CA3151879A1 - Tenofovir alafenamide acesulfamate salt - Google Patents

Abstract

The present invention provides a novel tenofovir alafenamide acesulfamate salt, a crystalline form thereof, compositions and processes for its preparation, and its use in the treatment of a human immunodeficiency virus (HIV) infection or a hepatitis B virus (HBV) infection.

Description

TENOFOVIR ALAFENAMIDE ACESULFAMATE SALT
TECHNICAL FIELD
[0001] The present invention is directed to a novel tenofovir alafenamide acesulfamate salt, a crystalline form thereof, pharmaceutical compositions containing this salt, processes for its preparation, and its use in the treatment of a human immunodeficiency virus (HIV) infection or a hepatitis B virus (HBV) infection.
BACKGROUND

[0002] Tenofovir alafenamide (1), or L-alanine, N-RSHR1R)-2-(6-am ino-9H-purin-9-y1)-1-methylethoxy]methyl]phenoxyphosphinylF, 1-methylethyl ester, in the form of a hemifumarate, is the active ingredient in VEMLIDY , which is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver disease. Further combination drug products which also comprise Tenofovir alafenamide hem ifumarate include GENVOYA , ODEFSEY , and DESCOVY , which are indicated for the treatment of human immunodeficiency virus (HIV-1) infections.

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[0003] Salts and crystalline forms of tenofovir alafenamide, including co-crystals, are reported in, for example, WO 2002/008241 A2, WO 2013/025788 A2, Date Recue/Date Received 2022-03-14

4 Al, WO 2015/040640 A2, WO 2015/107451 A2, WO
2015/176602 Al, CN 105237571 B, CN 104926872 B, WO 2016/192692 Al, WO
2016/205141 Al, WO 2018/115046 Al, CN 108341841 A, WO 2018/144390 Al, IN 201721005563 A, CN 108484672 A, CN 108997428 A, CN 110283208 A, KR
2020084713 A, WO 2020/222393 Al, CN 110746461 A, WO 2021/165995 Al, KR
2021125298 A, CN 112375103 A, and CN 112457345 A.
[0004] According to the review published by the U.S. Center for Drug Evaluation and Research (CDER) in connection with the approval of GENVOYA
(NDA 207561), the drug substance tenofovir alafenamide hem ifumarate has high solubility but low permeability, placing it in Class III of the Biopharmaceutics Classification System (BCS).

[0005] Different salts and/or crystalline forms of the same compound may have different crystal packing, thermodynamic, spectroscopic, kinetic, surface and mechanical properties. For example, different salts and/or crystalline forms may have different stability properties such that a particular crystalline form may be less sensitive to heat, relative humidity (RH) and/or light. Different salts and/or crystalline forms of a compound may also be more susceptible to moisture uptake, resulting in a potential alteration of physical characteristics of the form such as flowability, density or compressibility, which can lead to problems during formulation/tabletting and/or to changes in dissolution rate of the formulated drug product.

[0006] For example, unintended absorption of moisture by a hygroscopic salt or crystalline form of a drug substance can alter its compressibility during tabletting, resulting in a softer tablet having a faster dissolution rate following administration. A particular salt or crystalline form may provide more favourable compressibility and/or density properties, thereby providing more desirable characteristics for formulation and/or product manufacturing. Differences in stability between salts or crystalline forms of a drug may result from changes in chemical reactivity, such as differential oxidation. Such properties may provide for Date Recue/Date Received 2022-03-14 more suitable product qualities, including a dosage form that is more resistant to discolouration when comprised of a specific salt or crystalline form.

[0007] Particular salts or crystalline forms may also have different solubilities, thereby providing different pharmacokinetic parameters, which allow for specific salts or crystalline forms to be used in order to achieve specific pharmacokinetic targets.

