Crystalline forms of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylmethyl)phenol and their salts

Abstract

The present invention relates to novel crystalline 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylmethyl)phenol and salts thereof, and processes for the preparation of the same and their use in pharmaceutical formulations and in the treatment of parasitic infections such as malaria.

Description

Technical Field

[0001] Technical field The present invention relates to novel crystals of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylmethyl)phenol and their salts, as well as a process for their production, and pharmaceutical preparations, and their use.

Background Art

[0002] Background of the present invention Pyronaridine ((4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylmethyl)phenol tetraphosphate) is a commercially available antimalarial agent, first synthesized in 1970 by the Institute of Chinese Parasitic Disease, Chinese Academy of Preventative Medicine. The commercially available API pyronaridine is the tetraphosphate salt shown below:

Chemical Formula

[0003] The tetraphosphate salt monohydrate form of pyronaridine is also described in CN 105461713 A. Regarding the potential use of pyronaridine in a fixed-dose formulation (single-dose solid preparation containing two active ingredients), the use of the commercially available API (tetraphosphate salt) has certain drawbacks due to the high weight fraction of the inert mass within the tetraphosphate salt (43 wt% due to the tetraphosphate counterion in the anhydrous tetraphosphate) and the strong water absorption behavior. Commercial APIs are classified as hygroscopic according to Ph. Eur. based on the difference in water uptake between 40% rh and 80% rh (see experimental data described in Example 1 in the Experimental Section). The hygroscopicity of pyronarizines is particularly unfavorable in terms of manufacturing and physical stability behavior at high relative humidity, due to the risk of significantly increased water uptake during drug manufacture and storage.

[0004] Different salt forms of a compound are known to have different properties, and therefore, different salt forms of pharmaceutically active ingredients can provide a basis for improving formulations, solubility profiles, stability, or shelf life. Different salts can also give rise to different polymorphisms, which can provide additional opportunities to improve the properties and characteristics of pharmaceutical ingredients. Polymorphism in materials science is the ability of a solid material to exist in two or more crystalline forms with different arrangements and / or conformations of molecules within the crystal lattice. A solvate is a crystalline solid adduct containing a stoichiometric or non-stoichiometric amount of solvent incorporated into its crystal structure. When the incorporated solvent is water, the solvate is also commonly known as a hydrate. Polymorphs can be distinguished from one another by various techniques, such as powder X-ray diffraction (XRD), thermogravimetric analysis, and differential scanning calorimetry. Using one or more of these techniques, a particular polymorph can be characterized, and different polymorphic forms of a compound can be distinguished.

[0005] Different polymorphs (including solvated forms) of solid materials may have different properties such as melting point, chemical reactivity, apparent solubility, dissolution rate, vapor pressure, hygroscopicity, particle shape, fluidity, compressibility, and density. These properties can directly affect the ability to process and manufacture solid active ingredients, as well as the stability, solubility, and bioavailability of drugs. Therefore, polymorphism can affect the quality, safety, and efficacy of drugs. For example, metastable pharmaceutical solid forms may change their crystalline structure or solvate / desolvate in response to changes in environmental conditions or the passage of time. As a result, stability and shelf life may differ between different polymorphs of solid materials. Novel polymorphs and solvates of pharmaceutically useful compounds can offer opportunities to improve the performance characteristics of pharmaceutical products. The object of the present invention was to provide a novel form of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyrizin-10-yl)amino]-2,6-bis(pyrrolidine-1-ylmethyl)phenol that exhibits solid-state properties beneficial for pharmaceutical development, particularly a lower weight fraction of inert mass in the API entity and improved water uptake behavior. [Overview of the project] [Problems that the invention aims to solve]

[0006] Description of the present invention The present invention provides a novel crystalline form of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyrizin-10-yl)amino]-2,6-bis(pyrrolidine-1-ylmethyl)phenol having solid-state properties beneficial for pharmaceutical development. In particular, the novel crystalline form of the present invention is advantageous from the viewpoint of pharmaceutical development because it has little to no inert mass in the API entity and exhibits improved water uptake behavior (compared to commercially available tetraphosphorate salts). In particular, the present invention provides the following novel solid-state forms: [Means for solving the problem]

[0007] • The tosylate salt form of the new crystal - referred to as form I; • The vesylate salt form of the new crystal - referred to as form II; • The hemi-edisylate salt form of the new crystal - referred to as form III; • The napsylate salt form of the new crystal - referred to as form IV; • The napsylate salt form of the new crystal - referred to as form V; • Anhydrous free base form VI; and • Anhydrous free base form VII [Brief explanation of the drawing]

[0008] [Figure 1] Figure morphology Ia shows a typical powder X-ray diffractogram of morphology I; [Figure 2] Morphology Ib shows a typical DSC scan of Morphology I; [Figure 3] Morphology Ic shows a typical TGA scan of Morphology I; [Figure 4] Morphology Id shows a typical water vapor sorption isotherm of Morphology I; [Figure 5] Morphology IIa shows a typical powder X-ray diffractogram of Morphology II; [Figure 6] Morphology IIb shows a typical DSC scan of Morphology II; [Figure 7] Morphology IIc shows a typical TGA scan of Morphology II; [Figure 8] Morphology IId shows a typical water vapor sorption isotherm of Morphology II; [Figure 9] Morphology IIIa shows a typical powder X-ray diffractogram of Morphology III; [Figure 10] Morphology IIIb shows a typical DSC scan of Morphology III; [Figure 11] Morphology IIIc shows a typical TGA scan of Morphology III; [Figure 12] Morphology IIId shows a typical water vapor sorption isotherm of Morphology III; [Figure 13] Morphology IVa shows a typical powder X-ray diffractogram of Morphology IV; [Figure 14] Morphology IVb shows a typical DSC scan of Morphology IV; [Figure 15] Morphology IVc shows a typical TGA scan of Morphology IV; [Figure 16] Morphology IVd shows a typical water vapor sorption isotherm of Morphology IV; [Figure 17] Morphology Va shows a typical powder X-ray diffractogram of Morphology V; [Figure 18] Morphology Vb shows a typical DSC scan of Morphology V; [Figure 19] Morphology Vc shows a typical TGA scan of Morphology V; [Figure 20]Figure morphology Vd shows a typical water vapor sorption isotherm of morphology V; [Figure 21] Figure morphology VIa shows a typical powder X-ray diffractogram of morphology VI; [Figure 22] Figure morphology VIb shows a typical DSC scan of morphology VI; [Figure 23] Figure morphology VIc shows a typical TGA scan of morphology VI; [Figure 24] Figure morphology VId shows a typical water vapor sorption isotherm of morphology VI; [Figure 25] Figure morphology VIIa shows a typical powder X-ray diffractogram of morphology VII; [Figure 26] Figure morphology VIIb shows a typical DSC scan of morphology VII; [Figure 27] Figure VIIc shows a typical TGA scan of 3; [Figure 28] Figure morphology VIId shows a typical water vapor sorption isotherm of morphology VII; [Figure 29] Figure a shows a typical powder X-ray diffractogram of tetraphosphate (prior art form); [Figure 30] Figure b shows a typical DSC scan of tetraphosphate (prior art form); [Figure 31] Figure c shows a typical TGA scan of tetraphosphate (prior art form); and [Figure 32] Figure d shows a typical water vapor sorption isotherm of tetraphosphate (prior art form).

