阅读说明：本技术 奥拉帕尼新晶型和其制备方法 (Novel crystal form of olaparib and preparation method thereof ) 是由 林文炜 王冠勋 黄原章 张永宏 胡聪成 于 2020-03-27 设计创作，主要内容包括：本发明提供了奥拉帕尼的新晶型。本发明还提供了制备所述奥拉帕尼新晶型的方法,所述方法包括形成含有粗奥拉帕尼和有机溶剂的溶液；将所述溶液添加到反溶剂中以形成含有沉淀物的浆液；分离所述沉淀物；和干燥所述沉淀物以获得奥拉帕尼的晶型III。(The present invention provides novel crystalline forms of olaparib. The present invention also provides a process for preparing the novel crystalline form of olaparib, comprising forming a solution comprising crude olaparib and an organic solvent; adding the solution to an anti-solvent to form a slurry containing a precipitate; separating the precipitate; and drying the precipitate to obtain form III of olaparib.)

1. Crystalline modification III of olaparib characterized by an X-ray powder diffraction pattern comprising characteristic peaks with 2 Θ values of 6.4, 6.8, 8.3, 12.7, 15.0, 19.7, 22.0, and 23.0 ± 0.2 degrees and a differential scanning calorimetry thermogram substantially free of exothermic peaks between 50 ℃ and 250 ℃.

2. Crystalline modification III olaparib according to claim 1, characterized in that its X-ray powder diffraction pattern further comprises characteristic peaks with 2 Θ values of 7.5, 13.6, 15.8, 16.4, 16.7, 18.0, 18.6, 23.5, 26.2 and 26.8 ± 0.2 degrees.

3. Crystalline modification III olaparib according to claim 2, characterized by an X-ray powder diffraction pattern substantially as shown in figure 1.

4. Crystalline modification III olaparib according to any of claims 1 to 3, characterized in that it has a weight loss, measured by thermogravimetric analysis, of from about 5% to about 6% when heated at about 120 ℃.

5. Crystalline modification III of olaparib according to any one of claims 1 to 4, characterized by a differential scanning calorimetry thermogram comprising endothermic peaks at about 72.0, 144.6 and 212.5 ℃.

6. Crystalline modification III olaparib according to claim 5, characterized by a differential scanning calorimetry thermogram substantially as shown in figure 3.

7. A process for preparing olaparib form III of any one of claims 1-6, comprising:

a) forming a solution comprising crude olaparib and an organic solvent;

b) mixing the solution with an anti-solvent to form a slurry containing a precipitate;

c) separating the precipitate; and

d) drying the precipitate to obtain form III of olaparib.

8. The method of claim 7, wherein said forming a solution comprising crude olaparib and an organic solvent comprises heating said solution, preferably said solution is heated to a temperature of about 55 ℃ to about 65 ℃.

9. The process of claim 7, wherein prior to step b) further comprises adding seeds of Olaparib to the antisolvent.

10. The process of claim 8, wherein step c) is preceded by the step of replacing the solvent in the slurry by removing the solvent containing said organic solvent and adding an anti-solvent.

11. The process of claim 10, further comprising cooling said slurry, preferably said slurry is cooled to a temperature of from about 10 ℃ to about 30 ℃.

12. The method of claim 7, wherein the organic solvent is C_1-4An alcohol, for example, methanol.

13. The process of claim 7, wherein the anti-solvent is water.

14. The method of claim 8, wherein the solution comprising crude olaparib and an organic solvent comprises crude olaparib in an amount of about 1% (w/w) to 10% (w/w).

15. The method of claim 8, wherein the slurry contains the anti-solvent in an amount of about 10% (w/w) to 40% (w/w).

16. The method of claim 8, wherein drying the precipitate comprises heating the precipitate to a temperature of about 40 ℃ to about 70 ℃.

Technical Field

The invention relates to the field of pharmaceutical crystal forms and preparation. In particular, the present invention relates to novel crystalline forms of olaparib and processes for their preparation.

Background

Olaparib (Olaparib), chemically known as 4- [ (3- [ (4-cyclopropanecarbonyl) piperazin-4-yl) carbonyl) -4-fluorophenyl ] methyl (2H) phthalazin-1-one or 4- [3- (4-cyclopropanecarbonyl-piperazine-1-carbonyl) -4-fluorobenzyl ] -2H-phthalazin-1-one, having the formula:

olaparib (Olaparib) is a poly (ADP-ribose) polymerase (PARP) inhibitor and is useful in the treatment of cancers including ovarian, breast and prostate cancers. Olaparib has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of women with advanced ovarian cancer associated with a BRCA gene deficiency.

