WO2018084817A2

WO2018084817A2 - A new form of active agent

Info

Publication number: WO2018084817A2
Application number: PCT/TR2017/000115
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Si̇ma Patent Ve Li̇sanslama Hi̇zmetleri̇ Ltd. Şti̇
Priority date: 2016-11-04
Filing date: 2017-11-03
Publication date: 2018-05-11
Also published as: WO2018084817A3; EP3430011A2; EP3430011A4

Abstract

The present invention relates to a new crystalline form of an active agent, the preparation processes of said crystalline form, the pharmaceutical compounds containing said crystalline form and the use of said compounds in the treatment of respiratory system diseases.

Description

DESCRIPTION A NEW FORM OF ACTIVE AGENT

Technical Field of Invention

Prior Art

The present invention relates to a new crystalline form of the tiotropium bromide active agent, the preparation processes of said crystalline form, the pharmaceutical compounds containing said crystalline form and the use of said compounds in the treatment of respiratory system diseases.

Tiotropium, the chemical name of which is (IR, 2R, 4S, 5S, 7S)-7-[(hydroxide - 2- thienyl acetyl)oxi]-9,9-dimethyl-3-oxa-9- azoniatricyclo [3.3.1.0^2,4] nonan, has been first described in the patent application document numbered EP0418716 The application comprises processes for preparing tiotropium, pharmaceutical compounds containing tiotropium, long acting and potent anticholinergic activity of tiotropium.

Formula I. Tiotropium Bromide

Inhalation treatment is commonly preferred for the treatment of respiratory system diseases, particularly chronic diseases, such as asthma and chronic obstructive pulmonary disease (COPD). The primary reason is that the drug reaches the impact zone directly and quickly, thereby allowing lower doses to exhibit the desired effect when compared to other forms of dosage.

The active agent for inhalation treatment can be filled into proper capsules and blisters in its dry powder form or alternatively it can be used in aerosol form. During the administration of the active agent in aerosol form as aerosols and inhalable solutions, HFA134a, HFA227 or inhalable aerosols in powder form which contain a mixture of the former two may be used as the propellant gas.

The active agent particles to be transferred via inhalation need to ideally meet the basic requirements such as appropriate aerodynamic particle size, appropriate particle shape, uniformity of particle size distribution, low aerodynamic dispersion forces, low density, moisture content, polymorphic form of active agent, high physical and chemical stability, as well as the active agent, Which is used in inhalation treatment, exhibiting the desired effect even in low doses.

What is meant by stability is the stability experienced by the active agent when subjected to environmental conditions, the stability exhibited during the manufacturing of the formulation and the stability exhibited after taking the form of the final product. The reason why the concept of stability is at the forefront is the requirement for the active agent content arriving at the impact zone to not be lower than desired, due to the transferred dose being low. For example, moisture absorption of the active agent will cause physical stability to be affected and the active agent content to be lower than the desired amount. In addition to these, the chemical stability and shelf life of the active agent are other important criteria. Chemically, these criteria are usually not met through amorphous active agents. Amorphous active agents have higher thermodynamic energy compared to the crystalline form and are less resistant in the physical and chemical sense.

Usually they are the forms which do not have the sufficient level of solubility, which are unstable and chemically impure and therefore, manufacturing amorphous active agents, formulating and storing them in a pharmaceutical compound is harder.

In the known art, there are various forms (salts, solvates, anhydrates, crystalline and amorphous forms etc.) of the tiotropium active agent, For example; patent application numbered WO 2005/042527 Al defines the crystal anhydrate form.

European Patent numbered EP 1869035 describes the crystalline form of Tiotropium bromide characterized with theta values of 20.2, 26.5, 28.0, and 31.2 XRD 2, and the manufacturing methods thereof. In addition to crystalline forms, studies related to the amorphous form of the active agent have also been conducted. For example, patent numbered WO2013107434 describes the amorphous and crystalline forms for tiotropium iodide. However, amorphous forms are also not preferred due to the aforementioned disadvantages.

