IL323337A - Crystalline forms of an antiviral prodrug - Google Patents

Description

Attorney Docket No. 1902446-0003-018-WO1 CRYSTALLINE FORMS OF AN ANTIVIRAL PRODRUG CROSS-REFERENCE TO RELATED APPLICATION id="p-1" id="p-1" id="p-1"

[0001]This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/490,999, filed March 17, 2023, which application is hereby incorporated by reference in its entirety.

SUMMARY id="p-2" id="p-2" id="p-2"

[0002]Disclosed herein, in certain embodiments, are solid forms of an antiviral prodrug and their methods of use. id="p-3" id="p-3" id="p-3"

[0003]Disclosed herein, in certain embodiments, is a crystalline form of a compound represented by: characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees at about 17.8. id="p-4" id="p-4" id="p-4"

[0004]Disclosed herein, in certain embodiments, is a crystalline form of a compound represented by: Attorney Docket No. 1902446-0003-018-WO1 characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees at about 5.6. id="p-5" id="p-5" id="p-5"

[0005]Disclosed herein, in certain embodiments, is a crystalline form of a compound represented by: characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees at about 21.6.

BRIEF DESCRIPTION OF THE DRAWINGS id="p-6" id="p-6" id="p-6"

[0006] Figure 1 depicts an exemplary XRPD pattern of Form 1. id="p-7" id="p-7" id="p-7"

[0007] Figure 2 depicts an exemplary XRPD pattern of Form 2. id="p-8" id="p-8" id="p-8"

[0008] Figure 3 depicts an exemplary XRPD pattern of Form 4. id="p-9" id="p-9" id="p-9"

[0009] Figure 4 depicts an exemplary XRPD pattern of Form 1+4. id="p-10" id="p-10" id="p-10"

[00010]Figure 5 depicts an overlay of M2CAB Form 1 powder patterns identified in the polymorph screen. From bottom to top: Form 1 (starting material) and mixtures of Forms 1+4 from AS 11 (pyridine (solvent)/water (antisolvent)), PSM1 (Acetone/MeOH (50/50, v/v)), TCP21 (TBME), TCP13 (EtOH/water (90/10, v/v) and SLP47 (EtOH). id="p-11" id="p-11" id="p-11"

[00011] Figure 6 depicts an exemplary DSC trace of Form 1. id="p-12" id="p-12" id="p-12"

[00012] Figure 7 depicts a HT-XRPD patterns of (from bottom to top) Form 1 (SM,reference), Form 1 (pyridine (S) and water (AS)), Form 1 (p-Xylene/ACN 50/50) and Form (1,4-Dioxane/diisopropyl ether 50/50). id="p-13" id="p-13" id="p-13"

[00013]Figure 8 depicts High Resolution (HR-) XRPD patterns collected (from bottom to top) for M2CAB, Form 1 obtained from the cooling crystallization experiment Attorney Docket No. 1902446-0003-018-WO1 performed in 1,4-dioxane/diisopropyl ether (50/50, v/v) and Form I obtained in the forward antisolvent experiment performed in pyridine (solvent) and water (antisolvent). id="p-14" id="p-14" id="p-14"

[00014] Figure 9 depicts High Resolution (HR-) XRPD patterns between 6-28° 20 (from bottom to top) of M2CAB, Form 1 obtained from the cooling crystallization experiment performed in 1,4-dioxane/diisopropyl ether (50/50, v/v) and Form I obtained in the forward antisolvent experiment performed in pyridine (solvent) and water (antisolvent). id="p-15" id="p-15" id="p-15"

[00015]Figure 10 depicts a TGMS analysis (heating rate of 10 °C/min) of Form from the forward antisolvent experiment performed in pyridine (solvent) and water (antisolvent). id="p-16" id="p-16" id="p-16"

[00016]Figure 11 depicts a TGMS analysis (heating rate of 10 °C/min) of Form obtained from the cooling crystallization experiment performed in 1,4-dioxane/diisopropyl ether (50/50, v/v). id="p-17" id="p-17" id="p-17"

[00017]Figure 12 depicts a UPLC chromatogram of Form 1 from the forward antisolvent experiment performed in pyridine (solvent) and water (antisolvent) id="p-18" id="p-18" id="p-18"

[00018]Figure 13 depicts a UPLC chromatogram of Form 1 obtained from the cooling crystallization experiment performed in 1,4-dioxane/diisopropyl ether (50/50, v/v). id="p-19" id="p-19" id="p-19"

[00019] Figure 14 depicts a DVS measurement of M2CAB with DVS profile 40-95-0-95-0-40% in steps of 10% RH. The change in mass of the same as a function of the time and the relative humidity % is shown in picture A. In picture B, the sorption and desorption cycles are shown as function of the RH %. id="p-20" id="p-20" id="p-20"

[00020]Figure 15 depicts HT-XRPD patterns of M2CAB measured before (bottom pattern) and after (top pattern) DVS measurement. id="p-21" id="p-21" id="p-21"

[00021]Figure 16 depicts High Throughput (HT-) XRPD patterns collected (from bottom to top) for M2CAB and Form 2 obtained in the screen and in the scale-up. id="p-22" id="p-22" id="p-22"

[00022]Figure 17 depicts High Resolution (HR-) and High Throughput (HT-) XRPD patterns collected for a Form 2 scale-up sample. id="p-23" id="p-23" id="p-23"

[00023]Figure 18 depicts a TGMS analysis (heating rate of 10 °C/min) of Form scale-up.

Attorney Docket No. 1902446-0003-018-WO1 id="p-24" id="p-24" id="p-24"

[00024]Figure 19 depicts a DSC measurement of a Form 2 scale-up sample. id="p-25" id="p-25" id="p-25"

[00025] Figure 20 depicts a UPLC chromatogram of a Form 2 scale-up sample. id="p-26" id="p-26" id="p-26"

[00026] Figure 21 depicts an overlay of powder patterns (from bottom to top) of Formobtained from single crystal attempt performed in ACN (HR-XRPD), Form 4 obtained in the scale-up experiment and M2CAB. id="p-27" id="p-27" id="p-27"

[00027]Figure 22 depicts a simulated powder pattern from the single crystal data of Form 4 and High Resolution (HR-) XRPD patterns collected for Form 4 scale-up. id="p-28" id="p-28" id="p-28"

[00028]Figure 23 depicts a variable temperature XRPD performed on Form 4 with a temperature profile: 25-50-75-60-90-70-105-80-25 °C with a heating rate of 20 °C/minute and relaxation of 5 minutes upon reaching the temperature before XRPD measurement. id="p-29" id="p-29" id="p-29"

[00029] Figure 24 depicts a UPLC chromatogram of a Form 4 scale-up sample. id="p-30" id="p-30" id="p-30"

[00030] Figure 25 depicts a diffractogram collected for bulk material of M2 CABForm 4. id="p-31" id="p-31" id="p-31"

[00031]Figure 26 depicts a comparison of simulated powder pattern for M2CAB Form (bottom line) with the obtained diffraction pattern of the solid from the cooling crystallization experiment in acetonitrile (top line). id="p-32" id="p-32" id="p-32"

[00032]Figure 27 depicts a Rietveld analysis of M2CAB solid obtained from the cooling crystallization experiment in acetonitrile using single crystal data of M2CAB Form 4. id="p-33" id="p-33" id="p-33"

[00033]Figure 28 depicts an exemplary DSC trace of Form 1+4. id="p-34" id="p-34" id="p-34"

[00034]Figure 29 depicts High Resolution (HR-) XRPD patterns collected (from bottom to top) for M2CAB, Form 4 from the single crystal experiment performed in ACN and Forms 1+4 from the evaporative crystallization experiment performed in p-xylene/ACN (50/50, v/v). Vertical lines are used to highlight the main differences observed when comparing with Form I starting material. id="p-35" id="p-35" id="p-35"

[00035]Figure 30 depicts a TGMS analysis (heating rate of 10 °C/min) of Forms 1+from the cooling crystallization experiment performed in acetone/MeOH (50/50, v/v).