[0009] Unless otherwise stated, this invention describes the solid-state forms of chemically pure pyronaridine and its salts (chemical purity ≥ 98% by NMR analysis). All forms are characterized according to standard methods found, for example, in Rolf Hilfiker, 'Polymorphism in the Pharmaceutical Industry', Wiley-VCH. Weinheim 2006 (Chapter 6: X-Ray Diffraction, Chapter 6: Vibrational Spectroscopy, Chapter 3: Thermal Analysis, Chapter 9: Water Vapor Sorption, and references therein) and HG Brittain, 'Polymorphism in Pharmaceutical Solids', Vol. 95, Marcel Dekker Inc., New York 1999 (Chapter 6 and its references). When used herein, unless otherwise stated, X-ray powder diffraction measurements are performed using monochromatic Cu-Kα1 radiation at a wavelength of 1.5406 Å. Furthermore, unless otherwise stated, X-ray powder diffraction measurements are performed at room temperature.

[0010] The solid-state forms of pyronaridine and its salts include crystalline forms or crystalline morphs. As used herein, solid-state forms, crystalline forms, crystalline morphs, polymorphs, and polymorphs are used interchangeably. It may be referred to herein that crystalline morphologies are characterized by graph data “substantially shown” or “shown” in the figures. Such graph data include, for example, powder X-ray diffraction diffractograms and DSC or TGA. Graph data may provide additional technical information that can help define certain solid-state morphologies that cannot be explained, or cannot be easily explained, by referring to numerical values ​​of peak positions and / or relative intensities. Those skilled in the art will understand that such graph representations of data may be affected by small variations; for example, relative peak intensities and peak positions may differ due to factors such as instrument response and variations in sample concentration and purity. Those skilled in the art will be able to easily compare the graph data shown in the figures herein with graph data generated for an unknown crystalline morphology and determine whether the two sets of graph data characterize the same crystalline morphology or two different crystalline morphologies.

[0011] The solid state morphology may be referred to as being characterized by analytical data selected from a more diverse set of data, such as by an X-ray powder diffractogram pattern having a specific group of peaks, or by an X-ray powder diffractogram as shown in the figure, or by a combination thereof (or a combination of these data). These expressions, for example, “the combination thereof,” are intended to indicate that a person skilled in the art can characterize the solid state morphology using any combination of the enumerated characteristic analytical data. For example, a person skilled in the art can characterize a crystalline form using a group, for example, four, five, or six characteristic X-ray powder diffraction peaks, and supplement the characterization with one or more additional features observed in the powder diffraction pattern, such as additional peaks, characteristic peak shapes, peak intensities, or even the absence of peaks at certain positions in the powder X-ray powder diffractogram pattern. Alternatively, a person skilled in the art may characterize a crystal form using, for example, a group of 4, 5, 6, 7, 8, 9, or 10 characteristic powder X-ray diffraction peaks, and supplement that characterization data with one or more additional features observed using, for example, DSC thermogram features of the characterized crystal form, using another analytical method.

[0012] The crystalline forms (or polymorphs) described herein are pure or substantially free of other crystalline forms (or polymorphs). When used herein, a crystalline form means that it contains less than 10% of any other known forms of the compound in question, as measured, for example, by PXRD. As used herein, unless otherwise stated, the term “powder” means a solid compound in the form of particles or granules, which may be poured. When used herein, unless otherwise stated, DSC measurements are performed using a Mettler-Toledo DSC 821 with a heating rate of 5 K / min and a nitrogen purge gas of 50 mL / min. When used herein, unless otherwise stated, TGA measurements are performed using a Mettler-Toledo DSC 821 with a heating rate of 5 K / min and a nitrogen purge gas of 50 mL / min.

[0013] When used herein, unless otherwise stated, water vapor adsorption isotherm measurements are performed from the SMS to the DVS-1 or DVS-specific system. As used herein and unless otherwise stated, the term “anhydrous” refers to a crystalline material containing either 1% or less (w / w) water or an organic solvent, as measured by TGA. In the context of the present invention, the anhydrous solid form of a compound refers to a form that does not contain the defined amount of crystalline water (or other solvent) within the crystal. As used herein, unless otherwise stated, the term “solvate” refers to a crystalline form in which a solvent is incorporated into the crystalline structure. When the solvent is water, such a form is often referred to as a “hydrate.” The following abbreviations refer to those used herein: iso-BuOH (iso-butanol), n-BuOH (n-butanol), dec (degradation), DSC (differential scanning calorimetry), DI (deionization), DMSO (dimethyl sulfoxide), EtOH (ethanol), FeSSIF (fed-state simulated intestinal fluid), FaSSIF (fasted-state simulated intestinal fluid), g (gram), HPLC (high-performance liquid chromatography), hr (hour), MHz (megahertz), MeOH (methanol), min (minute), mL (milliliters), mmol (millimoles), mM (millimoles), mp (melting point), MS (mass spectrometry), MW (microwave), NMR (nuclear magnetic resonance), Ph.Eur. (pharmacopoeia) Europaea), PTFE (polytetrafluoroethylene), 2-PrOH (2-propanol), RH (relative humidity), RT (room temperature), TGA (thermogravimetric analysis), THF (tetrahydrofuran), TMS (trimethylsilyl), UV (ultraviolet light), wt% (weight percentage), X-ray powder diffractogram (XRPD), powder X-ray diffraction (PXRD).

[0014] In one aspect, the present invention provides a crystalline form of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridine-10-yl)amino]-2,6-bis(pyrrolidine-1-ylmethyl)phenol, referred to as Form I. Crystalline Form I is a tosylate salt and is characterized by the following data and combinations thereof: a) Powder X-ray diffraction patterns having 1, 2, 3, 4, or 5 peaks at diffraction angles (2-theta) of 7.1°±0.2°, 12.9°±0.2°, 15.4°±0.2°, 18.2°±0.2°, and / or 21.2°±0.2°; b) Powder X-ray diffraction patterns having peaks 1, 2, 3, 4, or 5 at diffraction angles (2-theta) of 7.1° ± 0.2°, 12.9° ± 0.2°, 15.4° ± 0.2°, 18.2° ± 0.2° and / or 21.2° ± 0.2°, and also having additional peaks 1, 2, 3, 4, or 5 at diffraction angles (2-theta) of 11.9° ± 0.2°, 14.1° ± 0.2°, 14.6° ± 0.2°, 16.7° ± 0.2° and / or 19.3° ± 0.2°; c) Powder X-ray diffraction pattern according to form I of the table; or d) The XRPD pattern substantially shown in morphology Ia of the figure. The peak list corresponding to XRPD in Figure Ia is shown in Table I.

[0015] [Table 1]

[0016] Tosylate salt form I may be further characterized by the following physical properties: - Tosylate content: 1.05 eq. of tosylate; - The thermal behavior of tosylate form I exhibits a small endothermic phenomenon up to ~135°C and a melting point of 151°C. DSC and TGA profiles are shown in Figures 1b and 1c. TTGA shows an extremely small weight loss of less than 1 wt% before alteration. The water vapor sorption behavior of Form I exhibits a moderate water uptake level of 2.4 wt% in the relative humidity (rh) range of 40-80% rh. Tosilate salt Form I can be classified as hygroscopic based on the difference in water uptake between 40-80% rh (Section 5.11) according to Ph.Eur. The water vapor sorption isotherm of Form I (25°C) is shown in the figure for Form Id. - The solubility levels of Form I in fasting-simulated intestinal fluid [FaSSIF, pH 6.5] at 37°C were approximately 0.56 mg / mL (after 15 min), approximately 0.55 mg / mL (after 60 min), and approximately 0.54 mg / mL (after 120 min), respectively. Morphology I exhibits extremely good crystallinity and is a hydrated form.

