RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application Serial No. 63/319,243, filed March 11, 2022, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to the field of solvates of apomorphine hydrochloride, a method for obtaining the same, and its use in the purification of apomorphine.

BACKGROUND OF THE INVENTION

[0003] Apomorphine is a drug approved for the treatment of acute hypomobility or “off’ episodes in patients with Parkinson’s disease. The most practiced clinically administered route for apomorphine is by intermittent sublingual administration (e.g., Kynmobi®), subcutaneous injection via a pre-filled injection pen (e.g., Apokyn®, or Apo- Go®), or by continuous infusion pump (e.g., Dacepton®).

[0004] Apomorphine (I) has the following chemical structure: and chemical name (6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline -10,ll- diol. Apomorphine is marketed as hydrochloride hemihydrate salt (11).

1/2 H ₂ O HCI

[0005] WO2016103262 discloses several apomorphine free base (I) solvates, including apomorphine mono isopropanol solvate, apomorphine formamide solvate, apomorphine acetone solvate, apomorphine TBME solvate, apomorphine methyl acetate solvate, apomorphine THF solvate, apomorphine ethanol solvate, apomorphine acetonitrile solvate, apomorphine hydrate, sample apomorphine 1 ,4-dioxane solvate, apomorphine nitromethane solvate, apomorphine pyridine solvate, apomorphine ethylene glycol solvate, apomorphine- 0.5*acetone solvate, apomorphine- 0.5*EtOH solvate, and apomorphine- 0.5*THF solvate.

[0006] It is known in the art that having a drug with high purity is a regulatory requirement to market such drug and there is always the need to find cheap and easy methods to obtain drugs with high purity, and pharmaceutical compositions containing the same. Monitoring impurities of the active ingredient is necessary to ensure effectiveness of the drug.

[0007] There is a need to provide new forms of apomorphine that could be used in the purification of apomorphine.

SUMMARY OF THE INVENTION

[0008] The first aspect of the invention is apomorphine hydrochloride trimethanolate (III): and its polymorphs.

[0009] The second aspect is a composition comprising the apomorphine hydrochloride trimethanolate (III) of the first aspect of the invention.

[0010] The third aspect is a method of preparation of the apomorphine hydrochloride trimethanolate (III) of the first aspect of the invention: a) dissolving apomorphine hydrochloride hemihydrate (II) in methanol comprising less than 0.5 % water by weight, b) allowing the apomorphine hydrochloride trimethanolate (III) to precipitate, and c) isolating the apomorphine hydrochloride trimethanolate (III). [0011] The fourth aspect of the invention is a method of purification of apomorphine hydrochloride hemihydrate (II) comprising: a) exposing the apomorphine hydrochloride trimethanolate (III), of the first aspect of the invention, to an environment having a relative humidity of 50% or higher, b) allowing the methanol in the crystal structure to evaporate, and c) collecting the apomorphine hydrochloride hemihydrate (II).

[0012] The fifth aspect of the invention is the use of the apomorphine hydrochloride trimethanolate (III), of the first aspect of the invention, for the purification of the apomorphine hydrochloride hemihydrate (II).

[0013] The sixth aspect of the invention is apomorphine hydrochloride hemihydrate (II) comprising apomorphine hydrochloride trimethanolate (III), of the first aspect of the invention, in an amount greater than zero and less than 0.1% by weight determined by X-Ray diffraction or FTIR.

[0014] The seventh aspect of the invention is a pharmaceutical composition comprising apomorphine hydrochloride hemihydrate (II) comprising apomorphine hydrochloride trimethanolate (III), of the first aspect of the invention 3, in an amount greater than zero and less than 0.1% by weight determined by X-Ray diffraction, and optionally one or more excipients.

[0015] The eighth aspect of the invention is a method of selecting apomorphine hydrochloride hemihydrate (II) purer batches comprising the use of apomorphine hydrochloride trimethanolate (III), of the first aspect of the invention, as a reference standard. [0016] The ninth aspect of the invention is a method for analysing the purity of apomorphine hydrochloride hemihydrate (II) in a sample comprising determining the amount of apomorphine hydrochloride trimethanolate (III).