[0008] There exists a need for novel forms of tenofovir alafenamide having improved properties for use in providing drug products containing tenofovir alafenamide, and commercially amenable processes for their manufacture.
SUMMARY

[0009] The tenofovir alafenamide acesulfamate salt of the present invention comprises tenofovir alafenamide and acesulfame. Acesulfame, in the form of acesulfamate potassium, is used as a sweetener in the food industry and as an inactive ingredient in drug products. Accordingly, it is expected that acesulfame can safely be used in materials intended for use in the preparation of pharmaceutical compositions intended for administration to humans.

[0010] The tenofovir alafenamide acesulfamate of the present invention can be prepared by an efficient and industrially compatible process.

[0011] Accordingly, in a first aspect of the present invention, there is provided an acesulfamate salt of tenofovir alafenamide. In a preferred embodiment of the first aspect, the molar ratio of tenofovir alafenamide to acesulfame in the salt is approximately 1:1. In a more preferred embodiment of the first aspect, the salt is a crystalline solid.

[0012] In a second aspect of the present invention, there is provided a crystalline form of tenofovir alafenamide acesulfamate, characterized by a PXRD
diffractogram comprising peaks, expressed in degrees 28 ( 0.2 ), at 3.6 , 6.7 , and 8.6 . More preferably, the salt of the second aspect is characterized by a Date Recue/Date Received 2022-03-14 PXRD diffractogram further comprising at least three peaks in the PXRD
diffractogram, expressed in degrees 28 ( 0.2 ), selected from the group consisting of: 6.9 , 7.6 , 9.8 , 10.8 , 12.7 , and 13.5 . In a further preferred embodiment of the second aspect, the PXRD diffractogram further comprises peaks, expressed in degrees 28 ( 0.2 ), at 6.9 , 7.6 , 9.8 , 10.8 , 12.7 , and 13.5 .
Preferably, the salt of the second aspect of the invention provides a PXRD diffractogram comprising peaks in substantially the same positions ( 0.2 28) as those shown in Figure 1. In another preferred embodiment of the second aspect, the crystalline form is characterized by a DSC thermogram comprising an endothermic peak with a peak onset at approximately 123 C and a peak maximum at approximately 127 C. More preferably, the DSC thermogram is substantially the same in appearance as the DSC thermogram provided in Figure 2. In a further preferred embodiment of the second aspect, the molar ratio of tenofovir alafenamide to acesulfame is approximately 1:1.

[0013] In a third aspect of the present invention, there is provided a pharmaceutical composition comprising the tenofovir alafenamide acesulfamate salt according to the first aspect, or the tenofovir alafenamide acesulfamate crystalline form according to the second aspect, and one or more pharmaceutically acceptable excipients. Preferably, the pharmaceutical composition is in the form of a solid oral dosage form. Most preferably, the pharmaceutical composition is a tablet. In a further preferred embodiment of the third aspect, the pharmaceutical composition comprises an additional therapeutic agent, preferably selected from the group consisting of HIV protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV
integrase inhibitors, and CCR5 inhibitors. More preferably, the additional therapeutic agent is selected from the group consisting of emtricitabine, darunavir, cobicistat, bictegravir, and rilpivirine. Preferably, the pharmaceutical composition of the third aspect comprises an amount of the tenofovir alafenamide acesulfamate salt or Date Recue/Date Received 2022-03-14 crystalline form according to the first or second aspects that is equivalent to 10 mg or 25 mg tenofovir alafenamide free base.

[0014]
In a fourth aspect of the present invention, there is provided the use of the tenofovir alafenamide acesulfamate salt according to the first aspect, or the tenofovir alafenamide acesulfamate crystalline form according to the second aspect, in the treatment of a human immunodeficiency virus (HIV) infection or a hepatitis B virus (HBV) infection. In a further preferred embodiment of the fourth aspect, the tenofovir alafenamide acesulfamate salt or crystalline form is used in combination with an additional therapeutic agent, preferably selected from the group consisting of HIV protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV
integrase inhibitors, and CCR5 inhibitors. More preferably, the additional therapeutic agent is selected from the group consisting of emtricitabine, darunavir, cobicistat, bictegravir, and rilpivirine.