The synthesis of olaparib and characterization of solid forms of its compounds are disclosed in U.S. patent nos. 8,247,416, 7,692,006, 8,183,369, 9,981,951 and 8,475,842. Specifically, U.S. Pat. No.8,247,416 discloses 4- [ (3- (4-cyclopropylcarbonyl-piperazine-1-carbonyl) -4-fluorobenzyl ] -2H-phthalazin-1-one (4- [3- (4-cyclopropanecarbonyl-1-carbonyl) -4-fluoro-benzyl ] -2H-phthalazin-1-one) (Compound A) in substantially crystalline form, in particular, crystalline form A. the patent also discloses a process for synthesizing 4- [ (3- (4-cyclopropylcarbonyl) -4-phthalonitrile) from 2-fluoro-5- (4-oxo-3, 4-dihydrophthalocyanin-1-ylmethyl) -benzoic acid (2-fluoro-5- (4-oxo-3, 4-dihydrophthalocyanin-1-ylmethyl) -benzoic acid) Piperazine-1-carbonyl) -4-fluorobenzyl ] -2H-phthalazin-1-one.

U.S. patent No.7,692,006 discloses additional methods for preparing 4- [ (3- (4-cyclopropylcarbonyl-piperazine-1-carbonyl) -4-fluorobenzyl ] -2H-phthalazin-1-one (compound a) in crystalline form a. this patent also discloses an intermediate, 2-fluoro-5- (4-oxo 3, 4-dihydrophthalocyanin-1-ylmethyl) -benzoic acid (ED), useful in the preparation of olaparib and a method for synthesizing this intermediate.

U.S. patent No.8,183,369 discloses 4- [ (3- (4-cyclopropylcarbonyl-piperazine-1-carbonyl) -4-fluorobenzyl ] -2H-phthalazin-1-one as crystalline form L and a process for obtaining this crystalline form L from 4- [ (3- (4-cyclopropylcarbonyl-piperazine-1-carbonyl) -4-fluorobenzyl ] -2H-phthalazin-1-one as crystalline form a.

U.S. patent No.9,981,951 discloses a solid (a hydrated crystalline form) of olaparib, known as form B.

U.S. patent No.8,475,842 discloses 4- [ (3- (4-cyclopropylcarbonyl-piperazine-1-carbonyl) -4-fluorobenzyl ] -2H-phthalazin-1-one (compound I) known as crystalline form H.

Chinese patent application CN105439961A discloses an olaparib referred to as form I. CN105439961A also discloses a method for preparing olaparib crystalline form I from olaparib of crystalline form a.

Chinese patent CN 105753789B discloses an olaparib and urea eutectic and a preparation method thereof, wherein olaparib and urea are reacted in one or more solvent systems of alcohols, ketones, alkyl nitriles and cyclic ethers, and the olaparib and urea eutectic is obtained by volatilization, stirring or crystallization at a reduced temperature.

The pharmaceutical industry places high demands on the quality and purity of the active compounds used in pharmaceutical preparations. Therefore, the regulatory authorities have very strict rules regarding the preparation, reproducible preparation, by-products and stability of the active compounds in the medicaments.

Therefore, although the art has disclosed the various crystalline forms of olaparib described above, there is still a need for new solid forms of olaparib to enhance the proven efficacy of the compound in the treatment of cancer, as well as to improve the stability, especially the long-term stability, of pharmaceutical formulations containing the solid forms of olaparib. The present invention satisfies this need and provides a novel crystalline form of olaparib and a process for preparing the crystalline form.

Disclosure of Invention

The present invention provides a novel crystal of olaparib, which is characterized by excellent crystallinity and stability. The novel solid forms of olaparib provided by the present invention have various advantages, including being preparable using a high yield process under mild conditions, and being suitable for large scale production. In addition, the novel solid forms of olaparib provided by the present invention can be stored for long periods of time and are suitable for use in the manufacture of medicaments without conversion to other crystalline or amorphous forms.

In particular, in one aspect of the invention, provided is olaparib form III. In yet another aspect of the invention, the crystalline modification III of olaparib has characteristic X-ray powder diffraction data and/or thermogravimetric analysis data and/or differential scanning calorimetry analysis data.