[0017] The tenth aspect of the invention is a method for determining the presence of apomorphine hydrochloride trimethanolate (III), of the first aspect of the invention, in a sample comprising apomorphine hydrochloride hemihydrate (II), wherein the compound (III) is used as reference standard, said method comprising: a) acquiring a spectrum of apomorphine hydrochloride trimethanolate (III), b) selecting one or more selective peaks in the spectrum of step (a), c) acquiring a spectrum of a sample, and d) determining if the one or more of the selective peaks of step (b) are in the spectrum of step (c), wherein the spectrum is an X-Ray diffraction spectrum, and infrared spectrum or a Raman spectrum.

BRIEF DESCRIPTION OF THE FIGURES

[0018] Figure 1 illustrates an X-Ray diffractogram of apomorphine hydrochloride hemihydrate (II).

[0019] Figure 2 illustrates an X-Ray diffractogram of apomorphine hydrochloride trimethanolate (III).

[0020] Figure 3 illustrates an overlay of X-Ray diffractograms of apomorphine hydrochloride trimethanolate (III) and apomorphine hydrochloride hemihydrate (II). [0021] Figure 4 illustrates an FTIR spectrum of apomorphine hydrochloride hemihydrate (II).

[0022] Figure 5 illustrates an FTIR spectrum of apomorphine hydrochloride trimethanolate (III).

[0023] Figure 6 illustrates an overlay of FTIR spectrum of apomorphine hydrochloride trimethanolate (III) and apomorphine hydrochloride hemihydrate (II). [0024] Figure 7 illustrates the tridimensional (3D) structure of apomorphine hydrochloride trimethanolate (III) calculated from X-Ray diffraction of an apomorphine hydrochloride trimethanolate (III) monocrystal.

DEFINITIONS

[0025] As used herein, the term “composition” comprises a pure drug, two or more drugs, or one or more drugs in combination with additional components and/or related impurities. Additional components can include, for example, pharmaceutically acceptable excipients, carriers, and the like.

[0026] As used herein, the phrase “pharmaceutically acceptable excipient” refers to any substance, other than the pharmacologically active drug or prodrug, that is useful in preparing a pharmaceutical composition, which is generally safe and non-toxic and that is approved or approvable by a regulatory agency.

[0027] As used herein, the phrase “solid drug film” is a layer of a composition.

[0028] As used herein, the phrase “area density” in a two-dimensional object (such as the solid drug film) is calculated as the mass per area unit.

[0029] As used herein, the term “FTIR” refers to Fourier-Transform Infra-Red spectroscopy.

DETAILED DESCRIPTION OF THE INVENTION

[0030] While preparing high concentration solutions of apomorphine hydrochloride hemihydrate (II) in methanol the inventors observed the precipitation of a white solid. The solid was isolated and it was identified as a lower solubility apomorphine solvate being apomorphine hydrochloride trimethanolate (III).

[0031] To meet the regulatory standards of purity for a pharmaceutical product, the content of apomorphine hydrochloride trimethanolate (III) in the apomorphine hydrochloride hemihydrate (II) should be controlled.

[0032] This apomorphine hydrochloride trimethanolate (111) is useful in the process of apomorphine purification. However, it is preferred that the content of apomorphine hydrochloride trimethanolate (III) in the apomorphine hydrochloride hemihydrate (II) obtained is low in order to maintain the pharmacokinetic properties of apomorphine hydrochloride hemihydrate (II).

[0033] Isolated apomorphine hydrochloride trimethanolate (III) is also useful in methods to measure the purity of apomorphine hydrochloride hemihydrate (II). Isolated apomorphine hydrochloride trimethanolate (III) is also useful as a reference standard for qualitatively or quantitatively determining the content of this product in apomorphine hydrochloride batches.

