical methods or by combining two or more of them. In particular, the anhydrous crystalline 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 one embodiment the present invention relates to anhydrous crystalline rucaparib mesylate (form A) characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of:
(9.9 0.2) , (12.2 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (16.3 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (16.3 0.2) , (17.7 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (16.3 0.2) , (17.7 0.2) , (20.7 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (15.0 0.2) , (16.3 0.2) , (17.7 0.2) , (20.7 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (15.0 0.2) , (16.3 0.2) , (17.7 0.2) (19.8 0.2) , (20.7 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (13.9 0.2) , (15.0 0.2) , (16.3 0.2) , (17.7 0.2) (19.8 0.2) , (20.7 0.2) and (22.5 0.2) ;
when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
In another embodiment, the present invention relates to anhydrous crystalline rucaparib mesylate (form A) characterized by having a powder X-ray diffractogram 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-Kalpha radiation having a wavelength of 0.15419 nm.
In a further embodiment, the present invention relates to anhydrous crystalline rucaparib mesylate (form A) characterized by having a differential scanning calorimetry curve showing an endothermic peak, preferably a sole endothermic peak in the range of from 290 to 300 C, preferably from 294 to 297 C, when measured at a heating rate of 10 K/min.
Hence, in one embodiment the present invention relates to anhydrous crystalline rucaparib mesylate (form A) characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of:
(9.9 0.2) , (12.2 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (16.3 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (16.3 0.2) , (17.7 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (16.3 0.2) , (17.7 0.2) , (20.7 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (15.0 0.2) , (16.3 0.2) , (17.7 0.2) , (20.7 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (15.0 0.2) , (16.3 0.2) , (17.7 0.2) (19.8 0.2) , (20.7 0.2) and (22.5 0.2) ;
(9.9 0.2) , (11.7 0.2) , (12.2 0.2) , (13.9 0.2) , (15.0 0.2) , (16.3 0.2) , (17.7 0.2) (19.8 0.2) , (20.7 0.2) and (22.5 0.2) ;
when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
In another embodiment, the present invention relates to anhydrous crystalline rucaparib mesylate (form A) characterized by having a powder X-ray diffractogram 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-Kalpha radiation having a wavelength of 0.15419 nm.
In a further embodiment, the present invention relates to anhydrous crystalline rucaparib mesylate (form A) characterized by having a differential scanning calorimetry curve showing an endothermic peak, preferably a sole endothermic peak in the range of from 290 to 300 C, preferably from 294 to 297 C, when measured at a heating rate of 10 K/min.
9 PCT/EP2018/079815 In yet a further embodiment, the present invention relates to anhydrous crystalline rucaparib mesylate (form A) characterized by having a differential scanning calorimetry curve showing an endothermic peak, preferably a sole endothermic peak with an onset temperature in the range of from 290 to 298 C, preferably of from 292 to 296 C, for example with an onset temperature of about 294 C, when measured at a heating rate of 10 K/min.
In still a further embodiment, the present invention relates to anhydrous crystalline rucaparib mesylate (form A) characterized by having a differential scanning calorimetry curve showing an endothermic peak, preferably a sole endothermic peak with a peak temperature in the range of from 294 to 300 C, preferably of from 296 to 298 C, for example with an onset temperature of about 297 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 rucaparib mesylate (form A) of the present invention.
In another embodiment, the present invention relates to anhydrous crystalline rucaparib mesylate (form A) characterized by having a thermogravimetric analysis curve showing a mass loss of not more than 1.0 weight-%, preferably of not more than 0.8 weight-%, based on the weight of the crystalline form, when measured from 25 to 250 C at a heating rate of 10 K/min.
In a particular preferred embodiment, the present invention relates to anhydrous crystalline rucaparib mesylate as defined in any one of the above described embodiments, which is non-solvated.
In yet another embodiment, the present invention relates to anhydrous non-hygroscopic crystalline rucaparib mesylate (form A), characterized by having a water content of less than 1.0 weight-%, preferably less than 0.9 weight-%, based on the weight of the crystalline form, when measured at 25 C at a relative humidity in the range of from 0 to 90%, preferably of from 1 to 90%, even more preferably of from 10 to 90%.
In another aspect the invention relates to a composition comprising at least 90 weight-%, preferably at least 95 weight-% of the anhydrous crystalline rucaparib mesylate (form A) as defined in any one of the above described embodiments, based on the total weight of the composition.
In a preferred embodiment, the invention relates to a composition comprising at least 90 weight-%, preferably at least 95 weight-% of the anhydrous crystalline rucaparib mesylate (form A) as defined in any one of the above described embodiments characterized by a powder X-ray diffractogram comprising reflections at 2-Theta angles selected from the group consisting of (9.9 0.2) , (12.2 0.2) and/or (22.5 0.2) , when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
It was surprisingly found by the present inventors that the anhydrous crystalline mesylate salt 5 of the present invention possesses advantageous properties compared to the mesylate salt of WO 2004/087713 Al, which render the anhydrous crystalline mesylate salt of the present invention especially suitable for the formulation of safe and efficacious drug products. For example, the anhydrous crystalline meslyate salt of the present invention is non-hygroscopic and shows a reversible water uptake of less than 0.9 weight-% in the range of from 0 to 90%
In still a further embodiment, the present invention relates to anhydrous crystalline rucaparib mesylate (form A) characterized by having a differential scanning calorimetry curve showing an endothermic peak, preferably a sole endothermic peak with a peak temperature in the range of from 294 to 300 C, preferably of from 296 to 298 C, for example with an onset temperature of about 297 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 rucaparib mesylate (form A) of the present invention.
In another embodiment, the present invention relates to anhydrous crystalline rucaparib mesylate (form A) characterized by having a thermogravimetric analysis curve showing a mass loss of not more than 1.0 weight-%, preferably of not more than 0.8 weight-%, based on the weight of the crystalline form, when measured from 25 to 250 C at a heating rate of 10 K/min.
In a particular preferred embodiment, the present invention relates to anhydrous crystalline rucaparib mesylate as defined in any one of the above described embodiments, which is non-solvated.
