CN107098862A - A kind of olaparib dihydrate and preparation method thereof - Google Patents
A kind of olaparib dihydrate and preparation method thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
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Abstract
The invention belongs to pharmaceutical technology field, a kind of olaparib dihydrate and preparation method thereof is disclosed.The X-ray powder diffraction collection that olaparib dihydrate disclosed by the invention is represented with the 2 θ ± 0.2 ° angles of diffraction shows characteristic diffraction peak at 6.75 °, 7.04 °, 9.16 °, 10.53 °, 15.20 °, 17.46 °, 20.68 °, 22.21 °, 27.43 °, 28.62 °, 29.30 °, 35.23 °, 37.14 °, the X-ray powder diffraction spectrogram obtained using Cu-K alpha ray measurements is as shown in figure 1, entirely different with prior art.Surprisingly find that the olaparib dihydrate dissolubility that the present invention is obtained is significantly improved through experiment.The invention also discloses the preparation method of olaparib dihydrate, the preparation method is simple to operation, and yield and purity are high, and reaction condition is gentle, are adapted to large-scale production.The capsule dissolubility and stability that the olaparib dihydrate of the present invention is made are significantly improved, and are especially suitable for clinical practice.
Description
Technical field
The invention belongs to pharmaceutical technology field, a kind of olaparib dihydrate and preparation method thereof is disclosed.
Background technology
Olaparib, chemical entitled 4- [3- (4- cyclopropane carbonyl piperazine -1- carbonyls) -4- luorobenzyls] -2H- phthalazines -1-
Ketone, English entitled Olaparib, structural formula is as shown in Equation 1：
Olaparib (Olaparib) is the KuDOS drugmakers of wholly-owned subsidiary by AstraZeneca (AstraZeneca)
A kind of small molecule of research and development, is a kind of potent PARP inhibitors, and it promotes tumour by suppressing DNA of tumor cell injury repair
Apoptosis, so as to strengthen the curative effect of radiotherapy and alkylating agent and platinum-based chemotherapy, is mainly used in treating mastocarcinoma gene
The gene mutation cancer (being primarily present in breast cancer, oophoroma and prostate cancer) of No. one or No. two (BRCA-1 or BRCA-2).It is difficult to understand
La Pani can selectivity act on tumour cell, normal cell is due to remaining double-strand repair function without destroyed.Cancer
Cell is all lacked or is mutated due to two allele, and double-strand repair function is lost, and cell is finally dead, this new medicine
Treatment to refractory neoplasm brings hope.
CN101528714A discloses the crystal formation A of the solvent-free compound of olaparib, and its X-ray powder diffraction figure (2 θ) exists
12.0 °, 17.8 °, 21.1 °, 22.3 °, 29.2 °, 10.5 °, 14.0 °, 21.7 °, 24.3 °, 26.1 ° of existing characteristics peaks, DSC are shown
There is endothermic peak at 210.1 DEG C ± 1 DEG C, the stability of crystal form is good, it is without hydrate after testing.
The A of patent CN 105439961 disclose crystal formation I of olaparib and preparation method thereof, the crystal formation that the present invention is provided
I, it is characterised in that its X-ray powder diffraction figure is 6.4 ° ± 0.2 °, 12.7 ° ± 0.2 °, 15.1 ° ± 0.2 ° in 2theta values
Place has characteristic peak, after testing its crystallization water for containing 1.5 molecules.Its preparation method is：The solid of olaparib is placed in pure
Stirring is obtained in water or aqueous solvent, the aqueous solvent, including aqueous volume is not less than 80% mixed solvent, described aqueous
Solvent, including alcohols, ketone, ethers, alkanes, aromatic solvents.The stability of crystal form is than in patent CN101528714A
Crystal formation A more preferably, can keep stable during preparation, storage and formulation development, will not occur to turn crystalline substance；Solubility, draw
Moist to meet medicinal requirements, and preparation method solvent for use asepsis environment-protecting, optimization and exploitation to the future medicine have important
Value, a preferably selection is provided for pharmaceutical solid preparation.
