WO2021133811A1

WO2021133811A1 - Solid state forms of cenicriviroc and process for preparation thereof

Info

Publication number: WO2021133811A1
Application number: PCT/US2020/066631
Authority: WO
Inventors: Nikolina JANTON; Helena CERIĆ
Original assignee: Teva Pharmaceuticals International Gmbh; Teva Pharmaceuticals Usa, Inc.
Priority date: 2019-12-26
Filing date: 2020-12-22
Publication date: 2021-07-01

Abstract

The present disclosure encompasses solid state forms of Cenicriviroc, in embodiments crystalline polymorphs, salts and/or co-crystals of Cenicriviroc, processes for preparation thereof, and pharmaceutical compositions thereof.

Description

SOLID STATE FORMS OF CENICRIVIROC AND PROCESS FOR PREPARATION THEREOF

FIELD OF THE DISCLOSURE

[0001] The present disclosure encompasses solid state forms of Cenicriviroc, in embodiments crystalline polymorphs, salts and/or co-crystals of Cenicriviroc, processes for preparation thereof, and pharmaceutical compositions thereof.

BACKGROUND OF THE DISCLOSURE

[0002] Cenicriviroc, fS',/'//-8-(4-(2-Butoxyethoxy)phenyl)-l -isobutyl -N-(4-(((l -propyl -1 H- imidazol-5-yl)methyl)sulfmyl)phenyl)-l,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide, has the following chemical structure:

[0003] Cenicriviroc is developed for the treatment of several liver diseases, including non alcoholic steatohepatitis, as well as for the treatment of HIV infections and cognition disorders. [0004] The compound and salts thereof, including mesylate salt, is described in International Publication No. WO 2003/014105 (US counterpart U.S. Patent No. 7,371,772) and International Publication No. WO 2005/116013. International Publication No. WO 2003/076411 (US Patent Application Publication No. 2005/107606), International Publication No. WO 2016/105527 (U.S. Patent Application Publication No. 2018/0327428) and International Publication No. WO 2017/223155 (U.S. Patent No. 10,407,411) describe processes and intermediates of Cenicriviroc. International Publication No. WO 2018/042043 (U.S. Patent No. 10,301,287) describes an amorphous and crystalline polymorphs of Cenicriviroc mesylate. Menning et al. (Mol. Pharm. 4006(10), 2013, 4005-4015) describe a tablet formulation of crystalline Cenicriviroc mesylate. [0005] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state (¹³C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0006] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

[0007] Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Cenicriviroc.

SUMMARY OF THE DISCLOSURE

[0008] The present disclosure encompasses solid state forms of Cenicriviroc, in embodiments crystalline polymorphs, salts and/or co-crystals of Cenicriviroc, processes for preparation thereof, and pharmaceutical compositions thereof. These crystalline polymorphs, salts and co-crystals can be used to prepare other solid state forms of Cenicriviroc, Cenicriviroc salts, co-crystals and their solid state forms.

[0009] The present disclosure also provides uses of the said solid state forms of Cenicriviroc, salts and co-crystals in the preparation of other solid state forms of Cenicriviroc or salts or co crystals thereof.

[0010] The present disclosure provides crystalline polymorphs, salts and co-crystals of Cenicriviroc for use in medicine, including for the treatment of liver diseases, such as non alcoholic steatohepatitis, or for the treatment of HIV infections, or for the treatment of cognition disorders.

[0011] The present disclosure also encompasses the use of crystalline polymorphs, salts and co-crystals of Cenicriviroc of the present disclosure for the preparation of pharmaceutical compositions and/or formulations.

[0012] In another aspect, the present disclosure provides pharmaceutical compositions comprising crystalline polymorphs, salts and co-crystals of Cenicriviroc according to the present disclosure.

[0013] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorphs of Cenicriviroc, salts and co-crystals with at least one pharmaceutically acceptable excipient.

[0014] The crystalline polymorph of Cenicriviroc, salts and co-crystals as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorph, salts and co crystals of Cenicriviroc may be used as medicaments, such as for the treatment of liver diseases, such as non-alcoholic steatohepatitis, or for the treatment of HIV infections, or for the treatment of cognition disorders.

[0015] The present disclosure also provides methods of treating liver diseases, such as non alcoholic steatohepatitis, or treating HIV infections, or treating cognition disorders, by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs, salts and co-crystals of Cenicriviroc of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from liver diseases, such as non alcoholic steatohepatitis, or HIV infections, or a cognition disorder, or otherwise in need of the treatment. [0016] The present disclosure also provides uses of crystalline polymorphs, salts and co crystals of Cenicriviroc of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g., liver diseases, such as non alcoholic steatohepatitis, or HIV infections, or a cognition disorder.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Cenicriviroc: fumaric acid Form 1.