[0034] Further, the isolated apomorphine hydrochloride trimethanolate (III) is also useful in the manufacture of medicaments.

[0035] Embodiment 1: Apomorphine hydrochloride trimethanolate (III): and its polymorphs.

[0036] Embodiment 2: A polymorph of the apomorphine hydrochloride trimethanolate (III) of the previous embodiment characterized by an X-Ray diffractogram comprising peaks at 9.2 ± 0.2 °20; preferably at 9.2 and 20.0 ± 0.2 °20; more preferably at 9.2, 14.2, 20.0 and 26.2 + 0.2 °20; still more preferably at 9.2, 9.9, 14.2, 20.0, 25.1 and

26.2 + 0.2 °20; even more preferably at 9.2, 9.9, 14.2, 14.4, 14.8, 20.0, 21.3, 25.1 and 26.2 ± 0.2 °20; still even more preferably at 9.2, 9.9, 14.2, 14.4, 14.7, 14.8, 20.0, 21.3, 24.6, 24.8, 25.1, 26.2 and 28.8 ± 0.2 °20; still even more preferably at 9.2, 9.9, 10.2, 14.2, 14.4, 14.7, 14.8, 16.2, 16.7, 20.0, 20.4, 20.5, 21.0, 21.3, 24.4, 24.6, 24.8, 25.1, 25.3, 26.2 27.5, 28.8 and 29.9 ± 0.2 °20, still even more preferably at one or more of 9.2, 9.9, 10.2, 14.2, 14.4, 14.7, 14.8, 16.2, 16.7, 20.0, 20.4, 20.5, 21.0, 21.3, 24.4, 24.6, 24.8, 25.1, 25.3, 26.2 27.5, 28.8 and 29.9 + 0.2 °20, measured with Mo Ka radiation ( = 0.71073 A).

[0037] Embodiment 3: A polymorph of the apomorphine hydrochloride trimethanolate (III) of any of the previous embodiments characterized by an X-Ray diffractogram substantially as shown in Figure 2 obtained using Mo Ka radiation (1 = 0.71073 A).

[0038] Embodiment 4: A polymorph of the apomorphine hydrochloride trimethanolate (III) of any of the previous embodiments characterized by having characteristic FTIR absorptions at 1019 ± 5 cm ¹ ; more preferably at 3333, 1019 + 5 cm ¹ ; still more preferably at 3333, 3270, 1019 + 5 cm ^-1 ; even more preferably at 3333, 3270, 2832, 1019 + 5 cm' ¹ ; still even more preferably at 3333, 3270, 2832, 1494, 1019 ± 5 cm ¹ ; still even more preferred at one or more of 3333, 3270, 2832, 1494, 1019 ± 5 cm ¹ .

[0039] Embodiment 5: A polymorph of the apomorphine hydrochloride trimethanolate (III) of any of the previous embodiments characterized by an FTIR spectrum substantially as shown in Figure 5.

[0040] Embodiment 6: A composition comprising the apomorphine hydrochloride trimethanolate (III) of any of the previous embodiments.

[0041] Embodiment 7 : A pharmaceutical composition comprising the apomorphine hydrochloride trimethanolate (III) of any of the previous embodiments.

[0042] Embodiment 8: The pharmaceutical composition of the previous embodiment further comprising apomorphine hydrochloride hemihydrate (II).

[0043] Embodiment 9: The pharmaceutical composition of the previous embodiment, wherein the ratio of apomorphine hydrochloride trimethanolate (III) to apomorphine hydrochloride hemihydrate (II) is 1:100000 to 100000:1 by weight.

[0044] Embodiment 10: A method of preparation of the apomorphine hydrochloride trimethanolate (III) of any of the [0035] to [0039] comprising: a) dissolving apomorphine hydrochloride hemihydrate (II) in methanol comprising less than 0.5 % water by weight, b) allowing the apomorphine hydrochloride trimethanolate (III) to precipitate, and c) isolating the apomorphine hydrochloride trimethanolate (III).

