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WO2023105222A1 - Composition pharmaceutique - Google Patents

Composition pharmaceutique Download PDF

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Publication number
WO2023105222A1
WO2023105222A1 PCT/GB2022/053123 GB2022053123W WO2023105222A1 WO 2023105222 A1 WO2023105222 A1 WO 2023105222A1 GB 2022053123 W GB2022053123 W GB 2022053123W WO 2023105222 A1 WO2023105222 A1 WO 2023105222A1
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WO
WIPO (PCT)
Prior art keywords
psilocybin
polymorph
hydrate
batch
optionally
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2022/053123
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English (en)
Inventor
Jason Gray
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beckley Psytech Ltd
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Beckley Psytech Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/GB2021/053199 external-priority patent/WO2022123232A1/fr
Priority claimed from GBGB2208464.4A external-priority patent/GB202208464D0/en
Application filed by Beckley Psytech Ltd filed Critical Beckley Psytech Ltd
Publication of WO2023105222A1 publication Critical patent/WO2023105222A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This invention relates to polymorph A' (prime) of psilocybin and methods of making the same.
  • Psilocybin [3-(2-Dimethylaminoethyl)-lH-indol-4-yl] dihydrogen phosphate
  • Psilocybin is a pharmacologically active compound of the tryptamine class and has the chemical formula:
  • Psilocybin is a psychoactive/psychedelic prodrug substance found in nature. Psilocybin is rapidly dephosphorylated in the body to psilocin, which is a partial agonist for several serotonin receptors, which are also known as 5-hydroxytryptamine (5-HT) receptors. It is believed that psilocin binds with high affinity to 5-HT 2 receptors and low affinity to 5-HTi receptors, including 5-HTIA and 5-HTI D ; effects are also mediated via 5-HT2C receptors. Psilocybin is not easy to handle, and is often taken with the consumption of mushrooms containing the substance, and there are challenges in formulating it for effective delivery in a controlled way in pharmaceutically useful compositions.
  • psilocybin polymorph A' a method of producing the same, in particular in producing psilocybin polymorph A' in high polymorphic purity.
  • psilocybin polymorph A' in high polymorphic purity is challenging.
  • it is known that producing highly polymorphically pure psilocybin is challenging (e.g. Sherwood et al., Acta Crystallographica Section C, Volume 781 Part 11 January 20221 Pages 36-55).
  • the previously described controlled drying processes result in a mixture of psilocybin polymorphs.
  • a method of producing polymorph A' of psilocybin comprising passing a flow of an inert gas under reduced pressure over a hydrated form of psilocybin.
  • the invention provides polymorph A' of psilocybin with a high polymorphic purity, and where the resultant powder has beneficial physical properties, in particular for formulation in nasal administration. This result is unknown, surprising and useful.
  • Figure 1 is a schematic route for the synthesis of psilocybin and psilocin.
  • Figure 2 is a schematic route for the preparation of a powder form of psilocybin or psilocin.
  • Figure 3 is an XRPD diffractogram of Polymorph A' of psilocybin.
  • Figure 4 is an XRPD diffractogram of Polymorph A' of psilocybin.
  • Figure 5 is an XRPD diffractogram of Polymorph A' of psilocybin.
  • Figure 6 shows an XRPD diffractogram of psilocybin batch PSC.40(3)0820 of psilocybin.
  • Figure 7 to Figure 9 shows an optical micrograph of psilocybin particles.
  • Figure 10 shows DSC and TGA thermographs of batch 136-01.
  • Figure 11 to Figure 13 show micrograph images of psilocybin particles (batch 136-01) dispersed in immersion oil, under plan-polarised light.
  • Figure 14 shows DSC and TGA thermographs of batch 136-02.
  • Figure 15 to Figure 18 show micrograph images of psilocybin particles (batch 136-02) dispersed in immersion oil, under plan-polarised light.
  • Figure 19 shows DSC and TGA thermographs of batch 136-03.
  • Figure 20 to Figure 26 show micrograph images of psilocybin particles (batch 136-03) dispersed in immersion oil, under plan-polarised light.
  • Figure 27 shows DSC and TGA thermographs of batch 136-04.
  • Figure 28 shows DCS and TGA thermographs of batch 136-04 dried for 18 hrs.
  • Figure 29 shows DCS and TGA thermographs of batch 06-01.
  • Figure 30 to Figure 32 show micrograph images of psilocybin particles (batch 06-01).
  • Figure 33 shows a micrograph image of psilocybin particles (batch 06-02).
  • Figure 34 to Figure 36 show micrograph images of psilocybin particles (batch 06-02) dispersed in immersion oil, under plan-polarised light.
  • Figure 37 shows a micrograph image of psilocybin particles (batch 09-01).
  • Figure 38 shows a micrograph image of psilocybin particles (batch 09-01) dispersed in immersion oil, under plan-polarised light.
  • Figure 39 and Figure 40 show micrograph images of psilocybin particles (batch 09-01) dispersed in immersion oil.
  • Figure 41 shows a micrograph image of psilocybin particles (batch 142-01) dispersed in immersion oil, under plane-polarised light.
  • Figure 42 to Figure 46 show a micrograph image of psilocybin particles (batch 11-5C) dispersed in immersion oil, under plan-polarised light.
  • Figure 47 to Figure 49 show a micrograph image of psilocybin particles (batch 11-20C) dispersed in immersion oil, under plan-polarised light.
  • Figures 50 to 54 show micrograph images of batch 16-01 damp which revealed a mixture of birefringent needles and short columns/rods.
  • Figures 55 to 60 show micrograph images of batch 16-02 damp which revealed a mixture of birefringent long columns.
