Improved azacitidine composition

Abstract

The presented invention relates to Azacitidine (compound of formula (1)) particles characterized by bimodal particle size distribution, process for preparation thereof and composition comprising them.

Description

[0001] P1821PC00

[0002] IMPROVED AZACITIDINE COMPOSITION

[0003] BACKGROUND OF THE PRESENT INVENTION

[0004] The presented invention relates Azacitidine (Compound of formula (1)) particles in polymorph Form I characterized by an XRPD pattern comprising peaks at 12.2°, 13.0°, 19.0°, 20.1°and 23.0° degrees 2 theta ( 12 degrees 2 theta) when measured with CuKal radiation ( = 1.54060 A), characterized by bimodal particle size distribution that comprises: a. A first particle population having particle size D90 lower than 20 pm, preferably between 12 pm and 20 pm; b. A second particle population having particle size D90 higher than 120 pm, preferably between 120 pm and 350 pm, and the particle volume ratio between the first and the second particle population is between 70%: 30% and 30%: 70%.

[0005] The presented invention further relates to a process for preparation of the particles and to a tablet composition comprising the particles.

[0006] Azacitidine, 4-Amino-l-(beta-D-ribofuranosyl)-l,3,5-triazin-2(lH)-one is a DNA methyltransferase inhibitor, that is useful for the treatment of myelodysplastic syndromes or chronic myelomonocytic leukemia or myelodysplastic syndromes can lead to acute myeloid leukaemia or acute myeloid leukaemia that has developed from a myelodysplastic syndrome. Several solid forms of Azacitidine are described in prior art, for example in W02004082619, W02004082822, W02008088779, W02010014883 or CN107827944 applications. Among described forms the solid Form I described in W02004082619 shows improved properties and is used in Azacitidine marketed product. Azacitidine oral compositions are described for example in W02004041195, WO2009139888, WO201 1107750 or WO2018204317 applications.

[0007] We have surprisingly found that when Azacitidine particles in polymorph Form I, characterized by bimodal particle size distribution that comprises: a. A first particle population having particle size D90 lower than 20 pm, preferably between 12 pm and 20 pm; b. A second particle population having particle size D90 higher than 120 pm, preferably between 120 pm and 350 pm, and the particle volume ratio between the first and the second particle population is between 70%: 30% and 30%: 70%; show bimodal particle size distribution according to presented invention are used for preparation of a tablet composition, the properties of the tablet composition prepared from the particles are significantly improved.

[0008] SUMMARY OF THE INVENTION

[0009] The presented invention relates Azacitidine particles in polymorph Form I characterized by 12.2°, 13.0°, 19.0°, 20.1°and 23.0° degrees 2 theta ( +_0.2 degrees 2 theta) when measured with CuKal radiation ( = 1.54060 A), characterized by bimodal particle size distribution that comprises: a. A first particle population having particle size D90 lower than 20 pm, preferably between 12 pm and 20 pm; b. A second particle population having particle size D90 higher than 120 pm, preferably between 120 pm and 350 pm, and the particle volume ratio between the first and the second particle population is between 70%: 30% and 30%: 70%.

[0010] The presented invention further relates to a process for preparation of Azacitidine particles in polymorph Form I characterized by 12.2°, 13.0°, 19.0°, 20.1°and 23.0° degrees 2 theta ( 4^0.2 degrees 2 theta) when measured with CuKal radiation (X = 1.54060 A), characterized by bimodal particle size distribution that comprises: a. A first particle population having particle size D90 lower than 20 pm, preferably between 12 pm and 20 pm, b. A second particle population having particle size D90 higher than 120 pm, preferably between 120 pm and 350 pm, and the particle volume ratio between the first and the second particle population is between 70%: 30% and 30%: 70%.

[0011] The process comprising:

[0012] 1. Dissolving Azacitidine in dimethylsulfoxide to obtain a mixture;

[0013] 2. Cooling the mixture to a temperature between 15°C and 25°C;

[0014] 3. Adding methanol in the course of between 45 and 120 minutes while stirring at 40 - 60 RPM;

[0015] 4. Stirring the mixture for between 20 and 60 min at 40 - 60 RPM;

[0016] 5. Isolating the Azacitidine particles.

[0017] The presented invention also relates to a composition, preferably a tablet composition, comprising Azacitidine particles in polymorph Form I characterized by 12.2°, 13.0°, 19.0°, 20. l°and 23.0° degrees 2 theta ( 4^0.2 degrees 2 theta) when measured with CuKal radiation (X = 1.54060 A), characterized by bimodal particle size distribution that comprises: a. A first particle population having particle size D90 lower than 20 pm, preferably between 12 pm and 20 pm; b. A second particle population having particle size D90 higher than 120 pm, preferably between 120 pm and 350 pm, and the particle volume ratio between the first and the second particle population is between 70%: 30% and 30%: 70%.