[0017] In one aspect, the present invention provides a crystalline form of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridine-10-yl)amino]-2,6-bis(pyrrolidine-1-ylmethyl)phenol, referred to as Form II. Crystalline Form II is a besilate salt and is characterized by the following data and combinations thereof: a) Powder X-ray diffraction patterns having 1, 2, 3, 4, or 5 peaks at diffraction angles (2-theta) of 7.8° ± 0.2°, 15.0° ± 0.2°, 17.6° ± 0.2°, 20.7° ± 0.2°, and / or 23.3° ± 0.2°; b) Powder X-ray diffraction patterns having peaks 1, 2, 3, 4, or 5 at diffraction angles (2-theta) of 7.8° ± 0.2°, 15.0° ± 0.2°, 17.6° ± 0.2°, 20.7° ± 0.2° and / or 23.3° ± 0.2°, and also having additional peaks 1, 2, 3, 4, or 5 at diffraction angles (2-theta) of 8.7° ± 0.2°, 12.6° ± 0.2°, 16.1° ± 0.2°, 18.3° ± 0.2° and / or 19.1° ± 0.2°; c) Powder X-ray diffraction pattern according to form II of the table; or d) The XRPD pattern substantially shown in Figure II. The peak list corresponding to XRPD in Figure IIa is shown in Table II.

[0018] [Table 2]

[0019] The besilate salt of form II may be further characterized by the following physical properties: -Besilate content 1.15 eq. besilate; - The thermal behavior of vesylate form II shows a small endothermic phenomenon at 126°C and a melting point of 171°C. TGA shows an extremely small weight loss of less than 1 wt% before alteration. DSC and TGA profiles are shown in the figures for forms IIb and IIc. The water vapor sorption behavior of Form II shows an extremely low water uptake level of 1.4 wt% in the relative humidity (rh) range of 40–90% rh. According to Ph.Eur., Form II of the vesylate salt can be classified as slightly hygroscopic based on the difference in water uptake between 40–80% rh (Section 5.11). The water vapor sorption isotherm of Form II (25°C) is shown in the figure for Form IId. - The solubility levels of Form II in fasting-simulated intestinal fluid [FaSSIF, pH 6.5] at 37°C were approximately 0.45 mg / mL (after 15 min), approximately 0.44 mg / mL (after 60 min), and approximately 0.44 mg / mL (after 120 min), respectively. Form II exhibits extremely good crystallinity and is a hydrate form.

[0020] In another aspect, the present invention provides 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridine-10-yl)amino]-2,6-bis(pyrrolidine-1-ylmethyl)phenol, shown as form III. Crystal form III is a hemiedisylate and can be characterized by the following data and combinations thereof: a) Powder X-ray diffraction patterns with 1, 2, 3, 4, or 5 peaks at diffraction angles of 2 theta of 10.2° ± 0.2°, 13.8° ± 0.2°, 15.1° ± 0.2°, 18.8° ± 0.2°, and / or 19.9° ± 0.2°; b) Powder X-ray diffraction patterns having peaks 1, 2, 3, 4, or 5 at diffraction angles 2-theta of 10.2° ± 0.2°, 13.8° ± 0.2°, 15.1° ± 0.2°, 18.8° ± 0.2° and / or 19.9° ± 0.2°, and also having an additional peak of 1, 2, 3, 4, or 5 at diffraction angles 2-theta of 11.8° ± 0.2°, 17.7° ± 0.2°, 20.6° ± 0.2°, 21.2° ± 0.2° and / or 23.2°; c) Powder X-ray diffraction pattern according to form III of the table; or d) XRPD pattern substantially shown in Figure IIIa, The peak list corresponding to XRPD in Figure IIIa is shown in Table III.

[0021] [Table 3]

[0022] Hemiedisylate salt form III may be further characterized by the following physical properties: - Edisylate content: 0.5 eq. edisylate -The thermal behavior shows overlapping melting / alteration at 220°C. The total weight loss (TGA) is extremely small, less than 1 wt% before alteration. The DSC and TGA profiles are shown in figures IIIb and IIIc. —The water vapor sorption behavior of Form III shows a water uptake level of 1.5 wt% in the relative humidity (rh) range of 40 to 80% rh. Form III can be classified as slightly hygroscopic based on the difference in water uptake between 40 and 80% rh (Section 5.11) according to Ph.Eur. The water vapor sorption isotherm of Form III (25°C) is shown in Figure IIId. - The solubility levels of Form III in fasting-simulated intestinal fluid [FaSSIF, pH 6.5] at 37°C were approximately 0.46 mg / mL (after 15 min), approximately 0.48 mg / mL (after 60 min), and approximately 0.47 mg / mL (after 120 min), respectively. Form III exhibits excellent crystallinity and is a hydrated form. Form III is slightly hygroscopic according to Ph.Eur., but this form does not tend to form hydrates even when exposed to high RH levels (up to 90% RH).

[0023] In another aspect, the present invention provides 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridine-10-yl)amino]-2,6-bis(pyrrolidine-1-ylmethyl)phenol, shown as form IV. Crystalline form IV is a napsylate salt and can be characterized by the following data and combinations thereof: a) Powder X-ray diffraction patterns having 1, 2, 3, 4, or 5 peaks at diffraction angles (2-theta) of 6.9° ± 0.2°, 12.6° ± 0.2°, 15.0° ± 0.2°, 15.7° ± 0.2°, and / or 22.2° ± 0.2°; b) Powder X-ray diffraction patterns having peaks 1, 2, 3, 4, or 5 at diffraction angles (2-theta) of 6.9° ± 0.2°, 12.6° ± 0.2°, 15.0° ± 0.2°, 15.7° ± 0.2° and / or 22.2° ± 0.2°, and also having additional peaks 1, 2, 3, 4, or 5 at diffraction angles (2-theta) of 9.5° ± 0.2°, 17.2° ± 0.2°, 18.7° ± 0.2°, 19.7° ± 0.2° and / or 20.8° ± 0.2°; c) Powder X-ray diffraction pattern according to form IV of the table; or d) The XRPD pattern substantially shown in morphology IVa of the figure. The peak list corresponding to the XRPD in Figure IVa is shown in Table IV.

[0024] [Table 4]

[0025] Napsilate salt form IV may be further characterized by the following physical properties: - Napsylate content (determined by NMR): 1 eq. napsylate - The thermal behavior of Form IV shows a melting point at ~169°C. TGA shows an extremely small weight loss of less than 1 wt% before alteration. DSC and TGA profiles are shown in Forms IVb and IVc in the figure. —The water vapor sorption behavior of Form IV shows a water uptake level of 0.6 wt% in the relative humidity (rh) range of 40–80% rh. Form IV can be classified as slightly hygroscopic based on the difference in water uptake between 40–80% rh (Section 5.11) according to Ph.Eur. The water vapor sorption isotherm of Form IV (25°C) is shown in Form IVd in the figure. - The solubility levels of Form IV in fasting-simulated intestinal fluid [FaSSIF, pH 6.5] at 37°C were approximately 0.17 mg / mL (after 15 min), approximately 0.56 mg / mL (after 60 min), and approximately 0.82 mg / mL (after 120 min), respectively. Form IV exhibits excellent crystallinity and is a hydrated form. Form IV is slightly hygroscopic according to Ph.Eur., but this form does not tend to form hydrates even when exposed to high RH levels (up to 90% RH).

