阅读说明：本技术 奥扎莫德加成盐晶型、制备方法及药物组合物和用途 (Crystal form of addition salt of ozapimod, preparation method, pharmaceutical composition and application ) 是由 盛晓红 盛晓霞 郑剑锋 于 2017-04-07 设计创作，主要内容包括：公开了奥扎莫德加成盐晶型,与已知的奥扎莫德固体形态相比,其具有一种或多种改进的特性。还公开了奥扎莫德加成盐晶型的制备方法、其药物组合物、及其用于制备在医学上需要选择性鞘氨醇-1-磷酸酯受体的调节、活化、激动、抑制或拮抗的病症或不良状况的药物中的用途。<Image he="378" wi="700" file="DDA0002262938450000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(Disclosed are crystalline forms of an ozatimod addition salt having one or more improved properties compared to known solid forms of ozatimod. Also disclosed are processes for the preparation of the azamod addition salt crystalline forms, pharmaceutical compositions thereof, and their use for the preparation of medicaments for conditions or disorders for which modulation, activation, agonism, inhibition, or antagonism of a selective sphingosine-1-phosphate receptor is medically indicated.)

An addition salt crystal form of ozagrimod with the structure shown in formula (A),

characterized in that the crystal form of the addition salt is the crystal form of the azamod mono-salt or the azamod half-salt.

The addition salt crystalline form of otimod according to claim 1, characterized in that it is an addition salt crystalline form as follows: ozatimod benzenesulfonate form 1, ozatimod citrate form 1, ozatimod hemi L-malate form 1, ozatimod dihydrogen phosphate form 1, ozatimod hydrogen sulfate form 1, ozatimod hemi sulfate form 1, ozatimod L-tartrate form 1, ozatimod hemi fumarate form 1, ozatimod maleate form 1, ozatimod hydrobromide form 1, or ozatimod mesylate form 1.

The crystalline addition salt form of ozagrimod according to any one of claims 1-2, in a substantially solid crystalline state, preferably in the anhydrous, hydrated or unsolvated state.

The crystalline form of ozatimod addition salt according to claim 1 or 2, wherein the crystalline form of addition salt is crystalline form 1 besylate having the following characteristic peaks in X-ray powder diffraction diagram expressed in degrees 2 Θ: 5.7 ° ± 0.2 °, 9.1 ° ± 0.2 °, 13.9 ° ± 0.2 ° and 14.7 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 4, wherein the besylate salt form 1 further has an X-ray powder diffraction pattern expressed in terms of 2 Θ angles with characteristic peaks at one or more of: 6.9 ° ± 0.2 °, 11.4 ° ± 0.2 °, 18.8 ° ± 0.2 ° and 21.6 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 5, wherein the besylate salt form 1 further has an X-ray powder diffraction pattern expressed in terms of 2 Θ angles with characteristic peaks at one or more of: 23.0 ° ± 0.2 °, 23.3 ° ± 0.2 °, 25.1 ° ± 0.2 ° and 26.3 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to any one of claims 4 to 6, wherein the besylate form 1 has a Fourier infrared spectrum at a wave number of 1612cm^-1±2cm^-1、1489cm^-1±2cm^-1、1284cm^-1±2cm^-1、1230cm^-1±2cm^-1、1158cm^-1±2cm^-1、1123cm^-1±2cm^-1、1102cm^-1±2cm^-1、1029cm^-1±2cm^-1、1014cm^-1±2cm^-1、759cm^-1±2cm^-1、727cm^-1±2cm^-1And 614cm^-1±2cm^-1Has characteristic peaks.