  • Figure 61 shows XRPD pattern comparison of batch 58-01 (black) with batch 136-04, Hydrate (red) and PSC40(9)1120 bottle 4, Form A prime (blue).
  • Figure 62 shows DSC and TGA thermographs of batch 58-01.
  • Figures 63 to 65 show micrograph images of batch 58-01, dispersed in immersion oil, under partially plane- polarised light.
  • Figure 66 shows a DSC thermograph overlay of a batch of psilocybin polymorph A' (PSC.40(3)0820) pre- and post-185°C thermal manipulation.
  • Figure 67 shows a DSC and TGA thermograph overlay of a batch of psilocybin polymorph A' (PSC.40(3)0820), acquired at 10°C min 1 heating rate.
  • the term 'hydrated form of psilocybin' and the term 'hydrate of psilocybin' as used in this application are intended to be equivalent terms and so are used interchangeably within this application.
  • the 'hydrated form of psilocybin' is any form of psilocybin containing water of crystallization, but may additionally include free water trapped within the crystal lattice structure, or trace water trapped between crystals within a mass of crystals.
  • the term 'psilocybin polymorph A' ' and the term 'polymorph A' ' used in this application are intended to be equivalent terms and so are used interchangeably within this application.
  • passing the flow of the inert gas under reduced pressure over the hydrated form of psilocybin is used to dry/dehydrate the hydrated form of psilocybin. In an embodiment, passing the flow of the inert gas under reduced pressure over the hydrated form of psilocybin is used to form a substantially dry/dehydrated/anhydrous form of psilocybin. In an embodiment, passing the flow of an inert gas under reduced pressure over the hydrated form of psilocybin is used to dry/dehydrate the hydrated form of psilocybin.
  • passing the flow of an inert gas under reduced pressure over the hydrated form of psilocybin is used to form a substantially dry/dehydrated/anhydrous form of psilocybin.
  • the polymorph A' product is substantially polymorphically pure.
  • the polymorph A' product comprises at least 90, 95, 96, 97, 98, 98.5, 99, 99.5, 99.8, or 99.9% polymorph A'.
  • the polymorph A' product is substantially free of any other polymorphic forms of psilocybin, and optionally comprises no more than 1, 2, 3, 4 or 5% of any other polymorphic forms of psilocybin.
  • the polymorph A' product is substantially free of polymorph A, B, Hydrate A and/or amorphous psilocybin, and optionally comprises no more than 1, 2, 3, 4 or 5% of polymorph A, B, Hydrate A and/or amorphous psilocybin.
  • the inert gas is substantially free of water and/or oxygen. In an embodiment, the inert gas is nitrogen.
  • the reduced pressure is a mild vacuum. In an embodiment, the reduced pressure is below atmospheric pressure, optionally the pressure is between 0.1 and lOOmbar, further optionally between 0.5 and 20mbar, still further optionally between 1 and lOmbar. In an embodiment, the flow rate of the inert gas is adapted to maintain the selected pressure.
  • the flow rate of the inert gas is selected from: between 10 to lOOml/min, between 20 to 80ml/min, between 30 to 70ml/min, between 40 to 60ml/min, and about 50ml/min.
  • the flow rate of the gas mentioned hereinabove is per an initial mass of the psilocybin hydrate, wherein the initial mass is 0.1, 0.5, 1, 2, 5, 10, 100, 250, 500 or 1000g of the hydrated form of psilocybin.
  • the polymorph A' product is a uniform powder, optionally wherein the powder is suitable for nasal delivery. In an embodiment, the polymorph A' product is a free-flowing powder.
  • the polymorph A' product is substantially free from, or has low levels of, crystal surface defects or amorphous psilocybin.
  • the polymorph A' product has a narrow particle size distribution.
  • the particle size distribution can be between 5 microns and 200 microns. In an embodiment, the particle size distribution can be between 50 microns and 150 microns. In an embodiment, the particle size distribution can be between 100 microns and 125 microns.
  • the particle size distribution can be further controlled by the combination of quadratic cooling and controlled drying.
  • the invention and embodiments thereof, provide a polymorph A' product with fewer polymorphic impurities than found in prior art methods and that the resultant particle sizes produced can be controlled to be of a useful size.
  • the hydrated form of psilocybin is formed prior to use, by the cooling of a saturated aqueous solution of psilocybin. In an embodiment, the hydrated form of psilocybin is formed by the cooling of a saturated aqueous solution of psilocybin.
  • the cooling is quadratic cooling.
  • the hydrated form of psilocybin is recovered from the solution as a solid mass. In an embodiment, the hydrated form of psilocybin is recovered from the solution by filtration. In an embodiment, the recovered solid mass is washed. In an embodiment, the recovered solid mass is washed with cooled water. In an embodiment, the saturated aqueous solution of psilocybin is cooled from between 70 to 50°C to 10 to 0°C, and optionally cooled from between 60 to 5°C. In an embodiment, the recovered hydrated form of psilocybin comprises fewer impurities than prior to recovery. In an embodiment, the recovered hydrated form of psilocybin is purified in the process. In an embodiment, the hydrated form of psilocybin is recovered substantially free of impurities.
  • the cooling rate is between 1 and 10°C/hr, optionally between 3 and 7°C/hr and further optionally at about 5°C/hr.
  • the saturated aqueous solution of psilocybin is stirred at between 100 and 200rpm.
  • the saturated aqueous solution of psilocybin is seeded with a seed material comprising or consisting of a hydrated form of psilocybin.
  • the saturated aqueous solution of psilocybin is seeded with 0.01 to 0.5%, optionally 0.05 to 0.2%, and further optionally about 0.1% of the seed material. For example, if the solution contains 100g of psilocybin then 0.5g of the seed material is added and this equates to seeding at 0.5%.