In yet another embodiment, the present invention relates to anhydrous non-hygroscopic crystalline rucaparib mesylate (form A), characterized by having a water content of less than 1.0 weight-%, preferably less than 0.9 weight-%, based on the weight of the crystalline form, when measured at 25 C at a relative humidity in the range of from 0 to 90%, preferably of from 1 to 90%, even more preferably of from 10 to 90%.
In another aspect the invention relates to a composition comprising at least 90 weight-%, preferably at least 95 weight-% of the anhydrous crystalline rucaparib mesylate (form A) as defined in any one of the above described embodiments, based on the total weight of the composition.
In a preferred embodiment, the invention relates to a composition comprising at least 90 weight-%, preferably at least 95 weight-% of the anhydrous crystalline rucaparib mesylate (form A) as defined in any one of the above described embodiments characterized by a powder X-ray diffractogram comprising reflections at 2-Theta angles selected from the group consisting of (9.9 0.2) , (12.2 0.2) and/or (22.5 0.2) , when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
It was surprisingly found by the present inventors that the anhydrous crystalline mesylate salt 5 of the present invention possesses advantageous properties compared to the mesylate salt of WO 2004/087713 Al, which render the anhydrous crystalline mesylate salt of the present invention especially suitable for the formulation of safe and efficacious drug products. For example, the anhydrous crystalline meslyate salt of the present invention is non-hygroscopic and shows a reversible water uptake of less than 0.9 weight-% in the range of from 0 to 90%
10 relative humidity. The powder X-ray diffractograms before and after gravimetric moisture sorption do not show any significant differences, indicating that the anhydrous crystalline rucaparib mesylate is physically stable under moisture stress. In contrast, the molecular formula of the rucaparib mesylate salt provided in example A of WO 2004/087713 Al indicates that the obtained rucaparib mesylate contains about 2 mol equivalents of water.
In addition, it was found that the anhydrous crystalline rucaparib mesylate of the present invention shows increased water solubility (> 18 g/L, see example 1) compared to the mesylate salt disclosed in WO 2004/087713 Al (15.5 mg/mL, see table "water solubilities of different salt forms", page 8 of WO 2004/087713 Al). The latter property may not only translate into higher bioavailability for oral drug products but also allow for the preparation of more customized liquid formulations.
Also from a process perspective, the anhydrous crystalline rucaparib mesylate of the present invention possesses favorable characteristics over the mesylate salt of WO
2004/087713 Al. It can be prepared by a simple controlled crystallization process from a solvent which is attractive from an economic point of view. In contrast, the process provided in example A
of WO
.. 2004/087713 Al involves a solvent exchange from methanol to water after the salt formation, followed by lyophilization.
Hence, in a further aspect, the invention relates to a process for the preparation of the anhydrous crystalline rucaparib mesylate as defined in any one of the embodiments described above or the composition comprising the same as defined in any one of the embodiments described above comprising:
(i) reacting rucaparib with methane sulfonic acid in the presence of a suitable solvent or solvent mixture;
In addition, it was found that the anhydrous crystalline rucaparib mesylate of the present invention shows increased water solubility (> 18 g/L, see example 1) compared to the mesylate salt disclosed in WO 2004/087713 Al (15.5 mg/mL, see table "water solubilities of different salt forms", page 8 of WO 2004/087713 Al). The latter property may not only translate into higher bioavailability for oral drug products but also allow for the preparation of more customized liquid formulations.
Also from a process perspective, the anhydrous crystalline rucaparib mesylate of the present invention possesses favorable characteristics over the mesylate salt of WO
2004/087713 Al. It can be prepared by a simple controlled crystallization process from a solvent which is attractive from an economic point of view. In contrast, the process provided in example A
of WO
.. 2004/087713 Al involves a solvent exchange from methanol to water after the salt formation, followed by lyophilization.
Hence, in a further aspect, the invention relates to a process for the preparation of the anhydrous crystalline rucaparib mesylate as defined in any one of the embodiments described above or the composition comprising the same as defined in any one of the embodiments described above comprising:
(i) reacting rucaparib with methane sulfonic acid in the presence of a suitable solvent or solvent mixture;
11 (ii) crystallizing rucaparib mesylate from the mixture provided in step (i);
(iii) optionally separating at least a part of the crystals obtained in step (ii) from the mother liquor;
(iv) optionally drying the crystals obtained in any one of previous steps (i) or (ii);
(v) optionally equilibrating the crystals obtained in any one of previous steps (i) to (iii) with an atmosphere having a temperature of 40 C and a relative humidity of 75%.
The rucaparib free base starting material of step (i) above may be prepared according to the process provided in example IIII of WO 00/42040 Al. A suitable solvent or solvent mixture in step (i) of the process for the preparation of the anhydrous crystalline rucaparib mesylate of the present invention is selected from acetone, tetrahydrofuran or a mixture thereof. Rucaparib is treated with methane sulfonic acid in the presence of a suitable solvent or solvent mixture, wherein the molar ratio of rucaparib and methanesulfonic acid applied is preferably in the range of from about 1.0 (rucaparib): 0.8 to 1.2 (methanesulfonic acid), more preferably from about 1.0 (rucaparib): 0.9 to 1.1 (methanesulfonic acid) and most preferably from about 1.0 (rucaparib): 0.95 to 1.05 (methanesulfonic acid) e.g. the molar ratio is about 1.0 to 1Ø
The reaction is preferably carried out at a temperature in the range of from about 0 to 60 C.
For example, as a first step the reaction mixture in step (i) above may be heated to a temperature in the range of from about 40 to 60 C in order to promote dissolution of solid components followed by cooling the mixture in step (ii) above to a temperature in the range of from 0 to 25 C in order to initiate crystallization of rucaparib mesylate. The final rucaparib mesylate concentration of the mixture is preferably in the range of from about 20 to 80 g/L, more preferably from about 40 to 60 g/L.
The mixture obtained in step (ii), may further be slurried, wherein slurrying in the context of the present invention relates to any motion of the mixture comprising rucaparib mesylate, which is caused by stirring, shaking and/or ultrasonic irradiation. Slurrying may be performed for a period in the range of from about 0.5 to 48 hours, preferably from about 1 to 24 hours, more preferably from about 2 to 12 hours. The mixture may instead be allowed to stand without slurrying for a period in the range of from several hours to several days.
