Solid forms of ortataxel

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to solid forms of 1,14-carbonate 13-(N-Boc-β-isobutylserinyl)-14-b-hydroxybaccatineIII (Ortataxel) of formula

.

There are presented an amorphous form A, a crystalline form B, a mixture thereof and a method for preparing them. The amorphous form A is prepared by rapid deposition of ortataxel from the mixture of acetone and water. The form A is transformed into the form B when suspending and mixing in the mixture of ethanol and water for 4-8 hours. The suspension mixed for at least 4 hours is used to prepared the mixture of the form B and the form A. The form B or the mixtures of the forms A and B can be also produced by dissolving ortataxel in a proton organic solvent with water added thereafter; this compounds possess anticancer activity.

EFFECT: invention refers to the pharmaceutical composition on the basis of the crystalline form A and B or the mixture thereof for treating cancer.

26 cl, 4 ex, 13 dwg

The SCOPE of the INVENTION

The present invention relates to solid forms of Ortataxel (1,14-carbonate 13-N-Boc-β-isobutylene)-14-β-hydroxyacetone III) (1), their mixtures and methods for their preparation.

BACKGROUND of the INVENTION

Ortataxel (1) is an anticancer compound, in particular, applicable to tumors of the breast, lung, ovary, colon, prostate, kidney and pancreas, even in the case of resistance to known anticancer tools such as adriamycin, vinblastine and some derivatives of platinum.

Ortataxel can be obtained in accordance with the methods described in U.S. patent No. 7232916, 6737534 and 6906101. These patents discuss the examples in the final purification step consisting of crystallization from a mixture of acetone and hexane, resulting in the formation of Ortataxel in the form of MES with the content of acetone in the range from 4.5 to 6.5%.

X-ray powder diffractometry (XRPD) of acetone MES shows characteristic peaks at approximately 7,9, 9,8, 10,6, 10,9, 14,6, 16,9, 19,7, 21,3 degrees 2-theta. The curve of differential scanning calorimetry (DSC) shows an endothermic peak appearing at approximately 164°C in the melting and release of solvent of crystallization [podtverzdaetsa weight of approximately 5.0% in thermogravimetric/differential thermal analysis (TG/DTA)], and weak exothermic peak with a maximum at approximately 212°C With subsequent intensive endothermic peak with maximum at about 247°C in the melting and beginning of decomposition. IR shows a characteristic frequency absorption at 3521, 3321, 2971, 2953, 1826, 1762, 1706, 1526, 1366, 1238, 1165, 1072, 723 cm^-1.

It is well known that volatile impurities in active pharmaceutical ingredients must meet the requirements of the manual (Q3C) ICH (International Conference on Harmonization); in this particular case, the content of acetone in the range from 4.5 to 6.5% will not be permitted. Thus, it would be desirable to find a stable crystalline form of Ortataxel, which does not contain residual impurities solvents in quantities not acceptable from a regulatory point of view. This crystalline form must also be chemically and thermodynamically stable, i.e. it must maintain a constant quality during storage and should be accessed using the playback method.

Description of the INVENTION

It is found that Ortataxel exists in two resolutiony physical Forms, hereinafter as Form a and b, which can also be obtained in the form of mixtures.

The form is an amorphous substance, because it does not show distinct peaks in powder x-ray. About the and can be easily obtained from Ortataxel, for example, acetone of MES of Ortataxel obtained in accordance with the methods of synthesis described in the aforementioned patents, by dissolving in a suitable mixing with the water solvent, followed by rapid addition of water containing trace amounts (usually 0,001-0,003%, weight/volume) of an organic acid, such as acetic or ascorbic acid, preferably citric acid. "Suitable water-soluble solvent" means ketone or bipolar aprotic solvent or their mixture; the preferred solvents are acetone, dimethylsulfoxide or mixtures thereof. The method is generally performed at a temperature in the range from 20 to 30°C; and the preferred organic acid is citric acid. Organic acid prevents the formation of 7-epimer and gives Form And the physical and chemical stability for at least 36 months. In accordance with a preferred embodiment of the invention, obtaining Forms And is carried out by dissolving Ortataxel in acetone (8 ml/g_ortataxeland his deposition by water (40 ml/g_ortataxelcontaining 0,001-0,003% citric acid (weight/volume) at room temperature.

