Crystalline form

Abstract

The present invention relates to Human immunodeficiency Virus (HIV) prevention and treatment, in particular, the invention relates to a polymorphic form of a prodrug of cabotegravir.

Description

[0001]CRYSTALLINE FORM FIELD OF THE INVENTION This invention relates to a crystalline form of a prodrug of Cabotegravir and its use inpharmaceutical compositions as well as in therapy, in particular use in the treatment and prevention of Human Immunodeficiency Virus (HIV) infection. BACKGROUND TO THE INVENTION Patients with HIV infection commonly undergo complex treatment regimens which involve taking multiple pills at regular intervals each day. Patient non-compliance is a known problem accompanying these complex HIV treatment regimens and can lead to the emergence of multiple drug resistant strains of HIV. The application of long-acting parenteral pharmaceuticals has been established in clinical practice for decades, notably in the areas of contraception, anti-psychotics, and opiate addiction. More recently, long-acting parenteral pharmaceuticals have been proposed as a way of overcoming the non-compliance problem with HIV treatment regimens. Long-acting injectable formulations, some of which are approved and marketed, such as CABENUVA®,have demonstrated prolonged exposures (≥ 30 days) following injection, enabling dosing atonce-monthly and bimonthly intervals. Achieving an injectable suspension comprising an anti-HIV drug in order to dose lessfrequently and overcome the non-compliance problem with HIV treatment regimens, whilst keeping the same or similar injection volume as previous HIV treatment regimens in order to maintain patient experience, is desirable. Similarly, where an anti-HIV drug may be used for prevention of HIV (e.g., pre-exposure prophylaxis, or PrEP), achieving an injectablesuspension with an anti-HIV drug that provides a longer-acting effect could increaseadherence due to less frequent dosing. WO 2017 / 223280 and WO 2020 / 086555 disclose integrase inhibitor prodrugs, specifically prodrugs of cabotegravir. These prodrugs may have an extended drug half-life andtherefore allow for less frequent dosing compared to the parent compound which could helpalleviate issues with patient non-compliance. The steric acid ester prodrug of cabotegravir hasbeen shown to have particularly desirable properties. In the pursuit of a developable form of a pharmaceutical compound, a number ofspecific features are sought. Although an amorphous form of a pharmaceutical compound may be developed, compounds having high crystallinity are generally preferred. It is expected that drug substance polymorphism could impact pharmacokinetics and / or bioavailability of suspensions, due to potential solubility difference of different solid- state forms. Identification of a stable, crystalline form of a compound with suitable properties for long-acting administration and a pharmaceutical composition that arrests form conversionwould be highly desirable for the treatment and prevention of HIV infection.There is therefore a need in the art to find a single component stable polymorphicform of the steric acid ester prodrug of cabotegravir. There is also be a need in the art to findsuch a polymorphic form that is suitable for use as a long acting injectable. SUMMARY OF THE INVENTION According to a first aspect, there is provided a crystalline form (Form 1) of CompoundA . to a aspect, a comprisingForm 1 of Compound A as described herein.According to a third aspect, there is provided a method of treating human immunodeficiency virus (HIV) in a human in need thereof comprising administering to saidhuman a therapeutically effective amount of Form 1 of Compound A as described herein.According to a further aspect of the invention, there is provided Form 1 of Compound Aas described herein for use in therapy.According to a further aspect, there is provided Form 1 of Compound A as describedherein, for use in treatment or prevention of human immunodeficiency virus (HIV). According to a further aspect of the invention, there is provided a method of making Form1 of a Compound A, said method comprising a step of crystalising Compound A fromcyclopentyl methyl ether (CPME).The crystalline form of Compound A described here, i.e. Form 1, may be advantageous ina number of respects. Compound A has been found to be useful in the treatment andprevention of HIV infection. The present inventors have now managed to isolate Form 1 ofCompound A and are able to produce polymorphically pure Form 1 (as confirmed by XRPD).Form 1 is the most thermodynamically stable single component solid state form of CompoundA. In particular, Form 1 of Compound A has been shown to remain stable during storage, i.e.does not convert to another form over time, as well as remaining stable when exposed toconditions of varying temperature and humidity. Further, it has been shown that Form 1maintains its stability when formulated into a pharmaceutical composition, specifically alyophilised formulation of Compound A suitable as a long acting injectable.BRIEF DESCRIPTION OF THE DRAWINGSFig. 1 shows an X-ray powder diffraction pattern (XRPD) of Form 1 of Compound A measuredat room temperature with Cu Ka1 radiation at 1.54 Angstroms.Fig. 2 shows a high resolution X-ray powder diffraction pattern (XRPD) of Form 1 of CompoundA measured at room temperature with Cu Ka1 radiation at 1.54 Angstroms.Fig. 3 shows a Raman spectrum of Form 1 of Compound A. Raman spectra was collected usinga Kaiser Optical Systems Raman RXN2-785 controlled by iCRaman software v4.4.21. Resampling Intervals were: 1 cm-1; Channel 2. A RXN Probe + Hastelloy C276 Immersion Optic Laser with a Wavelength of 785nm (short focus, 6mm dia, 203mm long) was used. Parameters are as follows: Laser Power set at 400mW, detector Temperature -40°C, cosmic Ray Removal ON, Peak Intensity Correction ON, 1s Acquisition Time.Fig. 4 shows a differential scanning calorimetry thermogram of Form 1 of Compound A.Collected at room temperature up to 160 deg C at a heating rate of 10 deg C / min using asealed hermetic aluminium pan with a pinhole.Fig. 5 shows a thermogravimetric analysis trace of Form 1 of Compound A. Collected at roomtemperature up to 400 deg C at a heating rate of 15 deg C / min in an open aluminium pan.Fig. 6 shows an X-ray powder diffraction pattern of a form, Group B of Compound A.Fig. 7 shows an X-ray powder diffraction pattern of a multicomponent form, Group E ofCompound A.Fig. 8 shows a 19F solid-state Nuclear Magnetic Resonance (NMR) spectrum of Form 1 ofCompound A.Fig. 9 shows DSC Traces of Class 1 (from Bottom Groups A, B, C, E, F) and Group D (Form 1)(Top).Fig. 10 shows DSC Traces of Ripening Products from CMPE at 20 °C after 5h (Top, Group D)and MeCN (Bottom, Groups B / C)Fig. 11 shows PXRD Pattern of Group B from the form screen in Example 1.Fig. 12 shows PXRD Pattern of Group C from the form screen in Example 1.Fig. 13 shows PXRD Pattern of Group D (Form 1) from the form screen in Example 1.Fig. 14 shows PXRD Pattern of Group E from the form screen in Example 1.Fig. 15 shows PXRD Pattern of Group F from the form screen in Example 1.Fig. 16 shows an XRPD of Form 1 made from a method without using a seeding step accordingto Example 2.Fig. 17 shows a DSC of Form 1 made from a method without using a seeding step accordingto Example 2.Fig. 18 shows form stability of Form 1 of Compound A after 9 months of storage at 30 °C with65% relative humidity (Top line) overlaid with Form 1 (bottom line) and Group B (middle line).Fig. 19 shows a DSC of Group B (made using impurities from the drug substance process andForm 1).Fig. 20 shows a DSC of Form 1 as made according to Example 3c.Fig. 21 shows a PXRD of Form 1 as made according to Example 3c.Fig. 22 shows an overlay of XRPDs of several mixtures of Group B and Form 1 (Top to bottom(50:50, 70:30, 90:10, 95:5 Form 1: Grp B)), second from the bottom pure Group B, bottompure Form 1.Fig. 23 shows an overlay of XRPDs of several mixtures of Group B and Form 1 (Top to bottom(50:50, 70:30, 90:10, 95:5 Form 1: Grp B)), second from the bottom pure Group B, bottompure Form 1 in the range of 4.5 to 9.5 °2θ.Fig. 24 shows an overlay of XRPDs of several mixtures of Group B and Form 1 (Top to bottom(50:50, 70:30, 90:10, 95:5 Form 1: Grp B)), second from the bottom pure Group B, bottompure Form 1 in the range of 19.0 to 24.5 °2θ. DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS The term “treatment” refers to ameliorating or stabilising the specified condition, reducing or eliminating the symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying reoccurrence of the condition in a previously afflicted patient or subject. The term “prevention” refers to avoidance of the stated disease in a subject who is not suffering from the stated disease. The term “therapeutically effective amount” refers to the quantity of a compound of Compound A, or a pharmaceutically acceptable salt thereof, which will elicit the desired biological response in a human body. It may vary depending on the compound, the disease and its severity and the age and weight of the subject to be treated. As used herein, the term “lyophilization,” also known as freeze-drying or cryodesiccation, is a dehydration process which involves freezing the product without destroying the physical structure of the matter. As used herein, the terms "lyophilized" and "freeze-dried" can be used interchangeably herein and refer to a condition and / or state of a sample, formulation, or product obtained by means of lyophilization. As used interchangeably herein, the terms “lyophilized pharmaceuticalcomposition” and “lyophilized composition” refer to a pharmaceutical composition inlyophilized form, as taught herein. As used herein, the term “pharmaceutical composition” means a composition that is suitable for pharmaceutical use. As used herein, "reconstitution" refers to the process of restoring a dried, lyophilized, dehydrated, or concentrated matter to its original or liquid state by adding a solvent to the lyophilized matter, allowing the lyophilized matter to rehydrate, followed by agitating the mixture of the solvent and lyophilized matter. The reconstituted matter may be part of a product, formulation, sample, raw material, or any biological material but is certainly not limited to matter falling under the common definition of these terms. Reconstitution can be assessed visually with the naked eye. The lyophilized matter is deemed reconstituted when a homogeneous suspension is observed. In particular, a suspension with a cloudy appearance is considered suitably reconstituted. As used herein, the term “self-administered” means administration by someone other than a healthcare professional, for example, a patient may administer the pharmaceutical composition to their self or someone else, other than a healthcare professionaladministering the pharmaceutical composition to the patient.As used herein, the term “subject” or “patient” refers to a human. DESCRIPTION OF THE EMBODIMENTS In a first aspect, the present invention provides a crystalline form (Form 1) of CompoundA: Compound A (3R,6S)-12-{[(2,4-difluorophenyl)methyl]carbamoyl}-6-methyl-8,11-dioxo-4-oxa-1,7-diazatricyclo[7.4.0.0³,⁷]trideca-9,12-dien-10-yl octadecenoate is a stearoyl esterprodrug of cabotegravir, also referred to herein as the steric acid ester prodrug of cabotegravir. Cabotegravir (3S,11AR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo [3,2-a] pyrido[1,2-d]pyrazine-8-carboxamide isdescribed in US 8,129,385 in example Z-1, which example is incorporated herein by reference. Cabotegravir is an integrase strand transfer inhibitor (INSTI) that exhibits subnanomolarpotency and antiviral activity against a broad range of HIV-1 strains. Oral administration ofcabotegravir has exhibited acceptable safety and tolerability profiles, a long half-life, and few drug-drug interactions. Cabotegravir has been demonstrated to be efficacious in treatment and prevention of HIV both in oral and parenteral dosage forms, see for instance, Margolis DA, Brinson CC, Eron JJ, et al. 744 and Rilpivirine as Two Drug Oral Maintenance Therapy: LAI116482 (LATTE) Week 48 Results. 21stConference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA, Margolis DA, Podzamczer D, Stellbrink H-J, et al. Cabotegravir + Rilpivirine as Long-Acting Maintenance Therapy: LATTE-2 Week 48 Results, 21stInternational AIDS Conference; July 18-22, 2016; Durban, South Africa, Abstract THAB0206LB. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2016, and Markowitz M, Frank I, Grant R, et al. ÉCLAIR: Phase 2A Safety and PK Study of Cabotegravir LA in HIV-Uninfected Men. Abstract presented at 23rdCROI; February22-25, 2016; Boston, MA. Cabotegravir has been approved by the FDA for long-actingprevention of HIV infection dosed every two months; and in combination with Rilpivirine forlong-acting treatment of HIV infection dosed once a month or once every two months.Cabotegravir is represented by Compound B: (Compound B). Compound A is a stearoyl ester prodrug of cabotegravir which is less soluble thancabotegravir thus providing opportunity for longer dosing intervals.Form 1 is a crystalline form of Compound A. Specifically, Form 1 is the mostthermodynamically stable single component form of Compound A.In an embodiment, crystalline Form 1 of Compound A is characterised by an X-raypowder diffraction (XRPD) pattern substantially in accordance with Fig. 1.An XRPD pattern will be understood to comprise a diffraction angle (expressed indegrees 2 ) of “about” a value specified herein when the XRPD pattern comprises a diffractionangle within 0.3 degrees 2 of the specified value. Further, it is well known and understoodto those skilled in the art that the apparatus employed, humidity, temperature, orientation of the powder crystals, and other parameters involved in obtaining an X-ray powder diffraction (XRPD) pattern may cause some variability in the appearance, intensities, and positions of the lines in the diffraction pattern. An X-ray powder diffraction pattern that is “substantially inaccordance” with that of Fig. 1 provided herein is an XRPD pattern that would be consideredby one skilled in the art to represent a compound possessing the same crystal form as thecompound that provided the XRPD pattern of Fig. 1. That is, the XRPD pattern may beidentical to that of Fig. 1 or more likely it may be somewhat different. Such an XRPD patternmay not necessarily show each of the lines of the diffraction pattern presented herein, and / or may show a slight change in appearance, intensity, or a shift in position of said lines resultingfrom differences in the conditions involved in obtaining the data. A person skilled in the art is capable of determining if a sample of a crystalline compound has the same form as, or adifferent form from, the form disclosed herein by comparison of their XRPD patterns. Forexample, one skilled in the art can overlay an XRPD pattern of a sample of a different form orgroup of Compound A, with Fig. 1 and, using expertise and knowledge in the art, readilydetermine whether the XRPD pattern of the sample is substantially in accordance with theXRPD pattern of Form 1 of Compound A. If the XRPD pattern is substantially in accordancewith Fig. 1, the sample form can be readily and accurately identified as being Form 1 ofCompound A. In an embodiment, Form 1 is characterised by an XRPD pattern exhibiting reflections at 2θ angles when measured using Cu Kα radiation at 1.54 Angstroms. As discussed above, a XRPD pattern of Form 1 is shown in Fig.1. The corresponding reflections and heights are provided in Table 1 below. Table 1 Pos. [°2θ] Height [counts]3.4 121053.26.8 4443.27.4 5438.511.2 1148.615.5 2035.316.7 6175.816.9 5587.917.5 7519.117.9 5006.618.2 6936.618.7 7237.519.2 2033.420.2 1847.620.7 2638.821.1 2489.521.4 3073.721.9 3286.522.2 6338.123.5 3730.324.0 1806.325.7 2332.127.2 1541.131.8 570.934.2 442.3In an embodiment, Form 1 is characterised by an an XRPD pattern exhibiting reflectionsat 2θ angles when measured using Cu Kα radiation at 1.54 Angstroms. An XRPD pattern ofForm 1 is shown in Fig.2. The corresponding reflections and relative intensity heights areprovided in Table 2 below. In an embodiment, crystalline Form 1 of Compound A is characterised by an X-ray powder diffraction (XRPD) pattern substantially in accordance withFig. 