  • the seed material is added to the saturated aqueous solution of psilocybin at, or below, 61°C. In an embodiment, the seed material is added to the saturated aqueous solution of psilocybin at a temperature of between 56 to 61°C.
  • the seed material is in the form of large needles.
  • the needles are about 300pm to 2mm in size when measured along their largest dimension/axis.
  • the needles are 50pm to 10mm, 100pm to 5mm, 200pm to 2mm, 0.25m to 1mm, or about 0.5mm in size when measured along their largest dimension/axis.
  • the needles are from about 300pm to 1.7mm in size, and optionally have an aspect ratio ranging from 6:1 to 35:1.
  • the method of producing the hydrated form of psilocybin described herein provides large crystals with less imperfections, accretions and fines that when treated according to the first aspect of the invention (and embodiments thereof), gives the polymorph A' product with controllable and desirable physical properties, such as having controllable and/or narrow particle size distribution.
  • the polymorph A' of psilocybin is characterised by one or more peaks in an XRPD diffractogram at 11.5, 12.0 and 14.5°20 ⁇ O.l°20.
  • Polymorph A' of psilocybin obtained using the method of the first aspect of the invention, and/or any embodiments thereof.
  • a pharmaceutically acceptable product comprising Polymorph A' of psilocybin obtained using the method of the first aspect of the invention, and/or any embodiments thereof.
  • a pharmaceutically acceptable product comprising the Polymorph A' of psilocybin obtained using the method of the first aspect of the invention, and/or any embodiments thereof, for use in a medical treatment.
  • a method of forming polymorph A' of psilocybin from a hydrated form of psilocybin comprising the step of passing a flow of an inert gas under reduced pressure over the hydrated form of psilocybin to give a product comprising the polymorph A' of psilocybin.
  • a crystalline psilocybin Polymorph A' characterised by one or more of: a. Peaks in an XRPD diffractogram at 11.5, 12.0 and 14.5°20 + O.l°20; b. Peaks in an XRPD diffractogram at 11.5, 12.0 and 14.5°20 ⁇ O.l°20, but absent or substantially absent of a peak at 17.5°20 ⁇ O.l°20; c.
  • psilocybin Polymorph A' exhibits an XRPD diffractogram characterised by the diffractogram summarised in anyone of Tables 1, 2 or 3.
  • psilocybin Polymorph A' exhibits an XRPD diffractogram characterised by the diffractogram summarised in anyone of Tables la, 2a or 3a.
  • XRPD Data Ambient temperature XRD (30 deg. C) was performed. Data was collected using a copper x-ray anode tube, 2-Theta range from 4-40 degrees, with step size 0.02, 1 second per step. All samples have identical patterns, with crystallinity > 95%. The data shows that the samples are polymorph A'. It is noted that Polymorph A has a characteristic small peak at 17.5 deg. 2-Theta, but this peak is absent in the XRPD for the measured samples. These samples have a peak at 10.1 deg. 2-Theta, which is absent from Polymorph A. Polymorphs A' in the prior art is thought to only form in small scale recrystallizations. However, it was found that it was possible to make polymorph A' on a large scale in accordance with the disclosure herein.
  • the psilocybin Polymorph A' comprises at least a peak at 1O.1°20 ⁇ O.l°20 in the XRPD.
  • the psilocybin Polymorph A' does not have, or does not substantially have, a peak at 17.5°20 ⁇ O.l°20 in the XRPD.
  • the peak at 17.5°20 ⁇ O.l°20 is characteristic of psilocybin Polymorph A.
  • the psilocybin Polymorph A' comprises at least 4 peaks (+ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 + O.l°20.
  • the psilocybin Polymorph A' comprises at least 5 peaks (+ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 + 0.1’20.
  • the psilocybin Polymorph A' comprises at least 6 peaks (+ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 ⁇ O.l°20.
  • the psilocybin Polymorph A’ comprises at least 7 peaks ( ⁇ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 ⁇ O.l°20.
  • the psilocybin Polymorph A' comprises at least 8 peaks ( ⁇ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 ⁇ O.l°20.
  • the psilocybin Polymorph A' comprises at least 9 peaks (+ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 + O.l°20. In an embodiment, the psilocybin Polymorph A' comprises at least 10 peaks ( ⁇ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 ⁇ O.l°20.
  • the psilocybin Polymorph A' comprises at least 11, 12, 13, 14, 15 or 16 peaks ( ⁇ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5’20 + 0.1’20.
  • the psilocybin Polymorph A' exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram of Figure 3.
  • the psilocybin Polymorph A' exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram of Figure 4.
  • the psilocybin Polymorph A' exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram of Figure 5.
  • the polymorph is polymorph A' as characterised by an XRPD diffractogram as substantially illustrated in Figure 6.
  • the psilocybin Polymorph A' exhibits peaks in an XRPD diffractogram at 10.1, 14.9, 18.7, 19.4, 21.1, 25.1, 26.3 and 28.6 + 0.1 °20.
  • the peaks in an XRPD diffractogram according to polymorph A' are within the scope of experimental error based on conditions and device used for 29.
  • the peaks in an XRPD diffractogram according to polymorph A' are + 0.05°29.
  • the peaks in an XRPD diffractogram according to polymorph A' are + 0.1°29.
  • the peaks in an XRPD diffractogram according to polymorph A' are + O.15°20.
  • the peaks in an XRPD diffractogram according to polymorph A' are ⁇ 0.2°29. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ⁇ 0.25’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ⁇ O.3°20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ⁇ O.4°20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ⁇ O.5°20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ⁇ 1°20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ⁇ 1.5°20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are + 2’20.
