CRYSTALLINE FORMS OF TAFAMIDIS NICOTINAMIDE ADDUCT

The invention relates to Tafamidis nicotinamide adduct, a solid form thereof, a crystalline form thereof and processes for preparation thereof.

BACKGROUND OF THE PRESENT INVENTION

This invention relates to Tafamidis nicotinamide adduct, a solid form thereof, crystalline form thereof and processes for preparation thereof. Tafamidis, compound of formula (1): chemically 2-(3,5-Dichlorophenyl)benzoxazole-6-carboxylic acid is a transthyretin protein stabilizer and antiamyloidogenic agent which was launched for the treatment of transthyretin amyloid polyneuropathy. Tafamidis is marketed in a form of meglumine salt. Tafamidis was first disclosed in W02004056315 application. Polymorphic forms of Tafamidis are disclosed in W02016038500 or WO2019175263 applications. Meglumine salt and solid form thereof is disclosed in WO2013038351 or WO2017190682 applications. Tafamidis meglumine was first marketed in a 20 mg strength. Later studies demonstrated that a dose of 61 mg was more effective than the 20 mg dose, however the meglumine and other salts of Tafamidis had concentration depending gelling problems. The use of Tafamidis free acid solves this gelling problems. Unfortunately, the Tafamidis free acid has a lower solubility than meglumine Tafamidis salt. The inventors have surprisingly found that the tafamidis nicotinamide adduct according to presented invention overcomes the problems of the prior art (low solubility of Tafamidis free acid and gelling problems related to Tafamidis meglumine salt). BRIEF DESCRIPTION OF THE INVENTION

The presented invention relates to Tafamidis nicotinamide adduct, a solid form thereof, a crystalline form thereof and processes for preparation thereof.

Crystalline form of Tafamidis nicotinamide adduct of the presented invention shows improved solubility, crystallinity and stability in comparison with Tafamidis or Tafamidis meglumine solid forms disclosed in the prior art.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of crystalline Form 1 of Tafamidis nicotinamide adduct prepared according to Example lor Example 2 or Example 3.

Figure 2 depicts the DSC pattern of crystalline Form 1 of Tafamidis nicotinamide adduct, Form 1 prepared according to Example lor Example 2 or Example 3.

Figure 3 depicts the TGA pattern of crystalline Form 1 of Tafamidis nicotinamide adduct prepared according to Example 1 or Example 2 or Example 3.

Figure 4 depicts the DSC pattern of crystalline form of Tafamidis meglumine salt prepared according to Example 1 of WO2013/038351A1 application.

Figure 5 depicts the NMR pattern of crystalline Form 1 of Tafamidis nicotinamide adduct prepared according to Example 1 or Example 2 or Example 3.

DETAILED DESCRIPTION OF THE INVENTION

The presented invention relates to Tafamidis nicotinamide adduct, a solid form thereof, a crystalline form thereof and processes for preparation thereof. The presented invention further relates to a formulation comprising the solid forms. Nicotinamide, chemically 3-pyridinecarboxamide is a compound of formula (2);

The crystalline form of Tafamidis nicotinamide adduct, Form 1 can be characterized by XRPD pattern having 20 values 7.0°, 11.8° and 13.0° degrees 2 theta (± 0.2 degrees 2 theta). The solid Form 1 can be also characterized by XRPD pattern having 20 values 7.0°, 11.8°, 13.0°, 19.6°, 25.2° and 26.7° degrees 2 theta (± 0.2 degrees 2 theta). The solid form can be further characterized by XRPD pattern described in the following table: The solid Form 1 can be also characterized by XRPD pattern depicted in Figure 1 or

DSC pattern depicted in Figure 2 or TGA pattern depicted in Figure 3 or NMR pattern depicted in Figure 5.

The solid Form 1 of Tafamidis, compound of formula (1), can be prepared by a process comprising: a. Dissolving Tafamidis in a solvent selected from tetrahydrofurane or dioxane; b. Adding nicotinamide; c. Isolating the crystalline Form 1 of Tafamidis nicotinamide adduct.

