Novel crystalline form of prerarivir

Abstract

The invention relates to a novel crystal form of perralevir, a pharmaceutical composition containing the crystal form, a preparation method of the crystal form, application of the crystal form in medicines and application of the crystal form in treatment of herpes viruses.

Description

Field of the Invention

[0001] The present invention relates to a novel crystalline form of Priligy, a pharmaceutical composition comprising the crystalline form, a preparation method of the crystalline form, an application of the crystalline form in medicine, and a method for treating herpes virus. Background Art

[0002] Human herpesviruses are large enveloped double-stranded DNA viruses that have the common characteristic of infecting humans for life. This is due to their ability to persist in the host as an asymptomatic latent infection, where the virus lies dormant, or, after activation, as a lytic infection with associated symptoms. These viral infections are widespread worldwide, and it is noteworthy that more than 90% of humans are chronically infected with more than one human herpesvirus.

[0003] Human herpesviruses are divided into three subfamilies (α, β and γ) based on their biological characteristics. The family consists of eight members, namely herpes simplex virus subtypes 1 and 2 (HSV1, HSV2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpesvirus 6-8 (HHV 6-8).

[0004] Infection with HSV1 and 2 can cause disease in immunocompetent individuals. Both subtypes cause lesions on the skin, genital / anal and oral / nasal (cold sores), but HSV2 is usually associated with the former (genital / anal lesions) and HSV1 with the latter (oral / nasal lesions). >80% of genital infections are believed to be caused by HSV2. Globally, more than 500 million people are infected with genital herpes, and approximately 50% to 80% of the world's population is infected with oral HSV, which is the main cause of cold sores. HSV, especially HSV1, can also cause lesions on the fingers (Whitlows) and other skin sites.

[0005] The vast majority of people infected with HSV do not experience any noticeable symptoms. However, some people experience repeated (and often severe) outbreaks of the infection. In the United States, 20% to 40% of the population will have recurring HSV lesions on the lips. Of note, oral herpes and Whitlow's provide a very easy way for the virus to spread to other people, which can lead to rare but more serious HSV-related conditions. For example, HSV-related keratitis is a leading cause of blindness, and HSV can also cause neonatal encephalitis, a life-threatening condition. Other diseases believed to be caused by HSV include herpes grappula, Molaret's meningitis, and possibly Bell's palsy.

[0006] Primary infection or reactivation of an existing herpesvirus infection may be the main cause of illness in immunocompromised individuals. The main high-risk groups include patients undergoing solid organ or stem cell transplantation, patients undergoing cancer treatment, HIV / AIDS patients, and ICU patients.

[0007] Currently, there is no cure for HSV. Drugs have been developed that can reduce the incidence and / or shorten the duration of symptoms to some extent, but there is still a need for improved treatments.

[0008] Currently, nucleoside analogs (such as acyclovir and its prodrugs, such as valacyclovir and famciclovir) are used as drugs against herpes viruses (such as HSV). In order to exert their effects, these nucleoside analogs must be phosphorylated by viral thymidine kinase (TK) and subsequently converted to nucleoside triphosphates by cellular kinases, thereby inhibiting the activity of viral DNA polymerase. If the virus does not have a functionally active TK, for example, in the case of resistant HHV1 mutants or TK-negative viruses, nucleoside analogs cannot exert their effects.

[0009] Nucleoside analogs are clinically administered at very high doses, for example, doses of up to several hundred milligrams to several grams are often administered daily. Even at these high doses, which are often administered during long-term treatment, these drugs cannot completely prevent the recurrence of symptoms of HSV infection. Nucleoside analogs are also powerless to address the problem of viral shedding, which can promote the spread of HSV to more people asymptomatically. Certain nucleoside analogs, especially when used in high doses, also raise safety concerns. For example, because these drugs can be integrated into the host's genomic DNA by host DNA polymerases, their mutagenicity is a concern, as documented for the nucleoside analog ganciclovir (Aoki, Chapter 45 in Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases (Eighth Edition) 2015).

[0010] Given the inadequacy of existing treatments, there is an urgent need to develop improved, well-tolerated anti-herpes treatments. One class of compounds currently under investigation is the helicase-primase inhibitors. Helicase-primase inhibitors are antiviral drugs with a novel mechanism of action. They inhibit the viral heterotrimeric complex composed of helicase, primase, and cofactor subunits, which has functions that are essential for viral DNA replication. These drugs are not nucleoside analogs and do not require TK phosphorylation to inhibit HSV replication. Therefore, they have potential activity against TK-deficient HSV, which, as mentioned above, is the main mechanism of resistance to nucleoside analogs.

[0011] An example of a helicase-primase inhibitor is priligyvir, a thiazole amide derivative with the chemical name N-methyl-N-(4-methyl-5-sulfamoyl-1,3-thiazol-2-yl)-2-[4-(pyridin-2-yl)phenyl]acetamide. This compound has been disclosed in WO 2001 / 47904.

[0012] WO 2006 / 103011 generally mentions that priligy free base can exist in hydrated or solvated form; however, it does not actually disclose any experimental details about the preparation or characterization of these forms. WO 2013 / 045491 and WO 2013 / 045479 relate to the mesylate salt of priligy. They both mention the existence of polymorphic and solvated forms of the free base, but none of them actually disclose these forms through experiments. WO 2013 / 045491 concludes that priligy free base is not suitable for long-term stable formulations, and the low solubility of the free base compared to the methanesulfonic acid monohydrate salt leads to poor drug release and absorption performance, while WO 2013 / 045497 concludes that the free base has low thermal stability and polymorphic stability and is not suitable for tableting. WO 2013 / 045491 and WO 2013 / 045479 both disclose that the mesylate salt is particularly suitable for oral compositions.

[0013] WO 2018 / 096170 discloses polymorph screening of priligy free base and mentions that 14 different forms and one additional form were observed during the scale-up phase. Most of these forms are solvated forms; only 3 hydrates and one anhydrous form were observed. The explicit focus of WO 2018 / 096170 is Form C (hemihydrate). This is the only form for which XRPD characterization data is provided. WO 2018 / 096170 states that the free base hemihydrate Form C is the only stable polymorph.

[0014] The present invention is designed in consideration of the above circumstances. Summary of the invention

[0015] A novel crystalline solid form of priligy that can be used in medicine is provided herein. Priligy has the following structural formula:

[0016]

[0017] The present disclosure relates to certain novel solid forms of priligy that possess promising and advantageous solid-state and / or biopharmaceutical properties.

[0018] In a first aspect, the present disclosure provides a crystalline form of Priligy, wherein the crystalline form is Form 4 and is characterized by data selected from one or more of the following:

[0019] a) Use Cu Ka The measured X-ray powder diffraction (XRPD) pattern comprises peaks at the following 2-theta values: 12.1, 14.6, and 18.3° 2θ ± 0.2° 2θ; and

[0020] b) the DSC thermogram comprises at least one endothermic event with an onset temperature selected from the group consisting of: 60, 108 and 185°C±2°C, suitably 60, 108 and 185°C±1°C.

[0021] Form 4 is a sesquihydrated crystalline form of Priligy. Advantageously, Form 4 has been shown to be stable over a wide range of humidity levels (see Example 1 of the present application).