  • the polymorph is polymorph A' as characterised by a minor endotherm peaking at 155.43 °C (10.767 J/g) with a preceding shoulder peaking at 142.49°C and a main endotherm peaking at 221.09’C (79.782 J/g) in a DSC thermograph.
  • the polymorph is polymorph A' as characterised by a endotherm peaking at ca. 155°C with a preceding shoulder peaking at around 142 °C and a main endotherm peaking at ca. 221°C in a DSC thermograph.
  • the polymorph is polymorph A' as characterised by an onset of melt during hot stage microscopy from 227°C.
  • the polymorph is polymorph A' as characterised by a completion of melt during hot stage microscopy by 234°C.
  • polymorph is polymorph A' as characterised by a DSC thermograph as substantially illustrated in Figure 66 or Figure 67. In an embodiment, polymorph is polymorph A' as characterised by a TGA thermograph as substantially illustrated in Figure 67
  • Thermal examination of a batch of psilocybin polymorph A' demonstrated an (moderate) endotherm peaking at 155.43°C (ca. 155°C) and a main endotherm peaking at 221.09°C (co. 221°C), which is believed to be the main melt-endotherm.
  • TGA examination ( Figure 67) revealed a minor weight reduction of 0.27 wt% from co. 25 to 100°C which is believed to be due to residual solvent and/or water and no other events until the onset degradation that coincided with what is believed to be the main melt endotherm from co. 210°C.
  • the DSC thermograph for the batch is considered to be substantially similar to that reported for polymorph A', and is believed to be influenced by the crystallinity of the solids under examination.
  • the crystalline psilocybin hydrate is characterised by XRPD diffractogram peaks at 8.9, 12.6 and 13.8°20 ⁇ O.1°20. In an embodiment, crystalline psilocybin hydrate is further characterised by at least one peak appearing at 6.5, 12.2, 19.4, 20.4 or 2O.8°20 ⁇ O.1°20. In an embodiment, crystalline psilocybin hydrate is further characterised by at least two peaks appearing at 6.5, 12.2, 19.4, 20.4 or 2O.8°20 ⁇ O.1°20.
  • the hydrated form of Psilocybin is psilocybin Hydrate A. In an embodiment the hydrated form of Psilocybin is the psilocybin Trihydrate.
  • the hydrated form of Psilocybin is characterised by one or more peaks in an XRPD diffractogram at 8.9, 12.6 and 13.8°20+O.1°20.
  • a method of drying a polymorph of psilocybin comprising passing a flow of an inert gas under reduced pressure over the polymorph of psilocybin.
  • a method of removing water of crystallization from a polymorph of psilocybin comprising passing a flow of an inert gas under reduced pressure over the polymorph of psilocybin.
  • a method of de-solvating a polymorph of psilocybin comprising passing a flow of an inert gas under reduced pressure over the polymorph of psilocybin.
  • a method of removing solvent of crystallization from a polymorph of psilocybin comprising passing a flow of an inert gas under reduced pressure over the polymorph of psilocybin.
  • Production of psilocybin hydrate resulted in large needles and acicular particles of varying length which ranged from ca. 300 microns to ca.l.7mm and fines of co. 15-18 microns, as shown in Figure 7.
  • the aspect ratio of the particles ranged from 6.5:1 up to 35:1.
  • the particle morphologies of the resultant psilocybin hydrate may not be suitable for the manufacture of a pharmaceutical product, causing powder flow related issues, filtration issues and a lack of ability to uniformly dose the drug substance into a drug product.
  • the hydrate of psilocybin was not readily suitable from making a uniformly dose drug product.
  • Drying the hydrated particles in a vacuum oven afforded irregular shaped particles ranging from ca. 7 to 170 microns with a maximum aspect ratio of ca. 9:1, but achieving a low water content e.g. >0.5% required a prolonged period. Drying the hydrated particles under a relative humidity of 1% also afforded irregular shaped particles ranging from ca. 4 to 260 microns with a maximum aspect ratio of ca. 13:1.
  • the psilocybin obtained was not readily suitable from making a uniformly dose drug product.
  • polymorph A' is obtained from psilocybin hydrate. In an embodiment, polymorph A' is obtained from dehydration of psilocybin hydrate. In an embodiment, polymorph A' is obtained from dehydration under vacuum of psilocybin hydrate. In an embodiment, polymorph A' is obtained from dehydration under vacuum, in the presence of an inert atmosphere, of psilocybin hydrate. In an embodiment, polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere, of psilocybin hydrate. In an embodiment, the psilocybin hydrate is psilocybin Hydrate A. In an embodiment, the vacuum pressure is lmbar.
  • the vacuum pressure is between lmbar and lOmbar. In an embodiment, the vacuum pressure is between 0.5mbar and lOmbar. In an embodiment, the vacuum pressure is between 0.25mbar and 20mbar.
  • polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of 50ml/min, of psilocybin hydrate. In an embodiment, polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of between 40 to 60ml/min, of psilocybin hydrate.
  • polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of between 30 to 70ml/min, of psilocybin hydrate. In an embodiment, polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of between 20 to 80ml/min, of psilocybin hydrate. In an embodiment, polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of between 10 to 90ml/min, of psilocybin hydrate. In an embodiment, polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of between 10 to lOOml/min, of psilocybin hydrate.
  • high purity polymorph A' with a particle size and morphology which is suitable for direct use in a pharmaceutical product is obtained from psilocybin hydrate.
  • high purity polymorph A' with a particle size and morphology which is suitable for direct use in a pharmaceutical product is obtained from psilocybin hydrate by promoting the formation of large hydrated psilocybin particles prior to drying under a (mild) vacuum.