The obtained rucaparib mesylate crystals or at least a part thereof may optionally be separated from the mother liquor by any conventional method such as filtration or centrifugation, most
(iii) optionally separating at least a part of the crystals obtained in step (ii) from the mother liquor;
(iv) optionally drying the crystals obtained in any one of previous steps (i) or (ii);
(v) optionally equilibrating the crystals obtained in any one of previous steps (i) to (iii) with an atmosphere having a temperature of 40 C and a relative humidity of 75%.
The rucaparib free base starting material of step (i) above may be prepared according to the process provided in example IIII of WO 00/42040 Al. A suitable solvent or solvent mixture in step (i) of the process for the preparation of the anhydrous crystalline rucaparib mesylate of the present invention is selected from acetone, tetrahydrofuran or a mixture thereof. Rucaparib is treated with methane sulfonic acid in the presence of a suitable solvent or solvent mixture, wherein the molar ratio of rucaparib and methanesulfonic acid applied is preferably in the range of from about 1.0 (rucaparib): 0.8 to 1.2 (methanesulfonic acid), more preferably from about 1.0 (rucaparib): 0.9 to 1.1 (methanesulfonic acid) and most preferably from about 1.0 (rucaparib): 0.95 to 1.05 (methanesulfonic acid) e.g. the molar ratio is about 1.0 to 1Ø
The reaction is preferably carried out at a temperature in the range of from about 0 to 60 C.
For example, as a first step the reaction mixture in step (i) above may be heated to a temperature in the range of from about 40 to 60 C in order to promote dissolution of solid components followed by cooling the mixture in step (ii) above to a temperature in the range of from 0 to 25 C in order to initiate crystallization of rucaparib mesylate. The final rucaparib mesylate concentration of the mixture is preferably in the range of from about 20 to 80 g/L, more preferably from about 40 to 60 g/L.
The mixture obtained in step (ii), may further be slurried, wherein slurrying in the context of the present invention relates to any motion of the mixture comprising rucaparib mesylate, which is caused by stirring, shaking and/or ultrasonic irradiation. Slurrying may be performed for a period in the range of from about 0.5 to 48 hours, preferably from about 1 to 24 hours, more preferably from about 2 to 12 hours. The mixture may instead be allowed to stand without slurrying for a period in the range of from several hours to several days.
The obtained rucaparib mesylate crystals or at least a part thereof may optionally be separated from the mother liquor by any conventional method such as filtration or centrifugation, most
12 preferably by filtration. Optionally, the isolated crystals may be washed with a solvent, preferably with the same solvent or solvent mixture as used in step (i).
Finally, the rucaparib mesylate crystals may optionally be dried at a temperature of about 60 C or less, preferably of about 50 C or less, more preferably of about 40 C
or less, for example at about 40 C or at about room temperature. Drying may be performed for a period in the range of from about 1 to 72 hours, preferably from about 2 to 48 hours, more preferably from about 4 to 24 hours and most preferably 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.
Preferably, the rucaparib mesylate crystals are further equilibrated with an atmosphere having a relative humidity of about 75% and a temperature of about 40 C. This treatment helps to mature the crystalline material, yielding the highly crystalline rucaparib mesylate form A of example 1.
In another aspect, the invention relates to the use of the crystalline rucaparib mesylate as defined in any one of the embodiments described above for the preparation of a pharmaceutical composition.
In a further aspect the invention relates to a pharmaceutical composition comprising the crystalline rucaparib mesylate as defined in any one of the embodiments described above or the composition comprising the same as defined in anyone of the embodiments described above, 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, diluents, binders, disentegrants, lubricants and glidants.
Finally, the rucaparib mesylate crystals may optionally be dried at a temperature of about 60 C or less, preferably of about 50 C or less, more preferably of about 40 C
or less, for example at about 40 C or at about room temperature. Drying may be performed for a period in the range of from about 1 to 72 hours, preferably from about 2 to 48 hours, more preferably from about 4 to 24 hours and most preferably 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.
Preferably, the rucaparib mesylate crystals are further equilibrated with an atmosphere having a relative humidity of about 75% and a temperature of about 40 C. This treatment helps to mature the crystalline material, yielding the highly crystalline rucaparib mesylate form A of example 1.
In another aspect, the invention relates to the use of the crystalline rucaparib mesylate as defined in any one of the embodiments described above for the preparation of a pharmaceutical composition.
In a further aspect the invention relates to a pharmaceutical composition comprising the crystalline rucaparib mesylate as defined in any one of the embodiments described above or the composition comprising the same as defined in anyone of the embodiments described above, 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, diluents, binders, disentegrants, lubricants and glidants.
13 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.
A preferred film-coated tablet of the present invention invention consists of a tablet core comprising the crystalline rucaparib mesylate as defined in any one of the embodiments described above or the composition comprising the same as defined in anyone of the embodiments described above, 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 embodiments described above, wherein the predetermined and/or effective amount of the crystalline 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.
More preferably, the pharmaceutical composition as defined in any one of the embodiments described above is administered twice daily such that a daily dose of 100 to 1200 mg, preferably of 300 to 600 mg, for example of 300 mg, 400 mg, 500 mg or 600 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 embodiments described above, 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 pharmaceutical composition as defined above for use as a medicament.
In still another aspect, the invention relates to the pharmaceutical composition as defined above for the treatment of cancer. 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 pharmaceutical compostion as defined above for the treatment of solid tumours.
A preferred film-coated tablet of the present invention invention consists of a tablet core comprising the crystalline rucaparib mesylate as defined in any one of the embodiments described above or the composition comprising the same as defined in anyone of the embodiments described above, 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 embodiments described above, wherein the predetermined and/or effective amount of the crystalline 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.
More preferably, the pharmaceutical composition as defined in any one of the embodiments described above is administered twice daily such that a daily dose of 100 to 1200 mg, preferably of 300 to 600 mg, for example of 300 mg, 400 mg, 500 mg or 600 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 embodiments described above, 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 pharmaceutical composition as defined above for use as a medicament.
In still another aspect, the invention relates to the pharmaceutical composition as defined above for the treatment of cancer. 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 pharmaceutical compostion as defined above for the treatment of solid tumours.