The form is a crystalline polymorphs, melting at 159°C; ratio pseudopolymorphic acetone is on MES Form In a low solvent content, easy selection by filtration or centrifugation and chemical and physical stability for at least 36 months. The form can be obtained by dissolving Ortataxel, for example, acetone of the MES or the above Form And in proton organic solvent such as methanol, ethanol or isopropanol, preferably ethanol, containing trace amounts of organic acids (0,01-0,03%, weight/volume), for example, acetic, ascorbic, but preferably citric acid, and then adding water to sedimentation and mixing the resulting mixture at a temperature in the range from 0 to 60°C, preferably at 40°C. for a time ranging from 4 to 8 hours. In accordance with a preferred embodiment of the invention, the Form is received by the dissolution of Ortataxel in ethanol (8-12 ml/g_ortataxelcontaining 0,01-0,03% citric acid (weight/volume), followed by addition of water (13-20 ml/g_ortataxel) so that the ratio of ethanol/water was in the range of 0.5-0.7, and stirring for 6 hours. If mixing is performed in less than 4 hours, Ortataxel receive in the form of a mixture of Form a and Form C.

Forms a and b of Ortataxel and mixtures thereof can be preferably used to obtain the pharmaceutical composition is for the treatment of cancer. In particular, a mixture of forms a and b, which have different bioavailability, suitable for the production of solid dosage Forms with controlled release. In this regard, an additional object of the present invention are pharmaceutical compositions containing the crystalline Form a or b of Ortataxel or mixtures thereof with a mixture of pharmaceutically acceptable carriers and/or ingredients, for example, those discussed in "Remington''s Pharmaceutical Sciences", Mack Publishing Co., N.Y., USA.

The invention is now illustrated in more detail in the following experimental section.

EXPERIMENTAL SECTION

Description of the drawings

X-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC), thermogravimetric/differential thermal analysis (TG/DTA), infrared (IR) and optical microscopy were used to characterize new solid Forms, which were compared with analytical data of acetone MES.

Figure 1-4: spectra XRPD, DSC, TG/DTA and IR Forms;

Figure 5-8: spectra XRPD, DSC, TG/DTA and IR Forms;

Fig.9-12: spectra XRPD, DSC, TG/DTA and IR mixture of Form a and Form B, containing approximately 75% of the Form;

Fig: DSC profile of different quantitative ratios of Form a and Form C.

Form And

X ray powder Form (figure 1) is typical for amorphous products with complete absence of diffraction Pico is.

DSC curve of Form a (figure 2) shows a weak and broad endothermic signal with a maximum at approximately 80°C, the baseline shift due to T_gbetween 133°C and 143°C, an exothermic peak with a maximum at approximately 214°C due to recrystallization of the molten product and the subsequent melting peak with a maximum at about 246°C., followed by decomposition.

Range IR Form (figure 3) shows a characteristic frequency absorption at 3442, 2960, 1821, 1732, 1714, 1368, 1236, 1162, 1085, 1068, 984, 907, 776, 763, 711 cm^-1.

TG/DT analysis Form (figure 4) confirms the DSC analysis, showing the profile DT, characterized by the baseline shift due to T_gbetween 130°C and 143°C, an exothermic peak with maximum at about 211°C due to recrystallization of the molten product and the subsequent peak melting with a maximum at about 249°C., followed by decomposition. The TG profile shows a weight loss of approximately 1.0% from 30 to 150°C due to the evaporation of residual moisture and weight loss of approximately 1.6%, which occurs when recrystallization, followed by a huge weight loss in the decomposition reaction.

Optical microscopy shows that the solid Form And is formed fragile, irregular particles with a large variety of sizes and the lack of clearly marked Crist is lychesky Forms.

Form

X ray powder Form (figure 5) shows a crystalline structure with the corresponding characteristic peaks at approximately 3,5, 6,8, 9,9, 10,1, 10,7, 12,1, 13,1, 14,8, 18,2, 19,7, 21,3, 29,3 degrees 2-theta.

DSC curve of the Form In (6) shows a weak and broad endothermic signal with a maximum below 100°C, the first melting peak with a maximum at approximately 166°C and ∆H_fusapproximately -20 j/g, an exothermic peak with a maximum at approximately 196°C due to recrystallization of the molten product and the second melting peak with a maximum at about 252°C., followed by decomposition.

Range IR Form In (Fig.7) shows a characteristic frequency absorption at 3444, 2961, 1816, 1735, 1720, 1689, 1368, 1237, 1163, 1085, 1068, 1047, 989, 949, 907, 776, 764, 710 cm^-1. TG/DT analysis Form (Fig) confirms DSC analysis, identifying weak and broad endothermic signal with a maximum below 100°C due to the loss of residual moisture, the first melting peak with a maximum at about 164°C., an exothermic peak with a maximum at approximately 200°C. as a result of recrystallization of the molten product and the second melting peak with a maximum at about 253°C., followed by decomposition. In the TG profile for weight loss of approximately 1.4% from 30 to 150°C due to the evaporation of residual moisture should be a huge loss of weight, the which is above 240°C due to the decomposition reaction.