  • high purity polymorph A' with a particle size and morphology which is suitable for direct use in a pharmaceutical product is obtained from psilocybin hydrate by promoting the formation of large hydrated psilocybin particles prior to drying under a (mild) vacuum accompanied by a flow of nitrogen gas.
  • the flow rate is between 10 to lOOml/min.
  • the flow rate is 50ml/min.
  • a process of controlled crystallization to produce psilocybin or a polymorph thereof for direct use in a pharmaceutical product there is provided a process of controlled crystallization to produce psilocybin particles with high polymorphic purity and morphology suitable for direct use in a pharmaceutical product.
  • a process of controlled crystallization to produce highly crystalline psilocybin particles with a particle size range suitable for direct use in a pharmaceutical product there is provided.
  • a process of controlled crystallization to produce highly crystalline psilocybin polymorph A' particles with a particle size range suitable for direct use in a pharmaceutical product there is provided psilocybin particles with a particle size range suitable for direct use in a pharmaceutical product. In an embodiment, there is provided psilocybin polymorph A' particles with a particle size range suitable for direct use in a pharmaceutical product.
  • highly crystalline psilocybin polymorph A' there is provided highly crystalline psilocybin polymorph A'. In an embodiment, there is provided highly crystalline psilocybin polymorph A' with a particle size range suitable for direct use in a pharmaceutical product. In an embodiment, there is provided highly crystalline psilocybin polymorph A' as substantially illustrated in Figure 9. In an embodiment, there is provided a process that employs nitrogen or another suitable inert gas under a pressure to produce psilocybin polymorph A'. In an embodiment, there is provided a process that employs nitrogen or another suitable inert gas under a pressure in combination with vacuum to produce psilocybin polymorph A'. l.Comparison of the effect of drying procedures on the particle habit of psilocybin hydrate
  • Hot-stage microscopy examination of psilocybin hydrate revealed destruction of the particle habit during the transition from psilocybin hydrate to psilocybin polymorph A'. It is proposed that the breaks were potentially the consequence of either the rapid loss of water vapour from the crystal structure forcing the crystal apart, or the crystal structure transition to psilocybin polymorph A' induced internal stress on the crystal that overpower the needle-like habit of psilocybin hydrate.
  • a batch of damp psilocybin hydrate (batch 128-01; 3 x ca. 50mg) was weighed into 2 sample vials and 1 isolute cartridge. Sample 1 was dried in vacuo at 20°C, 1 mBar, for 24 hours. Sample 2 was dried in a desiccator at 1.1% RH, 20 ⁇ 2°C for 24 hours. Sample 3 was dried in vacuo in an isolute cartridge with a stream of dry nitrogen pulled through the sample for 1 hour at 20 ⁇ 2°C. Weights are detailed in the table below.
  • a second batch of psilocybin hydrate (batch 126-01; 158.22mg) was weighed into a tared isolute cartridge. Sample 4 was then dried in vacuo under air at 20 ⁇ 2°C for 1 hour, then an additional 1 hour. LOD between 1 and 2 hours was negligible. Following data collection, the 2-hour dried solid was dried for an additional 18 hours.
  • Residual water was then removed from psilocybin hydrate by drying in vacuo in an isolute cartridge or Buchner funnel within 2 hours on a lOOmg scale. Drying for a further 18 hours reduced the water content by 0.049%, which may have slowed dehydration of psilocybin hydrate or removal of residual water that was not fully removed within 2 hours.
  • Psilocybin hydrate was dehydrated to psilocybin polymorph A' by drying in a vacuum oven at 1 mBar, 20°C within 24 hours, by drying in a desiccator at 1.1% RH for 24 hours, and by drying in vacuo under a stream of dry nitrogen. All methods destroy the needle-like particle habit of psilocybin hydrate by non-axial fracturing of the needles to afford columnar rod-like particles with surface imperfections and fissures. All psilocybin polymorph A' samples produced were white solids.
  • the solubility of psilocybin in deionised water was determined between 5 and 80°C and ranges from ca. 2.5mg/ml at 5°C to ca. 160mg/ml at 80°C.
  • the DSC thermograph of batch 136-01 revealed an endotherm with a peak temperature of 72.02°C, coincident with a weight reduction of 0.722% in the TGA thermograph ( Figure 10). This was followed by an endotherm with a peak temperature of 160.59°C, then an endotherm with a peak temperature of 220.57°C.
  • Microscopy examination of batch 136-01 revealed highly birefringent columnar rods ranging from ca. 7 to 170pm with a maximum aspect ratio of ca. 9:1 ( Figure 11 to Figure 13).
  • the columnar rods had fissures and cracks that appeared to perpetuate into the crystals ( Figure 13), which was concordant with the previous examination of psilocybin polymorph A' material. Fine particles were not common, and no accretions were present.
  • the DSC thermograph of batch 136-02 (dried in a desiccator at 1.1% RH, for 24 hours) revealed an endotherm with a peak temperature of 68.40°C, coincident with a weight reduction of 0.442% in the TGA thermograph ( Figure 14). This was followed by an endotherm with a peak temperature of 158.18°C, then an endotherm with a peak temperature of 220.47°C.
  • Microscopy examination of batch 136-02 revealed highly birefringent columnar rods ranging from ca. 4 to 260pm with a maximum aspect ratio of ca. 13:1 (Figure 15 to Figure 18).
  • the columnar rods had fissures and cracks that appeared to perpetuate into the crystals ( Figure 17 and Figure 18).
