Crystalline aceclidine HCl hemihydrate and process for preparing same

Abstract

Crystalline aceclidine HCl hemihydrate of formula I, having a DSC onset peak at a value between 137.08°C and 139.08°C and / or an X-ray powder diffraction pattern with characteristic peaks at two-theta values ​​(2θ) of 17.7±0.2 and / or 20.47±0.2. Formula I JPEG2026504189000010.jpg5169

Description

[Technical Field]

[0001] The present invention relates to a hemihydrate form of aceclidine HCl having formula I: Formula I: [ka]

[0002] The present invention further relates to a process for preparing the hemihydrate form of aceclidine HCl of formula I. [Background technology]

[0003] Aceclidine is a known pharmaceutical active ingredient (API) that acts as a muscarinic acetylcholine receptor agonist and is particularly used in the field of ophthalmology. Aceclidine is a known parasympathomimetic miotic used in the treatment of narrow-angle glaucoma. It reduces intraocular pressure.

[0004] US Patent Application Publication No. 2016 / 193193 discloses compositions and related methods for treating presbyopia, including aceclidine, which further includes a polyol.

[0005] With particular reference to aceclidine HCl, US Pat. No. 3,997,543 discloses methods for its preparation.

[0006] Furthermore, in Maria Kuhnert-Brandstaetter & Friedrich Proell (Thermische Analyse von Hydraten organischer Verbindungen, 1983) the anhydrous and hydrate forms of aceclidine are characterized.

[0007] An important aspect of API manufacturing is the availability of a stable form that does not undergo undesired conversion to other forms. Generally, it is common practice to work under strictly controlled conditions (e.g., glove box) to avoid conversion to other forms.

[0008] For example, some anhydrous forms can absorb moisture unless under controlled conditions and, as a result, can be difficult to handle.

[0009] However, controlled conditions are not always available or convenient, so it would be highly advantageous to provide a stable form that does not undergo undesired transformations.

[0010] This general technical problem also applies to aceclidine, and there is a need for a stable form of aceclidine that would allow for easier handling of such materials. Summary of the Invention [Problem to be solved by the invention]

[0011] The applicant has now discovered a novel crystalline form of aceclidine (in particular aceclidine HCl hemihydrate) which makes it possible to advantageously solve the above and other problems, as further demonstrated below. [Means for solving the problem]

[0012] Thus, according to a first aspect, the present invention relates to a crystalline Aceclidine HCl hemihydrate according to claim 1.

[0013] According to a further aspect, the present invention relates to a process for preparing crystalline Aceclidine HCl hemihydrate according to claim 5.

[0014] According to a further aspect, the present invention relates to a process for preparing the crystalline Aceclidine HCl hemihydrate form of formula I according to claim 11.

[0015] Advantageously, the aceclidine HCl hemihydrate form of the present invention is a stable form. In particular, this form has low hygroscopicity (especially compared to the corresponding anhydrous form), so it does not need to be handled under controlled conditions. Indeed, unlike the corresponding anhydrous form, the form of formula (I) of the present invention does not undergo any transformation, so there is no need to work under controlled conditions (e.g., glove box). Therefore, there is no need to establish humidity-controlled conditions. This is particularly relevant considering that the inventors consider that the optimum relative humidity in the workplace is generally in the range of 40% to 60%. Safe ranges such as k are defined, for example, in the Italian law degree "Testo unico sulla Salute e Sicurezza sul Lavoro, Decreto Legislativo 81 / 2008."

[0016] Furthermore, pharmaceutical formulations based on aceclidine are usually aqueous formulations, and for this reason it is important to have a form of aceclidine that is stable in an aqueous environment.

[0017] Further aspects, features and advantages of the present invention will become more apparent from the following detailed description. [Brief explanation of the drawings]

[0018] [Figure 1] FIG. 1 shows the XPRD diffractogram of aceclidine HCl hemihydrate. [Figure 2] FIG. 2 shows the XPRD diffractogram of anhydrous aceclidine HCl. [Figure 3] FIG. 3 shows the DSC of aceclidine HCl hemihydrate. [Figure 4] FIG. 4 shows the DVS (Dynamic Vapor Sorption Isotherm) of aceclidine HCl. DETAILED DESCRIPTION OF THE INVENTION

[0019] With respect to the scope of the present invention, in the following description and claims, definitions of numerical ranges include single values ​​and the corresponding endpoints subsumed within that range, unless otherwise stated.

[0020] With respect to the scope of the present invention, in the following description and claims, the term "comprising" also includes the terms "consisting of" or "consisting essentially of."

[0021] Crystalline aceclidine HCl hemihydrate of formula I has a DSC onset peak at a value between 137.08°C and 139.08°C and / or an X-ray powder diffraction pattern with characteristic peaks at two-theta values ​​(2θ) of 17.7±0.2 and / or 20.47±0.2.

[0022] According to a preferred embodiment, the crystalline aceclidine HCl hemihydrate of formula I has an X-ray powder diffraction pattern with a DSC onset peak at a value between 137.08°C and 139.08°C, or with characteristic peaks at two-theta values ​​(2θ) of 17.7±0.2 and / or 20.47±0.2.