The A of patent CN 105254572 disclose a kind of crystal formation of olaparib and preparation method thereof, are radiated using CuK α,
The powder x-ray diffraction represented with 2 θ angles 22.9 ± 0.5,23.4 ± 0.5,21.0 ± 0.5,17.1 ± 0.5,17.3 ±
0.5,14.2 ± 0.5,15.0 ± 0.5,13.5 ± 0.5,18.6 ± 0.5,20.6 ± 0.5,10.2 ± 0.5,20.3 ± 0.5,
21.9 ± 0.5,25.8 ± 0.5,26.5 ± 0.5 have diffraction maximum, and it is without hydrate after testing.It is shown as when heating rate is
There is 1 endothermic peak in 10 DEG C per minute of DSC collection of illustrative plates at 175.3 DEG C ± 1 DEG C.Present invention also offers olaparib crystal formation
Preparation method, including：1) olaparib is mixed into backflow with solvent, obtains olaparib solution, the solvent be normal propyl alcohol,
One or more in isopropanol, n-butanol, isobutanol and the tert-butyl alcohol；2) olaparib solution is filtered, natural cooling is obtained
Described olaparib crystal formation.The granularity for the crystal formation olaparib that the present invention is provided is small, and dissolution rate is fast.Crystalline substance of the present invention
The granularity of type olaparib is that D50 is 2.45 microns, and granularity is smaller, and then when causing it as preparation, dissolution rate is fast, improves
The drug effect of product；And the preparation method that the present invention is provided is simple, obtained crystal formation olaparib performance is also stablized.
CN101821242A discloses the crystal formation L of the solvent-free compound of olaparib, and its X-ray powder diffraction figure (2 θ) exists
14.4 °, 17.2 °, 17.5 °, 18.8 °, 23.0 °, 10.4 °, 13.6 °, 25.1 ° of existing characteristics peaks, DSC are shown in 198.5 DEG C ± 1
DEG C there is endothermic peak, the stability of crystal form is good, it is without hydrate after testing.
CN106554315A discloses a kind of olaparib monohydrate, and its X-ray powder diffraction figure (2 θ) exists
5.620°、6.420°、7.420°、9.340°、10.120°、11.240°、14.020°、16.880°、17.540°、18.120°、
20.200 °, 22.460 °, 24.180 °, 26.720 °, 30.200 °, 33.100 °, 34.640 °, 37.340 °, 39.420 ° have spy
Peak is levied, its preparation method is that olaparib adds 4-5 times of weight/volume acetone-water=3-4:In 2-1 mixed liquor, heating
To 70-75 DEG C, filter while hot, filtrate naturally cools to room temperature, then is incubated 5-10 hours, separate out crystallization, filtering, through dry
Arrive.The crystal of the present invention has the advantage that：Purity is high, and stability is good, is increased weight even if moisture absorption under high humidity conditions also unobvious.
Olaparib belongs to insoluble drug, is usually prepared into solid pharmaceutical preparation administration, and for the solid system of crystal formation medicine
For agent, the stability and dissolution rate of preparation and the crystal formation of bulk drug have very big relation, olaparib in crystallization, if
Using different solvent and process conditions, then its molecule differs in the number of permutations of each crystal formation structure cell and position and latticed form
Sample, forms different crystal structures, and the polymorphous change of olaparib can change its property, quality and drug effect.Therefore, Aura handkerchief
The stable crystalline of Buddhist nun, the physicochemical properties for further studying the compound study its drug regimen and clinical practice, tool
It is of great significance.
Compound polymorphic is a kind of universal phenomenon, for premium properties one such as the stability, hygroscopicity, dissolubility of crystal formation
It is directly a kind of long-range pursuit.Invention finds by substantial amounts of experimental study, and most of existing crystal formation is from stability, hygroscopicity solution
The certainly stable problem of its preparation, and the dissolution of preparation then often passes through the addition and the control of raw material crystal formation of auxiliary material in production process
System is angularly solved.The slightly solubility of olaparib raw material is always the technological difficulties of this area, can not be broken through always.
The present invention passes through substantial amounts of experimental study, using new method for crystallising, has obtained a kind of new olaparib crystal formation,
It is dihydrate after testing, and the olaparib dihydrate purity that the present invention is provided is high, stability is good, is surprisingly sent out through experiment
The olaparib dihydrate dissolubility that the existing present invention is obtained is significantly improved.The invention also discloses olaparib dihydrate
Preparation method, the preparation method is simple to operation, and reaction condition is gentle, and yield and purity are high, are adapted to large-scale production.The present invention
The capsule dissolubility that is made of olaparib dihydrate and stability significantly improve, be especially suitable for clinical practice.
The content of the invention
It is an object of the invention to provide a kind of different from olaparib dihydrate of prior art and preparation method thereof.