In another aspect of the invention, there is provided a process for preparing the novel crystalline form of olaparib, the process comprising forming a solution comprising crude olaparib and an organic solvent; adding the solution to an anti-solvent to form a slurry containing a precipitate; separating the precipitate; and drying the precipitate to obtain form III of olaparib.

Definition of

By "crude product" is meant a mixture comprising the desired compound (e.g., olaparib) and at least one other substance (e.g., a solvent, a reagent such as an acid or base, a starting material, or a byproduct of a reaction to produce the desired compound).

By "solvent" is meant a liquid substance capable of dissolving olaparib at a concentration of at least about 2.5% (w/w) at 60 ℃. "antisolvent (or antisolvent)" refers to a liquid substance that does not dissolve olaparib at a concentration of about 2.5% (w/w) at 60 ℃. More specifically, suitable anti-solvents and solvents for olaparib are shown in the following table:

table 1 solubility of olaparib

TABLE 2 Olaparib solvents and anti-solvents

Suitable solvents described herein refer to solvents with high solubility at 60 ℃ with an olaparib concentration of at least about 2.5% (w/w). Anti-solvents are generally considered "poor solvents," meaning solvents in which the solubility of olaparib is less than about 2.5% (w/w) at 60 ℃. Examples of suitable solvents include, but are not limited to, alcohols (e.g., methanol or ethanol), acetic acid, dimethylacetamide, dimethylsulfoxide, and pyridine, as described in table 2. Examples of poor solvents (anti-solvents) include, but are not limited to, water, toluene, acetonitrile, cyclohexane, isopropanol, tetrahydrofuran, n-butanol, xylene, ethyl acetate, and n-heptane.

"alcohol" refers to an alkyl group having a hydroxyl group attached to the carbon chain, wherein the alkyl group is defined as a straight or branched chain saturated aliphatic group (i.e., C) having the indicated number of carbon atoms_1-4Representing 1 to 4 carbons). E.g. C_1-4The alcohol includes methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol and tert-butanol. Fully saturated alcohols are useful in the present invention. Those skilled in the art will appreciate that other alcohols may be used in the present invention.

"PPW" means "Purified Water (Purified Process Water)".

"precipitation" refers to the process of coalescing a compound in solution into a solid form of the substance (i.e., a precipitate). All or any portion of the compound in solution may be precipitated. The solid form of the material may be amorphous or crystalline.

"crystalline form" refers to a solid form of a compound whose constituent molecules are packed in a regular, ordered, repeating pattern. The crystalline form may include geometric forms of triclinic, monoclinic, orthorhombic, tetragonal, trigonal, hexagonal and cubic crystals. The crystalline form may include one or more regions with significant crystal boundaries, i.e., grains. The crystalline solid may comprise two or more crystal geometries.

"amorphous" refers to a solid form of a compound that has no defined crystalline structure, i.e., lacks a regular, ordered, repeating pattern of constituent molecules.

"separation" refers to the process of separating at least a portion of a first material (e.g., a precipitate) from a mixture comprising the first material and at least one other material. In some cases, the isolated material is substantially free of at least one other material present in the original mixture.

By "substantially free of an exothermic peak," e.g., "substantially free of an exothermic peak" as in a Differential Scanning Calorimetry (DSC) thermogram herein, it is meant that an exothermic peak is not visually present in the DSC thermogram. The presence of an exothermic peak can be determined by the enthalpy change (Δ H) calculated by integration of the area under the curve (mJ) (i.e., peak area) over the weight (mg) of the sample. For example, as in U.S. Pat. No.9,981,951 (see DSC thermogram in FIG. 4), the change in enthalpy (Δ H) of any exothermic peak at 192.8 ℃ is about 33.2J/g. More specifically, the term "substantially free of exothermic peaks" as used herein in Differential Scanning Calorimetry (DSC) thermograms refers to any exothermic peak having an enthalpy change (Δ H) of no more than about 2.0J/g.

The terms "about" and "approximately" as used herein to describe a numerical value refer to a range of values that are close together around the exact value. If "X" is the exact value, "about X" or "about X" refers to a value from 0.9X to 1.1X, more preferably, from 0.95X to 1.05X. In the present invention, "about X" or "about X" means at least a value including X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, 1.05X, and the like.