Moreover, the inventor has observed, as a result of the studies they conducted, that the solvate forms of tiotropium also have stability problems.

In pharmaceutical technology, solvates are created by solvent molecules settling inside the crystal lattice or the intermolecular spaces. When solvents are settled inside the crystal lattice, they usually act as the filler between the spaces and the solvent molecules do not exhibit a strong interaction. Due to this chemical structure, they tend to degrade under the mechanical action and thermal effect they have.

Dichioromethane solvate of tiotropium bromide described in patent numbered WQ2011015883, mixed solvate of propyleneglycol/ethanol of tiotropium bromide described in patent numbered WO2013079040; 1,4-dioxane solvate of tiotropium bromide, ethanol solvate of tiotropium bromide, methanol solvate of tiotropium bromide, anisol solvate of tiotropium bromide, n-butanol solvate of tiotropium bromide, N,N-dimethylformamide solvate of tiotropium bromide, tetrahydrofuran solvate of tiotropium bromide described in the European patent numbered EP2085396 can be given as examples to the aforementioned solvates.

Taking these problems in the known art into account, it can be obviously seen that different forms of said active agent are needed in order to be used in inhalation treatment.

Thanks to the present invention on the crystal form of tiotropium, the inventor has not experienced the stability problem experienced with the other forms in the known art. The solvent water being added to the crystal lattice by forming hydrogen bonds is defined as hydrate. These hydrogen bonds inside the structure allow the crystal to adhere and thus exhibit a higher stability.

Detailed Description of the Invention

Another attribute of the present invention is that the tiotropium bromide crystal form has peaks in wave numbers 3069, 3054, 2929, 1742, 1529, 1478, 1347, 1163, 1018 and 959 in the Raman spectrum.

Yet another characteristic of the present invention is that it is a new form of the crystal tiotropium bromide, which has a simple monoclinie cell having the dimensions of a= 9,944 A, b= 1 1 ,901 A , c= 18,039 A, β =103,746° , V= 2073,66 A³.

Still another characteristic of the present invention is that the new crystal form of tiotropium bromide has peaks in the values of 236.5, 234, 229, 164, 145, 143, 124, 121, 121.1, 120, 116, 72, 60, 58, 51, 49, 49.2, 48.6, 42, 41.8, 24, 23, 23.3, 11, 8 and 3 ppm ± 0.2 ppm in the ss- NMR spectrum.

The new crystal form of tiotropium bromide of the present invention is characterized with the values of 234, 164, 121.1 , 116, 58 ppm ± 0.2 ppm in the ss-NMR (solid state nuclear magnetic resonance) spectrum.

The new crystal form of tiotropium bromide of the present is characterized with a water loss of approximately 1.3% by weight in the thermogravimetric analysis.

Another method used in the characterization of the new crystal form of the present invention is differential scanned calorimetry. According to this analysis, a fairly wide endothermic peak has been observed around 130°C. Additionally, a second endothermic peak has been observed at 226.2°C, 232.7°C and 233.4 °C, whereby said peaks denote the specific attributes of the new crystal form according to the present invention.

In other words, the present invention is the new crystal form of tiotropium bromide, characterized in that it has: a) peaks in wave numbers 3069, 3054, 2929, 1742, 1529, 1478, 1347, 1163, 1018 and

959 in the Raman spectrum.,

b) a simple monoclinic cellular structure with the dimensions of a- 9,944 A, b= 11,901 A, e= 18,039 A, β =103,746°, V= 2073,66 A³,

c) peaks at the values of 236.5, 234, 229, 164, 145, 143, 124, 121, 121.1, 120, 116, 72, 60, 58, 51, 49, 49.2, 48.6, 42, 41.8, 24, 23, 23.3, 1 1 , 8 and 3 ppm ± 0.2 ppm in the ss-

NMR spectrum and

d) a first endo thermic transition at 130°C, and a second one at 226.2°C, 232.7°C and 233.4 °C in differential scanned calorimetry.