The crystalline form of ozatimod addition salt according to claim 2, wherein the crystalline form of addition salt is crystalline form 1 citrate having the following characteristic peaks in its X-ray powder diffraction pattern expressed in degrees 2 Θ: 4.4 ° ± 0.2 °, 14.0 ° ± 0.2 °, 20.9 ° ± 0.2 ° and 24.9 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 8, wherein the citrate form 1 further has characteristic peaks in an X-ray powder diffraction pattern expressed in terms of 2 Θ angles at one or more of: 12.5 ° ± 0.2 °, 13.5 ° ± 0.2 °, 14.3 ° ± 0.2 ° and 15.9 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 9, characterized in that the X-ray powder diffraction pattern of form citrate 1, expressed in terms of 2 Θ angles, further has characteristic peaks at one or more of: 20.6 ° ± 0.2 °, 22.7 ° ± 0.2 °, 24.5 ° ± 0.2 ° and 29.2 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to any one of claims 8 to 10, wherein the fourier spectrogram of form 1 of the citrate salt is 1617cm in wave number^-1±2cm^-1、1516cm^-1±2cm^-1、1489cm^-1±2cm^-1、1464cm^-1±2cm^-1、1353cm^-1±2cm^-1、1288cm^-1±2cm^-1、1106cm^-1±2cm^-1、1079cm^-1±2cm^-1、945cm^-1±2cm^-1、837cm^-1±2cm^-1And 762cm^-1±2cm^-1Has characteristic peaks.

The crystalline form of ozatimod addition salt according to claim 2, wherein the crystalline form of addition salt is hemi-L-malate form 1 having the following characteristic peaks in its X-ray powder diffraction pattern expressed in degrees 2 Θ: 3.7 ° ± 0.2 °, 14.8 ° ± 0.2 °, 18.5 ° ± 0.2 ° and 22.2 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 12, wherein the crystalline form of addition salt is hemil-malate form 1, further having characteristic peaks in one or more of the following X-ray powder diffraction patterns expressed in degrees 2 Θ: 7.3 ° ± 0.2 °, 12.0 ° ± 0.2 °, 24.5 ° ± 0.2 ° and 26.0 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 13, wherein the semi L-malate form 1 further has characteristic peaks in one or more of the following X-ray powder diffraction patterns expressed in terms of 2 Θ angles: 12.6 ° ± 0.2 °, 13.9 ° ± 0.2 °, 19.7 ° ± 0.2 ° and 20.1 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to any one of claims 12 to 14, wherein the half L-malate crystalline form 1 has a fourier infrared spectrum at wave number of 1710cm^-1±2cm^-1、1618cm^-1±2cm^-1、1496cm^-1±2cm^-1、1354cm^-1±2cm^-1、1284cm^-1±2cm^-1、1100cm^-1±2cm^-1、942cm^-1±2cm^-1、833cm^-1±2cm^-1、758cm^-1±2cm^-1And 663cm^-1±2cm^-1Has characteristic peaks.

The crystalline form of ozatimod addition salt according to claim 2, wherein the crystalline form of addition salt is form 1 dihydrogenphosphate having the following characteristic peaks in its X-ray powder diffraction pattern expressed in degrees 2 Θ: 3.3 ° ± 0.2 °, 5.5 ° ± 0.2 °, 11.2 ° ± 0.2 ° and 20.8 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 16, wherein the dihydrogenphosphate form 1 further has characteristic peaks in the X-ray powder diffraction pattern expressed in degrees 2 Θ at one or more of: 3.6 ° ± 0.2 °,7.4 ° ± 0.2 °, 13.1 ° ± 0.2 ° and 22.7 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 17, wherein the dihydrogenphosphate form 1 further has characteristic peaks in an X-ray powder diffraction pattern expressed in degrees 2 Θ at one or more of: 13.8 ° ± 0.2 °, 17.0 ° ± 0.2 °, 24.3 ° ± 0.2 ° and 28.9 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to any one of claims 16 to 18, wherein the dihydrogen phosphate salt form 1 has a Fourier infrared spectrum with a wavenumber of 1618cm^-1±2cm^-1、1490cm^-1±2cm^-1、1464cm^-1±2cm^-1、1354cm^-1±2cm^-1、1288cm^-1±2cm^-1、1103cm^-1±2cm^-1、1006cm^-1±2cm^-1、957cm^-1±2cm^-1、835cm^-1±2cm^-1And 762cm^-1±2cm^-1Has characteristic peaks.