[0015]
In a fifth aspect of the present invention, there is provided a process for the preparation of the crystalline form of tenofovir alafenamide acesulfamate of the second aspect, the process comprising: (i) combining tenofovir alafenamide and acesulfame in a suitable solvent at a suitable temperature to form a mixture;
(ii) cooling the mixture, if necessary, to form a suspension comprising tenofovir alafenamide acesulfamate crystals; and (iii) isolating the tenofovir alafenamide acesulfamate crystals from the suspension. In a preferred embodiment of the fifth aspect, the suitable solvent is selected from the group consisting of isobutanol, isopropanol and ethyl acetate. In another embodiment, step (i) comprises dissolving tenofovir alafenamide and acesulfame. In a further preferred embodiment, the suitable temperature is between approximately 50 C and approximately 70 C.

Date Recue/Date Received 2022-03-14

[0016] Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying figures.
BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Embodiments of the present invention are described, by way of example only, with reference to the attached Figures.

[0018] Figure 1 is a representative PXRD diffractogram of tenofovir alafenamide acesulfamate Form APO-I as prepared in Example 1.

[0019] Figure 2 is a representative DSC thermogram of tenofovir alafenamide acesulfamate Form APO-I as prepared in Example 1.
DETAILED DESCRIPTION

[0020] The present invention provides a novel tenofovir alafenamide acesulfamate salt. Acesulfame, in the form of its potassium salt, is used as a sweetener in the food industry and is also included in both the U.S. Food &
Drug Administration's (FDA's) Substances Added to Food inventory (formerly Everything Added to Food in the United States (EAFUS)) list and the Inactive Ingredient Database (IID). The Substances Added to Food inventory contains approximately 4,000 substances, and includes information on food additives, colour additives, Generally Recognized As Safe (GRAS) substances, and prior-sanctioned substances. The IID list provides information on inactive ingredients present in FDA-approved drug products. Once an inactive ingredient has appeared in an approved drug product, the inactive ingredient is not considered new, and may require a less extensive review the next time it is included in a new drug product. In addition to pharmaceutical acceptability, acesulfame may offer a dual purpose by imparting a sweet taste that could be exploited in certain pharmaceutical formulations such as oral solutions.

Date Recue/Date Received 2022-03-14

[0021] Additionally, a process for the manufacture of tenofovir alafenamide acesulfamate of the present invention is efficient and industrially compatible, using Class 3 solvents established by the ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) as having low toxicity.

[0022] Depending on the manner in which a crystalline form of the present invention is prepared, and the methodology and instrument used for PXRD
analysis, the intensity of a given peak observed in a PXRD diffractogram of the crystalline form may vary when compared to the same peak in the representative PXRD diffractogram provided in Figure 1. Thus, differences in relative peak intensities between peaks in a PXRD diffractogram for a given crystalline form may be observed when compared to the relative peak intensities of the peaks in the representative PXRD diffractogram of Figure 1. Any such differences may be due, in part, to the preferred orientation of the sample and its deviation from the ideal random sample orientation, the preparation of the sample for analysis, and the methodology applied for the analysis. Such variations are known and understood by a person of skill in the art, and any such variations do not depart from the invention disclosed herein.

[0023] In addition to the differences in relative peak intensities that may be observed in comparison to the representative PXRD diffractogram provided in Figure 1, it is understood that individual peak positions may vary between 0.2 28 from the values observed in the representative PXRD diffractograms provided in Figure 1 for a crystalline form of the invention, or listed in Table 1.
Such variations are known and understood by a person of skill in the art, and any such variations do not depart from the invention disclosed herein.