Attorney Docket No. 1902446-0003-018-WO1 id="p-36" id="p-36" id="p-36"

[00036]Figure 31 depicts a UPLC chromatogram of Forms 1+4 from the cooling crystallization experiment performed in acetone/MeOH (50/50, v/v).

DETAILED DESCRIPTION Definitions id="p-37" id="p-37" id="p-37"

[00037]As used herein the specification, "a" or "an" may mean one or more. As used herein, when used in conjunction with the word "comprising", the words "a" or "an" may mean one or more than one. As used herein "another" may mean at least a second or more. Still further, the terms "having", "including", "containing" and "comprising" are interchangeable and one of skill in the art is cognizant that these terms are open ended terms. Some embodiments of the disclosure may consist of or consist essentially of one or more elements, method steps, and/or methods of the disclosure. It is contemplated that any method, compound, or composition described herein can be implemented with respect to any other method, compound, or composition described herein. id="p-38" id="p-38" id="p-38"

[00038]"About" and "approximately" shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values. id="p-39" id="p-39" id="p-39"

[00039]As used herein, all numerical values or numerical ranges include whole integers within or encompassing such ranges and fractions of the values or the integers within or encompassing ranges unless the context clearly indicates otherwise. Thus, for example, reference to a range of 90-100%, includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. 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, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5, fold, etc., 2.1, 2.2, 2.3, 2.4, 2.5, fold, etc., and so forth. id="p-40" id="p-40" id="p-40"

[00040]As used herein, "pharmaceutically acceptable excipient" refers to any substance in a pharmaceutical formulation other than an active pharmaceutical ingredient(s). Exemplary pharmaceutical excipients include those that aid the manufacturing process; protect, support or enhance stability; increase bioavailability; or increase patient Attorney Docket No. 1902446-0003-018-WO1 acceptability. They may also assist in product identification or enhance the overall safety or function of the product during storage or use. id="p-41" id="p-41" id="p-41"

[00041]As used herein, a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. 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 require the active supervision of medical personnel. id="p-42" id="p-42" id="p-42"

[00042]Disease, disorder, and condition are used interchangeably herein. id="p-43" id="p-43" id="p-43"

[00043]As used herein, and unless otherwise specified, the terms "treat," "treating" and "treatment" contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or reverses or slows the progression of the disease, disorder or condition (also "therapeutic treatment"). id="p-44" id="p-44" id="p-44"

[00044]In general, the "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may 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 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 means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment 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 condition, or enhances the therapeutic efficacy of another therapeutic agent. A "prophylactically effective amount" of a compound is an amount sufficient to prevent a Attorney Docket No. 1902446-0003-018-WO1 disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention 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 "prophylactic treatment" contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition. id="p-45" id="p-45" id="p-45"

[00045]As used herein, "M2CAB" refers to a compound of the following structure: Crystalline forms Form 1 id="p-46" id="p-46" id="p-46"

[00046] In certain embodiments, provided herein is a crystalline form of a compoundrepresented by: characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees at about 17.8. id="p-47" id="p-47" id="p-47"

[00047] In certain embodiments, the crystalline form is characterized by a powder X- ray diffraction pattern having characteristic peaks in degrees 20 at about 7.4, 17.8, and 22.2.

Attorney Docket No. 1902446-0003-018-WO1 In certain embodiments, the crystalline form is, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 20 at 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 in degrees 20 at 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 depicted in Figure 1. In certain embodiments, the crystalline form is wherein the powder X-ray diffraction pattern was obtained using Cu Ka radiation. In certain embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 118 °C and a peak of about 120 °C.

Form 2 id="p-48" id="p-48" id="p-48"

[00048]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 in degrees at about 5.6. id="p-49" id="p-49" id="p-49"

[00049]In certain embodiments, the crystalline form is characterized by a powder X- ray diffraction pattern having a characteristic peak in degrees 20 at about 5.6, 16.0, and 21.8. In certain embodiments, the crystalline form is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at 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 a characteristic peak in degrees 20 at 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 Figure 2. In certain embodiments, the crystalline form is wherein the powder X-ray diffraction pattern was Attorney Docket No. 1902446-0003-018-WO1 obtained using Cu Ka radiation. In certain embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 117 °C and a peak of about 120 °C.

Form 4 id="p-50" id="p-50" id="p-50"

[00050]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 in degrees at about 21.6. id="p-51" id="p-51" id="p-51"

[00051]In certain embodiments, the crystalline form is characterized by a powder X- ray diffraction pattern having a characteristic peak in degrees 20 at about 7.0, 21.6, and 22.9. In certain embodiments, the crystalline form is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at 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 a characteristic peak in degrees 20 at 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 Figure 3. In certain embodiments, the crystalline form is wherein the powder X-ray diffraction pattern was obtained using Cu Ka radiation. In certain embodiments, the crystalline form is characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset at about 119 °C and a peak at about 122 °C.

Attorney Docket No. 1902446-0003-018-WO1 Form 1+4 id="p-52" id="p-52" id="p-52"

[00052]In certain embodiments, provided herein is a mixture of crystalline forms of a compound represented by: characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees at about 21.6. id="p-53" id="p-53" id="p-53"

[00053]In certain embodiments, the mixture of crystalline forms is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 26 at about 7.0, 17.8, and 21.6. id="p-54" id="p-54" id="p-54"

[00054]In certain embodiments, the mixture of crystalline forms is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 26 at about 7.0, 7.4, 17.8, 21.6, and 23.6. In certain embodiments, the mixture of crystalline forms is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 26 at about 7.0, 7.4, 14.0, 16.3, 16.8, 17.8, 21.6, 23.6, 24.3, and 26.1. In certain embodiments, the mixture of crystalline forms is characterized by an XRPD pattern substantially as depicted in Figure 4. In certain embodiments, the mixture of crystalline forms is characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 119 °C and a peak of about 122 °C. In certain embodiments, the mixture of crystalline forms is wherein the powder X-ray diffraction pattern was obtained using Cu Ka radiation.

Pharmaceutical Compositions id="p-55" id="p-55" id="p-55"

[00055]Disclosed herein, in certain embodiments, are pharmaceutical compositions comprising: (a) a crystalline solid form of a M2CAB, and (b) a pharmaceutically acceptable excipient.