[0018] Figure 2 shows a characteristic XRPD of Cenicriviroc: fumaric acid Form 2.

[0019] Figure 3 shows a characteristic XRPD of Cenicriviroc: fumaric acid Form 3.

[0020] Figure 4 shows a characteristic DSC thermogram of Cenicriviroc: fumaric acid Form 2.

[0021] Figure 5 shows a characteristic TGA thermogram of Cenicriviroc: fumaric acid Form 2.

[0022] Figure 6 shows a characteristic DSC thermogram of Cenicriviroc: fumaric acid Form 3.

[0023] Figure 7 shows a characteristic TGA thermogram of Cenicriviroc: fumaric acid Form 3.

[0024] Figure 8 shows a characteristic 'H NMR of Cenicriviroc: fumaric acid Form 2.

[0025] Figure 9 shows a characteristic 'H NMR of Cenicriviroc: fumaric acid Form 3.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0026] The present disclosure encompasses solid state forms of Cenicriviroc, including crystalline polymorphs of Cenicriviroc, processes for preparation thereof, and pharmaceutical compositions thereof.

[0027] Solid state properties of Cenicriviroc and crystalline polymorphs thereof, as well as salts and co-crystals can be influenced by controlling the conditions under which Cenicriviroc and crystalline polymorphs, salts and co-crystals thereof are obtained in solid form.

[0028] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to mean that the solid state form contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. Thus, a crystalline polymorph of Cenicriviroc, or a Cenicriviroc salt or a co-crystal described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject crystalline polymorph of Cenicriviroc, or a Cenicriviroc salt or a co-crystal. In some embodiments of the disclosure, the described crystalline polymorph of Cenicriviroc, or a Cenicriviroc salt or a co-crystal may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other crystalline polymorph of Cenicriviroc or a Cenicriviroc salt or a co-crystal.

[0029] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Cenicriviroc, or a Cenicriviroc salt or a co-crystal of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.

[0030] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Cenicriviroc, or a Cenicriviroc salt or a co-crystal referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Cenicriviroc, or a Cenicriviroc salt or a co crystal characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0031] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of Cenicriviroc, or a Cenicriviroc salt or a co-crystal relates to a crystalline form of Cenicriviroc, salt or co-crystal which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w/w), of either water or organic solvents as measured for example by TGA.

[0032] The term "solvate," as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0033] "Co-Crystal" or "Co-crystal" as used herein is defined as a crystalline material including two or more molecules in the same crystalline lattice and associated by non-ionic and non-covalent bonds. In some embodiments, the co-crystal includes two molecules which are in natural state. In embodiments the molar ratio between the active pharmaceutical ingredient (Cenicriviroc) and the coformer (i.e., fumaric acid) is between 2:1 and 1:2, in embodiments 1:

1.5 and 1.5: 1, in some embodiments between 1: 1.25 and 1.25: 1, in other embodiments about 1:1.

In another embodiment the molar ratio between the active pharmaceutical ingredient (Cenicriviroc) and the coformer (i.e., fumaric acid) is 4:3.

[0034] As used herein, crystalline Cenicriviroc: fumaric acid is a distinct molecular species. Crystalline Cenicriviroc: fumaric acid may be a co-crystal of Cenicriviroc and fumaric acid (e.g., in a molar ratio of 2: 1) or a co-crystal of Cenicriviroc and fumaric acid (e.g., in a molar ratio of 4:3). Alternatively, crystalline Cenicriviroc: fumaric acid may be a salt (i.e., Cenicriviroc fumarate or Cenicriviroc hemifumarate). Alternatively, crystalline Cenicriviroc: fumaric acid may be a co-crystal comprising a salt of Cenicriviroc (i.e., Cenicriviroc fumarate and/or Cenicriviroc hemifumarate) with Cenicriviroc or fumaric. Thus, crystalline Cenicriviroc: fumaric acid may be: a co-crystal comprising a salt of Cenicriviroc (i.e., Cenicriviroc fumarate) and Cenicriviroc (1:1); a co-crystal comprising a salt of Cenicriviroc (i.e., Cenicriviroc fumarate) and Cenicriviroc (3:1); or a co-crystal comprising a salt of Cenicriviroc (i.e., Cenicriviroc hemifumarate) and fumaric acid (2:1).