[0022] Advantageously, Form 4 also has certain properties that make it particularly suitable for formulation and delivery via certain routes of administration. The solubility of Form 4 over 24 hours was determined to be approximately 18.2 μg / mL at room temperature in an aqueous medium containing 0.9% NaCl and 0.5% polysorbate 80 (see Example 2 of the present application).

[0023] In another aspect, the present disclosure provides a pharmaceutical composition comprising a crystalline form of priligy, wherein the crystalline form is Form 4, and a pharmaceutically acceptable carrier, diluent or excipient.

[0024] In another aspect the invention provides a method of treating a herpes virus (suitably HSV) infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of Priligy, wherein the crystalline form is Form 4.

[0025] In another aspect the invention provides a method of treating a herpes virus (suitably HSV) infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of priligy and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form 4.

[0026] In another aspect, there is provided a crystalline form of Priligy for use in treating a herpes virus (suitably HSV) infection, wherein the crystalline form is Form 4.

[0027] In another aspect, there is provided a pharmaceutical composition comprising a crystalline form of Priligy and a pharmaceutically acceptable carrier, diluent or excipient for use in treating a herpes virus (suitably HSV) infection, wherein the crystalline form is Form 4.

[0028] In another aspect, there is provided the use of a crystalline form of priligy or a pharmaceutical composition comprising priligy for treating a herpes virus (suitably HSV) infection, wherein the crystalline form is Form 4.

[0029] In another aspect, there is provided the use of a crystalline form of priligy or a pharmaceutical composition comprising a crystalline form of priligy in the preparation of a medicament for treating a herpes virus (suitably HSV) infection, wherein the crystalline form is Form 4.

[0030] In another aspect, a method for preparing a crystalline form of priligy is provided, wherein the crystalline form is Form 4.

[0031] In another aspect, there is provided a crystalline form of Priligy obtainable by the process described herein, wherein the crystalline form is Form 4. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The abstract and the following detailed description of the invention can be further understood by reading in conjunction with the accompanying drawings. In order to illustrate the disclosed compositions and methods, exemplary embodiments of the compositions and methods are shown in the drawings; however, the compositions and methods are not limited to the specific embodiments disclosed. In the drawings:

[0034] Figure 1 : XRPD diffraction pattern of Form 4.

[0035] Figure 2 : PLM diagram of type 4.

[0036] Figure 3 : DSC and TGA thermograms of type 4.

[0037] Figure 4 : Analysis of type 4 DVS.

[0038] Figure 5 : XRPD diffraction patterns of Form 4 before and after DVS.

[0039] Figure 6 : XRPD diffraction pattern of Form C. DETAILED DESCRIPTION OF THE INVENTION

[0041] The features and other details of the present disclosure will now be described in more detail. Before further describing the present disclosure, certain terms used in the specification, examples, and appended claims are collected here. These definitions should be read in light of the remainder of the present disclosure and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art are generally understood.

[0042] definition

[0043] Unless otherwise stated, the following terms used in the specification and claims have the meanings listed below.

[0044] As used herein, "prilivir" refers to N-methyl-N-(4-methyl-5-sulfamoylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide free base.

[0045] As used herein, "API" refers to an active pharmaceutical ingredient, eg, priligy.

[0046] Unless the context requires otherwise, throughout the specification and claims, the words "include", "comprising", etc. should be interpreted in an open, inclusive sense; the words "a", "an", etc. should be deemed to mean at least one and not limited to only one. Terms not specifically defined herein should be given the meanings given to them by those skilled in the art based on the disclosure and context.

[0047] When a value is expressed as an approximation using the antecedent "about," it should be understood that the particular value constitutes another embodiment. Furthermore, unless otherwise stated or inferred, the term "about" refers to a variation of ±10% from the nominal value.

[0048] The term "about" when used to refer to a numerical range, cutoff value, or specific value is used to indicate that the listed value may vary up to 10% from the listed value. Since many of the numerical values ​​used herein are determined experimentally, those skilled in the art will understand that such determinations may and typically will vary from experiment to experiment. The values ​​used herein should not be considered to be overly limited due to this inherent variation. Therefore, the term "about" is used to cover variations of ±10% or less, ±5% or less, ±1% or less, ±0.5% or less, or ±0.1% or less from the specified value.

[0049] As used herein, when a composition is described as having, including, or comprising particular components, or when a method is described as having, including, or comprising particular process steps, it is contemplated that the compositions of the present teachings also consist essentially of or consist of those components, and that the methods of the present teachings also consist essentially of or consist of those process steps.

[0050] Any and all examples or exemplary language used herein, such as "for example," "including," or "such as," are intended only to better illustrate the present teachings and are not intended to limit the scope of the present invention unless otherwise stated. No language in the specification should be construed as indicating any non-stated element is essential to the practice of the present teachings.

[0051] The terms "individual", "patient" or "subject" are used interchangeably and include any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, and most preferably humans. The compounds or pharmaceutical compositions of the present disclosure can be administered to mammals such as humans, but can also be administered to other mammals, such as animals in need of veterinary treatment, such as livestock (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.) and experimental animals (e.g., rats, mice, guinea pigs, dogs, primates, etc.). The mammal treated in the methods of the present disclosure is ideally a mammal in which treatment of HSV infection is required.

[0052] The term "modulate" includes antagonism (eg, inhibition), agonism, partial antagonism, and / or partial agonism.

[0053] The term "pharmaceutically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans, as desired.

[0054] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein refers to any and all solvents, dispersion media, coatings, fillers, etc. that are compatible with drug administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds to provide supplementary, additional or enhanced therapeutic functions.

[0055] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharmaceutically acceptable carriers, diluents or excipients.

[0056] As used herein, the terms "therapeutically effective amount" or "effective amount" refer to the amount of the subject compound that will elicit a biological or medical response in a tissue, system, or animal (e.g., a mammal or human) that is sought by a researcher, veterinarian, physician, or other clinician. The compounds or pharmaceutical compositions disclosed herein are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound refers to the amount required to achieve the desired therapeutic and / or preventive effect. The therapeutically effective dose may vary depending on factors such as the disease state, age, sex, and weight of the individual, as well as the ability of the composition to elicit the desired response in the subject. These results include, but are not limited to, reduction, alleviation, and / or regression of diseases caused by or associated with HSV, or prevention of the development of diseases caused by or associated with HSV, which can be determined by any suitable method in the art.

[0057] It is understood that "treatment" or "therapy" includes prevention as well as alleviation of established symptoms of a disease. Thus, "treatment" or "therapy" of a disease, disorder or condition includes: (1) preventing or delaying the clinical symptoms of the disease, disorder or condition in a person who may have or is susceptible to the disease, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the disease, disorder or condition, (2) inhibiting the disease, disorder or condition, i.e., preventing, reducing or delaying the development of the disease or its recurrence (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof, or (3) alleviating or relieving the disease, i.e., causing the disease, disorder or condition or at least one clinical or subclinical symptom thereof to disappear. "Treatment" and similar terms as used herein may specifically include reducing the severity and / or frequency of HSV-induced symptoms, eliminating HSV-induced symptoms and / or the underlying causes of the symptoms, reducing the frequency or likelihood of HSV-induced symptoms and / or their underlying causes, delaying, preventing and / or slowing the progression of HSV-induced conditions, and ameliorating or remedying damage caused directly or indirectly by HSV infection.

[0058] As used herein, the term "preventing" or "preventing" with respect to HSV infection or HSV-related disease means reducing the likelihood of HSV infection.

