Crystalline forms of antiviral prodrugs

Abstract

Disclosed herein, in part, are crystalline forms of prodrugs of antiviral agents and methods of using them in the treatment of viral infections.

Description

[0001] Cross Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 490,999, filed March 17, 2023, which is incorporated by reference herein in its entirety.

[0002] SUMMARY In certain embodiments, disclosed herein are solid forms of antiviral prodrugs and methods of use thereof.

[0003] In certain embodiments, disclosed herein are crystalline forms of a compound represented by the following formula: characterized by a powder X-ray diffraction pattern having a characteristic peak at a 2 theta angle of about 17.8.

[0004] In certain embodiments, disclosed herein are crystalline forms of a compound represented by the following formula: characterized by a powder X-ray diffraction pattern having a characteristic peak at a 2 theta angle of about 5.6.

[0005] In certain embodiments, disclosed herein are crystalline forms of a compound represented by the following formula: characterized by a powder X-ray diffraction pattern having a characteristic peak at a 2 theta angle of about 21.6. BRIEF DESCRIPTION OF DRAWINGS Figure 1 An exemplary XRPD pattern of Form 1 is depicted.

[0007] Figure 2 An exemplary XRPD pattern of Form 2 is depicted.

[0008] Figure 3 An exemplary XRPD pattern of Form 4 is depicted.

[0009] Figure 4 An exemplary XRPD pattern of Form 1+4 is depicted.

[0010] Figure 5 An overlay of M2CAB Form 1 powder patterns identified in polymorph screening is depicted. From bottom to top: Form 1 (starting material) and Form 1+4 from AS11 (pyridine (solvent) / water (anti-solvent)), PSM1 (acetone / MeOH (50 / 50, v / v)), TCP21 (TBME), TCP13 (EtOH / water (90 / 10, v / v), and SLP47 (EtOH).

[0011] Figure 6An exemplary DSC trace of Form 1 is depicted.

[0012] Figure 7 HT-XRPD patterns of Form 1 (from bottom to top) (SM, reference), Form 1 (pyridine (S) and water (AS)), Form 1 (p-xylene / ACN 50 / 50) and Form 1 (1,4-dioxane / diisopropyl ether 50 / 50) are depicted.

[0013] Figure 8 High resolution (HR-) XRPD patterns collected for M2CAB, Form 1 obtained from cooling crystallization experiment in 1,4-dioxane / diisopropyl ether (50 / 50, v / v) and Form 1 obtained in a forward anti-solvent experiment in pyridine (solvent) and water (anti-solvent) are depicted (from bottom to top) between 6-28° 2 theta.

[0014] Figure 9 High resolution (HR-) XRPD patterns of M2CAB, Form 1 obtained from cooling crystallization experiment in 1,4-dioxane / diisopropyl ether (50 / 50, v / v) and Form 1 obtained in a forward anti-solvent experiment in pyridine (solvent) and water (anti-solvent) are depicted (from bottom to top) between 6-28° 2 theta.

[0015] Figure 10 TGMS analysis of Form 1 from a forward anti-solvent experiment in pyridine (solvent) and water (anti-solvent) is depicted (heating rate of 10 °C / min).

[0016] Figure 11 TGMS analysis of Form 1 obtained from cooling crystallization experiment in 1,4-dioxane / diisopropyl ether (50 / 50, v / v) is depicted (heating rate of 10 °C / min).

[0017] Figure 12 UPLC chromatogram of Form 1 from a forward anti-solvent experiment in pyridine (solvent) and water (anti-solvent) is depicted.

[0018] Figure 13 UPLC chromatogram of Form 1 obtained from cooling crystallization experiment in 1,4-dioxane / diisopropyl ether (50 / 50, v / v) is depicted.

[0019] Figure 14 DVS measurement of M2CAB with a DVS profile of 40-95-0-95-0-40% in steps of 10% RH is depicted. The change in mass as a function of time and relative humidity % is shown in panel A. In panel B, the adsorption and desorption cycles as a function of RH % are shown.

[0020] Figure 15 HT-XRPD patterns of M2CAB measured before (bottom plot) and after (top plot) DVS measurement are depicted.

[0021] Figure 16 High-throughput (HT-) XRPD patterns collected for M2CAB and Form 2 (from bottom to top) obtained in screening and scale-up are depicted.

[0022] Figure 17 High-resolution (HR-) XRPD pattern and high-throughput (HT-) XRPD pattern collected for Form 2 scale-up sample are depicted.

[0023] Figure 18 TGMS analysis of Form 2 scale-up (heating rate of 10 °C / min) is depicted.

[0024] Figure 19 DSC measurement of Form 2 scale-up sample is depicted.

[0025] Figure 20 UPLC chromatogram of Form 2 scale-up sample is depicted.

[0026] Figure 21 Superimposition of powder patterns of Form 4 obtained from single crystal attempt in ACN (HR-XRPD), Form 4 obtained in scale-up experiment and M2CAB (from bottom to top) is depicted.

[0027] Figure 22 Simulated powder pattern from single crystal data of Form 4 and high-resolution (HR-) XRPD pattern collected for Form 4 scale-up are depicted.

[0028] Figure 23 Variable temperature XRPD performed on Form 4 with the following temperature profile: 25-50-75-60-90-70-105-80-25 °C, heating rate of 20 °C / min and 5 min relaxation upon reaching temperature followed by XRPD measurement is depicted.

[0029] Figure 24 UPLC chromatogram of Form 4 scale-up sample is depicted.

[0030] Figure 25 Diffraction pattern collected for bulk material of M2CAB Form 4 is depicted.

[0031] Figure 26 Comparison of simulated powder pattern of M2CAB Form 4 (bottom line) with solid diffraction pattern obtained from cooling crystallization experiment in acetonitrile (top line) is depicted.

[0032] Figure 27Rietveld analysis of M2CAB solids obtained from cooling crystallization experiments in acetonitrile is depicted using single crystal data for Form 4 of M2CAB.

[0033] Figure 28 Exemplary DSC trace of Form 1+4 is depicted.

[0034] Figure 29 High resolution (HR-) XRPD patterns collected for M2CAB, Form 4 from single crystal experiments in ACN and Form 1+4 from evaporative crystallization experiments in p-xylene / CAN (50 / 50, v / v) are depicted (from bottom to top). Vertical lines are used to highlight the main differences observed when compared to Form 1 starting material.

[0035] Figure 30 TGMS analysis of Form 1+4 from cooling crystallization experiments in acetone / MeOH (50 / 50, v / v) is depicted (10 °C / min heating rate).

[0036] Figure 31 UPLC chromatogram of Form 1+4 from cooling crystallization experiments in acetone / MeOH (50 / 50, v / v) is depicted.

[0037] DETAILED DESCRIPTION DEFINITIONS As used in this specification, “one,” “an,” or “the” can mean one or more or more than one. The phrase “one or more” as used herein can refer to one or more than one. As used herein, “another” can mean at least a second or more. Yet further, the terms “having,” “including,” “containing,” and “comprising” are interchangeable and are not intended to be limiting. Some embodiments of the present disclosure can consist of or consist essentially of one or more elements, method steps and / or methods of the present disclosure. It is contemplated that any method, compound or composition described herein can be implemented relative to any other method, compound or composition described herein.