Optical microscopy shows that the solid Shape formed In a pointed needle crystals.

A mixture of Form a and Form

X ray powder mixture of Form a and Form B (Fig.9) shows a crystalline structure with characteristic peaks at approximately 3,4, 6,8, 9,9, 10,6, 12,1, 13,1, 14,8, 18,1, 19,7, 21,2 degrees 2-theta at the expense of the fraction Form in the mixture.

DSC curve (figure 10) shows a weak and broad endothermic signal with a maximum below 100°C, the first melting peak with a maximum at about 163°C and ∆H_fusapproximately -15 j/g, an exothermic peak with a maximum at approximately 202°C as a result of recrystallization of the molten product and the second melting peak with a maximum at about 251°C., followed by decomposition.

The spectrum of the IR (11) shows a characteristic frequency absorption at 3448, 2960, 1816, 1735, 1719, 1688, 1368, 1237, 1164, 1085, 1068, 1048, 989, 949, 906, 776, 764, 710 cm^-1.

TG/DT analysis (Fig) confirms DSC analysis, identifying weak and broad endothermic signal with a maximum below 100°C due to the loss of residual moisture, the first melting peak with a maximum at about 162°C., an exothermic peak with a maximum at approximately 202°C as a result of recrystallization of the molten product and the second melting peak with a maximum at approximately 250°C, with subsequent different is feared. In the TG profile for weight loss of approximately 2.7% from 30 to 150°C due to the evaporation of residual moisture should be a huge weight loss, which occurs at 240°C in the decomposition reaction.

Optical microscopy shows that the Mixture of Form a and Form formed prismatic crystals.

These data clearly indicate that the polymorphic Forms a and b of Ortataxel readily distinguishable from pseudopolymorphic acetone of MES using XRPD, DSC, IR, and analyses of the content of the solvent (such as Tg or gas chromatography).

MATERIALS AND METHODS

Powder x-ray (XRPD)

The x ray powder patterns were obtained on a diffractometer Philips PW1800. The x-ray generator operated at 45 kV and 40 mA tube Cu Kα source of radioactive radiation. The sample was positioned in the respective slots, and the exposed length was 10 mm, Data were collected in the interval of angles from 2 to 65 degrees 2-theta with a step size equal to 0.02 degrees 2-theta.

Differential Scanning Calorimetry (DSC)

Measurements of differential scanning calorimetry was performed using a Mettler TC15, equipped with measuring cuvette DSC20 using sealed aluminum crucibles (volume 40 μl) with a small hole. The heat flow was recorded from 30 up to 30°C with a linear heating rate, equal to 10°C/min under a flow of nitrogen 50 ml/min for Approximately 5 mg of powder was used for each dimension.

Thermogravimetry and differential thermal analysis

Studies were performed using a simultaneous system of Seiko TG/DTA6200 using open aluminum cuvette (volume 40 μl). The signals TG/DT were recorded from 30 to 300°C with a linear heating rate (10°C/min) at a flow of nitrogen (200 ml/min to Approximately 10 mg of powder was used for each dimension.

Infrared spectroscopy with Fourier transform (FTIR)

Infrared spectra were recorded by ATR method using a spectrometer with Fourier transform Perkin Elmer Spectrum One. Spectra were the result of receiving and converting 16 layered scanogram in the spectral region 4000-550 cm^-1with a resolution equal to 4 cm^-1.

Optical microscopy

Studies were performed using transmitted light microscope Zeiss Axioskop. For each study a small amount of sample was dispersed in silicone oil deposited on a glass slide and covered with cover glass. The observations were conducted in suitable lighting conditions, contrast and magnification.

EXAMPLE 1 - Getting Forms And

Ortataxel (13 g) was dissolved in acetone (112,5 ml). Purified water (555 ml)containing citric acid (12 mg), b is La instantly added with stirring, causing the precipitation of an amorphous solid, which was filtered and washed with water (65 ml)containing citric acid (18 mg). The sample was dried at 40°C for 48 hours, providing 12 grams of white solids having characteristic XRPD, DSC, IR and TG/DTA, described in figure 1-4, respectively.

EXAMPLE 2 - get your Forms In

Ortataxel (14 g) was dissolved in 95% ethanol (168 ml)containing citric acid (28 mg)at 50°C. Cold demineralized water (280 ml) was added to the resulting solution for 15 minutes. The suspension was stirred at 40°C for 6 hours. The mixture was cooled to 20°C. and the white solid was filtered. The solid was washed with ethanol (168 ml) and water (280 ml). The solid was dried under vacuum at 50°C for 40 hours, providing a 13.4 g of a white solid substance having a characteristic XRPD, DSC, IR and TG/DTA, described in figure 5-8, respectively.

