TECHNICAL FIELD

The present invention is directed to novel crystalline forms of niraparib tosylate, processes for the preparation thereof, pharmaceutical compositions containing these forms, and their use for the treatment or prevention of conditions which can be ameliorated by the inhibition of poly(ADP-ribose) polymerase (PARP), including certain forms of cancer.

BACKGROUND

Niraparib (1), or 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7-carboxamide, in the form of its 4-methylbenzenesulfonate (tosylate) salt monohydrate (1:1:1), exhibits activity as a poly(ADP-ribose) polymerase inhibitor, and is the active ingredient in ZEJULA®, which is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.



WO 2018/183354 A1 discloses crystalline Forms I-III of niraparib tosylate. Monohydrate crystalline Form I is described as a non-hygroscopic solid form having suitable solubility properties, as well as favourable physical and chemical stability. Crystalline Form II is characterized as a non-stoichiometric hydrate and anhydrous crystalline Form III is designated as a very hygroscopic solid showing a 15.8% weight gain up to 95% relative humidity (RH) in dynamic vapour sorption (DVS) studies.

Further crystalline forms of niraparib tosylate are described in, for example, CN108530425 A,IP.com Journal2018, 18 (1B), 1-7 andIP.com Journal2018, 18 (3A), 1-5.

According to the European CHMP Assessment Report for ZEJULA® (EMEA/H/C/004249/0000), the drug substance niraparib tosylate in the approved drug product is a non-hygroscopic monohydrate form, which is believed to correspond with crystalline Form I of WO 2018/183354 A1. In the report, the drug substance is further described as having low, pH-independent aqueous solubility but high permeability, placing Niraparib tosylate monohydrate in Class II of the Biopharmaceutics Classification System (BCS). Generally, in the case of solid oral dosage forms of Class II drug substances, the limiting factor controlling drug absorption and bioavailability is adequate solubilization of the drug in the aqueous environment of the gastrointestinal tract. As such, improvements in aqueous solubility of the drug substance can be directly correlated with improved drug effectiveness.

Approaches to improving the solubility of a drug substance include, for example, particle size reduction techniques, dispersion of the drug substance onto an inert carrier, and formulation of the drug substance together with solubilizing excipients. However, WO 2018/183349 A1, which is directed to pharmaceutical capsule compositions of niraparib tosylate, including compositions comprising crystalline Form I of niraparib tosylate, states that there are multiple challenges associated with niraparib tosylate due to its cohesive nature. Cohesive powders, such as crystalline Form I of niraparib tosylate, have a tendency to develop agglomerates and lumps during formulation processing operations, such as mixing and blending, which can lead to problems with flowability and content uniformity of dosage units. The cohesiveness of a powder and the tendency to form agglomerates can also increase as particle size is reduced. Further, as noted in WO 2018/183349 A1, applying strong mechanical agitation processes to a cohesive solid such as crystalline Form I of niraparib tosylate, such as milling, can induce the development of static charge in the material, which can further reduce powder flow properties. Thus, although niraparib tosylate monohydrate exhibits poor aqueous solubility, particle size reduction techniques comprising vigorous mechanical agitation such as milling and spray drying may not be suitable techniques to address the problems with this crystalline form.

One important measure of the solubility of a drug substance is intrinsic dissolution rate (IDR), which is the dissolution rate of a substance under constant surface area conditions. For low solubility substances such as niraparib tosylate that are classified as BCS Class II, higher IDR values can correlate with higher bioavailability following administration. Prediction of the solubility and IDR of an as yet undiscovered crystalline form of a substance is currently not possible.

Different crystalline forms of the same compound may have different packing, thermodynamic, spectroscopic, kinetic, surface, and mechanical properties. For example, different crystalline forms may have different stability properties. A particular crystalline form may be more sensitive to heat, relative humidity (RH) and/or light. Alternatively or additionally, a particular crystalline form may have different compressibility and/or density properties thereby providing more desirable characteristics for formulation and/or product manufacturing. Particular crystalline forms may also have different dissolution rates, thereby providing different pharmacokinetic parameters, which allow for specific forms to be used in order to achieve specific pharmacokinetic targets. Additionally, the particular solubility characteristics of a given crystalline form in relation to undesired impurities can result in differences in the chemical purity of different crystalline forms upon isolation. Differences in stability may result from changes in chemical reactivity, such as differential oxidation. Such properties may provide for more suitable product qualities, such as a dosage form that is more resistant to discolouration when comprised of a specific crystalline form. Different physical properties of crystalline forms may also affect their processing. For example, a particular crystalline form may be more cohesive, more resistant to flow, less capable of dispersing static charge or may be more difficult to filter and/or wash.