[0024] Further, depending on the instrument used for X-ray analysis and its calibration, uniform offsets in the peak position of each peak in a PXRD
diffractogram of greater that 0.2 28 may be observed when compared to the representative PXRD diffractogram provided in Figure 1. Thus, the PXRD

Date Recue/Date Received 2022-03-14 diffractogram of a crystalline form of the present invention may, in some circumstances, display the same relative peak positions as observed in the representative PXRD diffractograms provided in Figure 1, with the exception that each peak is offset in the same direction, and by approximately the same amount, such that the overall PXRD diffractogram is substantially the same in appearance as the PXRD diffractogram of Figure 1, with the exception of the uniform offset in peak positions. The observation of any such uniform peak shift in a PXRD
diffractogram does not depart from the invention disclosed herein given that the relative peak positions of the individual peaks within the PXRD diffractogram remain consistent with the relative peak positions observed in the PXRD
diffractogram of Figure 1.

[0025] Depending on the manner in which a crystalline form is prepared, the methodology and instrument used for DSC analysis, it is understood that peaks corresponding with thermal events in a DSC thermogram may vary between 2 C
from the values observed in the representative DSC thermogram provided in Figure 2 and described herein. Such variations are known and understood by a person of skill in the art, and any such variations do not depart from the invention disclosed herein.

[0026] As used herein, the term 'crystalline form' refers to a uniform substance which may be identified by physical characterization methods such as PXRD
and/or DSC.

[0027] As used herein, the term "room temperature" refers to a temperature in the range of 20 C to 25 C.

[0028] Unless defined otherwise herein, the term "approximately", when used in reference to molar ratios, allows for a variance of plus or minus 10%.

[0029] When describing the embodiments of the present invention there may be a common variance to a given temperature or time that would be understood or expected by the person skilled in the art to provide substantially the same result.

Date Recue/Date Received 2022-03-14 For example, when reference is made to a particular temperature, it is to be understood by the person skilled in the art that there is an allowable variance of 5 C associated with that temperature. When reference is made to a particular time, it is to be understood that there is an allowable variance of 10 minutes when the time is one or two hours, and 1 hour when longer periods of time are referenced.

[0030] In one embodiment of the present invention, there is provided a new crystalline form of tenofovir alafenamide acesulfam ate salt, tenofovir alafenamide acesulfamate Form APO-I, wherein the molar ratio of tenofovir alafenamide to acesulfame is approximately 1:1.

[0031] Tenofovir alafenamide acesulfamate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 28 ( 0.2 ), at 3.6 , 6.7 , and 8.6 . Preferably, the PXRD
diffractogram further comprises at least three peaks, expressed in degrees 28 ( 0.2 ), selected from the group consisting of 6.9 , 7.6 , 9.8 , 10.8 , 12.7 , and 13.50 .
More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 28 ( 0.2 ), at 6.9 , 7.6 , 9.8 , 10.8 , 12.7 , and 13.5 . PXRD
studies of uncapped samples of tenofovir alafenamide acesulfamate Form APO-I maintained in a40 C/75 % RH (relative humidity) stability chamber for at least 1 week showed that no change in the crystalline form occurred.

[0032] An illustrative PXRD diffractogram of tenofovir alafenamide acesulfamate Form APO-I, as prepared in Example 1, is shown in Figure 1. A
peak listing, comprising representative peaks from the PXRD diffractogram in Figure 1, and their relative intensities, is provided in Table 1. Although illustrative of the PXRD diffractogram that is provided for the tenofovir alafenamide acesulfamate Form APO-I of the present invention, the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.

Date Recue/Date Received 2022-03-14 Table 1: Relative peak intensities of tenofovir alafenamide acesulfamate Form APO-I from Figure 1 Angle (20) Relative intensity (%) 3.63 100.0 6.69 18.7 6.92 11.4 7.59 2.7 8.58 20.7 9.80 7.0 10.76 4.5 12.66 7.5 13.45 7.9 14.35 18.5 15.80 3.5 18.32 8.9 20.84 2.2 25.39 6.0

[0033] An illustrative DSC thermogram of tenofovir alafenamide acesulfamate Form APO-I is shown in Figure 2. The DSC thermogram may be further characterized by an endothermic peak with a peak onset at approximately 123 C

and a peak maximum at approximately 127 C.