Crystalline modification III of Olaparib

In one aspect of the invention, there is provided crystalline modification III of olaparib. In yet another aspect of the invention, crystalline form III of olaparib is characterized by an X-ray powder diffraction pattern comprising one or more characteristic peaks (e.g., 1, 2, 3,4, 5, 6, 7, or 8 peaks) with 2 Θ values of about 6.4, 6.8, 8.3, 12.7, 15.0, 19.7, 22.0, and 23.0 ± 0.2 degrees, and is further characterized by a differential scanning calorimetry thermogram in which there is substantially no exothermic peak during heating between 50 ℃ and 250 ℃. In yet another aspect of the invention, the olaparib form III X-ray powder diffraction pattern further comprises one or more characteristic peaks (e.g., 1, 2, 3,4, 5, 6, 7, 8, 9, or 10 peaks) having 2 Θ values of about 7.5, 13.6, 15.8, 16.4, 16.7, 18.0, 18.6, 23.5, 26.2, and 26.8 ± 0.2 degrees.

In one aspect of the present invention, there is provided crystalline modification III of olaparib characterized by an X-ray powder diffraction pattern comprising characteristic peaks with 2 Θ values of about 6.4, 6.8, 8.3, 12.7, 15.0, 19.7, 22.0, and 23.0 ± 0.2 degrees, and further characterized by a differential scanning calorimetry thermogram with substantially no exothermic peaks during heating between 50 ℃ and 250 ℃. In yet another aspect of the present invention, the olaparib form III X-ray powder diffraction pattern further comprises characteristic peaks with 2 Θ values of about 7.5, 13.6, 15.8, 16.4, 16.7, 18.0, 18.6, 23.5, 26.2, and 26.8 ± 0.2 degrees.

In one aspect of the present invention, there is provided crystalline form III of olaparib characterized by an X-ray powder diffraction pattern comprising characteristic peaks with 2 Θ values of about 6.4, 6.8, 7.5, 8.312.7, 13.6, 15.0, 15.8, 16.4, 16.7, 18.0, 18.6, 19.7, 22.0, 23.0, 23.5, 26.2, and 26.8 ± 0.2 degrees, and further characterized by a differential scanning calorimetry thermogram in which there is substantially no exothermic peak during heating between 50 ℃ and 250 ℃.

In one aspect of the present invention, there is provided crystalline modification III of olaparib having an X-ray powder diffraction pattern substantially as shown in figure 1.

Methods for obtaining the X-ray powder diffraction pattern of crystals are well known in the art, and any of these methods can be used to obtain the X-ray powder diffraction pattern of crystalline form III of olaparib. For example, the X-ray powder diffraction patterns referred to in this disclosure are obtained by using Cu K α 1 radiation.

In one aspect of the invention, the crystalline modification III of olaparib is characterized by a weight loss of about 5% to about 6% when heated at about 120 ℃ as determined by thermogravimetric analysis. In yet another aspect of the invention, the thermogravimetric analysis assay uses a sample of about 15-20mg weight subjected to a temperature of 30 ℃ to 300 ℃ at a slope of 10 ℃/min to measure weight loss.

In one aspect of the invention, the crystalline form III of olaparib is characterized by a differential scanning calorimetry thermogram comprising one or more endothermic peaks (i.e., 1, 2, or 3 endothermic peaks) at about 72.0, 144.6, and 212.5 ℃. In yet another aspect of the invention, the differential scanning calorimetry thermogram of crystalline form III of olaparib comprises endothermic peaks at about 72.0, 144.6 and 212.5 ℃. In yet another aspect of the invention, the differential scanning calorimetry thermogram of crystalline form III of olaparib comprises an endothermic peak and substantially no exothermic peak during heating between 50 ℃ and 250 ℃. In yet another aspect of the invention, the differential scanning calorimetry thermogram of crystalline form III of olaparib comprises endothermic peaks at about 72.0, 144.6 and 212.5 ℃ and substantially no exothermic peaks during heating between 50 ℃ and 250 ℃.

In yet another aspect of the present invention, the substantial absence of an exothermic peak in the differential scanning calorimetry thermogram is determined by visual inspection, wherein the absence of an exothermic peak is visually identified. In yet another aspect of the invention, the substantial absence of an exothermic peak in the differential scanning calorimetry thermogram is defined by the change in enthalpy (Δ H) of the exothermic peak, wherein the change in enthalpy (Δ H) of any exothermic peak is no greater than about 2.0J/g. In yet another aspect of the invention, the change in enthalpy (Δ H) of any exothermic peak in the differential scanning calorimetry thermogram is no greater than about 1.0J/g, about 0.5J/g, about 0.2J/g, or about 0.1J/g. In yet another aspect of the invention, the change in enthalpy (Δ H) of any exothermic peak in the differential scanning calorimetry thermogram is near 0J/g.