The crystalline form of ozatimod addition salt according to claim 2, wherein the crystalline form of addition salt is crystalline form 1 bisulfate having an X-ray powder diffraction pattern expressed in terms of 2 Θ angles with the following characteristic peaks: 4.1 ° ± 0.2 °, 8.3 ° ± 0.2 °, 11.1 ° ± 0.2 ° and 16.8 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 20, wherein the bisulfate salt form 1 further has an X-ray powder diffraction pattern, expressed in terms of 2 Θ angles, having characteristic peaks at one or more of: 14.6 ° ± 0.2 °, 18.5 ° ± 0.2 °, 21.3 ° ± 0.2 ° and 22.8 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 21, wherein the bisulfate salt form 1 further has an X-ray powder diffraction pattern, expressed in terms of 2 Θ angles, having characteristic peaks at one or more of: 17.0 ° ± 0.2 °, 22.4 ° ± 0.2 °, 24.7 ° ± 0.2 ° and 25.8 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to any one of claims 20 to 22, wherein the form 1 bisulfate has a Fourier infrared spectrum at a wave number of 1614cm^-1±2cm^-1、1488cm^-1±2cm^-1、1461cm^-1±2cm^-1、1287cm^-1±2cm^-1、1179cm^-1±2cm^-1、1155cm^-1±2cm^-1、1051cm^-1±2cm^-1、867cm^-1±2cm^-1And 759cm^-1±2cm^-1Has characteristic peaks.

The crystalline form of ozatimod addition salt according to claim 2, wherein the crystalline form of addition salt is hemisulfate form 1, having the following characteristic peaks in its X-ray powder diffraction pattern expressed in degrees 2 Θ: 3.8 ° ± 0.2 °, 11.6 ° ± 0.2 °, 13.3 ° ± 0.2 ° and 19.5 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 24, wherein the crystalline form 1 hemisulfate salt further has characteristic peaks in an X-ray powder diffraction pattern expressed in terms of 2 Θ angles at one or more of: 9.9 ° ± 0.2 °, 15.3 ° ± 0.2 °, 22.1 ° ± 0.2 ° and 24.6 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 25, wherein the X-ray powder diffraction pattern, expressed in degrees 2 Θ, of crystalline form 1 hemisulfate further has characteristic peaks at one or more of: 15.7 ° ± 0.2 °, 20.1 ° ± 0.2 °, 25.3 ° ± 0.2 ° and 27.9 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to any one of claims 24 to 26, wherein the form 1 hemisulfate has a fourier infrared spectrum at a wave number of 1620cm^-1±2cm^-1、1462cm^-1±2cm^-1、1406cm^-1±2cm^-1、1284cm^-1±2cm^-1、1128cm^-1±2cm^-1、1090cm^-1±2cm^-1、1041cm^-1±2cm^-1、1013cm^-1±2cm^-1、941cm^-1±2cm^-1、838cm^-1±2cm^-1And 761cm^-1±2cm^-1Has characteristic peaks.