[0035] As used herein, the term "isolated" in reference to crystalline polymorph of Cenicriviroc or a Cenicriviroc salt or a co-crystal of the present disclosure corresponds to a crystalline polymorph of Cenicriviroc or a Cenicriviroc salt or a co-crystal that is physically separated from the reaction mixture in which it is formed.

[0036] As used herein, unless stated otherwise, the XRPD measurements are taken using copper Ka radiation wavelength 1.5418 A. XRPD peaks reported herein are measured using CuK a radiation, l = 1.5418 A, typically at a temperature of 25 ± 3°C.

[0037] As used herein, unless stated otherwise, ¹³C NMR reported herein are measured at 125 MHz at a magic angle spinning frequency w_G/2p = 11 kHz, preferably at a temperature of 293 K ± 3°C.

[0038] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature”, often abbreviated as “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0039] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term "v/v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added. [0040] A process or step may be referred to herein as being carried out "overnight." This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.

[0041] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.

[0042] As used herein and unless indicated otherwise, the term "ambient conditions" refer to atmospheric pressure and a temperature of 22-24°C.

[0043] The present disclosure encompasses crystalline Cenicriviroc: fumaric acid.

Crystalline Cenicriviroc: fumaric acid may be a co-crystal of Cenicriviroc and fumaric acid. Alternatively, crystalline Cenicriviroc: fumaric acid may be a salt (i.e., Cenicriviroc fumarate or Cenicriviroc hemifumarate). Alternatively, crystalline Cenicriviroc: fumaric acid may be a co crystal comprising a salt of Cenicriviroc (i.e., Cenicriviroc fumarate or Cenicriviroc hemifumarate) and Cenicriviroc or fumaric acid.

[0044] The disclosure encompasses a crystalline form of Cenicriviroc and fumaric acid, designated Form 1. Crystalline Form 1 of Cenicriviroc: fumaric acid may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 3.9, 7.3, 10.4, 16.1 and 20.4 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data. [0045] Crystalline Form 1 of Cenicriviroc: fumaric acid may be further characterized by an X-ray powder diffraction pattern having peaks at 3.9, 7.3, 10.4, 16.1 and 20.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one or two additional peaks selected from 5.1 and 9.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0046] In embodiments of the present disclosure, crystalline Form 1 of Cenicriviroc: fumaric acid is isolated.

[0047] Crystalline Form 1 of Cenicriviroc: fumaric acid may be characterized by each of the above characteristics alone or by all possible combinations, e.g., an XRPD pattern having peaks at 3.9, 7.3, 10.4, 16.1 and 20.4 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1; and combinations thereof.

[0048] The disclosure further encompasses a crystalline form of Cenicriviroc and fumaric acid, designated Form 2.

[0049] Crystalline Form 2 of Cenicriviroc: fumaric acid may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2; an X-ray powder diffraction pattern having peaks at 4.4, 7.7, 12.0, 13.2 and 17.5 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0050] Crystalline Form 2 of Cenicriviroc: fumaric acid may be further characterized by an X-ray powder diffraction pattern having peaks at 4.4, 7.7, 12.0, 13.2 and 17.5 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one or two additional peaks selected from 15.5 and 18.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0051] In embodiments of the present disclosure, crystalline Form 2 of Cenicriviroc: fumaric acid is isolated.

[0052] In a further embodiment, crystalline Form 2 of Cenicriviroc: fumaric acid is a hydrate; preferably monohydrate.

[0053] In any of the embodiments disclosed herein, the crystalline Form 2 of Cenicriviroc: fumaric acid may be a salt (e.g., Cenicriviroc hemifumarate), or a co-crystal of a salt of Cenicriviroc (e.g., Cenicriviroc fumarate) with Cenicriviroc (e.g., in a molar ratio of 1 : 1), or a co-crystal of Cenicriviroc with fumaric acid (e.g., in a molar ratio of 2: 1).

[0054] In some embodiment the stoichiometry (molar ratio) of Cenicriviroc to fumaric acid in Form 2, is 2:1.

[0055] Crystalline Form 2 of Cenicriviroc: fumaric acid may be characterized by each of the above characteristics alone or by all possible combinations, e.g., an XRPD pattern having peaks at 4.4, 7.7, 12.0, 13.2 and 17.5 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2; and combinations thereof.