[0038] “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured taking into account the nature of the measurement or the precision of the instrument used to make the measurement. An exemplary degree of error is within 20 (20%) percent, typically within 10%, and more typically within 5% of a given value or range of values.

[0039] As used herein, unless the context clearly indicates otherwise, all numerical values or numerical ranges include the whole integers within such ranges or encompassing such ranges and fractions of the values or integers within ranges or encompassing ranges. Thus, for example, reference to a range of 90-100% includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, and the like, as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, and the like, 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, and the like, and the like. In another example, reference to a range of 1-5,000 fold includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 fold, and the like, as well as 1.1, 1.2, 1.3, 1.4, 1.5 fold, and the like, 2.1, 2.2, 2.3, 2.4, 2.5 fold, and the like, and the like.

[0040] As used herein, “pharmaceutically acceptable excipient” refers to any substance other than the active pharmaceutical ingredient in a pharmaceutical formulation. Exemplary pharmaceutical excipients include those that aid in the manufacturing process; those that protect, support, or enhance stability; those that improve bioavailability; or those that increase patient acceptability. They can also aid in product identification or enhance overall safety or functionality of the product during storage or use.

[0041] As used herein, “subject” for which administration is contemplated includes, but is not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, such as mammals like primates (e.g., cynomolgus monkeys, rhesus monkeys), bovines, porcines, equines, ovines, caprines, rodents, felines, and / or canines. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms “human,” “patient,” “subject,” and “individual” are used interchangeably herein. None of these terms requires active supervision by medical personnel.

[0042] Diseases, disorders, and conditions are used interchangeably herein.

[0043] As used herein, and unless otherwise indicated, the term “treatment” contemplates an action that occurs when a subject is afflicted with a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or reverses or slows the progression of the disease, disorder, or condition (also referred to as “therapeutic treatment”).

[0044] Generally, an“effective amount” of a compound refers to an amount that is sufficient to elicit a desired biological response. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the present disclosure can vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. A“therapeutically effective amount” of a compound is an amount that is sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of therapeutic agent alone, or in combination with other therapies, which will elicit the therapeutic response of the disease, disorder, or condition. The term“therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease, or enhances the therapeutic efficacy of another therapeutic agent. A“prophylactically effective amount” of a compound is an amount that is sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of therapeutic agent alone, or in combination with other agents, which will elicit the prophylactic response of the disease, disorder, or condition. The term“prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. A“preventive treatment” contemplates an action that occurs before a subject begins to suffer from a particular disease, disorder, or condition.

[0045] As used herein,“M2CAB” refers to a compound having the following structure: Crystalline Form Form 1 In certain embodiments, provided herein is a crystalline form of a compound represented by: characterized by a powder X-ray diffraction pattern having a characteristic peak at a 2 theta angle of about 17.8.

[0046] In certain embodiments, the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks at 2 theta angles of about 7.4, 17.8, and 22.2. In certain embodiments, the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks at 2 theta angles of about 7.4, 17.5, 17.8, 18.7, and 22.2. In certain embodiments, the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks at 2 theta angles of about 6.8, 7.4, 16.7, 16.9, 17.5, 17.8, 18.2, 18.7, 21.9, and 22.2. In certain embodiments, the crystalline form is characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 1. Figure 1the powder X-ray diffraction pattern depicted in FIG. 2. In certain embodiments, the crystalline form is one wherein the powder X-ray diffraction pattern is obtained using Cu Ka radiation. In certain embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) curve having an endotherm with an onset at about 118 °C and a peak at about 120 °C.

[0047] Form 2 In certain embodiments, provided herein is a crystalline form of the compound represented by: characterized by a powder X-ray diffraction pattern having a characteristic peak at a 2 theta angle of about 5.6.

[0048] In certain embodiments, the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks at 2 theta angles of about 5.6, 16.0, and 21.8. In certain embodiments, the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks at 2 theta angles of about 5.6, 16.0, 21.8, 23.1, and 23.4. In certain embodiments, the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks at 2 theta angles of about 5.6, 7.4, 16.0, 16.9, 17.8, 18.3, 19.0, 21.8, 23.1, and 23.4. In certain embodiments, the crystalline form is characterized by a powder X-ray diffraction pattern substantially as depicted in FIG. 2. Figure 2 the powder X-ray diffraction pattern depicted in FIG. 2. In certain embodiments, the crystalline form is one wherein the powder X-ray diffraction pattern is obtained using Cu Ka radiation. In certain embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) curve having an endotherm with an onset at about 118 °C and a peak at about 120 °C.

[0049] Form 4 In certain embodiments, provided herein is a crystalline form of the compound represented by: characterized by a powder X-ray diffraction pattern having a characteristic peak at a 2 theta angle of about 21.6.

[0050] In certain embodiments, the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks at 2 theta angles of about 7.0, 21.6, and 22.9. In certain embodiments, the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks at 2 theta angles of about 7.0, 16.4, 21.6, 22.9, and 23.6. In certain embodiments, the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks at 2 theta angles of about 6.8, 7.0, 16.4, 16.6, 20.0, 21.6, 22.0, 22.7, 22.9, and 23.6. In certain embodiments, the crystalline form is characterized by a powder X-ray diffraction pattern substantially as depicted in FIG. 4. Figure 3The powder X-ray diffraction pattern depicted is shown in the figure. In some embodiments, the crystal form is in which the powder X-ray diffraction pattern is obtained using Cu Kα radiation. In some embodiments, the crystal form is characterized by a differential scanning calorimetry (DSC) curve with the following endothermic characteristics: an onset at about 119 °C and a peak at about 122 °C.

[0051] Form 1+4 In some embodiments, this document provides mixtures of crystal forms of compounds represented by the following: Its characteristic feature is that the powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of approximately 21.6.

[0052] In some embodiments, the mixture of crystal forms is characterized by powder X-ray diffraction patterns with characteristic peaks at 2θ angles of approximately 7.0, 17.8, and 21.6.

[0053] In some embodiments, the mixture of crystalline forms is characterized by powder X-ray diffraction patterns with characteristic peaks at 2θ angles of approximately 7.0, 7.4, 17.8, 21.6, and 23.6. In some embodiments, the mixture of crystalline forms is characterized by powder X-ray diffraction patterns with characteristic peaks at 2θ angles of approximately 7.0, 7.4, 14.0, 16.3, 16.8, 17.8, 21.6, 23.6, 24.3, and 26.1. In some embodiments, the mixture of crystalline forms is characterized by substantially as... Figure 4 The XRPD pattern depicted is shown in the figure. In some embodiments, the mixture of crystalline forms is characterized by a differential scanning calorimetry (DSC) curve with the following endothermic characteristics: an onset of about 119 °C and a peak of about 122 °C. In some embodiments, the mixture of crystalline forms is the crystalline form in which a powder X-ray diffraction pattern is obtained using Cu Kα radiation.

[0054] Pharmaceutical Composition In some embodiments, this document discloses pharmaceutical compositions comprising: (a) a crystalline solid form of M2CAB, and (b) a pharmaceutically acceptable excipient.