[0034] As described in the Examples, tenofovir alafenamide acesulfamate Form APO-I can be prepared by combining approximately equimolar amounts of tenofovir alafenamide free base with acesulfame in a suitable solvent, preferably an alcohol such as isobutanol or isopropanol or an ester such as ethyl acetate, and maintaining the mixture at a suitable temperature, preferably at an elevated temperature, preferably in the range of approximately 50 C and approximately C, for a suitable time, preferably between 4 and 6 hours. Following cooling, if desired, the resulting suspension is isolated and dried, if necessary, preferably in vacuo and at room temperature.

Date Recue/Date Received 2022-03-14

[0035]
In a further embodiment of the invention, there is provided a pharmaceutical composition comprising tenofovir alafenamide acesulfamate, preferably tenofovir alafenamide acesulfamate Form APO-I, with one or more pharmaceutically acceptable excipients.
Preferably, the pharmaceutical composition is a solid dosage form suitable for oral administration, such as a capsule, tablet, pill, powder, or granulate. Most preferably, the pharmaceutical composition is a tablet. Preferably, the pharmaceutical composition provides a dose of tenofovir alafenamide acesulfamate that is equivalent to the 10 mg of tenofovir alafenamide that is found in SYMTUZA drug products or to the 25 mg of tenofovir alafenamide that is found in VEMLIDY , ODEFSEY , BIKTARVY , and DESCOVY drug products.

[0036]
Suitable pharmaceutically acceptable excipients are preferably inert with respect to the tenofovir alafenamide acesulfamate salt of the present invention, and may include, for example, one or more excipients selected from binders such as lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatine, polyvinylpyrrolidone (PVP), and sodium alginate; fillers or diluents such as lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g., microcrystalline cellulose, cellulose), calcium sulphate, xylitol, and lactitol;
disintegrants such as croscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycollate, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; lubricants such as magnesium stearate, magnesium lauryl stearate, sodium stearyl fumarate, stearic acid, calcium stearate, zinc stearate, potassium benzoate, sodium benzoate, myristic acid, palm itic acid, mineral oil, hydrogenated castor oil, medium-chain triglycerides, poloxamer, polyethylene glycol, and talc; and dispersants or solubility enhancing agents, such cyclodextrins, glyceryl monostearate, hypromellose, meglumine, Poloxamer, polyoxyethylene castor oil derivatives, polyoxyethylene Date Recue/Date Received 2022-03-14 stearates, polyoxylglycerides, povidone, and stearic acid. Other excipients including preservatives, stabilisers, anti-oxidants, silica flow conditioners, antiadherents, or glidants may be added as required. Other suitable excipients and the preparation of solid oral dosage forms is well known to person of skill in the art, and is described generally, for example, in Remington The Science and Practice of Pharmacy 21st Edition (Lippincott Williams & Wilkins:
Philadelphia;
2006; Chapter 45).

[0037] Optionally, when the pharmaceutical compositions are solid dosage forms, the solid dosage forms may be prepared with coatings, such as enteric coatings and extended-release coatings, using standard pharmaceutical coatings.
Such coatings, and their application, are well known to persons skilled in the art, and are described, for example, in Remington The Science and Practice of Pharmacy 21st Edition (Lippincott Williams & Wilkins: Philadelphia; 2006;
Chapter 46).

[0038] Optionally, pharmaceutical compositions according to the present invention can be prepared with other medicinal ingredients for use in combination therapy. Alternatively, combination therapy using the tenofovir alafenamide acesulfamate of the present invention can involve individual pharmaceutical compositions for each medicinal ingredient, which are administered concurrently or sequentially.