In order to realize the purpose of the present invention, the technical scheme used for：
A kind of olaparib dihydrate, it is characterised in that its molecular formula is：C24H23FN4O3·2H2O, structural formula is as follows
(Formula II), its X-ray powder diffraction collection represented with the 2 θ ± 0.2 ° angles of diffraction 6.75 °, 7.04 °, 9.16 °, 10.53 °,
Feature is shown at 15.20 °, 17.46 °, 20.68 °, 22.21 °, 27.43 °, 28.62 °, 29.30 °, 35.23 °, 37.14 ° to spread out
Penetrate peak.
Preferably, the olaparib dihydrate that the present invention is provided, the X-ray powder obtained using Cu-K alpha ray measurements
Diffraction pattern is as shown in Figure 1.
The olaparib dihydrate that the present invention is provided, its preparation method comprises the following steps：
1) olaparib crude product is dissolved in the mixed solvent, crude product is made with 220~250 revs/min of speed agitating and heating
It is completely dissolved, to solution clarification, filtering；
2) by solution slow cooling obtained above, when being down to -5~0 DEG C into solution by 2.0~3.0mL/min's
Flow velocity adds the purified water of precooling to crystalline substance is gone out, and continues to be cooled to -20 DEG C~-10 DEG C crystallizations, insulated and stirred to crystallization completely, is supported
It is brilliant；
3) suction filtration, collects crystal, water washing is purified on a small quantity, is dried in vacuo, obtains white crystalline powder.
Preferably, step 1) described in mixed solvent be dimethyl sulfoxide and water mixed solvent；Olaparib crude product and mixed
The mass volume ratio of bonding solvent is 1g:15~20ml.
Preferably, step 1) described in the mixed solvent, the volume ratio of dimethyl sulfoxide and water is 2~4:1.
Preferably, step 1) described in mixed solvent and step 2) described in the volume ratio of purified water be 1:3~4.
Preferably, step 2) described in cooling extent be every 10 minutes 1 DEG C~3 DEG C, rearing crystal time be 2~4h.
Preferably, step 3) described in vacuum drying refer at 40~50 DEG C be dried in vacuo 4~6h.
In the present invention, described olaparib dihydrate crude product can be the hydration of olaparib two to be further purified
Thing solid mixture, or marketable material is prepared by art methods, the crystal formation result of gained is by mistake
It is novel crystal forms of the present invention in poor scope.
The formation mechenism of crystal is very complicated, and the acquisition of a new crystal also has very big contingency, and sometimes different is molten
Agent, identical crystal structure can be produced under different crystallization conditions.Some specific crystal formations also can not necessarily obtain more added with
The physicochemical property of profit.The properties such as stability, hygroscopicity, dissolubility, bioactivity, the toxicity of medicine can be produced because of the difference of crystal formation
Raw huge difference.
The present invention passes through substantial amounts of experiment sieving, by selecting different solvents to dissolve and different solvent crystallizations, obtains
The preparation method of the present invention, by the control to mixing speed, solvent load, temperature and rearing crystal time, is unexpectedly obtained
A kind of olaparib novel crystal forms, it is dihydrate after testing.Aura handkerchief dihydrate Buddhist nun purity that the present invention is provided is high, stably
Property it is good, surprisingly find that the obtained olaparib dihydrate dissolubility of the present invention is significantly improved through experiment.Invention additionally discloses
The preparation method of olaparib dihydrate, the preparation method is simple to operation, and reaction condition is gentle, is adapted to extensive raw
Production.The capsule dissolubility and stability that the olaparib dihydrate of the present invention is made are significantly improved, and are especially suitable for clinical practice.
Research shows that in the X-ray powder diffraction pattern, the diffraction spectrogram obtained by novel crystal forms is for specific crystal formation
Often characteristic, the wherein relative intensities of bands of a spectrum (especially in low angle) may because of crystallization condition, particle diameter and its
The difference of its condition determination and the advantage orientation effect that produces and change.Therefore, the relative intensity of diffraction maximum is to targeted crystalline substance
Type is not characteristic, when judging whether identical with known crystal formation, it should be noted that the relative position at peak rather than
Their relative intensity.
Olaparib dihydrate crystallization provided by the present invention confirms the crystallization water containing 2 molecules, and its character is white
Crystalline powder, the loss that the crystallization water will not occur under the conditions of air drying.And its powder x-ray diffraction collection of illustrative plates with it is existing
Technology has the relative position at visibly different peak, it is seen that it is a kind of novel crystal forms unlike the prior art.