In one aspect of the invention, the differential scanning calorimetry thermogram of crystalline form III of olaparib of the present invention is substantially as shown in figure 3. In yet another aspect of the invention the thermograms are recorded using samples of about 2-5mg weight, subjected to a temperature of 30 ℃ to 270 ℃ at a slope of 10 ℃/min.

In one aspect of the invention, the olaparib crystalline form III of the invention has an X-ray powder diffraction pattern substantially as shown in figure 1 and a differential scanning calorimetry thermogram substantially as shown in figure 3.

In yet another aspect of the invention, the crystalline modification III of olaparib of the invention is a hydrated form. In yet another aspect of the invention, the hydrated form of olaparib form III contains from about 5% to about 6% (w/w) water.

In one aspect of the invention, a process for preparing crystalline modification III of olaparib is provided. In one aspect of the invention, the crystalline modification III of olaparib has the characteristic X-ray powder diffraction data and/or thermogravimetric analysis data and/or differential scanning calorimetry analysis data as described above. The method for preparing the crystal form III of Olaparib comprises the following steps:

a) forming a solution comprising crude olaparib and an organic solvent;

b) mixing the solution with an anti-solvent to form a slurry containing a precipitate;

c) separating the precipitate; and

d) drying the precipitate to obtain form III of olaparib.

The crude olaparib used in the process of the present invention may comprise olaparib and at least one other substance (e.g., a solvent, starting materials or intermediates, a reagent, such as an acid or base, or a combination thereof) associated with the synthesis and/or purification of olaparib. Typically, the crude olaparib may comprise at least 50% (w/w) of olaparib. The crude olaparib may include, for example, about 50% (w/w) to about 55% (w/w) olaparib, about 55% (w/w) to about 60% (w/w) olaparib, about 60% (w/w) to about 65% (w/w) olaparib, about 65% (w/w) to about 70% (w/w) olaparib, about 70% (w/w) to about 75% (w/w) olaparib, about 75% (w/w) to about 80% (w/w) olaparib, about 80% (w/w) to about 85% (w/w) olaparib, about 85% (w/w) to about 90% (w/w) olaparib, about 90% (w/w) to about 95% (w/w) olaparib, or about 95% (w/w) olaparib 99% (w) olaparib. In some embodiments, the crude olaparib comprises about 50% (w/w) to about 99% (w/w) olaparib, about 55% (w/w) to about 95% (w/w) olaparib, 60% (w/w) to about 90% (w/w) olaparib, about 65% (w/w) to about 85% (w/w) olaparib, or about 70% (w/w) to about 80% (w/w) olaparib. In the process provided by the present invention, crude olaparib can be obtained in various forms before dissolution. For example, crude olaparib may be in crystalline form, amorphous form, glassy or foamed.

Any solvent suitable for dissolving crude olaparib may be used to form the solution in the process of the invention. In one aspect of the present invention, the organic solvent comprises C_1-4An alcohol. In some embodiments, the organic solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, or a combination thereof. In some embodiments, the organic solvent comprises methanol. In some embodiments, the organic solvent is methanol.

Any amount of solvent suitable for dissolving crude olaparib may be used to form the solution. Generally, the solvent is used in an amount such that the solution may comprise at least about 1% (w/w) crude olaparib. In some embodiments, the solution comprises crude olaparib in an amount from about 1% (w/w) to about 25% (w/w). The solution may include, for example, crude olaparib in an amount of about 1% (w/w) to about 10% (w/w), about 5% (w/w) to about 10% (w/w), about 10% (w/w) to about 15% (w/w), about 15% (w/w) to about 20% (w/w), or about 20% (w/w) to about 25% (w/w). In some embodiments, the solution comprises crude olaparib in an amount from about 1% (w/w) to about 10% (w/w). In some embodiments, the solution comprises crude olaparib in an amount from about 1% (w/w) to about 10% (w/w), from about 3% (w/w) to about 10% (w/w), from about 4% (w/w) to about 8% (w/w), or from about 4% (w/w) to about 7% (w/w). In some embodiments, the solution comprises about 5% (w/w) crude olaparib.