[0018] BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 : Picture of a sample having inadequate punch die filling.

[0020] Figure 2: XRPD pattern of solid Form I of Azacitidine.

[0021] Figure 3: Particle size distribution of Azacitidine particles characterized by bimodal particle size distribution.

[0022] Figure 4: Azacitidine particles having bimodal particle size distribution.

[0023] DETAILED DESCRIPTION OF THE INVENTION

[0024] RPM means stirring revolutions per minute.

[0025] The presented invention relates Azacitidine particles in polymorph Form I characterized by 12.2°, 13.0°, 19.0°, 20.1°and 23.0° degrees 2 theta ( +_0.2 degrees 2 theta) when measured with CuKal radiation (X = 1.54060 A), characterized by bimodal particle size distribution that comprises a. A first particle population having particle size D90 lower than 20 pm, preferably between 12 pm and 20 pm; b. A second particle population having particle size D90 higher than 120 pm, preferably between 120 pm and 350 pm, and the particle volume ratio between the first and the second particle population is between 70%: 30% and 30%: 70%.

[0026] XRPD pattern of Form I is depicted in Figure 2.

[0027] Particles having bimodal size distribution comprise two particles populations, each of the populations has a different particle sizes. An example of such particles is depicted in Figure 3.

[0028] The particle volume ratio between the first and the second population can be between 70%:30% and 30%:70%, preferably it is between 60%:40% and 40%:60%, more preferably it is between 55%:45% and 45%:55%.

[0029] The first Azacitidine particles population can be further characterized by having particle size Dio between 2.3 pm and 3.1 pm and D50 between 5.0 pm and 7.0 pm. The second Azacitidine particles population can be further characterized by having particle size Dio between 38 pm and 60 pm and D50 between 70 pm and 140 pm.

[0030] Azacitidine particles according to presented invention can be prepared by a process comprising:

[0031] 1. Dissolving Azacitidine in dimethylsulfoxide to obtain a mixture;

[0032] 2. Cooling the mixture to a temperature between 15°C and 25°C;

[0033] 3. Adding methanol in the course of between 45 and 120 minutes while stirring at 40 - 60 RPM;

[0034] 4. Stirring the mixture for between 20 and 60 min at 40 - 60 RPM;

[0035] 5. Isolating the Azacitidine particles.

[0036] The concentration of Azacitidine in dimethylsulfoxide can be between 0.1 g / ml and 0.3 g / ml, preferably it is between 0.15 g / ml and 0.25 g / ml. Azacitidine is preferably dissolved at a temperature between 20°C and 40°C but it can be dissolved also at higher or lower temperatures, for example between 40°C and 90°C or between -10°C and 20°C. The mixture is then cooled to a temperature between 15°C and 25°C. To the mixture methanol is added. The volume ratio between methanol and dimethylsulfoxide can be between 2.5: 1 and 3.2: 1, preferably it is between 2.7: 1 and 3: 1. Methanol is added slowly, for example in the course of 45 and 120 minutes while the mixture is stirring at between 40 - 60 RPM. After methanol addition the mixture is stirred for between 20 and 60 minutes at 40 - 60 RPM. Obtained solid Azacitidine particles are isolated, for example by use of filtration or by use of a centrifuge. Isolated Azacitidine particles can be optionally washed for example with Ci-Ce alcohol such as methanol or ethanol or propanol or isopropanol or butanol or tert-butanol and optionally dried, preferably under a protective atmosphere, for example under nitrogen, without stirring the mixture.

[0037] The process can optionally further comprising

[0038] 1. Mixing Azacitidine with Ci-Ce alcohol such as such as methanol or ethanol or propanol or isopropanol or butanol or tert-butanol to obtain a mixture, preferably a suspension;

[0039] 2. Stirring the mixture at a temperature between 30°C and 50°C for between 10 and 30 minutes at between 20 and 40 RPM;

[0040] 3. Isolating Azacitidine particles.

[0041] The concentration of Azacitidine in Ci-Ce alcohol can be between 0.05 g / ml and 0.4 g / ml, preferably it is between 0.1 g / ml and 0.2 g / ml. The mixture, preferably suspension, is stirred at a temperature between 30°C and 50°C for between 10 minutes and 30 minutes at between 20 and 40 RPM. Obtained solid Azacitidine particles were isolated, for example by using filtration or by use of centrifuge. Isolated Azacitidine particles can optionally be washed for example with Ci-Ce alcohol such as methanol or ethanol or propanol or isopropanol or butanol or tert-butanol. Obtained Azacitidine particles can be optionally dried for example under a flow of an inert gas, for example nitrogen without stirring.