[0039] In one embodiment, when used in combination therapy, tenofovir alafenamide acesulfamate of the present invention is used in combination with emtricitabine. In this embodiment of the present invention, there is provided a pharmaceutical composition comprising a fixed dose combination of tenofovir alafenamide acesulfamate, preferably tenofovir alafenamide acesulfamate Form APO-I, with emtricitabine. Pharmaceutical compositions containing a combination of active ingredients may be prepared in the same manner as described above.
Preferably, in such fixed dose combinations, the pharmaceutical composition provides doses of tenofovir alafenamide acesulfamate and emtricitabine that are Date Recue/Date Received 2022-03-14 equivalent to those found in DESCOVY tablets. Thus, for example, a preferred fixed dose combination tablet may comprise 35.6 mg of tenofovir alafenamide acesulfamate (providing 25 mg tenofovir alafenamide free base) and 200 mg emtricitabine.

[0040] In a further embodiment, when used in combination therapy, tenofovir alafenamide acesulfamate of the present invention is used in combination with emtricitabine and rilpivirine hydrochloride. In this embodiment of the present invention, there is provided a pharmaceutical composition comprising a fixed dose combination of tenofovir alafenamide acesulfamate, preferably tenofovir alafenamide acesulfamate Form APO-I, with emtricitabine and rilpivirine hydrochloride. Pharmaceutical compositions containing a combination of active ingredients may be prepared in the same manner as described above. Preferably, in such fixed dose combinations, the pharmaceutical composition provides doses of tenofovir alafenamide acesulfamate, emtricitabine, and rilpivirine hydrochloride that are equivalent to those found in ODEFSEY tablets. Thus, for example, a preferred fixed dose combination tablet may comprise 35.6 mg of tenofovir alafenamide acesulfamate (providing 25 mg tenofovir alafenamide free base), mg emtricitabine, and 27.5 mg rilpivirine hydrochloride (providing 25 mg rilpivirine free base).

[0041] In a further embodiment, when used in combination therapy, tenofovir alafenamide acesulfamate of the present invention is used in combination with emtricitabine, cobicistat, and darunavir. In this embodiment of the present invention, there is provided a pharmaceutical composition comprising a fixed dose combination of tenofovir alafenamide acesulfamate, preferably tenofovir alafenamide acesulfamate Form APO-I, with emtricitabine, cobicistat, and darunavir. Pharmaceutical compositions containing a combination of active ingredients may be prepared in the same manner as described above. Preferably, in such fixed dose combinations, the pharmaceutical composition provides doses of tenofovir alafenamide acesulfamate, emtricitabine, cobicistat, and darunavir that are equivalent to those found in SYMTUZA tablets. Thus, for example, a preferred Date Recue/Date Received 2022-03-14 fixed dose combination tablet may comprise 14.2 mg of tenofovir alafenamide acesulfamate (providing 10 mg tenofovir alafenamide free base), 200 mg emtricitabine, 150 mg cobicistat, and 800 mg darunavir.

[0042] In a further embodiment, when used in combination therapy, tenofovir alafenamide acesulfamate of the present invention is used in combination with emtricitabine and bictegravir sodium. In this embodiment of the present invention, there is provided a pharmaceutical composition comprising a fixed dose combination of tenofovir alafenamide acesulfamate, preferably tenofovir alafenamide acesulfamate Form APO-I, with emtricitabine and bictegravir sodium.
Pharmaceutical compositions containing a combination of active ingredients may be prepared in the same manner as described above. Preferably, in such fixed dose combinations, the pharmaceutical composition provides doses of tenofovir alafenamide acesulfamate, emtricitabine, and bictegravir sodium that are equivalent to those found in BIKTARVY tablets. Thus, for example, a preferred fixed dose combination tablet may comprise 35.6 mg of tenofovir alafenamide acesulfamate (providing 25 mg tenofovir alafenamide free base), 200 mg emtricitabine, and 52.5 mg bictegravir sodium (providing 50 mg bictegravir free acid).
EXAMPLES

[0043] The following non-limiting examples are illustrative of some of the aspects and embodiments of the invention described herein.

[0044] The tenofovir alafenamide free base used as a starting material in the following examples was consistent with the crystalline form reported in WO
2015/040640 Al. Other forms are equally suitable as starting material, provided dissolution of the form occurs when preparing the tenofovir alafenamide acesulfamate of the present invention.