In some embodiments of the invention, the solution further comprises an anti-solvent. In some embodiments, the solution further comprises water. Typically, water is used in an amount such that the solution can comprise water in an amount of at least about 10% (w/w) water. In some embodiments, the solution comprises water in an amount of about 10% (w/w) to about 30% (w/w). The solution may include, for example, water in an amount of about 10% (w/w) to about 15% (w/w), about 15% (w/w) to about 20% (w/w), about 20% (w/w) to about 25% (w/w), or from about 25% (w/w) to about 30% (w/w). In some embodiments, the solution comprises water in an amount of about 10% (w/w) to about 15% (w/w), about 15% (w/w) to about 20% (w/w), or from about 20% (w/w) to about 25% (w/w). In some embodiments, the solution comprises water in an amount of about 20% (w/w) to about 25% (w/w). In some embodiments, the solution comprises about 23% (w/w) water.

In some embodiments of the invention, the solution comprises C_1-4An alcohol, wherein the amount of crude olaparib is from about 1% (w/w) to about 25% (w/w). In some embodiments, the solution comprises methanol and crude olaparib in an amount from about 1% (w/w) to about 10% (w/w). In some embodiments, the solution comprises methanol, water, and crude olaparib, wherein the ratio of methanol to water is about 4:1(v/v), and the amount of crude olaparib is about 1% (w/w) to about 10% (w/w). In some embodiments, the solution comprises methanol, water, and crude olaparib, wherein the ratio of methanol to water is about 4:1(v/v), and the amount of crude olaparib is about 4% (w/w) to about 7% (w/w). In some embodiments, the solution comprises methanol, water, and crude olaparib, wherein the ratio of methanol to water is about 4:1(v/v) and the amount of crude olaparib is about 5% (w/w).

In some embodiments of the invention, forming the solution (i.e., step a) comprises heating the solution. In some embodiments, the solution is heated to a temperature of at least about 50 ℃. The solution can be heated, for example, at a temperature of about 50 ℃ to about 55 ℃, about 55 ℃ to about 60 ℃, about 60 ℃ to about 65 ℃, about 65 ℃ to about 70 ℃, about 70 ℃ to about 75 ℃, about 75 ℃ to about 80 ℃, about 80 ℃ to about 85 ℃, about 85 ℃ to about 90 ℃, about 90 ℃ to about 95 ℃, or about 95 ℃ to about 100 ℃. In some embodiments, the solution is heated at a temperature in the range of about 50 ℃ to about 100 ℃, about 55 ℃ to about 95 ℃, about 60 ℃ to about 90 ℃, about 65 ℃ to about 85 ℃, or about 70 ℃ to about 80 ℃. In some embodiments, forming the solution comprises heating the solution to a temperature of about 55 ℃ to about 65 ℃.

One skilled in the art will appreciate that the heating temperature will depend on one or more factors, including the particular organic solvent, the amount of solvent, and the purity of the crude olaparib product, among others. These factors will also determine to some extent the length of time required to dissolve the crude compound. Any suitable length of time may be used, ranging from a few minutes to a few hours. For example, the mixture comprising crude olaparib and organic solvent may be mixed with or without heating for about 10 minutes or about 20 minutes or about 30 minutes or about 40 minutes or about 1 hour.

Typically, step b) is performed by mixing the solution formed by step a) with an anti-solvent to form a slurry (otherwise known as a slurry solution) comprising the precipitate.

In some embodiments of the invention, step b) is carried out by adding an anti-solvent to the solution formed by step a).

In still further embodiments of the present invention, step b) is performed by adding the solution formed by step a) to an anti-solvent.

Any liquid substance suitable for precipitating olaparib may be used as antisolvent in the process of the invention for preparing olaparib form III. In some embodiments of the invention, the anti-solvent comprises water. In some embodiments of the invention, the anti-solvent is water. Any amount of anti-solvent can be used to form the slurry. Typically, the anti-solvent may be used in an amount such that the slurry comprises at least about 10% (w/w) anti-solvent. In some embodiments, the slurry comprises an anti-solvent in an amount of about 10% (w/w) to about 40% (w/w), about 10% (w/w) to about 35% (w/w), about 10% (w/w) to about 30% (w/w), about 20% (w/w) to about 40% (w/w), about 20% (w/w) to about 35% (w/w), about 25% (w/w) to about 40% (w/w), about 25% (w/w) to about 35% (w/w), about 30% (w/w) to about 40% (w/w), or about 30% (w/w) to about 35% (w/w). In some embodiments, the slurry comprises an anti-solvent in an amount of about 20% (w/w) to about 40% (w/w), about 20% (w/w) to about 35% (w/w), about 25% (w/w) to about 40% (w/w), about 25% (w/w) to about 35% (w/w), about 30% (w/w) to about 40% (w/w), or about 30% (w/w) to about 35% (w/w). In some embodiments, the slurry comprises an anti-solvent in an amount of about 25% (w/w) to about 40% (w/w), about 25% (w/w) to about 35% (w/w), about 30% (w/w) to about 40% (w/w), or about 30% (w/w) to about 35% (w/w). In some embodiments, the slurry comprises an anti-solvent in an amount of about 30% (w/w). In some embodiments, the slurry comprises an anti-solvent in an amount of about 35% (w/w).