Carry out the explanation and illustration present invention below by being studied the olaparib dihydrate crystal formation that the present invention is provided
Technical scheme：
1st, elementary analysis C24H23FN4O3·2H2O
Instrument：VarioELcube elemental analysers；It is C, H, O, N to measure element；
DIOENXDX-500 type ion chromatographs；Measurement element is F.
Elementary analysis (%) theoretical value：H (5.78), C (61.27), N (11.91), O (17.00), F (4.04).
Elementary analysis (%) measured value is：H (5.76), C (61.26), N (11.94), O (16.99), F (4.05).
It is consistent substantially with the theoretical value of elementary analysis.
2nd, crystal formation is detected
The olaparib dihydrate for taking the present invention to prepare, the X-ray powder obtained using Cu-K alpha ray measurements
Diffraction pattern as shown in figure 1, its X-ray powder diffraction figure for being represented with the angles of diffraction of 2 θ ± 0.2 6.75 °, 7.04 °, 9.16 °,
Shown at 10.53 °, 15.20 °, 17.46 °, 20.68 °, 22.21 °, 27.43 °, 28.62 °, 29.30 °, 35.23 °, 37.14 °
Characteristic peak.
3rd, differential thermal analysis and thermogravimetric analysis
Thermogravimetric and differential thermal analysis are carried out to olaparib dihydrate prepared by the present invention, as a result as shown in Figures 2 and 3；
As a result show, this product is in 115 DEG C or so the quick weight for losing about 2 hydrones；This product has endothermic peak at about 204.2 DEG C,
It is demonstrated for a kind of different crystal formation from side.
4th, water analysis
Determined using cassette moisture teller, the water content of olaparib dihydrate of the invention is 7.67%, with two
The theoretical water content 7.66% of hydrate is consistent, it was demonstrated that the present invention contains the crystallization water of 2 molecules.
5th, purity detecting
Through HPLC purity detectings, the purity of the olaparib dihydrate that the present invention is prepared can reach 99.97~
99.99%.
6th, fusing point is detected
The olaparib dihydrate for taking the present invention to prepare is detected that fusing point is 203~205 DEG C.
Compared with prior art, the invention has the advantages that：
(1) olaparib dihydrate provided by the present invention is a kind of novel crystal forms different from prior art；The present invention
The preparation method of the olaparib dihydrate provided is simple to operation, and reaction condition is gentle, and yield is more than 99.8%, purity
Height, is adapted to large-scale production.
(2) the olaparib dihydrate purity height of the invention provided, stability are good, and the present invention is surprisingly found through experiment
Obtained olaparib dihydrate dissolubility is significantly improved.The capsule dissolubility that the olaparib dihydrate of the present invention is made
And stability is significantly improved, clinical practice is especially suitable for.
Brief description of the drawings
The X-ray powder diffraction collection for the olaparib dihydrate that Fig. 1 is prepared for the present invention.
Fig. 2 is the thermogravimetric analysis TGA collection of illustrative plates of olaparib dihydrate prepared by the embodiment of the present invention 1.
Fig. 3 is the DSC collection of illustrative plates of olaparib dihydrate prepared by the embodiment of the present invention 1.
Specific embodiment
Technical scheme is described in detail with embodiment below, it will help to technical scheme
Advantage, effect have and further understand, embodiment does not limit protection scope of the present invention, and protection scope of the present invention is by weighing
Profit requires to determine.
The preparation of embodiment 1, olaparib dihydrate
1) olaparib crude product 100g is dissolved in the dimethyl sulfoxide and water (dimethyl sulfoxide of (1500ml)：Water=2:1) mixed
In bonding solvent, crude product is completely dissolved with 220 revs/min of speed agitating and heating, to solution clarification, filtering；
2) by solution obtained above with every 10 minutes 3 DEG C of speed slow coolings, when being down to 0 DEG C into solution by
2.0mL/min flow velocity adds the purified water 6000ml of precooling to crystalline substance is gone out, and continues to be cooled to -20 DEG C of crystallizations, insulated and stirred to analysis
It is brilliant complete, growing the grain 2h；
3) suction filtration, collects crystal, purifies be dried in vacuo 4h at water washing, 50 DEG C on a small quantity, obtain white crystalline powder
99.90g, yield 99.90%, purity 99.98%.
The X-ray powder diffraction spectrogram that obtained white crystalline powder is obtained using Cu-K alpha ray measurements is shown in Fig. 1.
