Crystalline polymorphic forms of monosodium N-[-8-(2-hydroxybenzoyl)amino]caprylate
View Patent ↗The present invention relates to crystalline polymorphic forms of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate (“SNAC”), including two hydrates, a methanol solvate, and an ethanol solvate, of SNAC. More specifically, the present invention provide six polymorphic forms of SNAC (hereafter referred to as Forms I-VI). The present invention also provides an amorphous form of SNAC.
1. A polymorph of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate, wherein the polymorph is a ⅓ hydrate of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate exhibiting an X-ray powder diffraction pattern comprising peaks at 3.29, 11.96, and 17.76 degrees 2Θ±0.20° 2Θ.
2. The polymorph of claim 1 , exhibiting an X-ray powder diffraction pattern substantially as shown in FIG. 6 .
3. A polymorph of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate, wherein the polymorph is a trihydrate of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate exhibiting an X-ray powder diffraction pattern comprising peaks at 6.69, 13.58, and 16.80 degrees 2Θ±0.2° 2Θ.
4. The polymorph of claim 3 , exhibiting an X-ray powder diffraction pattern substantially as shown in FIG. 11 .
5. A polymorph of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate, wherein the polymorph is anhydrous and exhibits an X-ray powder diffraction pattern comprising characteristic peaks at 8.61, 17.04, and 23.28 degrees 2Θ±0.2° 2Θ.
6. The polymorph of claim 5 , exhibiting an X-ray powder diffraction pattern substantially as shown in FIG. 16 .
7. A polymorph of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate, which is a methanol-water co-solvate of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate exhibiting an X-ray powder diffraction pattern comprising peaks at 6.59, 9.96, 10.86, 13.57, 17.29, and 19.92 degrees 2Θ±0.2° 2Θ.
8. The polymorph of claim 7 , wherein the ratio of methanol to water to monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate in the polymorph is approximately 0.8:2:1.
9. The polymorph of claim 7 , exhibiting an X-ray powder diffraction pattern substantially as shown in FIG. 21 .
10. A polymorph of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate, which is an ethanol-water co-solvate of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate exhibiting an X-ray powder diffraction pattern comprising peaks at 9.60, 10.43, 12.68, and 16.58 degrees 2Θ±0.2° 2Θ.
11. The polymorph of claim 10 , wherein the ratio of ethanol to water to monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate in the polymorph is approximately 0.6:2:1.
12. The polymorph of claim 10 , exhibiting an X-ray powder diffraction pattern substantially as shown in FIG. 26 .
13. Amorphous monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate containing approximately 10% Form III of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate and exhibiting an X-ray powder diffraction pattern substantially as shown in FIG. 43 .
14. A pharmaceutical composition comprising
(A) one or more compounds selected from:
(i) a polymorph of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate, wherein the polymorph is a ⅓ hydrate of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate exhibiting an X-ray powder diffraction pattern comprising peaks at 3.29, 11.96, and 17.76 degrees 2Θ±0.20° 2Θ;
(ii) a polymorph of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate, wherein the polymorph is a trihydrate of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate exhibiting an X-ray powder diffraction pattern comprising peaks at 6.69, 13.58, and 16.80 degrees 2Θ±0.2° 2Θ;
(iii) amorphous monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate; and
(iv) a polymorph of an anhydrate of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate, which is an anhydrate of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate and exhibits an X-ray powder diffraction pattern comprising characteristic peaks at 8.61, 17.04, and 23.28 degrees 2Θ±0.2° 2Θ; and
(B) heparin.
15. The pharmaceutical composition of claim 14 , wherein the biologically active agent is low molecular weight heparin.
16. A method for administering a biologically active agent to an animal in need thereof comprising the step of orally administering the pharmaceutical composition of claim 14 to the animal.
17. A composition comprising
(A) one or more compounds selected from:
(i) a polymorph of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate, wherein the polymorph is a ⅓ hydrate of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate and exhibits an X-ray powder diffraction pattern having characteristic peaks at 3.29, 11.96 and 17.76 degrees 2Θ±0.20° 2Θ;
(ii) a polymorph of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate, wherein the polymorph is a trihydrate of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate and exhibits an X-ray powder diffraction pattern having characteristic peaks at 6.69, 13.58 and 16.80 degrees 2Θ±0.2° 2Θ;
(iii) amorphous monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate;
(iv) a polymorph of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate, which is a methanol-water co-solvate of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate and exhibits an X-ray powder diffraction pattern having characteristic peaks at 6.59, 9.96, 10.86, 13.57, 17.29, and 19.92 degrees 2Θ±0.2° 2Θ;
(v) a polymorph of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate, which is an ethanol-water co-solvate of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate and exhibits an X-ray powder diffraction pattern having characteristic peaks at 9.60, 10.43, 12.68 and 16.58 degrees 2Θ±0.2° 2Θ; and
(vi) a polymorph of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate, which is an anhydrate of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate and exhibits an X-ray powder diffraction pattern having characteristic peaks at 8.61, 17.04, and 23.28 degrees 2Θ±0.2° 2Θ; and
(B) a pharmaceutically acceptable excipient.
18. The polymorph of claim 1 , wherein the polymorph has a melting point onset as determined by differential scanning calorimetry at about 199° C.
19. The polymorph of claim 3 , wherein the polymorph has a melting point onset as determined by differential scanning calorimetry at about 198° C.
20. The polymorph of claim 5 , wherein the polymorph has a melting point onset as determined by differential scanning calorimetry at about 198° C.
21. The polymorph of claim 5 , wherein the polymorph has a melting point onset as determined by differential scanning calorimetry at about 197° C.
22. The polymorph of claim 10 , wherein the polymorph has a melting point onset as determined by differential scanning calorimetry at about 197° C.
23. The method of claim 16 , wherein the animal is a human.