[0026] In another aspect, the present invention provides 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridine-10-yl)amino]-2,6-bis(pyrrolidine-1-ylmethyl)phenol, shown as form V. Crystalline form V is a napsylate form and can be characterized by the following data and combinations thereof: a) Powder X-ray diffraction patterns having 1, 2, 3, 4, or 5 peaks at diffraction angles (2-theta) of 6.9° ± 0.2°, 15.7° ± 0.2°, 17.5° ± 0.2°, 22.2° ± 0.2°, and / or 25.4 ± 0.2°; b) Powder X-ray diffraction patterns having peaks 1, 2, 3, 4, or 5 at diffraction angles (2-theta) of 6.9° ± 0.2°, 15.7° ± 0.2°, 17.5° ± 0.2°, 22.2° ± 0.2° and / or 25.4° ± 0.2°, and also having additional peaks 1, 2, 3, 4, or 5 at diffraction angles (2-theta) of 20.8° ± 0.2°, 21.7° ± 0.2° and / or 29.3° ± 0.2°; c) Powder X-ray diffraction pattern according to morphology V in the table; or d) The XRPD pattern substantially shown in morphology Va in the figure. The peak list corresponding to the XRPD of the figure's form Va is shown in the table's form V.

[0027] [Table 5]

[0028] Napsilate salt form V may be further characterized by the following physical properties: - Napsylate content (determined by NMR): 1 eq. napsylate - The thermal behavior of morphology V shows a melting point at ~169°C. TGA shows an extremely small weight loss of less than 1 wt% before alteration. DSC and TGA profiles are shown for morphology Vb and morphology Vc in the figure. The water vapor sorption behavior of Form V shows a water uptake level of 0.6 wt% in the relative humidity (rh) range of 40-80% rh. Form V can be classified as slightly hygroscopic based on the difference in water uptake amount of 40-80% rh (Section 5.11) according to Ph.Eur. The water vapor sorption isotherm of Form V (25°C) is shown as Form Vd in the figure. - The solubility levels of form V in fasting-simulated intestinal fluid [FaSSIF, pH 6.5] at 37°C were approximately 0.17 mg / mL (after 15 min), approximately 0.56 mg / mL (after 60 min), and approximately 0.82 mg / mL (after 120 min), respectively. Morphology V exhibits excellent crystallinity and is in hydrate form. According to Ph.Eur., morphology V is non-hygroscopic and does not tend to form hydrates even when exposed to high RH levels (up to 90% RH).

[0029] In another aspect, the present invention provides 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridine-10-yl)amino]-2,6-bis(pyrrolidine-1-ylmethyl)phenol, shown as form VI. Crystal form VI is the free base form and can be characterized by the following data and combinations thereof: a) Powder X-ray diffraction patterns having 1, 2, 3, 4, or 5 peaks at diffraction angles (2-theta) of 6.7° ± 0.2°, 9.3° ± 0.2°, 16.1° ± 0.2°, 19.4° ± 0.2°, and / or 25.0° ± 0.2°; b) Powder X-ray diffraction patterns having peaks 1, 2, 3, 4, or 5 at diffraction angles (2-theta) of 6.7° ± 0.2°, 9.3° ± 0.2°, 16.1° ± 0.2°, 19.4° ± 0.2° and / or 25.0° ± 0.2°, and also having additional peaks 1, 2, 3, 4, or 5 at diffraction angles (2-theta) of 10.0° ± 0.2°, 11.0° ± 0.2°, 13.4° ± 0.2°, 14.5° ± 0.2° and / or 20.7° ± 0.2°; c) Powder X-ray diffraction pattern according to morphology VI of the table; or d) The XRPD pattern substantially shown in morphology VIa of the figure. The peak list corresponding to the XRPD in Figure VIa is shown in Table VI.

[0030] [Table 6]

[0031] Free base form VI may be further characterized by the following physical properties: - The thermal behavior of form VI shows a small endothermic phenomenon at ~174°C. TGA shows an extremely small weight loss of less than 1 wt% before alteration. DSC and TGA profiles are shown in the figures for forms VIb and VIc. The water vapor sorption behavior of Form VI shows a water uptake level of 0.1 wt% in the relative humidity (rh) range of 40–80% rh. Form VI can be classified as non-hygroscopic based on the difference in water uptake amount of 40–80% rh (Section 5.11) according to Ph.Eur. The water vapor sorption isotherm of Form VI (25°C) is shown in Form VId in the figure. - Morphology VI exhibits excellent crystallinity and is in hydrate form. Morphology VI is non-hygroscopic according to Ph.Eur. and does not tend to form hydrates even when exposed to high RH levels (up to 98% RH). In another aspect, the present invention provides 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridine-10-yl)amino]-2,6-bis(pyrrolidine-1-ylmethyl)phenol, shown as form VII. Crystal form VII can be characterized by the following data and combinations thereof: a) Powder X-ray diffraction patterns having 1, 2, 3, 4, or 5 peaks at diffraction angles (2 theta) of 6.7° ± 0.2°, 9.9° ± 0.2°, 16.3° ± 0.2°, 19.1° ± 0.2°, and / or 24.3° ± 0.2°; b) Powder X-ray diffraction patterns having peaks 1, 2, 3, 4, or 5 at diffraction angles (2-theta) of 6.7° ± 0.2°, 9.9° ± 0.2°, 16.3° ± 0.2°, 19.1° ± 0.2°, and / or 24.3° ± 0.2°, and also having an additional peak 1, 2, 3, or 4 at diffraction angles (2-theta) of 17.6° ± 0.2°, 19.8° ± 0.2°, 25.0° ± 0.2°, and / or 25.5° ± 0.2°; c) Powder X-ray diffraction pattern according to morphology VII in the table; or d) The XRPD pattern substantially shown in morphology VIIa of the figure. The peak list corresponding to the XRPD in Figure VIIa is shown in Table VII.

[0032] [Table 7]

[0033] Free base form VII may be further characterized by the following physical properties: - The thermal behavior of morphology VII shows a melting point at 183°C. TGA shows an extremely small weight loss of less than 1 wt% before alteration. DSC and TGA profiles are shown in the figures for morphology VIIb and morphology VIIb. The water vapor sorption behavior of morphology VII shows a water uptake level of 0.1 wt% in the relative humidity (rh) range of 40–80% rh. According to Ph.Eur., morphology VII can be classified as non-hygroscopic based on the difference in water uptake between 40–80% rh (Section 5.11). The water vapor sorption isotherm of morphology VII (25°C) is shown in morphology VIId in the figure. Morphology VII exhibits excellent crystallinity and is in hydrate form. According to Ph.Eur., morphology VII is non-hygroscopic and does not tend to form hydrates even when exposed to high RH levels (up to 98% RH). Generally, the anhydrous solid state is particularly preferred with respect to the processing and / or manufacture of solid raw materials because anhydrous materials do not carry the risk of phase conversion due to dehydration during heat treatment. In a further aspect of the present invention, crystalline compounds according to the present invention are provided for use as pharmaceuticals. The present invention also relates to crystalline compounds according to the present invention for use in the treatment and / or prevention of malaria. The treatment and / or prevention of malaria as defined herein includes the treatment and / or prevention of infections caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and / or Plasmodium knowlesi. In addition, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one crystalline compound according to the present invention. In a particular embodiment, the pharmaceutical composition further comprises at least one additional compound selected from the group consisting of physiologically acceptable excipients, adjuvants, diluents, carriers and / or additional pharmacologically active substances (active ingredients, drugs) other than the crystalline compound according to the present invention.