[0055] In some embodiments, the crystal form of the compound is provided by: The compound is characterized by a powder X-ray diffraction pattern having a characteristic peak at a 2θ angle of approximately 17.8°. In some embodiments, the crystal form of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak at a 2θ angle of approximately 5.6°. In some embodiments, the crystal form of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak at a 2θ angle of approximately 21.6°.

[0056] In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.4, 17.8, and 22.2 in degrees 2 theta. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.4, 17.5, 17.8, 18.7, and 22.2 in degrees 2 theta. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.8, 7.4, 16.7, 16.9, 17.5, 17.8, 18.2, 18.7, 21.9, and 22.2 in degrees 2 theta. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 5.6, 16.0, and 21.8 in degrees 2 theta. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 5.6, 16.0, 21.8, 23.1, and 23.4 in degrees 2 theta. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 5.6, 7.4, 16.0, 16.9, 17.8, 18.3, 19.0, 21.8, 23.1, and 23.4 in degrees 2 theta. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.0, 21.6, and 22.9 in degrees 2 theta. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.0, 16.4, 21.6, 22.9, and 23.6 in degrees 2 theta. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.8, 7.0, 16.4, 16.6, 20.0, 21.6, 22.0, 22.7, 22.9, and 23.6 in degrees 2 theta. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.0, 17.8, and 21.6 in degrees 2 theta. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.0, 7.4, 17.8, 21.6, and 23.6 in degrees 2 theta. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.0, 7.4, 14.0, 16.3, 16.8, 17.8, 21.6, 23.6, 24.3, and 26.1 in degrees 2 theta.

[0057] In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern substantially as shown in Figures Figure 1 , 2 , 3, and 4. In some embodiments, the powder X-ray diffraction pattern is obtained using Cu Ka radiation.

[0058] In some embodiments, the crystalline form of the compound is characterized by a differential scanning calorimetry (DSC) curve having an endotherm with an onset at about 118 °C and a peak at about 120 °C. In some embodiments, the DSC curve has an endotherm with an onset at about 119 °C and a peak at about 122 °C.

[0059] In some embodiments, the composition has a physiologically compatible pH (e.g., a pH of about 3 to a pH of about 11, a range of about pH 3 to about pH 7, depending on the formulation and route of administration). In some cases, the pH is about pH 5.0 to about pH 8.

[0060] In some embodiments, depending on the particular mode of administration and dosage form, the pharmaceutically acceptable excipient is a carrier, a solvent, a stabilizer, an auxiliary agent, a diluent, and the like.

[0061] Suitable excipients include, for example, carrier molecules, which include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactivated virus particles. Other exemplary excipients can include antioxidants (e.g., and without limitation, ascorbic acid), chelating agents (e.g., and without limitation, EDTA), carbohydrates (e.g., and without limitation, cellulose, dextrin).

[0062] The pharmaceutical compositions disclosed herein are administered by any suitable route that results in an effective treatment in a subject. In some embodiments, the pharmaceutical compositions disclosed herein are administered systemically. In some embodiments, the pharmaceutical compositions disclosed herein are administered locally. The pharmaceutical compositions are administered via routes such as, but not limited to, enteral, gastrointestinal, oral, transdermal, subcutaneous, nasal, intravenous, intravenous bolus, intravenous drip, intra-arterial, intramuscular, transmucosal, insufflation, sublingual, buccal, conjunctival, dermal. Modes of administration include injection, infusion, drip, and / or ingestion. “Injection” includes, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intraventricular, intradermal, intraperitoneal, transtracheal, and subcutaneous. In some embodiments, the route is intramuscular. In some embodiments, the route is subcutaneous.

[0063] Methods of use In certain embodiments, disclosed herein are methods of treating an HIV-1 infection in an individual in need thereof, comprising administering to the individual a pharmaceutical composition disclosed herein. In some embodiments, further disclosed herein are methods of preventing an HIV-1 infection in an individual in need thereof, comprising administering to the individual a pharmaceutical composition disclosed herein. Additionally, in some embodiments, disclosed herein are methods of preventing the transmission of an HIV-1 virus from one individual to another (e.g., from a pregnant woman to a child, for example, during delivery or breastfeeding), comprising administering to the individual a composition disclosed herein.

[0064] In certain embodiments, disclosed herein are methods of treating an HIV-1 infection in an individual in need thereof, comprising administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of a compound represented by: and a pharmaceutically acceptable excipient. In some embodiments, further disclosed herein are methods of preventing an HIV-1 infection in an individual in need thereof, comprising administering to the individual a pharmaceutical composition comprising a prophylactically effective amount of a crystalline form of a compound represented by: and a pharmaceutically acceptable excipient. Additionally, in some embodiments, disclosed herein are methods of preventing the transmission of an HIV-1 virus from one individual to another (e.g., from a pregnant woman to a child, for example during childbirth or breastfeeding), comprising administering to the individual a pharmaceutical composition comprising a prophylactically effective amount of a crystalline form of a compound represented by: and a pharmaceutically acceptable excipient.

[0065] In certain embodiments, disclosed herein are methods of treating an HIV-1 infection in an individual in need thereof, comprising administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a mixture of crystalline forms of a compound represented by: and a pharmaceutically acceptable excipient. In some embodiments, further disclosed herein are methods of preventing an HIV-1 infection in an individual in need thereof, comprising administering to the individual a pharmaceutical composition comprising a prophylactically effective amount of a mixture of crystalline forms represented by: and a pharmaceutically acceptable excipient. Additionally, in some embodiments, disclosed herein are methods of preventing the transmission of an HIV-1 virus from one individual to another (e.g., from a pregnant woman to a child, for example during childbirth or breastfeeding), comprising administering to the individual a pharmaceutical composition comprising a prophylactically effective amount of a mixture of crystalline forms of a compound represented by: and a pharmaceutically acceptable excipient. In some embodiments, the method comprises administering the pharmaceutical composition to the individual once a month. In some embodiments, the method comprises administering the pharmaceutical composition to the individual once every two months. In some embodiments, the method comprises administering the pharmaceutical composition of the compound to the individual once every three months. In some embodiments, the method comprises administering the pharmaceutical composition to the individual once every six months. In some embodiments, the method comprises administering the pharmaceutical composition of the compound to the individual once every nine months. In some embodiments, the method comprises administering the pharmaceutical composition of the compound to the individual once every twelve months.

[0066] In certain embodiments, described herein are methods of treating, inhibiting, and / or preventing a viral infection in a patient in need thereof, the method comprising administering to the patient an effective amount of a crystalline form of M2CAB or a mixture thereof.

[0067] In some embodiments, the method comprises administering the crystalline form of the compound to the individual once a month. In some embodiments, the method comprises administering the crystalline form of the compound to the individual once every two months. In some embodiments, the method comprises administering the crystalline form of the compound to the individual once every three months. In some embodiments, the method comprises administering the crystalline form of the compound to the individual once every six months. In some embodiments, the method comprises administering the crystalline form of the compound to the individual once every nine months. In some embodiments, the method comprises administering the crystalline form of the compound to the individual once every twelve months.

[0068] In certain embodiments, described herein are methods of treating, inhibiting, and / or preventing a viral infection in a patient in need thereof, the method comprising administering to the patient an effective amount of a mixture of crystalline forms of M2CAB.