[0059] Unless the context clearly dictates otherwise, a reference to a particular value includes at least that particular value.

[0060] In different places of this specification, numerical value is disclosed in the form of group or range. In particular, the specification is intended to include all individual subcombinations of members of such groups and ranges and any combination of various endpoints of such groups or ranges. For example, the integer in the range of 0 to 40 is particularly intended to disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 and 40 individually, and the integer in the range of 1 to 20 is particularly intended to disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 individually. All ranges are inclusive and combinable.

[0061] The use of any and all examples, or exemplary language (eg, "such as," "including," or "for example") herein, is intended merely to better illustrate the present teachings and does not pose a limitation on the scope of the invention unless claimed.

[0062] A "crystalline form" is a solid material in which the components of the solid material are arranged in a highly ordered microstructure, forming a crystal lattice extending in all directions. A crystalline form may include an anhydrous crystalline form, a solvated crystalline form, and / or a hydrated crystalline form.

[0063] "Polymorphism" refers to the ability of a solid material to exist in more than one crystalline form.

[0064] As used herein, the term "amorphous" refers to a solid material that does not have long-range order in the position of its molecules. Amorphous solids are substances in which molecules are arranged in a random manner so that there is no clear arrangement (e.g., molecular stacking) and no long-range order. Amorphous solids are generally isotropic, i.e., they exhibit similar properties in all directions and do not have a clear melting point. For example, an amorphous material is a solid material that does not have sharp characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., it is not crystalline according to XRPD determination). On the contrary, one or more broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristics of amorphous solids.

[0065] A "hydrate" is a compound that exists in a solid composition together with water molecules. The composition may contain a stoichiometric amount of water, such as a monohydrate or a dihydrate, or may contain a random amount of water. The term "hydrate" as used herein refers to a solid form, i.e., a compound in aqueous solution, although it may be hydrated, is not a hydrate as the term is used herein. Hydrates may be crystalline, wherein both the compound and the water form part of the crystal lattice.

[0066] A "solvate" is a composition similar to a hydrate except that the water is replaced with a solvent other than water. For example, methanol or ethanol can form an "alcoholate", which can also be stoichiometric or non-stoichiometric. The term "solvate" as used herein refers to a solid form, i.e., a compound in solution in a solvent, which, although it may be solvated, is not a solvate as the term is used herein. A solvate can be crystalline, in which both the compound and the solvent form part of the crystal lattice.

[0067] "Anhydrous" refers to a solid form of a compound that does not have water incorporated into its structure. For example, an anhydrous crystalline form does not have water forming part of the crystalline structure. The skilled person will be aware of techniques that can be used to quantify the amount of water associated with a solid. For example, water content can be determined by Karl Fischer titration or thermogravimetric analysis (TGA). Suitably, the anhydrous solid form of the compound contains less than about 1.5% by weight, such as less than about 1, less than about 0.5, less than about 0.4, less than about 0.3, less than about 0.2, less than about 0.1, less than about 0.05, or less than about 0.01% by weight of water.

[0068] "Unsolvated" or "non-solvated" refers to a solid form of a compound that does not have a solvent incorporated into its structure. For example, an unsolvated crystalline form does not have a solvent that forms part of the crystal structure. The skilled artisan will be aware of techniques that can quantify the amount of solvent associated with a solid. For example, the solvent content can be determined by gas chromatography (GC). Suitably, the unsolvated or non-solvated solid form of the compound contains less than about 1.5% by weight, such as less than about 1.0, less than about 0.5, less than about 0.4, less than about 0.3, less than about 0.2, less than about 0.1, less than about 0.05, or less than about 0.01% by weight of solvent.

[0069] Herein, when a composition is referred to as "consisting essentially of" a particular component, the composition suitably comprises at least 70% by weight of the component, suitably at least 80% by weight of the component, suitably at least 90% by weight of the component, suitably at least 95% by weight of the component, most suitably at least 99% by weight of the component. Suitably, a composition referred to as "consisting essentially of" a particular component consists of the component except for one or more trace amounts of the component.

[0070] The phrase "substantially as shown" refers to an X-ray powder diffraction pattern or a DSC thermogram of which at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the features appear in the pattern.

[0071] Crystalline form of Priligy

[0072] In one aspect, the present disclosure provides a novel crystalline form of Priligy described and characterized as Form 4 herein.

[0073] The present disclosure also relates to pharmaceutical compositions comprising crystalline Form 4, and methods of preparing such forms. The present disclosure also relates to the use of crystalline Form 4 in treating or preventing HSV infection.

[0074] A variety of analytical methods can be used by those skilled in the art of solid-state chemistry to analyze solid forms. The term "analysis" as used herein refers to obtaining information about the solid-state structure of a solid form. For example, powder X-ray diffraction (PXRD / XRPD) is a technique suitable for distinguishing between amorphous solid forms and crystalline solid forms and for characterizing and identifying a specific crystalline solid form of a compound.

[0075] Due to instrumental, sample, and sample preparation variations, peaks are often reported with the modifier "±0.2° 2θ". This is common practice in the field of solid-state chemistry because of the inherent variation in peaks. Variations in peak intensity are due to the orientation of individual crystals in the sample container relative to the external X-ray source (called "preferred orientation"). This orientation effect does not provide structural information about the crystals.

[0076] Powder X-ray diffraction is only one of several analytical techniques that can be used to characterize and / or identify crystalline solid forms. Differential scanning calorimetry (DSC) can be used to characterize and / or identify crystalline solid forms. The typical variation in the value associated with the differential scanning calorimetry onset temperature is about plus or minus 2°C.

[0077] It should be noted that, unless otherwise stated, the DSC and TGA thermal data presented herein were obtained using heating rates of 2°C / min and 10°C / min, respectively. In addition, the DSC data were obtained using an aluminum punched disk.

[0078] In a first aspect, a crystalline form of Priligy is provided, wherein the crystalline form is Form 4 and is characterized by data selected from one or more of the following:

[0079] a) Use Cu The measured X-ray powder diffraction (XRPD) pattern comprises peaks at the following 2-theta values: 12.1, 14.6, and 18.3° 2θ ± 0.2° 2θ; and

[0080] b) the DSC thermogram comprises at least one endothermic event with an onset temperature selected from the group consisting of: 60, 108 and 185°C±2°C, suitably 60, 108 and 185°C±1°C.

[0081] In one embodiment, there is provided a method for using Cu A measured XRPD pattern comprising peaks at the following 2-theta values: 12.1, 14.6 and 18.3°2θ±0.2°2θ, and further comprising at least one, two or three specific peaks selected from the following 2-theta values: 10.3, 16.3 and 28.7°2θ±0.2°2θ.

[0082] In one embodiment, there is provided a method for using Cu The measured XRPD pattern comprises peaks at the following 2-theta values: 12.1, 14.6 and 18.3° 2θ ± 0.2° 2θ, and further comprises peaks at the following 2-theta values: 10.3, 16.3 and 28.7° 2θ ± 0.2° 2θ.

[0083] In one embodiment, there is provided a method for using Cu An XRPD pattern was measured comprising peaks at the following 2-theta values: 12.1, 14.6 and 18.3° 2θ ± 0.1° 2θ.