[0042] The present invention also relates to a composition, preferably tablet composition, comprising Azacitidine particles in polymorph Form I characterized by 12.2°, 13.0°, 19.0°, 20. l°and 23.0° degrees 2 theta ( 4^0.2 degrees 2 theta) when measured with CuKal radiation (X = 1.54060 A), characterized by bimodal particle size distribution that comprises: a. A first particle population having particle size D90 lower than 20 pm, preferably between 12 pm and 20 pm; b. A second particle population having particle size D90 higher than 120 pm, preferably between 120 pm and 350 pm, and the particle volume ratio between the first and the second particle population is between 70%: 30% and 30%: 70%.

[0043] XRPD pattern of Form I is depicted in Figure 2.

[0044] The particle volume ratio between the first and the second population can be between 70%:30% and 30%:70%, preferably it is between 60%:40% and 40%:60%, more preferably it is between 55%:45% and 45%:55%. The first Azacitidine particles population can be further characterized by having particle size Dio between 2.3 pm and 3.1 pm and D50 between 5.0 pm and 7.0 pm. The second Azacitidine particles population can be further characterized by having particle size Dio between 38 pm and 60 pm and D50 between 70 pm and 140 pm.

[0045] The composition, preferably tablet composition, of the presented invention comprises for example between 100 and 500 mg, preferably between 200 mg and 300 mg of Azacitidine. The tablet composition can further comprising one or more pharmaceutically acceptable excipients. The one or more pharmaceutically acceptable excipients to be used in accordance with the present invention can be chosen from, for example, diluents, binders, disintegrants, lubricants, and glidants.

[0046] The one or more pharmaceutically acceptable excipients to be used in accordance with the present invention can be chosen from, for example, fillers, binders, disintegrants, lubricants, and glidants.

[0047] Fillers which are used to increase the bulk volume of a tablet or capsule. By combining a filler with the active pharmaceutical ingredient, the final product is given adequate weight and size to assist in production and handling. Binders hold the excipients that are present in a tablet together. Binders ensure that tablets and granules can be formed having the desired or required mechanical strength, and they give volume to low active dose tablets. Fillers are preferably used in an amount of from 45 to 65% by weight based on the total weight of the composition. Suitable examples of fillers to be used in accordance with the present invention include starch or pregelatinized starch or microcrystalline cellulose or calcium phosphate. Lactose or sorbitol or mannitol or sucrose are suitable water-soluble fillers.

[0048] Binders which are suitable for use in accordance with the present invention include povidone or hydroxypropyl methylcellulose or dihydroxy propylcellulose or sodium carboxyl methylcellulose.

[0049] In a preferred embodiment the composition, preferably tablet composition, of the presented invention comprises a. At least one filler; b. At least one disintegrant; c. At least one lubricant.

[0050] In another preferred embodiment the composition, preferably tablet composition, of the present invention preferably contains at least two fillers. In a preferred embodiment of the present invention, the diluents to be used are mannitol or microcrystalline cellulose, preferably salicified microcrystalline cellulose, or mixtures thereof.

[0051] The composition, preferably tablet composition, of the present invention may also contain a disintegrant. Disintegrants are added to a tablet composition to promote the breakup of the tablet into smaller fragments in an aqueous environment, thereby increasing the available surface area and promoting a more rapid release of the active pharmaceutical ingredient. Suitable examples of disintegrants to be used in accordance with the present invention include croscarmellose sodium or crospovidone or sodium starch glycolate or mixtures of any of the foregoing. Disintegrants preferably are used in an amount of from 1% to 5% by weight based on the total weight of the composition

[0052] The composition, preferably tablet composition, of the invention may also contain a lubricant. Lubricants are generally used in order to reduce sliding friction. In particular, to decrease friction at the interface between a tablet’s surface and the die wall during ejection, and reduce wear on punches and dies. Suitable lubricants to be used in accordance with the present invention include magnesium stearate or calcium stearate or stearic acid or glyceryl behenate or hydrogenated vegetable oil or glycerine fumarate. The composition of the invention may also contain a glidant. Glidants enhance product flow by reducing interparticulate friction.

[0053] Lubricants and glidants preferably are used in a total amount of from 0.05% to 5% by weight based on the total weight of the composition.