Attorney Docket No. 1902446-0003-018-WO1 id="p-56" id="p-56" id="p-56"

[00056] In some embodiments, provided is a crystalline form of a compoundrepresented by: characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees at about 17.8. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 5.6. In some embodiments, the crystalline form of the compound is characterized by a powder X- ray diffraction pattern having a characteristic peak in degrees 20 at about 21.6. id="p-57" id="p-57" id="p-57"

[00057]In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 20 at about 7.4, 17.8, and 22.2. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 20 at about 7.4, 17.5, 17.8, 18.7, and 22.2. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees at about 6.8, 7.4, 16.7, 16.9, 17.5, 17.8, 18.2, 18.7, 21.9, and 22.2. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 5.6, 16.0, and 21.8. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 5.6, 16.0, 21.8, 23.1, and 23.4. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 5.6, 7.4, 16.0, 16.9, 17.8, 18.3, 19.0, 21.8, 23.1, and 23.4. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 7.0, 21.6, and 22.9. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 7.0, 16.4, 21.6, 22.9, and 23.6. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having a Attorney Docket No. 1902446-0003-018-WO1 characteristic peak in degrees 20 at about 6.8, 7.0, 16.4, 16.6, 20.0, 21.6, 22.0, Tl.lי and23.6. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 7.0, 17.8, and 21.6. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 7.0, 7.4, 17.8, 21.6, and 23.6. In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees at about 7.0, 7.4, 14.0, 16.3, 16.8, 17.8,21.6, 23.6, 24.3, and 26.1. id="p-58" id="p-58" id="p-58"

[00058]In some embodiments, the crystalline form of the compound is characterized by a powder X-ray diffraction pattern substantially such as in Figures 1, 2, 3 and 4. In some embodiments, the powder X-ray diffraction pattern is obtained using Cu Ka radiation. id="p-59" id="p-59" id="p-59"

[00059]In some embodiments, the crystalline form of the compound is characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 118 °C and a peak of about 120 °C. In some embodiments, the DSC profile has a characteristic endotherm with an onset of about 119 °C and a peak at about 122 °C. id="p-60" id="p-60" id="p-60"

[00060]In some embodiments, the composition has a physiologically compatible pH (e.g., a range from a pH of about 3 to a pH of about 11, about pH 3 to about pH 7, depending on the formulation and route of administration). In some cases, the pH is from about pH 5.to about pH 8. id="p-61" id="p-61" id="p-61"

[00061]In some embodiments, the pharmaceutically acceptable excipient is a carrier, solvent, stabilizer, adjuvant, diluent, etc., depending upon the particular mode of administration and dosage form. id="p-62" id="p-62" id="p-62"

[00062]Suitable excipients include, for example, carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles. Other exemplary excipients can include antioxidants (for example and without limitation, ascorbic acid), chelating agents (for example and without limitation, EDTA), carbohydrates (for example and without limitation, cellulose, dextrin). id="p-63" id="p-63" id="p-63"

[00063]A pharmaceutical composition disclosed herein is administered by any appropriate route that results in effective treatment in the subject. In some embodiments, a Attorney Docket No. 1902446-0003-018-WO1 pharmaceutical composition disclosed herein is administered systemically. In some embodiments, a pharmaceutical composition disclosed herein is administered locally. The pharmaceutical composition is administered via a route such as, but not limited to, enteral, gastroenteral, oral, transdermal, subcutaneous, nasal, intravenous, intravenous bolus, intravenous drip, intraarterial, intramuscular, transmucosal, insufflation, sublingual, buccal, conjunctival, cutaneous. Modes of administration include injection, infusion, instillation, 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.

Methods of Use id="p-64" id="p-64" id="p-64"

[00064]Disclosed herein, in certain embodiments, are methods of treating an HIV-infection in an individual in need thereof, comprising administering a pharmaceutical composition disclosed herein to the individual. Further disclosed herein, in some embodiments, are methods of preventing an HIV-1 infection in an individual in need thereof, comprising administering a pharmaceutical composition disclosed herein to the individual. Additionally, disclosed herein, in some embodiments, are methods of preventing transmission of an HIV-1 virus from one individual to another (for example, from a pregnant woman to a child, for example during birth or breast feeding), comprising administering a composition disclosed herein to the individual. id="p-65" id="p-65" id="p-65"

[00065]Disclosed herein, in certain embodiments, are methods of treating an HIV-infection in an individual in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of a compound represented by: and a pharmaceuticallyacceptable excipient to the individual. Further disclosed herein, in some embodiments, are methods of preventing an HIV-1 infection in an individual in need thereof, comprising Attorney Docket No. 1902446-0003-018-WO1 administering a pharmaceutical composition comprising a prophylactically effective amount of crystalline form of a compound represented by: acceptable excipient to the individual. Additionally, disclosed herein, in some embodiments, are methods of preventing transmission of an HIV-1 virus from one individual to another (for example, from a pregnant woman to a child, for example during birth or breast feeding), comprising administering a pharmaceutical composition comprising a prophylactically effective amount of a crystalline form of a compound represented by: acceptable excipient to the individual. id="p-66" id="p-66" id="p-66"

[00066] Disclosed herein, in certain embodiments, are methods of treating an HIV-1infection in an individual in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a mixture of crystalline forms of a compound represented by: and a pharmaceuticallyacceptable excipient to the individual. Further disclosed herein, in some embodiments, are methods of preventing an HIV-1 infection in an individual in need thereof, comprising and a pharmaceutically and a pharmaceutically Attorney Docket No. 1902446-0003-018-WO1 administering a pharmaceutical composition comprising a prophylactically effective amount of a mixture of crystalline forms represented by: and a pharmaceutically acceptable excipient to the individual. Additionally, disclosed herein, in some embodiments, are methods of preventing transmission of an HIV-1 virus from one individual to another (for example, from a pregnant woman to a child, for example during birth or breast feeding), comprising administering a pharmaceutical composition comprising a prophylactically effective amount of mixture of crystalline forms of a compound represented by: pharmaceutically acceptable excipient to the individual. In some embodiments, the method comprises administering the pharmaceutical composition to the individual once monthly. 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 mixture of the pharmaceutical composition of the compound to the individual once every twelve months.

Attorney Docket No. 1902446-0003-018-WO1 id="p-68" id="p-68" id="p-68"

[00068]Described herein, in certain embodiments, are methods of treating, inhibiting, and/or preventing a viral infection in a patient in need thereof, comprising administering to the patient an effective amount a crystalline form of M2CAB or a mixture thereof. id="p-69" id="p-69" id="p-69"

[00069]In some embodiments, the method comprises administering the crystalline form of the compound to the individual once monthly. 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. id="p-70" id="p-70" id="p-70"

[00070]Described herein, in certain embodiments, are methods of treating, inhibiting, and/or preventing a viral infection in a patient in need thereof, comprising administering to the patient an effective amount a mixture of crystalline forms of M2CAB. id="p-71" id="p-71" id="p-71"

[00071]In some embodiments, the viral infection is a retroviral infection. In some embodiments, the viral infection is an HIV infection. id="p-72" id="p-72" id="p-72"

[00072]In some embodiments, the method comprises administering the mixture of the crystalline form of the compound to the individual once monthly. In some embodiments, the method comprises administering the mixture of the crystalline form of the compound to the individual once every two months. In some embodiments, the method comprises administering the mixture of the crystalline form of the compound to the individual once every three months. In some embodiments, the method comprises administering the mixture of the crystalline form of the compound to the individual once every six months. In some embodiments, the method comprises administering the mixture of the crystalline form of the compound to the individual once every nine months. In some embodiments, the method comprises administering the mixture of the crystalline form of the compound of the compound to the individual once every twelve months. id="p-73" id="p-73" id="p-73"

[00073]In some embodiments, crystalline forms of a M2CAB described herein, mixtures of crystalline forms of M2CAB described herein, or pharmaceutical compositions Attorney Docket No. 1902446-0003-018-WO1 described herein, are administered in combination with an additional therapeutic agent to treat a disorder described herein.