The preparation of embodiment 2, olaparib dihydrate
1) olaparib crude product 100g is dissolved in 2000ml dimethyl sulfoxide and water (dimethyl sulfoxide：Water=3:1) mixing
In solvent, crude product is completely dissolved with 250 revs/min of speed agitating and heating, to solution clarification, filtering；
2) by solution obtained above with every 10 minutes 1 DEG C of speed slow coolings, when being down to -5 DEG C into solution by
2.2mL/min flow velocity adds the purified water 6000ml of precooling to crystalline substance is gone out, and continues to be cooled to -15 DEG C of crystallizations, insulated and stirred to analysis
It is brilliant complete, growing the grain 4h；
3) suction filtration, collects crystal, purifies be dried in vacuo 5h at water washing, 45 DEG C on a small quantity, obtain white crystalline powder
99.91g, yield 99.91%, purity 99.99%.
The X-ray powder diffraction spectrogram that obtained white crystalline powder is obtained using Cu-K alpha ray measurements is with implementing
Example 1 is similar.
The preparation of embodiment 3, olaparib dihydrate
1) olaparib crude product 100g is dissolved in 1800ml dimethyl sulfoxide and water (dimethyl sulfoxide：Water=3:1) mixing
In solvent, crude product is completely dissolved with 240 revs/min of speed agitating and heating, to solution clarification, filtering；
2) by solution obtained above with every 10 minutes 2 DEG C of speed slow coolings, when being down to -3 DEG C into solution by
2.5mL/min flow velocity adds the purified water 6300ml of precooling to crystalline substance is gone out, and continues to be cooled to -15 DEG C of crystallizations, insulated and stirred to analysis
It is brilliant complete, growing the grain 3h；
3) suction filtration, collects crystal, purifies be dried in vacuo 5h at water washing, 45 DEG C on a small quantity, obtain white crystalline powder
99.94g, yield 99.94%, purity 99.99%.
The X-ray powder diffraction spectrogram that obtained white crystalline powder is obtained using Cu-K alpha ray measurements is with implementing
Example 1 is similar.
The preparation of embodiment 4, olaparib dihydrate
1) olaparib crude product 100g is dissolved in the dimethyl sulfoxide and water (dimethyl sulfoxide of (1700ml)：Water=4:1) mixed
In bonding solvent, crude product is completely dissolved with 230 revs/min of speed agitating and heating, to solution clarification, filtering；
2) by solution obtained above with every 10 minutes 3 DEG C of speed slow coolings, when being down to -2 DEG C into solution by
2.7mL/min flow velocity adds the purified water 5950ml of precooling to crystalline substance is gone out, and continues to be cooled to -10 DEG C of crystallizations, insulated and stirred to analysis
It is brilliant complete, growing the grain 2h；
3) suction filtration, collects crystal, purifies be dried in vacuo 6h at water washing, 40 DEG C on a small quantity, obtain white crystalline powder
99.89g, yield 99.89%, purity 99.97%.
The X-ray powder diffraction spectrogram that obtained white crystalline powder is obtained using Cu-K alpha ray measurements is with implementing
Example 1 is similar.
The preparation of embodiment 5, olaparib dihydrate
1) olaparib crude product 100g is dissolved in the dimethyl sulfoxide and water (dimethyl sulfoxide of (1900ml)：Water=3:1) mixed
In bonding solvent, crude product is completely dissolved with 250 revs/min of speed agitating and heating, to solution clarification, filtering；
2) by solution obtained above with every 10 minutes 2 DEG C of speed slow coolings, when being down to -1 DEG C into solution by
2.9mL/min flow velocity adds the purified water 7600ml of precooling to crystalline substance is gone out, and continues to be cooled to -18 DEG C of crystallizations, insulated and stirred to analysis
It is brilliant complete, growing the grain 3h；
3) suction filtration, collects crystal, purifies be dried in vacuo 5h at water washing, 50 DEG C on a small quantity, obtain white crystalline powder
99.93g, yield 99.93%, purity 99.99%.
The X-ray powder diffraction spectrogram that obtained white crystalline powder is obtained using Cu-K alpha ray measurements is with implementing
Example 1 is similar.