The crystalline form of the ozatimod addition salt according to claim 2, wherein the crystalline form of the addition salt is L-tartrate form 1, having the following characteristic peaks in its X-ray powder diffraction pattern expressed in degrees 2 Θ: 6.4 ° ± 0.2 °, 9.9 ° ± 0.2 °, 12.7 ° ± 0.2 ° and 22.8 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 28, wherein the L-tartrate form 1, further has characteristic peaks in the X-ray powder diffraction pattern expressed in degrees 2 Θ at one or more of: 3.1 ° ± 0.2 °, 5.5 ° ± 0.2 °, 10.6 ° ± 0.2 ° and 14.8 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 29, wherein the L-tartrate form 1, further has characteristic peaks in the X-ray powder diffraction pattern expressed in degrees 2 Θ at one or more of: 7.0 ° ± 0.2 °, 13.0 ° ± 0.2 °, 16.6 ° ± 0.2 ° and 19.0 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to any one of claims 28 to 30, wherein the L-tartrate form 1 has a fourier spectrogram in wavenumber of 1610cm^-1±2cm^-1、1569cm^-1±2cm^-1、1486cm^-1±2cm^-1、1460cm^-1±2cm^-1、1362cm^-1±2cm^-1、1280cm^-1±2cm^-1、1155cm^-1±2cm^-1、1104cm^-1±2cm^-1、1061cm^-1±2cm^-1、942cm^-1±2cm^-1And 759cm^-1±2cm^-1Has characteristic peaks.

The crystalline form of ozatimod addition salt according to claim 2, wherein the crystalline form of addition salt is hemifumarate crystalline form 1, having the following characteristic peaks in its X-ray powder diffraction pattern expressed in degrees 2 Θ: 6.3 ° ± 0.2 °, 9.0 ° ± 0.2 °, 12.6 ° ± 0.2 ° and 13.7 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 32, wherein the crystalline form 1 hemifumarate further has an X-ray powder diffraction pattern expressed in terms of 2 Θ angles with characteristic peaks at one or more of: 12.9 ° ± 0.2 °, 14.5 ° ± 0.2 °, 17.3 ° ± 0.2 ° and 21.5 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 33, wherein the crystalline form 1 hemifumarate further has an X-ray powder diffraction pattern expressed in terms of 2 Θ angles with characteristic peaks at one or more of: 8.6 ° ± 0.2 °, 21.0 ° ± 0.2 °, 22.8 ° ± 0.2 ° and 25.7 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to any one of claims 32 to 34, wherein the semi-fumarate of form 1 has a Fourier infrared spectrum at a wave number of 1615cm^-1±2cm^-1、1576cm^-1±2cm^-1、1493cm^-1±2cm^-1、1405cm^-1±2cm^-1、1351cm^-1±2cm^-1、1284cm^-1±2cm^-1、1099cm^-1±2cm^-1、944cm^-1±2cm^-1、833cm^-1±2cm^-1、760cm^-1±2cm^-1And 652cm^-1±2cm^-1Has characteristic peaks.

The crystalline form of ozatimod addition salt according to claim 2, wherein the crystalline form of addition salt is crystalline form 1 fumarate, which has an X-ray powder diffraction pattern expressed in terms of 2 Θ angles with the following characteristic peaks: 3.9 ° ± 0.2 °,7.9 ° ± 0.2 °, 13.3 ° ± 0.2 ° and 17.0 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 36, wherein the fumarate crystalline form 1 further has an X-ray powder diffraction pattern expressed in terms of 2 Θ angles with characteristic peaks at one or more of: 7.5 ° ± 0.2 °, 15.8 ° ± 0.2 °, 24.6 ° ± 0.2 ° and 28.6 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 37, wherein the fumarate crystalline form 1 further has an X-ray powder diffraction pattern expressed in terms of 2 Θ angles with characteristic peaks at one or more of: 13.8 ° ± 0.2 °, 20.1 ° ± 0.2 °, 23.3 ° ± 0.2 ° and 23.8 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to any one of claims 36 to 38, wherein the fourier spectrogram of the fumarate crystalline form 1 is 1701cm wave number^-1±2cm^-1、1614cm^-1±2cm^-1、1484cm^-1±2cm^-1、1462cm^-1±2cm^-1、1342cm^-1±2cm^-1、1284cm^-1±2cm^-1、1103cm^-1±2cm^-1、986cm^-1±2cm^-1、759cm^-1±2cm^-1And 639cm^-1±2cm^-1Has characteristic peaks.