EXAMPLES Table A. Abbreviations AAC Accelerated Ageing Conditions (40 oC/75% RH)ACN AcetonitrileAm AmorphousAmb Ambient-dried solid sample (at RT)API Active Pharmaceutical IngredientCHC13 ChloroformCPME Cyclopentyl methyl etherDCM DichloromethaneDSC Differential Scanning CalorimetryDMA N,N-dimethylacetamideDME 1,2-DimethoxyethaneDMF N,N-dimethylformamideDMSO Dimethyl sulfoxideDVS Dynamic Vapor SorptionEtOH EthanolEvap Solid sample recovered by evaporationHR-XRPD High Resolution X-Ray Powder DiffractionHT-XRPD High Throughput X-Ray Powder DiffractionIPA Isopropanol/2-PropanolMEK 2-ButanoneMeOH MethanolMIBK Methyl isobutyl ketone/4-Methyl-2-pentanoneML Mother liquor (liquid phases)MS Mass SpectroscopyPc Poorly crystallinePLM Polarized light microscopyRH Relative HumidityRT Room Temperature Attorney Docket No. 1902446-0003-018-WO1 SCXRD Single Crystal X-Ray DiffractionSM Starting MaterialTBME tert-Butyl methyl etherTGA Thermogravimetric AnalysisTGMS Thermogravimetric Analysis coupled with Mass SpectroscopyTHF TetrahydrofuranUPLC Ultra-Performance Liquid chromatographyVac Vacuum-dried solid sample (at 5 mbar/RT)VT-XRPD Variable Temperature XRPD2-MeTHF 2-Methyltetrahydrofuran1+4 Mixture of Form 1 and Form 41+2 Mixture of Form 1 and Form 21+2+4 Mixture of Form 1, Form 2, and Form 4 Example 1. Preparation of Novel Forms id="p-74" id="p-74" id="p-74"

[00074]This is a study of various crystalline forms of M2CAB. Studies were conducted on crystalline forms such as Form 1, Form 2, Form 4, and Form 1+4, which are described below. id="p-75" id="p-75" id="p-75"

[00075]An exemplary XRPD pattern of Form 1 is provided as Figure 1. An exemplary XRPD pattern of Form 2 is provided as Figure 2. An exemplary XRPD pattern of Form 4 is provided as Figure 3. An exemplary XRPD pattern of Form 1+4 is provided as Figure 4.

Materials id="p-76" id="p-76" id="p-76"

[00076]All chemicals obtained are of research grade and at least 99% pure.

Preparation of Form 1 id="p-77" id="p-77" id="p-77"

[00077]Form I was prepared from a 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 before seed crystal was added (0.5%). The mixture was slowly cooled to °C over about 3 hours and held at the temperature for more than 12 hours before the Attorney Docket No. 1902446-0003-018-WO1 product was collected by a filtration, washed with ambient temperature MTBE, and dried under vacuum in about 80% yield.

Preparation of Form 2 id="p-78" id="p-78" id="p-78"

[00078]The amorphous M2CAB was prepared by dissolving 507.48 mg in 7.25 mL of THF/water (80/20, v/v). Subsequently, the solution was frozen in liquid nitrogen and dried in a Freeze Dryer Christ Alpha 2-4 LD overnight providing Form 2 which was confirmed by XRPD analysis.

Preparation of Form 4 id="p-79" id="p-79" id="p-79"

[00079]Form 4 was prepared by cooling crystallization in ethanol. For that, 204.3 mg of M2CAB were dissolved in 25.5 mL of ethanol (concentration of 8 mg/mL) at 50 °C.Subsequently, the solution was allowed to cool down to RT for several days. After 2 days, crystals were observed and the vial was left open to allow slow evaporation till dryness.

Preparation of Form 1 + Form 4 id="p-80" id="p-80" id="p-80"

[00080]An exemplary preparation of Form 1 + Form 4 is as follows: M2CAB powder was weighed out on a weighing boat. The powder was transferred into an aqueous solution, then a head of a propeller was inserted and mixing occurring until a uniform and flowable suspension was formed. The speed was 600 rpm with a duration of 2 mins.

Analytical Methods High Throughput X-Ray Power Diffraction (XRPD) id="p-81" id="p-81" id="p-81"

[00081]XRPD patterns were obtained using the a T2 high-throughput XRPD set-up. The plates were mounted on a Bruker General Area Detector Diffraction System (GADDS) equipped with a VANTEC-500 gas area detector corrected for intensity and geometric variations. The calibration of the measurement accuracy (peaks position) was performed using NIST SRM1976 standard (Corundum). id="p-82" id="p-82" id="p-82"

[00082]Data collection was carried out at room temperature using monochromatic Cu Ka radiation in the 20 region between 1.5° and 41.5°, which is the most distinctive part of the XRPD pattern. The diffraction pattern of each well was collected in two 20 ranges (1.5°< 20 Attorney Docket No. 1902446-0003-018-WO1 < 21.5° for the first frame, and 19.5°< 20 < 41.5° for the second) with an exposure time of 90 s for each frame. No background subtraction or curve smoothing was applied to the XRPD patterns.

High Resolution X-Ray Powder Diffraction (HR-XRPD) id="p-83" id="p-83" id="p-83"

[00083]Before transferring into the capillary, the solid was grounded in an agate mortar till all of the visible crystals disappeared and the material became a fine powder. The HR-XRPD data were collected on a D8 Advance diffractometer using Cu Kal radiation (1.54056 A) with germanium monochromator at RT. Diffraction data were collected in the 2□ range 2.15 - 41.5°. Detector scan on solid state LynxEye detector was performed using 0.0157° per step with 10 second/step scan speed. The samples were measured in 8 mm long glass capillary with 0.7 mm outer diameter. id="p-84" id="p-84" id="p-84"

[00084]Cell parameters as well as crystal system were obtained using LSI-Index (Coelho, 2003; Coelho & Kern, 2005) indexing program and were refined using Whole Powder Pattern Decomposition algorithm (Pawley, 1981; Toraya 2000). The space group was selected on reflections condition and density of the crystal. The cell parameters, purity as well as instrument parameters were refined using Whole Powder Pattern Decomposition method (Pawley, 1981, Toraya 2000). id="p-85" id="p-85" id="p-85"

[00085]The unit cell parameters of the solvated form were placed into Table 6 for comparison purposes. As it can be seen the following similarities and differences between these two forms can be observed: a axis in the solvated form is nearly twice bigger than in Form 1, and b and c axes as well as 0 angle in both forms are nearly the same.

Single Crystal Diffraction Using CuKa Radiation id="p-86" id="p-86" id="p-86"

[00086]A crystal of approximate dimensions 0.05 x 0.12 x 0.5 mm3 was used for the X-ray crystallographic analysis. The X-ray intensity data were measured (X = 1.54178 A) at RT. id="p-87" id="p-87" id="p-87"

[00087]A total of 5365 frames were collected. The total exposure time was 19.hours. The frames were integrated with the Bruker SAINT software package using a narrow- frame algorithm. The integration of the data using a monoclinic unit cell yielded a total of 74078 reflections to a maximum 0 angle of 72.50° (0.81 A resolution), of which 13997 were Attorney Docket No. 1902446-0003-018-WO1 independent (average redundancy 5.292, completeness = 91.4%, Rint = 5.25%, Rsig = 3.99%) and 12009 (85.80%) were greater than 2a(F2). The final cell constants of a = 53.203(4) A, b = 5.7766(5) A, c = 25.834(2) A, 0 = 100.609(3)°, volume = 7803.9(11) A3, are based upon the refinement of the XYZ-centroids of 9717 reflections above 20 0(1) with 8.282° < 29 < 143.8°. Data were corrected for absorption effects using the Multi-Scan method (SADABS). The ratio of minimum to maximum apparent transmission was 0.749. The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.7210 and 0.9660. id="p-88" id="p-88" id="p-88"

[00088]The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group C 1 2 1, with Z = 8 for the formula unit, C37H51F2N3O6. The final anisotropic full-matrix least-squares refinement on F2 with 947 variables converged at R1 = 5.97%, for the observed data and wR2 = 17.36% for all data. 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. On the basis of the final model, the calculated density was 1.146 g/cm3 and F(000), 2880 e-.