[0054] In a preferred embodiment, the composition, preferably tablet composition, of the present invention contains the following ingredients: a. At least one filler, preferably two filler, more preferably mannitol or microcrystalline cellulose, preferably salicified microcrystalline cellulose or a combination thereof; b. At least one disintegrant, preferably croscamellose sodium; c. At least one lubricant, preferably magnesium stearate.

[0055] In another preferred embodiment the composition, preferably tablet composition, comprises: a. Between 200 mg and 300 mg of Azacitidine; b. Between 200 mg and 320 mg of mannitol; c. Between 130 mg and 210 mg of cellulose, preferably salicified microcrystalline cellulose; d. Between 17 mg and 26 mg of croscamellose sodium; e. Between 8 mg and 13 mg of magnesium stearate.

[0056] The presented invention further relates to a process for preparation the composition, preferably tablet composition, comprising:

[0057] 1. Mixing Azacitidine and a first filler, preferably salicified microcrystalline cellulose and a disintegrant, preferably croscamellose sodium, to obtain a mixture;

[0058] 2. Adding of a second filler, preferably mannitol, into the mixture to obtain a second mixture;

[0059] 3. Adding a lubricant, preferably magnesium stearate, to the second mixture;

[0060] 4. Compressing the second mixture into a tablet; and optionally;

[0061] 5. Coating the tablet.

[0062] We have surprisingly found that when Azacitidine particles according to presented invention are used for the preparation of presented composition, the processability of the composition is significantly improved. We have also surprisingly found that the improved preparation of the composition depends mostly on the Azacitidine particles according to presented invention and the influence of the other excipients is small. The Azacitidine particles or the tablet composition of the presented invention can be used for the treatment of conditions that are treatable by Azacitidine such as a cancer, for example myelodysplastic syndromes or chronic myelomonocytic leukemia or myelodysplastic syndromes can lead to acute myeloid leukaemia or acute myeloid leukaemia that has developed from a myelodysplastic syndrome.

[0063] The invention will be further illustrated by the following examples.

[0064] EXAMPLES

[0065] Pictures of crystals were obtained by Tescan VEGA LMu. The particle size of the particles and particle volume ratio between the particles populations were measured by laser diffraction. For example by using the Mastersizer 3000 software from Malvern Instruments which operates in size range from 0.01pm to 3500pm.

[0066] 10 g of the sample was used for preparation of representative sample using quartering method. The dispersion unit was filed with the dispersant and degassed. The obscuration was set to 5% - 30% by adding the sample into dispersion unit and the measurement immediately run using following method parameters.

[0067]

[0068] The relative standard deviation was <15% for d(0.9), Mode(0) and Mode(l) and <15- 0% for d(0.1). XRPD spectrum of Azacitidine particles was obtained using the following measurement conditions:

[0069] Panalytical Empyrean diffractometer with 0 / 20 geometry (transmition mode), equipped with a PixCell 3D detector

[0070] Example 1

[0071] Two strengths of azacitidine tablets were prepared in a conventional way as described further herein below and have the following compositions:

[0072]

[0073] The tablets were prepared by mixing Azacitidine and ingredients (fillers, disintegrant, lubricant) to obtain a mixture and compressing the mixture into a tablet; and optionally coating the tablet.

[0074] Example 2

[0075] Samples of Azacitidine particles in polymorph Form I having different particle size and particle size distribution were prepared. Compositions comprising the Azacitidine particles were prepared according to procedure described in Example 1 and compressed into tablets. Compositions having an adequate punch die filling were consider “good”. Compositions having an adequate punch die filling can be defined: Powder flows in properly in the fill cam / die and is not neither underfilled or overfilled. The scraper removes any excess material leaving the die flushed with the correct dose weight. Compositions having inadequate punch die filling were consider “bad”, the example of the filling is depicted in Figure 1.

[0076] The composition were further characterized by average tablet weight variability of the prepared batches. The tablet weight variability of the process is measured by following procedure. During the tableting process, tablets are sampled and weighted in a predefined time moments. After compression is finished, the average weight and RSD% (Relative Standard deviation) from all the units (tablets) from all sampling points is calculated. The tablet weight variability is a significant indicator to whether the process is stable. If the weight variability is low, flow of the blend in the hoppers is controlled. The batches having average tablet weight variability equal or below 1.1% were consider „good”. The batches having average tablet weight variability higher than 1.5% were consider „bad”.

[0077] The results are summarized in following Table:

[0078] By comparing samples 1 and 2 with samples 3 to 6 it can be concluded that compositions prepared from Azacitidine particles according to presented invention show improved properties in comparison with composition prepared from Azacitidine particles having a different particle size distribution.