  • the DSC thermograph of batch 136-03 (dried under vacuum and a stream of dry nitrogen for 1 hour) revealed an endotherm with a peak temperature of 71.55°C, coincident with a weight reduction of 0.466% in the TGA thermograph ( Figure 19). This was followed by an endotherm with a peak temperature of 162.12°C, then an endotherm with a peak temperature of 220.24°C.
  • Microscopy examination of batch 136-03 revealed highly birefringent columnar rods ranging from ca. 9 to 305pm with a maximum aspect ratio of ca. 12:1 (Figure 20 to Figure 26).
  • the columnar rods had fissures and cracks that appeared to perpetuate into the crystals ( Figure 23 to Figure 26), which was concordant with the previous examination of psilocybin polymorph A' material. Fine particles were rare, and no accretions were present.
  • the DSC thermograph of batch 136-04 revealed an endotherm with a peak temperature of 95.94°C, coincident with a weight reduction of 15.888% in the TGA thermograph (Error! Reference source not found.). This was followed by an endotherm with a peak temperature of 226.28°C.
  • the amount of residual water was highest in the vacuum oven-dried sample which indicated this was the least effective method of dehydrating psilocybin hydrate, the water content was below 0.5% and comparable between desiccator dried psilocybin hydrate and dried under a stream of dry nitrogen.
  • Comparison of the particle size range of the three drying techniques revealed psilocybin hydrate dehydrated in vacuo at ImBar afforded a maximum particle length of 170pm in comparison to the ca. 300pm of the other two techniques.
  • psilocybin hydrate dried under a stream of nitrogen contained far fewer fine particles in comparison to the other two techniques.
  • the table below shows a summary of characteristics of dried psilocybin hydrate samples.
  • This psilocybin polymorph A' was composed of regularly shaped short rods produced from the large needles and fine needles that contained less fractures and imperfections than the larger particles.
  • Producing regularly shaped rods as the habit of psilocybin polymorph A' requires dehydrating the large rod/needle habit of psilocybin hydrate.
  • the large rods/needles dried fully and readily under a stream of dry nitrogen in vacuo in comparison to smaller psilocybin hydrate particle habit.
  • batch 06-01 Upon further cooling batch 06-02 developed into a thick mobile faint purple suspension, batch 06-01 was a static bulk of faint purple long needles. Solids were equilibrated at 20°C for 18 hours, then cooled to 5°C and equilibrated for 1 hour prior to isolation. Solids were isolated via isolute cartridge affording a white solid and light purple filtrate. Solids were dried in vacuo for 2 hours under air.
  • Recovery of batch 06-01 was 2.04728 g, 85.7% relative to psilocybin hydrate.
  • Recovery of batch 06-02 was 2.05855 g, 91.0% relative to psilocybin hydrate.
  • Batch 06-01 (390.39mg), was charged to isolute cartridge 08-01.
  • Batch 06-02 (481.83mg) was charged to isolute cartridge 08-02.
  • Solids were dried in vacuo under a stream of dry nitrogen for 3 hours, LOD indicated that 06-01 had dehydrated within 1 hour and indicated that 06-02 was slowly losing weight at 3 hours. The solids remained white.
  • the DSC thermograph of batch 06-01 revealed an endotherm with a peak temperature of 106.87°C coincident with a weight reduction of 15.920% in the TGA thermograph ( Figure 29). This was followed by an endotherm with a peak temperature of 224.76°C.
  • the large needles were light grey under plane-polarised light and ranged from ca. 300pm to ca. 1.7mm with an aspect ratio ranging from 6:1 to 35:1 ( Figure 31 and Figure 32).
  • the smaller needles were birefringent or one colour under plane-polarise light and ranged from ca. 15 to ca. 80pm, accretions of the finer needles were present but not common and ranged from ca. 300 to 400pm ( Figure 31 and Figure 32).
  • the larger needles had a smooth surface with a consistent colour indicating good crystal growth, the smaller needles were a mixture of smooth needles and birefringent irregularly shaped needles. The quality of the habit of the crystals was much better than any previously isolated psilocybin hydrate.
  • the DSC thermograph of batch 06-02 revealed an endotherm with a peak temperature of 102.22°C coincident with a weight reduction of 15.793% in a TGA thermograph. (This was followed by an endotherm with a peak temperature of 225.73°C.
  • the quality of the particle habit was considered worse than for previously isolated psilocybin hydrate, which was believed to be because the crystallisation was agitated via stirrer bar.
  • the solution was cooled from 65°C to 5°C at lO’C.hr 1 .
  • the solution was seeded at 60°C with batch 126-01 (ca. 2mg) with the seed visually held at 60°C and was freely mobile in solution. By 50°C the seed had developed into a light red (RE8) mobile suspension.
  • the suspension was equilibrated at 5°C for 18 hours which afforded a faint purple (PU10) thick mobile suspension with fine needles visible and minor fouling of the agitator shaft.
  • the suspension was isolated via isolute cartridge affording a white solid composed of fine needles (ca. 1mm long) and a faint red (RE10) filtrate.
  • the solid was dried in vacuo under air for 2 hours, LOD between 1 and 2 hours indicated the drying was complete. Recovery was 2.15152 g, 90.1% relative to psilocybin hydrate.
  • the solid was transferred to a sealed container and nominated batch 09- 01.
  • Microscopy of batch 09-01 revealed a particle habit of birefringent needles ranging from 25pm to 510pm with a maximum aspect ratio of 10:1 ( Figure 37 to Figure 40). Needles often appeared accreted together in parallel bundles of needles. Fine particles were present but not common and no accretions were present other than the bundles of needles.
  • Suspensions were equilibrated at 5°C for a total time of 18 hours.