[0056] Form 2 of Cenicriviroc: fumaric acid in certain embodiments be chracterized, alternatively or in addition, by DSC endotermic peak of melting at about 96°C (onset). A typical DSC thermogram of such an embodiment is depicted in Figure 4. [0057] In other embodiments, Form 2 of Cenicriviroc: fumaric acid may be characterized, alternatively or in addition, by a TGA loss of about 1.7% (25-125°C). A representative TGA thermogram for such embodiment is depicted in Figure 5.

[0058] Crystalline Form 2 of Cenicriviroc: fumaric acid is a non-hygroscopic form i.e., it does not absorb water, even when exposed to high relative humidity.

[0059] Another aspect of the present invention relates to a process for preparing Form 2 of Cenicriviroc: fumaric acid. The process may comprise isolation of Form 2 from a solution of Cenicriviroc and fumaric acid in an organic solvent, preferably in a Ci-₆ alcohol, or in a Ci-4 alcohol, or preferably in 2-butanol. Anti-solvent, preferably methyl tert-butyl ether, may be added to induce precipitation. The fumaric acid may be added in a molar ratio of: about 1.5 : 1 to about 1 : 1.5, about 1.2 :1 to about 1 : 1.2, about 1.1 : 1 to about 1 : 1.1, about 1.1 :1 or about 1:1.

[0060] The disclosure further encompasses a crystalline form of Cenicriviroc and fumaric acid, designated Form 3. Crystalline Form 3 of Cenicriviroc: fumaric acid may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 3; an X-ray powder diffraction pattern having peaks at 4.1,

7.6, 8.5, 11.3 and 20.5 ± 0.2 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0061] Crystalline Form 3 of Cenicriviroc: fumaric acid may be further characterized by an X-ray powder diffraction pattern having peaks at 4.1, 7.6, 8.5, 11.3 and 20.5 degrees 2-theta ±

0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 5.1, 9.3, 9.7, 10.3 and 18.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0062] In embodiments of the present disclosure, crystalline Form 3 of Cenicriviroc: fumaric acid is isolated.

[0063] In a further embodiment, crystalline Form 3 of Cenicriviroc: fumaric acid is anhydrous.

[0064] In any of the embodiments disclosed herein, the crystalline Form 3 of Cenicriviroc: fumaric acid may be a co-crystal comprising: Cenicriviroc with fumaric acid (e.g., in a molar ratio of 4:3), a salt of Cenicriviroc (i.e., Cenicriviroc fumarate) with Cenicriviroc (e.g., in a molar ratio of 3:1), or a salt of Cenicriviroc (i.e., Cenicriviroc hemifumarate) with fumaric acid (e.g., in a molar ratio of 2:1). [0065] In some embodiments the stoichiometry (molar ratio) of Cenicriviroc to fumaric acid in Form 3, is 4:3.

[0066] Crystalline Form 3 of Cenicriviroc: fumaric acid may be characterized by each of the above characteristics alone or by all possible combinations, e.g., an XRPD pattern having peaks at 4.1, 7.6, 8.5, 11.3 and 20.5 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 3; and combinations thereof.

[0067] Form 3 of Cenicriviroc: fumaric acid in certain embodiments can be chracterized, alternatively or in addition, by DSC endotermic peak of melting at about 100°C (onset). A typical DSC thermogram of such an embodiment is depicted in Figure 6.

[0068] In other embodiment, Form 3 of Cenicriviroc: fumaric acid may be characterized, alternatively or in addition, by a TGA loss of about 0.5% (25-125°C). A representative TGA thermogram for such embodiment is depicted in Figure 7.

[0069] Crystalline Form 3 of Cenicriviroc: fumaric acid exhibits some advantages over other salts of Cenicriviroc. For example, Form 3 is a non-hygroscopic form. It is an extremely stable form in high relative humidity; i.e., it does not absorb water and maintains its crystallinity, even when exposed to high relative humidity.

[0070] The present invention also provides a process for preparing Form 3 of Cenicriviroc: fumaric acid. The process may comprise isolation of From 3 from a solution of Cenicriviroc and fumaric acid in an organic solvent, preferably an ester, particularly a C3-6 ester, particularly i- propyl acetate. The fumaric acid may be added in a molar ratio of: about 1.5: 1 to about 1: 1.5, about 1.2: 1 to about 1: 1.2, about 1.1: 1 to about 1: 1.1, about 1.1: 1 or about 1: 1.

[0071] The above crystalline polymorphs can be used to prepare other crystalline polymorphs of Cenicriviroc, Cenicriviroc salts, co-crystals and their solid state forms.

