Macrolide compound in solid form, process for preparation thereof, and pharmaceutical composition containing the same
View Patent ↗The present invention provides the compound of formula (I) in a solid form which, as a bulk medicament for pharmaceutical manufacture, is uniform, has a high purity, and is easy to work with. The invention further provides a process for preparing this compound, and pharmaceutical compositions containing the same. A solid form of (8E,12E,14E)-7-{(4-cycloheptylpiperazin-1-yl)carbonyl}oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide which has uniform specifications and is easy to work with was developed.
1. A solid form of a compound (8E,12E,14E)-7-{(4-cycloheptylpiperazin-1-yl)carbonyl}oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide represented by formula (I):
wherein the solid form is amorphous.
2. A solid form of a compound (8E,12E,14E)-7-{(4-cycloheptylpiperazin-1-yl)carbonyl}oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide represented by formula (I):
wherein the solid form is crystalline; and
wherein the crystals have, in a powder x-ray diffraction pattern thereof, peaks at the diffraction angles (2θ±0.2°) 8.8°, 15.8° and 17.5°.
3. A process for preparing the crystals of claim 2 , comprising: dissolving the (8E,12E,14E)-7-{(4-cycloheptylpiperazin-1-yl)carbonyl}oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide in one or two solvents selected from the group consisting of a first ether-type solvent, aromatic hydrocarbon-type solvents, acetate ester-type solvents and alkylnitrile-type solvents to form a solution; then adding an aliphatic hydrocarbon-type solvent to the solution so as to induce crystal precipitation.
4. The process of claim 3 , wherein the one or two solvents selected from the group consisting of a first ether-type solvent, aromatic hydrocarbon-type solvents, acetate ester-type solvents and alkylnitrile-type solvents are an acetate ester-type solvent.
5. The process of claim 3 , wherein the acetate ester-type solvent is ethyl acetate.
6. The process of claim 3 , wherein the aliphatic hydrocarbon-type solvent is n-heptane.
7. The process of claim 3 , wherein crystal precipitation is induced under stirring.
8. The process for preparing the crystals of claim 3 , wherein crystal precipitation is induced at 20 to 30° C.
9. The process for preparing the crystals of claim 3 , wherein crystal precipitation is induced at 35 to 60° C.
10. The process for preparing the crystals of claim 3 , wherein crystal precipitation is induced at 65 to 75° C.
11. The process of claim 3 , wherein the (8E,12E,14E)-7-{(4-cycloheptylpiperazin-1-yl)carbonyl}oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide represented by formula (I) is prepared by the process comprising: reacting a compound represented by formula (VI):
(wherein EE is 1-ethoxyethyl group, and TES is a triethylsilyl group) with a compound represented by formula (VII):
(wherein R is a nitro group, a chlorine atom or a hydrogen atom) using a second ether-type solvent so as to obtain an ether solution of the compound of formula (IV):
(wherein EE, TES and R are as defined above); reacting the ether solution of the compound of formula (IV) with 1-cycloheptylpiperazine so as to form an ether solution of the compound represented by formula (III):
(wherein EE and TES are as defined above); treating the ether solution of the compound of formula (III) with a desilylating agent so as to deprotect the TES groups and thereby give an ether solution of the compound of formula (II):
(wherein EE is as defined above); and treating the ether solution of the compound of formula (II) with an acid so as to deprotect the EE group.
12. The process of claim 11 , wherein the second ether-type solvent is t-butyl methyl ether.
13. A pharmaceutical composition comprising the solid of claim 1 or 2 .