2.Table 2 Pos.[°2θ] Rel. Int. [%]3.3698 1006.7315 2.737.4005 6.4710.1169 0.4711.1797 0.8714.4579 0.1114.822 0.4214.8982 0.3915.4631 0.3516.6326 2.2116.8147 2.4217.4803 5.4717.8264 6.4818.1517 4.118.6537 5.118.8051 1.4319.1282 1.0920.1335 1.120.3043 0.8320.6023 1.6620.9643 1.8121.2623 1.8221.861 1.6522.1256 2.7922.3169 0.422.4952 1.5322.7597 0.2523.2415 2.423.4309 2.7123.6784 0.7423.8372 1.2524.0015 1.624.4777 0.8124.7979 1.1625.1382 0.0725.5726 1.6626.0349 0.126.6782 0.1626.9399 0.3827.0625 1.2127.6868 0.1428.0767 0.2428.4944 -0.0628.8843 0.1429.263 0.1129.3605 0.3329.5415 0.0629.7838 0.2530.1221 0.2530.292 -0.0230.8211 0.1630.9659 0.2731.6704 0.1332.1522 0.0332.5263 0.1132.6656 0.0933.5456 0.1434.8225 0.0435.2597 035.6607 0.0936.5713 0.1137.6017 0.0537.7743 0.0538.0055 0.0538.3199 0.0339.1469 0.0939.47 0.0739.729 0.1139.9768 0.0140.5883 0.03In an embodiment, Form 1 is characterised by an XRPD pattern exhibiting reflections at2θ angles of about 6.8, 7.4, 16.7, 16.9, 17.5, 17.9, 18.2, 18.7, 21.9, and 22.2o, whenmeasured using Cu Kα radiation at 1.54 Angstroms. In one embodiment, Form 1 ischaracterised by an XRPD pattern exhibiting reflections at 2θ angles of about 6.8, 7.4, 16.7,16.9, 17.5, 17.9, 18.2, and 18.7 o, when measured using Cu Kα radiation at 1.54 Angstroms.In one embodiment, Form 1 is characterised by an XRPD pattern exhibiting reflections at a 2θangle at about 7.4 o and at least 2, at least 3, or at least 4 of the 2θ angles selected fromabout 6.8, 16.7, 16.9, 17.5, 17.9, 18.2, 18.7, 21.9, and 22.2 o, when measured using Cu Kαradiation at 1.54 Angstroms. The absence of peaks between about 6.75 and 7.25 °2θ and at about 21.6 °2θ mayindicate that undetectable amounts of Group B of Compound A, discussed herein are present. In an embodiment Form 1 is characterised by a 19F solid-state NMR (SSNMR) spectrumsubstantially in accordance with Fig. 8.It is well known and understood to those skilled in the art that the apparatus employed, humidity, temperature, orientation of the powder crystals, and other parameters involved inobtaining an NMR spectrum may cause some variability in the appearance, intensities, andpositions of the peaks in the spectrum. An NMR spectrum that is “substantially in accordance”with that of Fig. 8 provided herein is an NMR spectrum that would be considered by one skilledin the art to represent Form 1 of Compound A. That is, the NMR spectrum may be identicalto that of Fig. 8 or more likely it may be somewhat different. Such an NMR spectrum maynot necessarily show each of the peaks of any one of the spectra presented herein, and / or may show a slight change in appearance, intensity, or a shift in position of said peaks resulting from differences in the conditions involved in obtaining the data. A person skilled in the art is capable of determining if a sample of a crystalline compound has the same form as, or adifferent form from, the form disclosed herein by comparison of their NMR spectra. Forexample, one skilled in the art can overlay a Raman spectrum of a different form or group ofCompound A with Fig. 8 and, using expertise and knowledge in the art, readily determinewhether the NMR spectrum of the sample is substantially in accordance with the NMRspectrum of Form 1 of Compound A. If the NMR spectrum is substantially in accordance withFig. 8, the sample form can be readily and accurately identified as having Form 1 of CompoundA. In an embodiment, Form 1 is characterised by a differential scanning calorimetry (DSC)spectrum substantially in accordance with Fig. 4. In an embodiment, the DSC thermogram ofForm 1 of Compound A exhibits a single endotherm, with an onset temperature of about 121 °C. In an embodiment, the DSC thermogram of Form 1 of Compound A exhibits a single endotherm, with an onset temperature of 121 °C. In an embodiment, the DSC thermogramof Form 1 of Compound A does not exhibit a broad peak at about 40 to about 80 °C. In an embodiment, the DSC thermogram of Form 1 of Compound A does not exhibit a broad peakat 40 to 80 °C. In an embodiment, the DSC thermogram of Form 1 of Compound A does notexhibit an endotherm at about 40 to about 80 °C. In an embodiment, the DSC thermogram of Form 1 of Compound A does not exhibit an endotherm at 40 to 80 °C. In an embodiment, Form 1 of Compound A is characterized by a DSC spectrum with asingle endotherm with an onset temperature of about 121oC. In a further embodiment, Form 1 of Compound A is characterized by a differentialscanning calorimetry trace substantially in accordance with Fig. 4 and / or a thermogravimetricanalysis trace substantially in accordance with Fig. 5. In an embodiment, Form 1 is characterized by a Raman spectrum substantially inaccordance with Fig. 3.A Raman spectrum will be understood to comprise a peak (expressed in cm-1) of “about” a value specified herein when the Raman spectrum comprises a peak within 5.0 cm-1of the specified value. Further, it is also well known and understood to those skilled in the art that the apparatus employed, humidity, temperature, orientation of the powder crystals, and other parameters involved in obtaining a Raman spectrum may cause some variability in the appearance, intensities, and positions of the peaks in the spectrum. A Raman spectrumthat is “substantially in accordance” with that of Fig. 3 provided herein is a Raman spectrumthat would be considered by one skilled in the art to represent a compound possessing thesame crystal form as the compound that provided the Raman spectrum of Fig. 3 i.e. Form 1of Compound A. That is, the Raman spectrum may be identical to that of Fig. 3 or more likelyit may be somewhat different. Such a Raman spectrum may not necessarily show each of the peaks of any one of the spectra presented herein, and / or may show a slight change in appearance, intensity, or a shift in position of said peaks resulting from differences in theconditions involved in obtaining the data. A person skilled in the art is capable of determiningif a sample of a crystalline compound has the same form as, or a different form from, a form disclosed herein by comparison of their Raman spectra. In an embodiment, Compound A is characterized by a Raman spectrum comprising atleast 3 peaks at positions selected from a group consisting of peaks at 1820 to 1720 cm-1, 670to 570 cm cm-1, and 270 to 200 cm-1. In still further embodiments, as a person having ordinary skill in the art will understand, Form 1 of Compound A is characterized by any combination of the analytical datacharacterizing the aforementioned embodiments. For example, in one embodiment, Form 1of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern substantiallyin accordance with Fig. 1 and a DSC spectrum substantially in accordance with Fig. 4. In oneembodiment, Form 1 of Compound A is characterized by an XRPD pattern substantially in accordance with Fig. 2 and a DSC spectrum substantially in accordance with Fig 4. In an embodiment, Form 1 of Compound A is characterized by an XRPD pattern exhibiting reflections at 2θ angles of about 7.4owhen measured using Cu Kα radiation at 1.54Angstroms and a DSC spectrum with a single endotherm with an onset temperature of about121oC. In an embodiment, A is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Fig. 1, a Ramen pattern substantially in accordance with Fig.3, a differential scanning calorimetry trace substantially in accordance with Fig. 4 and athermogravimetric analysis trace substantially in accordance with Fig. 5 and a 19F SSNMRspectrum substantially in accordance with Fig. 8. In another embodiment, Form 1 ofCompound A is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Fig. 1 and a Raman spectrum substantially in accordance with Fig. 3. In another embodiment, Form 1 of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Fig. 1 and a differential scanning calorimetry trace substantially in accordance with Fig. 4. In another embodiment, Form 1 of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Fig. 1 and a thermogravimetric analysis trace substantially in accordance with Fig. 5. The inventors have found that Form 1 is the most thermodynamically stable singlecomponent crystalline form of Compound A. Form 1 is a single component solid state form that displays ideal physical attributes for manufacturability. Solid forms of Compound A disclosed in the art are believed to be mixtures ofmulticomponent forms. Specifically, the XRPD pattern of such solid forms show high amountsof Group B (shown in Fig. 6 and described in Example 1). Having mixtures of groups or formscould impact pharmacokinetics and / or bioavailability of suspensions, due to potential solubilitydifference of different solid-state forms. The present inventors have now prepared Form 1 inat least 90% polymorphic purity. In an embodiment, Form 1 of Compound A is in at least 90% polymorphic purity. In an embodiment, Form 1 of Compound A is in at least 95% polymorphic purity. In an embodiment, Form 1 of Compound A is in at least 97% polymorphic In an embodiment, Form 1 of Compound A is in at least 99% polymorphic purity. Pharmaceutical Compositions In a second aspect, the present invention provides a pharmaceutical compositioncomprising Form 1 of Compound A as described herein. In an embodiment, the pharmaceutical composition comprises Form 1 in at least 90% polymorphic purity. In an embodiment, Form 1 of Compound A is in at least 90% polymorphicpurity. In an embodiment, Form 1 of Compound A is in at least 95% polymorphic purity .In an embodiment, the pharmaceutical compositions of the present invention compriseparticles of crystalline Compound A. In an embodiment, Compound A particles of the pharmaceutical composition have amass median size (X50) value greater than or equal to 1 μm and less than or equal to 15 μm(i.e., 1 μm ≤ X50 ≤ 15 μm). Particle size distribution may be measured by any suitable method, for example, by laser diffraction as described in the Examples section herein. In an embodiment, Compound A is present in the composition as Form 1 i.e. the mostthermodynamically stable single component form of Compound A. Form 1 is as describedherein. In an embodiment, Compound A is present at a concentration of 100 to 600 mg / mL. In a further embodiment, the pharmaceutical composition contains about 200 mg / mL to about 400 mg / mL of Compound A. In a further embodiment, the composition comprises,about 200 mg / mL, about 300 mg / mL, or about 400 mg / mL of Compound A.In another embodiment, the pharmaceutical composition contains Compound A in an amount between about 600 mg to about 1800 mg. Wetting agents or surfactants are compounds that, when dissolved in a liquid, can reduce the surface tension of a gas, liquid, or solid surface in that liquid. They are often amphiphilic and may aid in wetting and enhance manufacturability of the drug product. In addition, a surfactant may additionally impart long-term product stability by steric or electrostatic repulsion. Non-ionic surfactants are preferred over ionic surfactants as they aregenerally non-toxic, non-irritating, and inert. Examples of surfactants which could be used inthe pharmaceutical composition include, but are not limited to, polysorbate 20 (Tween-20),polysorbate 80 (Tween-80), sorbitan monolaurate (Span-20), sorbitan monooleate (Span-80), poloxamer 188 (Kolliphor P188), poloxamer 338 (Kolliphor P338), and poloxamer 407 (Kolliphor P407). Pharmaceutical compositions of the invention comprise a poloxamer as a wetting agent. Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide) flanked by two hydrophilic chains of polyoxyethylene (polyethylene glycol). Poloxamers are represented by Formula II. Poloxamers are also known by the trade names Synperonics, Pluronics, and Kolliphor. Poloxamers are commonly named with the letter "P" followed by three digits, the first two digits x 100 give the approximate molecular mass of the polyoxypropylene core, and the last digit x 10 gives the percentage polyoxyethylene content (e.g., P407 = Poloxamer with a polyoxypropylene molecular mass of 4,000 g / mol and a 70% polyoxyethylene content). In an embodiment of the present invention, the poloxamer may be P188, P338 or P407. P188, P338 and P407 are commercially available. In an embodiment of the invention, the poloxamer is P338. Without wishing to be bound by theory, it is thought that poloxamer may play a role in limiting form conversion in the pharmaceutical composition. Further, the present inventors have found that using poloxamer in the pharmaceutical composition of the present invention, compared to other surfactants or wetting agents. In an embodiment, the pharmaceutical composition contains from about 5 mg / mL toabout 15 mg / mL of the poloxamer. In a further embodiment, the pharmaceutical compositioncontains from about 10mg / mL to about 15 mg / mL of the poloxamer. In an embodiment the pharmaceutical composition contains from about 1 to 5 % w / vof the poloxamer. In an embodiment, the pharmaceutical composition contains about 1 to 2%w / v of the poloxamer. In an embodiment, a weight ratio of the poloxamer to Compound A is in a range of from 1:10 to 1:50. In another embodiment, the weight ratio of the poloxamer to Compound A is in a range of from 1:10 to 1:40. In another embodiment, the weight ratio of the poloxamer to Compound A is in a range of from 1:25 to 1:35. In another embodiment, the weight ratio of the poloxamer to Compound A is about 1:30. In an embodiment, the pharmaceutical composition further comprises a stabilizer and a tonicity adjuster. Stabilizers are components added to help preserve critical product attributes throughout shelf life. In the case of suspensions, stabilizers can be used to induce charge effects, add steric stabilization, increase viscosity of the vehicle, etc. These factors can preserve particle size, product resuspendability, and / or improve manufacturability. Examples of stabilizers include, but are not limited to, sodium carboxymethylcellulose (CMC), polyethylene glycol 3350, polyethylene glycol 4000, and polyvinylpyrrolidone (PVP) (e.g.,povidone K12 (PVP K12) and povidone K17 (PVP K17)).In an embodiment, the pharmaceutical composition of the invention comprises sodiumCMC (NaCMC) or polyvinylpyrrolidone (PVP) as the stabilizer. In an embodiment, thepharmaceutical composition of the invention comprises sodium CMC as the stabilizer. In another embodiment, the pharmaceutical composition of the invention comprises polyvinylpyrrolidone (PVP) as the stabiliser. In an embodiment the PVP is PVP K12. The present inventors have found that PVP and NaCMC, in comparison to other stabilisers (for example polyethylene glycol (PEG)), lower viscosity of the composition allowing for effective reconstitution / resuspension. The present inventors have also found that PVP, in comparison to NaCMC, lowers viscosity of the composition allowing for effective reconstitution / resuspension. In an embodiment, the pharmaceutical composition contains about 1 mg / mL to about30 mg / mL of the stabilizer. In a further embodiment, the pharmaceutical composition containsabout 1 mg / mL to about 25 mg / mL, from about 2 mg / mL to about 15 mg / mL, or from about 5 mg / mL to about 15 mg / mL of the stabilizer. In an embodiment, the pharmaceuticalcomposition contains about 5 mg / mL of the stabilizer. In an embodiment, the pharmaceuticalcomposition contains about 10 mg / mL of the stabilizer. In an embodiment, the pharmaceuticalcomposition contains about 15 mg / mL of the stabilizer. In an embodiment, the pharmaceuticalcomposition contains about 20 mg / mL of the stabilizer.In an embodiment the pharmaceutical composition contains from about 0.1 to 5 %w / v of the stabilizer. In an embodiment, the pharmaceutical composition contains about 0.1to 2% w / v of the stabilizer. In an embodiment, the stabilizer is NaCMC and the pharmaceutical composition comprises about 0.5 % w / v of NaCMC. In another embodiment, the stabilizer is PVP and the pharmaceutical composition comprises about 1.5 % w / v of PVP. In anotherembodiment, the stabilizer is PVP K12 and the pharmaceutical composition comprises about1.5 % w / v of PVP K12.In an embodiment, a weight ratio of the stabilizer to Compound A is in a range of from 1:5 to 1:100. In another embodiment, the weight ratio of the stabilizer to Compound A is in a range of from 1:10 to 1:80. In an embodiment, the stabiliser is PVP and the weight ratio of the stabilizer to Compound A is in a range of 1:5 to 1:40. In another embodiment, the stabiliser is PVP and the weight ratio of the stabilizer to Compound A is in a range of 1:10 to 1:30. In an embodiment, the stabiliser is PVP and the weight ratio of the stabilizer to Compound A is about 1:15 to 1:25. In an embodiment, the stabiliser is PVP and the weight ratio of the stabilizer to Compound A is about 1:20. In an embodiment, the stabiliser is PVP K12 and the weight ratio of the stabilizer toCompound A is in a range of 1:5 to 1:40. In another embodiment, the stabiliser is PVP K12 and the weight ratio of the stabilizer to Compound A is in a range of 1:10 to 1:30. In anembodiment, the stabiliser is PVP K12 and the weight ratio of the stabilizer to Compound A isabout 1:15 to 1:25. In an embodiment, the stabiliser is PVP K12 and the weight ratio of the stabilizer to Compound A is about 1:20. In an embodiment, the stabiliser is NaCMC and the weight ratio of the stabilizer to Compound A is in a range of 1:40 to 1:80. In another embodiment, the stabiliser is NaCMCand the weight ratio of the stabilizer to Compound A is in a range of 1:50 to 1:70. In anembodiment, the stabiliser is NaCMC and the weight ratio of the stabilizer to Compound A is about 1:60. Tonicity adjusters act to provide and maintain a stable tonicity for the pharmaceuticalcomposition disclosed herein. In some embodiments, tonicity adjusters also function as a non- aqueous solvent, a solubilizer, and / or a stabilizer. In such instances, tonicity adjusters may be used at concentrations higher than needed for tonicity if their primary purpose is stabilizationor may be used at concentrations higher than needed for stabilization if their primary purposeis tonicity adjustment. In some embodiments, the tonicity adjuster is a pharmaceutically acceptable inorganicchloride, e.g., potassium chloride, sodium chloride, magnesium chloride or calcium chloride.In yet other embodiments, the tonicity adjuster is a saccharide such as mannitol, sorbitol,lactose, trehalose, raffinose, dextrose, maltose, galactose, sucrose, or polysucrose. In stillfurther aspects, the tonicity adjuster is mannitol. In other aspects, the tonicity adjuster is anon-aqueous polar aprotic or protic materials such as polyethylene glycol, N,N- dimethylacetamide, N-methyl pyrrolidone, glycerol, propylene glycol, ethanol, t-butyl alcohol, benzyl alcohol, benzyl benzoate, dimethyl sulfoxide, or glycerol. In further aspects, the tonicityadjuster is a polymer such as polyethylene glycol (PEG) (for example, PEG 300, PEG 400, PEG3350, PEG 6000, or PEG 8000), polygalacturonic acid, galacturonic acid, or polyvinylpyrrolidine(PVP). In still other aspects, the tonicity adjuster is an amino acid such as lysine, arginine,glycine, methionine, or other amino acids. In yet further aspects, the tonicity adjuster is acyclodextrin such as dextran, Ficoll, or polyvinylpyrrolidone, or other similar excipients andcombinations of these agents. In an embodiment, the pharmaceutical composition of the invention comprises mannitol as the tonicity adjuster. In an embodiment, the pharmaceutical composition contains about 0.1 mg / mL toabout 250 mg / mL of the tonicity adjuster. In a further embodiment, the pharmaceuticalcomposition contains about 10 mg / mL to about 50 mg / mL, from about 25 mg / mL to about 50mg / mL, from about 30 mg / mL to about 45 mg / mL of the tonicity adjuster. In an embodiment,the pharmaceutical composition contains about 35 mg / mL of the tonicity adjuster. In an embodiment the pharmaceutical composition contains from about 0.1 to 5 %w / v of the tonicity adjuster. In an embodiment, the pharmaceutical composition containsabout 2 to 4 % w / v of the tonicity adjuster. In an embodiment, the pharmaceuticalcomposition contains about 3.5 % w / v of the tonicity adjuster. In an embodiment, a weight ratio of the tonicity adjuster to Compound A is in a rangeof from 1:5 to 1:50. In another embodiment, the weight ratio of the tonicity adjuster toCompound A is in a range of from 1:5 to 1:35. In another embodiment, the weight ratio ofthe tonicity adjuster to Compound A is in a range of from 1:5 to 1:25. In another embodiment,the weight ratio of the tonicity adjuster to Compound A is in a range of from 1:5 to 1:10. Inanother embodiment, the weight ratio of the tonicity adjuster to cabotegravir is in a range offrom 1:5 to 1:12. In another embodiment, the weight ratio of the tonicity adjuster toCompound A is about 1:9. In another embodiment, the weight ratio of the tonicity adjuster toCompound A is about 1:8.5.Dissolution properties of the pharmaceutical composition are affected, inter alia, by particle size and particle size distribution of the active pharmaceutical ingredient (i.e., Compound A). In an embodiment, the pharmaceutical composition has a particle size distribution byvolume such that 50% of the Compound A particles have a particle size less than or equal to10 μm (i.e. mass median size, or X50, is 10 μm). In an embodiment, Compound A particleshave an X50 value greater than or equal to 3 μm and less than or equal to 8.5 μm (i.e., 3 μm≤ X50 ≤ 8.5 μm). In an embodiment, Compound A particles have a mass median size (X50)of between (and including) 3 μm and 6 μm. In an embodiment, Compound A particles have amass median size (X50) of between (and including) 3 μm and 5 μm.In an embodiment, the pharmaceutical composition has a mass median size (X50) of3.0 μm, 3.1 μm, 3.2 μm, 3.3 μm, 3.4 μm, 3.5 μm, 3.6 μm, 3.7 μm, 3.8 μm, 3.9 μm, 4.0 μm, 4.1 μm, 4.2 μm, 4.3 μm, 4.4 μm, 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm or 5.0 μm. In anembodiment, the pharmaceutical composition has a mass median size (X50) of about 3 μm.In an embodiment, the pharmaceutical composition has a mass median size (X50) of about 4μm. In an embodiment, the pharmaceutical composition has a mass median size (X50) ofabout 5 μm. In an embodiment, the pharmaceutical composition has a particle size distribution byvolume such that 90% of the Compound A particles have a particle size less than or equal to25 μm (i.e., X90 is 25 μm). In an embodiment, Compound A particles of the pharmaceutical composition have an X90 value greater than or equal to 5 μm and less than or equal to 25 μm (i.e., 5 μm ≤ X90 ≤ 25 μm). In an embodiment, the pharmaceutical composition has a particle size distribution by volume such that 90% of the Compound A particles have a particlesize less than or equal to 20 μm (i.e., X90 is 20 μm). In an embodiment, Compound A particlesof the pharmaceutical composition have an X90 value greater than or equal to 8 μm and less than or equal to 13 μm (i.e., 8 μm ≤ X90 ≤ 13 μm). In an embodiment, the pharmaceutical composition has a particle size distribution byvolume such that 90% of the Compound A particles (X90) have a particle size smaller than orequal to 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 7.6 μm, 7.7 μm, 7.8 μm, 7.9 μm, 8.0 μm, 8.1 μm, 8.2 μm, 8.3 μm, 8.4 μm, 8.5 μm, 8.6 μm, 8.7 μm, 8.8 μm, 8.9 μm, 9.0 μm, 9.1 μm, 9.2 μm, 9.3 μm, 9.4 μm, 9.5 μm, 9.6 μm, 9.7 μm, 9.8 μm, 9.9 μm, 10.0 μm, 10.1 μm, 10.2 μm, 10.3 μm, 10.4 μm, 10.5 μm, 10.6 μm, 10.7 μm, 10.8 μm, 10.9 μm, 11.0 μm, 11.1 μm, 11.2 μm, 11.3 μm, 11.4 μm, 11.5 μm, 11.6 μm, 11.7 μm, 11.8 μm, 11.9 μm, 12.0 μm, 12.1 μm, 12.2 μm, 12.3 μm, 12.4 μm, 12.5 μm, 12.6 μm, 12.7 μm, 12.8 μm, 12.9 μm, 13.0 μm, 13.1 μm, 13.2 μm, 13.3 μm, 13.4 μm, 13.5 μm, 13.6 μm, 13.7 μm, 13.8 μm, 13.9 μm or 14.0 μm. In another embodiment, the pharmaceutical composition has a particle sizedistribution by volume such that 90% of the Compound A particles (X90) have a particle sizesmaller than or equal to 9 μm (i.e., X90 is 9 μm). In another embodiment, the pharmaceutical composition has a particle size distribution by volume such that 90% of the Compound Aparticles (X90) have a particle size smaller than or equal to 9.5 μm (i.e., X90 is 9.5 μm). Inanother embodiment, the pharmaceutical composition has a particle size distribution byvolume such that 90% of the Compound A particles (X90) have a particle size smaller than orequal to 11 μm (i.e., X90 is 11 μm). In an embodiment, the pharmaceutical composition has a particle size distribution byvolume such that 10% of the Compound A particles have a particle size smaller than or equalto 4 μm (i.e., X10 is 4 μm). In an embodiment, Compound A particles of the pharmaceutical composition have an X10 value greater than or equal to 0.5 μm and less than or equal to 4 μm (i.e., 0.5 μm ≤ X10 ≤ 4 μm). In an embodiment, the pharmaceutical composition has a particle size distribution by volume such that 10% of the Compound A particles have a particlesize less than or equal to 3.5 μm. In an embodiment, Compound A particles of the pharmaceutical composition have an X10 value greater than or equal to 1 μm and less than or equal to 3.5 μm (i.e., 1 μm ≤ X10 ≤ 3.5 μm). In an embodiment, the pharmaceutical composition has a particle size distribution by volume such that 10% of the Compound Aparticles have a particle size less than or equal to 3 μm. In an embodiment, Compound Aparticles of the pharmaceutical composition have an X10 value greater than or equal to 1.5 μm and less than or equal to 3 μm (i.e., 1.5 μm ≤ X10 ≤ 3 μm). In an embodiment, the pharmaceutical composition has a particle size distribution byvolume such that 10% of the Compound A particles (X10) have a particle size smaller than orequal to 1.0 μm, 1.1 μm, 1.2 μm, 1.3 μm, 1.4 μm, 1.5 μm, 1.6 μm, 1.7 μm, 1.8 μm, 1.9 μm, 2.0 μm, 2.1 μm, 2.2 μm, 2.3 μm, 2.4 μm, 2.5 μm, 2.6 μm, 2.7 μm, 2.8 μm, 2.9 μm, 3.0 μm, 3.1 μm, 3.2 μm, 3.3 μm, 3.4 μm, 3.5 μm, 3.6 μm, 3.7 μm, 3.8 μm, 3.9 μm, or 4.0 μm. In another embodiment, the pharmaceutical composition has a particle size distribution byvolume such that 10% of the Compound A particles (X10) have a particle size smaller than orequal to 1.7 μm (i.e., X10 is 1.7 μm). In another embodiment, the pharmaceutical composition has a particle size distribution by volume such that 10% of the Compound A particles (X10)have a particle size smaller than or equal to 2.2 μm (i.e., X10 is 2.2 μm).The value X90 refers to the 90% value of the volume distribution measured using a laser diffractometer. For purposes of the present disclosure, the X90 value denotes the particle size below which 90% of the quantity of particles is found based on the volume distribution. Analogously, the value X50 refers to the 50% value (median) of the volume distribution measured using a laser diffractometer. For purposes of the present disclosure,the X50 value denotes the particle size below which 50% of the quantity of particles is foundbased on the volume distribution. Analogously, the value X10 refers to the 10% value of the volume distribution measured using a laser diffractometer. For purposes of the present disclosure, the X10 value denotes the particle size below which 10% of the quantity of particles is found based on the volume distribution. In an embodiment, all X90, X50, and X10 values described herein are by volume and determined by laser diffraction method. The laser diffraction method is sensitive to the volume of a particle and provides a volume-average particle size, which is equivalent to the weight- average particle size if the density is constant. It will be apparent to those skilled in the art that the results of the particle size distribution determination by one technique can be correlated with that from another technique, for example on an empirical basis by routine experimentation. Alternatively, particle size distribution can