In some embodiments of the invention, the slurry comprises C_1-4Alcohol in an amount of about 1% (w/w) to about 25% (w/w)w) olaparib; and water in an amount of about 25% (w/w) to about 40% (w/w). In some embodiments, the slurry comprises methanol; olaparib in an amount of about 1% (w/w) to about 10% (w/w); and water in an amount of about 25% (w/w) to about 40% (w/w). In some embodiments, the slurry comprises methanol; and olaparib in an amount from about 1% (w/w) to about 10% (w/w); and water in an amount of about 25% (w/w) to about 35% (w/w). In other embodiments of the present invention, the slurry comprises methanol, water, and olaparib; wherein the ratio of methanol to water is about 2:1(v/v) and the amount of olaparib is about 1% (w/w) to about 10% (w/w). In some embodiments, the slurry comprises methanol, water, and olaparib; wherein the ratio of methanol to water is about 2:1(v/v) and the amount of olaparib is about 4% (w/w) to about 7% (w/w). In some embodiments, the slurry comprises methanol, water, and olaparib; wherein the ratio of methanol to water is about 2:1(v/v) and the amount of olaparib is about 5% (w/w).

In some embodiments of the invention, the anti-solvent comprises a seed crystal of olaparib. In some embodiments, prior to step b), the methods provided herein further comprise adding seed crystals of olaparib to the antisolvent. In some embodiments, step b) of the method comprises adding the solution to an antisolvent comprising olaparib seeds to form a slurry comprising a precipitate. In some embodiments, the water in step b) contains seeds of olaparib. In some embodiments, step b) of the method comprises adding the solution to water comprising olaparib seeds to form a slurry comprising precipitates.

In some embodiments of the invention, prior to isolating the precipitate (i.e. step c), the method further comprises exchanging the solvent of the slurry by removing the solvent comprising the organic solvent in said slurry and adding thereto further anti-solvent. In some embodiments, the solvent, including the organic solvent, in the slurry is removed under vacuum. In some embodiments, removing the solvent including the organic solvent in the slurry is performed under vacuum at a temperature not exceeding 40 ℃. In some embodiments, prior to isolating the precipitate (i.e., step c), the method further comprises exchanging the solvent of the slurry by removing the solvent comprising methanol from the slurry and adding additional water to the slurry. In some embodiments, the solvent comprising methanol in the slurry is removed under vacuum. In some embodiments, removing the solvent including methanol in the slurry is performed under vacuum at a temperature not exceeding 40 ℃.

In some embodiments of the invention, the method further comprises cooling the slurry and/or adding seeds of olaparib to the slurry prior to separating the precipitate. In some embodiments, the method further comprises cooling the slurry prior to isolating the precipitate (i.e., step c). Typically, the slurry may be cooled to a temperature below 30 ℃. In some embodiments, the slurry may be cooled to a temperature of from about 10 ℃ to about 30 ℃. The slurry may be cooled to a temperature of, for example, about 25 ℃, about 20 ℃, or about 4 ℃. One skilled in the art will appreciate that the cooling temperature may depend in part on the solubility of olaparib in the solvent/anti-solvent mixture and the amount of solvent and anti-solvent used in the process. The cooling may be performed for any suitable length of time, typically from a few minutes to a few hours.

After the slurry is formed, the precipitated olaparib can be separated from the solvent/anti-solvent mixture by a variety of techniques, including passing the mixture through a filter to separate solid materials, centrifuging the mixture, or removing the solvent/anti-solvent supernatant. Alternatively, the slurry may be frozen and the solvent/anti-solvent mixture may be removed from the precipitate by sublimation. In some embodiments, the precipitate of olaparib is isolated from the suspension by filtration. In some embodiments, the method further comprises washing the separated precipitate. Washing may be carried out by milling the precipitate with the anti-solvent or other part of the solvent/anti-solvent mixture. Washing may remove residual impurities (if present). In some embodiments, the method of preparing crystalline form III of olaparib comprises washing the isolated precipitate with one or more water, or one or more water/methanol solutions.

