The invention relates to solid forms of Copanlisib hydrogen phosphate salt or

Copanlisib fumarate salt or Copanlisib ditosylate salt or Copanlisib hydrogen citrate salt or Copanlisib maleate salt or Copanlisib malate salt or Copanlisib tartrate salt or Copanlisib dilactate salt or Copanlisib diacetate salt or Copanlisib dihydrochloride salt.

BACKGROUND OF THE PRESENT INVENTION

This invention relates to Copanlisib, compound of formula (1), salts thereof, solid form of the salts and processes for preparation thereof,

Copanlisib, 2-Amino-N-[7-methoxy-8-[3-(4-morpholinyl)propoxy]-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamid e, is a phosphatidylinositol 3- kinase (PI3K) inhibitor. Copanlisib was launched for a treatment for adults with relapsed follicular lymphoma who have received at least two prior therapy regimens.

Copanlisib was first disclosed in W02008070150 by Bayer. Several salts and their solid forms of Copanlisib were disclosed for example in WO2012136553 or WO2016071435 applications.

There is still a need to prepare Copanlisib salts and solid forms thereof having improved properties such as solubility, crystallinity and stability in comparison with solid forms of

Copanlisib salts disclosed in the prior art. BRIEF DESCRIPTION OF THE INVENTION

The invention relates to solid forms of Copanlisib hydrogen phosphate salt or Copanlisib fumarate salt or Copanlisib ditosylate salt or Copanlisib hydrogen citrate salt or Copanlisib maleate salt or Copanlisib malate salt or Copanlisib tartrate salt or Copanlisib dilactate salt or Copanlisib diacetate salt or Copanlisib dihydrochloride salt.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Copanlisib hydrogenphosphate salt, Form 3, prepared according-to Example 1

Figure 2 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Copanlisib hydrogenphosphate salt, Form 2, prepared according to Example 3

Figure 3 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Copanlisib fumarate salt, Form 1, prepared according to Example 5

Figure 4 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Copanlisib hydrogen citrate salt, Form 1, prepared according to Example 6

Figure 5 depicts the DSC pattern of solid form of Copanlisib hydrogen citrate salt, Form

1, prepared according to Example 6

Figure 6 depicts the TGA pattern of solid form of Copanlisib hydrogen citrate salt,

Form 1, prepared according to Example 6

Figure 7 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Copanlisib maleate salt, Form 1, prepared according to Example 7

Figure 8 depicts the DSC pattern of solid form of Copanlisib maleate salt, Form 1, prepared according to Example 7

Figure 9 depicts the TGA pattern of solid form of Copanlisib maleate salt, Form 1, prepared according to Example 7 Figure 10 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Copanlisib malate salt, Form 1, prepared according to Example 8

Figure 11 depicts the DSC pattern of solid form of Copanlisib malate salt, Form 1, prepared according to Example 8

Figure 12 depicts the TGA pattern of solid form of Copanlisib malate salt, Form 1, prepared according to Example 8

Figure 13 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Copanlisib (L)-(+)-tartarate salt, Form 1, prepared according to Example 9

Figure 14 depicts the DSC pattern of solid form of Copanlisib (L)-(+)-tartarate salt, Form 1, prepared according to Example 9

Figure 15 depicts the TGA pattern of solid form of Copanlisib (L)-(+)-tartarate salt, Form 1, prepared according to Example 9

Figure 16 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Copanlisib dilactate salt, Form 1, prepared according-to Example 10

Figure 17 depicts the DSC pattern of solid form of Copanlisib dilactate salt, Form 1, prepared according to Example 10

Figure 18 depicts the TGA pattern of solid form of Copanlisib dilactate salt, Form 1, prepared according to Example 10

Figure 19 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Copanlisib diacetate salt, Form 1, prepared according-to Example 11

Figure 20 depicts the DSC pattern of solid form of Copanlisib diacetate salt, Form 1, prepared according to Example 11

Figure 21 depicts the TGA pattern of solid form of Copanlisib diacetate salt, Form 1, prepared according to Example 11 Figure 22 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Copanlisib ditosylate salt, Form 1, prepared according-to Example 12