EXAMPLE 3 a mixture of about 25% of the Forms a and 75% of the Form

Ortataxel (14 g) was dissolved in 95% ethanol (168 ml)containing citric acid (28 mg)at 50°C. Cold demineralized water (280 ml) was added to the final solution for 15 minutes. The mixture was immediately cooled to 20°C. and the white solid was filtered. The solid was washed with ethanol (168 ml) and water is th (280 ml), containing citric acid (25 mg). The solid was dried under vacuum at 50°C for 40 hours, providing a 13.4 g of white matter having characteristic XRPD, DSC, IR and TG/DTA described in figures 9-12, respectively.

EXAMPLE 4 to Obtain mixtures of Form a and Form in different proportions

Form A (1 g) was suspended in a mixture of 95% ethanol (12 ml) and water (20 ml)containing citric acid (2 mg), at 40°C. Samples were selected at different times (t=0, t=5 min, t=30 min, t=6 h) to demonstrate that different quantitative ratios Form a and Form b can be obtained. Fig illustrates DSC analysis of the samples when compared with the curve of the pure forms of the Century

1. Amorphous Form of Ortataxel [1,14-carbonate 13-N-Boc-β-isobutylene)-14-β-hydroxyacetone III]

2. The way to obtain the amorphous Form A according to claim 1, which includes the dissolution of Ortataxel in the ketone or bipolar aprotic organic solvent or their mixtures with further addition of water containing 0,001-0,003% (weight/volume) of the organic acid.

3. The method of claim 2 where the solvent is acetone or dimethylsulfoxide, or mixtures thereof.

4. The method according to claim 2 or 3, where the organic acid is citric or ascorbic acid.

5. The method according to claim 4, where the organic acid is citric acid.

6. To istoricheskaya Form B of Ortataxel [1,14-carbonate 13-N-Boc-β-isobutylene)-14-in-hydroxyacetone III]

with XRPD, characterized by the following peaks 3,5, 6,8, 9,9, 10,1, 10,7, 12,1, 13,1, 14,8, 18,2, 19,7, 21,3, 29,3 degrees 2-theta.

7. The way to obtain Form B of Ortataxel according to claim 6, which includes the dissolution of Ortataxel in proton organic solvent containing trace amounts of organic acids, with subsequent addition of water and stirring at a temperature in the range from 0 to 60°C for a time ranging from 4 to 8 p.m.

8. The method according to claim 7, where Ortataxel, dissolved in ethanol, acetone is the MES of Ortataxel or Form Ortataxel according to claim 1.

9. The method according to claim 7 or 8, where the temperature is 40°C.

10. The method according to claim 9, where the mixing occurs within 6 hours

11. The method according to any of claims 7-10, where the organic acid is citric acid.

12. The method according to any of claims 7-11, where the concentration of the organic acid is from 0.01 to 0.03% (weight/volume).

13. The mixture Forms Ortataxel according to claim 1 and Form B of Ortataxel 6.

14. The mixture according to item 13, where the amount of Form B is approximately equal to 75% by weight.

15. A method of producing mixtures of Form A and Form B item 13 or 14, which includes the suspension of Ortataxel in a mixture of proton organic solvent and water containing organic acid, and stirring is less than 4 hours and at a temperature in the range from 0 to 60°C.

16. The method according to clause 15, where ORT is the Axel, suspended in the mixture, acetone is the MES of Ortataxel or Form Ortataxel.

17. The method according to clause 16, where the proton organic solvent and water are in the ratio of 0.5-0.7.

18. The method according to 17, where the temperature is 40°C.

19. The method according to any of PP-18, where the organic acid is citric acid or ascorbic acid.

20. The method according to claim 19, where the organic acid is citric acid.

21. Pharmaceutical compositions for treating cancer containing the amorphous Form of Ortataxel according to claim 1, or a crystalline Form B of Ortataxel according to claim 6, or a mixture thereof according to item 13 or 14 in a mixture with suitable excipients and/or carriers.

22. The use of an amorphous Form of Ortataxel according to claim 1, or a crystalline Form B of Ortataxel according to claim 6, or mixtures thereof according to item 13 or 14 to obtain pharmaceutical compositions for the treatment of cancer.

23. The method according to any of claims 7 to 12, where the proton organic solvent is methanol, ethanol or isopropanol.

24. The method according to any of claims 7 to 12, where the proton organic solvent is ethanol.

25. The method according to any of PP-20, where the proton organic solvent is methanol, ethanol or isopropanol.

26. The method according to any of PP-20, where the proton organic solvent is ethanol.