[0023] According to a preferred embodiment, the crystalline aceclidine HCl hemihydrate of formula I has an X-ray powder diffraction pattern with a DSC onset peak at a value between 137.08°C and 139.08°C and characteristic peaks at two-theta values ​​(2θ) of 17.7±0.2 and / or 20.47±0.2.

[0024] Preferably, the crystalline aceclidine HCl hemihydrate of Formula I has an X-ray powder diffraction pattern with an additional characteristic peak at 28.84±0.2 two-theta (2θ).

[0025] As demonstrated and evident from Figure 4, the conversion of the anhydrous form of Formula II to the hemihydrate form of Formula I is irreversible. In fact, the weight remained stable as the environmental humidity content decreased.

[0026] As already reported above, the present invention also includes the step of converting the anhydrous form of formula II to aceclidine HCl hemihydrate of formula I: Formula II [ka] The present invention also relates to a process for preparing the crystalline Aceclidine HCl hemihydrate form of Formula I, wherein said converting step is carried out by hydrating the anhydrous form of Formula II.

[0027] According to a preferred embodiment, said hydration is carried out by insufflation with wet-air or wet-nitrogen.

[0028] According to an alternative preferred embodiment, said hydration is carried out by dissolving in water or in a mixture of water and a co-solvent, preferably until an environmental reaction humidity content of not more than 16% by weight, more preferably not more than 8% by weight, even more preferably between 4% and 8% by weight, based on the weight of the starting anhydrous aceclidine HCl form, is reached.

[0029] The hydration is preferably carried out by dissolving in a mixture of water and a co-solvent, and the co-solvent is preferably selected from esters and cyclic ethers. The ester is preferably selected from ethyl acetate and isopropyl acetate, more preferably ethyl acetate. The cyclic ether is preferably selected from THF (tetrahydrofuran), methyl THF, and dioxane.

[0030] As already reported above, the present invention also relates to an alternative process for preparing the aforementioned crystalline aceclidine HCl hemihydrate form of formula I. This alternative process comprises the steps of converting aceclidine free base of formula III to aceclidine HCl hemihydrate of formula I: Formula III [ka] The process is carried out by adding HCl and water to a suspension of aceclidine free base, preferably in an amount of 16% by weight or less, preferably 8% by weight or less, more preferably 4% to 8% by weight, based on the weight of the starting aceclidine free base.

[0031] In this process, the solvent used to suspend aceclidine free base is preferably selected from esters and cyclic ethers. The ester is preferably ethyl acetate or isopropyl acetate, more preferably ethyl acetate. The cyclic ether is preferably selected from THF, methyl THF, and dioxane. [Example]

[0032] The following examples are provided for illustrative purposes only, and therefore no limitations on the scope of the invention should be intended based on such examples.

[0033] Example 1: Hydration of Anhydrous Acecidine HCl The conversion of aceclidine HCl (4 mg) from the anhydrate to the hemihydrate form was analyzed by dynamic vapor sorption (DVS) isotherm. The observed conversion behavior (% weight change / % relative humidity) showed that the hemihydrate morphology was obtained with a weight change of approximately 4% (see Figure 4). This form was apparently irreversible upon decreasing the relative humidity.

[0034] Example 2: Synthesis of aceclidine free base (formula III) A 500 mL jacketed reactor equipped with an overhead stirrer, nitrogen, and reflux condenser was charged with 3-quinuclidinol (60 g) and ethyl acetate (300 mL) and stirred at 20.0°C to form a suspension. Acetic anhydride (68.4 g) was then slowly charged to the vessel via syringe over 10 minutes. A clear solution was obtained. The temperature rose from 20°C to 30°C during this process.

[0035] The bath temperature was adjusted to 53°C, and the solution was stirred for 3 hours (longer if necessary) to ensure complete reaction. After 3 hours, IPC was performed by GC-HP (90 μL of solution in 20 mL of ethyl acetate) to confirm that 3-quinuclidinol was ≦0.5%. The reaction mixture was then cooled to room temperature, and aceclidine free base crystallized. The product was filtered through a 60 mL Chemrus disposable funnel. The panel (funnel) was rinsed with ethyl acetate (21.6 mL). Finally, the product solution (409.5 g) was returned to the reactor.

[0036] Example 3: Synthesis of aceclidine HCl hemihydrate (Formula I) The above-obtained solution of aceclidine free base of Formula III (137 g) was further diluted with ethyl acetate (40 mL), and the bath temperature was adjusted to 17°C. HCl gas (6.3 g) was then bubbled in to maintain the internal temperature below 30°C. After the HCl was charged, the temperature was decreased. When the internal temperature reached a value below 20°C, H2O was charged at a concentration of 8% by weight (2.6 g) based on a theoretical yield of 100% of aceclidine HCl salt. After precipitation of the product, the reaction mass was then stirred at 17°C for 2 hours. The resulting solid was filtered through a 60 mL Chemrus disposable filter funnel. The filtration was performed under nitrogen. The solid appeared as a very fine powder. The powder was washed with ethyl acetate (3 x 10 mL) under nitrogen. Finally, the solid was dried under vacuum at 50-55°C; during this process, the solid was periodically crushed.