Thermal Analysis id="p-89" id="p-89" id="p-89"

[00089]Mass loss due to solvent or water loss from the crystals was determined by TGA/DSC. Monitoring the sample weight, during heating in a TGA/DSC system , resulted in a weight vs. temperature curve and a heat flow signal. The TGA/DSC was calibrated for temperature with samples of indium and aluminum. Samples (circa 2 mg) were weighed into 100 pL aluminum crucibles and sealed. The seals were pin-holed, and the crucibles heated in the TGA from 25 to 300 °C at a heating rate of 10 °C minutes-1. Dry N2 gas was used for purging. id="p-90" id="p-90" id="p-90"

[00090]The gases coming from the TGA samples were analyzed by a mass spectrometer. This is a quadrupole mass spectrometer, which analyzes masses in the temperature range of 0-200 amu. id="p-91" id="p-91" id="p-91"

[00091]Thermal events were obtained from DSC thermograms, recorded with a heat flux DSC system. The DSC was calibrated for temperature and enthalpy with a small piece of indium (m.p. = 156.6 °C; 3Hf = 28.45 J/g) and zinc (m.p. = 419.6 °C; 3Hf= 107.5 J/g). Samples (circa 2 mg) were sealed in standard 40 pL aluminum pans, pin-holed and heated in Attorney Docket No. 1902446-0003-018-WO1 the DSC from 25 °C to 300 °C, at a heating rate of 10 oC/minute. Dry N2 gas, at a flow rate of 50 mL/minute was used to purge the DSC equipment during measurement.

UPLC Analytical Method UPLC System: UPLC: Agilent 1290Detector 1: UV detector set at 230 nmDetector 2: MSD XT in Positive Scan Mode UPLC Conditions: Auto sampler temp.: RTColumn: Agilent Eclipse Plus C8 HD (50 x 2.1mm; 1.8pm)Column temp: 40 °CGradient: Mobile phase A: 10 mM ammonium acetate in waterMobile phase B: AcetonitrileFlow: 0.6 mL/minGradient: Time [min]: Eluent A: Eluent B: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 minutes Sample Concentration: ca. 0.40 mg/mLSolvent: ACNInjection volume: IplRetention time: 2.09 min id="p-92" id="p-92" id="p-92"

[00092]The compound integrity is expressed as a peak-area percentage, calculated from the area of each peak in the chromatogram, except the ‘injection peak’, and the total peak-area, as follows: Attorney Docket No. 1902446-0003-018-WO1 peak areapeak area (%) =----- : -------- 7—------— ■ 100% total area of all peaks id="p-93" id="p-93" id="p-93"

[00093] The peak area percentage of the compound of interest is employed as an indication of the purity of the component in the sample.

Dynamic Vapor Sorption id="p-94" id="p-94" id="p-94"

[00094] Moisture sorption isotherms were collected on a DVS Adventure system fromSurface Measurement Systems (London, UK). The sample size was circa 10 mg of solid material. A full sorption and desorption isotherm was recorded by varying the relative humidity from 40-95-0-95-0-40% in steps of 10% at a constant temperature of 25 °C.Weight equilibration per step was set at dm/dt 0.002%/minute (holding for at least minutes) or a maximum equilibration time of 6 hours. Afterwards the sample was measured by HT-XRPD. id="p-95" id="p-95" id="p-95"

[00095]The hygroscopicity classification of APIs is according to the percent water uptake at 25 oC/82% RH during first adsorption cycle of sorption isotherm.

Table 1. Hygroscopic class Criteria 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 Novel Forms Polymorph Screen id="p-96" id="p-96" id="p-96"

[00096]The polymorph screening on M2CAB was carried out by applying the following crystallization methods: solvent equilibration, slow cooling crystallization, slow evaporative crystallization, thermocycling, antisolvent (reverse & forward) precipitation, and vapor diffusion into solutions and onto solids.

Attorney Docket No. 1902446-0003-018-WO1 id="p-97" id="p-97" id="p-97"

[00097]From most of the crystallization experiments, Form 1 was recovered; however, differences in the powder pattern of Form 1 were observed, in some cases additional peaks were present or shifts in some diffraction peaks were seen. The additional peaks observed in the powder patterns could be attributed to the solvated Form 4. Therefore, all these powder patterns were classified as mixtures of Form 1 + Form 4. The differences between the different patterns could be attributed to different contents of Form 1 and Form 4. An overlay of the different mixtures of Form 1 + Form 4 patterns is presented in Figure 5. id="p-98" id="p-98" id="p-98"

[00098]Based on the similarities observed in the powder patterns collected in this study, we can confirm that all the forms clustered in the mixture of Forms 1+4 contained both forms but with slightly different solvent content and therefore, different content of Form I and Form 4.

Solid State Characterization id="p-99" id="p-99" id="p-99"

[00099]Analytical characterization (HR-XRPD, PLM, DSC, TGMS and HPLC) has been done on the following samples. A summary of the analytical results is presented in Table 2.

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

Table 2. Results of the analytical characterization performed on the different powder patterns identified in this polymorph screen including the characterization performed on the four different M2CAB batches provided. The endothermic events are classified as "br" for broad endotherms, "en" for endothermic events, "exo" for exothermic event and "m" for melting events. The notation "TBD" refers to "To be determined".

Attorney Docket No. 1902446-0003-018-WO1 Form Crystallization solvent Thermal events by DSC (°C) Solvent content by TGMS (%) Solvent nature Chemical purity by HPLC (area %) Crystal morphology 1 TBME 40-80(br), 118.0(m) 0.1 Anhydrous 99.2 Needles<0.05>0.mm1+4 - 75.1 (br),120.5 (m)0.3 - - Plates0.05-0.1 mm1+4 ACN 73.5 (br),125.7 (m)0.2 Plates<0.05+0.mm1+4 ACN 84.5 (br),123.5 (m)0.2 Plates<0.05+0.mmCPME 40-80(br), 122.7(m) Anhydrous Long needles>0.2 mm 1 Pyridine (solvent), water (anti solvent) 72.2 (br),120.7 (m)0.8 Residual pyridine (0.1 molec. pyridine/API ) 98.5 Plates 0.02-0.05 mm 1,4-Dioxane/dii sopro pyl ether (50/50, v/v) 40-100(br), 122.6(m) 0.5 Residual 1,4-dioxane (0.04 molec. dioxane/API ) 98.5 Needles0.05-0.2 mm p-Xylene/ACN (50/50, v/v)68.1 (en),122.4 (m)3.2 p-xylene (0.2 molec.P- xylene/API) 98.6 Plates 0.05-0.2 mm 1+4 Acetone/MeOH(50/50, v/v)73.0 (en),125.5 (m)1.1 Acetone (0.1 molec. acetone/API) 97.9 Needle0.05-0.2 mm 1+4 TBME 72.0 (br),118.9 (m)3.8 TBME (0.3 molec. TBME/API) 98.5 Needles<0.01 mm 1+4 EtOH/water(90/10, v/v)76.6 (br),122.7 (m)3.0 EtOH(0.5 molec. EtOH/API) 98.3 Plates<0.01 mm 2 Water 92.1 (br), 96.00.7 Anhydrous 97.9 - Attorney Docket No. 1902446-0003-018-WO1 Characterization of Form 1 (exo),119.9(m)(containing residual water)(scale- up) THE/water(80/20, v/v)92.5 (hr), 96.(exo), 120.4 (m) <0.01 Anhydrous 98.9 4 Acetonitrile Non- stoichiometri c solvate Plate needle crystal (scale- up) Ethanol TBD TBD TBD 96.8 id="p-100" id="p-100" id="p-100"