Although general approaches to crystalline form screening of active pharmaceutical ingredients are known, it is well established that the prediction of whether any given compound will exhibit polymorphism is not possible. Furthermore, prediction of the properties of any unknown crystalline forms, and how they will differ from other crystalline forms of the same compound, remains even more elusive (Joel Bernstein,Polymorphism in Molecular Crystals, Oxford University Press, New York, 2002, page 9).

Therefore, there exists a need for novel crystalline forms of niraparib tosylate for use in providing improved drug products containing niraparib tosylate and their manufacture.

SUMMARY OF THE INVENTION

The crystalline forms of the present invention comprise niraparib tosylate co-crystallized with an equimolar amount of either urea or oxalic acid, each co-former having an established safety record. Owing to the use of co-formers with an established safety record, it is expected that both urea and oxalic acid can safely be used in materials intended for use in the preparation of pharmaceutical compositions intended for administration to humans or animals. Further, the crystalline forms of the present invention exhibit advantageous properties, for example higher IDR values and/or lower chargeability in comparison to crystalline Form I niraparib tosylate described in WO 2018/183354 A1, which is believed to be the form of niraparib tosylate used in ZEJULA® tablets. Thus, the crystalline forms of the present invention offer opportunities to address problems associated with the formulation and use of niraparib tosylate as a drug product, such as low solubility and poor flowability.

In addition, the processes for the manufacture of the niraparib tosylate crystalline forms of the present invention are efficient and substantially solvent-free processes.

Accordingly, in a first aspect of the present invention, there is provided a crystalline form of niraparib tosylate comprising niraparib tosylate and urea. In a preferred embodiment of the first aspect, the molar ratio of niraparib tosylate to urea is between approximately 1:0.75 and 1:1.25. In a more preferred embodiment of the first aspect, the molar ratio of niraparib tosylate to urea is approximately 1:1.

In a second aspect of the present invention, there is provided a crystalline form of niraparib tosylate, APO-I, comprising niraparib tosylate and urea, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 2θ (±0.2°), at 5.2°, 6.6° and 8.4°. In a preferred embodiment of the second aspect, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 2θ (±0.2°), selected from the group consisting of: 12.2°, 14.3°, 14.8°, 15.5°, 18.5° and 21.8°. In a further preferred embodiment of the second aspect, the PXRD diffractogram further comprises peaks, expressed in degrees 2θ (±0.2°), at 12.2°, 14.3°, 14.8°, 15.5°, 18.5° and 21.8°. Preferably, the crystalline form of the second aspect of the invention provides a PXRD diffractogram comprising peaks in substantially the same positions (±0.2° 2θ) as those shown inFIG. 1. In a further preferred embodiment of the second aspect, the molar ratio of niraparib tosylate to urea is approximately 1:1.

In a third aspect of the present invention, there is provided a crystalline form of niraparib tosylate comprising niraparib tosylate and oxalic acid. Preferably, in the crystalline form of the third aspect, the molar ratio of niraparib tosylate to oxalic acid is between approximately 1:0.75 and 1:1.25. Most preferably, the molar ratio of niraparib tosylate to oxalic acid is approximately 1:1.

In a fourth aspect of the present invention, there is provided a crystalline form of niraparib tosylate, APO-II, comprising niraparib tosylate and oxalic acid, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 2θ (±0.2°), at 5.8°, 7.6° and 10.6°. In a preferred embodiment of the fourth aspect, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 2θ (±0.2°), selected from the group consisting of: 12.8°, 14.2°, 15.2°, 16.7°, 17.3° and 20.9°. In a further preferred embodiment of the fourth aspect, the PXRD diffractogram further comprises peaks, expressed in degrees 2θ (±0.2°), 12.8°, 14.2°, 15.2°, 16.7°, 17.3° and 20.9°. Preferably, the crystalline form of the fourth aspect of the invention provides a PXRD diffractogram comprising peaks in substantially the same positions (±0.2° 2θ) as those shown inFIG. 2. In a further preferred embodiment of the fourth aspect, the molar ratio of niraparib tosylate to oxalic acid is approximately 1:1.

