Pyrroloquinoline quinone lithium salt crystal and preparation method and application thereof
The present invention provides pyrroloquinoline quinone lithium salt crystal and a preparation method and application thereof. Characteristic absorption peaks appear when the diffraction angles are 6.222±0.2°, 7.379±0.2°, 7.941±0.2°, 23.631±0.2°, 24.044±0.2°, 25.497±0.2°, 27.541±0.2°, 30.736±0.2°, and 32.306±0.2° degrees in a powder X-ray diffraction pattern of the pyrroloquinoline quinine lithium salt crystal. The maximum value of thermal absorption of the pyrroloquinoline quinine lithium salt crystal appears between 90° C. and 96° C. through differential scanning calorimetry. Peaks appear when infrared spectroscopy of the pyrroloquinoline quinine lithium salt crystal is at 3396.03 cm −1 , 1652.70 cm −1 , 1604.48 cm −1 , 1500.35 cm −1 , 1355.71 cm −1 , 1243.86 cm −1 , 1147.44 cm −1 , 808.03 cm −1 , 761.74 cm −1 , and 570.83 cm −1 . The pyrroloquinoline quinine lithium salt polymorphism can be applied to preparation of medicines for curing memory damage.
1. A pyrroloquinoline quinine lithium salt crystalline form B, characterized by an X-ray powder diffraction pattern with significant peaks at diffraction angles (2θ values) of about 6.222±0.2°, 7.379±0.2°, 7.941±0.2°, 23.631±0.2°; endothermic peak of the pyrroloquinoline quinine lithium salt crystal is around 90-96° C. in the differential scanning calorimetry thermogram; and the pyrroloquinoline quinine lithium salt crystal shows peaks around 3396.03 cm−1, 1652.70 cm−1, 1604.48 cm−1, 1355.71 cm−1 on infrared spectroscopy (IR) pattern.
2. The pyrroloquinoline quinine lithium salt crystalline form B according to claim 1 , characterized by an X-ray powder diffraction pattern with more significant peaks at diffraction angles (2θ values) of about 24.044±0.2°, 25.497±0.2°, 27.541±0.2°, 30.736±0.2°, 32.306±0.2°; the pyrroloquinoline quinine lithium salt crystal also shows more peaks around 1500.35 cm−1, 1243.86 cm−1, 1147.44 cm−1, 808.03 cm−1, 761.74 cm−1, 570.83 cm−1 on infrared spectroscopy (IR) pattern.
3. The pyrroloquinoline quinine lithium salt crystalline form B according to claim 1 , characterized by stably existing as a nonahydrate by dynamic vapor sorption analysis; the pyrroloquinoline quinine lithium salt crystal forms monohydrate under the scope of relative humidity (RH) from 20% to 50%, and forms dihydrate under the scope of relative humidity (RH) from 70% to 100%.
4. The pyrroloquinoline quinine lithium salt crystalline form B according to claim 1 , characterized by endothermic peak of 93° C. in the differential scanning calorimetry (DSC) thermogram.
5. A method for preparing pyrroloquinoline quinine (PQQ) lithium salt crystalline form B according to claim 1 comprising step A and step B, wherein,
Step A comprises:
mixing PQQ with lithium hydroxide (LiOH), wherein, the weight ratio of PPQ to LiOH is 4:1;
adding 16 mL ddH 2 O;
stirring at 0-5° C. for 2 hours;
adding 8 mL acetonitrile;
continuing stirring for 1 hour to precipitate PQQ lithium salt form A;
filtering the PQQ lithium salt form A precipitates to obtain PQQ lithium salt form A; and
Step B comprises:
(i) dissolving the PQQ lithium salt form A precipitate in water, wherein, the ratio of PQQ lithium salt form A to water is 20 mg:1 mL;
adding a solvent to form a complete mixture, wherein, the solvent is selected from the group consisting of tetrahydrofuran and isopropanol, and, wherein, the ratio of PQQ lithium salt form A precipitate to the solvent is 10 mg:4 mL; and
standing overnight at room temperature to obtain PQQ lithium salt crystalline form B;
or
(ii) dissolving the PQQ lithium salt form A precipitate in a 1:1 mixture of methanol and methyl tert-butyl ether, wherein, the ratio of PQQ lithium salt form A to the solvent mixture is 10 mg:1 mL; and
standing overnight at room temperature to obtain PQQ lithium salt crystalline form B.
6. A pharmaceutical composition comprising the pyrroloquinoline quinine lithium salt crystalline form B according to claim 1 and at least one pharmaceutically acceptable excipients.
7. The pharmaceutical composition of claim 6 , wherein the excipients are selected from fillers, disintegrants, binders, lubricants and a combination of two or more thereof.
8. The pharmaceutical composition of claim 7 , wherein the fillers are selected from starch, lactose, crystalline cellulose, dextrin, mannitol, oxidase, calcium sulfate and a combination of two or more thereof.
9. The pharmaceutical composition of claim 7 , wherein the disintegrants are selected from carboxymethylcellulose and salt thereof, crosslinked carboxymethylcellulose and salt thereof, crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose and a combination of two or more thereof.
10. The pharmaceutical composition of claim 7 , wherein the binders are selected from polyvinylpyrrolidone, hydroxypropyl methyl cellulose, starch slurry and a combination of two or more thereof.
11. The pharmaceutical composition of claim 7 , wherein the lubricants are selected from magnesium stearate, calcium stearate and a combination of two thereof.