The preparation of embodiment 6, olaparib dihydrate
1) olaparib crude product 100g is dissolved in the dimethyl sulfoxide and water (dimethyl sulfoxide of (1600ml)：Water=2:1) mixed
In bonding solvent, crude product is completely dissolved with 220 revs/min of speed agitating and heating, to solution clarification, filtering；
2) by solution obtained above with every 10 minutes 1 DEG C of speed slow coolings, when being down to -4 DEG C into solution by
3.0mL/min flow velocity adds the purified water 4800ml of precooling to crystalline substance is gone out, and continues to be cooled to -12 DEG C of crystallizations, insulated and stirred to analysis
It is brilliant complete, growing the grain 4h；
3) suction filtration, collects crystal, purifies be dried in vacuo 6h at water washing, 40 DEG C on a small quantity, obtain white crystalline powder
99.90g, yield 99.90%, purity 99.97%.
The X-ray powder diffraction spectrogram that obtained white crystalline powder is obtained using Cu-K alpha ray measurements is with implementing
Example 1 is similar.
The present invention is further illustrated below by experimental example：
Experimental example 1：Solvent screening is tested
Operated using the preparation method of the present invention, it is specific as follows：
1) olaparib crude product 100g is dissolved in 1500ml solvent orange 2 A and solvent B in the mixed solvent, with 240 revs/min
Speed agitating and heating be completely dissolved crude product, to solution clarification, filtering；
2) by solution obtained above with every 10 minutes 1 DEG C of speed slow coolings, when being down to -5 DEG C into solution by
3.0mL/min flow velocity adds the solvent C of precooling to crystalline substance is gone out, and continues to be cooled to -15 DEG C of crystallizations, insulated and stirred is complete to crystallization,
Growing the grain 3h；
3) suction filtration, collects crystal, purifies be dried in vacuo 5h at water washing, 45 DEG C on a small quantity, obtain white crystalline powder.
The solvent screening experimental result of table 1
Inventor is screened during solvent screening to most of organic solvents, different combination crystallization effects
Difference, only enumerates the data of part screening test herein.
Inventor surprisingly has found thick in dimethyl sulfoxide and water mixed solvent system dissolving olaparib in process of the test
Product, and it is brilliant with elutriation, and effect is more preferable relative to other alone dicyandiamide solutions.Then the mixing further to dimethyl sulfoxide and water is molten
The ratio of agent is screened, and is found when the volume ratio of dimethyl sulfoxide and water is less than 2:1 or more than 4:When 1, its yield and purity
It is a bit weaker.When the volume ratio of dimethyl sulfoxide and water is 2~4:When 1, effect is best, and not only purity is high, high income, and
Surprisingly find that its dissolubility is significantly improved by experiment.Therefore final determination selection is with dimethyl sulfoxide：Water 2~4:1 is molten to dissolve
Agent, add water crystallization, to do further screening.
Experimental example 2：Crystallization trial conditional filtering
1) olaparib crude product 100g is dissolved in the in the mixed solvent of dimethyl sulfoxide and water, agitating and heating makes crude product completely molten
Solution, to solution clarification, filtering；
2) by solution slow cooling obtained above, the purified water of precooling is added extremely into solution when being down to -5~0 DEG C
Go out crystalline substance, continue the crystallization that cools, insulated and stirred is complete to crystallization, growing the grain；
3) suction filtration, collects crystal, water washing is purified on a small quantity, is dried in vacuo, obtains white crystalline powder.
Table 2-1 crystallization trial conditional filtering results
Table 2-2 crystallization trial conditional filtering results
Table 2-3 crystallization trial conditional filtering results
Table 2-4 crystallization trial conditional filtering results
Screening test on crystallization trial condition is extremely complex, and we only enumerate A partial experiment knot therein herein
Really.There is too many variable, the change of each technological parameter in the crystallization process that can be seen that crystal from above-mentioned result of the test
May all influence be produced on result.Inventor passes through lot of experiments, the technique that technical solution of the present invention is finally determined.
Experimental example 3：Solubility test
Trial target：Sample prepared by 1-6 of the embodiment of the present invention；
Reference substance 1：The olaparib crystal formation I prepared with reference to the A embodiments 1,2 of patent CN 105439961.
Reference substance 2：The olaparib crystal formation prepared with reference to patent CN 105254572A embodiments 1-3.
Reference substance 3：The olaparib crystal formation A prepared with reference to patent 101528714A embodiments 1,3,5.
Reference substance 4：The olaparib crystal formation L prepared with reference to patent CN101821242A embodiments 1-5.
Reference substance 5：The olaparib monohydrate crystal form compound prepared with reference to patent CN106554315A embodiments 1.