  • Batch 11-5C was a light grey/faint purple (NE8/PU10) suspension composed of visible needles.
  • Batch 11-20C was a faint purple/pink (PU10/PI6) suspension.
  • Suspensions were isolated via vacuum filtration by isolute cartridge and dried in vacuo, after 3 hours LOD slowed, which indicated drying was approaching completion.
  • Recovery of batch 11-5C was 2.10682g, 88.5% relative to psilocybin hydrate and afforded a white solid and a light red filtrate.
  • Recovery of batch 11-20C was 2.18016g, 91.5% relative to psilocybin hydrate and afforded a white solid and a light red filtrate.
  • Microscopy of batch 11-5C revealed a mixture of birefringent columns and thin needles.
  • the columns ranged from ca. 50pm to 500pm with an aspect ratio of ca. 6:1, the columns were birefringent and were not a consistent colour throughout and closer inspection revealed the particles were composed of bundles of thin needles ( Figure 42 to Figure 46).
  • the thin needles ranged from co. 50pm to co. 400pm with an aspect ratio of GT 10:1. Fine needle-like particles (LT 20pm) were common and no accretions were present.
  • Microscopy of batch 11-20C revealed a particle habit of short irregularly shaped rods ranging from co. 5pm to co. 50pm with an aspect ratio of co. 4:1 ( Figure 47 to Figure 49). Accretions of particles were common and ranged from co. 60pm to co. 200pm.
  • Psilocybin hydrate seed 0.1% was necessary to produce large columnar rods of psilocybin hydrate, when the seed was not used the particle size was 10 times smaller.
  • the cooling rate from 65°C to 60°C was considered a non-critical clarification step so the cooling profile was not be applied until 60°C to reduce any potential degradation of psilocybin.
  • Solutions were cooled from 65°C to 60°C at lO’C.hr 1 and confirmed to be clear solutions. Solutions were seeded with SPS5531 batch 21-35-06-01, 2mg. Solutions were cooled as detailed in the tables below, which provided an approximate rate of deposition of psilocybin from solution of 50%.hr -1 and 6.25%.hr -1 respectively. Suspensions were equilibrated at 5°C at 200rpm for a total cooling time of 18 hours. Batch 16-01 was a faint red (RE10) suspension, batch 16-02 was a light grey suspension.
  • Microscopy of batch 16-01 damp revealed a mixture of birefringent needles and short columns/rods.
  • the needles ranged from ca. 50pm to 200pm with an aspect ratio of ca. 10:1 ( Figure 50 to Figure 54).
  • the short columns/rods ranged from co. 5pm to 100pm with an aspect ratio of co.4:l. No accretions were present, but some fines were present, however, there were fewer fines than previous crystallisations.
  • Microscopy of batch 16-02 damp revealed a mixture of birefringent long columns.
  • the columns ranged from co. 100pm to 700pm with an aspect ratio ranging from 4:1 to 12:1 ( Figure 55 to Figure 60).
  • the columns appeared to be composed of bundles of needle-like particles, but this habit appeared to be of a high quality. No accretions were present and fine particles were not common, these appeared to be a result of fragmentation of the large columns.
  • Quadratic cooling over 16 hours afforded psilocybin hydrate with a larger more regular shape in comparison to the particles afforded from a quadratic cooling profile over 2 hours. This was likely a consequence of uncontrolled crystallisation of psilocybin from a supersaturated solution.
  • the seed point tolerance was identified for the seed generation process with 'pure psilocybin' polymorph A' input material, this identified the seed held at or below 62°C and spontaneously crystallised when cooled to 59°C 7.
  • the solution was cooled to 60°C over 30 minutes at lO’C.hr 1 , then cooled according to the cooling profile detailed in the table below, then equilibrated at 5°C for 2 hours.
  • the solution crystallised at 57°C and developed into a mesh of interlacing needles during the cool to 5°C.
  • the mesh of interlacing needles was agitated at 250rpm at 5°C for 2 minutes, this afforded a mostly mobile suspension but a large mass of solid was floating above the stirrer blades. This mass partially dispersed following an additional 2 minutes of agitation, but some was still present.
  • Solids were broken apart into a coarse powder and transferred to sealed containers.
  • the XRPD pattern of batch 46-01 (dried in vacuo under atmospheric lab air for 24 hours) was concordant with the psilocybin hydrate.
  • the XRPD pattern of batch 46-02 (dried in vacuo under compressed air for 6 hours) was concordant with a mixture of PSC40(9)1120 bottle 3, psilocybin polymorph A' and the psilocybin hydrate.
  • Drying batches 46-01 and 46-02 revealed the portion dried in vacuo under ambient atmospheric lab air (ca. 45% RH) for 24 hours afforded a dry hydrate material with no residual water, however, the portion dried in vacuo under compressed air ( ⁇ 3% RH) for 6 hours afforded a mixture of hydratend psilocybin polymorph A' material by XRPD.
  • the TGA thermograph revealed the weight reduction was concordant with dehydration of ca. 40% of the hydrate material to psilocybin polymorph A' following drying in vacuo under compressed air for 6 hours. This was believed to be due to the low humidity of the compressed air but did not dehydrate the hydrate material to the extent expected. As such, the use of compressed air is not optimal.
  • Psilocybin hydrate seed material was shown to dehydrate to psilocybin polymorph A' when dried under an atmosphere of dry nitrogen, which were co. 1% RH. To prevent the dehydration of psilocybin hydrate to psilocybin polymorph A' the solid must be dried in a humid atmosphere. An atmosphere of nitrogen bubbled through deionised water was investigated for the drying of psilocybin hydrate seed material.