14 The present invention is further illustrated by the following embodiments and combinations of embodiments resulting from the given dependencies and back-references:
1) Anhydrous crystalline 8-fluoro-2-(4-methylaminomethyl-pheny1)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indo1-6-one mesylate (rucaparib mesylate).
2) The crystalline rucaparib mesylate of item 1, characterized by the chemical structure according to formula (II) HN /
/
NH2+
formula (II).
3) The anhydrous crystalline rucaparib mesylate according to any one of items 1 or 2, wherein the water content is at most 1.5 weight-%, the water content being determined according to Karl Fischer Coulometry.
4) The anhydrous crystalline rucaparib mesylate according to any one of items 1 or 2, wherein the water content is at most 1.0 weight-%, the water content being determined according to Karl Fischer Coulometry.
5) The anhydrous crystalline rucaparib mesylate according to any one of items 1, 2, 3 or 4, wherein the anhydrous crystalline rucaparib mesylate takes up at most 2.0 weight %
water between 10% relative humidity and 90% relative humidity at 25 C.
6) The anhydrous crystalline rucaparib mesylate according to any one of items 1, 2, 3 or 4, wherein the anhydrous crystalline rucaparib mesylate takes up at most 1.5 weight %
water between 10% relative humidity and 90% relative humidity at 25 C.
7) The anhydrous crystalline rucaparib mesylate according to any one of items 1, 2, 3 or 4, wherein the anhydrous crystalline rucaparib mesylate takes up at most 1.0 weight %
water between 10% relative humidity and 90% relative humidity at 25 C.
8) The anhydrous crystalline rucaparib mesylate according to any one of items 1 to 7, 5 characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (9.9 0.2) , (12.2 0.2) and (22.5 0.2) , when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
9) The anhydrous crystalline rucaparib mesylate according to item 8, characterized by 10 having a powder X-ray diffractogram comprising further 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-Kalpha radiation having a wavelength of 0.15419 nm.
10) The anhydrous crystalline rucaparib mesylate according to any one of items 1 to 7, characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta
1) Anhydrous crystalline 8-fluoro-2-(4-methylaminomethyl-pheny1)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indo1-6-one mesylate (rucaparib mesylate).
2) The crystalline rucaparib mesylate of item 1, characterized by the chemical structure according to formula (II) HN /
/
NH2+
formula (II).
3) The anhydrous crystalline rucaparib mesylate according to any one of items 1 or 2, wherein the water content is at most 1.5 weight-%, the water content being determined according to Karl Fischer Coulometry.
4) The anhydrous crystalline rucaparib mesylate according to any one of items 1 or 2, wherein the water content is at most 1.0 weight-%, the water content being determined according to Karl Fischer Coulometry.
5) The anhydrous crystalline rucaparib mesylate according to any one of items 1, 2, 3 or 4, wherein the anhydrous crystalline rucaparib mesylate takes up at most 2.0 weight %
water between 10% relative humidity and 90% relative humidity at 25 C.
6) The anhydrous crystalline rucaparib mesylate according to any one of items 1, 2, 3 or 4, wherein the anhydrous crystalline rucaparib mesylate takes up at most 1.5 weight %
water between 10% relative humidity and 90% relative humidity at 25 C.
7) The anhydrous crystalline rucaparib mesylate according to any one of items 1, 2, 3 or 4, wherein the anhydrous crystalline rucaparib mesylate takes up at most 1.0 weight %
water between 10% relative humidity and 90% relative humidity at 25 C.
8) The anhydrous crystalline rucaparib mesylate according to any one of items 1 to 7, 5 characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (9.9 0.2) , (12.2 0.2) and (22.5 0.2) , when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
9) The anhydrous crystalline rucaparib mesylate according to item 8, characterized by 10 having a powder X-ray diffractogram comprising further 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-Kalpha radiation having a wavelength of 0.15419 nm.
10) The anhydrous crystalline rucaparib mesylate according to any one of items 1 to 7, characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta
15 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-Kalpha radiation having a wavelength of 0.15419 nm.
11) The anhydrous crystalline rucaparib mesylate according to any one of items 1 to 7, 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) , (17.7 0.2) and (22.5 0.2) , when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
12) The anhydrous crystalline rucaparib mesylate according to any one of items 1 to 7, 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) , (17.7 0.2) , (20.7 0.2) and (22.5 0.2) , when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
13) The anhydrous crystalline rucaparib mesylate according to any one of items 1 to 7, 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) , (15.0 0.2) , (16.3 0.2) , (17.7 0.2) , (20.7 0.2) and (22.5 0.2) , when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
11) The anhydrous crystalline rucaparib mesylate according to any one of items 1 to 7, 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) , (17.7 0.2) and (22.5 0.2) , when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
12) The anhydrous crystalline rucaparib mesylate according to any one of items 1 to 7, 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) , (17.7 0.2) , (20.7 0.2) and (22.5 0.2) , when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
13) The anhydrous crystalline rucaparib mesylate according to any one of items 1 to 7, 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) , (15.0 0.2) , (16.3 0.2) , (17.7 0.2) , (20.7 0.2) and (22.5 0.2) , when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
16 14) The anhydrous crystalline rucaparib mesylate according to any one of items 1 to 7, 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) , (15.0 0.2) , (16.3 0.2) , (17.7 0.2) (19.8 0.2) , (20.7 0.2) and (22.5 0.2) , when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
15) The anhydrous crystalline rucaparib mesylate according to any one of items 1 to 7, 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) , (13.9 0.2) , (15.0 0.2) , (16.3 0.2) , (17.7 0.2) (19.8 0.2) , (20.7 0.2) and (22.5 0.2) , when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
16) The anhydrous crystalline rucaparib mesylate as defined in any one of items 1 to 15, characterized by having a powder X-ray diffractogram comprising no reflections at 2-Theta angles of (12.7 0.2) and/or (24.6 0.2) , when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
15) The anhydrous crystalline rucaparib mesylate according to any one of items 1 to 7, 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) , (13.9 0.2) , (15.0 0.2) , (16.3 0.2) , (17.7 0.2) (19.8 0.2) , (20.7 0.2) and (22.5 0.2) , when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
16) The anhydrous crystalline rucaparib mesylate as defined in any one of items 1 to 15, characterized by having a powder X-ray diffractogram comprising no reflections at 2-Theta angles of (12.7 0.2) and/or (24.6 0.2) , when measured at a temperature in the range of from 20 to 30 C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
17) The anhydrous crystalline rucaparib mesylate as defined in any one of items 1 to 16, characterized by having a differential scanning calorimetric curve showing an endothermic peak in the range of from 290 to 300 C, when measured at a heating rate of 10 K/min.