[0037] (Analysis 1: XPRD pattern of the hemihydrate form of aceclidine (corresponding to Figure 1)) [Table 1]

[0038] (Analysis 2: XPRD pattern of anhydrous form of aceclidine (corresponding to Figure 2)) [Table 2]

[0039] (XPRD analysis method) Bruker D8 Discover X-ray Diffractometer Vantec-500 detector Samples were analyzed as received, and R00099-50-27 was prepared in a glove box to limit moisture exposure.

[0040] (Detector conditions) Voltage: 40kV Current: 40mA Radiation: Cu Temperature: Ambient temperature X-ray source exit slit size: 0.5 mm pinhole Nose collimator: 0.5 mm Sample holder: Polished quartz plate (R00099-50-21, R00099-50-24) or silicon disk in a sealed holder with a Mylar sheet cover (R00099-50-27).

[0041] (Operating conditions) Detector distance: 30.3 cm Chi integral range: 4 to 40°, 2θ Counting time: 120 seconds / frame Frame number: 3 θ1 position: 4 degrees on the quartz plate, 6 degrees on the silicon disk θ2 position: 4 degrees on the quartz plate, 6 degrees on the silicon disk Frame width: 12 Amplitude: 2mm

[0042] (DSC analysis method) TA Instruments DSC Q2000 Samples were analyzed as received. 2-10 mg was weighed and added to a Tzero aluminum pan, which was then sealed with a crimp lid. Equilibrated at 25°C. The mixture was heated from 25°C to 250°C at a rate of 10°C / min. There was a continuous nitrogen purge at 50 mL / min.

Claims

1. Crystalline aceclidine HCl hemihydrate of formula I: Formula I 【Chemistry 1】 The crystalline aceclidine HCl hemihydrate has a DSC onset peak at a value between 137.08°C and 139.08°C and / or an X-ray powder diffraction pattern having characteristic peaks at two-theta values ​​(2θ) of 17.7±0.2 and / or 20.47±0.

2.

2. 2. The crystalline aceclidine HCl hemihydrate of claim 1, having an X-ray powder diffraction pattern with a DSC onset peak at a value between 137.08°C and 139.08°C, or with characteristic peaks at 17.7±0.2 and / or 20.47±0.2 two-theta values ​​(2θ).

3. 2. The crystalline aceclidine HCl hemihydrate of claim 1, having an X-ray powder diffraction pattern with a DSC onset peak at a value between 137.08°C and 139.08°C and characteristic peaks at 17.7±0.2 and / or 20.47±0.2 two-theta values ​​(2θ).

4. 4. The crystalline aceclidine HCl hemihydrate of any one of claims 1 to 3, having an X-ray powder diffraction pattern with an additional characteristic peak at 28.84±0.2 two-theta (2θ) value.

5. converting the anhydrous form of formula II to aceclidine HCl hemihydrate of formula I: Formula II 【Chemistry 2】 5. A process for preparing the crystalline aceclidine HCl hemihydrate form of formula I according to any one of claims 1 to 4, wherein said converting step is carried out by hydrating the anhydrous form of formula II.

6. 6. The process of claim 5, wherein the hydration is carried out by insufflation with wet air or wet nitrogen.

7. 6. The process of claim 5, wherein the hydration is carried out by dissolving in water or in a mixture of water and a co-solvent.

8. 8. The process of claim 7, wherein the co-solvent is selected from esters (preferably ethyl acetate or isopropyl acetate) and cyclic ethers (preferably THF (tetrahydrofuran), methyl THF or dioxane).

9. 9. The process of claim 7 or claim 8, wherein the hydration is carried out until an environmental reaction humidity content of 16% by weight or less is achieved, based on the weight of the starting anhydrous aceclidine HCl form.

10. 10. The process of claim 9, wherein the environmental reaction humidity content is less than or equal to 8% by weight (preferably 4% to 8% by weight) based on the weight of the starting anhydrous aceclidine HCl form.

11. Aceclidine free base of formula III is converted into aceclidine HCl hemihydrate of formula I, comprising: Formula III 【Transformation 3】 5. The process for preparing the crystalline Aceclidine HCl hemihydrate form according to any one of claims 1 to 4, wherein said step is carried out by adding HCl and water to a suspension of Aceclidine free base.

12. 12. The process of claim 11, wherein the water is added in an amount of 16% by weight or less (preferably 8% by weight or less, more preferably 4% to 8% by weight) based on the weight of the starting Aceclidine free base.

13. 13. The process of claim 11 or claim 12, wherein a solvent is used, said solvent being selected from esters (preferably ethyl acetate or isopropyl acetate) and cyclic ethers (preferably THF, methyl THF or dioxane).

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