[0072] The present disclosure encompasses a process for preparing other solid state forms of Cenicriviroc, Cenicriviroc salts or co-crystals and their solid state forms thereof. The process includes preparing any one of the crystalline polymorphs of Cenicriviroc, or a Cenicriviroc salt or a co-crystal by the processes of the present disclosure, and converting that crystalline polymorph, salt or co-crystal to said other crystalline polymorphs of Cenicriviroc, Cenicriviroc salts, co-crystals.

[0073] The present disclosure provides the above described crystalline polymorphs of Cenicriviroc, Cenicriviroc salt or Cenicriviroc co-crystal for use in the preparation of pharmaceutical compositions comprising crystalline polymorphs, salts and co-crystals of Cenicriviroc thereof.

[0074] The present disclosure also encompasses the use of crystalline polymorphs of Cenicriviroc, Cenicriviroc salt or Cenicriviroc co-crystal of the present disclosure for the preparation of pharmaceutical compositions of crystalline polymorph Cenicriviroc or Cenicriviroc salt or Cenicriviroc co-crystal.

[0075] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorphs of Cenicriviroc or Cenicriviroc salt or Cenicriviroc co-crystal of the present disclosure with at least one pharmaceutically acceptable excipient.

[0076] Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid state forms of Cenicriviroc or Cenicriviroc salt or Cenicriviroc co-crystal of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[0077] Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0078] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch. [0079] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[0080] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0081] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. [0082] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0083] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.

[0084] In liquid pharmaceutical compositions of the present invention, Cenicriviroc, or Cenicriviroc salt or Cenicriviroc co-crystal and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin. [0085] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0086] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.

[0087] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0088] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[0089] According to the present disclosure, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[0090] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts. [0091] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs. [0092] The dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and/or sorbitol, an opacifying agent and/or colorant.

[0093] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0094] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.

[0095] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.

[0096] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

[0097] A capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[0098] A pharmaceutical formulation of Cenicriviroc or Cenicriviroc salt or Cenicriviroc co crystal can be administered. Cenicriviroc, its salts or co-crystals may be formulated for administration to a mammal, in embodiments to a human, by injection. Cenicriviroc its salts or co-crystals can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection. The formulation can contain one or more solvents. A suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[0099] The crystalline polymorphs of Cenicriviroc, or Cenicriviroc salt or Cenicriviroc co crystal and the pharmaceutical compositions and/or formulations of Cenicriviroc or Cenicriviroc salt or Cenicriviroc co-crystal of the present disclosure can be used as medicaments, in embodiments in the treatment of liver diseases, such as non-alcoholic steatohepatitis, or an HIV infection or a cognition disorder.

[00100] The present disclosure also provides methods of treating liver diseases, such as non alcoholic steatohepatitis, or an HIV infection or a cognition disorder, by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Cenicriviroc or Cenicriviroc salt or Cenicriviroc co-crystal of the present disclosure, or at least one of the above pharmaceutical compositions and/or formulations, to a subject in need of the treatment.

[00101] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way.

ANALYTICAL METHOD

Powder X-ray Diffraction ("XRPD") method

[00102] Sample after being powdered in a mortar and pestle is applied directly on a silicon plate holder. The X-ray powder diffraction pattern was measured with Philips X'Pert PRO X-ray powder diffractometer, equipped with Cu irradiation source =1.54184 A (Angstrom), X’Celerator (2.022° 2Q) detector. Scanning parameters: angle range: 3-40 deg., step size 0.0167, time per step 37 s, continuous scan.

Differential scanning calorimetry ("DSC") method

[00103] DSC analysis was performed on instrument Q1000 MDSC TA with a heating rate of 10°C/minute and under nitrogen flow of 50 mL/minute. Standard aluminum closed pan (with hole) was used, sample mass was 1-5 mg.

Thermogravimetric analysis ("TGA") method

[00104] TGA was performed on instrument Discovery TGA TA with a heating rate of 10°C/min and under nitrogen flow of 50 mL/minute. Standard aluminum open pan was used, sample mass was 3-5 mg.

Nuclear magnetic resonance method

[00105] 'H NMR spectra were recorded on a Bruker Avance AV400 NMR spectrometer operating at 400.1 MHz. DMSO-di was used as a solvent and TMS as a reference standard.

EXAMPLES

Preparation of starting materials

[00106] Cenicriviroc can be prepared according to methods known from the literature, for example U.S. Patent No. 8,741,943.