be determined by microscopy, in particular electron microscopy or scanning electron microscopy. The inventors have found that lyophilized pharmaceutical compositions of Compound A with particle size sizes in the microns achieve an extended long-acting profile compared to other formulations, for example compositions of smaller particle sizes and which are not lyophilized. Lyophilized compositions of the invention have been shown to have greater Cmaxand longer half-life. Further, the inventors have found that lyophilized compositions, compared to, for example, compositions that have been wet bead milled, limit form conversion from Form 1 of Compound A. Lyophilization comprises at least a freezing step and a sublimation step. Lyophilization may be used in the manufacturing of pharmaceutical products and intermediates thereof. During freezing, the material is cooled to a temperature wherein the solid, liquid, and gasphases of the material may exist. Active pharmaceutical product ingredients (APIs) may belyophilized to achieve chemical and physical stability allowing room temperature storage. Thisis different from a conventional method that evaporates water using heat. Advantages of lyophilization may include, but are not limited to, enhanced stability of a dry powder, the removal of water without excessive heating of the product, and enhanced product stability in a dry state. In an exemplary method of preparing a lyophilized formulation of the invention, micronized Compound A is packaged in antistatic linear low-density polyethylene bags. The packaged Compound A is enclosed in a corrugated plastic box and gamma irradiated as a bioburden reduction step and referred to as gamma irradiated Compound A. Gamma irradiated Compound A is dispersed in a filtered aqueous vehicle comprising a stabilizer (e.g., PVP or sodium CMC), a tonicity agent (e.g., mannitol), and a wetting agent (e.g., Poloxamer e.g. Poloxamer 338). The resulting suspension is homogenized, filled into washed, sterilized / depyrogenated 10 mL Type I clear glass vials. Container materials are then processed: vials are depyrogenated by dry heat, and stoppers and overseals are sterilized by steam. Product vials are lyophilized, backflushed with nitrogen, sealed with halobutyl rubber stoppers and secured by an aluminum overseal. The sealed vials are terminally sterilized by gamma irradiation. As evidenced in the examples, which illustrate certain representative embodiments of the invention, the inventors have developed lyophilized pharmaceutical compositions and methods to obtain said compositions that allow for larger-size particles of Compound A. Data provided herein indicate that such lyophilized pharmaceutical compositions contribute to improved pharmacokinetic properties, thus addressing one or more above-mentioned problems in the art. In an embodiment, the lyophilized pharmaceutical composition is a suspension. The lyophilized pharmaceutical composition advantageously suspends when reconstituted in an aqueous or non-aqueous solution, that is, all or substantially all, such as at least 90 percent, at least 95 percent, at least 96 percent, at least 97 percent, at least 98 percent, at least 99percent, at least 99.5 percent or 100 percent of the lyophilized pharmaceutical composition issuspended when reconstituted. Reconstitution can be assessed visually with the naked eye. The lyophilized matter isdeemed reconstituted when a homogeneous suspension is observed. In particular, asuspension with a cloudy appearance is considered suitably reconstituted.It will be apparent to those skilled in the art that pharmaceutical compositions of the invention may be reconstituted in an aqueous or non-aqueous solution to a desired concentration. For example, the pharmaceutical composition described below in Example 2may be reconstituted in 1.1 mL water for injection (WFI) to achieve a Compound Aconcentration of 400 mg / mL. Similarly, the same pharmaceutical composition described belowin Example 2 may be reconstituted in 1.7 mL WFI to achieve a Compound A concentration of300 mg / mL.In an embodiment, the present disclosure provides a lyophilized pharmaceutical composition comprising Compound A, wherein Compound A is present in the form of particleshaving a mass median size (X50) of between (and including) 1.5 μm and 15 μm; a poloxamer;a stabilizer; and a tonicity adjuster; wherein the formulation, when reconstituted in an aqueous solution, has a reconstitution time of 15 minutes or less, 10 minutes or less, or 5minutes or less.In another embodiment, the present disclosure provides a lyophilized pharmaceutical composition comprising Compound A, wherein Compound A is present in the form of particleshaving a mass median size (X50) of between (and including) 1.5 μm and 15 μm; poloxamer;sodium CMC; and mannitol; wherein the formulation, when reconstituted in an aqueous or non-aqueous solution, has a reconstitution time of 15 minutes or less, 10 minutes or less, or5 minutes or less.In another embodiment, the present disclosure provides a lyophilized pharmaceutical composition comprising Compound A, wherein Compound A is present in the form of particleshaving a mass median size (X50) of between (and including) 1.5 μm and 15 μm; poloxamer;PVP; and mannitol; wherein the formulation, when reconstituted in an aqueous or non- aqueous solution, has a reconstitution time of 15 minutes or less, 10 minutes or less, or 5 minutes or less. In an embodiment, Compound A is present in the pharmaceutical composition as crystalline Form 1 of Compound A. Pharmaceutical compositions of the present invention surprisingly prevent form conversion of Form 1 to other forms. Form landscape studies for Compound A identified Form 1 as the mostthermodynamically stable single component polymorphic form in the solid state. The drugsubstance has been shown to convert to Group B (shown in Fig. 6), and multicomponentGroup E (shown in Fig. 7) of Compound A which can form through multiple avenues includingin the presence of formulation excipients (for example, if polysorbates are used instead of poloxamers) as well as aliphatic impurities. Development work conducted using wet bead milling process resulted in in-situ formconversion of drug substance from stable single component Form 1 to Group B, with estimated form conversion of approximately 90% conversion if uncontrolled. Selection of: (i) poloxamers in comparison to other wetting agents, for examplepolysorbates; (ii) drug substance particle size; and (iii) lyophilization, which due to resultant solid cake prevents further form change risk during shelf life of the product in comparison to a nano-suspension dosage form wherein significantly higher form conversion happens duringmanufacturing and on shelf life, have all been found to be important in arresting formconversion of Compound A. The pharmaceutical compositions disclosed herein limit polymorphic form conversion of the drug substance in the formulation and therefore offer enhanced control over solid state form in the drug product, with form conversion estimated to be less than 10%. ^ In an embodiment, the pharmaceutical composition comprises Form 1 of CompoundA, P338, NaCMC. In another embodiment, the pharmaceutical composition comprises Form 1of Compound A, P338 and PVP. In another embodiment, the pharmaceutical compositioncomprises Form 1 of Compound A, P338 and PVP K12.In an embodiment, the pharmaceutical composition comprises Form 1 of CompoundA, P338, NaCMC, and mannitol; and Form 1 of Compound A is present in the form of particleshaving a mass median size (X50) of between (and including) 1.5 μm and 15 μm. In thisembodiment the pharmaceutical composition may comprise Form 1 of Compound A in anamount of 30 % w / v, mannitol in an amount of 3.5 % w / v, P338 in an amount of 1 % w / v,and NaCMC in an amount of 0.5 % w / v.In another embodiment, the pharmaceutical composition comprises Form 1 ofCompound A, P338, PVP, and mannitol; and Form 1 of Compound A is present in the form ofparticles having a mass median size (X50) of between (and including) 1.5 μm and 15 μm. Inthis embodiment the pharmaceutical formulation may comprise Form 1 of Compound A in anamount of 30 % w / v, mannitol in an amount of 3.5% w / v, P338 in an amount of 1% w / v,and PVP in an amount of 1.5 % w / v.In another embodiment, the pharmaceutical composition comprises Form 1 ofCompound A, P338, PVP K12, and mannitol; and Form 1 of Compound A is present in the formof particles having a mass median size (X50) of between (and including) 1.5 μm and 15 μm.In this embodiment the pharmaceutical formulation may comprise Form 1 of Compound A inan amount of 30 % w / v, mannitol in an amount of 3.5% w / v, P338 in an amount of 1% w / v,and PVP K12 in an amount of 1.5 % w / v.In an embodiment, the pharmaceutical composition comprises Form 1 of CompoundA, P338, NaCMC, and mannitol; and Form 1 of Compound A is present in the form of particleshaving a mass median size (X50) of between (and including) 1.5 μm and 15 μm. In thisembodiment mannitol is present at a weight ratio of mannitol to Form 1 of Compound A ofabout 1:8.5; P338 is present at a weight ratio of P338 to Form 1 of Compound A of about1:30; and NaCMC is present at a weight ratio of NaCMC to Form 1 of Compound A of about1:60. In another embodiment, the pharmaceutical composition comprises Form 1 ofCompound A, P338, PVP, and mannitol; and Form 1 of Compound A is present in the form ofparticles having a mass median size (X50) of between (and including) 1.5 μm and 15 μm. Inthis embodiment mannitol is present at a weight ratio of mannitol to Form 1 of Compound Aof about 1:8.5; P338 is present at a weight ratio of P338 to Form 1 of Compound A of about1:30; and PVP is present at a weight ratio of PVP to Form 1 of Compound A of about 1:20.In another embodiment, the pharmaceutical composition comprises Form 1 ofCompound A, P338, PVP K12, and mannitol; and Form 1 of Compound A is present in the formof particles having a mass median size (X50) of between (and including) 1.5 μm and 15 μm.In this embodiment mannitol is present at a weight ratio of mannitol to Form 1 of Compound A of about 1:8.5; P338 is present at a weight ratio of P338 to Form 1 of Compound A of about1:30; and PVP K12 is present at a weight ratio of PVP to Form 1 of Compound A of about1:20. In another embodiment, the pharmaceutical composition comprises Compound A, poloxamer P338, PVP, and mannitol; and Compound A is present in the form of particleshaving a mass median size (X50) of between (and including) 2 μm and 5 μm.In another embodiment, the pharmaceutical composition comprises Compound A, poloxamer P338, PVP, and mannitol; and Compound A is present in the form of particleshaving a mass median size (X50) of between (and including) 3 μm and 5 μm. In another embodiment, the pharmaceutical composition comprises Compound A,poloxamer P338, PVP, and mannitol and has the weight ratios (either pre-or post-reconstitution) as shown in table 1aa and 1ab. In an embodiment, the pharmaceutical composition may further comprise a buffer solution In an embodiment the buffer solution has the ratios shown in table 1ac: Table 1aa Ingredient Ratio to compound ACompound A Poloxamer 338 1:25 to 1:35PVP K12 1:15 to 1:25Mannitol 1:5 to 1:12Table 1ab Ingredient Ratio to compound A Ratio to compound ACompound A Poloxamer 338 1:30 1:30PVP K12 1:20 1:20Mannitol 1:8.5 1:11.5Table 1ac Ingredient Ratio to compound A Ratio to Compound ACompound A Citric acid1:400 1:350-450monohydrate Sodium citrate1:171.4 1:100-200dihydrate In another embodiment, the pharmaceutical composition, before lyophilisation and reconstitution, is as described in Tables 1a to 1e. In this embodiment, weights of each component are measured as mg / mL in a pre-lyophilised slurry: Table 1a Ingredient Concentration (mg / mL)Compound A 100 to 600 (X50 = 3 to 6 μm and X90 = 7 to 14 μm)Poloxamer 338 5 to 15PVP K12 5 to 20Mannitol 30 to 45Table 1b Ingredient Concentration (mg / mL)Compound A 100 to 600 (X50 = 3 to 6 μm and X90 = 7 to 14 μm)Poloxamer 338 5 to 15NaCMC 2 to 10Mannitol 30 to 45Table 1c Ingredient Concentration (mg / mL)Compound A 300 (X50 = 3 to 6 μm and X90 = 7 to 14 μm)Poloxamer 338 10PVP K12 15Mannitol 35Table 1d Ingredient Concentration (mg / mL)Compound A 300 (X50 = 3 to 6 μm and X90 = 7 to 14 μm)Poloxamer 338 10NaCMC 5Mannitol 35Table 1e Ingredient Concentration (mg / mL)Compound A, 400.0 PVPK12 20.0Poloxamer 338 13.3Mannitol 35.0In an embodiment, the pharmaceutical composition, after reconstitution, is asdescribed in Tables 1f, 1g, 1h and 1i wherein Compound A is present as Form 1 ofCompound A: Table 1fIngredient Concentration (mg / ml)Compound A, micronized 300.0 (X50 = 3 to 5 μm and X90= 7 to 14 μm)PVP K12 15.0Poloxamer 338 10.0Mannitol 35.0Table 1gIngredient Concentration (mg / mL)Compound A, micronized 350.0 (X50 = 3 to 5 μm and X90= 7 to 14 μm)PVP K12 17.5Poloxamer 338 11.7Mannitol 40.8Table 1hIngredient Concentration (mg / mL)Compound A, micronized 400.0 (X50 = 3 to 5 μm and X90= 7 to 14 μm)PVP K12 20Poloxamer 338 13.3Mannitol 46.7Table 1iIngredient Concentration (mg / mL)Compound A, micronized 450.0 (X50 = 3 to 6 μm and X90 = 7 to14 μm)PVP K12 22.5Poloxamer 338 15.0Mannitol 52.5In an embodiment the pharmaceutical composition of the invention has a pH of about 4 or greater. A pH of about 4 or more reduces pain to the patient if the composition is administered via injection. In an embodiment, the pharmaceutical composition of the invention has a pH of between 4 and 5. In an embodiment, the pharmaceutical composition of the invention comprises a buffer. As used herein, the term "buffer" means a bufferedsolution that resists changes in pH by the action of its acid- base conjugate components. Thebuffer may be any suitable buffer. In an embodiment, the buffer is an acetate buffer. In anembodiment the acetate buffer is an acetate buffer solution comprising sodium acetatetrihydrate and acetic acid or glacial acetic acid. In another embodiment the buffer is a citrate buffer. In an embodiment the citrate buffer is a citrate buffer solution comprising citric acidmonohydrate and sodium citrate or trisodium citrate dihydrate. In an embodiment thepharmaceutical composition comprises a buffer solution comprising citric acid monohydrateand sodium citrate dihydrate. In an embodiment, the pharmaceutical composition comprisesabout 5 to about 10 mM of the buffer. In an embodiment the pharmaceutical composition comprises less than 3 mg / mL of the total buffer. In an embodiment the pharmaceuticalcomposition comprises less than 2 mg / mL of the total buffer solution. In an embodiment thepharmaceutical composition comprises about 2.5 mg / mL of the total buffer solution. In anembodiment the ratio of buffer solution to Compound A is 1:100 