[0069] In some embodiments, the viral infection is a retroviral infection. In some embodiments, the viral infection is an HIV infection.

[0070] In some embodiments, the method comprises administering the mixture of crystalline forms of the compound to the individual once a month. In some embodiments, the method comprises administering the mixture of crystalline forms of the compound to the individual once every two months. In some embodiments, the method comprises administering the mixture of crystalline forms of the compound to the individual once every three months. In some embodiments, the method comprises administering the mixture of crystalline forms of the compound to the individual once every six months. In some embodiments, the method comprises administering the mixture of crystalline forms of the compound to the individual once every nine months. In some embodiments, the method comprises administering the mixture of crystalline forms of the compound to the individual once every twelve months.

[0071] In some embodiments, a crystalline form of M2CAB described herein, a mixture of crystalline forms of M2CAB described herein, or a pharmaceutical composition described herein is administered in combination with an additional therapeutic agent to treat a disorder described herein. Examples

[0072] Table A. Abbreviations AAC accelerated aging conditions (40 °C / 75% RH) ACN acetonitrile Am amorphous Amb ambient dried solid sample (at RT) API active pharmaceutical ingredient CHCl3 chloroform CPME cyclopentyl methyl ether DCM dichloromethane DSC differential scanning calorimetry DMA N,N-dimethylacetamide DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DVS dynamic vapor sorption EtOH ethanol Evap evaporated solid sample HR-XRPD high resolution X-ray powder diffraction HT-XRPD high throughput X-ray powder diffraction IPA isopropanol / 2-propanol MEK 2-butanone MeOH methanol MIBK methyl isobutyl ketone / 4-methyl-2-pentanone ML mother liquor (liquid phase) MS mass spectrometry Pc crystallinity difference PLM polarized light microscopy RH relative humidity RT room temperature SCXRD single crystal X-ray diffraction SM starting material TBME tert-butyl methyl ether TGA thermogravimetric analysis TGMS thermogravimetric analysis coupled with mass spectrometry THF tetrahydrofuran UPLC ultra performance liquid chromatography Vac vacuum dried solid sample (at 5 mbar / RT) VT-XRPD variable temperature XRPD 2-MeTHF 2-methyltetrahydrofuran 1+4 mixture of Form 1 and Form 4 1+2 mixture of Form 1 and Form 2 1+2+4 mixture of Form 1, Form 2 and Form 4 Example 1: Preparation of new forms This is a study of various crystalline forms of M2CAB. Forms such as Form 1, Form 2, Form 4, and Form 1+4 were studied, which are described below.

[0073] An exemplary XRPD pattern of Form 1 is provided in FIG. 1. Figure 1 An exemplary XRPD pattern of Form 2 is provided in FIG. 2. Figure 2 An exemplary XRPD pattern of Form 4 is provided in FIG. 4. Figure 3 An exemplary XRPD pattern of Form 1+4 is provided in FIG. 5. Figure 4

[0074] Materials All chemicals obtained were research grade and at least 99% pure.

[0075] Preparation of Form 1 Form 1 was prepared from crystallization from methyl tert-butyl ether (MTBE). A clear solution of M2CAB was prepared in 35 parts of MTBE at 50 °C, which was cooled to 45 °C, then seed crystals (0.5%) were added. The mixture was slowly cooled to 25 °C over about 3 hours and kept at this temperature for more than 12 hours, then the product was collected by filtration, washed with ambient temperature MTBE, and dried under vacuum with a yield of about 80%.

[0076] Preparation of Form 2 Amorphous M2CAB was prepared by dissolving 507.48 mg in 7.25 mL THF / water (80 / 20, v / v). Subsequently, the solution was frozen in liquid nitrogen and dried overnight in a freeze-dryer Christ Alpha 2-4 LD to provide Form 2, which was confirmed by XRPD analysis.

[0077] Preparation of Form 4 Form 4 was prepared by cooling crystallization in ethanol. For this, 204.3 mg M2CAB was dissolved in 25.5 mL ethanol at 50 °C (concentration of 8 mg / mL). Subsequently, the solution was allowed to cool to RT for several days. After 2 days, crystals were observed and the vial was opened to allow slow evaporation until dryness.

[0078] Preparation of Form 1+ Form 4 ​An exemplary preparation of Form 1 + Form 4 is as follows: M2CAB powder was weighed out on a weigh boat. The powder was transferred into an aqueous solution, then inserted into the head of a propeller and mixed until a homogeneous and flowable suspension was formed. The speed was 600 rpm for a duration of 2 minutes.

[0079] Analytical methods High throughput X-ray powder diffraction (XRPD) XRPD patterns were obtained using a T2 high throughput XRPD set-up. The plate was mounted on a Bruker General Area Detector Diffraction System (GADDS) equipped with a VANTEC-500 gas area detector that corrects for intensity and geometry variations. The measurement accuracy (peak position) was calibrated using the NIST SRM 1976 standard (Corundum).

[0080] Data collection was performed at room temperature using monochromatic Cu Ka radiation in the 2Q region between 1.5° and 41.5°, which is the most characteristic part of the XRPD pattern. The diffractogram of each well was collected within two 2Q ranges, 1.5° < 2Q < 21.5°, and 19.5° < 2Q < 41.5° for the first and second frame, respectively, with an exposure time of 90 seconds for each frame. No background subtraction or curve smoothing was applied to the XRPD patterns.

[0081] High resolution X-ray powder diffraction (HR-XRPD) The solid was ground in an agate mortar until all visible crystals were gone and the material became a fine powder before being transferred into a capillary. HR-XRPD data were collected on a D8 Advance diffractometer using Cu Ka1 radiation (1.54056 A) with a germanium monochromator at RT. Diffraction data were collected within the 2Q range 2.15-41.5°. Detector scans were performed on a solid state LynxEye detector with a scan speed of 10 seconds / step using 0.0157° per step. The sample was measured in an 8 mm long glass capillary with an outer diameter of 0.7 mm.

[0082] The cell parameters as well as the crystal system were obtained using the LSI-Index (Coelho, 2003; Coelho & Kern, 2005) indexing program and refined using the whole powder pattern decomposition algorithm (Pawley, 1981; Toraya 2000). The space group was chosen based on the crystal's reflections condition and density. The cell parameters, purity and instrument parameters were refined using the whole powder pattern decomposition method (Pawley, 1981, Toraya 2000).

[0083] The unit cell parameters of the solvated form are listed in Table 6 for comparison purposes. As can be seen, the following similarities and differences between the two forms can be observed: the a axis in the solvated form is almost twice that of Form 1, while the b and c axes and the beta angle are almost identical in both forms.

[0084] Single crystal diffraction using Cu Kα radiation X-ray crystallographic analysis was performed using a crystal of dimensions approximately 0.05 x 0.12 x 0.5 mm3. X-ray intensity data were measured at RT (l = 1.54178 A).