[0084] In one embodiment, there is provided a method for using Cu A measured XRPD pattern comprising peaks at the following 2-theta values: 12.1, 14.6 and 18.3°2θ±0.1°2θ, and further comprising at least one, two or three specific peaks selected from the following 2-theta values: 10.3, 16.3 and 28.7°2θ±0.1°2θ.

[0085] In one embodiment, there is provided a method for using Cu The measured XRPD pattern comprises peaks at the following 2-theta values: 12.1, 14.6 and 18.3° 2θ ± 0.1° 2θ, and further comprises peaks at the following 2-theta values: 10.3, 16.3 and 28.7° 2θ ± 0.1° 2θ.

[0086] In one embodiment, there is provided a method for using Cu An XRPD pattern measured, comprising peaks at the following 2-θ values: 12.1, 14.6 and 18.3°2θ±0.2°2θ, suitably 12.1, 14.6 and 18.3°2θ±0.1°2θ, and wherein Form 4 is a sesquihydrate crystalline form of priligy. Suitably, Form 4 comprises from about 4 to about 8% by weight of water, such as from about 4.5 to about 7.5% by weight, from about 5.0 to about 7.0% by weight or from about 5.5 to about 6.5% by weight. Suitably, Form 4 comprises about 6% by weight of water.

[0087] In one embodiment, a crystalline form of the compound of formula (I) is provided, wherein the crystalline form is Form 4, characterized in that Cu The measured XRPD pattern comprises peaks at the following 2-theta values: 12.1, 14.6 and 18.3 °2θ±0.2°2θ, and further comprises at least two, five, ten, fifteen, twenty, twenty-five, thirty, thirty-five or forty further peaks selected from the peaks listed in Table 1 at °2θ±0.2°2θ.

[0088] Table 1 - XRPD peak positions of Form 4

[0089]

[0090] In one embodiment, a crystalline form of the compound of formula (I) is provided, wherein the crystalline form is Form 4, characterized in that Cu The measured XRPD pattern comprises peaks at the following 2-θ values: 12.1, 14.6 and 18.3 °2θ±0.1 °2θ; and further comprises at least two, five, ten, fifteen, twenty, twenty-five, thirty, thirty-five or forty peaks selected from the peaks listed in Table 1 as °2θ±0.2 °2θ.

[0091] In one embodiment, there is provided a method for using Cu An XRPD pattern was measured comprising peaks at the following 2-theta values: 12.1, 14.6 and 18.3° 2-theta ± 0.2° 2-theta and wherein Form 4 is substantially pure.

[0092] In one embodiment, there is provided a method for using Cu An XRPD pattern was measured comprising peaks at the following 2-theta values: 12.1, 14.6 and 18.3° 2-theta ± 0.1° 2-theta and wherein Form 4 is substantially pure.

[0093] In one embodiment, a crystalline form of Priligy is provided, wherein the crystalline form is Form 4, characterized in that the crystalline form is prepared using Cu The XRPD pattern measured by radiometry is basically the same as Figure 1 Same as shown.

[0094] In one embodiment, there is provided a crystalline form of Priligy, wherein the crystalline form is Form 4, characterized by a DSC thermogram comprising at least one endothermic event with an onset temperature selected from the group consisting of: 60, 108 and 185°C ± 2°C, suitably 60, 108 and 185°C ± 1°C.

[0095] In one embodiment, there is provided a crystalline form of priligy, wherein the crystalline form is Form 4, characterized by a DSC thermogram comprising endothermic events at the following onset temperatures: 60, 108 and 185°C ± 2°C, suitably 60, 108 and 185°C ± 1°C.

[0096] In one embodiment, a crystalline form of priligy is provided, wherein the crystalline form is Form 4, characterized by a DSC thermogram comprising at least one endothermic event with an onset temperature selected from the group consisting of: 60, 108 and 185°C ± 2°C, suitably 60, 108 and 185°C ± 1°C, and an exothermic event at an onset temperature of: 153°C ± 2°C, suitably 153°C ± 1°C.

[0097] In one embodiment, there is provided a crystalline form of priligy, wherein the crystalline form is Form 4, characterized by a DSC thermogram comprising endothermic events at the following onset temperatures: 60, 108 and 185°C ± 2°C, suitably 60, 108 and 185°C ± 1°C, and an exothermic event at the following onset temperature: 153°C ± 2°C, suitably 153°C ± 1°C.

[0098] In one embodiment, there is provided a crystalline form of priligy, wherein the crystalline form is Form 4, characterized by a DSC thermogram comprising an endothermic event at an onset temperature of 185°C ± 2°C, suitably 185°C ± 1°C.

[0099] In one embodiment, there is provided a crystalline form of priligy, wherein the crystalline form is Form 4, characterized by a DSC thermogram comprising an endothermic event at an onset temperature of 185°C ± 2°C, suitably 185°C ± 1°C, and wherein Form 4 is a sesquihydrated crystalline form of priligy.

[0100] In one embodiment, a crystalline form of priligy is provided, wherein the crystalline form is Form 4, which is characterized by a DSC thermogram substantially similar to Figure 3 Same as shown.

[0101] In one embodiment, Form 4 is substantially pure.

[0102] In one embodiment, type 4 comprises about 4 to about 8 % by weight of water, for example, about 4.5 to about 7.5 % by weight, about 5.0 to about 7.0 % by weight, or about 5.5 to about 6.5 % by weight. Suitably, type 4 comprises about 6 % by weight of water. Those skilled in the art will know suitable analytical techniques for quantifying the amount of solvent / water associated with a solid. For example, water content can be determined by Karl Fischer titration. Thermogravimetric analysis (TGA) can also quantify the amount of volatile substances (i.e., solvents and water) associated with a solid (surface binding or incorporation into the crystal structure). Suitably, type 4 is a sesquihydrated crystalline form of priligy. The sesquihydrated form means that there are 1.5 water molecules in every 1 priligy molecule.

[0103] When the specification is described herein with reference to a crystalline form of Priligy, the degree of crystallinity is suitably greater than about 60%, more suitably greater than about 80%, more suitably greater than about 90%, and preferably greater than 95%, 98% or 99% by weight.

[0104] In one embodiment, type 4 is pure or substantially pure. As used herein, the term "substantially pure" refers to a solid form of priligy containing about 20% weight or less, or about 15% weight or less, or about 10% weight or less, or about 5% weight or less, or about 2% weight or less, or about 1% weight or less, or about 0.5% weight or less of any impurities or other priligy solid forms, including alternative crystalline forms, hydrates, solvates or amorphous forms, such as measured by XRPD. Therefore, the substantially pure type 4 described herein should be understood as containing more than about 80% weight, more than 85% weight, more than 90% weight, more than 95% weight, more than 98% weight, more than 99% weight, more than 99.5% weight of priligy crystal type 4. Suitably, type 4 is provided, wherein when type 4 is analyzed by solid-state technology (e.g., by X-ray powder diffraction), no other solid forms (amorphous and / or other crystalline forms) are detected. Suitably, there is provided a crystalline form of Priligy consisting essentially of Form 4. Suitably, there is provided a crystalline form of Priligy consisting essentially of Form 4.

[0105] Pharmaceutical compositions and kits

[0106] In another aspect, the present disclosure provides a pharmaceutical composition comprising a crystalline form of priligy disclosed herein, formulated together with one or more pharmaceutically acceptable carriers, diluents or excipients, wherein the crystalline form is Form 4.