[0045] Embodiment 11 : The method according to the previous embodiment, wherein the methanol in step a) comprises less than 0.2 % water by weight, preferably less than 0.1 % water by weight, more preferably less 0.05 % water by weight.

[0046] Embodiment 12: The method according to [0044] or [0045] , wherein step a) is performed at a temperature between 30 °C and the boiling point of the mixture; preferably between 45 °C and the boiling point of the mixture; more preferably at a temperature between 55 °C and the boiling point of the mixture; even more preferably at a temperature between 55 °C and 62 °C.

[0047] Embodiment 13: The method according to any of the [0044] to [0046] , wherein the apomorphine hydrochloride hemihydrate (II) is heated: i. for 5 to 30 minutes, and ii. at a temperature higher than 50°C prior to being dissolved in step a)

[0048] Embodiment 14: The method according to [0047] , wherein i) is 10 to 20 minutes.

[0049] Embodiment 15: The method according to any of the [0047] to [0048] , wherein ii) is a temperature between 50 and 150°C, preferably between 75°C and 125°C, more preferably between 80 and 110°C.

[0050] Embodiment 16: The method according to any of the [0044] to [0049] , wherein a desiccant is added after the apomorphine hydrochloride hemihydrate (II) is dissolved in step a), and then removed before step b).

[0051] Embodiment 17: The method according to the previous embodiment, wherein the desiccant is kept for 20 to 90 minutes after the apomorphine hydrochloride hemihydrate (II) is dissolved in step a), preferably kept for 30 to 60 minutes, more preferably 40-50 minutes,

[0052] Embodiment 18: The method according to any of the [0050] to [0051] , wherein the desiccant is selected form molecular sieves, calcium hydride, calcium chloride, barium oxide, silica, alumina, or phosphorous pentoxide.

[0053] Embodiment 19: A method of purification of apomorphine hydrochloride hemihydrate (II) comprising: a) exposing the apomorphine hydrochloride trimethanolate (III), as described in any of the [0035] to [0039] , to an environment having a relative humidity of 50% or higher, b) allowing the methanol in the crystal structure to evaporate, and c) collecting the apomorphine hydrochloride hemihydrate (II).

[0054] Embodiment 20: The method of the previous embodiment, wherein the step a) environment has a relative humidity of 50 to 95%, preferably 55% to 95%, preferably 60% to 95%.

[0055] Embodiment 21: The use of the apomorphine hydrochloride trimethanolate (III), as described in any of the [0035] to [0039] , for the purification of the apomorphine hydrochloride hemihydrate (II).

[0056] Embodiment 22: Apomorphine hydrochloride hemihydrate (II) comprising apomorphine hydrochloride trimethanolate (III), as described in any of the [0035] to [0039] , in an amount greater than zero and less than 0.1 % by weight determined by X-Ray diffraction or FTIR.

[0057] Embodiment 23 : The apomorphine hydrochloride hemihydrate (II) of the previous embodiment having a purity equal or greater than 98% by weight determined by UPLC, preferably equal or greater than 99% by weight determined by UPLC.

[0058] Embodiment 24: A pharmaceutical composition comprising apomorphine hydrochloride hemihydrate (II) comprising apomorphine hydrochloride trimethanolate (III), as described in any of the [0035] to [0039] , in an amount greater than zero and less than 0.1% by weight determined by X-Ray diffraction, and optionally one or more excipients.

[0059] Embodiment 25: The pharmaceutical composition of the previous embodiment which does not comprise any excipient.

[0060] Embodiment 26: The pharmaceutical composition of any of the [0058] or [0059] , wherein the apomorphine hydrochloride hemihydrate (II) has a purity equal or greater than 98% by weight determined by UPLC, preferably equal or greater than 99% by weight determined by UPLC.

[0061] Embodiment 27: The pharmaceutical composition of any of the [0058] to [0060] which is a solid drug film.