[0085] A total of 5365 frames were collected. The total exposure time was 19.37 hours. The frames were integrated using the narrow-frame algorithm with the Bruker SAINT software package. Integration of the data using monoclinic unit cell resulted in a total of 74078 reflections to a maximum theta angle of 72.50° (0.81 A resolution), of which 13997 reflections were independent (average redundancy 5.292, completeness = 91.4%, Rint = 5.25%, Rsig = 3.99%) and 12009 reflections (85.80%) were greater than 2sigma (F2). The final cell constants of a = 53.203(4) A, b = 5.7766(5) A, c = 25.834(2) A, beta = 100.609(3)°, volume = 7803.9(11) A3 were obtained from refinement on XYZ centroids of 9717 reflections above 20sigma (I) (8.282° < 2theta < 143.8°). The data were corrected for absorption effects using the multi-scan method (SADABS). The ratio of the minimum to the maximum apparent transmission was 0.749. The calculated minimum and maximum transmission coefficients (based on crystal size calculation) were 0.7210 and 0.9660.

[0086] The structure was solved and refined using the Bruker SHELXTL software package in space group C 1 2 1 with Z = 8 for the formula unit C37H51F2N3O6. The final anisotropic full matrix least squares refinement on F2converged to R1= 5.97% and wR2= 17.36% for all data using 947 variables. The goodness of fit was 1.045. The largest peak in the final difference electron density synthesis was 0.204 e- / A3 and the largest hole was -0.210 e- / A3 with an RMS deviation of 0.044 e- / A3. The calculated density based on the final model was 1.146 g / cm3 and F(000) was 2880 e-.

[0087] Thermal analysis Mass loss due to loss of solvent or water from the crystal was determined by TGA / DSC. During heating in a TGA / DSC system, the sample weight was monitored to give a weight versus temperature curve and a heat flow signal. The temperature of the TGA / DSC was calibrated with samples of indium and aluminum. A sample (about 2 mg) was weighed into a 100 μL aluminum crucible and sealed. The seal was pierced and the crucible was heated in the TGA from 25 °C to 300 °C at a heating rate of 10 °C min-1. Dry nitrogen was used for purging.

[0088] Gases from the TGA sample were analyzed by a mass spectrometer. This is a quadrupole mass spectrometer that analyzes mass over a temperature range of 0-200 amu.

[0089] Thermal events were obtained from DSC thermograms, recorded with a heat flux DSC system. The temperature and enthalpy of the DSC were calibrated with indium (m.p. = 156.6 °C; Hf = 28.45 J / g) and zinc (m.p. = 419.6 °C; Hf = 107.5 J / g) chips. A sample (about 2 mg) was sealed in a standard 40 μL aluminum pan, pierced, and heated in the DSC from 25 °C to 300 °C at a heating rate of 10 °C / minute. During the measurement, the DSC apparatus was purged with dry nitrogen gas at a flow rate of 50 mL / minute.

[0090] UPLC analysis method UPLC system: UPLC: Agilent 1290 Detector 1: UV detector set at 230 nm Detector 2: MSD XT in positive scan mode UPLC conditions: Auto-sampler temperature: RT Column: Agilent Eclipse Plus C8 HD (50 x 2.1mm; 1.8µm) Column temperature: 40 °C Gradient: Mobile Phase A: 10 mM ammonium acetate in water Mobile Phase B: Acetonitrile Flow rate: 0.6 mL / min Gradient: Time [min]: Eluent A: Eluent B: 0 90% 10% 0.1 90% 10% 1.5 3% 97% 2.50 3% 97% 2.51 90% 10% 3.5 90% 10% Run time: 3.5 min Sample Concentration: ~0.40 mg / mL Solvent: ACN Injection volume: 1 µl Retention time: 2.09 min Compound integrity is expressed as the percentage of peak area calculated from the area of each peak in the chromatogram, except the “injection peak”, and the total peak area as follows: The percentage of peak area of the compound of interest is used as an indication of the purity of the component in the sample.

[0091] Dynamic vapor sorption Moisture sorption isotherms were collected on a DVS Adveture system from Surface Measurement Systems (London, UK). The sample size was approximately 10 mg of solid material. Full sorption and desorption isotherms were recorded by changing the relative humidity from 40-95-0-95-0-40% at 10% steps at a constant temperature of 25 °C. The weight equilibrium for each step was set at dm / dt 0.002% / min (for at least 15 min) or a maximum equilibrium time of 6 hours. The sample was then measured by HT-XRPD.

[0092] The hygroscopicity classification of the API is based on the percentage of water uptake during the first sorption cycle of the sorption isotherm at 25 °C / 82% RH.

[0093] Table 1. moisture classification standard non-hygroscopic <0.2% (w / w) slightly hygroscopic 0.2-2% (w / w) moderately hygroscopic 2-15% (w / w) very hygroscopic >15% (w / w) Example 2: Characterization of the new forms Polymorph screening Polymorph screening was performed on M2CAB by applying the following crystallization methods: solvent equilibration, slow cooling crystallization, slow evaporation crystallization, thermal cycling, antisolvent (reverse & forward) precipitation and vapor diffusion into solution and onto solids.

[0094] Form 1 was recovered from most of the crystallization experiments; however, differences in the powder patterns of Form 1 were observed, with additional peaks present in some cases or with some shifts of the diffraction peaks seen. The additional peaks observed in the powder patterns can be attributed to solvated Form 4. Therefore, all of these powder patterns were classified as mixtures of Form 1 + Form 4. The differences between the different patterns can be attributed to different contents of Form 1 and Form 4. The superimposition of the patterns of different mixtures of Form 1 + Form 4 is shown in Figure 5 .

[0095] Based on the similarities observed in the powder patterns collected in this study, we can confirm that all the forms classified as mixtures of Form 1 + 4 contain both forms, but with slightly different solvent contents and, therefore, different contents of Form 1 and Form 4.

[0096] Solid state characterization The following samples have been analyzed for characterization (HR-XRPD, PLM, DSC, TGMS and HPLC). The summary of the results of the analysis is shown in Table 2.

[0097] • Form 1 (same as SM) (pyridine (S), water (AS)) (1,4-dioxane / diisopropyl ether (50 / 50, v / v).

[0098] • Form 1 + 4 from: o p-xylene / ACN (50 / 50, v / v), o acetone / MeOH (50 / 50, v / v), o TBME, o ethanol / water (90 / 10, v / v), and • Form 2 water.

[0099] Table 2. Results of the analytical characterization performed on the different powder patterns identified in this polymorph screening include the characterization performed on the four different batches of M2CAB provided. The endothermic events are classified as “br” for broad endotherm, “en” for endothermic event, “exo” for exothermic event and “m” for melting event. The notation “TBD” means “to be determined”.

[0100] Characterization of Form 1 An exemplary XRPD pattern of Form 1 is shown inFigure 1 An exemplary DSC trace is depicted in FIG. 1. Figure 6 In DSC, the T onset was about 117.5 °C, while the Tpeak was about 120.7 °C.

[0101] Three solid samples of Form 1 (same as starting material) were also selected for analytical characterization. The experiments selected were pyridine (S), water (AS), p-xylene / ACN (50 / 50, v / v), and 1,4-dioxane / diisopropyl ether (50 / 50, v / v). The powder patterns of the three samples are shown in FIGS. 2-4. Figure 7

[0102] During 3 sorption cycles and 2 desorption cycles, water uptake varied between -0.1 and 0.05%, which indicates that M2CAB Form 1 can be considered non-hygroscopic according to the hygroscopicity classification obtained by sorption analysis.