[000100]An exemplary XRPD pattern of Form 1 is provided as Figure 1. An exemplary DSC trace is depicted as Figure 6. In the DSC, Tonset was about 117.5 °C, while Tpeak was about 120.7 °C. id="p-101" id="p-101" id="p-101"

[000101]Three solid samples of Form I (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 presented in Figure 7. id="p-102" id="p-102" id="p-102"

[000102]During the 3 sorption and 2 desorption cycles, the water uptake varied between -0.1 and 0.05% which suggest that M2CAB Form 1 could be considered non- hygroscopic, according to the hygroscopicity classification by sorption analysis. id="p-103" id="p-103" id="p-103"

[000103]Figure 15 shows HT-XRPD patterns of M2CAB measured before (bottom pattern) and after (top pattern) the DVS measurement. Form I was recovered after the DVS measurement. id="p-104" id="p-104" id="p-104"

[000104]The HR-XRPD diffractogram collected for the three Form I samples are presented in Figure 8 and Figure 9. id="p-105" id="p-105" id="p-105"

[000105]Exemplary XRPD peak listings for Form 1 are provided as Table 3 below.

Attorney Docket No. 1902446-0003-018-WO1 Table 3. Peak Table of Form 1 26[°] d[A] I [%]3.39 26.03 1006.76 13.06 47.42 11.91 710.14 8.71 111.21 7.89 114.49 6.11 114.84 5.97 114.92 5.93 115.50 5.71 116.67 5.32 416.86 5.26 417.51 5.06 717.84 4.97 818.18 4.88 518.68 4.75 618.85 4.70 219.17 4.63 220.35 4.36 120.64 4.30 321.00 4.23 221.31 4.17 321.90 4.06 622.15 4.01 722.33 3.98 222.53 3.94 322.81 3.90 123.28 3.82 423.47 3.79 423.71 3.75 123.86 3.73 224.03 3.70 224.51 3.63 124.84 3.58 2 Attorney Docket No. 1902446-0003-018-WO1 34 25.18 3.53 125.60 3.48 3 id="p-106" id="p-106" id="p-106"

[000106]The observation under polarized light revealed that Form 1 consisted of very small plate-like and needle-like crystals. The crystals have sized between 0.02-0.05 mm. The crystals can be as small as < 0.05 mm in the longest direction and as big as > 0.2 mm in the longest directions. id="p-107" id="p-107" id="p-107"

[000107]The TGA/TGMS analysis of Form 1 (Figures 10 and 11) showed a mass loss of between 0.5-0.8% between 25-240 °C, which could be attributed to residual water/solvent. The traces of thermal decomposition appeared above 240 °C (Figure 11). id="p-108" id="p-108" id="p-108"

[000108]The UPLC chromatogram of Form 1 (Figures 12 and 13) showed the presence of the API peak at 2.12 minutes with a chemical purity of 98.5% (area%). id="p-109" id="p-109" id="p-109"

[000109]A DVS measurement was carried out on M2CAB Form 1 with an RH profile of 40-95-0-95-0-40% at a constant temperature of 25 °C. The relative humidity was changed in steps of 10%, after equilibration was reached within dm/dt of 0.002%/minute (holding for at least 15 min) or a maximum equilibration time of 6 h. The change in mass of the sample as a function of the time and the relative humidity % is shown in Figure 14 (picture A). The sorption and desorption cycles are shown as function of the RH % in Figure 14 (picture B).

Analytical Characterization of Form 2 id="p-110" id="p-110" id="p-110"

[000110]An exemplary XRPD pattern of Form 2 is provided as Figure 2. Form 2 was prepared at 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 experiment, Form was obtained immediately after freeze-dying therefore, no recrystallization was applied to the freeze-dried solid. The HT-XRPD of the scale-up Form 2 is compared to the Form 2 obtained in the screen in Figure 16 while in Figure 17 the High Resolution XRPD collected for the scale-up Form 2 is presented. id="p-111" id="p-111" id="p-111"

[000111]The TGA/TGMS analysis of Form 2 (Figure 18) showed a residual solvent content below 0.1% between 25-200 °C. The traces of thermal decomposition appeared above 240 °C.

Attorney Docket No. 1902446-0003-018-WO1 id="p-112" id="p-112" id="p-112"

[000112]The DSC trace (Figure 19) showed a broad endothermic event at Tpeak 92.°C (Tonset 89.4 °C) corresponding to the water loss followed by an exothermic event at Tpeak 96.4 °C and a sharp endothermic event at Tpeak 120.4 °C (Tonset 117.5 °C), probably corresponding to the melting of Form 1. id="p-113" id="p-113" id="p-113"

[000113]The UPLC chromatogram of Form 2 (Figure 20) showed the presence of the API peak at 2.12 minutes with a chemical purity of 98.9% (area%). id="p-114" id="p-114" id="p-114"

[000114]Exemplary XRPD peak listings are provided as Table 4 below.

Table 4. Exemplary Peak Listings Angle 2-Theta ° Intensity %2.742 83.54.355 1005.628 16.76.769 2.77.47 4.98.742 1.310.874 1.813.099 2.613.73 2.816.021 7.116.887 7.217.835 918.261 9.318.958 9.519.435 12.320.285 10.221.839 19.823.068 14.923.407 924.289 3.525.744 3.926.842 2.130.416 1.1 Analytical Characterization of Form 4 id="p-115" id="p-115" id="p-115"

[000115]Form 4 was initially isolated as pure crystalline phase in a single crystal experiment performed in ACN. Further investigations confirmed that the same (isostructural Attorney Docket No. 1902446-0003-018-WO1 solvate) form could be isolated from ethanol. Therefore, the scale-up of Form 4 was prepared by cooling crystallization in ethanol. The obtained dried solid were analyzed by HT-XRPD which confirmed that Form 4 was crystallized. In Figure 21, the HT-XRPD diffractogram collected for the scale-up Form 4 is compared to the simulated powder pattern of Form 4. In Figure 22, the simulated powder pattern obtained from single crystal data of Form 4 is compared to the HR-XRPD data collected for the scale-up Form 4. Based on the similarities and the absence of diffraction peaks attributed to Form 1, it is confirmed that Form 4 was produced as pure crystalline phase. id="p-116" id="p-116" id="p-116"

[000116]An exemplary XRPD pattern of Form 4 is provided as Figure 3. ExemplaryXRPD peak listings are provided as Table 5 below.