[0034] The present invention further encompasses at least one crystalline compound and / or at least one pharmaceutical composition according to the present invention in a therapeutically effective amount, and at least one further pharmacologically active substance (active ingredient, drug) other than the crystalline compound according to the present invention in a therapeutically effective amount. The present invention further encompasses methods for treating and / or preventing, comprising administering a therapeutically effective amount of a crystalline compound according to the present invention to a person in need of such treatment. The products of the present invention may be used in combination with one or more other pharmacologically active substances (components, drugs) in the treatment, prevention, suppression, or remission of diseases or conditions in which the products of the present invention or other substances are useful. Typically, drug combinations are safer or more effective than either drug alone, or safer or more effective than expected based on the additive properties of the individual drugs. Such other drugs may be administered in the routes and amounts commonly used concurrently or sequentially with the products of the present invention. When the products of the present invention are used concurrently with one or more other drugs, combination products containing such other drugs and the products of the present invention are preferred. However, combination therapy also includes therapies in which the products of the present invention and one or more other drugs are administered on different overlapping schedules. When used in combination with other active ingredients, the products of the present invention or other active ingredients, or both, are intended to be effective at lower doses than when each is used alone. Accordingly, pharmaceutical compositions of the present invention (pharmaceutical compositions described herein) include those containing one or more other active ingredients in addition to the products of the present invention.

[0035] Examples of other pharmacologically active substances (active ingredients, drugs) that may be administered in combination with the product of the present invention, or individually, or in the same pharmaceutical composition, include, but are not limited to, antimalarial agents such as the following compounds: Artemisinin or artemisinin derivatives (such as artemether, artesunate, or dihydroartemisinin), mefloquine, quinine, cycloguanyl, proguanyl, metformin, doxycycline, halophanthrine, lumefantrine, pyrimethamine, sulfadoxine, piperacine, atobacuone, 6-fluoro-2-(4-morpholine-4-ylmethylphenyl)-quinoline-4-carboxylic acid (2-pyrrolidine-1-ylethyl)-amide (CAS: 1469439-69-7) (or any pharmaceutically acceptable salt such as 6-fluoro-2-(4-morpholine-4-ylmethylphenyl)-quinoline-4-carboxylic acid (2-pyrrolidine-1-ylethyl)-amide or succinate, in particular), KAF156 (CAS: 1261113-96-5), tafenoquine (CAS: 106635-80-7), MMV390048 (CAS: 1314883-11-8), DSM265 (CAS: 1282041-94-4), AZ412 (or MMV253, CAS: 1821293-40-6) and / or SAR121. The pharmaceutical compositions of the present invention (as described herein) may be administered by any means necessary to achieve their intended purpose. For example, administration may be by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intra-articular, intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal, transdermal, or oral route. Alternatively, or simultaneously, administration may be by oral route. The dosage administered depends on the recipient's age, health condition, and weight, the type of concurrent treatment, if any, the frequency of treatment, and the nature of the desired effect. Parenteral administration is preferred. Oral administration is particularly preferred. Preferred dosage forms, though not limited to these, include capsules, tablets, pellets, sugar-coated tablets, semi-solids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, and emulsions, which can be produced according to methods known in the art.

[0036] Generally, non-chemical routes for the production of pharmaceutical compositions and / or pharmaceutical preparations include processing steps by preferred mechanical means known in the art, which transfer one or more products of the present invention into dosage forms suitable for administration to patients requiring such treatment. Typically, the transfer of one or more products of the present invention into such dosage forms involves the addition of one or more compounds of the present invention selected from the group consisting of carriers, excipients, auxiliaries, and pharmaceutically active ingredients other than the products of the present invention. Preferred processing steps, but not limited to these, include combinations of each active and inactive ingredient, milling, mixing, granulation, dissolution, dispersion, homogenization, casting, and / or compression. Mechanical means for carrying out such processing steps are known in the art, for example, from Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition. Specifically suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices, or intravenous infusions; suitable for rectal use are suppositories; suitable for parenteral use are solutions, preferably oil-based or aqueous solutions, and also suspensions, emulsions, or grafts; and suitable for topical use are ointments, creams, or powders. The products of the present invention may be lyophilized, and the resulting lyophilized product can be used, for example, in the preparation of injectable preparations. The indicated preparations may be sterilized and / or may contain auxiliary agents such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for altering osmotic pressure, buffers, dyes, flavors, and / or multiple further active ingredients such as one or more vitamins. Suitable excipients include organic or inorganic substances suitable for enteral (e.g., oral), parenteral or topical administration, and which do not react with the products of the present invention, such as water, vegetable oil, benzyl alcohol, alkylene glycol, polyethylene glycol, glycerol triacetate, gelatin, lactose, sucrose, mannitol, sorbitol, or starch (corn starch, wheat starch, rice starch, potato starch), carbohydrates such as cellulose preparations, and / or calcium phosphate, such as calcium triphosphate or calcium hydrogen phosphate, magnesium stearate, talc, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and / or petrolatum.

[0037] Optionally, disintegrants such as the aforementioned starches and carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or sodium alginate, or their salts, may be added. Auxiliaries, though not limited to those mentioned above, include flow regulators and lubricants, such as silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. The core of the sugar-coated tablet is optionally provided with a suitable coating resistant to gastric juice. For this purpose, optionally, a concentrated sugar solution may be used, which may include gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. To produce a gastric juice-resistant coating or to provide a dosage form that offers the advantage of sustained action, the tablet, sugar-coated tablet, or pill may contain an internally administered component and an externally administered component, the latter enclosing the former. The two components may be separated by an enteric coating, which resists disintegration in the stomach and allows the internal components to pass through the duodenum intact or delay release. Various materials may be used for such enteric coatings or coatings, including numerous polymer acids and mixtures of materials such as solutions of polymer acids with suitable cellulose preparations such as shellac, acetyl alcohol, acetyl-cellulose phthalate, cellulose acetate, or hydroxypropyl methylcellulose phthalate. Dyes or pigments may be added to the tablet or sugar-coated tablet coating, for example, for identification or to characterize combinations of active compound doses. Suitable carrier substances are organic or inorganic substances that do not react with the novel compound and are suitable for enteral (e.g., oral) or parenteral administration or topical application, such as water, vegetable oil, benzyl alcohol, polyethylene glycol, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, and petrolatum. In particular, tablets, coated tablets, capsules, syrups, suspensions, infusions or suppositories are used for intestinal administration; solutions, preferably oily or aqueous solutions, and further suspensions, emulsions or grafts are used for parenteral administration; and ointments, creams or powders may be used for topical application. The products of the present invention may be lyophilized, and the resulting lyophilized products may be used, for example, in the manufacture of injectable formulations.

[0038] The preparations shown may be sterilized and / or may contain excipients such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts that affect osmotic pressure, buffering agents, colorants, flavoring agents and / or fragrances. They may also contain, as desired, one or more further active compounds, for example, one or more vitamins. Pharmaceutical preparations that can be used orally include push-in capsules made of gelatin and soft-seal capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-in capsules may contain the active compound in granular form and can be mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid such as fatty oil or liquid paraffin. Further stabilizers may be added. Liquid forms into which the novel compositions of the present invention can be incorporated for oral administration include aqueous solutions, syrups of suitable flavors, aqueous or oily suspensions, and emulsions of flavors having edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersants or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginates, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, or gelatin.