Another characteristic of the present invention is that the new crystal form of tiotropium bromide forms an inhalable pharmaceutical compound with the appropriate excipients.

Yet another characteristic of the present invention is that the pharmaceutical compound of tiotropium bromide contains at least one excipient together with the active agent.

The excipient used in the pharmaceutical formulations containing the new crystal tiotropium bromide substance of the present invention can be selected from a group containing monosaccharides, disaccharides, sugar alcohols, oligosaccharides, polysaccharides, polyalcohols, salts or the mixtures thereof.

Still another characteristic of the present invention is that the pharmaceutical compound containing the new crystal tiotropium bromide substance additionally contains at least one active substance to be used separately, sequentially or simultaneously. At least one active substance selected among other anticholinergic agents, adrenergic agonists, anti-allergic agents, anti-inflammatory agents, anti-histamines, steroids, leukotriene receptor antagonists, anti-muscarinic agents, PDE inhibitors and EGFR inhibitors can be additionally selected in order to be used separately, sequentially or simultaneously in the pharmaceutical formulation. Yet another characteristic of the present invention is that the new tiotropium bromide crystal active agent and the pharmaceutical formulations thereof are used in the treatment of respiratory system diseases, particularly chronic diseases such as asthma and COPD.

The preparation process of the new crystal form of the present invention comprises the following steps: 1) Tiotropium bromide (formula 1), preferably tiotropium bromide anhydrous agent is obtained, A certain amount of tiotropium bromide (formula 1) is weighed in a flask.

2) Methyl ethyl ketone, ethyl acetate and water are added on top of the active agent.

3) Flask is tightly closed and agitated at 72°C for 5-10 days, preferably 8 days. The temperature and the reaction time in this step are important for the crystal yield to be achieved. The temperature applied for the crystal to be obtained with the highest yield is 72°C, and the reaction time is 5-10 days, preferably 8 days.

4) After agitation the temperature is raised to 80°C and the agitation process continues for one more night.

5) The obtained suspension is strained through vacuum filtration. 6) Following the straining of the main part of the suspension, rinsing is performed at least once with tert-butyl methyl ether which contains 0.5% water,

7) Solvent is removed with the aid of vacuum. In this step, the relative humidity of the air should be between 10 to 40%. The specified relative humidity is crucial for the obtained form.

Relative humidity of air between 10 to 40% enabled the crystal to be obtained in the most stable way.

8) Afterwards, the obtained solid matter is left to dry at room temperature inside a desiccator which contains saturated lithium chloride solution.

The solvents used in the aforementioned process can be methyl iso butyl ketone, ethyl acetate, tert-butyl methyl ether, n-butyl acetate, methyl ethyl ketone or acetone, but shall not be limited to these.

Analysis methods used for the characterization of the crystalline structure according to the present invention

Analysis method with Raman Spectroscopy

The parameters regarding the analysis are as follows: Device: 1064 run InGaAs laser (max. 2W) is used. Analysis method with ss-NMR The parameters regarding the analysis are as follows: Solid State High Power 300 MHz NMR Spectrometer Bruker Superconducting FT.NMR Spectrometer Avance TM 300 MHz WB Magnet

High powered UltrashieldTM 300 MHz super-conduetive magnet Probe: 4 mm MAS Spin rate: 8500 Hz ^l3C core is used.

Thermogravimetric Analysis Method (TGA)

The thennogravimetnc analysis utilized in the characterization of the crystal form of the present invention has been conducted on the Netzseh Thermo-Microbalance TG 209 device combined with a Bruker FTIR Spectrometer Vector 22 (sample pans with a pinhole, heating rate 10K;/min, Nitrogen environment).