[0103] Figure 15 The HT-XRPD patterns of M2CAB measured before (bottom graph) and after (top graph) DVS measurement are shown. Form 1 was recovered after the DVS determination.

[0104] The HR-XRPD diffractograms collected for the three Form 1 samples are shown in FIGS. 5-7. Figure 8 Figure 9

[0105] An exemplary XRPD peak list for Form 1 is provided in Table 3 below.

[0106] Table 3. Peak list for Form 1 2 theta [°] d [Å] I [%] 1 3.39 26.03 100 2 6.76 13.06 4 3 7.42 11.91 7 4 10.14 8.71 1 5 11.21 7.89 1 6 14.49 6.11 1 7 14.84 5.97 1 8 14.92 5.93 1 9 15.50 5.71 1 10 16.67 5.32 4 11 16.86 5.26 4 12 17.51 5.06 7 13 17.84 4.97 8 14 18.18 4.88 5 15 18.68 4.75 6 16 18.85 4.70 2 17 19.17 4.63 2 18 20.35 4.36 1 19 20.64 4.30 3 20 21.00 4.23 2 21 21.31 4.17 3 22 21.90 4.06 6 23 22.15 4.01 7 24 22.33 3.98 2 25 22.53 3.94 3 26 22.81 3.90 1 27 23.28 3.82 4 28 23.47 3.79 4 29 23.71 3.75 1 30 23.86 3.73 2 31 24.03 3.70 2 32 24.51 3.63 1 33 24.84 3.58 2 34 25.18 3.53 1 35 25.60 3.48 3 Observation under polarized light indicated that Form 1 was composed of very small plate-like and needle-like crystals. The crystals had dimensions between 0.02-0.05 mm. The crystals could be as small as <0.05 mm in the longest direction and as large as >0.2 mm in the longest direction.

[0107] TGA / TGMS analysis of Form 1 ( Figure 10 and 11 ) showed a mass loss between 25-240 °C between 0.5-0.8%, which can be attributed to residual water / solvent. The trace of thermal decomposition occurred above 240 °C ( Figure 11 ).

[0108] UPLC chromatogram of Form 1 ( Figure 12 and 13 ) showed the presence of an API peak at 2.12 min with a chemical purity of 98.5% (area%).

[0109] ​​​M2CAB Form 1 was subjected to DVS measurement at a constant temperature of 25 °C with a RH profile of 40-95-0-95-0-40%. After equilibration at a dm / dt of 0.002% / min (for at least 15 min) or a maximum equilibration time of 6 h, the relative humidity was changed in steps of 10%. The change in sample mass as a function of time and relative humidity % is shown in Figure 14 (Figure A). The adsorption and desorption cycle as a function of RH % is shown in Figure 14 (Figure B).

[0110] Analytical Characterization of Form 2 An exemplary XRPD pattern of Form 2 is provided in Figure 2 Form 2 was prepared at a 500 mg scale. Initially in the screen, Form 2 was obtained by solvent equilibration of amorphous M2CAB in water at RT. During the scale-up experiments, Form 2 was obtained immediately after lyophilization, thus, no recrystallization was applied to the lyophilized solid. The HT-XRPD of the scale-up Form 2 was compared to the Form 2 obtained in the screen in Figure 16 , while the high resolution XRPD collected for the scale-up Form 2 is shown in Figure 17 .

[0111] TGA / TGMS analysis of Form 2 ( Figure 18 ) showed a residual solvent content below 0.1% between 25-200 °C. The trace of thermal decomposition appeared above 240 °C.

[0112] The DSC trace ( Figure 19 ) showed a broad endothermic event (T onset 89.4 °C) at T peak 92.5 °C, which corresponds to loss of water, followed by an exothermic event at T peak 96.4 °C, and a sharp endothermic event (T onset 117.5 °C) at T peak 120.4 °C, which can correspond to the melting of Form 1.

[0113] The UPLC chromatogram of Form 2 ( Figure 20 ) showed the presence of an API peak at 2.12 min with a chemical purity of 98.9% (area %).

[0114] An exemplary XRPD peak list is provided in Table 4 below.

[0115] Table 4. Exemplary peak list 2 theta angle ° intensity % 2.742 83.5 4.355 100 5.628 16.7 6.769 2.7 7.47 4.9 8.742 1.3 10.874 1.8 13.099 2.6 13.73 2.8 16.021 7.1 16.887 7.2 17.835 9 18.261 9.3 18.958 9.5 19.435 12.3 20.285 10.2 21.839 19.8 23.068 14.9 23.407 9 24.289 3.5 25.744 3.9 26.842 2.1 30.416 1.1 Analytical Characterization of Form 4 Form 4 was initially isolated as a pure crystalline phase in single crystal experiments performed in ACN. Further studies confirmed that the same (isomorphic solvate) form could be isolated from ethanol. Therefore, Form 4 was prepared on a larger scale by cooling crystallization in ethanol. The dried solid obtained was analyzed by HT-XRPD, which confirmed that Form 4 was crystallized. In Figure 21 , the HT-XRPD diffractogram collected for Form 4 on a larger scale was compared to the simulated powder pattern of Form 4. In Figure 22 , the simulated powder pattern obtained from single crystal data of Form 4 was compared to the HR-XRPD data collected for Form 4 on a larger scale. Based on the similarity and absence of diffraction peaks due to Form 1, it was confirmed that Form 4 was produced as a pure crystalline phase.

[0116] An exemplary XRPD pattern of Form 4 is provided in Figure 3 . An exemplary XRPD peak list is provided below in Table 5.

[0117] Table 5. Peak table for Form 5. 2 theta [°] d [Å] I [%] 1 3.41 25.93 100 2 6.79 13.01 6 3 6.98 12.66 9 4 7.19 12.29 3 5 11.22 7.88 1 6 13.95 6.34 2 7 15.73 5.63 2 8 16.36 5.42 5 9 16.60 5.34 4 10 16.85 5.26 3 11 16.98 5.22 2 12 17.09 5.18 3 13 17.62 5.03 3 14 17.99 4.93 2 15 18.51 4.79 1 16 18.80 4.72 2 17 19.39 4.57 3 18 19.80 4.48 2 19 19.94 4.45 4 20 21.07 4.21 4 21 21.63 4.11 11 22 21.97 4.04 4 23 22.71 3.91 5 24 22.89 3.88 7 25 23.19 3.83 2 26 23.62 3.76 5 27 23.74 3.75 3 28 24.33 3.66 4 29 24.73 3.60 2 30 25.08 3.55 2 31 26.18 3.40 3 32 27.11 3.29 1 33 28.32 3.15 1

[0118] A variable temperature XRPD was performed on Form 4. A solid sample of Form 4 was heated / cooled with the following temperature profile: 25-50-75-60-90-70-105-80-25 °C, with a heating rate of 20 °C / min and a 5 min relaxation upon reaching temperature followed by an XRPD measurement. The overlay of the collected powder patterns is shown in Figure 23 . The powder patterns were compared to Form 1 collected during VT-XRPD. Very small shifts were observed at different temperatures, which can be the effect of the unit cell size expansion upon temperature application. No change in the solid form was observed, which indicates that in the case of solvent molecules release from the crystal, the lattice does not transform to the anhydrous Form 1.