The concentration of Tafamidis in the solvent can be between 0.015 g/ml and 0.025 g/ml, preferably it is between 0.18 g/ml and 0.22 g/ml. Tafamidis is preferably dissolved in the solvent at a temperature between 40°C and 65°C. After dissolution of Tafamidis, nicotinamide is added to the mixture. The molar ratio between Tafamidis, compound of formula (1), and nicotinamide can be between 1:1 and 1:1.5, preferably it is between 1:1 and 1:1.2. The mixture is stirred at a temperature between 40°C and 65°C to dissolve added nicotinamide and then stirred for between 10 and 30 minutes. The mixture is the cooled to a temperature between 20°C and 25°C and it can be optionally filtered off. The filtrate is then cooled to a temperature: i. Between 2-8°C in the case tetrahydrofurane is used as the solvent; or ii. Between 10°C and 15°C in the case dioxane is used as the solvent.

The mixture is left at this temperature for between 6 and 24 hours. Obtained solid can be isolated by any suitable technique, for example by filtration and can be optionally dried to provide solid Form 1 of Tafamidis nicotinamide adduct.

The solid Form 1 of Tafamidis nicotinamide adduct can be also prepared by a process comprising:

1. Mixing Tafamidis with nicotinamide and methyl tert-butyl ether (MTBE); 2. Stirring the mixture at a temperature between 20°C and 25°C for between 16 and

24 hours;

3. Isolating the solid Form 1 of Tafamidis nicotinamide adduct.

The concentration of Tafamidis in methyl tert-butyl ether can be between 0.015 g/ml and 0.025 g/ml, preferably it is between 0.18 g/ml and 0.22 g/ml. The molar ratio between Tafamidis and nicotinamide can be between 1:1 and 1:1.5, preferably it is between 1:1 and 1:1.2. The mixture is stirred at a temperature between 20°C and 25°C for between 16 and 24 hours. Obtained solid can be isolated by any suitable technique, for example by filtration and can be optionally dried to provide solid Form 1 of Tafamidis nicotinamide adduct.

Obtained solid form of Tafamidis nicotinamide adduct shows improved crystallinity, solubility and stability. The solid form can be used for example for purification of Tafamidis, compound of formula (1) by contacting of Tafamidis nicotinamide adduct with a base.

The solid form according to presented invention, preferably Form 1, can be also processed into a suitable pharmaceutical formulation. In the pharmaceutical formulation the solid form can be mixed with pharmaceutically acceptable adjuvants, diluents or carriers. The amount of solid form according to presented invention in the formulation depends on the condition and a patient to be treated. The pharmaceutical formulation can be if form of a solid oral formulation, for example a capsule, a pill, a powder or a granule. In the formulation the crystalline form according to presented invention can be mixed with one or more additives such as fillers or extenders or binders or wetting agents or disintegrating agents or absorbents or lubricants or buffering agents. The formulation in a form of a tablet or a dragee or a capsule or a pill or a granule can be coated with a coating or shell such as enteric or other coating. The oral formulation can be in a form of an oral emulsion or a solution or a suspension or a syrup. The formulation can contain suitable additives such as diluent(s) or wetting agent(s) or emulsifying agent(s) or suspending agent(s) or sweetening agent(s) or flavouring agent(s). The examples of suitable additive(s) are known to those skilled in the art.

The suitable pharmaceutical formulation can be in a parenteral form such as an injection or an infusion or an injectable depot or in a liposomal form comprising pharmaceutically acceptable aqueous or non-aqueous solution(s) or dispersion(s) or emulsions. The pharmaceutical formulation can be also in a form of a powder for reconstitution into an injection or infusion. The formulation can further comprise additives such as preservative(s) or wetting agent(s) or emulsifying agent(s) or dispersing agent(s) or antibacterial or antifungal agents. The examples of suitable additive(s) are known to those skilled in the art.

The suitable pharmaceutical formulation can be in a form suitable for rectal or vaginal administration further comprising suitable additive(s). The examples of suitable additive(s) are known to those skilled in the art.

Tafamidis nicotinamide adduct or a solid form thereof, for example Form 1 or a pharmaceutical formulation comprising the form can be used for the treatment of conditions treatable with Tafamidis or a salt thereof.

The invention will be further described with reference to the following examples.