Date Recue/Date Received 2022-03-14 PXRD Analysis:

[0045] PXRD diffractogram was recorded on a Bruker D8 Discover powder X-ray diffractometer (Bruker AXS LLC, Karlsruhe, Germany). The generator was a Incoatec Microfocus Source (IpS) Cu tube (A = 1.54060 A) with a voltage of 50 kV
and current of 1.00 mA, using a divergence slit of 0.1 mm and collimator of 2.0 mm. For the sample, two frames were collected using a still scan with a R 100K-A detector at the distance of 294.2 mm from the sample and then merged.

Raw data were evaluated using the program DIFFRAC.EVA (Bruker AXS LLC, Karlsruhe, Germany).
Differential Scanninq Calorimetry Analysis:

[0046] The DSC thermogram was collected on a Mettler-Toledo 821e instrument. The sample (2 0.2 mg) was weighed into a 40 pL aluminum pan and was crimped closed with an aluminum lid having a 50 pm perforation. The sample was analyzed under a flow of nitrogen (50 5 mL/min) at a scan rate of 10 C/minute between 25 C and 360 C.
Example 1: Preparation of tenofovir alafenamide acesulfamate Form APO-I

[0047] Tenofovir alafenamide free base (200 mg) and acesulfame (75 mg) were suspended in isobutanol (2.0 mL) and heated to 60 C. Once a solution was obtained, it was slowly cooled to room temperature over approximately 5 hours, during which time precipitation occurred. The thick suspension was further stirred at room temperature for approximately 18 hours, after which the solids were collected by filtration. Additional isobutanol (1.3 mL) was used to help transfer and wash the precipitate. The isolated solid was dried in vacuo at room temperature for 24 hours to afford tenofovir alafenamide acesulfam ate Form APO-I as a white, unsolvated solid (237 mg). A sample (13.3 mg) of this material fully dissolved in water (1 mL) adjusted to pH 8 with NaHCO3, which corresponds with the description 'sparingly soluble' in the U.S. Pharmacopeia (USP). The PXRD
diffractogram and DSC thermogram of a sample prepared by this method are Date Recue/Date Received 2022-03-14 shown in Figure 1 and Figure 2, respectively. 1H NMR analysis of the solid (DMSO-d6) identified a molar ratio of tenofovir alafenamide to acesulfame of 1:1.

[0048] 1H-NMR of tenofovir alafenamide acesulfamate Form APO-I
(DMSO-d6, 500 MHz) 6: 8.37 (s, 1H), 8.36 (s, 1H), 7.32 (t, J=7.9 Hz, 2H), 7.15 (t, J=7.4 Hz, 1H), 7.06 (d, J=8.3 Hz, 2H), 5.64 (t, J=11.2 Hz, 1H), 5.50 (s, 1H), 4.84 (sep, J=6.3 Hz, 1H), 4.38 (dd, J=3.3, 14.4 Hz, 1H), 4.22 (dd, J=6.7, 14.4 Hz, 1H), 3.99 (m, 1H), 3.89 (dd, J=8.2, 13.5 Hz, 1H), 3.77-3.86 (m, 2H), 1.99 (s, 3H), 1.15 (d, J=6.3 Hz, 6H), 1.13 (d, J=7.2 Hz, 3H), 1.10 (d, J=6.2 Hz, 3H).
Example 2: Preparation of tenofovir alafenamide acesulfamate Form APO-I

[0049] Tenofovir alafenamide free base (200 mg) and acesulfame (75 mg) were suspended in ethyl acetate (4.0 mL) and the resulting suspension was heated to 70 C for 4 hours. Heating was discontinued, and the suspension was further stirred at room temperature for approximately 18 hours. The solids were collected by filtration and dried in vacuo at room temperature for 24 hours to afford tenofovir alafenamide acesulfamate Form APO-I as a white, unsolvated solid (242 mg).