After isolation of the precipitated olaparib, the olaparib is dried to remove the solvent and anti-solvent from the solid material, with or without further washing steps. Drying may be carried out at ambient temperature and pressure. Evaporation of the solvent and anti-solvent may be promoted by contacting the solid material with a stream of air, nitrogen, argon or other gas or gas mixture. In some embodiments, the precipitate of olaparib is dried with a nitrogen purge at room temperature for a period of time. In some embodiments, the precipitate is dried under reduced pressure. In some embodiments, the precipitate is dried under reduced pressure and at elevated temperature. In some embodiments, drying the precipitate comprises heating the precipitate to a temperature of about 30 ℃ to about 80 ℃. In some embodiments, drying the precipitate comprises heating the precipitate to a temperature of about 30 ℃ to about 50 ℃. In some embodiments, drying the precipitate comprises heating the precipitate to a temperature of about 40 ℃. Any suitable pressure, temperature and drying time may be used to partially or completely remove the solvent and anti-solvent from the precipitated olaparib. Drying may be carried out, for example, under reduced pressure and at elevated temperature until the weight of olaparib remains constant.

In one aspect of the present invention, there is provided a process for preparing crystalline modification III of olaparib, comprising:

a) forming a solution comprising crude olaparib and methanol;

b) mixing the solution with water to form a slurry containing a precipitate;

c) separating the precipitate; and

d) drying the precipitate to obtain form III of olaparib.

In yet another aspect of the present invention, wherein the solution further comprises water. In yet another aspect of the invention, the solution comprises methanol, water and crude olaparib, wherein the ratio of methanol to water is about 4:1(v/v) and the amount of crude olaparib is about 1% (w/w) to about 10% (w/w).

In yet another aspect of the invention, step b) is carried out by adding water to the solution formed by step a).

In still further embodiments of the present invention, step b) is performed by adding the solution formed by step a) to water. In yet another aspect of the invention, the anti-solvent comprises seeds of olaparib. In some embodiments, step b) of the method comprises adding the solution to water comprising olaparib seeds to form a slurry comprising precipitates.

In yet another aspect of the invention, the slurry comprises methanol, water and olaparib; wherein the ratio of methanol to water is about 2:1(v/v) and the amount of olaparib is about 1% (w/w) to about 10% (w/w). In some embodiments, the slurry comprises methanol, water, and olaparib; wherein the ratio of methanol to water is about 2:1(v/v) and the amount of olaparib is about 5% (w/w).

In yet another aspect of the invention, prior to separating the precipitate (i.e., step c), the method further comprises exchanging the solvent of the slurry by removing the solvent comprising methanol from the slurry and adding additional water to the slurry. In some embodiments, the solvent comprising methanol in the slurry is removed under vacuum. In some embodiments, removing the solvent including methanol in the slurry is performed under vacuum at a temperature not exceeding 40 ℃.

In yet another aspect of the invention, the method further comprises cooling the slurry prior to separating the precipitate. In some embodiments, the slurry is cooled to a temperature of about 15 ℃ to about 25 ℃.

In yet another aspect of the invention, the precipitate of olaparib is separated from the suspension by filtration.

In yet another aspect of the invention, the precipitate of olaparib is dried by purging with nitrogen at room temperature for a period of time. In some embodiments, the precipitate is dried under reduced pressure. In some embodiments, the precipitate is dried at a temperature of about 40 ℃.

Drawings

Fig. 1 exemplarily shows an X-ray powder diffraction (XRPD) pattern of olaparib form III of the present invention.

Figure 2 exemplarily shows a thermogravimetric analysis (TGA) of crystalline modification III of olaparib of the present invention.

Fig. 3 exemplarily shows a Differential Scanning Calorimetry (DSC) thermogram of the crystalline modification III of olaparib of the present invention.

Fig. 4 is a Differential Scanning Calorimetry (DSC) thermogram of crystalline form B of olaparib disclosed in U.S. patent No.9,981,951.

Detailed Description

The spirit and advantages of the present invention will be further illustrated by the following examples, which are provided by way of illustration and are not intended to be limiting.

The following examples describe methods of characterizing olaparib form III and methods of preparing olaparib form III suitable for laboratory or industrial scale.