[0062] Embodiment 28: The pharmaceutical composition of the previous embodiment, wherein the solid drug film has an area density from 0.001 to 5 mg/cm ² ; preferably from 0.005 to 4 mg/cm ² ; more preferably from 0.01 to 3 mg/cm ² ; even more preferably 0.05 to 2.5 mg/cm ² ; still even more preferably from 0.1 to 2 mg/cm ² .

[0063] Embodiment 29: A method of selecting apomorphine hydrochloride hemihydrate (II) purer batches comprising the use of apomorphine hydrochloride trimethanolate (III), as described in any of the [0035] to [0039] , as a reference standard.

[0064] Embodiment 30: Apomorphine hydrochloride trimethanolate (III), as described in any of the [0035] to [0039] , for use in analysing the purity of apomorphine hydrochloride hemihydrate (II).

[0065] Embodiment 31 : A method for analysing the purity of apomorphine hydrochloride hemihydrate (II) in a sample comprising determining the amount of apomorphine hydrochloride trimethanolate (III), as described in any of the [0035] to [0039]

[0066] Embodiment 32: A method for determining the presence of apomorphine hydrochloride trimethanolate (III), as described in any of the [0035] to [0039] , in a sample comprising apomorphine hydrochloride hemihydrate (II), wherein the compound (III) is used as reference standard, said method comprising:

(a) acquiring a spectrum of apomorphine hydrochloride trimethanolate (III),

(b) selecting one or more selective peaks in the spectrum of step (a),

(c) acquiring a spectrum of a sample, and

(d) determining if the one or more of the selective peaks of step (b) are in the spectrum of step (c), wherein the spectrum is an X-Ray diffraction spectrum, and infrared spectrum or a Raman spectrum.

[0067] Embodiment 33: The method of the previous embodiment, wherein the spectrum is an X-Ray diffraction spectrum.

[0068] Embodiment 34: The method of the previous embodiment, wherein the one or more selective peaks in an X-Ray diffraction apomorphine hydrochloride trimethanolate (III) spectrum is 9.2 ± 0.2 °20; preferably at 9.2 and 20.0 ± 0.2 °20; more preferably at 9.2, 14.2, 20.0 and 26.2 ± 0.2 °20; still more preferably at 9.2, 9.9, 14.2, 20.0, 25.1 and 26.2 ± 0.2 °20; even more preferably at 9.2, 9.9, 14.2, 14.4, 14.8, 20.0, 21.3, 25.1 and 26.2 + 0.2 °20; still even more preferably at 9.2, 9.9, 14.2, 14.4, 14.7, 14.8, 20.0, 21.3, 24.6, 24.8, 25.1, 26.2 and 28.8 ± 0.2 °20; still even more preferably at 9.2, 9.9, 10.2, 14.2, 14.4, 14.7, 14.8, 16.2, 16.7, 20.0, 20.4, 20.5, 21.0, 21.3, 24.4, 24.6, 24.8, 25.1, 25.3, 26.2 27.5, 28.8 and 29.9 ± 0.2 °20, still even more preferably one or more of 9.2, 9.9, 10.2, 14.2, 14.4, 14.7, 14.8, 16.2, 16.7, 20.0, 20.4, 20.5, 21.0, 21.3, 24.4, 24.6, 24.8, 25.1, 25.3, 26.2 27.5, 28.8 and 29.9 ± 0.2 °20, measured with Mo Ka radiation (k = 0.71073 A).

[0069] Embodiment 35: The method of [0066] , wherein the spectrum is an infrared spectrum.

[0070] Embodiment 36: The method of the previous embodiment, wherein the one or more selective peaks in an infrared apomorphine hydrochloride trimethanolate (III) spectrum is at 1019 ± 5 cm ¹ ; more preferably at 3333, 1019 ± 5 cm ¹ ; still more preferably at 3333, 3270, 1019 ± 5 cm ¹ ; even more preferably at 3333, 3270, 2832, 1019 ± 5 cm ; even more preferably, at 3333, 3270, 2832, 1494, 1019 ± 5 cm ¹ , still even more preferably at one or more of 3333, 3270, 2832, 1494, 1019 ± 5 cm ¹ .