Figure 23 depicts the TGA pattern of solid form of Copanlisib ditosylate salt, Form 1, prepared according to Example 12 Figure 24 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Copanlisib dihydrochloride salt, Form 3, prepared according to Example 13

Figure 25 depicts the DSC pattern of solid form of Copanlisib dihydrochloride salt,

Form 3, prepared according to Example 13

Figure 26 depicts the TGA pattern of solid form of Copanlisib dihydrochloride salt, Form 3, prepared according to Example 13

DETAILED DESCRIPTION OF THE INVENTION

The presented invention relates to hydrogen phosphate salt of Copanlisib and solid forms thereof. The solid Form 3 of hydrogen phosphate salt of Copanlisib can be characterized by XRPD pattern having 20 values 8.5°, 24.3° and 25.3° degrees 2 theta (± 0.2 degrees 2 theta).-The solid Form 3 can be also characterized by XRPD pattern having 20 values 8.5°, 11.4°, 18.9°, 24.3° and 25.3° 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 3 can be also characterized by XRPD pattern depicted in Figure 1.

The solid Form 3 of hydrogen phosphate salt of Copanlisib can be prepared by a process comprising: a. Mixing of Copanlisib with phosphoric acid (H3PO4) and water to obtain a mixture; b. Adding 1/3 (vol) of methanol to the mixture; c. Seeding the mixture with solid Form 3 of hydrogen phosphate salt of Copanlisib; d. Adding 2/3 (vol) of methanol to the mixture; e. Isolating the solid Form 3.

Concentration of Copanlisib in water can be between 0.1 g/ml and 0.3 g/ml. The molar ratio between Copanlisib and phosphoric acid can be between 1:1 and 1:1.2. Phosphoric acid can be added as a solid or in a form of a solution in a suitable solvent, for example in water.

The volume ratio between water and methanol can be between 1:1 and 1: 1.5. Copanlisib is mixed with water. To the mixture phosphoric acid is added. To the obtained mixture methanol is added in the course of between 20 and 240 minutes, preferably dropwise. After approximately 1/3 (vol) of methanol is added, the mixture is seeded with solid Form 3 of hydrogen phosphate salt of Copanlisib. The seeds can be prepared for example by a process described in Example 2. After all methanol is added, obtained mixture is stirred at 20-25°C for between 8 and 12 hours. Obtained suspension is filtered off and obtained solid can be optionally dried to provide solid Form 3 of hydrogen phosphate salt of Copanlisib.

The solid Form 2 of hydrogen phosphate salt of Copanlisib can be characterized by XRPD pattern having 20 values 5.3°, 23.9° and 25.0° degrees 2 theta (± 0.2 degrees 2 theta). The solid Form 2 can be also characterized by XRPD pattern having 20 values 5.3°, 10.3°, 13.1°, 16.6°, 23.9° and 25.0° 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 2 can be also characterized by XRPD pattern depicted in Figure 3.

The solid Form 2 of hydrogen phosphate salt of Copanlisib can be prepared by a process comprising: a. Mixing of Copanlisib with phosphoric acid (H3PO4) and water to obtain a mixture; b. Adding 1/3 of methanol to the mixture; c. Seeding the mixture with solid Form 2 of hydrogen phosphate salt of Copanlisib; d. Adding 2/3 of methanol to the mixture; e. Isolating the solid Form 2.

Concentration of Copanlisib in water can be between 0.1 g/ml and 0.3 g/ml. The molar ratio between Copanlisib and phosphoric acid can be between 1:1 and 1:1.2. Phosphoric acid can be added as a solid or in a form of a solution in a suitable solvent, for example in water.