EXAMPLES

Nuclear magnetic resonance spectroscopy (NMR) was performed using Avance III 400 MHz NMR spectrometer. XRPD spectrum was obtained using the following measurement conditions:

Panalytical Empyrean diffractometer with 0/20 geometry (transmition mode), equipped with a PixCell 3D detector;

DCS patterns were obtained using the following conditions: 10°C/min -> 250°C.

TGA patterns were obtained using the following conditions: 10°C/min -> 280°C. Tafamidis was prepared according to a process disclosed in W02004056315. Tafamidis meglumine salt was prepared according to Example 1 of WO2013/038351A1 application.

Example 1: Preparation of Tafamidis nicotinamide adduct, Form 1

1 g of Tafamidis was mixed with 50 ml of tetrahydrofurane (THF). The formed suspension was mechanically stirred and heated to 50°C. 396 mg of nicotinamide was then added to the mixture. The mixture was stirred at 50°C till dissolution of solids. The mixture was then stirred at 50°C for 20 minutes. After, the solution was left freely cool down to room temperature (20-25°C), filtered to remove any undissolved solids, and placed into a refrigerator at temperature of 2-8 °C for 12 hours. The solid mass was filtered off to provide

Tafamidis nicotinamide adduct, Form 1, in 76% yield.

XRPD pattern of obtained solid corresponds to a pattern depicted in Figure 1. DSC pattern of obtained solid is depicted in Figure 2, TGA pattern is depicted in Figure 3 and NMR pattern is depicted in Figure 5.

Example 2: Preparation of Tafamidis nicotinamide adduct, Form 1

1 g of Tafamidis was mixed with 50 ml of dioxane. The formed suspension was mechanically stirred and heated to 55°C. 396 mg of nicotinamide was then added to the mixture. The mixture was stirred at 55°C till dissolution of solids. The mixture was then stirred at 55°C for 20 minutes. After, the solution is left freely cool down to room temperature (20-25°C), filtered to remove any undissolved solids. The mixture is then cooled to 13°C and left at this temperature for 12 hours. The solid mass was filtered off to provide Tafamidis nicotinamide adduct, Form 1, in yield 60%.

XRPD pattern of obtained solid corresponds to a pattern depicted in Figure 1. DSC pattern of obtained solid is depicted in Figure 2, TGA pattern is depicted in Figure 3 and NMR pattern is depicted in Figure 5.

Example 3: Preparation of Tafamidis nicotinamide adduct, Form 1

1 g of Tafamidis and 396 mg of nicotinamide was mixed with 50 ml of methyl tertbutyl ether (MTBE). The formed suspension was mechanically stirred at a temperature between 20°C and 25°C for 18 hours. The solid mass was filtered off to provide Tafamidis nicotinamide adduct, Form 1, in almost quantitative yield. XRPD pattern of obtained solid corresponds to a pattern depicted in Figure 1. DSC pattern of obtained solid is depicted in Figure 2, TGA pattern is depicted in Figure 3 and NMR pattern is depicted in Figure 5. Example 4: Comparative example 1, solubility of samples

Solubility of Tafamidis nicotinamide adduct, Form 1 was compared to Tafamidis and Tafamidis meglumine salt.

Sample preparations were placed into a stirring carousel at temperature +37 °C and 100 rpm and stirred. After 1 hour and 4 hours about 1 mL of each sample was taken and filtered through a 0.2 pm filter into a vial. One part of filtered sample was diluted in 1 : 1 ratio with the Solvent solution (to prevent precipitation in the autosampler) a transferred into a vial, second part of filtered sample was directly transferred into a vial. Both samples were measured by HPLC method. Because of no difference between results of diluted sample and directly measured sample, solubility results are given as average of these two measurements.

It can be concluded that solubility of Tafamidis nicotinamide adduct is higher than solubility of Tafamidis free acid and comparable to solubility of Tafamidis meglumine, Form 1. Example 5: Comparative example 1, thermal stability of samples

DSC pattern of Tafamidis nicotinamide adduct, Form 1 and Tafamidis meglumine salt were measured. Obtained pattern are depicted in Figures 2 and 4. It can be concluded that thermal stability of Tafamidis nicotinamide adduct, Form 1, is higher than thermal stability of Tafamidis meglumine salt.