18) A composition comprising at least 90 weight-% of the anhydrous crystalline rucaparib mesylate as defined in anyone of items 1 to 17, based on the total weight of the composition.
19) The composition of item 18 characterized by a powder X-ray diffractogram comprising reflections at 2-Theta angles selected from the group consisting of (9.9 0.2) , (12.2 0.2) and/or (22.5 0.2) , when measured at a temperature in the range of from 20 to C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
20) Use of the anhydrous crystalline rucaparib mesylate as defined in any one of items 1 to or the composition as defined in item 18 or 19 for the preparation of a pharmaceutical composition.
21) A pharmaceutical composition comprising the anhydrous crystalline rucaparib mesylate as defined in any one of items 1 to 17 or the composition as defined in items 18 or 19 and one or more pharmaceutically acceptable excipient(s).
22) The pharmaceutical composition as defined in item 21 for use as a medicament.
23) The pharmaceutical composition as defined in item 22 for use in the treatment of cancer.
24) The use according to item 23, wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, prostate cancer and pancreatic cancer.
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.
Comparative example: production of rucaparib mesylate according to example A
of 293 mg (0.91 mmol) of rucaparib base were suspended in 6 mL methanol. The addition of 0.91mL methanesulfonic acid (1M, methanol, 0.91 mmol) resulted in a clear yellow solution.
An additional amount of 11 mL methanol was added and the solution was then concentrated using a Rotavapor under reduced pressure. The appearance of a solid salt was observed, but the solid dissolved after the addition of 1.2 mL of water. The remaining methanol was evaporated (Rotavapor, reduced pressure) and the aqueous solution was frozen at -20 C.
The lyophilization (0.12 mbar) of this sample resulted in a crystalline yellow solid (yield: 380 mg). TGA showed a mass loss of 4.2% from room temperature to 175 C and Karl-Fischer titration indicated a water content of 4.9 +/- 0.3%. Thus, our reproduction of example A of produced a crystalline hydrate of rucaparib mesylate. Its powder X-ray diffractogram was clearly different from rucaparib mesylate form A of the present invention.
Example 1: composition comprising rucaparib mesylate form A
A vial was charged with rucaparib free base (60 mg, e.g. prepared according to the procedure disclosed in example IIII of WO 00/42040 Al), acetone (1.2 mL) and methane sulfonic acid (1.1 mol equivalents, 1M in THF). The reaction mixture was warmed to 50 C and subsequently cooled to 5 C at a cooling rate of -0.5 K/min. The reaction mixture was left for 10 days at 5 C before the solid material was isolated and dried.
Powder X-ray diffractometry The powder X-ray diffractogram was collected using the same instrument and settings as described in example 2 below.
A powder X-ray diffractogram of the obtained composition comprising rucaparib mesylate form A of the present invention is displayed in figure 4 herein and the corresponding reflection list is provided in table 1 below. Additional reflections, which appear in the composition obtained from example 1 compared to the crystalline form of rucaparib mesylate (form A) of example 2 are highlighted in bold print.
Angle Angle Angle [ 0.2 2-Theta] [ 0.2 2-Theta] [ 0.2 2-Theta]
7.8 17.7 24.6 9.9 18.4 25.2 11.7 18.7 25.3 12.2 19.1 25.6 12.7 19.3 26.4 13.7 19.9 26.9 13.9 20.8 27.2 14.3 21.4 28.1 15.1 22.3 28.9 16.3 22.6 30.0 16.9 23.0 17.4 23.5 Table 1: Reflection list of the composition obtained from example 1 between 2.0 and 32.0 2-Theta;
additional reflections, compared to the crystalline form of rucaparib mesylate (form A) are highlighted in bold print Gravimetric moisture sorption The gravimetric moisture sorption/desorption experiment was performed using the same instrument and settings as described in example 2. It was observed that some peaks in the powder x-ray diffractogram had changed upon exposure to moisture.
Example 2: crystalline rucaparib mesylate form A
The composition comprising crystalline rucaparib mesylate form A obtained from example 1 above was stored open in a climate chamber at a temperature of 40 C and a relative humidity of 75% for 7 days. Phase pure crystalline rucaparib mesylate form A was obtained quantitatively.
Powder X-ray diffractometry The powder X-ray diffractogram was collected on a Panalytical Empyrean diffractometer, using Cu Kalpha radiation (45 kV, 40 mA) having a wavelength of 0.15419 nm, in transmission geometry. A 0.5 slit, 4 mm mask and 0.04 rad Soller slits with a focusing mirror were used on the incident beam side. A Pixcel31 detector, placed on the diffracted beam side, was fitted with a receiving slit and 0.04 rad Soller slit. The software used for data collection was X'Pert Data Collector using X'Pert Operator Interface. The sample was prepared and analysed in a metal well-plate in transmission mode. X-ray transparent film was used between the metal sheets on the metal well-plate, and the powder (approximately 1 ¨ 2 mg) was used as received. The scan mode for the metal plate used the gonio scan axis. The details for the standard screening data collection method are:
= angular range: 2.5 to 32.0 2-Theta = step size: 0.0130 2-Theta = collection time: 12.75 s/step (total collection time 2.07 min) A typical precision of the 2-Theta values is in the range of 0.2 2-Theta.
Thus, the reflection of the rucaparib mesylate form A of the present invention that appears for example at 22.6 2-Theta can appear between 22.4 and 22.8 2-Theta on most X-ray diffractometers under .. standard conditions.
A representative powder X-ray diffractogram of the rucaparib mesylate form A
of the present invention is displayed in figure 1 herein and the corresponding reflection list is provided in table 2 below.