[0107] In one embodiment, a pharmaceutical composition is provided, comprising a crystalline form of priligy, wherein the crystalline form is form 4; and a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, a pharmaceutical composition is provided, comprising a crystalline form of priligy, wherein the crystalline form is pure or substantially pure form 4; and a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, a pharmaceutical composition comprising priligy is provided, wherein priligy consists essentially of crystalline form 4. In one embodiment, a pharmaceutical composition comprising priligy is provided, wherein priligy consists of crystalline form 4.

[0108] When it is stated herein that the specification refers to a crystalline form of Priligy, the degree of crystallinity is suitably greater than about 60%, more suitably greater than about 80%, still more suitably greater than about 90%, and preferably greater than 95%, 98% or 99% by weight.

[0109] These formulations include those suitable for oral, rectal, topical, buccal, parenteral, rectal, vaginal or aerosol administration, although the most suitable form of administration in any given case will depend on the extent and severity of the condition being treated, and the nature of the specific compound being employed.

[0110] In one embodiment, a pharmaceutical composition is provided, comprising a crystalline form of priligy disclosed herein, formulated together with one or more pharmaceutically acceptable carriers, diluents or excipients, wherein the crystalline form is Form 4, and wherein the composition is suitable for parenteral administration.

[0111] Exemplary pharmaceutical compositions of the present disclosure may be used in the form of pharmaceutical preparations, such as solid, semisolid or liquid forms, containing one or more compounds of the present disclosure as active ingredients mixed with organic or inorganic carriers or excipients suitable for external, enteral or parenteral administration. For example, the active ingredients may be mixed with non-toxic, pharmaceutically acceptable carriers for any form suitable for use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0112] Advantageously, the present disclosure also provides kits for use, for example, for consumers who need treatment for HSV infection. These kits include suitable dosage forms, such as those described above, and instructions describing methods for using these dosage forms to mediate, reduce or prevent HSV infection. The instructions can instruct consumers or medical personnel to apply the dosage form according to the mode of administration known to those skilled in the art. These kits can be advantageously packaged and sold in single kit units or multiple kit units. Such kits can advantageously be packaged and sold in single or multiple kit units. Such kits can also include information, such as scientific literature references, package insert materials, clinical trial results and / or summaries of these contents, etc., which indicate or determine the activity and / or advantages of the composition, and / or describe dosage, administration, side effects, drug interactions or other information useful to healthcare providers. Such information can be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kits described herein can be provided to healthcare providers, including doctors, nurses, pharmacists, prescribing officials, etc., to promote and / or promote them. In some embodiments, the kit can also be promoted directly to consumers.

[0113] It may be desirable to provide a memory aid on the kit, for example in the form of numbers next to the tablets or capsules, where the numbers correspond to the days on which the dosing regimen of the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on a card, for example, as follows "First Week, Monday, Tuesday, ... etc. ... Second Week, Monday, Tuesday, ..." etc. Other variations of the memory aid will become apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules taken on a given day. In addition, a daily dose of a first compound can consist of one tablet or capsule, while a daily dose of a second compound can consist of several tablets or capsules, or vice versa. The memory aid should reflect these contents.

[0114] Treatment

[0115] In one aspect, crystalline Priligy Form 4 is provided for use as a medicament.

[0116] In one aspect, a pharmaceutical composition is provided comprising a crystalline form of priligyvir and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form 4, for use as a medicament.

[0117] In one aspect, crystalline Priligy Form 4 is provided for use in therapy.

[0118] In one aspect, a pharmaceutical composition is provided comprising a crystalline form of priligyvir and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form 4, for use in therapy.

[0119] In one aspect, a method of treating a herpes virus (suitably HSV) infection in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of priligy, wherein the crystalline form is Form 4. In another aspect, a method of treating a herpes virus (suitably HSV) infection in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of priligy and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form 4.

[0120] In one embodiment, a method of inhibiting HSV replication in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of priligy, wherein the crystalline form is Form 4. In one embodiment, a method of inhibiting HSV replication in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of priligy and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form 4.

[0121] In one embodiment, a method of reducing the likelihood or severity of symptoms of HSV infection in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of priligy, wherein the crystalline form is Form 4. In one embodiment, a method of reducing the likelihood or severity of symptoms of HSV infection in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of priligy and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form 4.

[0122] In one embodiment, a method for inhibiting the development or progression of a disease or disorder caused or associated with HSV infection in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of priligy, wherein the crystalline form is Form 4. In one embodiment, a method for inhibiting the development or progression of a disease or disorder caused or associated with HSV infection in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of priligy and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form 4.

[0123] In one embodiment, a method for treating or preventing a disease or disorder caused by or associated with HSV infection in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of priligy, wherein the crystalline form is Form 4. In one embodiment, a method for treating or preventing a disease or disorder caused by or associated with HSV infection in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of priligy and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form 4.

[0124] In a specific embodiment, Priligy Form 4 according to the present invention or a pharmaceutical composition according to the present invention can reduce the lesion healing time (e.g., the time when the lesion is completely recovered) and the duration of symptoms caused by HSV infection in a disease or condition (e.g., herpes labialis or genital herpes). The lesion healing time can be defined as the complete epithelialization of mucocutaneous HSV lesions during treatment and the absence of new lesions, for example, as assessed by a physician.

[0125] In one embodiment, Priligy Form 4 according to the present invention or the pharmaceutical composition according to the present invention can reduce pain or pain intensity (eg, at the site of the lesion) caused by HSV infection in a disease or condition (eg, herpes labialis or genital herpes).

[0126] In another aspect, there is provided a crystalline form of priligy for use in treating a herpes virus (suitably HSV) infection, wherein the crystalline form is Form 4. In another aspect, there is provided a pharmaceutical composition comprising a crystalline form of priligy and a pharmaceutically acceptable carrier, diluent or excipient for use in treating a herpes virus (suitably HSV) infection, wherein the crystalline form is Form 4.

[0127] In one embodiment, a crystalline form of priligy is provided for use in inhibiting HSV replication in a subject, wherein the crystalline form is Form 4. In one embodiment, a pharmaceutical composition is provided comprising a crystalline form of priligy and a pharmaceutically acceptable carrier, diluent or excipient for use in inhibiting HSV replication in a subject, wherein the crystalline form is Form 4.

[0128] In one embodiment, a crystalline form of priligy is provided for use in reducing the likelihood or severity of symptoms of HSV infection in a subject in need thereof, wherein the crystalline form is Form 4. In one embodiment, a pharmaceutical composition is provided comprising a crystalline form of priligy and a pharmaceutically acceptable carrier, diluent or excipient for use in reducing the likelihood or severity of symptoms of HSV infection in a subject in need thereof, wherein the crystalline form is Form 4.

[0129] In one embodiment, a crystalline form of priligy is provided for use in inhibiting the development or progression of a disease or disorder caused or associated with HSV infection in a subject in need thereof, wherein the crystalline form is Form 4. In one embodiment, a pharmaceutical composition is provided comprising a crystalline form of priligy and a pharmaceutically acceptable carrier, diluent or excipient for use in inhibiting the development or progression of a disease or disorder caused or associated with HSV infection in a subject in need thereof, wherein the crystalline form is Form 4.