to 1:200. In an embodimentthe ratio of buffer solution to Compound A is 1:110 to 1:170. In an embodiment the ratio ofbuffer solution to Compound A is about 1:120. In an embodiment the ratio of buffer solution toCompound A is about 1:160. The amount of buffer solution is the combined amount of all buffer components. Any of the exemplary embodiments in Tables 1a to 1i may comprise a buffer solution.In an embodiment, the embodiments in Tables 1a to 1h comprise a buffer solution comprising citric acid monohydrate and sodium citrate dihydrate. In these embodiments, the ratio of buffer solution to Compound A may be 1:100 to 1:200. In these embodiments the ratio of buffersolution to Compound A may be 1:110 to 1:170. In these embodiments the ratio of buffersolution to Compound A may be about 1:120. In these embodiments the ratio of buffer solutionto Compound A may be about 1:160.Methods for treatment and prevention of HIV infectionIn a third aspect, the present invention provides: (a) a method of treating humanimmunodeficiency virus (HIV) infection in a human in need thereof comprising administeringto said human a therapeutically effective amount of Form 1 of Compound A as defined herein;and (b) a method of preventing human immunodeficiency virus (HIV) infection in a human inneed thereof comprising administering to said human an effective amount Form 1 ofCompound A as described herein. In an embodiment the present invention provides: (a) amethod of treating human immunodeficiency virus (HIV) infection in a human in need thereofcomprising administering to said human a therapeutically effective amount of apharmaceutical composition comprising Form 1 of Compound A as defined herein; and (b) amethod of preventing human immunodeficiency virus (HIV) infection in a human comprising administering to said human an effective amount of a pharmaceutical composition comprising Form 1 of Compound A as defined herein. In one embodiment, the method comprises administering the pharmaceutical composition via an injection. In an embodiment the method comprises administering the pharmaceutical composition parenterally. In an embodiment, the pharmaceutical composition is administered intramuscularly. In an embodiment, the pharmaceutical composition is administered subcutaneously.Use in treatment or prevention of HIV infection.In a fourth aspect, the present invention provides Form 1 of Compound A asdescribed herein for use in therapy. In an embodiment, Form 1 of Compound A as described herein is provided for use inthe treatment of prevention of HIV infection.In an embodiment, a pharmaceutical composition comprising Form 1 of Compound Aas described herein is provided for use in the treatment or prevention of HIV infection.In one embodiment the use comprises administering the pharmaceutical composition parenterally. In one embodiment, the pharmaceutical composition is suitable for use as an injectable composition. In an embodiment the use comprises administering the pharmaceutical composition intramuscularly. In another embodiment the use comprises administering the pharmaceutical composition subcutaneously. In a further aspect, the present invention provides use of Form 1 of Compound A inthe manufacture of a medicament for treatment of human immunodeficiency virus (HIV) infection. Process Methods disclosed in the art for making Compound A result in mixtures of multicomponent forms. Specifically, previously disclosed methods of making Compound Aresulted in multicomponent Group B and Group E shown in Figs. 6 and 7 respectively. Thepresent inventors have now found how to make Form 1 in at least 90% polymorphic purity. In an embodiment, methods of the invention make Form 1 in at least 95 % polymorphic purity. In an embodiment, methods of the invention make Form 1 in at least 99 % polymorphic purity. Polymorphic purity may be measured by any suitable method. An exemplary method of measuring polymorphic purity is shown in Example 5. The polymorphic purity of Form 1 is also shown by the presence of the singularendothermic peak in the DSC of Fig. 4. In one aspect the present invention provides a process for making Form 1 of Compound A. In an embodiment, the process comprises crystalising Compound A from Cyclopentylmethyl ether (CPME). In another embodiment, the process further comprises washing thecrystalised Compound A with cyclohexane. In another embodiment, the method comprisingcrystalising compound A from CPME and then washing the crystalised Compound A withcyclohexane. In another embodiment, the method comprises a further step of drying the resulting product. In an embodiment, the drying takes place at a temperature of 40 to 50oC. The following non-limiting embodiments illustrate the present invention: Embodiments: Exemplary embodiments (E) are set out below:E1: A crystalline form (Form 1) of Compound A: E2: The crystalline form according to E1, wherein the polymorphic purity of Form 1 is greater than 90%. E3: The crystalline form according to E1 or E2, which is characterised by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Fig. 1.E4: The crystalline form according to any one of E1 to E3, which is characterised by an XRPDpattern exhibiting reflections at a 2θ angle of about 7.4oand at least 2, at least 3, or at least4 of the 2θ angles selected from about 6.8, 16.7, 16.9, 17.5, 17.9, 18.2, 18.7, 21.9, and 22.2o, when measured using Cu Kα radiation at 1.54 Angstroms. E5: The crystalline form according to any one of E1 to E4, wherein the form is characterised by a19F solid-state NMR (SSNMR) spectrum substantially in accordance with Fig. 8.E6: The crystalline form according to any one of E1 to E5, wherein the form is characterisedby a differential scanning calorimetry (DSC) spectrum substantially in accordance with Fig. 4.E7: The crystalline form according to any one of E1 to E6, wherein the form is characterizedby a DSC spectrum with a single endotherm with an onset temperature of about 121oC.E8: The crystalline form according to any one of E1 to E7, wherein the form is characterisedby a Raman spectrum substantially in accordance with Fig. 3. E9: A pharmaceutical composition comprising the crystalline form of Compound A according to any one of E1 to E8. E10: The pharmaceutical composition according to E9, further comprising a poloxamer. E11: The pharmaceutical composition according to E10, wherein the poloxamer is poloxamer P338.E12: The pharmaceutical composition according to any one of E9 to E11, wherein thecomposition further comprises: a stabilizer; and a tonicity adjuster. E13: The pharmaceutical composition according to E12, wherein the stabilizer is selected from sodium carboxymethylcellulose (NaCMC) and polyvinylpyrrolidone (PVP). E14: The pharmaceutical composition according to E13, wherein the stabilizer is sodium carboxymethylcellulose. E15: The pharmaceutical composition according to E13, wherein the stabilizer is polyvinylpyrrolidone. E16: The pharmaceutical composition according to E15, wherein the stabilizer is PVP K12. E17: The pharmaceutical composition according to any of E12 to E16, wherein the tonicity adjuster is mannitol. E18: The pharmaceutical composition according to any of E9 to E17, wherein Compound A is present in the form of particles having a mass median size (X50) of between (and including)1 μm and 15 μm.E19: A method of treating human immunodeficiency virus (HIV) infection in a human in need thereof comprising administering to said human a therapeutically effective amount of the crystalline form according to any of E1 to E8 or the pharmaceutical composition according to any of E9 to E18. E20: A method of preventing HIV infection in a human in need thereof comprising administering to said human an effective amount of the crystalline form according to any of E1 to E8 or the pharmaceutical composition according to any of E9 to E18. E21: The method according to E19 or E20, wherein the crystalline form or pharmaceutical composition is administered to the human via an injection. E22: The method according to E21, wherein the injection is administered intramuscularly (IM). E23: The method according to E21, wherein the injection is administered subcutaneously (SC). E24: The crystalline form according to any of E1 to E8 or the pharmaceutical composition according to any of E9 to E18 for use in therapy. E25: The crystalline form according to any of E1 to E8 or the pharmaceutical composition according to any of E9 to E18 for use in treatment or prevention of HIV infection. E26: The crystalline form or pharmaceutical composition for use according to E25, wherein administration of the pharmaceutical formulation is via an injection. E27: The crystalline form or pharmaceutical composition for use according to E26, wherein the injection is administered intramuscularly (IM). E28: The crystalline form or pharmaceutical composition for use according to E26, wherein the injection is administered subcutaneously (SC). E29: Use of crystalline form according to any of E1 to E8 or the pharmaceutical composition according to any of E9 to E18, in the manufacture of a medicament for treatment of HIV infection. E30: A method of making a crystalline form according to any of E1 to E8 comprising crystalising Compound A from cyclopentyl methyl ether (CPME). E31: The method according to E30, wherein the method further comprises washing the crystalised Compound A with cyclohexane. E32: The method according to E30 or E31, wherein the method further comprises a step of drying the crystalised Compound A. The following non-limiting examples illustrate the present invention. EXAMPLESExample 1: Solid Forms of Compound AA crystal form screen was conducted, comprised of 144 crystallization experiments andinvolving 48 solvent systems, three crystallization modes (temperature cycling, cooling,evaporation), and a temperature range of 5-40 °C. The screen identified a class of structurallysimilar forms (Class 1) by PXRD (i.e., XRPD), which exhibited consistent final endotherms at~125-127 °C and differences below 120 °C in DSC traces: (1) Group A – less crystalline, likely a mixture of forms. DSC data showedinconsistent multiple events between 65-110 °C and a final endotherm at ~125 °C. (2) Group B – crystalline, likely non-solvated form with subtle variability in PXRDpatterns. DSC data showed events at ~89, 103, and 126 °C.(3) Group C – crystalline with subtle variability in PXRD patterns, may contain smallamount of crystallization solvents. DSC data showed events at ~74, 84, 103, and 125 °C. (4) Group E – crystalline form containing small amount of crystallization solvents.DSC data showed multiple events between 65-110 °C and a final endotherm at ~125 °C. (5) Group F – crystalline form containing small amount of DCM. DSC data showedmultiple events between approx. 65-100 °C and a final endotherm at 127 °C. The screen also identified a non-solvated form, Group D (i.e., Form 1). DSC datashowed two events between 65-110 °C and a final endotherm at 121 °C. See Fig. 9 for DSCtraces of Class 1 and Group D. Moderately crystalline Group A (by PXRD) was isolated from several screeningexperiments involving low-solubility solvents, for example, cooling from acetone or methyl acetate, and temperature cycling from 1-methoxy-2-propanol. The PXRD patterns of Group A samples remained unchanged after exposure to ambient conditions for 24h in open container. Group B was obtained from multiple screening experiments, for example, temperature cycling from methanol, acetonitrile, or ethyl acetate, cooling from methanol, ethanol, or 2- propanol, and evaporation from ethanol, ethyl acetate, or THF. Group B is a non-solvated crystal form with negligible (0.1%) weight loss up to 100 °C. Additional 1.5% wt loss of unknown volatile was observed above 100 °C. Group B exhibited a similar PXRD pattern tothat of Group A, with more pronounced peaks at 6.9 and 7.9° 2θ (see Fig. 11). The PXRDpattern of Group B sample remained unchanged after exposure to ambient conditions for 11days in open container. However, peaks of Group D appeared within 27 days, indicating physical instability of Group B. Group C was obtained from multiple screening experiments, for example, temperature cycling from 1-propanol, 2-propanol, and isopropyl acetate, and evaporation from acetone,THF, or toluene. Group C exhibited similar PXRD pattern to that of Groups A and B (classifiedinto Class 1), with a most pronounced peak at 6.9° 2Θ (see Fig. 12). After exposure to ambientconditions for 8-11 days in open container, the PXRD pattern of Group C sample showed peaks of Group D. Group D (Form 1) is a non-solvated form obtained from multiple screening experiments, temperature cycling from toluene, and cooling from toluene, chlorobenzene, or2-butanone. Group D exhibited similar PXRD pattern to that of Group A, with an additionalcharacteristic peak at 7.4° 2Θ (see Fig. 13). DSC traces of Group D showed final meltingendotherm at 121 °C (as opposed to 125-127 °C for Class 1), in addition to very small eventsat 74 and 103 °C. Group D showed negligible (0.1%) weight loss up to 100 °C and a smallamount (0.3% wt) of unknown volatile above 100 °C. PXRD pattern of Group D sampleremained unchanged after exposure to ambient conditions for 8-11 days in open container. Group E was obtained from a few experiments, for example, temperature cycling fromMethyl isobutyl ketone (MIBK) or isopropyl ether, and evaporation from MIBK. Group Eexhibited PXRD pattern and DSC data similar to those of Class 1 (see Fig. 14). Group E (fromMIBK) showed 2.1% wt loss of MIBK (0.1 eq.) up to 100 °C and 0.7% wt of unknown volatilebetween 100-225 °C. DSC data show a broad endotherm between 50-95 °C, a smallendotherm at 103 °C and 127 °C. After exposure to ambient conditions for 8-11 days in opencontainer, the PXRD pattern of Group E samples showed peaks of Group B.Group F was obtained from evaporation in DCM and its PXRD pattern and DSC datawere similar to those of Class 1 (see Fig. 15). Thermal data of Group F showed 0.8% wt lossof DCM (0.1 eq.) up to 90 °C and 1.5% wt of unknown volatile between 90-225 °C. DSC datashowed a complex trace with endotherms between 50-100 °C and a final endotherm at 126°C. After exposure to ambient conditions for 8-11 days in open container, PXRD pattern ofGroup F showed peaks of Group D. Relative thermodynamic stability of Groups A, B, C, and D was determined viacompetitive ripening studies in MeCN and cyclopentyl methyl ether (CPME) at 5, 20, and 40°C in saturated solutions. The competitive ripening results are summarized in Table 3 andindicate that Class 1 forms (Groups B, C, E) were isolated from all experiments. Class 1products from CPME converted to Group D within 5 h, whereas Class 1 products from MeCNremained unchanged at RT. Samples from both MeCN and CPME were