Angle Angle Angle [ 0.2 2-Theta] [ 0.2 2-Theta] [ 0.2 2-Theta]
9.9 18.6 25.1 11.7 19.0 25.3 12.2 19.2 25.5 13.9 19.8 26.3 14.3 20.7 26.9 15.0 21.4 27.1 16.3 22.2 28.0 17.3 22.5 28.8 17.7 23.0 29.9 18.3 23.4 Table 2: Reflection list of rucaparib mesylate form A of the present invention obtained from example 2 between 2.0 and 32.0 2-Theta Differential scanning calorimetry 5 Differential scanning calorimetry was performed with a TA Instruments Discovery DSC
equipped with a 50 position auto-sampler. A defined amount of sample (in the range of form 0.5-3.0 mg) was weighed into a pin-holed aluminium pan, and heated at 10 K/min from 25 to 350 C. A purge of dry nitrogen at 50 mL/min was maintained over the sample.
The instrument control software was TRIOS and the data were analysed using TRIOS or Universal Analysis.
10 The differential scanning calorimetric curve shows no thermal event until an endothermic peak having an onset temperature of about 294 C and a peak temperature of about 297 C occurs, which is due to the melting of the sample. A representative differential scanning calorimetric curve of rucaparib mesylate form A of the present invention is displayed in figure 2 herein.
Thermogravimetric analysis 15 Data were collected on a TA Instruments Discovery TGA, equipped with a
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.
Comparative example: production of rucaparib mesylate according to example A
of 293 mg (0.91 mmol) of rucaparib base were suspended in 6 mL methanol. The addition of 0.91mL methanesulfonic acid (1M, methanol, 0.91 mmol) resulted in a clear yellow solution.
An additional amount of 11 mL methanol was added and the solution was then concentrated using a Rotavapor under reduced pressure. The appearance of a solid salt was observed, but the solid dissolved after the addition of 1.2 mL of water. The remaining methanol was evaporated (Rotavapor, reduced pressure) and the aqueous solution was frozen at -20 C.
The lyophilization (0.12 mbar) of this sample resulted in a crystalline yellow solid (yield: 380 mg). TGA showed a mass loss of 4.2% from room temperature to 175 C and Karl-Fischer titration indicated a water content of 4.9 +/- 0.3%. Thus, our reproduction of example A of produced a crystalline hydrate of rucaparib mesylate. Its powder X-ray diffractogram was clearly different from rucaparib mesylate form A of the present invention.
Example 1: composition comprising rucaparib mesylate form A
A vial was charged with rucaparib free base (60 mg, e.g. prepared according to the procedure disclosed in example IIII of WO 00/42040 Al), acetone (1.2 mL) and methane sulfonic acid (1.1 mol equivalents, 1M in THF). The reaction mixture was warmed to 50 C and subsequently cooled to 5 C at a cooling rate of -0.5 K/min. The reaction mixture was left for 10 days at 5 C before the solid material was isolated and dried.
Powder X-ray diffractometry The powder X-ray diffractogram was collected using the same instrument and settings as described in example 2 below.
A powder X-ray diffractogram of the obtained composition comprising rucaparib mesylate form A of the present invention is displayed in figure 4 herein and the corresponding reflection list is provided in table 1 below. Additional reflections, which appear in the composition obtained from example 1 compared to the crystalline form of rucaparib mesylate (form A) of example 2 are highlighted in bold print.
Angle Angle Angle [ 0.2 2-Theta] [ 0.2 2-Theta] [ 0.2 2-Theta]
7.8 17.7 24.6 9.9 18.4 25.2 11.7 18.7 25.3 12.2 19.1 25.6 12.7 19.3 26.4 13.7 19.9 26.9 13.9 20.8 27.2 14.3 21.4 28.1 15.1 22.3 28.9 16.3 22.6 30.0 16.9 23.0 17.4 23.5 Table 1: Reflection list of the composition obtained from example 1 between 2.0 and 32.0 2-Theta;
additional reflections, compared to the crystalline form of rucaparib mesylate (form A) are highlighted in bold print Gravimetric moisture sorption The gravimetric moisture sorption/desorption experiment was performed using the same instrument and settings as described in example 2. It was observed that some peaks in the powder x-ray diffractogram had changed upon exposure to moisture.
Example 2: crystalline rucaparib mesylate form A
The composition comprising crystalline rucaparib mesylate form A obtained from example 1 above was stored open in a climate chamber at a temperature of 40 C and a relative humidity of 75% for 7 days. Phase pure crystalline rucaparib mesylate form A was obtained quantitatively.
Powder X-ray diffractometry The powder X-ray diffractogram was collected on a Panalytical Empyrean diffractometer, using Cu Kalpha radiation (45 kV, 40 mA) having a wavelength of 0.15419 nm, in transmission geometry. A 0.5 slit, 4 mm mask and 0.04 rad Soller slits with a focusing mirror were used on the incident beam side. A Pixcel31 detector, placed on the diffracted beam side, was fitted with a receiving slit and 0.04 rad Soller slit. The software used for data collection was X'Pert Data Collector using X'Pert Operator Interface. The sample was prepared and analysed in a metal well-plate in transmission mode. X-ray transparent film was used between the metal sheets on the metal well-plate, and the powder (approximately 1 ¨ 2 mg) was used as received. The scan mode for the metal plate used the gonio scan axis. The details for the standard screening data collection method are:
= angular range: 2.5 to 32.0 2-Theta = step size: 0.0130 2-Theta = collection time: 12.75 s/step (total collection time 2.07 min) A typical precision of the 2-Theta values is in the range of 0.2 2-Theta.
Thus, the reflection of the rucaparib mesylate form A of the present invention that appears for example at 22.6 2-Theta can appear between 22.4 and 22.8 2-Theta on most X-ray diffractometers under .. standard conditions.
A representative powder X-ray diffractogram of the rucaparib mesylate form A
of the present invention is displayed in figure 1 herein and the corresponding reflection list is provided in table 2 below.