[0119] The UPLC chromatogram of Form 4 Figure 24 shows the presence of an API peak at 2.11 min with a chemical purity of 96.8% (area %).

[0120] Single Crystal Analysis of Form 4 Single crystals of M2CAB were grown from cooling crystallization experiments performed in acetonitrile. About 20 mg of M2CAB was placed in an 8 ml vial. Then 2 ml of acetonitrile was added and the vial was sealed. The obtained suspension was heated to 80 °C until all the solid was dissolved. The solution was left at RT under seal, without stirring. After 4 days at RT, long plate-like needle-shaped crystals were obtained.

[0121] One crystal of about 0.5 x 0.12 x 0.05 mm3size was selected for single crystal X-ray diffraction (SCXRD) analysis.

[0122] The final crystal data and refined parameters can be found in Table 6. This new structure is named Form 4.

[0123] Table 6. Crystal data and final refined parameters for Form 4. form Form 4 empirical formula [C 37 H 51 F2N3O6+ solvent (ACN) formula weight 671.80 T [K] 296(2) K lambda [A] 1.54178 crystal system monoclinic space group 2 unit cell dimensions a [Å] 53.203(4) b [Å] 5.7766(5) c [Å] 25.834(2) β [°] 100.609(3) V[Å 3 ]]]> 7803.9(11) Z (z') 8 Dc [g / cm3] 1.146<x<1.200 mu [mm-1] 0.700 F(000) 2880 crystal size [mm3] 0.50 x 0.12 x 0.05 theta range [°] for data collection 1.7 → 72.5. reflections collected 74078 unique reflections 13997 [R int = 0.0525]]]> completeness [%] at theta = 22.0° 91.4 absorption correction semi-empirical values from equivalent maximum and minimum transmission 0.97 and 0.72 data / restraints / parameters 13997 / 4 / 947 goodness of fit to F2 1.045 final R indices [I > 2sigma(I)] R1 = 0.0597, wR2 = 0.1654 R indices (all data) R1 = 0.0678, wR2 = 0.1736 absolute structure parameters 0.07(6) extinction coefficient N / A maximum difference peak and hole [e / A3] 0.204 and -0.210

[0124] The crystal structure can be described as lamellar. One layer is formed by the alicyclic part with the fused ring, while the other layer is formed by the long aliphatic chain of the stearate ester. In such packing, channels along the [0 1 0] direction are formed, which are filled with solvent molecules. The solvent molecules show a lot of disorder and therefore cannot be quantified. Due to the disorder, it is assumed that acetonitrile molecules are present in the channels, as this is the crystallization solvent used in the single crystal growth experiment. As can be seen, removal or absorption of the solvent should not significantly change the structure.

[0125] In the crystal, there are no typical intermolecular hydrogen bonds, the only intermolecular interactions observed are C-H...O between aromatic and CH2.C atoms and amide O atoms. However, these interactions only form dimers. In addition to these, intramolecular interactions between the NH amide group and the O carbonyl atom were found. The complete geometry of the hydrogen bonds is shown in Table 7.

[0126] Table 7. Hydrogen bonds found in the crystal of Form 4. D-H...A D-H [A] H...A [A] D...A [A] D-H...A [°] C(110)-H(11B)...O(215) 0.97 2.35 3.222(4) 149 C(112)-H(112)...O(215) 0.93 2.39 3.248(4) 153 N(116)-H(116)...O(127) 0.88(4) 1.96(4) 2.703(4) 141(3) C(210)-H(21B)...O(115) 0.97 2.23 3.144(5) 156 C(212)-H(212)...O(115) 0.93 2.35 3.183(4) 148 N(216)-H(216)...O(227) 1.03(6) 1.92(6) 2.734(5) 134(4)

[0127] To confirm that the determined crystal structure represents the bulk material obtained in the crystallization attempt, the material recovered from the cooling crystallization experiment in ACN was subjected to high resolution XRPD (HR-XRPD) analysis. The bulk material was ground and transferred to a capillary for the HR-XRPD measurement. Figure 25 The diffractogram of the collected bulk material is shown, while Figure 26 The comparison of the powder pattern calculated based on the single crystal data of Form 4 with the HR-XRPD diffractogram collected from the bulk solid recovered from the crystallization is shown.

[0128] The obtained crystal crystallizes in the chiral monoclinic C2 space group and consists of M2CAB and non-stoichiometric solvent molecules arranged around a symmetry center. The two M2CAB molecules in the asymmetric unit form a dimer arranged around a pseudo-symmetry center. As Figure 27 As shown in Figure 2, the two molecules interact with each other through short C-H...O intermolecular interactions.

[0129] These figures are almost identical and minor differences in peak positions at high 2-theta angles can be observed. However, such differences can be explained by small differences between unit cell parameters obtained from single crystal and from powder data. To ensure that the single crystal analyzed is the same solid obtained in the crystallization, a Rietveld analysis was performed.

[0130] As Figure 27 As can be seen in Table 8, by applying a Rietveld analysis (Rietveld, 1969) to the HR-XRPD diffractogram of the bulk material, it was observed that the bulk material consisted of pure M2CAB Form 4 without detectable impurities.

[0131] Table 8. Rietveld analysis of the solid obtained from the cooling crystallization experiment in acetonitrile. Form Form 4 Empirical formula [C 37 H 51 F2N3O6+ solvent (ACN) Chemical formula weight 671.80 T [K] 296 λ [Å] 1.54056 Crystal system Monoclinic Space group C2 Capillary size [mm2] 0.7 x 8 2Θ step size [°] 0.0157 Number of steps 2541 Time per step [s] 10 2Θ range [°] 1.5 – 41.5 Rexp 3.96 Rwp 5.64 Rp 4.40 GOF 1.42 RBrag 1.10 Impurities, other forms [%] Below detection limit

[0132] Characterization of Form 1 + Form 4 An exemplary XRPD pattern of Form 1 + 4 is depicted in Figure 4 Table 8. Rietveld analysis of the solid obtained from the cooling crystallization experiment in acetonitrile. Figure 28 In DSC, the T onset was about 118.6 °C, while the Tpeak was about 122.4 °C.

[0133] In Figure 29 The HR-XRPD diffractogram of the solid collected from the evaporation crystallization experiment in p-xylene / CAN (50 / 50, v / v) was compared to the powder patterns collected for Form 1 (starting material) and Form 4 (from single crystal grown in ACN) in Table 8. For this sample, the HT-XRPD pattern was similar to the pattern of Form 1 starting material; however, the HR-XRPD pattern indicated that the solid consisted of a mixture of Form 1 + Form 4. An exemplary peak list is provided in Table 9 below.