  • the XRPD pattern of batch 58-01 was concordant with 136-04, psilocybin hydrate, and contained no diffractions indicative of batch PSC40(9)1120 bottle 4, Form A prime ( Figure 61).
  • the clear solution was equilibrated at 65°C for 30 minutes then cooled to 60°C at lO’C.hr 1 over 30 minutes. The solution was then subject to the cooling profile detailed in the table below, then equilibrated at 5°C for 1 hour. This afforded a mass of off-white solids and liquors. The contents were agitated via pitch blade turbine agitator at 250rpm for 5 minutes, agitation afforded a free-flowing mobile suspension within 3 minutes.
  • An Atmos bag was filled with nitrogen bubbled through deionised water, then evacuated via vacuum pump. This was repeated three times, the bag was then filled with humidified nitrogen and flow rate adjusted to match the amount removed by the vacuum pump.
  • the relative humidity ranged from 80 to 90%
  • the psilocybin hydrate seed suspension was isolated by vacuum filtration in the Atmos bag under an atmosphere of humidified nitrogen (80-90%RH) and dried for 4 hours, the relative humidity remained between 70 and 90% for the duration of the drying. No visual change was observed in the solid.
  • the solid was transferred to a sealed container and nominated batch 58-01.
  • the DSC thermograph of batch 58-01 revealed a broad endotherm with a peak temperature of 92.93°C coincident with a weight reduction of 15.917% in the TGA thermograph ( Figure 62). This was followed by a shallow endotherm with a peak temperature of 176.36°C, followed by an endotherm with a peak temperature of 214.85°C.
  • Microscopy of batch 58-01 revealed a mixture of birefringent short needles that were uniformly coloured under partially plan-polarised light, fine particles, and accretions of particles (Figure 63 to 65).
  • the short needles ranged from ca. lOto 130pm with an aspect ratio ranging from 4:1 to 25:1.
  • the accretions ranged from 100 to 400pm and did not disperse in immersion oil. Fine particles and accretions were common. Microscopy examination was consistent with previously examined psilocybin hydrate seed material.
  • Bubbling nitrogen gas through deionised water afforded an atmosphere of nitrogen ranging from 70 to 90% RH.

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Abstract

L'invention concerne un procédé de production d'un polymorphe A' de psilocybine, le procédé concernant à faire passer un flux d'un gaz inerte à pression réduite sur une forme hydratée de psilocybine.
PCT/GB2022/053123 2021-12-07 2022-12-07 Composition pharmaceutique Ceased WO2023105222A1 (fr)

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PCT/GB2021/053199 WO2022123232A1 (fr) 2020-12-07 2021-12-07 Composition pharmaceutique comprenant de la psilocybine ou ses polymorphes
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Citations (3)

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Publication number Priority date Publication date Assignee Title
US20080293695A1 (en) * 2007-05-22 2008-11-27 David William Bristol Salts of physiologically active and psychoactive alkaloids and amines simultaneously exhibiting bioavailability and abuse resistance
WO2019073379A1 (fr) * 2017-10-09 2019-04-18 Compass Pathways Limited Préparation de psilocybine, différentes formes polymorphes, intermédiaires, formulations et leur utilisation
GB2588505A (en) * 2017-10-09 2021-04-28 Compass Pathfinder Ltd Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080293695A1 (en) * 2007-05-22 2008-11-27 David William Bristol Salts of physiologically active and psychoactive alkaloids and amines simultaneously exhibiting bioavailability and abuse resistance
WO2019073379A1 (fr) * 2017-10-09 2019-04-18 Compass Pathways Limited Préparation de psilocybine, différentes formes polymorphes, intermédiaires, formulations et leur utilisation
US10519175B2 (en) * 2017-10-09 2019-12-31 Compass Pathways Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
GB2588505A (en) * 2017-10-09 2021-04-28 Compass Pathfinder Ltd Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use

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Title
KARGBO ROBERT B ET AL: "SUPPORTING INFORMATION Psilocybin: Characterization of Metastable Zone Width (MSZW), Control of Anhydrous Polymorph and Particle Size Distribution (PSD) 1 Experimental techniques", ACS OMEGA, 7 February 2022 (2022-02-07), XP093024792 *
KARGBO ROBERT B. ET AL: "Psilocybin: Characterization of the Metastable Zone Width (MSZW), Control of Anhydrous Polymorphs, and Particle Size Distribution (PSD)", ACS OMEGA, vol. 7, no. 6, 7 February 2022 (2022-02-07), US, pages 5429 - 5436, XP093024599, ISSN: 2470-1343, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acsomega.1c06708> DOI: 10.1021/acsomega.1c06708 *
KAYLO KRISTI ET AL: "Preparation and Characterization of Novel Crystalline Solvates and Polymorphs of Psilocybin and Identification of Solid Forms Suitable for Clinical Development Psilocybin View project 5-MeO-DMT View project", RESEARCH GATE, 1 February 2020 (2020-02-01), XP093024596, DOI: 10.13140/RG.2.2.32357.14560 *
SHERWOOD ALEXANDER M. ET AL: "Psilocybin: crystal structure solutions enable phase analysis of prior art and recently patented examples", ACTA CRYSTALLOGRAPHICA SECTION C STRUCTURAL CHEMISTRY, vol. 78, no. 1, 1 January 2022 (2022-01-01), pages 36 - 55, XP093024555, Retrieved from the Internet <URL:https://journals.iucr.org/c/issues/2022/01/00/wp3022/wp3022.pdf> DOI: 10.1107/S2053229621013164 *
SHERWOOD ET AL., ACTA CRYSTALLOGRAPHICA SECTION C, vol. 78, January 2022 (2022-01-01), pages 36 - 55

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