Angle Angle Angle [ 0.2 2-Theta] [ 0.2 2-Theta] [ 0.2 2-Theta]
9.9 18.6 25.1 11.7 19.0 25.3 12.2 19.2 25.5 13.9 19.8 26.3 14.3 20.7 26.9 15.0 21.4 27.1 16.3 22.2 28.0 17.3 22.5 28.8 17.7 23.0 29.9 18.3 23.4 Table 2: Reflection list of rucaparib mesylate form A of the present invention obtained from example 2 between 2.0 and 32.0 2-Theta Differential scanning calorimetry 5 Differential scanning calorimetry was performed with a TA Instruments Discovery DSC
equipped with a 50 position auto-sampler. A defined amount of sample (in the range of form 0.5-3.0 mg) was weighed into a pin-holed aluminium pan, and heated at 10 K/min from 25 to 350 C. A purge of dry nitrogen at 50 mL/min was maintained over the sample.
The instrument control software was TRIOS and the data were analysed using TRIOS or Universal Analysis.
10 The differential scanning calorimetric curve shows no thermal event until an endothermic peak having an onset temperature of about 294 C and a peak temperature of about 297 C occurs, which is due to the melting of the sample. A representative differential scanning calorimetric curve of rucaparib mesylate form A of the present invention is displayed in figure 2 herein.
Thermogravimetric analysis 15 Data were collected on a TA Instruments Discovery TGA, equipped with a
25 position auto-sampler. An accurately weighed amount of sample (5-10 mg) was loaded onto a pre-tared aluminium pan and heated at 10 K/min from 25 to 350 C. A nitrogen purge (25 mL/min) was maintained over the sample.
The crystalline form of rucaparib mesylate (form A) of the present invention showed a mass loss of only about 0.8 weight%, based on the initial weight of the sample up to a temperature of 250 C indicating the presence of an anhydrous and solvent free form.
Gravimetric moisture sorption The gravimetric moisture sorption/desorption experiment was performed on a SMS
DVS
Intrinsic moisture sorption analyser, controlled by DVS Intrinsic Control software. The sample temperature was maintained at 25 C by the instrument controls. The humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 200 mL/min. The relative humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0 -100% relative humidity), located near the sample. The weight change, (mass relaxation) of the sample as a function of % relative humidity was constantly monitored by a microbalance (accuracy 0.005 mg). 5-30 mg sample was placed in a tared mesh stainless steel basket under ambient conditions. The sample was loaded and unloaded at 40% relative humidity and 25 C. A
moisture sorption isotherm was performed as outlined below (2 scans per complete cycle). The standard isotherm was performed at 25 C at 10% relative humidity intervals over a 0-90%
relative humidity range. A double cycle (4 scans) was carried out with the parameters listed below. Data analysis was carried out within Microsoft Excel using the DVS
Analysis Suite.
adsorption ¨ scan 1: 40 ¨ 90 desorption, adsorption ¨ scan 2: 90 ¨ 0, 0 ¨ 40 intervals (% relative humidity): 10 number of scans: 4 flow rate (mL/min): 200 temperature ( C): 25 stability ( C/min): 0.2 sorption time (hours): 6-hour time out The corresponding gravimetric moisture sorption/desorption curves are presented in figure 3 herein. The powder X-ray diffractograms of the sample before and after the measurement showed good consistency. The absence of a significant hysteresis between the sorption and desorption curves also indicates that no significant structural changes occurred during the experiment. The reversible water uptake in the range of from 0 to 90% relative humidity was below 0.9 weight-%, indicating that almost no interaction with water vapor took place.
Crystalline rucaparib mesylate form A of the present invention can therefore be classified as non-hygroscopic.
Aqueous solubility The aqueous solubility was determined by suspending sufficient amount of rucaparib mesylate form A in water to give a maximum final concentration of? 18 mg/mL based on the amount of dissolved rucaparib free form. The suspension was equilibrated at 25 C on a Heidolph plate shaker set to 750 rpm for 24 hours. The pH of the saturated solution was then measured and the suspension filtered through a glass fibre C filter (particle retention 1.2 micrometer) and diluted appropriately. Quantitation was done by HPLC with reference to a standard solution of approximately 0.15 mg/mL in DMSO. Different volumes of the standard, diluted and undiluted sample solutions were injected. The solubility was calculated using the peak areas determined by integration of the peak found at the same retention time as the principal peak in the standard injection. The following HPLC method was used:
Type of method reverse phase with gradient elution Phenomenex Luna, C18 (2) 5 micrometer 50 column x mm column temperature ( C) 25 standard injections (microliter) 1, 2, 3, 4, 5, 7 test injections (microliter) 1, 2, 3, 10 ,15 , 20 detection: wavelength, bandwidth (nm) 260, 90 flow rate (mL/min 2 phase A 0.1% trifluoroacetic acid in water phase B 0.085% trifluoroacetic acid in acetonitrile timetable time (min) % phase A % phase B
0.0 95 5 1.0 80 20 2.3 5 95 3.3 5 95 3.5 95 5 4.4 95 5 The aqueous solubility of the crystalline rucaparib mesylate form A of the present invention was determined to be > 18 mg/mL (pH 3.6).
The crystalline form of rucaparib mesylate (form A) of the present invention showed a mass loss of only about 0.8 weight%, based on the initial weight of the sample up to a temperature of 250 C indicating the presence of an anhydrous and solvent free form.
Gravimetric moisture sorption The gravimetric moisture sorption/desorption experiment was performed on a SMS
DVS
Intrinsic moisture sorption analyser, controlled by DVS Intrinsic Control software. The sample temperature was maintained at 25 C by the instrument controls. The humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 200 mL/min. The relative humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0 -100% relative humidity), located near the sample. The weight change, (mass relaxation) of the sample as a function of % relative humidity was constantly monitored by a microbalance (accuracy 0.005 mg). 5-30 mg sample was placed in a tared mesh stainless steel basket under ambient conditions. The sample was loaded and unloaded at 40% relative humidity and 25 C. A
moisture sorption isotherm was performed as outlined below (2 scans per complete cycle). The standard isotherm was performed at 25 C at 10% relative humidity intervals over a 0-90%
relative humidity range. A double cycle (4 scans) was carried out with the parameters listed below. Data analysis was carried out within Microsoft Excel using the DVS
Analysis Suite.
adsorption ¨ scan 1: 40 ¨ 90 desorption, adsorption ¨ scan 2: 90 ¨ 0, 0 ¨ 40 intervals (% relative humidity): 10 number of scans: 4 flow rate (mL/min): 200 temperature ( C): 25 stability ( C/min): 0.2 sorption time (hours): 6-hour time out The corresponding gravimetric moisture sorption/desorption curves are presented in figure 3 herein. The powder X-ray diffractograms of the sample before and after the measurement showed good consistency. The absence of a significant hysteresis between the sorption and desorption curves also indicates that no significant structural changes occurred during the experiment. The reversible water uptake in the range of from 0 to 90% relative humidity was below 0.9 weight-%, indicating that almost no interaction with water vapor took place.