[0134] Table 9. Exemplary peak list 2Θ angle ° Intensity % 3.382 100 6.761 5.2 6.976 5.3 7.177 2.5 7.403 3.7 10.164 0.6 10.387 0.4 11.209 1.6 13.955 1.1 14.361 0.6 14.859 0.6 15.428 0.6 15.694 0.8 16.342 1.8 16.614 2.2 16.814 2.3 17.566 3.1 17.82 3 18.201 1.1 18.718 2.2 19.339 1.1 19.923 2.4 20.651 1.1 21.036 2.5 21.598 8.1 21.886 4 22.152 2.4 22.678 2.6 22.852 4.1 23.25 1.5 23.472 1.9 23.632 3 24.02 0.9 24.284 2.2 24.542 0.6 24.724 1 25.041 0.7 25.597 1 26.122 1.8 27.065 1.2 28.297 0.6 28.986 0.9 29.359 0.3 29.882 0.4 30.121 0.5 30.882 0.3 31.72 0.5 33.012 0.2 33.35 0.3 ( Figure 30 ) showed a mass loss of less than 1.1% based on MS signal, which corresponds to acetone (1.1% of acetone corresponds to 0.1 molecule of acetone per molecule of API). The trace of thermal decomposition occurred above 200 °C.

[0135] The UPLC chromatogram ( Figure 31 ) showed the presence of an API peak at 2.12 min with a chemical purity of 97.9% (area%).

[0136] Conclusion From this polymorph screening it was seen that the starting material Form 1 was the main solid form found in the screening. However, a class of isostructural solvates was discovered, which was named Form 4. Form 4 was confirmed by single crystal analysis to be a solvated form containing non-stoichiometric amounts of solvent. The solvent molecules are located in voids / channels present in the structure. From the single crystal attempts it was seen that Form 4 was isolated (as a pure crystalline phase) from ACN and EtOH; however, in this polymorph screening, mixtures of Form 1 + 4 were found from several crystallization methods and solvents. The powder patterns classified as mixtures of this form show strong similarities, although the intensity and position of the diffraction peaks vary from pattern to pattern.

[0137] Generation of competitive slurries The relative stability between Form 1, 2 and 4 was investigated by competitive slurry conversion experiments in water, MTBE and ACN at 25 °C and 40 °C.

[0138] Saturated stock solutions of M2CAB Form 1 were prepared in different solvent systems at 25 °C and 40 °C. The saturated solutions were added to a physical mixture containing Form 1, 2 and 4 in a 1:1:1 ratio (w / w). The suspensions were incubated at the set temperature under continuous stirring. After 2 weeks and 4 weeks (to be completed) of equilibration, solid samples were taken from the vials and analyzed by HR-XRPD. Experimental details are reported in Table 10.

[0139] Table 10. Experimental details and results of competitive slurries between Form 1, 2 and 4. The phase quantification was performed using the lattice parameters of the calculated crystal structure of Form 1 and Form 4. The content of Form 2 was assumed to be determined corresponding to the diffraction peaks of Form 2.

Claims

1. A crystal form of a compound represented by the following: Its features are, The powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of approximately 17.8°.

2. The crystal form according to claim 1, characterized in that... The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of approximately 7.4, 17.8, and 22.

2.

3. The crystal form according to claim 1 or 2, characterized in that... The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of approximately 7.4, 17.5, 17.8, 18.7, and 22.

2.

4. The crystal form according to any one of claims 1-3, characterized in that... The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of approximately 6.8, 7.4, 16.7, 16.9, 17.5, 17.8, 18.2, 18.7, 21.9, and 22.

2.

5. The crystal form according to any one of claims 1-4, characterized in that... Essentially, it is the powder X-ray diffraction pattern depicted in Figure 1.

6. The crystal form according to any one of claims 1-5, wherein the powder X-ray diffraction pattern is obtained using Cu Kα radiation.

7. The crystal form according to any one of claims 1-6, characterized in that... The differential scanning calorimetry (DSC) curve exhibits the following endothermic characteristics: an onset of approximately 118°C and a peak of approximately 120°C.

8. A crystal form of a compound represented by the following: Its features are, The powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of approximately 5.

6.

9. The crystal form according to claim 8, characterized in that... The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of approximately 5.6, 16.0, and 21.

8.

10. The crystal form according to claim 8 or 9, characterized in that... The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of approximately 5.6, 16.0, 21.8, 23.1, and 23.

4.

11. The crystal form according to any one of claims 8-10, characterized in that... The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of approximately 5.6, 7.4, 16.0, 16.9, 17.8, 18.3, 19.0, 21.8, 23.1, and 23.

4.

12. The crystal form according to any one of claims 8-11, characterized in that... Essentially, it is the powder X-ray diffraction pattern depicted in Figure 2.

13. The crystal form of any one of claims 8-12, wherein the powder X-ray diffraction pattern is obtained using Cu Kα radiation.

14. The crystal form according to any one of claims 8-13, characterized in that... The differential scanning calorimetry (DSC) curve exhibits the following endothermic characteristics: an onset of approximately 117°C and a peak of approximately 120°C.

15. A crystal form of a compound represented by the following: Its features are, The powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of approximately 21.6°.

16. The crystal form according to claim 15, characterized in that... The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of approximately 7.0, 21.6, and 22.

9.

17. The crystal form according to claim 15 or 16, characterized in that... The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of approximately 7.0, 16.4, 21.6, 22.9, and 23.

6.

18. The crystal form according to any one of claims 15-17, characterized in that... The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of approximately 6.8, 7.0, 16.4, 16.6, 20.0, 21.6, 22.0, 22.7, 22.9, and 23.

6.

19. The crystal form according to any one of claims 15-18, characterized in that... Essentially, it is the powder X-ray diffraction pattern depicted in Figure 3.

20. The crystal form of any one of claims 15-19, wherein the powder X-ray diffraction pattern is obtained using Cu Kα radiation.

21. The crystal form according to any one of claims 15-20, characterized in that... Differential scanning calorimetry (DSC) curves with the following endothermic characteristics: an onset at approximately 119 °C and a peak at approximately 122 °C.

22. A mixture of crystal forms of a compound represented by: Its features are, The powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of approximately 21.6°.

23. The mixture of claim 22, characterized in that... The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of approximately 7.0, 17.8, and 21.

6.

24. The mixture according to claim 22 or 23, characterized in that... The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of approximately 7.0, 7.4, 17.8, 21.6, and 23.

6.

25. The mixture according to any one of claims 22-24, characterized in that... The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of approximately 7.0, 7.4, 14.0, 16.3, 16.8, 17.8, 21.6, 23.6, 24.3, and 26.

1.

26. The mixture according to any one of claims 22-25, characterized in that... Basically, it is an XRPD diagram as depicted in Figure 4.

27. The mixture according to any one of claims 22-26, characterized in that... The differential scanning calorimetry (DSC) curve exhibits the following endothermic characteristics: an onset of approximately 119 °C and a peak of approximately 122 °C.

28. The mixture of any one of claims 33-27, wherein the powder X-ray diffraction pattern is obtained using Cu Kα radiation.

29. A method for treating, inhibiting, and / or preventing viral infection in a patient in need, the method comprising administering to the patient an effective amount of the crystal form according to any one of claims 1-21.

30. A method for treating, suppressing, and / or preventing viral infection in a patient in need, the method comprising administering to the patient an effective amount of the mixture according to any one of claims 22-28.

31. The method of claim 29 or 30, wherein the viral infection is a retroviral infection.

32. The method of any one of claims 29-31, wherein the viral infection is HIV infection.

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