The volume ratio between water and methanol can be between 1:1 and 1: 1.5. Copanlisib is mixed with water. To the mixture phosphoric acid is added. To the obtained mixture methanol is added in the course of between 20 and 240 minutes, preferably dropwise. After approximately 1/3 of methanol is added, the mixture is seeded with solid Form 2 of hydrogen phosphate salt of Copanlisib. The seeds can be prepared for example by a process described in Example 4. After all methanol is added, obtained mixture is stirred at 20-25°C for between 8 and 12 hours. To obtained suspension acetone is added to improve filterability of the suspension. The volume ration between methanol and acetone can be for example 1: 1. Obtained suspension is filtered off and obtained solid can be optionally dried to provide solid Form 2 of hydrogen phosphate salt of Copanlisib. The presented invention further relates to fumarate salt of Copanlisib and a solid form thereof. The solid form of fumarate salt of Copanlisib, Form 1, can be characterized by XRPD pattern having 20 values 3.3°, 13.9° and 25.6° degrees 2 theta (± 0.2 degrees 2 theta). The solid Form 1 can be also characterized by XRPD pattern having 20 values 3.3°, 13.9°, 16.4° and 25.6° 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 3. The solid Form 1 of fumarate salt of Copanlisib can be prepared by a process comprising: a. Mixing of Copanlisib with fumaric acid and water to obtain a mixture; b. Concentrating the mixture; c. Adding 2-methyltetrahydrofurane; d. Isolating the solid Form 1.

The concentration of Copanlisib in water can be between 0.1 g/ml and 0.3 g/ml. The molar ratio between Copanlisib and fumaric acid can be between 1:1 and 1:1.2. Fumaric acid can be added as a solid or in a form of a solution in a suitable solvent, for example in water. Copanlisib is mixed with fumaric acid and water. The mixture is concentrated, for example at 100 Pa, at 30°C in the course of 18 hours. To the rest 2-methyltetrahydrofurane is added. The volume ratio between water and 2-methyltetrahydrofurane can be between 18:1 and 23:1. The mixture is stirred at a temperature between 20°C and 30°C for between 12 and 48 hours. Obtained suspension is filtered off and obtained solid can be optionally dried to provide solid Form 1 of Copanlisib fumarate salt.

The invention further relates to ditosylate salt (ditoluene sulfonate salt) of Copanlisib and a solid form thereof. The solid form, Form 1, can be characterized by XRPD pattern having 20 values 5.7°, 9.6° and 15.6° degrees 2 theta (± 0.2 degrees 2 theta). The solid Form 1 can be also characterized by XRPD pattern having 20 values 5.7°, 9.6°, 12.0°, 15.6°, 25.5° and 26.5° 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 22. The solid form can be further characterized by DSC pattern depicted in Figure 23.

The solid Form 1 of ditosylate salt of Copanlisib can be prepared by a process comprising:

1. Mixing Copanlisib with p-toluenesulfonic acid in water;

2. Isolating the solid Form 1.

Concentration of Copanlisib in water can be between 0.1 g/ml and 0.3 g/ml. The molar ratio between Copanlisib and p-toluene sulfonic acid can be between 1:2 and 1 :2.2. p- toluenesulfonic acid can be added as solid or in a form of a solution in a suitable solvent, for example in water, p-toluenesulfonic acid can be optionally used in a form of hydrate, advantageously in a form of monohydrate. The mixture is stirred at 20°C-25°C for between 60 and 240 minutes. Obtained suspension is filtered off and obtained solid can be optionally dried to provide solid Form 1 of ditosylate salt of Copanlisib.

The presented invention also relates to hydrogen citrate salt of Copanlisib and a solid form thereof. The solid form of hydrogen citrate salt of Copanlisib, Form 1, can be characterized by XRPD pattern having 20 values 6.4°, 10.5° and 15.4° degrees 2 theta (± 0.2 degrees 2 theta). The solid Form 1 can be also characterized by XRPD pattern having 20 values 6.4°, 10.5°, 15.4°, 16.1° and 25.3° 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 4. The solid form can be further characterized by DSC pattern depicted in Figure 5. The solid form can be further characterized by TGA pattern depicted in Figure 6. The solid Form 1 of hydrogen citrate salt of Copanlisib can be prepared by a process comprising:

1. Mixing Copanlisib and citric acid in water; 2. Adding methanol;

3. Isolating the solid form. Concentration of Copanlisib in water can be between 0.18 g /ml and 0.35 g/ml. The molar ratio between Copanlisib and citric acid can be between 1:1 and 1:1.2. Citric acid can be added as solid or in a form of a solution in a suitable solvent, for example in water. Copanlisib and citric acid are mixed with water. To the mixture methanol is added. The volume ratio between water and methanol can be between 1 :2 and 1:3. The mixture can be optionally seeded with solid Form 1 of hydrogen citrate salt of Copanlisib. The mixture is stirred at 20°C-25°C for between 8 and 12 hours. Obtained suspension is filtered off and obtained solid can be optionally dried to provide solid Form 1 of hydrogen citrate salt of Copanlisib. The presented invention also relates to maleate salt of Copanlisib and a solid form thereof. The solid form of maleate salt of Copanlisib, Form 1, can be characterized by XRPD pattern having 20 values 6.3°, 16.1° and 25.7° degrees 2 theta (± 0.2 degrees 2 theta). The solid Form 1 can be also characterized by XRPD pattern having 20 values 6.3°, 10.9°, 12.5°, 16.1° and 25.7° 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 7. The solid form can be further characterized by DSC pattern depicted in Figure 8. The solid form can be further characterized by TGA pattern depicted in Figure 9.

The solid Form 1 of maleate salt of Copanlisib can be prepared by a process comprising:

1. Mixing Copanlisib and maleic acid with water;

2. Stirring the mixture at a temperature between 30°C and 40°C;

3. Cooling the mixture to a temperature between 20°C and 25°C;

4. Isolating the solid form.

Concentration of Copanlisib in water can be between 0.1 g/ml and 0.3 g/ml. The molar ratio between Copanlisib and maleic acid can be between 1:1 and 1:1.2. Maleic acid can be added as solid or in a form of a solution in a suitable solvent, for example in water. Copanlisib is mixed with water. A solid form of maleic acid or a mixture thereof with a solvent, for example with water, is added to the mixture of Copanlisib with water. The mixture is heated to a temperature between 30°C and 40°C and stirred at this temperature for between 60 and 240 minutes. The mixture is cooled to a temperature between 20°C and 25°C. Obtained suspension is filtered off and obtained solid can be optionally dried to provide solid Form 1 of maleate salt of Copanlisib.

The presented invention also relates to malate salt of Copanlisib and a solid form thereof. The solid form of malate salt of Copanlisib, Form 1, can be characterized by XRPD pattern having 20 values 2.8°, 10.9° and 26.5° degrees 2 theta (± 0.2 degrees 2 theta).-The solid Form 1 can be also characterized by XRPD pattern having 20 values 2.8°, 8.2°, 10.9°, 19.3° and 26.5° 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 10. The solid form can be further characterized by DSC pattern depicted in Figure 11. The solid form can be further characterized by TGA pattern depicted in Figure 12.

The solid Form 1 of malate salt of Copanlisib can be prepared by a process comprising:

1. Mixing Copanlisib and malic acid with water;

2. Adding methanol at a temperature between 30°C and 40°C;

3. Isolating the solid form.

The concentration of Copanlisib in water can be between 0.1 g/ml and 0.3 g/ml. The molar ratio between Copanlisib and malic acid can be between 1:1 and 1:1.2. Malic acid can be added either as solid or in a form of a mixture with a suitable solvent, for example water. Copanlisib is mixed with water. To the mixture malic acid (or a mixture thereof with a solvent) is added. The mixture is heated to a temperature between 30°C and 40°C. To the mixture methanol is added. The volume ratio between methanol and water can be between 1:2 and 1:3. The mixture is stirred at a temperature between 30°C and 40°C for between 60 and 240 minutes and cooled to a temperature between 20°C and 25°C. Obtained suspension is filtered off and obtained solid can be optionally dried to provide solid Form 1 of malate salt of Copanlisib.

The presented invention also relates to (L)-(+)-tartarate salt of Copanlisib and a solid form thereof. The solid form of (L)-(+)-tartarate salt of Copanlisib, Form 1, can be characterized by XRPD pattern having 20 values 6.0°, 8.6° and 16.3° degrees 2 theta (± 0.2 degrees 2 theta). The solid Form 1 can be also characterized by XRPD pattern having 20 values 6.0°, 8.6°, 12.6°, 15.5° and 16.3° 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 13. The solid form can be further characterized by DSC pattern depicted in Figure 14. The solid form can be further characterized by TGA pattern depicted in Figure 15.