[0039] Pharmaceutical preparations can be used as pharmaceuticals in human and veterinary medicine. As used herein, the term “effective dose” means the amount of a drug or pharmaceutical product that elicits a biological or medical response in a tissue, system, animal or human, as determined, for example, by a researcher or clinician. Furthermore, the term “therapeutably effective dose” means any amount that results in an improved treatment, healing, prevention, or remission of a disease, disorder, or side effect, or a reduction in the rate of progression of the disease or disorder, compared to a corresponding subject that has not received such a dose. The term also encompasses within its range amounts that are effective in enhancing normal physiological function. The therapeutically effective doses of one or more products of the present invention can be known to those skilled in the art or readily determined by standard methods known in the art. The products of the present invention and additional pharmacologically active substances are generally administered in the same manner as commercially available formulations. Typically, therapeutically effective preferred doses are in the range of 0.0005 mg to 1000 mg per dose unit, preferably between 0.005 mg and 500 mg, and particularly between 0.5 mg and 100 mg. The daily dose is preferably between approximately 0.001 mg / kg and 10 mg / kg per kg of body weight.

[0040] Those skilled in the art will readily understand that dose levels may vary depending on the specific compound, the severity of the symptoms, and the subject's sensitivity to side effects. Some particular compounds are more potent than others. A preferred dose for a given compound can be readily determined by various means by those skilled in the art. A preferred means is to measure the physiological potency of the given compound. For the purposes of the present invention, all mammalian species are considered to be included. In a preferred embodiment, such mammals are selected from the group consisting of "primates, humans, rodents, horses, cattle, dogs, felines, domesticated animals, livestock, pets, cows, sheep, pigs, goats, horses, ponies, donkeys, hinnies, mules, hares, rabbits, cats, dogs, guinea pigs, hamsters, rats, and mice." More preferably, such mammals are humans. Animal models are interesting for experimental investigation and provide therapeutic models for human diseases. However, the specific dosage for an individual patient depends on numerous factors, such as the effectiveness of the particular compound used, age, weight, general health status, sex, diet, time and route of administration, excretion rate, type of administration and dosage form, drug combination, and the severity of any specific disorders associated with the treatment. The specific therapeutically effective dose for an individual patient can be readily determined through routine experimentation, for example, by a physician or doctor advising or participating in the treatment procedure.

[0041] In many disorders, the sensitivity of specific cells to treatment with a target compound can be determined by in vitro testing. Typically, cell cultures are mixed with various concentrations of the target compound for a period sufficient for the activator to elicit the relevant response, usually about one hour to one week. In vitro testing may use cultured cells from biopsy samples. The present invention further encompasses methods for manufacturing modified crystals according to the present invention.

[0042] A particular embodiment includes a method for producing crystalline form I, which comprises the following steps: To provide a dispersion in which the concentration of the reagents (free base and p-toluenesulfonic acid) is preferably in the range of 50 to 100 mg / mL. • Stirring of the dispersion at ambient temperature (preferably between room temperature and 65°C, more preferably between 30°C and 55°C). Following multiple (preferably between 4 and 10) heating / cooling cycles (temperatures between 0°C and 10°C from ambient temperature, and vice versa), the mixture is slurryed at a temperature between 0°C and 10°C for several hours (preferably between 3 and 30 hours). • Separation of the solid material, and subsequent drying of the solid material at ambient temperature (preferably under a nitrogen atmosphere). Another specific embodiment includes a method for producing crystal form II, which comprises the following steps: To provide a dispersion having a free base concentration preferably in the range of 50 to 100 mg / mL; • Stirring of the dispersion at ambient temperature (preferably between room temperature and 65°C, more preferably between 30°C and 55°C). Following multiple (preferably between 4 and 10) heating / cooling cycles (temperatures between 0°C and 10°C from ambient temperature, and vice versa), the mixture is slurryed at a temperature between 0°C and 10°C for several hours (preferably between 3 and 30 hours). • Separation of the solid material, and subsequent drying of the solid material at ambient temperature (preferably under a nitrogen atmosphere).

[0043] Another specific embodiment includes a method for producing crystal form III, which comprises the following steps: To provide a dispersion having a free base concentration preferably in the range of 50 to 100 mg / mL; Stirring of the dispersion at ambient temperature (preferably between room temperature and 65°C, more preferably between 30°C and 55°C); • Following multiple (preferably between 4 and 10) heating / cooling cycles (temperatures between 0°C and 10°C from ambient temperature, and vice versa), the slurry is allowed to rise for several hours (preferably between 3 and 30 hours) at temperatures between 0°C and 10°C; • Separation of the solid material and subsequent drying of the solid material at ambient temperature (preferably under a nitrogen atmosphere). Another specific embodiment includes a method for producing crystalline form IV, which includes the following steps: To provide a dispersion having a free base concentration preferably in the range of 50 to 100 mg / mL; • Stirring of the dispersion at ambient temperature (preferably between room temperature and 65°C, more preferably between 30°C and 55°C). The slurry is formed after several (preferably between 4 and 10) heating / cooling cycles (temperatures between 0°C and 10°C from ambient temperature, and vice versa) at a temperature between 0°C and 10°C for several hours (preferably between 3 and 30 hours). • Separation of the solid material and subsequent drying of the solid material at ambient temperature (preferably under a nitrogen atmosphere). Another specific embodiment includes a method for producing crystalline form V, which includes the following steps: To provide a dispersion having a free base concentration preferably in the range of 50 to 100 mg / mL; • Stirring of the dispersion at ambient temperature (preferably between room temperature and 65°C, more preferably between 30°C and 55°C). The slurry is formed after several (preferably between 4 and 10) heating / cooling cycles (temperatures between 0°C and 10°C from ambient temperature, and vice versa) at a temperature between 0°C and 10°C for several hours (preferably between 3 and 30 hours). • The process involves preparing a solid material and subsequently drying the solid material at ambient temperature (preferably under a nitrogen atmosphere).

[0044] The present invention will be described in more detail by the following examples, but will not be limited thereto. example Example 1: Prior Art Forms - Characterization of Commercially Available Pyrronaridine (Tetraphosphonate Form) NMR data of the tetraphosphonate form: 1H NMR (500 MHz, DMSO-d6) δ 8.23 ​​(d, J = 9.2 Hz, 1H), 7.97 (d, J = 2.2 Hz, 1H), 7.87 (d, J = 9.3 Hz, 1H), 7.32 (d, J = 9.2 Hz, 1H), 7.26 (dd, J = 9.3, 2.2 Hz, 1H), 7.09 (d, J = 2.5 Hz, 2H), 3.97 (s, 4H), 3.88 (s, 3H), 2.84 (s, 9H), 2.09 (s, 1H), 1.83 (d, J = 3.8 Hz, 6H). The X-ray diffraction pattern of commercially available tetraphosphorate powder is shown in European Pharmacopeia 6. th The data is obtained by standard methods described in Edition chapter 2.9.33 and characterized by X-ray powder diffractograms shown in Figure tetraphosphorate (monochromatic Cu-Kα1 radiation, λ = 1.5406 Å, Stoe StadiP 611 KL transmission diffractometer). The following is a list of peaks corresponding to the powder X-ray diffraction diffractogram shown in Figure tetraphosphate:

[0045] [Table 8]

[0046] The tetraphosphorite form is characterized by the following physical properties: - The tetraphosphorate morphology exhibits a melting / degradation point >220°C. TGA scans show a weight loss step of approximately 2.1 wt% up to 90°C. DSC and TGA profiles are shown in Figures tetraphosphorate b and tetraphosphorate c. - The water vapor sorption behavior of the tetraphosphorate form exhibits a strong water uptake level of >4.9 wt% in the relative humidity (rh) range of 40-80% rh. The tetraphosphorate form can be classified as hygroscopic based on the difference in water uptake between 40% rh and 80% rh, according to the Ph.Eur. criteria (section 5.11). The water vapor sorption isotherm (25°C) of the tetraphosphorate form is shown in Figure tetraphosphorate d. - The solubility levels of tetraphosphate in simulated fasting intestinal fluid [FaSSIF, pH 6.5] at 37°C were determined to be approximately 0.50 mg / mL (after 15 minutes), approximately 0.50 mg / mL (after 60 minutes), and approximately 0.49 mg / mL (after 120 minutes), respectively.

[0047] Example 2: Preparation process for novel salt form I Approximately 41 mg of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyrizin-10-yl)amino]-2,6-bis(pyrrolidine-1-ylmethyl)phenol free base and 16 mg of p-toluenesulfonic acid were dispersed in 4 mL of siRNA at 50°C with stirring. Then, 4 to 5 cooling / heating cycles (50-4°C for approximately 10 hours, 4-50°C for 0.5 hours) were performed, followed by final slurrying at 4°C for 24 hours. The resulting solid residue was separated from the supernatant by centrifugation and dried under nitrogen purging at 80°C for 48 hours to obtain a powder sample. 1 H NMR (500 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.24 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 2.2 Hz, 1H), 7.85 (d, J = 9.3 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.39 - 7.24 (m, 2H), 7.18 - 6.99 (m, 4H), 4.06 (s, 4H), 3.89 (s, 3H), 2.92 (s, 8H), 2.29 (s, 3H), 1.86 (d, J = 3.5 Hz, 6H).

[0048] Example 3: Preparation process for novel salt form II Approximately 40 mg of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyrizin-10-yl)amino]-2,6-bis(pyrrolidine-1-ylmethyl)phenol free base and 13.2 mg of benzenesulfonic acid were dispersed in 4 mL of siRNA at 50°C with stirring. Subsequently, multiple cooling-heating cycles (50-4°C for approximately 10 hours, 4-50°C for 0.5 hours), 4-5 cooling / heating cycles, and then final slurry formation at 4°C for 24 hours were initiated. The resulting solid residue was separated from the supernatant by centrifugation and dried under nitrogen purging gas at 80°C for 48 hours to obtain a powder sample. 1 H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.24 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 2.3 Hz, 1H), 7.86 (d, J = 9.4 Hz, 1H), 7.67 - 7.51 (m, 2H), 7.31 (tdd, J = 6.7, 4.6, 1.5 Hz, 4H), 7.12 (s, 2H), 4.08 (s, 4H), 3.88 (s, 3H), 2.94 (s, 8H), 2.09 (s, 0H), 1.87 (s, 3H).

[0049] Example 4: Preparation process for novel salt form III Approximately 42 mg of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyrizin-10-yl)amino]-2,6-bis(pyrrolidine-1-ylmethyl)phenol free base and 15.5 mg of ethanedisulfonic acid were dispersed in 4 mL of siRNA at 50°C with stirring. Multiple cooling-heating cycles were then initiated (50-4°C for approximately 10 hours, 4-50°C for 0.5 hours), followed by 4-5 cooling / heating cycles and a final slurry formation at 4°C for 24 hours. The resulting solid residue was separated from the supernatant by centrifugation and dried under nitrogen purging at 80°C for 48 hours to obtain a powder sample. 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.24 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 2.3 Hz, 1H), 7.86 (d, J = 9.3 Hz, 1H), 7.40 - 7.23 (m, 2H), 7.11 (s, 2H), 4.07 (s, 4H), 3.89 (s, 3H), 2.94 (s, 8H), 2.63 (s, 2H), 1.87 (t, J = 3.6 Hz, 7H).

[0050] Example 5: Preparation process for novel salt form IV Approximately 39 mg of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyrizin-10-yl)amino]-2,6-bis(pyrrolidine-1-ylmethyl)phenol free base and 16 mg of naphthalene-2-sulfonic acid were dispersed in 4 mL of THF at 50°C with stirring. Then, the mixture was subjected to 4 to 5 cooling / heating cycles (50-4°C for approximately 10 hours, 4-50°C for 0.5 hours), followed by 24 hours at 4°C to finally form a slurry, and overnight poor solvent vapor diffusion was initiated. The resulting solid residue was separated from the supernatant by centrifugation and dried under nitrogen purging gas at 80°C for 48 hours to obtain a powder sample. 1 H NMR (500 MHz, DMSO-d6) δ 8.24 (d, J = 9.2 Hz, 0H), 8.14 (d, J = 1.6 Hz, 0H), 8.02 - 7.94 (m, 0H), 7.93 - 7.80 (m, 0H), 7.72 (dd, J = 8.5, 1.7 Hz, 0H), 7.52 (dd, J = 6.2, 3.2 Hz, 0H), 7.40 - 7.24 (m, 0H), 7.10 (s, 0H), 4.14 - 3.99 (m, 1H), 3.89 (s, 0H), 2.93 (s, 1H), 1.86 (d, J = 4.1 Hz, 1H).

[0051] Example 6: Preparation process for novel salt form V Approximately 39 mg of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyrizin-10-yl)amino]-2,6-bis(pyrrolidine-1-ylmethyl)phenol free base and 16 mg of naphthalene-2-sulfonic acid were dispersed in 4 mL of THF at 50°C with stirring. Then, the mixture was subjected to 4-5 cooling / heating cycles (50-4°C for approximately 10 hours, 4-50°C for 0.5 hours), followed by 24 hours at 4°C to finally form a slurry, and overnight poor solvent vapor diffusion was initiated. The resulting solid residue was separated from the supernatant by centrifugation and dried under nitrogen purging at 80°C for 48 hours to obtain a powder sample. 1 H NMR (500 MHz, DMSO-d6) δ 8.25 (d, J = 9.2 Hz, 0H), 8.14 (d, J = 1.6 Hz, 0H), 8.03 - 7.94 (m, 0H), 7.93 - 7.77 (m, 0H), 7.72 (dd, J = 8.5, 1.7 Hz, 0H), 7.52 (dd, J = 6.2, 3.2 Hz, 0H), 7.41 - 7.24 (m, 0H), 4.09 (s, 0H), 3.88 (s, 0H), 2.94 (s, 1H), 1.87 (s, 1H).