Reference substance 6：The olaparib prepared with reference to the A embodiments 1-4 of patent CN 105985294.
Reference substance 7：The olaparib prepared with reference to the A embodiments 1-4 of patent CN 105061328.
Reference substance 8：The olaparib prepared with reference to the A embodiments one, two, three of patent CN 105085407.
Reference substance 9：The olaparib prepared with reference to the A embodiments 1-4 of patent CN 105503739.
Reference substance 10：The olaparib prepared with reference to patent CN 105820126 A embodiments 4-1,4-2,4-3.
Reference substance 11：Reference literature J.Am.Chem.Soc.2014, olaparib made from 136,6142-6147.
Reference substance 12：Reference literature J.Med.Chem., 2008,51：Olaparib made from 6581-6591.
Reference substance 13：With reference to Nanjing University of Technology's Master's thesis in 2012《Olaparib and the like study on the synthesis》Report
Olaparib made from the method in road.
Above-mentioned reference substance is to test obtained crystal formation by being repeated several times, and repeatedly progress X-ray powder diffraction detection,
Treat that stable crystal form (testing result is basically identical) can (such as former patent discloses accompanying drawing, then will determine figure therewith as reference substance
Contrast, basically identical to be used as reference substance).
Its dissolubility, method are determined with reference to Chinese Pharmacopoeia two notes on the use of version in 2015：Take this product appropriate, be separately added into water,
Every strength shaking in 5 minutes 30 seconds, the dissolving situation in 30 minutes is observed, produces, the results are shown in Table 3.
Crystal formation and reference substance the dissolubility test result in water of the present invention of table 3
Above-described embodiment 1-6 aqueous samples dissolved are stirred 72 hours in 25 DEG C of constant temperature, 5ml is sampled.Sample is passed through
0.45 μm of filtering with microporous membrane, discards primary filtrate, and it is solubility (mg/ml) in water to take the μ L of subsequent filtrate 20 to determine medicament contg.
It the results are shown in Table 4：
Solubility of the crystal formation of the present invention of table 4 with prior art crystal formation in water is contrasted
As can be seen from the above table, at 25 DEG C, the solubility and prior art in water of olaparib novel crystal forms of the present invention
Compare, be significantly increased, achieve unexpected technique effect.
Experimental example 4：Stability test
Experimental example investigates the stability for the olaparib crystallization that the present invention is provided by accelerated test and long term test.
1st, accelerated test
Sample prepared by Example 1-3, is placed 6 months under conditions of 40 ± 2 DEG C of temperature, relative humidity 75 ± 5%,
Respectively at 0,1,2,3,6 the end of month character, relevant material, content is measured by sampling, the results are shown in Table 5.
The accelerated test result of table 5 (40 ± 2 DEG C of temperature, relative humidity 75 ± 5%)
As seen from Table 5, olaparib crystallization of the present invention is placed under conditions of 40 ± 2 DEG C of temperature, relative humidity 75 ± 5%
6 months, relevant content of material did not had significantly raised, and each index has no significant change, and water content is stable (two molecular waters), from another
The water that aspect demonstrates in the compound is that the crystallization water is not absorption water.
2nd, long term test
Sample prepared by Example 1-3, is placed 6 months under conditions of 25 ± 2 DEG C of temperature, relative humidity 60 ± 5%,
Respectively at 0,3,6,9,12,18,24 the end of month character, relevant material, content is measured by sampling, the results are shown in Table 6.
The long-term test results of table 6 (25 ± 2 DEG C of temperature, relative humidity 60 ± 5%)
As seen from Table 6, olaparib crystallization of the present invention is placed under conditions of 25 ± 2 DEG C of temperature, relative humidity 60 ± 5%
24 months stable, and each index has no significant change, and water content is stable (two molecular waters), demonstrates from another point of view in the compound
Water be the crystallization water be not absorption water.
Other embodiment accelerates consistent with long term test testing result.
Experimental example 5：Capsule dissolution rate is detected
Capsule is prepared with reference to the prescription and technique of patent CN106551916A embodiments 1, except that selection is different
Crystal-form compound, capsule is prepared respectively, dissolution rate detection is carried out to obtained capsule, 7 are the results are shown in Table.
Elution test method：Using basket method, under 37 DEG C and 100rpm mixing speeds, the 0.3%SDS for being placed in 900ml is molten
In liquid.After 90 min, 1ml samples are taken, and olaparib content is detected by HPLC.