Date Recue/Date Received 2022-03-14

Claims (23)

What is claimed is:

1. An acesulfamate salt of tenofovir alafenamide.

2. The acesulfamate salt of claim 1, wherein the molar ratio of tenofovir alafenamide to acesulfame is approximately 1:1.

3. The acesulfamate salt of claim 1 or 2, which is a crystalline solid.

4. A crystalline form of tenofovir alafenamide acesulfamate characterized by a PXRD diffractogram comprising peaks, expressed in degrees 28 ( 0.2 ), at 3.6 , 6.7 , and 8.6 .

5. The crystalline form of claim 4, further comprising at least three peaks in the PXRD diffractogram, expressed in degrees 28 ( 0.2 ), selected from the group consisting of: 6.9 , 7.6 , 9.8 , 10.8 , 12.7 , and 13.5 .

6. The crystalline form of claim 5, further comprising peaks in the PXRD
diffractogram, expressed in degrees 28 ( 0.2 ), at 6.9 , 7.6 , 9.8 , 10.8 , 12.7 , and 13.5 .

7. The crystalline form of any one of claims 4 to 6, providing a PXRD
diffractogram comprising peaks in substantially the same positions ( 0.2 28) as those shown in Figure 1.

8. The crystalline form of any one of claims 4 to 7, characterized by a DSC

thermogram comprising an endothermic peak with a peak onset at approximately 123 C and a peak maximum at approximately 127 C.

9. The crystalline form of any one of claims 4 to 8, characterized by a DSC

thermogram that is substantially the same in appearance as the DSC
thermogram provided in Figure 2.

10. The crystalline form of claim 4, wherein the molar ratio of tenofovir alafenamide to acesulfame is approximately 1:1.

Date Recue/Date Received 2022-03-14

11. A pharmaceutical composition comprising of tenofovir alafenamide acesulfamate according to any one of claims 1 to 10, and one or more pharmaceutically acceptable excipients.

12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is a tablet.

13. The pharmaceutical composition of claim 11 or 12, further comprising an additional therapeutic agent.

14. The pharmaceutical composition of claim 13, wherein the additional therapeutic agent is selected from the group consisting of HIV protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV
nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors.

15. The pharmaceutical composition of claim 14, wherein the additional therapeutic agent is selected from the group consisting of emtricitabine, darunavir, cobicistat, bictegravir, and rilpivirine.

16. Use of tenofovir alafenamide acesulfamate according to any one of claims 1 to 15 in the treatment of a human immunodeficiency virus (HIV) infection or a hepatitis B virus (HBV) infection.

17. The use of claim 16, wherein the tenofovir alafenamide acesulfamate is used in combination with an additional therapeutic agent.

18. The use of claim 17, wherein the additional therapeutic agent is selected from the group consisting of HIV protease inhibiting compounds, HIV
nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors.

Date Recue/Date Received 2022-03-14

19. The use of claim 18, wherein the additional therapeutic agent is selected from the group consisting of emtricitabine, darunavir, cobicistat, bictegravir, and rilpivirine.

20. A process for the preparation of the crystalline form of tenofovir alafenamide acesulfamate according to claim 4, the process comprising:
combining tenofovir alafenamide and acesulfame in a suitable solvent at a suitable temperature to form a mixture;
(ii) cooling the mixture, if necessary, to form a suspension comprising tenofovir alafenamide acesulfamate crystals;
(iii) isolating the tenofovir alafenamide acesulfamate crystals from the suspension.

21. The process of claim 20, wherein the suitable solvent is selected from the group consisting of isobutanol, isopropanol and ethyl acetate.

22. The process of claim 20 or 21, wherein the solvent is isobutanol or isopropanol and step (i) comprises dissolving tenofovir alafenamide and acesulfame.

23. The process of any one of claims 20 to 22, wherein the suitable temperature is between approximately 50 C and approximately 70 C.

Date Recue/Date Received 2022-03-14