EP3148988A1

EP3148988A1 - Polymorphic forms of furazidin

Info

Publication number: EP3148988A1
Application number: EP15753991.7A
Authority: EP
Inventors: Vilnis LIEPINS; Mikhail SKOMOROKHOV; Nina LUKJANOVA; Evgenij MATIUSHENKOV; Jekaterina REVJUKA
Original assignee: Olainfarm AS
Current assignee: Olainfarm AS
Priority date: 2014-05-29
Filing date: 2015-05-27
Publication date: 2017-04-05
Also published as: MA39860A; LV15081B; EA201692217A1; UA115290C2; WO2015181741A1; LV15081A

Abstract

The invention relates to the crystalline forms of Furazidin (1-{[(1E,2E)-3-(5-nitrofuran-2-yl)prop-2-ene-1-ylidene]amino}imidazolidin-2,4-dione) and methods of preparation thereof

Description

POLYMORPHIC FORMS OF FURAZIDIN

Field of invention

The current invention relates to the field of medical chemistry, namely to the crystalline polymorphic forms of a pharmaceutical industrial product Furazidin and method of preparation thereof. The current invention also relates to the use of said polymorphic forms for the preparation of a pharmaceutical composition.

Background of the invention

Furazidin (l-{[(lE,2E)-3-(5-nitrofuran-2-yl)prop-2-ene-l-ylidene]amino}imidazolidin-2,4- dione) is known at the pharmaceutical market under the trade name Furagin® (Furaginum, INN). It is an antibacterial agent with bacteriostatic action, which is effective against both gram- positive (Staphylococcus epidermidis, Staphylococcus aureus, Staphylococcus faecalis) and gram-negative (Enterobacteriaceae, Escherichia coli, Klebsiella spp, Salmonella, Shygella, Proteus, Enterobacter, etc.) bacteria. This medicament is widely used for the treatment of urinary infections in adults and children.

In the preparation of a pharmaceutical product, it is very important to control the crystalline form of an active agent. Solid crystalline substances may exist in different crystalline forms, which are called polymorphs. Different polymorphs may possess different physical and/or chemical properties, like solubility, solubility rate, melting temperature, stability etc. These properties may directly affect the possibility of preparation of the active substance and its corresponding pharmaceutical product, as well as stability and bioavailability of that product. Thus, polymorphism may affect the quality of a pharmaceutical product, and/or its safety and efficacy. Preparation of a pure polymorph and investigation of its properties provide for a better control of the pharmaceutical product manufacturing process. Controlled and reproducible methods for preparation of pure polymorphs are suitable for industrial application; pure polymorphs may be used for improvement of properties of the pharmaceutical compositions.

Several methods are known for characterizing the polymorphic forms of a crystalline substance. Polymorphism is proved with demonstration of the non-equivalent structures using single crystal X-ray structural analysis. X-ray powder diffraction may also be used to prove the polymorphism. To characterize individual polymorphic forms, various analytical methods are used, including microscopy, thermal analysis (DSC, TGA), spectroscopy (IR, Raman, solid state NMR).

Furazidin is synthesized by reaction of the 3-(5-nitro-2-furyl)acroleine and 1 -aminohydantoine or 3-(5-nitro-2-furyl)acroleine with semicarbazidacetic acid derivative following with hydantoine cycle formation (J. Pharm. Soc. Japan, 1955, 75; 117, FR1489091, 1966). Several preparation methods of furazidin from 1 -arylaminohydantoines in the presence of mineral acids (sulfuric acid, hydrochloric acid, sulfonic acids) also were disclosed (US 2990402; WO97/19930; WO98/41520). Furazidin polymorphic forms were not described so far. If a crystalline form is prepared with admixture of other crystalline forms, it may result in the instability of a dosage form during manufacturing process and its conversion into another polymorphic form. Therefore, it is very important to obtain polymorphic forms of a high polymorphic purity.

Brief description of the Figures

Fig.1 Powder X-ray diffraction pattern of the Furazidin polymorph I.

Fig.2 IR spectrum of the Furazidin polymorph I.

Fig.3 Powder X-ray diffraction pattern of the Furazidin polymorph II.