subjected to drying at40 °C under vacuum for 24 h to investigate physical stability. Both samples remainedunchanged. DSC data of the ripening products indicated that peak at 103 °C (observed in most screening batches) is absent (Fig. 10). This result suggests that peak at 103 °C could be related to a phase-impurity.Table 3. Results of Relative Stability StudyNo. Solvent TempGroup to Ripened Group at t1=7 Comment (°C) Saturate Groups d 1MeCN 5 C / D A, B, C, D Class 1 (C) n / a2 CPME 5 C / D A, B, C, D Class 1 (E) n / a3 MeCN 20 C / D A, B, C, D Class 1(B / C) Unchanged after 24 hat 40 °C 4CPME 20 C / D A, B, C, D Class 1 (E) Converted to D in 5 hat RT 5MeCN 40 C / D A, B, C, D Class 1 (B) Unchanged after 24 hat 40 °C 6CPME 40 C / D A, B, C, D Class 1 (E) Converted to D in 5 hat RT Example 2: Preparation of Form 1 of Compound A without seeding A slurry of Cabotegravir (3S,11AR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7- dioxo-2,3,5,7,11,11a-hexahydrooxazolo [3,2-a] pyrido[1,2-d]pyrazine-8-carboxamide (1 g, 2.467 mmol) and stearoyl chloride (0.897 g, 2.96 mmol) in N,N- Dimethylacetamide (DMA) (10 mL) at room temperature in a 20 mL scintillation vial fitted withthermocouple and magnetic bar. Hunig’s base (0.517 mL, 2.96 mmol) was then added, overapproximately 15 seconds at room temperature over stirring. Upon adding the base (at 22.5C), an exotherm was observed where the temperature increased to 30.5 C, within 3 minutes,then stabilized and decreased back to room temperature (22.5 C) within 5 minutes, all duringwhich time the reaction mixture thickened up but remained a stirrable slurry. The suspensionwas then heated to 55 °C where all almost all solids dissolved, at 60°C a solution (light orangein color) formed. After cooling to room temperature (+21°C), 5 vol% of water (0.5 mL) wasslowly added, at room temperature stirring was continued to induce crystallisation (for 15 minutes). This material was stirred for an additional hour. The solids were subsequently filtered off and rinsed with excess amounts of acetonitrile. The solid (48.5 mg) was then added to cyclopentyl methyl ether (1.5 ml). A pourablesuspension was made, then filtered producing a clear filtrate. The filter funnels with products were placed into vacuum oven at ambient temperature, loosely covered, under vacuum with slight air purge. Solid was placed in the oven overnight (25 hrs). After drying, the materialwas characterized using DSC (Fig. 17) and XRPD (Fig. 16). The DSC showed an onsettemperate of 118.0oC and a peak temperature of 120.4oC characteristic of Form 1. Fig. 16shows an overlay of the XRPD of the material produced from the above method (top line), anXRPD of Group B of Compound A (middle line) and an XRPD of Form 1 of Compound A (bottom line), showing that the XRPD of the material produced from the above method is characteristic of Form 1.Example 3: Preparation of Form 1 of Compound A (3R,6S)-12-{[(2,4-difluorophenyl)methyl]carbamoyl}-6-methyl-8,11-dioxo-4-oxa-1,7- diazatricyclo[7.4.0.0³,⁷]trideca-9,12-dien-10-yl octadecenoate Example 3a In a reactor, stearic acid (1.6 equiv) was slurried in dicholoromethane (3.8 vol) at 22-28 °C at a 200 gallon scale, with input material amounting to 13.1 kg of cabotegravir. Oxalylchloride (1.76 equiv) was added slowly over no less than 3 h at 22-28 °C. The reaction mixture was then stirred at 22-28 °C for no less than 6 h, and concentrated to 3.5 vol under slight vacuum with solution temperature controlled below 50 °C. The solvent was swapped to toluene (5.5 vol) via vacuum distillation with solution temperature controlled below 50 °C and again concentrated to 3.5 vol. N-Methylpyrrolidone (10 vol) and cabotegravir (1.00 equiv) were charged to the above stearoyl chloride solution, and the mixture was heated to 62-68 °C. N,N-Diisopropylethylamine (2.01 equiv) was added over no less than 1 h. The mixture was stirred for no less than 30 min. Water (2.5 vol) was charged over no less than 10 min while maintaining reaction temperature at 62-68 °C, and then methanol (10 vol) was charged over no less than 30 min at the same temperature. Compound A seed was slurried in methanol, and then this methanol seed slurry was charged to the reaction mixture at 47-49 °C. The addition of this Compound A seed is to control nucleation and crystal growth to ensure good manufacturability and uniformity, but the addition of seed is not required to synthesize Compound A. The mixture was held at this temperature for no less than 4 h to allow crystals to grow slowly. The reaction mixture was cooled to 17-23 °C at 0.1 °C / min, and then held at 17-23 °C for no less than 2 h. The slurry was then filtered in a filter dryer, washed with the crystallization composition solvents (2.04 vol N-Methylpyrrolidone, 2.04 vol methanol, 0.51 vol toluene, and0.41 vol water) and then filtered. The wet cake was reslurried in methanol (12 vol) for at least1 h and then filtered. Next, the wet cake was reslurried in 14 vol cyclohexane twice at 17-23 °C for at least 1 h each time and then filtered. The slurry was sampled and NMR analysis was used to confirm the stearic anhydride is ≤ 6.0 wt%. The wet cake was then washed with 7 vol cyclohexane and then filtered. Nitrogen was passed through the wet cake for not less than 1 h. The product was then dried at 45-50 °C under vacuum. The product (intermediate grade Compound A) was offloaded from a filter dryer once the loss on drying of a sample shows ≤3.0% weight change after 10 minutes at 110 °C. Material that is synthesised is predominantlyform 1 once dried (yielding 19.9 kg of intermediate grade compound A).Example 3b In a crystallizer at a 200 gallon scale, with input material amounting to 19.9 kg ofintermediate grade compound A., intermediate grade Compound A from Example 3a wasdissolved in cyclopentyl methyl ether at 57-63 °C. The solution was clarified by filtration to remove any potential particulates. Solution temperature was then decreased to 38-42 °C. The solution was seeded with 1.0% w / w Compound A of the primarily Form 1 crystal form. Before adding the seed to the crystallizer, the seed was slurried in isopropyl alcohol. The mixture washeld for 30 minutes at the seeding temperature. The slurry was then cooled to 12-18 °C at0.1 °C / min. The slurry was held at 12-18 °C for no less than 4 h. The slurry was then transferredto a filter dryer at 12-18 °C. Cyclopentyl methyl ether (CPME) (4 vol, filtered) was used torinse the cold crystallizer, and the rinse was transferred to the filter dryer to wash the wet cake. The cake wash was filtered. Cyclohexane (10 vol, filtered) was charged to the filter dryer and then agitated to suspend. Cyclopentyl methyl ether (4 vol, filtered) was transferred to the filter dryer to wash the wet cake once more. A sample of the wet cake in the filter dryer wastaken and dried in a lab vacuum oven. XRPD, NMR, and DSC analysis were performed on thedried sample. If the DSC and XRPD analyses were not consistent with Group D, Group E, or a mixture of the two forms, and / or NMR showed stearic anhydride levels > 1.0 wt%, an additional cyclohexane reslurry wash (10 vol, filtered) and CPME wash (4 vol filtered) were performed. The cake was dried in the filter dryer at 40 °C under vacuum until a well-blended sample showed ≤0.50% weight change after 10 minutes at 120 °C, and XRPD and DSC indicated that the product was Form 1. The differential scanning calorimetry (DSC) thermogram of Form 1 of Compound A was recorded on a TA Instruments Q100 Differential Scanning Calorimeter equipped with an autosampler and a refrigerated cooling system under N2purge and is shown in Fig. 4. Theexperiments were conducted using a heating rate of 10 °C / min in a crimped aluminum pan.The DSC thermogram of Form 1 of Compound A exhibits a single endotherm with an onsettemperature of about 120 °C.The thermogravimetric analysis (TGA) thermogram of Form 1 of Compound A was recorded on a TA Instruments Q500 Thermogravimetric Analyzer and is shown in Fig. 5. The experiments were conducted with N2flow and a heating rate of 15 °C / min. Example 3c At room temperature, 10 vols of acetone were added to Compound A.The mixture was stirred and heated to 50°C until full dissolution occurred. The mixturewas polish filtered while warm and transferred to a clean vessel. The mixture was cooledfrom 50°C to 20°C at a rate of 0.1°C / min. At 20°C, the mixture was seeded with ~2 mg ofForm 1 of Compound A. The mixture was allowed to stir for 30 mins at 20°C. The mixture wascontinued to cool to 10°C at a rate of 0.1°C / min and held at that temperature overnight (~16hrs). The mixture was then filtered. The cake was analysed by PXRD (Fig. 21) and DSC (Fig.20) and found to be consistent with Form 1. The cake was then dried in a vacuum ovenovernight at 40°C. The process in example 3c may be beneficial in manufacturing as it reduces thenumber of steps required to get to Form 1.Example 4: Stability of Form 1 of Compound ACompound A, Form 1 made as in Example 3b above was packaged in linear low-densitypolyethylene (LLDPE) bags and sealed using a twist tie twice (primary bag with twist tie, and secondary bag with twist tie). The bags were then placed in CurTec high density polyethylene bags) (HDPE Wide Neck Drums with PP Lids, Qorpak® which acts as an outer container. The lids were screw closed. The HPDE containers are representative of bulk HDPE drums. Thedrums were then placed in stability chambers with varying conditions. The data in Fig. 18shows the results of this material that was exposed to conditions of 30 °C with 65% relativehumidity for a total of 9 months. This diffractogram shows that there has been no change tosolid state form over the course of 9 months at these conditions. Fig. 18 shows an XRPDoverlay, the top line shows Form 1 of Compound A after 9 months at conditions of 30 deg C and 65% humidity. Middle line shows Group B and bottom line shows Form 1. The absenceof peaks between 6.75 and 7.25 deg 2 theta and at 21.6 deg 2 theta may indicate that anundetectable amount of Group B are present. The top line (material put on stability) isconsistent with the bottom (red line, reference Form 1 material) showing no other solid state forms were observed in this material.Example 5: Stability data of a pharmaceutical composition comprising Form 1 of Compound AA formulation vehicle was prepared by dissolving / diluting 15 g Poloxamer 338 (P338)(BASF, Kolliphor P338) in about 1050 g water. After P338 is fully dissolved in water forinjection (WFI), 22.5 g Polyvinyl pyrrolidone K12 (PVP K12) (Ashland, Plasdone C-12) was added until fully dissolved. Lastly, 52.5 g mannitol (Roquette Freres) was dissolved in the solution. The bulk vehicle was then filtered through a 0.22 μm filter. 300 g Compound Amicronized API (target X50 = 3-5μm particle size) was divided equally and added to 710 gfiltered vehicle one aliquot at a time. For each aliquot of API added, suspension was vacuum de-aerated for approximately 10 minutes and then stirred until API completely submerged into the vehicle. Once the full amount of API was added, 50 g of vehicle was used to rinse off the residual API left in the vessels. The suspension then continued to stir and vacuum de- aerate overnight. If there was any volume loss during overnight vacuum de-aeration, the amount lost was made up for with the appropriate amount of WFI added back into suspension. After stirring for approximately 30 minutes, the suspension was measured for density. Once target density was reached, 1.06 g / mL, the suspension proceeded to be homogenized (may be filtered and) is then filled into vials. The product was lyophilized by freezing at -45°C for 185 minutes, annealing at -18°C for 207 minutes, refreezing at -45°C for 207 minutes (each transition at a ramp rate of + / -1°C / min), primary drying at -10°C (ramp rate: 0.175°C / min) for approximately 24 hours atapproximately 150 mTorr, and secondary drying at 25°C (ramp rate: 0.145°C / min) for at least 10 hours at approximately 150 mTorr. The lyophilized vials were backflushed with nitrogen toabout 650 Torr, sealed, and sterilized by gamma irradiation at a minimum dose of 25kGy. Theformulation is reconstituted with WFI and briefly shaken to resuspend prior to administration. The lyophilized cake was reconstituted by injecting 1.7 mL of WFI into the vial. The vial was then reconstituted with a 10 second interval quick wrist movement. This action was repeated until the bottom of the vial was clear, and the cake was fully dissolved into a suspension. Table 4 shows two exemplary pharmaceutical compositions, (pharmaceuticalcompositions are also described in these examples as “suspensions”), made using the above method.Table 5 shows the stability of the composition in Batch 1 in Table 4. Table 6 showsstability of the composition shown as Batch 2 in Table 4. Methods for measuring stability of the composition are detailed below: Reconstitution time (Recon. Time) (sec): This was determined by adding the water for injection needed through the septum into the sample vial. The sample vial was then manually shaken with quick wrist motions in 10-second intervals until the lyophile cake was fully reconstituted. Resuspendability time (Resusp. Time) (sec) After reconstitution, the sample vial sat for approximately 2 hours, then was manually shaken for 10 seconds with quick wrist motions. The sample vial was inverted and checked to ensure the resuspension was uniform without any caking at the bottom of the vial. Shaking continued at 10-second intervals until fully resuspended. Content (% Label Claim) Content (% label claim) was calculated to confirm that the amount of Compound A inthe final composition compared to the amount expected to achieve – 90-110% is consideredan acceptable amount. Standard solution of Compound A at a nominal concentration of 0.25 mg / mL was prepared for determining system suitability for content. For example, 25 mg of Compound A drug substance standard was accurately weighed into a 100 mL volumetric flask and dissolved with 100% acetonitrile to volume with the aid of sonication. Compound A lyophile samples for content determination were prepared at a nominal concentration of 0.25 mg / mL in 100% acetonitrile solvent. Content was typically prepared in duplicate. The lyophile was reconstituted as detailed above (Reconstitution time (Recon. Time) (sec)). After reconstitution, the vial was decrimped and 0.167 mL of sample transferred directly into a tared 200 mL volumetric flask on an analytical balance and the accurate weightdetermined. Using 100% acetonitrile, the sample was dissolved to volume with the aid ofsonication to ensure complete dissolution. Solutions were then filtered and transferred to HPLC vials for analysis per the instrument parameters below. Impurity (% Area) Sensitivity solution at 0.05% w / w of the nominal Compound A standard (0.25 mg / mL prepared in the Content section above) was prepared and analysed as part of the system suitability. For example, 50 L of 0.25 mg / mL Compound A reference standard solution was transferred into a 100 mL volumetric flask and diluted to volume with 100% acetonitrile. Samples for HPLC analysis were filtered and transferred into HPLC vials for analysis per instrument parameters below.Column details Poroshell 120, SB-C8, 2.7 m, 4.6 x 150 mmPN 683975-906Column temperature 40°CMobile phase A 0.1% v / v TFA in waterMobile phase B 100% AcetonitrileFlow rate 1.0 mL / minGradient profile Time (minutes)% A % B 0 70 30 6.0 70 30 15.0 40 60 25.0 2 98 30.0 2 98 30.1 70 30 35 70 30Run time 35 minDetector wavelength 257 nmInjection volume 10 μLAutosampler wash solvent 100% AcetonitrilepH Determination pH is determined per USP<791> (official version as of 01-Nov-2020). Injection Force TestingSamples were analyzed to determine the extrusion force required to expel drug productthrough the selected administration components. Testing was performed via a Texture Analyzer TA-XT (Stable Micro Systems) utilizing a 3mL polypropylene syringe and 25G x 5 / 8” thin walled (TW) needle at a speed of 1.66mm / sec. XRPD (% Form 1) Group B was the only Group seen in any of the XRPD patterns therefore % Form 1 was calculated by deducting the % amount of Group B from 100%.The data was analyzed using HighScore Plus 4.8 (4.8.0.25518).The process used for data analysis is as follows:The XRPD pattern was opened in HighScore Plus software and a peak search conducted.Default parameters are used: Minimum Significance: 5.00; Minimum Tip Width Gonio: 0.05; Maximum Tip Width Gonio: 1.00; Peak base with Gonio: 2.00; Minimum 2nd Derivative. If thenumber of highlighted peaks and baseline fit appeared adequate, results were accepted. Allreflections were then selected. A Profile Fit (Caglioti) was then conducted. An inspection thatfitted profile matches of the raw data was conducted. The areas of select Group B peaks (6.9deg, 7.2 deg, and 21.6 deg 2theta) were normalised by the Group D peak (7.4 deg 2theta).The plot at 50% was then truncated for analysis of low Group B level quantities. Theexpressions obtained from the linear fit of wt% Group B vs peak area ratio were used todetermine level of Group B in unknown sample. A linear fit to the origin (0,0) was extrapolatedas there would be no Group B peaks in a pure Group D sample. Table 4 Batch # Formulation1 Compound A 300 mg / mL; 1.0 w / v% Poloxamer P338; 1.5 w / v%PVPK12; 3.5 w / v% Mannitol reconstituted to 300 mg / mL 2Compound A 300 mg / mL; 1.0 w / v% Poloxamer P338; 0.5 w / v% NaCMC;3.5 w / v% Mannitol reconstituted to 300 mg / mL Table 5 Batch 1 Storag XRPD Time Recon. Resusp. IF Content Impurit e (% (mont time Time PSD (μm) (25G) (% Label y (% pH Conditi form hs) (sec) (sec) (N) Claim) Area)1on 1) Initial postX10 – 2.2;gamma0 10; 10 N / A ^100 X50 – 5.1; N / A 101.6 0.81 4.27irradiaX90 – 11.0tion X10– 2.2;1 10; 10 10; 10 > 95 X50 – 5.2; 8.44 103.5 0.96 4.03X90– 11.5X10 – 2.2;3 10; 10 N / A > 95 X50 – 5.2; N / A 104.2 0.72 4.04X90 – 11.125 °C X10 – 2.2;6 10; 10 10; 10 > 95 X50- 5.2; 7.11 102.3 0.82 4.20X90- 11.6X10 – 2.3;9 10; 10 10; 10 > 95 X50 – 5.3; 5.25 99.5 0.78 3.56X90 – 11.7X10 – 2.2;X50 – 110; 10 10; 10 > 95 8.36 103.8 0.97 4.065.2; X90 –11.5 X10 – 2.3;40 °C 310; 10 10; 10 > 95 X50 – 5.3; 18.79 103.8 0.72 4.18X90 – 11.7X10 – 2.2;6 10; 10 10; 10 > 95 X50 – 5.2; 21.63 102.6 0.73 4.21X90- 11.4X10– 2.3;1 10; 20 10; 10 > 95 X50 – 5.2; 20.05 103.6 0.89 4.29X90– 11.050 °C X10 – 2.3;3 10; 10 10; 10 > 95 X50– 5.4; 16.76 103.7 0.71 4.23X90 – 11.5Table 6 Batch 2 TimeXRPD PSD Content ImpurityStorage Recon. IF Condition(months)Time(%(25G(% pH(sec)form (μm)) (N)Label(% )Ar 11) Claimea)Initial X10 - post 2.0; gamma 130; 100; 10; 90 X50 -6.24.1;17 102.8 1.510; 104irradiatio X90 - n 9.5 X10 - 1.9; 140; 92.5X50 -N / A 108 6.11404.1;.9 1.3 9X90 - 9.4 25 °C X10 – 2.0 ; 630; 93.2X50 –N / A 108.2 1 6.030; 304.1;.3 4X90 – 9.6 X10 – 2.0; 12 10; 90X50 –29.6 102. 6.020; 204.1;8 1.4 5X90 – 10 X10 – 2.0; 130; 70 91.7X50 –N 5.94.1; / A 107.4 1.3 8X90 - 10 X10 – 2.0; 360; 90 88X50 –4.1; N / A 102.9 1.2 6X90 – 9.5 40 °C X10 – 2.0; 630; 30; 90.6X50 – 304.2;N / A 105.4 1.3 5.9X90 – 9.9 X10 – 2.0; 140; 60 89.2X50 -6.04.1;N / A 108.7 1.4 9X90 - 9.5 50 °C X10 – 2.0; 360; 60 87X50N / A 102 6.1– 4.1; .4 1.3 4X90 – 9.5 Table 7 Ingredient Concentration measuredpre-lyophilization and pre- reconstitution (mg / mL) Compound A, micronized 300.0PVP K12 15.0Poloxamer 338 10.0Mannitol 35.0Citric acid monohydrate 0.75Sodium citrate dihydrate 1.75Table 7 shows an exemplary pharmaceutical composition of the invention which was madeusing the following method: Aformulation vehicle was prepared by dissolving 33.3 g Poloxamer 338 (BASF,Kolliphor P338) in about 2323 g water for injection (WFI). After P338 was fully dissolved inWFI, 49.95 g of PVP K12 (Ashland, Plasdone C-12), 116.55 g mannitol (Roquette Freres),2.50 g citric acid monohydrate (Merck Millipore) and 5.83 g sodium citrate dihydrate (Avantoror Jungbunzlauer) were added one at a time and dissolved in the solution. The bulk vehiclewas then filtered through a 0.22 μm filter.680.7 g Compound A gamma irradiated, micronizedAPI (target X50 = 3-5μm particle size) was slowly added to 1692 g of vehicle while stirring withvortex and may be deaerated. The suspension then continued to stir overnight. After stirringovernight, the suspension was homogenized for up to 11 minutes at 15 Hz rpm and up to 109minutes at 40 Hz. The suspension was filtered, deaerated (if needed) and filled into vials.The product was lyophilized by freezing at -45°C for 185 minutes, annealing at -18°C for 207 minutes, refreezing at -45°C for 207 minutes (each transition at a ramp rate of + / -1°C / min), primary drying at -10°C (ramp rate: 0.175°C / min) for approximately 28 hours atapproximately 150 mTorr, and secondary drying at 25°C (ramp rate: 0.145°C / min) forapproximately 34 hours at approximately 150 mTorr. The lyophilized vials were backflushedwith nitrogen to about 650 Torr, sealed, and sterilized by gamma irradiation at a minimumdose of 25kGy. The formulation was reconstituted with WFI and briefly shaken to resuspendprior to administration. Table 8 Ingredient Concentration postreconstitution (mg / mL) Compound A, micronized 300Povidone 15Poloxamer 338 10Mannitol 35Citric acid monohydrate 0.75Sodium citrate dihydrate 1.75Table 8 shows a lyophilized suspension reconstituted at drug concentration of 300 mg / mL.The lyophilized cake (manufactured at 300 mg / mL above in Table 7) was reconstituted to 300mg / mL by adding 1.7 mL WFI into the vial. The vial was then reconstituted with a 10-secondinterval quick wrist movement. The action was repeated until the bottom of the vial was clear,and the cake fully dispersed into a suspension. Table 9 summarizes the stability ofcomposition shown in Table 7 and Table 8.Table 9 Batch 3 Conten Storage Recon. Resusp. IF Time t (% Impurity Conditi time Time XRPD PSD (μm) (25G) pH (months) Label (% Area) on (sec) (sec) (N) Claim) Initial post X10: 1.9, Form 1 gamma0 10 10X50: 4.0,4.7 95.6 1.4 5.0irradiat X90: 8.2 ion X10: 1.9, 1M 10 10 Form 1X50: 4.1,4.3 98.9 1.3 5.05°C / Am X90: 8.2 bH X10: 1.9, 3M 10 10 Form 1X50: 4.1,4.3 101.1 1.5 5.0X90: 8.2 X10: 1.9, 1M 10 10 Form 1X50: 4.2,4.4 98.4 1.4 5.025 X90: 8.6 °C / 60% X10: 1.9, RH 3M 10 10 Form 1X50: 4.2,4.7 102.2 1.3 5.0X90: 8.5 Form 1, X10: 2.0, 1M 10 10<5% X50: 4.4,4.6 98.4 1.4 5.040 Group B X90: 9.3 °C / 75% Form 1, X10: 2.1, RH 3M 10 10<5% X50: 4.8,5.0 101.6 1.9 4.7Group B X90: 11.7 Table 10 Ingredient Concentration postreconstitution (mg / mL)Compound A, micronized 395Povidone 19.75Poloxamer 338 13.17Mannitol 46.07Citric acid monohydrate 0.99Sodium citrate dihydrate 2.30Table 10 shows a lyophilized suspension reconstituted at drug concentration of 395 mg / mL.The lyophilized cake (manufactured at 300 mg / mL above in Table 7) can be reconstituted to395 mg / mL by adding 1.2 mL WFI into the vial. The vial is then reconstituted with a 10-secondinterval quick wrist movement. The action is repeated until the bottom of the vial is clear, andthe cake fully dispersed into a suspension.Table 11 Ingredient Concentration postreconstitution (mg / mL) Compound A, micronized 450.0Povidone 22.5Poloxamer 338 15.0Mannitol 52.5Citric acid monohydrate 1.13Sodium citrate dihydrate 2.63Table 19 shows a lyophilized suspension reconstituted at drug concentration of 450 mg / mL.The lyophilized cake (manufactured at 300 mg / mL above in Table 7) can be reconstituted to450 mg / mL by adding 0.9 mL WFI into the vial. The vial is then reconstituted with a 10-secondinterval quick wrist movement. The action is repeated until the bottom of the vial is clear, andthe cake fully dispersed into a suspension.Table 12 Ingredient Concentration measuredpre-lyophilization and pre- reconstitution (mg / mL) Compound A, micronized 400.0Povidone 20.0Poloxamer 338 13.3Mannitol 35.0Citric acid monohydrate 0.75Sodium citrate dihydrate 1.75Table 12 shows an exemplary pharmaceutical composition of the invention which was madeusing the following method: Aformulation vehicle was prepared by dissolving 7.98 g Poloxamer 338 (BASF,Kolliphor P338) in about 364.9 g water for injection (WFI). After P338 was fully dissolved inWFI, 12 g of Povidone (Ashland, Plasdone C-12), 21 g mannitol (Roquette Freres), 0.45 gcitric acid monohydrate (Merck Millipore) and 1.05 g sodium citrate dihydrate (Avantor orJungbunzlauer) were added one at a time and dissolved in the solution. The bulk vehicle wasthen filtered through a 0.22 μm filter. 240 g Compound A gamma irradiated, micronized API(target X50 = 3-5μm particle size) was slowly added to 407.4 g of vehicle while stirring withvortex and may be deaerated. The suspension then continued to stir overnight. After stirringovernight, the suspension was homogenized for up to 10 minutes at 5000 rpm and up to 80minutes at 10000 rpm. The suspension was filtered, deaerated (if needed) and filled into vials.The product was lyophilized by freezing at -45°C for 185 minutes, annealing at -18°C for 207 minutes, refreezing at -45°C for 207 minutes (each transition at a ramp rate of + / -1°C / min), primary drying at -10°C (ramp rate: 0.175°C / min) for approximately 28 hours atapproximately 150 mTorr, and secondary drying at 25°C (ramp rate: 0.145°C / min) forapproximately 20 hours at approximately 150 mTorr. The lyophilized vials were backflushedwith nitrogen to about 650 Torr, sealed, and sterilized by gamma irradiation at a minimumdose of 25kGy. The formulation was reconstituted with WFI and briefly shaken to resuspendprior to administration. Table 13 Ingredient Concentration postreconstitution (mg / mL) Compound A, micronized 450.0Povidone 22.5Poloxamer 338 14.99Mannitol 39.4Citric acid monohydrate 0.84Sodium citrate dihydrate 1.97Table 13 shows a lyophilized suspension reconstituted at drug concentration of 450mg / mL. The lyophilized cake (manufactured at 400 mg / mL above in Table 12) can bereconstituted to higher drug concentrations by reconstituting with a smaller quantity of WFI.To get a 450 mg / mL drug load, 1.2 mL of WFI was injected into the vial. The vial was thenreconstituted with a 10-second interval quick wrist movement. The action was repeated untilthe bottom of the vial was clear, and the cake fully dispersed into a suspension.Table 14 Batch 4 Conten Storage Recon. Resusp. XRPD IF Impurity Time t (% Conditi time Time (% form PSD (μm) (25G) (% pH (months) Label on (sec) (sec) 1) (N) Area)1Claim) Initial post Form 1, X10: 1.9, gamma0 20 NA <5 wt%X50: 4.0,14.8 100.6 1.4 5.1irradiat Group B X90: 8.9 ionTable 14 shows stability data of the composition discussed in Table 12 and reconstituted to450 mg / mL (composition in Table 13).Example 6 – Preparation of Group B of Compound A from the impurities of a drug substanceprocess and form 1Compound A, as prepared in example 3b, was slurried in 20 volumes of ethanol and 8 wt%weight of stearic anhydride was added to the vessel and was slurried until solid formationoccurred. The slurry was vacuum filtered until the solid was solvent free. No wash wasperformed. The solid was placed in a vacuum oven at 40°C under vacuum and nitrogenpurge to dry material further. The differential scanning calorimetry (DSC) thermogram of Group B of Compound Aas prepared in this example was recorded on a TA Instruments Q100 Differential ScanningCalorimeter equipped with an autosampler and a refrigerated cooling system under N2purge and is shown in Fig. 19. The experiments were conducted using a heating rate of 10 °C / min in a crimped aluminum pan.The DSC thermogram of Group B of Compound A exhibits two endotherms; the firstendotherm has an onset temperature at 87°C and the second endotherm has an onsettemperature at 121 °C.Example 7 – Mixtures of Group B and Form 1A mixture of Form 1 and Group B of a ratio of 50:50 was formed by physically mixingForm 1 (made using the methods stated in Example 3a and 3b) and Group B (made by the methods stated in Example 6). Amixture of Form 1 and Group B of a ratio of 70:30 was formed by physically mixingForm 1 (made using the methods stated in Example 3a and 3b) and Group B (made by the methods stated in Example 6). Amixture of Form 1 and Group B of a ratio of 90:10 was formed by physically mixingForm 1 (made using the methods stated in Example 3a and 3b) and Group B (made by the methods stated in Example 6). Pure group B was formed by the method stated in Example 6.Pure Form 1 was formed by the method stated in Example 3b, it was then purified toremove all chemical impurities using preparative chromatography. XRPDs were taken of the mixtures and pure group B and Form 1. These XRPDs areoverlayed and shown in Fig. 22 where top to bottom is (50:50, 70:30, 90:10, 95:5 Form 1:Grp B), second from the bottom pure Grp B, bottom pure Form 1.The portions of the XRPD indicating the presence of group B in the mixtures are in the range6.0 to 7.0 °2θ and in the range of 21.0 to 22.0 °2θ. Separate overlayed XRPDs are shown inhigher resolution in the ranges of 4.5 to 9.5 °2θ (Fig. 23) and 19.0 to 24.5 °2θ (Fig. 24).The presence of the additional peaks in pure Group B in the specified regions leads toshouldering and less defined peaks in the range of 6.0 to 7.0 °2θ and in the range of 21.0 to22.0 °2θ. spectra in mixtures of Group B and Form 1.It will be understood that the present invention has been described purely by way of example, and modification of detail can be made within the scope of the invention. Each feature disclosed in the description, and where appropriate the claims and drawings, may be provided independently or in any appropriate combination.