[0130] In one embodiment, a crystalline form of priligy is provided for use in treating or preventing a disease or disorder caused by or associated with HSV infection in a subject in need thereof, wherein the crystalline form is Form 4. In one embodiment, a pharmaceutical composition is provided comprising a crystalline form of priligy and a pharmaceutically acceptable carrier, diluent or excipient for use in treating or preventing a disease or disorder caused by or associated with HSV infection in a subject in need thereof, wherein the crystalline form is Form 4.

[0131] In another aspect, there is provided the use of a crystalline form of priligy or a pharmaceutical composition comprising a crystalline form of priligy for treating a herpes virus, suitably an HSV infection, wherein the crystalline form is Form 4.

[0132] In one embodiment, there is provided a use of a crystalline form of priligy or a pharmaceutical composition comprising a crystalline form of priligy for inhibiting HSV replication in a subject, wherein the crystalline form is Form 4.

[0133] In one embodiment, there is provided a use of a crystalline form of priligy or a pharmaceutical composition comprising a crystalline form of priligy for reducing the likelihood or severity of symptoms of HSV infection in a subject in need thereof, wherein the crystalline form is Form 4.

[0134] In one embodiment, there is provided a use of a crystalline form of priligy or a pharmaceutical composition comprising a crystalline form of priligy for inhibiting the development or progression of a disease or disorder caused or associated with HSV infection in a subject in need thereof, wherein the crystalline form is Form 4.

[0135] In one embodiment, there is provided a use of a crystalline form of priligy or a use of a pharmaceutical composition comprising a crystalline form of priligy for treating or preventing a disease or disorder caused by or associated with HSV infection, wherein the crystalline form is Form 4.

[0136] In another aspect, there is provided the use of a crystalline form of priligy or a pharmaceutical composition comprising a crystalline form of priligy in the preparation of a medicament for treating a herpes virus (suitably HSV) infection, wherein the crystalline form is Form 4.

[0137] In one embodiment, provided is the use of a crystalline form of priligy in the preparation of a medicament or a pharmaceutical composition comprising a crystalline form of priligy in the preparation of a medicament for inhibiting HSV replication in a subject, wherein the crystalline form is Form 4.

[0138] In one embodiment, provided is the use of a crystalline form of priligy in the preparation of a medicament or the use of a pharmaceutical composition comprising a crystalline form of priligy in the preparation of a medicament for reducing the likelihood or severity of symptoms of HSV infection in a subject in need thereof, wherein the crystalline form is Form 4.

[0139] In one embodiment, provided is the use of a crystalline form of priligy in the preparation of a medicament or the use of a pharmaceutical composition comprising a crystalline form of priligy in the preparation of a medicament for inhibiting the development or progression of a disease or disorder caused or associated with HSV infection in a subject in need thereof, wherein the crystalline form is Form 4.

[0140] In one embodiment, provided is the use of a crystalline form of priligy in the preparation of a medicament or the use of a pharmaceutical composition comprising a crystalline form of priligy in the preparation of a medicament for treating or preventing a disease or disorder caused by or associated with HSV infection in a subject in need thereof, wherein the crystalline form is Form 4.

[0141] In certain embodiments, the disease or disorder caused by or associated with HSV infection is selected from herpes labialis (e.g., herpes labialis or Whitlow's herpes), genital herpes, HSV-associated keratitis, HSV-associated encephalitis, herpes combatis, primary HSV gingivostomatitis, Molaret's meningitis, and Bell's palsy.

[0142] In certain embodiments, the disease or disorder caused by or associated with HSV infection is selected from herpes labialis (e.g., herpes labialis or Whitlow's herpes) or genital herpes. In one embodiment, the disease or disorder is recurrent herpes labialis or recurrent genital herpes. An individual with a history of multiple herpes labialis or recurrent genital herpes (e.g., HSV recurring six or more times per year) may be considered to have recurrent HSV.

[0143] In one embodiment, the herpes virus treated is HSV2. In a further embodiment, the herpes virus treated is HSV2 and the subject in need of treatment has recurrent genital herpes due to HSV2.

[0144] In one embodiment, the herpes virus treated is HSV 1. In yet another embodiment, the herpes viruses treated are both HSV-1 and HSV-2.

[0145] In one embodiment, the herpes virus being treated is resistant to a nucleoside antiviral therapy. In one embodiment, the nucleoside antiviral therapy is selected from acyclovir, penciclovir, famciclovir, ganciclovir and valacyclovir.

[0146] In one embodiment, the herpes virus treated is resistant to nucleoside antiviral therapy, for example, a mucocutaneous HSV infection resistant to acyclovir. In a further embodiment, the HSV infection treated is a mucocutaneous HSV infection resistant to antiviral therapy using a nucleoside analog (e.g., acyclovir, penciclovir, famciclovir, ganciclovir or valacyclovir).

[0147] In certain embodiments, a subject in need of the methods disclosed herein is immunocompromised. The subject may be immunocompromised due to conditions including HIV infection, cancer, hematopoietic cell or solid organ transplantation and long-term use of glucocorticoids, or inherited immunodeficiency.

[0148] In certain embodiments, a subject in need of the methods disclosed herein is a neonate or infant.

[0149] In certain embodiments, the subject is a herpes positive patient.

[0150] In certain embodiments, a subject in need of the methods disclosed herein has an acyclovir-resistant mucocutaneous HSV infection. The subject may have been diagnosed with the condition based on clinical failure, e.g., no improvement after at least 7 days of oral or intravenous administration of approved doses of acyclovir.

[0151] In a specific embodiment, the subject in need of the methods disclosed herein suffers from primary genital HSV-related herpes infection. In one embodiment, the subject in need of the methods disclosed herein suffers from severe or progressive genital HSV-related herpes infection.

[0152] For use according to this aspect, appropriate dosages are expected to vary depending on, for example, the mode of administration, the nature and severity of the infection to be treated, and the specific infection to be treated, and are within the purview of the treating physician. Typically, indicated dosages may be in the range of about 0.1 to about 1000 μg / kg body weight.

[0153] The compounds of the present disclosure may be administered by any conventional route, in particular: enteral, topical, oral, nasal (e.g., in the form of tablets or capsules), by suppository or parenteral administration. Suitable formulations and pharmaceutical compositions will include those formulated in a conventional manner using one or more physiologically acceptable carriers or excipients, as well as any known and commercially available formulations and pharmaceutical compositions currently used in clinical settings. Thus, the compounds may be formulated for oral, buccal, topical, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (oral or nasal).

[0154] In addition to being useful in human therapy, the crystalline forms of the invention are also useful in veterinary therapy of companion animals, exotic animals, and farm animals, including mammals, rodents, etc. Conveniently, such animals include horses, dogs, and cats.

[0155] combination

[0156] The priligy form 4 of the present invention or the pharmaceutical composition comprising priligy form 4 can be administered alone as a monotherapy, or can be administered together with one or more other substances and / or treatments. Such combined treatment can be achieved by simultaneous, sequential or separate administration of the individual components of the treatment.

[0157] Also contemplated herein are methods comprising administering a second active agent. For example, in addition to infection with HSV, a subject or patient may also suffer from complications associated with HSV infection, i.e., diseases and other adverse health conditions associated with HSV infection, exacerbated or aggravated by HSV infection. Contemplated herein are combinations of the priligy crystalline form 4 of the present invention or a pharmaceutical composition comprising the priligy crystalline form 4 of the present invention with at least one other agent that has previously been shown to treat these HSV infection-related conditions. This combination therapy can be achieved independently (by administering the individual components of the treatment simultaneously, sequentially or separately) and / or by a pharmaceutical composition of the present invention comprising a second active agent.