The solid Form 1 of L-(+)-tartarate salt of Copanlisib can be prepared by a process comprising:

1. Mixing Copanlisib and L-(+)-tartaric acid with water;

2. Adding the mixture into methanol;

3. Isolating the solid form.

The concentration of Copanlisib in water can be between 0.18 g/ml and 0.35 g/ml. The molar ratio between Copanlisib and L-(+)-tartaric acid can be between 1 : 1 and 1:1.2. L-(+)- tartaric acid can be added either as solid or in a form of a mixture with a suitable solvent, for example water. Copanlisib is mixed with water. To the mixture L-(+)-tartaric acid is added. The mixture is stirred for between 60 and 240 minutes. The mixture id added into methanol in the course of between 45 and 180 minutes in 2 or 3 or 4 or 5 or 6 or 7 or 8 parts, preferably it is added dropwise. The volume ratio between methanol and water can be between 2:1 and 3:1. The mixture is stirred at between 20°C and 25°C for between 8 and 15 hours. Obtained suspension is filtered off and obtained solid can be optionally dried to provide solid Form 1 of L-(+)-tartarate salt of Copanlisib.

The presented invention further relates to dilactate salt of Copanlisib and a solid form thereof. The solid form of dilactate salt of Copanlisib, Form 1, can be characterized by XRPD pattern having 20 values 2.7°, 10.7° and 26.5° degrees 2 theta (± 0.2 degrees 2 theta). The solid Form 1 can be also characterized by XRPD pattern having 20 values 2.7°, 8.7°, 10.7° and 26.5° 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 16. The solid form can be further characterized by DSC pattern depicted in Figure 17. The solid form can be further characterized by TGA pattern depicted in Figure 18.

The solid Form 1 of dilactate salt of Copanlisib can be prepared by a process comprising: 1. Mixing Copanlisib and lactic acid with water;

2. Adding a mixture of methanol and 2-propanol;

3. Isolating the solid form.

The concentration of Copanlisib can be between 0.1 g/ml and 0.3 g/ml. The molar ratio between Copanlisib and lactic acid can be between 1:2 and 1:2.2. Lactic acid can be added either as solid or in a form of a mixture with a suitable solvent, for example water. Copanlisib is mixed with water. To the mixture lactic acid, preferably in form of a mixture of lactic acid with a solvent, is added. The mixture is stirred at 20°C-25°C for between 60 and 240 minutes. To the mixture a mixture of methanol and 2-propanol is added. The volume ratio between methanol and 2-propanol can be between 2: 1 and 2.5:1. The volume ratio between water and the mixture of methanol and 2-propanol can be between 1:2 and 1:2.5. The mixture is stirred for between 3 and 10 hours. Obtained suspension is filtered off and obtained solid can be optionally dried to provide solid Form 1 of dilactate salt of Copanlisib.

The presented invention further relates to diacetate salt of Copanlisib and a solid form thereof. The solid form of diacetate salt of Copanlisib, Form 1, can be characterized by XRPD pattern having 20 values 12.3°, 16.9° and 25.5° degrees 2 theta (± 0.2 degrees 2 theta). The solid Form 1 can be also characterized by XRPD pattern having 20 values 6.6°, 12.3°, 13.2°, 16.9° and 25.5° 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 19. The solid form can be further characterized by DSC pattern depicted in Figure 20. The solid form can be further characterized by TGA pattern depicted in Figure 21. The solid Form 1 of diacetate salt of Copanlisib can be prepared by a process comprising:

1. Mixing Copanlisib and acetic acid with water;

2. Adding 2-propanol;

3. Isolating the solid form.

The concentration of Copanlisib in water can be between 0.18 g/ml and 0.35 g/ml. The molar ratio between Copanlisib and acetic acid can be between 1:2 and 1:2.2. Acetic acid can be added either as concentrated acetic acid or in a form of a mixture with a suitable solvent, for example water. Copanlisib is mixed with water. To the mixture acetic acid is added. The mixture is stirred for between 60 and 240 minutes. To the mixture 2-propanol is added. The volume ratio between 2-propanol and water can be between 1:1 and 1.5:1. The mixture is stirred for between 3 and 10 hours to obtain a suspension. The suspension is filtered off and obtained solid can be optionally dried to provide solid Form 1 of diacetate salt of Copanlisib.