The dissolution rate testing result of table 7
| Sample | Dissolution (%) | Sample | Dissolution (%) |
| Capsule made from the crystal formation of embodiment 1 | 99.3 | Capsule made from the crystal formation of reference substance 5 | 97.9 |
| Capsule made from the crystal formation of embodiment 2 | 99.1 | Capsule made from the crystal formation of reference substance 6 | 98.2 |
| Capsule made from the crystal formation of embodiment 3 | 99.4 | Capsule made from the crystal formation of reference substance 7 | 98.3 |
| Capsule made from the crystal formation of embodiment 4 | 99.2 | Capsule made from the crystal formation of reference substance 8 | 97.9 |
| Capsule made from the crystal formation of embodiment 5 | 99.6 | Capsule made from the crystal formation of reference substance 9 | 97.8 |
| Capsule made from the crystal formation of embodiment 6 | 99.4 | Capsule made from the crystal formation of reference substance 10 | 98.1 |
| Capsule made from the crystal formation of reference substance 1 | 98.1 | Capsule made from the crystal formation of reference substance 11 | 98.8 |
| Capsule made from the crystal formation of reference substance 2 | 97.9 | Capsule made from the crystal formation of reference substance 12 | 98.1 |
| Capsule made from the crystal formation of reference substance 3 | 97.0 | Capsule made from the crystal formation of reference substance 13 | 98.4 |
| Capsule made from the crystal formation of reference substance 4 | 98.4 |
Using capsule made from crystal formation of the present invention than capsule made from existing crystal formation it can be seen from above-mentioned testing result
Agent dissolution rate is significantly improved.
Claims (8)
1. a kind of olaparib dihydrate, it is characterised in that its molecular formula is：C24H23FN4O3·2H2O, it is with 2 θ ± 0.2 °
The X-ray powder diffraction collection that the angle of diffraction is represented 6.75 °, 7.04 °, 9.16 °, 10.53 °, 15.20 °, 17.46 °,
Characteristic diffraction peak is shown at 20.68 °, 22.21 °, 27.43 °, 28.62 °, 29.30 °, 35.23 °, 37.14 °.
2. olaparib dihydrate as claimed in claim 1, it is characterised in that the X- obtained using Cu-K alpha ray measurements
Ray powder diffraction pattern is as shown in Figure 1.
3. the preparation method of olaparib dihydrate as claimed in claim 1 or 2, it is characterised in that comprise the following steps：
1) olaparib crude product is dissolved in the mixed solvent, makes crude product complete with 220~250 revs/min of speed agitating and heating
Dissolving, to solution clarification, filtering；
2) by solution slow cooling obtained above, the flow velocity when being down to -5~0 DEG C into solution by 2.0~3.0mL/min
The purified water of precooling is added to crystalline substance is gone out, continues to be cooled to -20 DEG C~-10 DEG C crystallizations, insulated and stirred is complete to crystallization, growing the grain；
3) suction filtration, collects crystal, water washing is purified on a small quantity, is dried in vacuo, obtains white crystalline powder.
4. the preparation method of olaparib dihydrate as claimed in claim 3, it is characterised in that：Step 1) described in mix
Solvent is the mixed solvent of dimethyl sulfoxide and water；The mass volume ratio of olaparib crude product and mixed solvent is 1g:15~20ml.
5. the preparation method of olaparib dihydrate as claimed in claim 3, it is characterised in that：Step 1) described in mix
In solvent, the volume ratio of dimethyl sulfoxide and water is 2~4:1.
6. the preparation method of olaparib dihydrate as claimed in claim 3, it is characterised in that：Step 1) described in mix
Solvent and step 2) described in the volume ratio of purified water be 1:3~4.
7. the preparation method of olaparib dihydrate as claimed in claim 3, it is characterised in that：Step 2) described in cool
Amplitude be every 10 minutes 1 DEG C~3 DEG C, rearing crystal time be 2~4h.
8. the preparation method of olaparib dihydrate as claimed in claim 3, it is characterised in that：Step 3) described in vacuum
Dry and refer to be dried in vacuo 4~6h at 40~50 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107162985A (en) * | 2017-06-05 | 2017-09-15 | 山东裕欣药业有限公司 | A kind of olaparib compound and preparation method thereof |
| US10662178B2 (en) | 2018-01-31 | 2020-05-26 | Apotex Inc. | Crystalline form of Olaparib |
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