The crystalline form of ozatimod addition salt according to claim 2, wherein the crystalline form of addition salt is crystalline form 1 maleate having an X-ray powder diffraction pattern expressed in terms of 2 Θ angles with the following characteristic peaks: 8.2 ° ± 0.2 °, 11.5 ° ± 0.2 °, 12.4 ° ± 0.2 ° and 13.6 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 40, wherein the maleate form 1 further has an X-ray powder diffraction pattern expressed in terms of 2 θ angles with characteristic peaks at one or more of: 5.3 ° ± 0.2 °, 6.7 ° ± 0.2 °, 10.2 ° ± 0.2 ° and 11.0 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 41, wherein the maleate form 1 further has an X-ray powder diffraction pattern expressed in terms of 2 θ angles with characteristic peaks at one or more of: 14.1 ° ± 0.2 °, 15.8 ° ± 0.2 °, 16.4 ° ± 0.2 ° and 18.1 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to any one of claims 40 to 42, wherein the Fourier infrared spectrum of the crystalline form 1 maleate form is 1700cm in wavenumber^-1±2cm^-1、1614cm^-1±2cm^-1、1487cm^-1±2cm^-1、1461cm^-1±2cm^-1、1353cm^-1±2cm^-1、1281cm^-1±2cm^-1、1102cm^-1±2cm^-1、1087cm^-1±2cm^-1、865cm^-1±2cm^-1、759cm^-1±2cm^-1And 653cm^-1±2cm^-1Has characteristic peaks.

The crystalline form of ozatimod addition salt according to claim 2, wherein the crystalline form of addition salt is crystalline form 1 hydrobromide having an X-ray powder diffraction pattern expressed in degrees 2 Θ with the following characteristic peaks: 3.9 ° ± 0.2 °, 12.1 ° ± 0.2 °, 13.7 ° ± 0.2 ° and 20.3 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 44, wherein the X-ray powder diffraction pattern, expressed in terms of 2 Θ angles, of the hydrobromide form 1 further has characteristic peaks at one or more of: 12.9 ° ± 0.2 °, 22.7 ° ± 0.2 °, 24.5 ° ± 0.2 ° and 26.2 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 45, wherein the X-ray powder diffraction pattern, expressed in terms of 2 Θ angles, of the hydrobromide form 1 further has characteristic peaks at one or more of: 12.4 ° ± 0.2 °, 19.5 ° ± 0.2 °, 21.3 ° ± 0.2 ° and 26.8 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to any one of claims 44 to 46, wherein the Fourier infrared spectrum of the hydrobromide form 1 is 3276cm at a wave number^-1±2cm^-1、1620cm^-1±2cm^-1、1498cm^-1±2cm^-1、1443cm^-1±2cm^-1、1405cm^-1±2cm^-1、1353cm^-1±2cm^-1、1285cm^-1±2cm^-1、1099cm^-1±2cm^-1、1074cm^-1±2cm^-1、942cm^-1±2cm^-1、837cm^-1±2cm^-1And 761cm^-1±2cm^-1Has characteristic peaks.

The crystalline form of ozatimod addition salt according to claim 2, wherein the crystalline form of addition salt is mesylate form 1, which has an X-ray powder diffraction pattern expressed in terms of 2 Θ angles with the following characteristic peaks: 11.6 ° ± 0.2 °, 12.6 ° ± 0.2 °, 18.2 ° ± 0.2 ° and 19.5 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 48, wherein the mesylate salt form 1 further has an X-ray powder diffraction pattern, expressed in terms of 2 θ, with characteristic peaks at one or more of: 4.9 ° ± 0.2 °,7.9 ° ± 0.2 °, 9.9 ° ± 0.2 ° and 16.8 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to claim 49, wherein the mesylate salt form 1 further has an X-ray powder diffraction pattern, expressed in terms of 2 θ, with characteristic peaks at one or more of: 20.1 ° ± 0.2 °, 23.1 ° ± 0.2 °, 23.4 ° ± 0.2 °, 24.3 ° ± 0.2 ° and 25.0 ° ± 0.2 °.