The invention further relates to solid form of Copanlisib dihydrochloride salt, Form 3.

The solid form can be characterized by XRPD pattern having 20 values 12.3°, 16.9° and 25.5° degrees 2 theta (± 0.2 degrees 2 theta). The solid Form 1 can be also characterized by XRPD pattern having 20 values 6.6°, 12.3°, 13.2°, 16.9° and 25.5° 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 3 can be also characterized by XRPD pattern depicted in Figure 24. The solid form can be further characterized by DSC pattern depicted in Figure 25. The solid form can be further characterized by TGA pattern depicted in Figure 26.

The solid Form 3 of Copanlisib dihydrochloride can be prepared by a process comprising:

1. Mixing Copanlisib with hydrochloric acid and water to obtain a mixture;

2. Concentrating the mixture;

3. Adding methanol ;

4. Isolating the solid form of Copanlisib hydrochloride.

The concentration of Copanlisib in water can be between 0.1 g/ml and 0.2 g/ml. The molar ratio between Copanlisib and hydrochloric acid can be between 1:2 and 1:2.2. Copanlisib is mixed with hydrochloric acid and water to obtain a mixture. The mixture can be optionally filtered. The filtrate can be optionally extracted for example with an acetate such as methyl acetate or ethyl acetate. The mixture is then concentrated for example by freeze vacuum dried (cooled with liquid nitrogen to solidify and then freeze vacuum dried at 0°C and 200 mtorr). The rest is mixed with methanol. The volume ratio between water and methanol can be between 1:1.8 and 1:2.2. Obtained suspension is filtered off and obtained solid can be optionally dried to provide solid Form 3 of Copanlisib dihydrochloride salt.

The crystalline forms according to presented invention can be processed into a suitable pharmaceutical formulation. In the pharmaceutical formulation the solid forms can be mixed with pharmaceutically acceptable adjuvants, diluents or carriers. The amount of crystalline forms according to presented invention in the formulation depends on the condition and a patient to be treated. The crystalline forms according to presented invention or a pharmaceutical formulation comprising the form can be used for the treatment of conditions treatable with Copanlisib or a salt thereof.

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

EXAMPLES

DCS patterns were obtained using the following conditions: 10°C/min -> 350°C.

XRPD spectrum was obtained using the following measurement conditions:

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

Example 1: Preparation of solid Form 3 of Copanlisib hydrogenphosphate salt

3 g of Copanlisib were mixed with 18 ml of water. To the mixture 0.78 g of phosphoric acid was added. To the mixture 18 ml of methanol were dropped during 1 hour at 30-32 °C. After methanol was added, the mixture was seeded by solid Form 3 of Copanlisib hydrogenphosphate salt prepared according to Example 2. Obtained mixture was stirred for 10 hours with mechanical stirring (150 RPM). Obtained suspension was filtered and the filter cake was washed with 9 ml of methanol. Obtained solid was dried in the drier (25 °C, 130 mbar, N2 bleed, 24 hour) to provide 3.48 g, (93% of theoretical yield) of solid Form 3 of Copanlisib hydrogenphosphate salt.

Example 2: Preparation of solid Form 3 of Copanlisib hydrogenphosphate salt (seeds for seeding)

0.5 g of Copanlisib was mixed with 3 ml of water. To the mixture a solution prepared from 0.12 g phosphoric acid and 2 ml of water was added. 0.18 ml of the mixture was concentrated to dryness (-100 Pa, 30°C, 18 h, vacuum drier). The rests after concentration was mixed with 0.1 ml of water and was left to crystallize a week to provide solid Form 3 of Copanlisib hydrogenphosphate salt.