Crystalline rucaparib mesylate form A of the present invention can therefore be classified as non-hygroscopic.
Aqueous solubility The aqueous solubility was determined by suspending sufficient amount of rucaparib mesylate form A in water to give a maximum final concentration of? 18 mg/mL based on the amount of dissolved rucaparib free form. The suspension was equilibrated at 25 C on a Heidolph plate shaker set to 750 rpm for 24 hours. The pH of the saturated solution was then measured and the suspension filtered through a glass fibre C filter (particle retention 1.2 micrometer) and diluted appropriately. Quantitation was done by HPLC with reference to a standard solution of approximately 0.15 mg/mL in DMSO. Different volumes of the standard, diluted and undiluted sample solutions were injected. The solubility was calculated using the peak areas determined by integration of the peak found at the same retention time as the principal peak in the standard injection. The following HPLC method was used:
Type of method reverse phase with gradient elution Phenomenex Luna, C18 (2) 5 micrometer 50 column x mm column temperature ( C) 25 standard injections (microliter) 1, 2, 3, 4, 5, 7 test injections (microliter) 1, 2, 3, 10 ,15 , 20 detection: wavelength, bandwidth (nm) 260, 90 flow rate (mL/min 2 phase A 0.1% trifluoroacetic acid in water phase B 0.085% trifluoroacetic acid in acetonitrile timetable time (min) % phase A % phase B
0.0 95 5 1.0 80 20 2.3 5 95 3.3 5 95 3.5 95 5 4.4 95 5 The aqueous solubility of the crystalline rucaparib mesylate form A of the present invention was determined to be > 18 mg/mL (pH 3.6).
Claims (15)
1) Anhydrous crystalline 8-fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one mesylate (rucaparib mesylate).
2) The anhydrous crystalline rucaparib mesylate of claim 1, characterized by the chemical structure according to formula (II)
3) The anhydrous crystalline rucaparib mesylate according to any one of claims 1 or 2, wherein the water content is at most 1.5 weight %, the water content being determined according to Karl Fischer Coulometry.
4) The anhydrous crystalline rucaparib mesylate according to any one of the claims 1 to 3, wherein the anhydrous crystalline rucaparib mesylate takes up at most 0.9 weight %
water between 10% relative humidity and 90% relative humidity at 25°C.
water between 10% relative humidity and 90% relative humidity at 25°C.
5) The abhydrous crystalline rucaparib mesylate as defined in any one of claims 1 to 4, characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (9.9 ~ 0.2)°, (12.2 ~ 0.2)° and (22.5 ~ 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
6) The anhydrous crystalline rucaparib mesylate of claim 5 characterized by having a powder X-ray diffractogram comprising further 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-Kalpha radiation having a wavelength of 0.15419 nm.
0.2)° and/or (16.3 ~ 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
7) The anhydrous crystalline rucaparib mesylate as defined in any one of claims 1 to 6, characterized by having a powder X-ray diffractogram comprising no reflections at 2-Theta angles of (12.7 ~ 0.2)° and/or (24.6 ~ 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
8) The anhydrous crystalline rucaparib mesylate as defined in any one of claims 1 to 7, characterized by having a differential scanning calorimetric curve showing an endothermic peak in the range of from 290 to 300 °C, when measured at a heating rate of 10 °K/min.
9) A composition comprising at least 90 weight-% of the anhydrous crystalline rucaparib mesylate as defined in anyone of the preceding claims, based on the total weight of the composition.
10) The composition of claim 9 characterized by a powder X-ray diffractogram comprising reflections at 2-Theta angles selected from the group consisting of (9.9 ~
0.2)°, (12.2 ~
0.2)° and/or (22.5 ~ 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
0.2)°, (12.2 ~
0.2)° and/or (22.5 ~ 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalpha radiation having a wavelength of 0.15419 nm.
11) Use of the anhydrous crystalline rucaparib mesylate as defined in any one of claims 1 to 8 or the composition as defined in claim 9 or 10 for the preparation of a pharmaceutical composition.
12) A pharmaceutical composition comprising the anhydrous crystalline rucaparib mesylate as defined in any one of claims 1 to 8 or the composition as defined in claim 9 or 10 and one or more pharmaceutically acceptable excipient(s).
13) The pharmaceutical composition as defined in claim 12 for use as a medicament.
14) The pharmaceutical composition as defined in claim 12 for use in the treatment of cancer.
15) The use according to claim 14, wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, prostate cancer and pancreatic cancer.
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EP17199999.8 | 2017-11-03 | ||
PCT/EP2018/079815 WO2019086509A1 (en) | 2017-11-03 | 2018-10-31 | Crystalline salt of a tricyclic poly(adp-ribose) polymerase inhibitor |
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EP (1) | EP3704124A1 (en) |
JP (1) | JP2021501771A (en) |
CA (1) | CA3080657A1 (en) |
MX (1) | MX2020004545A (en) |
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EP1140936B1 (en) | 1999-01-11 | 2004-03-17 | Agouron Pharmaceuticals, Inc. | Tricyclic inhibitors of poly(adp-ribose) polymerases |
JP4756229B2 (en) * | 2000-05-10 | 2011-08-24 | 日本農薬株式会社 | Process for producing 1,3-diiodohydantoins |
JP2006522088A (en) * | 2003-03-31 | 2006-09-28 | ファイザー・インク | Salts of tricyclic inhibitors of poly (ADP-ribose) polymerase |
MX2007002461A (en) * | 2004-09-22 | 2008-03-13 | Pfizer | Polymorphic and amorphous forms of the phosphate salt of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6 h-azepino[5,4,3-cd]indol-6-one. |
PT2534153T (en) | 2010-02-12 | 2016-12-27 | Pfizer | 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 |
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- 2018-10-31 EP EP18795631.3A patent/EP3704124A1/en active Pending
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