[0079] Example 3: Preparation of Azacitidine particles

[0080] 3.21 kg of Azacitidine was dissolved in 16.8 kg of dimethysulfoxide (DMSO) at temperature 30 °C. The mixture was then cooled down to 20 °C and stirring was set to 50-55 RPM. 33.7 kg of methanol was slowly dosed during 1 hour. The mixture was stirred for 30 minutes and filtered. The filtration cake was washed with 9.6 kg of ethanol to provide Azacitidine particles. The particle size distribution of prepared particles is depicted in Figure 3. Picture of prepared Azacitidine particles is depicted in Figure 4.

[0081] 3.22

[0082] Example 4: Treatment of Azacitidine particles with Ci-Ce alcohol

[0083] The product prepared in Example 3 was suspended by stirring at 30 rpm in 17.7 kg of ethanol. The mixture was heated to 40 °C and stirred for 15 minutes at 30-35 RPM. The mixture was filtered, filtration cake was washed with 9.6 kg of ethanol and dried overnight at 25 °C in the flow on nitrogen gas with no stirring to give Azacitidine particles in yield 3.05 kg (95% of theoretical yield) and in purity 99.98% (HPLC IN).

[0084] The particle size distribution of prepared particles is depicted in Figure 3. Picture of prepared Azacitidine particles is depicted in Figure 4.

Claims

CLAIMS1. Azacitidine particles in polymorph Form I characterized by an XRPD pattern comprising peaks at 12.2°, 13.0°, 19.0°, 20.1°and 23.0° degrees 2 theta ( 4^0.2 degrees 2 theta) when measured with CuKal radiation ( = 1.54060 A), characterized by a bimodal particle size distribution that comprises: a. A first particle population having particle size D90 lower than 20 pm; b. A second particle population having particle size D90 higher than 120 pm, and the particle volume ratio between the first and the second particle population is between 70%:30% and 30%:70%.

2. The particles according to claim 1 wherein the bimodal particle size distribution comprises: a. The first particle population having particle size D90 between 12 pm and 20 pm; b. The second particle population having particle size D90 between 120 pm and 350 pm;3. The particles according to claims 1 or 2 wherein the ratio between the first and the second particle population is between 60%:40% and 40%:60%.

4. The particles according to any one of claims 1 to 3 wherein the azacitidine particles are further characterized by:The first particle population having particle size D10 between 2.3 pm and3.1 pm and D50 between 5.0 pm and 7.0 pm;The second particle population having particle size D10 between 38 pm and 60 pm and D50 between 70 pm and 140 pm.

5. A process for preparation of azacitidine particles according to any one of claims 1 to 4 comprising:a. Dissolving Azacitidine in dimethylsulfoxide to obtain a mixture; b. Cooling the mixture to a temperature between 15°C and 25°C; c. Adding methanol in the course of between 45 and 120 minutes while stirring at 40 - 60 RPM; d. Stirring the mixture for between 20 and 60 minutes at 40 - 60 RPM; e. Isolating the Azacitidine particles.

6. Tablet composition comprising the azacitidine particles according to any one of claims 1 to 4.

7. The tablet composition according to any one of claims 6 further comprising a. At least one filler; b. At least one disintegrant; c. At least one lubricant.

8. The tablet composition according to claim 7 wherein the filler is selected from mannitol or cellulose or starch or pregelatinized starch or calcium phosphate or lactose or sorbitol, the disintegrant is selected from croscamellose sodium or crospovidone or sodium starch glycolate and the lubricant is selected from magnesium stearate or calcium stearate or stearic acid or glyceryl behenate or hydrogenated vegetable oil or glycerine fumarate.

9. The tablet composition according to any one of claims 6 to 8 manufactured by direct compression.

10. The tablet composition according to claim 9 wherein the composition is coated.

11. The tablet composition according to any one of claims 6 to 10 wherein the composition comprises between 100 and 500 mg of azacitidine.

12. The tablet composition according to any one of claims 6 to 11 comprising: a. Between 200 mg and 300 mg of azacitidine;b. Between 200 mg and 320 mg of mannitol; c. Between 130 mg and 210 mg of cellulose; d. Between 17 mg and 26 mg of croscamellose sodium; e. Between 8 mg and 13 mg of magnesium stearate.

12. The Azacitidine particles according to any one of claims 1 to 4 or the tablet composition according to any one of claims 6 to 12 for use for the treatment a cancer.

13. The Azacitidine particles or the tablet composition according to claim 12 wherein the cancer is of myelodysplastic syndromes or chronic myelomonocytic leukemia or myelodysplastic syndromes can lead to acute myeloid leukaemia or acute myeloid leukaemia that has developed from a myelodysplastic syndrome.

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