Analysis Method with Differential Scanned Calorimeter (DSG)

The differential scanned calorimeter measurements utilized in the characterization of the tiotropium crystal form of the present invention have been performed on a TA Instruments Q2000 instrument (closed gold/aluminum sample chamber, heating rate: 20K/min).

Description of the drawings:

Figure 1

Raman Spectrum of the tiotropium bromide crystal form

Figure 2

ss-NMR Spectrum of the tiotropium bromide crystal form

Figure 3

Thermogravimetric analysis spectrum of the tiotropium bromide crystal form Figure 4

Differential scanned calorimeter spectrum of the tiotropium bromide crystal form

Example 1

1) 23.03 gr tiotropium bromide anhydrous is weighed to be placed inside a 200 ml flask.

2) 100 ml methyl ethyl ketone, 5,0 ml water and 50 ml ethyl acetate is added on top of said active agent and the mixture is agitated at 72°C for 8 days.

3) After 8 days, agitation temperature is raised to 80°C and the agitation process continues for one more night.

4) The suspension is strained on the 9th day.

5) The solid matter obtained after straining is rinsed twice with 20 ml tert-butyl methyl ether which contains 0.5% water. Solvent is removed with the aid of vacuum.

6) The obtained yield before drying through exposure to air at room temperature is 18.9 grams.

7) Afterwards, the obtained solid matter is left to dry at room temperature inside a desiccator which contains saturated lithium chloride solution.

Claims

1. The new crystal form of tiotropium bromide, characterized in that it comprises the following:

a) peaks in wave numbers 3069, 3054, 2929, 1742, 1529, 1478, 1347, 1163, 1018 and 959 in the Raman spectrum,

b) a simple monoclinic cellular structure with the dimensions of a= 9,944 A, b= 11 ,901 A , c= 18,039 A, β =103,746° , V= 2073,66 A³,

c) peaks at the values of 236.5, 234, 229, 164, 145, 143, 124, 121, 121.1, 120, 116, 72, 60, 58, 51, 49, 49.2, 48.6, 42, 41.8, 24, 23, 23.3, 11, 8 and 3 ppm ± 0.2 ppm in the ss- NMR spectrum and

d) a first endothermic transition at 130 °C, and a second one at 226.2°C, 232.7°C and 233.4 °C in differential scanned calorimetry.

2. The method of manufacturing the new crystal form of tiotropium bromide according to Claim 1, characterized in that it comprises the steps of:

a) Adding methyl ethyl ketone, ethyl acetate and water on top of the active agent of tiotropium bromide (formula 1), preferably tiotropium bromide anhydrous, b) Performing agitation in a closed flask at 72°C for 5-10 days, preferably 8 days, e) Raising the temperature to 80°C after agitation and continuing the agitation process for one more night,

d) Straining the obtained suspension,

e) Following the straining of the main part of the suspension, rinsing at least once with tert-butyl methyl ether which contains 0.5% water,

f) Removing the solvent under conditions where the relative humidity of the air is between 10 to 40% and

g) Drying.

3. Pharmaceutical formulation according to Claim 1 , comprising the new crystal form of tiotropium bromide.

4. An inhalable pharmaceutical formulation according to Claim 3, comprising the new- crystal form of tiotropium bromide.

5. A pharmaceutical formulation according to Claim 3, comprising at least one excipient.

6. A pharmaceutical formulation according to Claim 3, characterized in that the pharmaceutical compound additionally contains at least one active agent selected among anticholinergic agents, adrenergic agonists, anti-allergic agents, antiinflammatory agents, anti-histamines, steroids, leukotriene receptor antagonist, anti- muscarinic agents, PDE inhibitors and EGFR inhibitors in order to be used separately, sequentially or simultaneously.

7. A pharmaceutical formulation according to any of the Claims 3-6, characterized in that it is used in the treatment of respiratory system diseases, particularly asthma and COPD.