In a fifth aspect of the present invention, there is provided a pharmaceutical composition comprising a crystalline form of niraparib tosylate according to any one of the first, second, third or fourth aspects of the invention, and one or more pharmaceutically acceptable excipients. Preferably, the pharmaceutical composition is in the form of a solid dosage form. Most preferably, the pharmaceutical composition is a capsule.

In a sixth aspect of the present invention, there is provided a use of a crystalline form of niraparib tosylate according to any one of the first, second, third or fourth aspects of the invention, or the pharmaceutical composition of the fifth aspect of the invention, in the treatment of conditions which can be ameliorated by the inhibition of poly(ADP-ribose) polymerase (PARP). In a preferred embodiment of the sixth aspect, the condition which can be ameliorated by the inhibition of poly(ADP-ribose) polymerase (PARP) is cancer. In a further preferred embodiment of the sixth aspect, the cancer is selected from the group consisting of epithelial ovarian, fallopian tube, primary peritoneal and combinations thereof. In a further preferred embodiment of the sixth aspect, the cancer is a recurrent cancer that has partially or completely responded to previous treatment with a platinum-based chemotherapy. Also provided is the use of the crystalline form of niraparib tosylate according to any one of the first, second, third or fourth aspects of the invention, or the pharmaceutical composition of the fifth aspect of the invention, in the treatment of a cancer that is selected from the group consisting of epithelial ovarian, fallopian tube, primary peritoneal and combinations thereof.

In a seventh aspect of the present invention, there is provided a process for the preparation of the crystalline form of niraparib tosylate of the first or second aspects of the invention, comprising mixing together a solid phase of niraparib tosylate and a solid phase of urea for a suitable time to afford the crystalline form of niraparib tosylate. In a preferred embodiment of the seventh aspect, mixing is conducted in the presence of a limited amount of a suitable solvent so as to maintain a solid phase throughout mixing. In a further preferred embodiment of the seventh aspect, the suitable solvent is acetonitrile. In a further preferred embodiment of the seventh aspect, the amount of suitable solvent used in the process is between approximately 5 wt % and approximately 20 wt %. Preferably, the amount of suitable solvent used is between approximately 10 wt % and approximately 15 wt %. In a further preferred embodiment of the seventh aspect, the molar ratio of niraparib tosylate to urea used in the process is approximately 1:1. In a further preferred embodiment of the seventh aspect, the mixing comprises grinding.

In an eighth aspect of the present invention, there is provided a process for the preparation of the crystalline form of niraparib tosylate of the third or fourth aspects of the invention, comprising mixing together a solid phase of niraparib tosylate and a solid phase of oxalic acid for a suitable time to afford the crystalline form of niraparib tosylate. In a preferred embodiment of the eighth aspect, mixing is conducted in the presence of a limited amount of a suitable solvent so as to maintain a solid phase throughout mixing. In a further preferred embodiment of the eighth aspect, the suitable solvent is methanol. In a further preferred embodiment of the eighth aspect, the amount of suitable solvent used in the process is between approximately 5 wt % and approximately 20 wt %. Preferably, the amount of suitable solvent used is between approximately 10 wt % and approximately 15 wt %. In a further preferred embodiment of the eighth aspect, the molar ratio of niraparib tosylate to oxalic acid used in the process is approximately 1:1. In a further preferred embodiment of the eighth aspect, the mixing comprises grinding.

In a ninth aspect of the present invention, there is provided a method for treating cancer selected from the group consisting of epithelial ovarian, fallopian tube, primary peritoneal and combinations thereof comprising administering an effective amount of the crystalline form of niraparib tosylate according to any one of first, second, third or fourth aspects of the invention, or the pharmaceutical composition of the fifth aspect of the invention.

Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying figures.