Fig.4 IR spectrum of the Furazidin polymorph II.

Fig.5 Microscopic image of crystals of the Furazidin polymorph I.

Fig.6 Microscopic image of crystals of the Furazidin polymorph II.

Fig.7 Comparison of the Furazidin polymorph I and polymorph II dissolution dynamics.

Fig.8 DSC curve of the Furazidin polymorph I.

Fig.9 DSC curve of the Furazidin polymorph II.

Description of the invention

We have unexpectedly discovered that in the Furazidin preparation process non-identical substances are formed. IR spectra used for identity test were also non-identical. We have isolated stable crystalline forms, which were identified as Polymorph I and Polymorph II. Said polymorphs were characterized with various analytical methods, including X-ray powder diffraction (XRPD) and infrared (IR) spectroscopy. Polymorph I characteristic XRPD pattern is represented at Fig.1. Diffraction pattern peaks position and its relative intensity are summarized in the Table 1. Peaks position 2Θ angles are presented as ±0.2°. IR spectrum of the Polymorph I is represented at Fig.2.

Polymorph II characteristic XRPD pattern is represented at Fig.3. Diffraction pattern peaks position and its relative intensity are summarized in the Table 1. Peaks position 2Θ angles are presented as ±0.2°. IR spectrum of the Polymorph II is represented at Fig.4.

According to the current invention, pure Furazidin polymorphs I and II may be obtained by 3- (5-nitrofuran-2-yl)acroleine condensation with 1 -aminohydantoine in the presence of the required polymorph crystal seeds. Depending on the crystal seed used, polymorph I or polymorph II are obtained with polymorphic purity of over 90%. If said condensation reaction is performed without crystal seeds, Polymorph I or a mixture of Polymorph I and Polymorph II is usually obtained.

According to the current invention, we have unexpectedly discovered, that synthesizing Polymorph II, the obtained Furazidin is of a higher quality than in the case of synthesizing Polymorph I. Polymorph II contains less impurities in comparison with Polymorph I. Polymorph II is filtered much better than Polymorph I. During visual comparison of the crystals size using microscopy, it was found that Polymorph II has bigger crystals (Fig. 5, 6). In a sieving analysis, Polymorph I was found to conglutinate, clump and block cells of the sieve, thus complicating preparation of the pharmaceutical composition and deteriorating its properties.

Table 1. Positions and relative intensity of the diffraction pattern peaks for Polymorphs I and II.

We have also investigated and compared the dissolution dynamics of both polymorphs in the sodium hydrogen carbonate water solution (Fig. 7, Table 2).

Table 2.

From the obtained results it can be seen that Polymorph II dissolves better than Polymorph I. The dissolution dynamics of the Polymorph II is also substantially better than of Polymorph I. Already after 15 minutes 91.3% of the Polymorph II were dissolved, in comparison to 59.9% of Polymorph I. Faster dissolution may positively affect the bioavailability of the pharmaceutical substance upon dissolution of a dosage form in a body.

Polymorph I and II characteristic DSC curves are shown at Fig. 8 and 9 and it reveals a difference between two polymorphs. Polymorph II curve demonstrates an exothermic effect with a maximum at 212 °C, which corresponds to the form II turning into from I.

Polymorphs, obtained according to the current invention, are suitable to prepare pharmaceutical compositions. A pharmaceutical composition comprising a polymorph of Furazidin, according to the current invention, is suitable for use as an antibacterial medicament.

Examples

X-ray powder diffraction (XRPD)

XRPD were recorded using Bruker D8 Advance apparatus equipped with LynxEye position- sensitive detector. Recording mode: 3-35 ⁰ 2Θ, speed 0.2s/0.02 °. Samples were powdered in an agate mortar prior to analysis.

Infrared spectra (TR)

Infrared spectra were recorded using Nicolet IR200 photometer in KBr pellets in the range of 4000 - 650 cm^"1. Differencing scanning calorimetry (DSC)

Differencing scanning calorimetry curves were recorded using Mettler TA 4000 calorimeter according to the manufacturer's instructions. DSC curves were recorded at a temperature range from 50 °C to 250 °C with heating rate of 5.0 °C/min in the nitrogen atmosphere.