Example 1: Preparation of Cenicriviroc : fumaric acid Form 1

[00107] Cenicriviroc base (0.10 grams; 0.14 mmol) and fumaric acid (0.02 grams; 0.17 mmol) were suspended in methyl /ert-butyl ether ("MTBE", 2.5 mL) at a temperature of about 40°C. Isopropyl acetate (2.2 mL) was added and a clear solution was obtained at a temperature of about 40°C. The solution was cooled down to about room temperature (25°C) and was maintained over night with stirring. The obtained precipitate was filtered and dried at a temperature of about 40°C over a period of about 30 minutes. The obtained solid was analyzed by XRPD, Form 1 was obtained. The XRPD pattern is shown in Figure 1.

Example 2: Preparation of Cenicriviroc : fumaric acid Form 2

[00108] Cenicriviroc base (0.10 grams; 0.14 mmol) and fumaric acid (0.017 grams; 0.15 mmol) were dissolved in 2-butanol (2.0 mL) at about room temperature (25°C) and a solution formed. Methyl tert-butyl ether (8.0 mL) was added drop wise to the solution at about room temperature (25°C). The obtained second clear solution maintained over night with stirring at room temperature (25°C). The obtained precipitate was filtered and analyzed by XRPD, Form 2 was obtained. The XRPD pattern is shown in Figure 2.

Example 3: Preparation of Cenicriviroc : fumaric acid Form 2

[00109] Cenicriviroc base (0.430 grams) and fumaric acid (0.072 grams) were dissolved in 2- butanol (3.5 mL) at 40°C. Solution was cooled to room temperature and stirred for 12 hours. Obtained suspension was filtered by vacuum filtration and dried under reduced pressure at 50°C for 2 hours. Solid was analyzed by XRPD and Cenicriviroc: fumaric acid Form 2 was obtained. [00110] The molar ratio of Cenicriviroc to fumaric acid was found to be 4:3; as determined by ¹HNMR (Figure 8) and HPLC assay. ¾ NMR (DMSO-ds): 10.13 ppm (s, 1H, Cenicriviroc-NH); 6.62 ppm (s, 2H, fumaric acid CH=CH).

Example 4: Preparation of Cenicriviroc : fumaric acid Form 3

[00111] Cenicriviroc base (0.195 grams) and fumaric acid (0.033 grams) were dissolved in i- propyl acetate (8 mL) at 40°C. Solution was cooled to room temperature and stirred for 12 hours. Obtained suspension was filtered by vacuum filtration and dried under reduced pressure at 50°C for 2 hours. Solid was analyzed by XRPD, Form 3 was obtained. The XRPD pattern is shown in Figure

3.

[00112] The molar ratio of Cenicriviroc to fumaric acid was found to be 4:3; as determined by ¹HNMR (Figure 9) and HPLC assay. Ή NMR (DMSO-rie): 10.13 ppm (s, 1H, Cenicriviroc-NH); 6.63 ppm (s, 2H, fumaric acid CH=CH).

Further aspects and embodiments of the present disclosure are set out in the numbered clauses below:

1. Crystalline Cenicriviroc: fumaric acid

2. Crystalline Cenicriviroc: fumaric acid which is a co-crystal

3. Crystalline Cenicriviroc fumarate

4. A crystalline product according to Clauses 1, 2, or 3, wherein the molar ratio between Cenicriviroc and fumaric acid is between 2:1 and 1:2.

5. A crystalline product according to Clause 4, wherein the molar ratio between Cenicriviroc and fumaric acid is between 1: 1.5 and 1.5:1.