[0158] Therefore, the present invention provides a method for treating HSV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Priligy Form 4 according to the present invention or a pharmaceutical composition comprising Priligy Form 4 according to the present invention, and co-administering to the subject a therapeutically effective amount of an additional therapeutic agent.

[0159] In an embodiment, the additional therapeutic agent is selected from one or more of the following:

[0160] i. Nucleoside polymerase inhibitors, such as acyclovir, valacyclovir, famciclovir, penciclovir and ganciclovir;

[0161] ii. Pyrophosphate polymerase inhibitors, such as foscarnet;

[0162] iii. saturated fatty alcohols, such as behenyl alcohol;

[0163] iv. Drugs such as iodoxuridine, trifluridine and vidarabine;

[0164] v. Corticosteroids; and

[0165] vi. Other helicase-primase inhibitors, such as aminavir.

[0166] In some embodiments, pralivir Form 4 or a pharmaceutical composition comprising pralivir Form 4 may be administered as part of a combination therapy with one or more antiviral drugs, including nucleoside analogs such as acyclovir, foscarnet, ganciclovir or penciclovir or the corresponding prodrugs valacyclovir or famciclovir.

[0167] In some embodiments, the first and second amounts together constitute a pharmaceutically effective amount. The first amount, the second amount, or both may be the same, greater than, or less than the effective amount of each compound administered as a monotherapy. A therapeutically effective amount of a disclosed compound and an antiviral drug may be co-administered to a subject, i.e., administered to a subject simultaneously or separately in any given order and by the same or different routes of administration. In some cases, it may be advantageous to first begin administering priligy, such as one or more days or weeks before beginning administration of the antiviral drug. In addition, other drugs may be used in combination with the above-mentioned combination therapy.

[0168] Method for preparing type 4

[0169] In one aspect, a method for preparing a crystalline form of Priligy is provided, wherein the crystalline form is Form 4.

[0170] In one embodiment, the method of preparing Form 4 comprises the following steps:

[0171] a) providing a solution of Priligy in a first solvent system;

[0172] b) stirring the solution in step a) for at least one hour;

[0173] c) adding the solution in step b) into a second solvent system;

[0174] d) stirring the mixture obtained in step c) for at least 10 minutes;

[0175] e) optionally, isolating the solid formed in step d); and

[0176] f) optionally, drying the solid separated in step e).

[0177] In one embodiment, the first solvent system comprises a solvent wherein priligy has a solubility of at least 100 mg / mL at room temperature, such as at least 200 or 500 mg / mL. Suitably, the first solvent system comprises DMF. Suitably, the first solvent system consists essentially of DMF. Suitably, the first solvent system consists of DMF.

[0178] Suitably, step a) is carried out at a temperature between 15 and 25°C.

[0179] Suitably, the stirring in step b) is carried out for at least 2 hours, such as at least 4, 6, 8, 10, 12, 16, 20, 24 or 30 hours.

[0180] Suitably, the stirring in step b) is carried out under a nitrogen atmosphere.

[0181] Suitably, the second solvent system comprises a solvent in which priligy has a solubility of less than 0.1 mg / mL at room temperature, such as less than 0.05 mg / mL. Suitably, the second solvent system comprises water. Suitably, the second solvent system consists essentially of water. Suitably, the second solvent system consists of water.

[0182] Suitably, the second solvent system is an anti-solvent system.

[0183] Suitably, in step c), the solution from step b) is added to the second solvent system over a period of at least 2 minutes, such as at least 5 minutes. Suitably, in step c), the solution from step b) is added to the second solvent system over a period of about 10 minutes.

[0184] Suitably, in step c), it is carried out at a temperature between 15 and 25°C.

[0185] Suitably, the stirring in step d) is carried out for at least 10 minutes, such as at least 20 minutes.

[0186] Suitably, step e) comprises isolating the solid by filtration.

[0187] Suitably, step f) comprises drying the solid at a temperature above room temperature, for example above 30°C or above 40°C. Suitably, step e) comprises drying the solid at a temperature of about 50°C.

[0188] Suitably, step f) comprises drying the solid under reduced pressure (relative to ambient pressure).

[0189] Suitably, step f) comprises drying the solid for at least 1 hour, for example at least 2, 4, 6, 8 or 10 hours.

[0190] The present invention is now illustrated by the following non-limiting examples. Example

[0191] The following abbreviations are used in this manual:

[0192] DMF: Dimethylformamide

[0193] DSC: Differential Scanning Calorimetry

[0194] DVS: Dynamic Vapor Sorption

[0195] EDCl:1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0196] HOBT: Hydroxybenzotriazole

[0197] KF:Karl Fischer

[0198] PLM: Polarized Light Microscopy

[0199] PXRD: Powder X-ray Diffraction

[0200] TGA: Thermogravimetric analysis

[0201] XRPD: Powder X-ray Diffraction

[0202] Instruments and methods:

[0203] Polarized light microscopy (PLM): Micrographs were collected using an Olympus BX53 polarized light microscope. The samples were dispersed on a glass slide with methyl silicone oil.

[0204] Powder X-ray Diffraction (PXRD): Used on a Rigaku Smartlab SE diffractometer The PXRD diffraction pattern was obtained by radiation, and the Kα2:Kα1 intensity ratio was 0.50. The X-ray tube was set to 40 kV, 15 mA, and scanning mode 1D. The scanning range (2θ) was 3-40°, the step size (2θ) was 0.02°, and the scanning speed (2θ) was 10° / min.

[0205] Differential Scanning Calorimetry (DSC): DSC was performed using a TA Instruments DSC2500 differential scanning calorimeter using a temperature ramp from room temperature to 300°C with a heating rate of 2°C / min. The purge gas was N2 (>99.999%). A perforated aluminum pan was used.

[0206] Thermogravimetric analysis (TGA): TGA thermograms were obtained using a TA Instrument TGA500 thermogravimetric analyzer using a temperature ramp from room temperature to 300°C at a heating rate of 10°C / min. The purge gas was N2 (>99.999%). An open aluminum pan was used.

[0207] Dynamic Vapor Sorption (DVS): DVS analysis was performed on an Adventure DVS instrument using a partial pressure range of 0-90%, a step size of 10%, and dm / dt = 0.002. DVS data were collected at 25°C. Two cycles were performed for each analysis. The gas flow used was N2 (200 sccm).

[0208] Example 1: Preparation and characterization of Form 4

[0209] Preparation of Type 4

[0210] 2-(4-(Pyridin-2-yl)phenyl)acetic acid (38.40 g, 80%, 180.074 mmol, 1.00 eq) was added to DMF (385 mL). HOBT (17.38 g, 128.624 mmol, 0.71 eq) was added at 20 ° C, and then stirred for 10 minutes. 2-Chloro-4-methylthiazole-5-sulfonamide (26.66 g, 128.624 mmol, 0.71 eq) and EDCI (27.12 g, 141.486 mmol, 0.79 eq) were added. The mixture was stirred at 20 ° C for 36 hours under N2. The mixture was added to water (780 mL) and stirred for 30 minutes. The solid was collected by filtration. The filter cake was washed twice with water (2 x 100 mL) and then dried under reduced pressure at 50 ° C for 12 hours to obtain priligy (type 4) as a white solid (yield 78.4%).