[0052] Example 7: Non-sink solubility evaluation of salt form The results of the miniaturized, non-sink dissolution tests of the selected configurations are summarized below. Approximately 10-20 mg of solid sample was weighed and placed in a glass vial. 7 ml of each FaSSIF (pH 6.5) medium (preheated to 37°C) was added, and the suspension was shaken at 450 rpm at 37°C. After 5, 15, 60, and 120 minutes, 1 ml of the suspension was taken out and filtered through a 0.2 μm syringe filter. After appropriate dilution to measure the amount of dissolved API, the clear filtrate was analyzed by HPLC. To obtain non-sink conditions, 1 ml of preheated FaSSIF solution was added after taking out the sample. The clear solution was collected in an HPLC vial, the filtrate was further diluted as needed, and finally, HPLC analysis was performed. pH-dependent solubility and miniaturized non-sink HPLC methods: • Column: Chromolith RP-18e 100 - 3 mm Solvent A: Water / Formic acid (999:1;v / v) Solvent B: Acetonitrile / Formic acid (999:1;v / v) ·Injection volume: 5 μL Column temperature: 37℃ • Wavelength detector: 218 nm

[0053] [Table 9]

[0054] Example 8: Preparation process for novel anhydrous form VI of free bases Approximately 20 mg of the free base of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyrizin-10-yl)amino]-2,6-bis(pyrrolidine-1-ylmethyl)phenol was prepared in a DSC Al pan (100 μL) and heated to 140°C under a nitrogen atmosphere (50 mL / min) using a linear heating rate of 5 K / min in a DSC instrument. After reaching 140°C, the sample was removed from the DSC cell and kept at ambient temperature. The sample was dissolved in water (1.0 mL) and passed through an SCX column (500 mg pre-packed tosic acid resin). The column was eluted with water (10 mL), followed by methanol (10 mL) to remove acidic impurities. Finally, the column was treated with ammonia methanol to obtain the free base (10 mL), and the eluate was concentrated.

[0055] Example 9: Preparation process for novel anhydrous form VII of free bases Approximately 20 mg of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyrizin-10-yl)amino]-2,6-bis(pyrrolidine-1-ylmethyl)phenol free base (material obtained from the salt-hydrolyzed alteration of the tetraphosphate salt [pyronalizine tetraphosphate {0.1 g}, dissolved in water {1.0 mL}, and passed through an SCX column {500 mg pre-packed tosic acid resin}. The column was eluted with water {10 mL}, followed by methanol {10 mL} to remove acidic impurities. Finally, the column was treated with ammonia methanol to obtain the free base {10 mL}, and the eluate was concentrated.) was prepared in a DSC Al pan (100 μL) and heated in a DSC instrument at a linear heating rate of 5 K / min under a nitrogen atmosphere (50 mL / min) to approximately 175°C. After reaching 175°C, the sample was removed from the DSC cell and kept at ambient conditions.

[0056] Example 10: Comparison of solubility data for tetraphosphonate salts and free base forms VI and VII. The results of the thermodynamic solubility study for the selected form are summarized below. Approximately 5 mg of solid sample was weighed into a 4 ml glass vial. 1 ml of aqueous buffer was added to each vial, and the suspension was shaken at 37°C and 450 rpm for 24 hours. The vials were checked for the presence of undissolved compounds and the pH was measured at 1 hour, 6 hours, and 24 hours. The pH was adjusted as necessary. After 24 hours, solid-liquid separation was performed using a 1 ml syringe and a 0.2 μm syringe filter. After suitable dilution to determine the amount of dissolved API, the clear filtrate was analyzed by HPLC.

[0057] pH-dependent solubility and miniaturized non-sink HPLC methods: • Column: Chromolith RP-18e 100 - 3 mm Solvent A: Water / Formic acid (999:1;v / v) Solvent B: Acetonitrile / Formic acid (999:1;v / v) ·Injection volume: 5 μL Column temperature: 37℃ • Wavelength detector: 218 nm

[0058] [Table 10]

Claims

1. Crystalline form of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylmethyl)phenol, representing the sulfonate salt or the free base form.

2. 10. The crystalline form of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylmethyl)phenol of claim 1, designated as Form I, characterized by an X-ray powder diffraction pattern having 1, 2, 3, 4, or 5 peaks at diffraction angles (2-theta) of 7.1°±0.2°, 12.9°±0.2°, 15.4°±0.2°, 18.2°±0.2°, and / or 21.2°±0.2°.

3. 10. The crystalline form of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylmethyl)phenol of claim 1, designated as Form II, characterized by an X-ray powder diffraction pattern having 1, 2, 3, 4, or 5 peaks at diffraction angles (2-theta) of 7.8°±0.2°, 15.0°±0.2°, 17.6°±0.2°, 20.7°±0.2°, and / or 23.3°±0.2°.

4. 10. The crystalline form of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylmethyl)phenol of claim 1, designated as Form III, characterized by an X-ray powder diffraction pattern having 1, 2, 3, 4, or 5 peaks at diffraction angles (2-theta) of 10.2°±0.2°, 13.8°±0.2°, 15.1°±0.2°, 18.8°±0.2°, and / or 19.9°±0.2°.

5. 10. The crystalline form of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylmethyl)phenol of claim 1, designated as Form IV, characterized by an X-ray powder diffraction pattern having 1, 2, 3, 4, or 5 peaks at diffraction angles (2-theta) of 6.9°±0.2°, 12.6°±0.2°, 15.0°±0.2°, 15.7°±0.2°, and / or 22.2°±0.2°.

6. 10. The crystalline form of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylmethyl)phenol of claim 1, designated as Form V, characterized by an X-ray powder diffraction pattern having 1, 2, 3, 4, or 5 peaks at diffraction angles (2-theta) of 6.9°±0.2°, 15.7°±0.2°, 17.5°±0.2°, 22.2°±0.2°, and / or 25.4±0.2°.

7. 10. The crystalline form of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylmethyl)phenol of claim 1, designated as Form VI, characterized by an X-ray powder diffraction pattern having 1, 2, 3, 4, or 5 peaks at diffraction angles (2-theta) of 6.7°±0.2°, 9.3°±0.2°, 16.1°±0.2°, 19.4°±0.2°, and / or 25.0°±0.2°.

8. 10. The crystalline form of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylmethyl)phenol of claim 1, designated as Form VII, characterized by a powder X-ray diffraction pattern having 1, 2, 3, 4, or 5 peaks at diffraction angles (2-theta) of 6.7°±0.2°, 9.9°±0.2°, 16.3°±0.2°, 19.1°±0.2°, and / or 24.3°±0.

2.

9. 9. The crystalline compound of any one of claims 1 to 8 for use as a medicament.

10. 9. The crystalline compound according to any one of claims 1 to 8 for use in the treatment and / or prevention of a parasitic infection, wherein the parasitic infection is preferably malaria or a parasitic infection caused by a Plasmodium species.

11. A pharmaceutical composition comprising a therapeutically effective amount of at least one crystalline compound according to any one of claims 1 to 8, preferably comprising a therapeutically effective amount of a second pharmacologically active agent, and wherein the pharmacologically active agent is preferably antimalarial.

12. 12. The pharmaceutical composition according to claim 11, further comprising at least one additional compound selected from the group consisting of pharmaceutically acceptable excipients, auxiliaries, adjuvants, diluents, carriers and / or additional pharmaceutically active substances other than the compound according to any one of claims 1 to 8.

13. A kit comprising a therapeutically effective amount of at least one crystalline compound according to any one of claims 1 to 8 and / or at least one pharmaceutical composition according to claim 11 or 12, and a therapeutically effective amount of at least one further pharmacologically active substance other than a crystalline compound according to any one of claims 1 to 8, the further one preferably being an antimalarial agent.

14. 10. A method for treating and / or preventing rheumatoid arthritis, comprising administering a therapeutically effective amount of a crystalline compound according to any one of claims 1 to 8 to a human in need of such treatment.

15. A process for the preparation of a modification of a crystal according to any one of claims 1 to 8.

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