Claims

Claims1. A crystalline form (Form 1) of Compound A:

2. The crystalline form according to Claim 1, wherein the polymorphic purity of Form 1 isgreater than 90%.

3. The crystalline form according to Claim 2, wherein the polymorphic purity of Form 1 isgreater than 95%.

4. The crystalline form according to any one of claims 1 to 3, which is characterised byan X-ray powder diffraction (XRPD) pattern substantially in accordance with Fig.1.

5. The crystalline form according to any preceding claim, which is characterised by anXRPD pattern exhibiting reflections at a 2θ angle of about 7.4oand at least 2, at least 3, or at least 4 of the 2θ angles selected from about 6.8, 16.7, 16.9, 17.5, 17.9, 18.2,18.7, 21.9, and 22.2 o, when measured using Cu Kα radiation at 1.54 Angstroms.

6. The crystalline form according to any one of claims 1 to 5, which is characterised byan X-ray powder diffraction (XRPD) pattern substantially in accordance with Fig.2.

7. The crystalline form according to any preceding claim, wherein the form ischaracterised by a19F solid-state NMR (SSNMR) spectrum substantially in accordance with Fig.8.

8. The crystalline form according to any preceding claim, wherein the form ischaracterised by a differential scanning calorimetry (DSC) spectrum substantially in accordance with Fig.4.

9. The crystalline form according to any preceding claim, wherein the form ischaracterized by a DSC spectrum with a single endotherm with an onset temperature of about 121oC.

10. The crystalline form according to any one of claims 1 to 9, wherein the form ischaracterized by a DSC spectrum which does not exhibit an endotherm in the rangeof about 40 to about 80 oC.

11. The crystalline form according to any preceding claim, wherein the form ischaracterised by a Raman spectrum substantially in accordance with Fig.3.

12. A pharmaceutical composition comprising the crystalline form of Compound Aaccording to any of Claims 1 to 11.

13. A method of treating human immunodeficiency virus (HIV) infection in a human in needthereof comprising administering to said human a therapeutically effective amount of the crystalline form according to any of Claims 1 to 11 or the pharmaceuticalcomposition according to claim 12.

14. A method of preventing HIV infection in a human in need thereof comprisingadministering to said human an effective amount of the crystalline form according to any of Claims 1 to 11 or the pharmaceutical composition according to claim 12.

15. The crystalline form according to any of Claims 1 to 11 or the pharmaceuticalcomposition according to claim 12 for use in therapy.

16. The crystalline form according to any of Claims 1 to 11 or the pharmaceuticalcomposition according to claim 12 for use in treatment or prevention of HIV infection.

17. Use of crystalline form according to any of Claims 1 to 11 or the pharmaceuticalcomposition according to claim 12, in the manufacture of a medicament for treatment of HIV infection.

18. A method of making a crystalline form according to any of Claims 1 to 11 comprisingcrystalising Compound A from cyclopentyl methyl ether (CPME).

19. The method according to Claim 18, wherein the method further comprises washing thecrystalised Compound A with cyclohexane.

20. A method of making the crystalline form according to any one of claims 1 to 11comprising a step of adding cabotegravir to a solution of stearoyl chloride in the presence of N-methyl-2-pyrrolidione.

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