[0071] Embodiment 37 : The method of [0066] , wherein the spectrum is a Raman spectrum.

[0072] Embodiment 38: The apomorphine hydrochloride hemihydrate (II) of any of the [0056] or [0057] , wherein the content of apomorphine hydrochloride trimethanolate (III), as described in any of the [0035] to [0039] , is determined using any of the methods of [0066] to [0071] .

EXAMPLES

Method 1: X-Ray diffraction

[0073] The X-Ray diffraction data collection were performed using Mo Ka radiation (k = 0.71073 A) on a Bruker AXS D8 Quest CMOS diffractometer equipped with a fixed-chi- angle stage, a sealed X-ray tube with a curved graphite crystal for incident-beam monochromatization, a Photonll area detector, and an Oxford Cryosystems low temperature device. The initial unit cell was determined, and data were collected using Apex4 v. 2021.10- RC6 (Bruker (2021). Apex4 v2021.10-RC6, Bruker AXS Inc.: Madison (WI), USA, 2013/2014) at a temperature of 150 K. Frames were integrated using SAINT v. 8.40B (Bruker (2020). Apex3 v2019.11-0, Saint V8.40B, Bruker Nano Inc., Madison (WI), USA). A total of 64,738 reflections were collected, of which 7972 were unique. Cell constants for data collection were obtained from least-squares refinement using 9705 reflections between 2.2972 and 32.9850°. Figures 1, 2 and 3 were obtained using this method.

Method 2: Infrared spectroscopy (IR) [0074] IR spectra were acquired using a Thermo Scientific model iS50 Fourier- transform (FT) IR spectrophotometer equipped with a deuterated triglycine sulfate (DTGS) detector, a potassium bromide (KBr) beamsplitter, and a Polaris™ long-life IR source. A diamond attenuated total reflectance (ATR) sampling accessory with a spectral range of 4000 cm ^-1 to 400 cm ^-1 was used. Each spectrum was the result of 128 co-added scans acquired at 2 cm ^-1 resolution. A single beam background scan of air was acquired before the sample scan, allowing presentation of the spectra in log 1/R units. Wavelength calibration was performed using polystyrene. OMNIC v9.11 software package (Thermo-Nicolet) was used to acquire, process, and evaluate the spectral data. Figures 4, 5 and 6 were obtained using this method.

Method 3: UPLC analysis

[0075] The solution is analysed by UPLC with water (ammonium formate/formic acid) and acetonitrile as mobile phases using UV detection at 275 nm as acquisition wavelength. The amount of any product is adjusted based on its response to the 275 nm acquisition wavelength. The response is determined by a previous calibration curve.

Example 1 : Synthesis of apomorphine hydrochloride trimethanolate (III)

[0076] 114.1 mg of apomorphine hydrochloride hemi-hydrate (II) was placed in a 4 mL glass vial. 1.3 mL of HPLC grade methanol was added to the vial and the slurry was stirred magnetically on a hot plate set to 60 °C. The solid was dissolved within 5 minutes. 1 gram of 3A molecular sieves was added and the stirring continued for 45 minutes. The solution was filtered through a 0.45 pm nylon syringe filter into a pre-warmed 4 mL glass vial on the same hot plate. The heat was turned off and the sample was allowed to cool to room temperature while stirring. Upon cooling, white solid was observed within 20 minutes. The slurry was allowed to stir at room temperature overnight. The sample was centrifuged, the mother liquor decanted, and the wet paste was immediately analysed using Method 1 and Method 2.

[0077] The X-Ray diffractogram obtained was similar to that of Figure 2, and the FTIR spectrum was similar to that of Figure 5. Method 3 can be used to determine the content of impurities.