The current invention is illustrated by the following non-limiting examples.

Example 1. Preparation of the Furazidin Polymorph II

3-(5-Nitrofuran-2-yl)acroleine (45 g) was placed into 2 L three-neck flask equipped with stirrer, thermometer and reflux condenser and isopropanol (750 mL), water (150 mL) and acetic acid (15 mL) were added thereto. Reaction mixture was stirred at 60-80 °C until 3-(5-nitrofuran-2- yl)acroleine was completely dissolved.

1 - Aminohydantoine (49 g) solution in water (250 mL) was prepared in a separate flask upon heating of the solution to 50-60 °C.

Furazidin Polymorph II seed crystals (3 g) were added to the warm solution of 3-(5-nitrofuran-

2- yl)acroleine and warm 1 -amminohydantoine solution was poured thereto. At that time precipitation starts in the solution, and the solution temperature increased. The obtained solution mixture was kept for 1 h and then let to cool down. Precipitate was filtered off, washed with water, and dried at 50-60 °C. l-{[(lE,2E)-3-(5-nitrofuran-2-yl)prop-2-ene-l- ylidene]amino}imidazolidin-2,4-dione (69 g, 97%) was obtained.

Example 2. Preparation of the Furazidin Polymorph I

Polymorph I was obtained similarly to the Polymorph II as described in the Example 1, but optionally adding the Polymorph I seed crystals.

Example 3. Study of dissolution dynamics

Furazidin sample for analysis (0.05 g) was placed in a capsule No.3. For the dissolution study a solid dosage form dissolution apparatus equipped with the stirrer and the capsule immersion helping device was used. 900 mL of sodium hydrogen carbonate 1.5% water solution was used as a solution media. The solution was heated to 37±0.5 °C. One capsule was placed in each vessel using immersion device and the apparatus was turned on. Solution aliquots were taken, cooled down and filtered through a paper filter, discarding the first portion of the filtrate. Filtrate (5.0 mL) was placed in the 50 mL measuring flask and diluted with 1.5% sodium hydrogen carbonate solution to the mark level and well stirred. Light absorption maximum of the analyzed solution was measured using Agilent 8453 No. CN22805904 spectrophotometer at wavelength of 410±2 nm relatively to the absorption of the standard sample. From the obtained data dissolution curves were drawn.

Claims

1. Furazidin crystalline form I, characterized in that the XRPD diffraction pattern has peaks at the diffraction angle 2Θ of 10.5±0.2; 11.0±0.2; 11.7±0.2; 13.0±0.2; 13.7±0.2; 18.1±0.2; 18.7±0.2; 19.2±0.2; 20.2±0.2; 21.2±0.2; 22.2±0.2; 24.0±0.2; 27.4±0.2; 27.8±0.2; 28.3±0.2.

2. Furazidin crystalline form I, characterized with XRPD diffraction pattern as shown at the Fig. 1.

3. Furazidin crystalline form I, characterized with IR spectrum as shown at the Fig. 2.

4. Furazidin crystalline form I according to any of the claims 1 to 3, comprising less than 10% of other crystalline form of Furazidin.

5. Furazidin crystalline form II, characterized in that the XRPD diffraction pattern has peaks at the diffraction angle 2Θ of 7.8±0.2; 11.0±0.2; 13.7±0.2; 15.8±0.2; 17.3±0.2; 17.5±0.2; 19.2±0.2; 21.6±0.2; 22.5±0.2; 27.3±0.2; 27.8±0.2; 28.4±0.2.

6. Furazidin crystalline form II, characterized with XRPD diffraction pattern as shown at the Fig. 3.

7. Furazidin crystalline form II, characterized with IR spectrum as shown at the Fig. 4.

8. Furazidin crystalline form II according to any of the claims 5 to 7, comprising less than 10% of other crystalline form of Furazidin.

9. A pharmaceutical composition comprising the Furazidin crystalline form according to any of claims 1 to 4 and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising the Furazidin crystalline form according to any of claims 5 to 8 and a pharmaceutically acceptable carrier.