Table 5. Peak Table of Form 5. 26[°] d [A] I [%] 3.41 25.93 1006.79 13.01 66.98 12.66 97.19 12.29 311.22 7.88 113.95 6.34 215.73 5.63 216.36 5.42 516.60 5.34 416.85 5.26 316.98 5.22 217.09 5.18 317.62 5.03 317.99 4.93 218.51 4.79 118.80 4.72 219.39 4.57 319.80 4.48 219.94 4.45 4 Attorney Docket No. 1902446-0003-018-WO1 21.07 4.21 421.63 4.11 1121.97 4.04 422.71 3.91 522.89 3.88 723.19 3.83 223.62 3.76 523.74 3.75 324.33 3.66 424.73 3.60 225.08 3.55 226.18 3.40 327.11 3.29 128.32 3.15 1 id="p-117" id="p-117" id="p-117"

[000117]Form 4 was subjected to Variable Temperature XRPD. 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 oC/minute and relaxation of 5 minutes upon reaching the temperature before XRPD measurement. The overlay of the collected powder patterns are presented in Figure 23. The powder patterns are compared to Form 1 collected during the VT-XRPD. Very small shifts were observed at the different temperatures which can be an effect of expanding the unit cell dimensions after applying temperature. No changes in the solid form were observed which suggest that if the solvent molecules are released from the crystal, the crystal cell does not convert to the anhydrous Form 1. id="p-118" id="p-118" id="p-118"

[000118]The UPLC chromatogram of Form 4 (Figure 24) showed the presence of the API peak at 2.11 minutes with a chemical purity of 96.8% (area%).

Single Crystal Analysis of Form 4 id="p-119" id="p-119" id="p-119"

[000119]Single crystals of M2CAB were grown from a cooling crystallization experiment performed in acetonitrile. Approximately 20 mg of M2CAB was placed in 8 ml vial. Then 2 ml of acetonitrile were added and the vial was sealed. The obtained suspension was heated up to 80 °C till all solid was dissolved. The solution was left at RT seal without stirring. After 4 days at RT, long plate like needles crystals were obtained.

Attorney Docket No. 1902446-0003-018-WO1 id="p-120" id="p-120" id="p-120"

[000120]One crystal of approximately size 0.5 x 0.12 x 0.05 mm3 was selected for single crystal X-Ray diffraction (SCXRD) analysis. id="p-121" id="p-121" id="p-121"

[000121]The final crystal data and refinement parameters can be found in Table 6. This novel structure was designated as Form 4.

Table 6. Crystal data and final refinement parameters of Form 4.

Form Form 4 Empirical formula C37H51F2N3O6 + solvent (ACN)Formula weight 671.80T[K] 296(2)KX [A]1.54178Crystal system MonoclinicSpace group C2Unit cell dimensionsa [A] 53.203(4)b [A] 5.7766(5)c [A] 25.834(2) 3 [°]100.609(3)V[A3] 7803.9(11)Z(z’) 8De [g/cm3] 1.146 72.5.Reflections collected 74078Independent reflections 13997 [Rim = 0.0525]Completeness to 9 = 22.0° [%]91.4Absorption correction Semi-empirical from equivalentsMaximum and minimum transmission0.97 and 0.72 Data / restraints / parameters 13997/4/947 Attorney Docket No. 1902446-0003-018-WO1 Goodness-of-fit on F2 1.045Final R indices [I>2a(I)] RI = 0.0597, wR2 = 0.1654R indices (all data) RI = 0.0678, wR2 = 0.1736Absolute structure parameter 0.07(6)Extinction coefficient N/ALargest diff, peak and hole [e/A3]0.204 and-0.210 id="p-122" id="p-122" id="p-122"

[000122]The crystal structure can be described as layered. One layer is formed by the alicyclic part with fused rings, while the other is formed by the long aliphatic chains of stearic esters. In such packing the tunnels along the [0 1 0] direction are formed that are fulfilled with the solvent molecules. The solvent molecules showed a lot of disorder and therefore, there could not be quantified. Due to the disorder, it is assumed that acetonitrile molecules are present in the tunnels since this was the crystallization solvent used in the single crystal growth experiment. As it can be seen the removal or uptake of the solvent should not significantly change the structure. id="p-123" id="p-123" id="p-123"

[000123]In the crystal, there are no classical intermolecular hydrogen bonds, the only intermolecular interactions observed were C-H... 0 between aromatic and CH2.C atoms and amide O atoms. However, these interactions form only dimmers. Apart from these, intramolecular interactions between NH amide group and O carbonyl atom were found. The full geometry of the hydrogen bonds is presented in Table 7.

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(llB)...O(215) 0.97 2.35 3.222(4) 149C(112)-H(112)...O(215) 0.93 2.39 3.248(4) 153N(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) 156C(212)-H(212)...O(115) 0.93 2.35 3.183(4) 148N(216)-H(216)...0(227) 1.03(6) 1.92(6) 2.734(5) 134(4) id="p-124" id="p-124" id="p-124"

[000124]To verify that the determined crystal structure is representative of the bulk material obtained in the crystallization attempt, High Resolution XRPD (HR-XRPD) analysis Attorney Docket No. 1902446-0003-018-WO1 was carried out on the material recovered from the cooling crystallization experiment in ACN. The bulk material was grounded and transferred into a capillary for HR-XRPD measurement. Figure 25 shows the collected diffractogram of the bulk material, while Figure shows the comparison of the calculated powder pattern based on the single crystal data of Form 4 with the HR-XRPD diffractogram collected from the bulk solid recovered from the crystallization. id="p-125" id="p-125" id="p-125"

[000125]The obtained crystal crystallized in chiral monoclinic C2 space group and consisted of M2CAB and non-stoichiometric solvent molecules arranged around the symmetry center. Two M2CAB molecules are in the asymmetric unit forming a dimmer arranged around the pseudo-symmetry center. The two molecules interact with themselves by short C-H... 0 intermolecular interactions as it is presented in Figure 27. id="p-126" id="p-126" id="p-126"

[000126]The patterns are nearly identical and slight differences can be observed for peaks positions at high 20 angle. However, such differences can be explained by the small differences between unit cell parameters obtained from the single crystal and from the powder data. To make sure that the analyzed single crystal is the same as solid obtained in the crystallization, Rietveld analysis was done. id="p-127" id="p-127" id="p-127"

[000127]As it can be seen in Figure 27 and Table 8, by applying 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 with no detectable impurities.

Table 8. Rietveld analysis of solid obtained from the cooling crystallization experiment in acetonitrile.

Form Form 4 Empirical formula C37H51F2N3O6 + solvent (ACN)Formula weight 671.80T[K] 296mA]1.54056Crystal system MonoclinicSpace group C2Cap. size [mm2] 0.7x8Step size [°]0.0157 Attorney Docket No. 1902446-0003-018-WO1 No of steps 2541Time per step [s] 10range [°]1.5-41.5Rexp 3.96Rwp 5.64Rp 4.40GOF 1.42RBrag 1.10Impurities, other forms [%] Below Detection limits Characterization of Form 1 + Form id="p-128" id="p-128" id="p-128"

[000128]An exemplary XRPD pattern of Form 1+4 is provided as Figure 4. An exemplary DSC trace for Form 1+4 is depicted as Figure 28. In the DSC, Tonset was about 118.6 °C, while Tpeak was about 122.4 °C. id="p-129" id="p-129" id="p-129"

[000129]The HR-XRPD diffractogram of the solid collected from the evaporative crystallization experiment performed in p-xylene/ACN (50/50, v/v) is compared in Figure with the powder pattern collected for Form 1 (starting material) and Form 4 (from single crystal grown in ACN). For this sample, the HT-XRPD pattern was similar to that of Form I starting material; however, the HR-XRPD pattern indicated that this solid consisted of a mixture of Form 1 + Form 4. Exemplary peak listings are provided as Table 9 below.