A crystalline product according to Clause 5, wherein the molar ratio between Cenicriviroc and fumaric acid is between 1: 1.25 and 1.25: 1 A crystalline product according to any of Clauses 1, 2, 3, 4, 5, or Clause 6, wherein the molar ratio between Cenicriviroc and fumaric acid is about 1:1. A crystalline product according to any of Clauses 1, 2, 3 or 4 wherein the molar ratio between Cenicriviroc and fumaric acid is 2:1. A crystalline product according to Clause 1, 2, or 3, wherein the product is Cenicriviroc hemifumarate. A crystalline product according to Clause 8 wherein the product is a 1 : 1 co-crystal of Cenicriviroc fumarate salt and Cenicriviroc. A crystalline product according to Clause 1,2 or 3 wherein the product is a 2: 1 co-crystal of Cenicriviroc and fumaric acid. A crystalline product according to clause 5 wherein the molar ratio between Cenicriviroc and fumaric acid is 4:3. A crystalline product according to Clause 12 wherein the product is a 3 : 1 co-crystal of Cenicriviroc fumarate salt and Cenicriviroc. A crystalline product according to Clause 12 wherein the product is a 2: 1 co-crystal of Cenicriviroc hemi-fumarate salt and fumaric acid. A crystalline product according to Clause 12 wherein the product is a 4:3 co-crystal of Cenicriviroc and fumaric acid. A crystalline product according to any one of Clauses 1-7, designated Form 1, which is characterized by data selected from one or more of the following: a. an XRPD pattern having peaks at 3.9, 7.3, 10.4, 16.1 and 20.4 degrees 2- theta ± 0.2 degrees 2-theta; b. an XRPD pattern as depicted in Figure 1; and c. combinations of these data. A crystalline product according to any one of Clauses 1-8, designated Form 1, characterized by the XRPD pattern having peaks at 3.9, 7.3, 10.4, 16.1 and 20.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having one or two additional peaks selected from 5.1 and 9.3 degrees two theta ± 0.2 degrees two theta. A crystalline product according to any of Clauses 1-9, designated Form 1, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Cenicriviroc: fumaric acid or crystalline Cenicriviroc fumarate. A crystalline product according to any of Clauses 1-9, designated Form 1, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Cenicriviroc: fumaric acid or crystalline Cenicriviroc fumarate. A crystalline product according to any one of Clauses 1-4, 8, 9, 10 or 11, designated Form 2, which is characterized by data selected from one or more of the following: a. an XRPD pattern having peaks at 4.4, 7.7, 12.0, 13.2 and 17.5 degrees 2- theta ± 0.2 degrees 2-theta; b. an XRPD pattern as depicted in Figure 2; and c. combinations of these data. A crystalline product according to any of Clauses 1-4, 8, 9, 10, or 11, or 20, designated Form 2, characterized by the XRPD pattern having peaks at 4.4, 7.7, 12.0, 13.2 and 17.5 degrees 2-theta ± 0.2 degrees 2-theta, and also having one or two additional peaks selected from 15.5 and 18.9 degrees two theta ± 0.2 degrees two theta. A crystalline product according to any of Clauses 1-4, 8, 9, 10, or 11, or 20, or 21 designated Form 2, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Cenicriviroc: fumaric acid or crystalline Cenicriviroc fumarate. A crystalline product according to any of Clauses 1-4, 8, 9, 10, or 11 or 20, 21, or 22, designated Form 2, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Cenicriviroc: fumaric acid or crystalline Cenicriviroc fumarate. A crystalline product according to any one of Clauses 1-5, 12, 13, 14, or 15 designated Form 3, which is characterized by data selected from one or more of the following: a. an XRPD pattern having peaks at 4.1, 7.6, 8.5, 11.3 and 20.5 degrees 2- theta ± 0.2 degrees 2-theta; b. an XRPD pattern as depicted in Figure 3; and c. combinations of these data. A crystalline product according to any of Clauses 1, 2, 3, 4, or 5, or 12, 13, 14, 15, or 24, designated Form 3, characterized by the XRPD pattern having peaks at 4.1, 7.6, 8.5, 11.3 and 20.5 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks selected from 5.1, 9.3, 9.7, 10.3 and 18.2 degrees two theta ± 0.2 degrees two theta. A crystalline product according to any of Clauses 1, 2, 3, 4, or 5, or 12, 13, 14, or 15, or 24 or 25, designated Form 3, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Cenicriviroc: fumaric acid or crystalline Cenicriviroc fumarate. A crystalline product according to any of Clauses 1, 2, 3, 4, or 5, or 12, 13, 14, 15, or 16, or 24, 25, or 26, designated Form 3, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Cenicriviroc: fumaric acid or crystalline Cenicriviroc fumarate. A pharmaceutical composition comprising a crystalline product according to any of Clauses 1-25, or 26-27, and at least one pharmaceutically acceptable excipient. Use of a crystalline product according to any of Clauses 1-25, or 26 or 27 for the preparation of a pharmaceutical composition and/or formulation, preferably wherein the pharmaceutical formulation is a tablet, capsule, etc. A process for preparing the pharmaceutical composition according to Clause 28, comprising combining a crystalline product according to any of Clauses 1-25, or 26-27 with at least one pharmaceutically acceptable excipient. A crystalline product according to any of Clauses 1-25 or 26-27, or a pharmaceutical composition according to Clause 28, for use as a medicament. A crystalline product according to any of Claims 1-25 or 26-27, or a pharmaceutical composition according to Claim 28, for use in the treatment of liver diseases, such as non-alcoholic steatohepatitis, or for the treatment of HIV infections, or for the treatment cognition disorders. A method of treating liver diseases, such as non-alcoholic steatohepatitis, or treating HIV infections, or treating cognition disorders, comprising administering a therapeutically effective amount of a crystalline product according to any of Clauses 1-25 or 26-27, or a pharmaceutical composition according to Clause 28, to a subject in need of the treatment. Use of a crystalline product according to any of Clauses 1-25 or 26-27, in the preparation of another solid state form of Cenicriviroc: fumaric acid or crystalline Cenicriviroc fumarate. A process for preparing a solid state form of Cenicriviroc: fumaric acid or crystalline Cenicriviroc fumarate comprising preparing any one or a combination of a crystalline product according to any one of Clauses 1-25 or 26-27, and converting it to another a solid state form thereof.