Example 2: Synthesis of apomorphine hydrochloride trimethanolate (III)

[0078] 103.7 mg of apomorphine hydrochloride hemi-hydrate (11) was placed in a 4 mL glass vial. The vial was placed, uncapped, in an oven at 100 °C for 15 minutes. The vial was removed from the oven, capped, and allowed to cool to room temperature. 1.3 mL of HPLC grade methanol was added to the vial and stirred the slurry magnetically on a hot plate set to 60 °C. The solid dissolved within 5 minutes. The heat was turned off and the sample was allowed to cool to room temperature while stirring. Upon cooling, white solid was observed within 1 hour. The slurry was allowed to stir at room temperature overnight. The sample was centrifuged, the mother liquor decanted, and the wet paste was immediately analysed using Method 1 and Method 2.

[0079] The X-Ray diffractogram obtained was similar to that of Figure 2, and the FTIR spectrum was similar to that of Figure 5. Method 3 can be used to determine the content of impurities.

Example 3 : Synthesis of apomorphine hydrochloride hemihydrate (II) from apomorphine hydrochloride trimethanolate (III)

[0080] 10.3 mg of apomorphine hydrochloride trimethanolate (III) (prepared as in

Example 2) was placed in a 10 x 0.2 mm low background silicon X-ray holder. The solid was levelled in the holder with a glass slide. The holder was placed in a stability chamber at 25 °C and 60% RH for 23 hours. The sample was immediately analysed using Method 1 and Method 2.

[0081] The X-Ray diffractogram obtained was similar to that of Figure 1, and the FTIR spectrum was similar to that of Figure 4. Method 3 can be used to determine the content of impurities, other than apomorphine hydrochloride trimethanolate (III).

Example 4: Apomorphine hydrochloride hemihydrate (II) pharmaceutical composition [0082] 100 mg of the product of the Example 3 was dissolved in 2 mL of methanol and sprayed onto a stainless-steel drug foil substrate to obtain a solid drug film. Table 1 shows the amount sprayed to each area for each specific doses.

Table 1:

Dose (mg) Area (mm ² ) Volume sprayed (mL)

1.0 20 x 20 0.02

2.0 20 x 20 0.04

4.0 20 x 20 0.08

5.0 (20 x 20) x 2 sides 0.10

8.0 (20 x 20) x 2 sides 0.16 Example 5: Apomorphine hydrochloride trimethanolate (III) X-Ray diffraction monocrystal and structure [0083] A colourless, blocky crystal having approximate dimensions of 0.45 x 0.43 x 0.36 mm obtained similarly to Example 2 and was mounted on a Mitegen micromesh mount in a random orientation. Preliminary examination and data collection were performed using Mo Ka radiation (X = 0.71073 A) on a Bruker AXS D8 Quest CMOS diffractometer equipped with a fixed-chi-angle stage, a sealed X-ray tube with a curved graphite crystal for incident-beam monochromatization, a Photonll area detector, and an Oxford Cryosystems low temperature device. The initial unit cell was determined and data were collected using Apex4 v. 2021.10-RC6 (Ref. 1) at a temperature of 150 K. Frames were integrated using SAINT v. 8.40B (Ref. 2). A total of 64,738 reflections were collected, of which 7972 were unique. Cell constants for data collection were obtained from least-squares refinement using 9705 reflections between 2.2972 and 32.9850°. The orthorhombic cell parameters and calculated volume are a = 11.4769(5) A, b = 13.0398(6) A, c = 13.9630(6) A and V = 2089.65(16) A3. For Z = 4 and a formula weight of 399.90 the calculated density is 1.271 g/cm ³ . The linear absorption coefficient is 0.212/mm for Mo Ka radiation. Scaling and a multi-scan absorption correction using SADABS 2016-2 (Ref. 3) was applied. Transmission coefficients ranged from 0.6860 to 0.7465. Intensities of equivalent reflections were not averaged during data processing.