Example 3: Preparation of solid Form 2 of Copanlisib hydrogenphosphate salt

1.5 g of Copanlisib was mixed with 10 ml of water. To the mixture 0.38 g of phosphoric acid was added. To the mixture 0.85 g charcoal was added and the suspension was filtered to provide the solution after carbofiltration.

0.5 ml of obtained solution was seeded with 2 mg of solid Form 2 of Copanlisib hydrogenphosphate salt prepared according to example 4. To the mixture 5-10 drops of methanol were added, obtained mass was sonicated for 10 minutes to obtain a suspension. Obtained suspension was poured into solution after carbofiltration. To the mixture 30 ml of methanol was dropped in the course of 15 minutes at 20-25°C. The mixture was stirred for 30 minutes. To the mixture 30 ml of acetone was added. Obtained mixture was stirred for 1 hour to provide a suspension. The suspension was filtered and the filter cake was washed with 10 ml of acetone. Obtained solid was dried in the drier (25 °C, 130 mbar, N2 bleed, overnight) to provide 1.275 g of solid Form 2 of Copanlisib hydrogenphosphate salt.

Example 4: Preparation of solid Form 2 of Copanlisib hydrogenphosphate salt (seeds for seeding)

0.5 g of solid Form 3 of Copanlisib hydrogenphosphate salt was stored for 1 month at 90% RH/55°C to provide solid Form 2 of Copanlisib hydrogen.

Example 5: Preparation of solid Form 1 of Copanlisib fumarate salt

0.5 g of Copanlisib was mixed with 3 ml of water. To the mixture a solution prepared from 0.12 g of fumaric acid and 2 ml of water was added to obtain a solution. 0.18 ml of the solution was concentrated in drier (lOOPa, at 30°C, for 18 hours). Obtained solid was suspended in 0.25 ml of 2-methyltetrahydrofuran and the mixture was added to the mixture of Copanlisib with fumaric acid previously prepared. The mixture was stirred at 20-25°C over weekend to provide a suspension. The suspension was filtrated to provide solid Form 1 of Copanlisib fumarate salt.

Example 6: Preparation of solid Form 1 of Copanlisib hydrogen citrate salt

3 g of Copanlisib and 1.26 g of citric acid were suspended in 12 ml of water. To the mixture 12 ml of methanol was added. The mixture was seeded with 5 mg of solid Form 1 of Copanlisib hydrogen citrate. The seeds were prepared by a process described later.

The mixture was stirred overnight. To the mixture 12 ml of methanol was added. The mixture was stirred for 3 hours. The mixture was filtered to provide solid. Obtained solid was dried in drier (25 °C, 130 mbar, N2 bleed, 24 hour) to provide 4.26 g of solid Form 1 of Copanlisib hydrogen citrate salt (96% theory).

The seeds was prepared by dissolving of 0.5 g of Copanlisib in 3 ml of water. To the mixture 0.2 g of citric acid in 3 ml of water was added. 0.36 ml of the solution was taken away and dried for 18 hours in vacuum (0.1 atm) at 30°C. To the rest 100 pl of water was added. The mixture was left stand for 1 week at 20-25°C.

Example 7: Preparation of solid Form 1 of Copanlisib maleate salt

3 g of Copanlisib were mixed with 18 ml of water. To the mixture a solution prepared from 0.73 g of maleic acid and 4 ml of water was added within 1 minute. The mixture was heated to 35 °C and stirred at this temperature for 2 hours. The mixture was filtered and the filter cake was washed with 9 ml of methanol. Obtained solid was dried in the drier (25 °C, 130 mbar, N2 bleed, for 24 hours) to provide 3.4 g of solid Form 1 of Copanblisib maleate salt (90% of theoretical yield).

Example 8: Preparation of solid Form 1 of Copanlisib malate salt

3 g of Copanlisib were mixed with 18 ml of water. To the mixture a solution prepared from 0.879 g of (S)-2-hydroxysuccinic acid and 4 ml of water was added within 1 minute. To the mixture 9 ml of methanol at 34-35 °C was added. The mixture was seeded with a suspension of solid Form 1 of Copanlisib malate salt prepared according to process described later. The suspension was added to water-methanol mixture. The mixture was stirred for 2 hours. Obtained suspension was filtered and the filter cake was washed with 9 ml of methanol. Obtained solid was dried in the drier (25 °C, 130 mbar, N2 bleed, for 24 hours) to provide 3.43 g of solid Form 1 of Copanlisib malate salt (87% of theoretical yield).