Table 9. Exemplary Peak ListingsAngle 2-Theta ° Intensity %3.382 1006.761 5.26.976 5.37.177 2.57.403 3.710.164 0.610.387 0.411.209 1.613.955 1.114.361 0.614.859 0.615.428 0.6 Attorney Docket No. 1902446-0003-018-WO1 .694 0.816.342 1.816.614 2.216.814 2.317.566 3.117.82 318.201 1.118.718 2.219.339 1.119.923 2.420.651 1.121.036 2.521.598 8.121.886 422.152 2.422.678 2.622.852 4.123.25 1.523.472 1.923.632 324.02 0.924.284 2.224.542 0.624.724 125.041 0.725.597 126.122 1.827.065 1.228.297 0.628.986 0.929.359 0.329.882 0.430.121 0.530.882 0.331.72 0.533.012 0.233.35 0.3 id="p-130" id="p-130" id="p-130"

[000130]The TGA/TGMS analysis of (Figure 30) showed a mass loss of less than 1.1% corresponding to acetone based on the MS signal (1.1% of acetone corresponds to 0.molecule of acetone per molecule of API). The traces of thermal decomposition appeared above 200 °C.

Attorney Docket No. 1902446-0003-018-WO1 id="p-131" id="p-131" id="p-131"

[000131]The UPLC chromatogram (Figure 31) showed the presence of the API peak at 2.12 minutes with a chemical purity of 97.9% (area%).

Conclusions id="p-132" id="p-132" id="p-132"

[000132]From this polymorph screen, the starting material Form I was the main solid form found in the screen. However, a class of isostructural solvates was found, designated 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, Form 4 (as pure crystalline phase) was isolated from ACN and EtOH; however, in this polymorph screen, mixtures of Forms 1 + were found from several crystallization methods and solvents. The power patterns clustered in this mixture of forms showed strong similarities although the intensity and position of the diffraction peaks varied from patter to pattern.

Generation of Competitive Slurries id="p-133" id="p-133" id="p-133"

[000133]The relative stability between Forms 1, 2 and 4 was investigated by competitive slurry conversion experiments in water, MTBE and ACN at 25 °C and 40 °C. id="p-134" id="p-134" id="p-134"

[000134]A saturated stock solution of the M2CAB Form I was prepared in the different solvent systems at 25 °C and 40oC. The saturated solutions were added to the physical mixtures composed of Forms 1, 2 & 4 in 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 done) equilibration, a solids sample was drawn from the vials and analyzed by HR-XRPD. Experimental details are reported in Table 10.

Table 10. Experimental details and results of the competitive slurries between Forms 1, and 4. Phase quantification was done using the cell parameters calculated for Form 1 and the crystal structure of Form 4. The content of Form 2 was determined assuming the diffraction peaks that correspond to Form 2.

Attorney Docket No. 1902446-0003-018-WO1 T (°C) Form 1 (mg) Form 2 (mg) Form 4 (mg) Solvent Volume (pL) HR-XRPD (form) 2 weeks 4 weeks - 16.62 16.52 16.5 Blank physical mixture- - - 250C 15.23 15.68 15.01 Water 600 1+2+4 1+215.38 15.06 15.31 Acetonitrile 600 1+4 1+415.19 15.24 15.27 MTBE 600 1+4 1+440°C 15.19 15.82 15.55 Water 600 1+2 1+414.97 14.93 14.95 Acetonitrile 600 1+4 1+415.24 15.42 15.04 MTBE 600 1+4 1+4

Claims (32)

Attorney Docket No. 1902446-0003-018-WO1 CLAIMS

1. A crystalline form of a compound represented by: characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees at about 17.8.

2. The crystalline form of claim 1, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 20 at about 7.4, 17.8, and 22.2.

3. The crystalline form of claim 1 or 2, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 20 at about 7.4, 17.5, 17.8, 18.7, and 22.2.

4. The crystalline form of any one of claims 1-3, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 20 at about 6.8, 7.4, 16.7, 16.9, 17.5, 17.8, 18.2, 18.7, 21.9, and 22.2.

5. The crystalline form of any one of claims 1-4, characterized by a powder X-ray diffraction pattern substantially as depicted in Figure 1.

6. The crystalline form of any one of claims 1-5, wherein the powder X-ray diffraction pattern was obtained using Cu Ka radiation.

7. The crystalline form of any one of claims 1-6, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 118 °C and a peak of about 120 °C. Attorney Docket No. 1902446-0003-018-WO1

8. A crystalline form of a compound represented by: characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees at about 5.6.

9. The crystalline form of claim 8, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 5.6, 16.0, and 21.8.

10. The crystalline form of claim 8 or 9, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 5.6, 16.0, 21.8, 23.1, and 23.4.

11. The crystalline form of any one of claims 8-10, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 5.6, 7.4, 16.0, 16.9, 17.8, 18.3, 19.0,21.8, 23.1, and 23.4.

12. The crystalline form of any one of claims 8-11, characterized by a powder X-ray diffraction pattern substantially as depicted in Figure 2.

13. The crystalline form of any one of claims 8-12, wherein the powder X-ray diffraction pattern was obtained using Cu Ka radiation.

14. The crystalline form of any one of claims 8-13, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 117 °C and a peak of about 120 °C. Attorney Docket No. 1902446-0003-018-WO1

15. A crystalline form of a compound represented by: characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees at about 21.6.

16. The crystalline form of claim 15, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 7.0, 21.6, and 22.9.

17. The crystalline form of claim 15 or 16, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 7.0, 16.4, 21.6, 22.9, and 23.6.

18. The crystalline form of any one of claims 15-17, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 6.8, 7.0, 16.4, 16.6, 20.0, 21.6, 22.0, 22.7, 22.9, and 23.6.

19. The crystalline form of any one of claims 15-18, characterized by a powder X-ray diffraction pattern substantially as depicted in Figure 3.

20. The crystalline form of any one of claims 15-19, wherein the powder X-ray diffraction pattern was obtained using Cu Ka radiation.

21. The crystalline form of any one of claims 15-20, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset at about 119 °C and a peak at about 122 °C. Attorney Docket No. 1902446-0003-018-WO1

22. A mixture of crystalline forms of a compound represented by: characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees at about 21.6.

23. The mixture of claim 22, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 29 at about 7.0, 17.8, and 21.6.

24. The mixture of claim 22 or 23, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 7.0, 7.4, 17.8, 21.6, and 23.6.

25. The mixture of any one of claims 22-24, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 7.0, 7.4, 14.0, 16.3, 16.8, 17.8, 21.6, 23.6, 24.3, and 26.1.

26. The mixture of any one of claims 22-25, characterized by an XRPD pattern substantially as depicted in Figure 4.

27. The mixture of any one of claims 22-26, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 119 °C and a peak of about 122 °C.

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

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

30. A method of treating, inhibiting, and/or preventing a viral infection in a patient in need thereof, comprising administering to the patient an effective amount the mixture of any one of claims 22-28. Attorney Docket No. 1902446-0003-018-WO1

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 an HIV infection.