SOLID STATE FORMS OF HIV INHIBITOR
The invention relates to novel crystalline forms of (2S)-2-tert-butoxy-2-(4-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-methylquinolin-3-yl)acetic acid, the hydrochloride salt thereof, novel crystalline forms of the hydrochloride salt, methods for the preparation thereof, pharmaceutical compositions thereof and their use in the treatment of Human Immunodeficiency Virus (HIV) infection.
1 . A hydrochloride salt of Compound (I):
in crystalline form Type A.
2 . (canceled)
3 . The crystalline hydrochloride salt of Compound (I) according to claim 1 in crystalline Type A having an X-ray powder diffraction pattern comprising peaks at 8.1, 9.3, 11.2, 28.4 and 28.6 degrees 2θ (±0.2 degrees 2θ) when measured using CuKα radiation.
4 . The crystalline hydrochloride salt of Compound (I) according to claim 3 in crystalline Type A having an X-ray powder diffraction pattern further comprising a peak at 13.0 degrees 2θ (±0.2 degrees 2θ) when measured using CuKα radiation.
5 . The crystalline hydrochloride salt of Compound (I) according to claim 4 in crystalline Type A having an X-ray powder diffraction pattern further comprising peaks at 10.4, 12.1, 18.8, 19.8, 22.1 and 22.4 degrees 2θ (±0.2 degrees 2θ) when measured using CuKα radiation.
6 . The crystalline hydrochloride salt of Compound (I) according to claim 1 in crystalline Type A having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1 .
7 . The crystalline hydrochloride salt of Compound (I) according to claim 1 in crystalline Type A having a DSC thermal curve substantially the same as that shown in FIG. 2 indicated as Type A.
8 . The crystalline hydrochloride salt of Compound (I) according to claim 1 in crystalline Type A having an X-ray powder diffraction pattern comprising peaks at 8.1, 9.3, 11.2, 28.4 and 28.6 degrees 2θ (±0.2 degrees 2θ) when measured using CuKα radiation and having a DSC thermal curve substantially the same as that shown in FIG. 2 indicated as Type A.
9 . The crystalline hydrochloride salt of Compound (I) in crystalline Type A according to claim 1 having a 13 C-ssNMR spectrum having chemical shift peaks at 146.7, 140.4, 136.9, 123.1, 121.4, and 21.8 ppm (each peak is ±0.2 ppm).
10 . The crystalline hydrochloride salt of Compound (I) according to claim 9 in crystalline Type A having a 13 C-ssNMR spectrum further comprising a chemical shift peak at 171.0 ppm (±0.2 ppm).
11 . The crystalline hydrochloride salt of Compound (I) according to claim 10 in crystalline Type A having a 13 C-ssNMR spectrum further comprising chemical shift peaks at 158.7, 154.2, 150.5 and 28.7 ppm (each peak is ±0.2 ppm).
12 . The crystalline hydrochloride salt of Compound (I) according to claim 11 in crystalline Type A having a 13 C-ssNMR spectrum further comprising chemical shift peaks at 133.0, 129.8, 128.8, 125.8, 118.5, 115.9, 110.7, 78.1, 72.2 and 65.2 ppm (each peak is ±0.2 ppm).
13 . The crystalline hydrochloride salt of Compound (I) according to claim 1 in crystalline Type A having an X-ray power diffraction pattern comprising peaks at 8.1, 9.3, 11.2, 28.4 and 28.6 degrees 2θ (±0.2 degrees 2θ) when measured using CuKα radiation and a 13 C-ssNMR spectrum having chemical shift peaks at 146.7, 140.4, 136.9, 123.1, 121.4, and 21.8 ppm (each peak is ±0.2 ppm).
14 . The crystalline hydrochloride salt of Compound (I) according to claim 1 in crystalline Type A having a 13 C-ssNMR spectrum substantially the same as that shown in FIG. 3 .
15 - 48 . (canceled)
49 . A pharmaceutical composition comprising a hydrochloride salt of Compound (I) according to claim 1 , and at least one pharmaceutically acceptable carrier or diluent.
50 . (canceled)
51 . The pharmaceutical composition according to claim 49 further comprising at least one other antiviral agent.
52 . (canceled)
53 . A process to prepare crystalline form Type A of the hydrochloride salt of Compound (I) according to claim 1 comprising the following steps:
(i) dissolving Compound (I) in a suitable solvent, and then adding an aqueous solution of HCl;
(ii) slowly heating the mixture in step (i) with stirring to a temperature to obtain a solution or slurry;
(iii) slowly cooling the mixture obtained in step (ii);
(iv) slowly adding an anti-solvent; and
(v) collecting the solid material obtained in step (iv) to obtain the hydrochloride salt of Compound (I) according to claim 1 .
54 . A process to prepare crystalline form Type A of the hydrochloride salt of Compound (I) according to claim 1 comprising the following steps:
(a) dissolving Compound (I) in a suitable solvent at a temperature greater than room temperature and then polish-filtering;
(b) optionally, adjusting the solution volume;
(c) cooling the solution temperature;
(d) adding dilute HCl in water or an aliphatic alcohol;
(e) initiating crystallization by seeding with crystals of the hydrochloride salt of Compound (I) according to claim 1 ;
(f) continuing crystallization by controlled slow addition of dilute HCl in water or an aliphatic alcohol;
(g) crystallizing the product further out of solution with the addition of non-polar solvents; and
(h) filtering and drying to provide crystals of the hydrochloride salt of Compound (I) according to claim 1 .
55 - 58 . (canceled)
59 . A method of treating or preventing an HIV infection in a human having or at risk of having the infection by administering to the human a therapeutically effective amount of a hydrochloride salt of Compound (I) according to claim 1 or a pharmaceutical composition according to claim 49 .