[0211] The isolated solid was analyzed by XRPD, DSC, TGA, DVS, PLM, KF, HPLC and 1 The results were characterized by H-NMR.

[0212] Symptoms of Type 4

[0213] pass 1 H NMR confirmed the chemical identity of the isolated solid. The chemical purity of the solid was determined to be 98.3% (HPLC) and 89.6% (NMR, excluding water). KF detected 5.9% water.

[0214] XRPD( Figure 1 ) and PLM( Figure 2 ) showed that Form 4 was crystalline. DSC showed multiple thermal events; they were endothermic events with onset temperatures of 60, 108, and 185 °C, and an exothermic event with an onset temperature of 153 °C ( Figure 3 ). TGA showed a weight loss of 5.6% between 35 and 101°C ( Figure 3 ). DVS analysis showed that Form 4 was stable at relative humidity greater than 20%, while weight loss was observed at relative humidity less than 10% ( Figure 4 The solid after the DVS experiment was confirmed to be type 4 by XRPD ( Figure 5 ).

[0215] Characterization data showed that Form 4 is a sesquihydrate of Priligy (containing 1.5 water molecules per 1 Priligy molecule) that is stable over a wide humidity range.

[0216] Example 2: Type 4 Solubility Determination

[0217] method

[0218] Sample preparation: Excess Form 4 was added to a vehicle containing 0.9% NaCl and 0.5% polysorbate 80. The mixture was sonicated for 15 minutes and then stirred at 500 rpm at room temperature. At 24 hours, the mixture was filtered and the filtrate was analyzed by HPLC to determine solubility.

[0219] HPLC Method:

[0220] Instrument: Agilent 1260

[0221] Column: ACE ultracore super C18 (100mm*4.6mm*2.5μm) (P / N: CORE-25A-1046U)

[0222] Wavelength: 234nm

[0223] Column temperature: 20℃

[0224] Column flow rate: 1.0mL / min

[0225] Collection time: 25min

[0226] Injection volume: 5 μL

[0227] Retention time: ~14min

[0228] Mobile phase A: 5mM (NH4)2HPO4 and 5mM NH4H2PO4 in H2O

[0229] Mobile phase B: ACN

[0230]

[0231] result:

[0232] The solubility of Form 4 at 24 hours in 0.9% NaCl and 0.5% polysorbate 80 at room temperature was approximately 18.2 μg / mL.

[0233] Comparative solubility determination of Form C (hemihydrate) as disclosed in WO2018 / 096170

[0234] method

[0235] The solubility of Form C (hemihydrate as disclosed in WO 2018 / 096170) was determined in the same medium as described above for determining the solubility of Form 4.

[0236] Form C was prepared by slurrying Form 4 in ethanol:water (v:v=1:1) and then filtering at 50°C. Form C was confirmed to be crystalline by XRPD ( Figure 6 ).

[0237] Sample preparation: Excess Form C was added to a carrier containing 0.9% NaCl and 0.5% polysorbate 80, and sonicated for 15 minutes with stirring at 500 rpm at room temperature. The mixture was filtered after 24 hours and the filtrate was analyzed by HPLC to determine the solubility.

[0238] HPLC Method:

[0239] Instrument: Agilent 1260

[0240] Column: ACE ultracore super C18 (100mm*4.6mm*2.5μm) (P / N: CORE-25A-1046U)

[0241] Wavelength: 234nm

[0242] Column temperature: 20℃

[0243] Column flow rate: 1.0mL / min

[0244] Collection time: 25min

[0245] Injection volume: 5 μL

[0246] Retention time: ~14min

[0247] Mobile phase A: 5mM (NH4)2HPO4 and 5mM of NH4H2PO4 in H2O

[0248] Mobile phase B:CAN

[0249]

[0250] result:

[0251] The solubility in 0.9% NaCl and 0.5% polysorbate 80 at room temperature over 24 hours was about 8.4 μg / mL, which is lower than the solubility of Form 4 determined in the same medium.

Claims

1. A crystalline form of priligy, wherein the crystalline form is Form 4 and is characterized by one or more of the following data: a) Using Cu Ka The measured X-ray powder diffraction (XRPD) pattern comprises peaks at the following 2-theta values: 12.1, 14.6, and 18.3° 2θ ± 0.2° 2θ; and b) The DSC thermogram comprises at least one endothermic event with an onset temperature selected from the group consisting of: 60, 108, and 185°C ± 2°C.

2. The crystalline form of claim 1, wherein the form is characterized by the use of Cu The measured XRPD pattern contained peaks at the following 2-theta values: 12.1, 14.6, and 18.3° 2θ ± 0.2° 2θ.

3. A crystalline form according to any one of the preceding claims, wherein the form is characterized by the use of Cu Ka The radiometric XRPD pattern comprises peaks at the following 2-theta values: 12.1, 14.6 and 18.3°2θ±0.2°2θ, and further comprises at least one, two or three specific peaks selected from the following 2-theta values: 10.3, 16.3 and 28.7°2θ±0.2°2θ.

4. A crystalline form according to any one of the preceding claims, wherein the form is characterized by the use of Cu Ka The radiometric XRPD pattern contains peaks at the following 2-theta values: 12.1, 14.6 and 18.3° 2θ ± 0.2° 2θ, and further comprising peaks at the following 2-θ values: 10.3, 16.3 and 28.7°2θ±0.2°2θ.

5. A crystalline form according to any one of the preceding claims, wherein the form is characterized by the use of Cu Ka The radiometric XRPD pattern comprises at least two, five, ten, fifteen, twenty, twenty-five, thirty, thirty-five or forty further peaks selected from the peaks listed in Table 1 as °2θ±0.2°2θ.

6. The crystalline form of claim 5, wherein said form is characterized by the use of Cu Ka The radiometric XRPD pattern was essentially the same as that shown in FIG1 .

7. The crystalline form of any one of the preceding claims, wherein the form is characterized by a DSC thermogram comprising at least one endothermic event with an onset temperature selected from the group consisting of: 60, 108, and 185°C ± 2°C.

8. The crystalline form of any one of the preceding claims, wherein the form is characterized by a DSC thermogram substantially the same as that shown in Figure 3.

9. The crystalline form of any one of the preceding claims, wherein the form is substantially pure.

10. The crystalline form of claim 9, wherein the crystalline form comprises about 20% or less of any other solid form of Priligy.

11. The crystalline form of any one of the preceding claims, wherein the form comprises from about 4% to about 8% by weight water.

12. A pharmaceutical composition comprising a crystalline form of priligy and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form 4 according to any one of claims 1 to 11.

13. A method of treating a herpes virus (suitably HSV) infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of Priligy or a pharmaceutical composition according to claim 12, wherein the crystalline form is Form 4 according to any one of claims 1 to 11.

14. A crystalline form of Priligy according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 for use in the treatment of a herpes virus (suitably HSV) infection.

15. A method for preparing a crystalline form of Priligy, wherein the crystalline form is Form 4 and the method comprises the following steps: a. providing a priligy solution in a first solvent system; b. stirring the solution from step a) for at least one hour; c. adding the solution from step b) to a second solvent system; d. stirring the mixture obtained in step b) for at least 10 minutes; e. optionally, isolating the solid formed in step d); and f. Optionally, drying the solid separated from step e).

16. A crystalline form of Priligy obtainable by a process according to claim 15.

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