Claims

CLAIMS What is claimed is:

1. Crystalline Cenicriviroc: fumaric acid.

2. A crystalline product according to claim 1, wherein the molar ratio between Cenicriviroc and fumaric acid is between 2: 1 and 1 :2.

3. A crystalline product according to claim 2, wherein the molar ratio between Cenicriviroc and fumaric acid is between 1: 1.5 and 1.5:1.

4. A crystalline product according to any of claims 1 or 2 wherein the molar ratio between Cenicriviroc and fumaric acid is 2:1.

5. A crystalline product according to any 1, 2, or 3 , wherein the molar ratio between Cenicriviroc and fumaric acid is 4:3.

6. A crystalline product according to any one of claims 1-2, or 4, designated Form 2, which is characterized by data selected from one or more of the following: a. an XRPD pattern having peaks at 4.4, 7.7, 12.0, 13.2 and 17.5 degrees 2- theta ± 0.2 degrees 2-theta; b. an XRPD pattern as depicted in Figure 2; and c. combinations of these data.

7. A crystalline product according to any of claims 1-2, 4, or 6, designated Form 2, characterized by the XRPD pattern having peaks at 4.4, 7.7, 12.0, 13.2 and 17.5 degrees 2-theta ± 0.2 degrees 2-theta, and also having one or two additional peaks selected from 15.5 and 18.9 degrees two theta ± 0.2 degrees two theta.

8. A crystalline product according to any of claims 1-2, 4, 6, or 7, designated Form 2, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Cenicriviroc: fumaric acid or crystalline Cenicriviroc fumarate.

9. A crystalline product according to any of claims 1-2, 4, 6, 7, or 8, designated form 2, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Cenicriviroc: fumaric acid or crystalline Cenicriviroc fumarate.

10. A crystalline product according to any one of claims 1-3, or 5, designated Form 3, which is characterized by data selected from one or more of the following: a. an XRPD pattern having peaks at 4.1, 7.6, 8.5, 11.3 and 20.5 degrees 2-theta ± 0.2 degrees 2-theta; b. an XRPD pattern as depicted in Figure 3; and c. combinations of these data.

11. A crystalline product according to any of claims 1-3, 5, or 10, designated Form 3, characterized by the XRPD pattern having peaks at 4.1, 7.6, 8.5, 11.3 and 20.5 degrees 2- theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks selected from 5.1, 9.3, 9.7, 10.3 and 18.2 degrees two theta ± 0.2 degrees two theta.

12. A crystalline product according to any of claims 1-3, 5, 10 or 11, designated Form 3, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Cenicriviroc: fumaric acid or crystalline Cenicriviroc fumarate.

13. A crystalline product according to any of claims 1-3, 5, 10, 11, or 12, designated Form 3, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Cenicriviroc: fumaric acid or crystalline Cenicriviroc fumarate.

14. A pharmaceutical composition comprising a crystalline product according to any of claims 1-13 and at least one pharmaceutically acceptable excipient.

15. Use of a crystalline product according to any of claims 1-13 for the preparation of a pharmaceutical composition and/or formulation.

16. A process for preparing the pharmaceutical composition according to claim 14, comprising combining a crystalline product according to any of claims 1-13 with at least one pharmaceutically acceptable excipient.

17. A crystalline product according to any of claims 1-13 or a pharmaceutical composition according to claim 14 for use as a medicament.

18. A crystalline product according to any of claims 1-13, or a pharmaceutical composition according to Claim 14, for use in the treatment of liver diseases, such as non-alcoholic steatohepatitis, or for the treatment of HIV infections, or for the treatment cognition disorders.

19. A method of treating liver diseases, such as non-alcoholic steatohepatitis, or treating HIV infections, or treating cognition disorders, comprising administering a therapeutically effective amount of a crystalline product according to any of Claims 1-13, or a pharmaceutical composition according to claim 14, to a subject in need of the treatment.