[0084] The space group was determined by the program XPREP as embedded in SHELXTL (Ref. 4) Intensity statistics and systematic absences indicated the space group to be P212121 (# 19). The structure was solved by dual methods using SHELXT6 and refined by full matrix least squares against F2 with all reflections using SHELXL-2018 (Ref. 5 and Ref. 6) and the graphical user interface ShelXle (Ref. 7) Additional atoms were located in succeeding difference Fourier syntheses. Additional atoms were located in succeeding difference Fourier syntheses. The structure was refined using full-matrix least squares where the function minimized was Sw(IFol ² -IFcl ² ) ² and the weight w is defined as w = l/[o ² (Fo ² ) + (0.0519P) ² + 0.2013P] where P = (Fo ² + 2Fc ² )/3. Scattering factors were taken from the International Tables for Crystallography (Vol. C Tables 4.2.6.8 and 6.1.1.4). A total of 7972 independent reflections were used in the refinements. A total of 7160 reflections with F ² > 2o(F ² ) were used in the calculation of R1.

[0085] Hydrogen atoms attached to carbon were positioned geometrically and constrained to ride on their parent atoms. C-H bond distances were constrained to 0.95 A for aromatic C-H moieties, and to 1.00, 0.99 and 0.98 A for aliphatic C-H, CH2 and CH3 moieties.

[0086] Methyl hydrogen atoms were allowed to rotate but not to tip to best fit the experimental electron density. The position of the hydroxyl and ammonium hydrogen atoms were refined. Methanol O-H bond distances were restrained to a target value of 0.84(2) A. Uiso(H) values were set to a multiple of Ueq(C/N/O) with 1.5 for OH and CH3, and 1.2 for NH, CH, and CH2 units, respectively.

[0087] The chiral atoms (N1 and C8) were found to have R configurations. The absolute structure (Flack x) was determined from 2965 quotients [(!+)- (I- )]/[(I+)+(I- )] using the method by Parsons et al (Ref. 8) and refined to -0.009(11).

[0088] The final cycle of refinement included 266 variable parameters and 5 r4e converged (largest parameter shift was smaller than 0.001 times its standard uncertainty) with unweighted and weighted agreement factors of:

R1 = S IFol - IFcl ! E IFol = 0.0308 wR ² = {E [w (Fo ² — Fc ² ) ² ] / E [w(Fo ² ) ² ]} ⁰⁵ = 0.0865

[0089] The goodness-of-fit parameter was 1.037. The highest peak in the final difference Fourier had a height of 0.291 e/A ³ . The minimum negative peak had a height of -0.301 e/A ³ .

[0090] The resulting tridimensional structure of apomorphine hydrochloride trimethanolate (III) can be seen in Figure 7 and shows that the product is a trimethanolate.

REFERENCES

Ref. 1 : Bruker (2021). Apex4 v2021.10-RC6, Bruker AXS Inc.: Madison (WI), USA, 2013/2014.

Ref. 2: Bruker (2020). Apex3 v2019.11-0, Saint V8.40B, Bruker Nano Inc., Madison (WI),

USA.

Ref. 3: Krause, C. B.; Herbst-Inner, R.; Sheldrick, G. M.; Stalke, D. J. Appl. Cryst. 2015, 48, 3-10.

Ref. 4: Bruker AXS (2003). SHELXTL (Version 6.14), Bruker AXS Inc., Madison (WI), USA. Ref. 5: Sheldrake, G. M. Acta Cryst. 2015, C71, 3-8.

Ref. 6: Sheldrick, G. M. (2018). SHELXL2018. University of Gottingen, Germany.

Ref. 7: Hubschle, C. B.; Sheldrake, G. M.; Dittrich, B. J. Appl. Cryst. 2011, 44, 1281 — 1284.

Ref. 8: Parsons, S.; Flack, H.; Wagner, T. Acta Cryst. 2013, B69, 249-259.