Preparation of suspension of solid Form 1 for seeding: 3 g of Copanlisib were mixed with 18 ml of water. To the mixture a solution prepared from 0.879 g of (S)-2-hydroxy- succinic acid and 4 ml of water was added within 1 minute. 0.36 ml of the mixture was mixed with 0.36 ml of methanol. The mixture was heated to 35°C for 1 hour, cooled to 20-25°C and used for seeding. Example 9: Preparation of solid Form 1 of Copanlisib (L)-(+)-tartarate salt

3 g of Copanlisib was suspended in 8 ml of water. To the mixture a solution prepared from 0.984 g of L-(+)-tartaric acid and 4 ml of water was added. The mixture was stirred 2 hours. Obtained mixture was dropped during 1 hour into 14 ml of methanol. The mixture was stirred for 12 hours. To the mixture 10 ml of methanol (10 ml) was added. The mixture was stirred for next 2 hours. The mixture was filtered and the filter cake was washed with 5 ml of methanol. Obtained solid was dried in the drier (25 °C, 130 mbar, N2 bleed, for 24 hours) to provide 3.5 g of solid Form 1 of Copanlisib (L)-(+)-tartarate salt (92% of theoretical yield).

Example 10: Preparation of solid Form 1 of Copanlisib dilactate salt

3 g of Copanlisib were mixed with 18 ml of water. To the mixture a solution prepared from 1.153 g of lactic acid and 4 ml of water was added. The mixture was stirred for 2 hours. To the mixture 24 ml of methanol and 12 ml of 2-Propanol was added. The mixture was stirred 5 hours. Obtained suspension was filtered and obtained solid was dried in the drier (25 °C, 130 mbar, N2 bleed, for 24 hours) to provide 2.02 g of solid Form 1 of Copanlisib dilactate salt.

Example 11: Preparation of solid Form 1 of Copanlisib diacetate salt

3 g of Copanlisib were mixed with 12 ml of water. To the mixture 0.75 ml of acetic acid was added. The mixture was stirred for 2 hours. To the mixture 12 ml of 2-Propanol was added. The mixture was stirred for 6 hours. Obtained suspension was filtered and obtained solid was washed with 12 ml of 2-Propanol. Obtained solid was dried in the drier (25 °C, 130 mbar, N2 bleed, for 24 hours) to provide 3.36 g of solid Form 1 of Copanlisib diacetate salt.

Example 12: Preparation of solid Form 1 of Copanlisib ditosylate salt

3 g of Copanlisib were suspended in 18 ml of water. To the mixture 2.411 g of p- toluenesulfonic acid monohydrate was added. The solution was stirred for 2 hours. The mixture was filtered and the filter cake was washed with 12 ml of 2-Propanol. Obtained solid was dried in the drier (25 °C, 130 mbar, N2 bleed, for 24 hour) to provide 5.1 g of solid Form

1 of Copanlisib ditosylate salt.

Example 13: Preparation of solid Form 3 of Copanlisib dihydrochloride salt

0.7 g of copanlisib were mixed with 0.35 g of hydrochloric acid (35%) and 5 ml of water. The reaction mixture was filtered with degassed carbon (340 mg in 1.5 ml water heated to boil, cooled under argon), washed with 2 ml water degassed sonification. The mixture was extracted with 5 ml ethyl acetate and was freeze-vacuum dried (cooled with liquid nitrogen to solidify and then freeze vacuum dried at 0°C and 200 mtorr). The rest after drying was diluted with 10 ml methanol and the mixture was stirred for 10 hours. Obtained suspension was filtered and the filter cake was washed with 2 ml methanol and was dried on air to provide

608 mg (75% theory) of solid Form 3 of Copanlisib dihydrochloride salt.