The crystalline form of ozatimod addition salt according to any one of claims 48 to 50, wherein the mesylate salt form 1 has a Fourier infrared spectrum at a wave number of 1617cm^-1±2cm^-1、1492cm^-1±2cm^-1、1406cm^-1±2cm^-1、1357cm^-1±2cm^-1、1285cm^-1±2cm^-1、1152cm^-1±2cm^-1、1105cm^-1±2cm^-1、1044cm^-1±2cm^-1、940cm^-1±2cm^-1、780cm^-1±2cm^-1And 760cm^-1±2cm^-1Has characteristic peaks.

Method for preparing the crystalline form of an addition salt of ozagrimod according to any one of claims 1 to 2, characterized in that: respectively dissolving ozatimod and an acid corresponding to the salt of claim 2 in a good solvent, mixing, and completing the preparation of the crystal form by the following mode I or mode II:

mode I: and stirring the mixed solution, and separating and drying the precipitated crystals to obtain the crystal form of the otimod monoacid addition salt or the otimod hemiacid addition salt.

Mode II: adding an antisolvent into the mixed solution, stirring, separating and drying the precipitated crystals to obtain the crystal form of the otimod mono-acid addition salt or the otimod semi-acid addition salt.

The method for preparing the crystal form of addition salt according to claim 52, wherein in mode I or mode II, the good solvent is an alcohol organic solvent, a ketone organic solvent or a mixture thereof.

Preferably, in the mode I or the mode II, the good solvent is selected from C₁～C₄Alcohol, C₃～C₄Ketones or mixtures thereof, more preferably n-propanol, acetone or mixtures thereof;

preferably, in the mode I, the concentration of the ozapimod in the good solution is 0.5 to 1.05 times of the solubility of the ozapimod in the solution;

preferably, in the mode II, the concentration of the ozapimod in the good solution is 0.1 to 1.05 times, and more preferably 0.1 to 0.4 times of the solubility of the ozapimod in the solution;

preferably, in mode II, the anti-solvent is selected from an ester organic solvent, an ether organic solvent, an alkane organic solvent, or a mixture thereof, more preferably ethyl acetate, methyl tert-butyl ether, n-heptane, or a mixture thereof;

preferably, in the preparation of the azalomod mono-salt, the charging molar ratio of azalomod and acidic counter ions is 1: 1.0-1: 1.5, more preferably 1: 1.0-1: 1.2;

preferably, in the preparation of the azalomod hemite, the charging molar ratio of azalomod and acidic counter ions is 1: 0.5-1: 0.8, more preferably 1: 0.5-1: 0.6;

preferably, the stirring time is 1 to 7 days, and more preferably 3 to 7 days;

preferably, the operation temperature of the preparation method is 10-40 ℃, and more preferably room temperature;

preferably, the drying temperature is room temperature, and the drying time is 16-48 hours.

A pharmaceutical composition comprising one or more of the crystalline forms of the ozatimod addition salt according to any one of claims 1 to 51, in a disease-treating and/or-preventing effective amount, and at least one pharmaceutically acceptable carrier.

Use of a crystalline form of an otimod addition salt as claimed in any one of claims 1 to 51, or a pharmaceutical composition as claimed in claim 54, for the manufacture of a medicament for the treatment and/or prevention of one or more conditions or disorders, which are diseases for which modulation, activation, agonism, inhibition or antagonism of a selective sphingosine-1-phosphate receptor is medically indicated.

A method of treating and/or preventing one or more conditions or disorders which are medically indicated for modulation, activation, agonism, inhibition or antagonism of the selective sphingosine-1-phosphate receptor, including but not limited to multiple sclerosis, ulcerative colitis, arthritis, transplant rejection or adult respiratory distress syndrome, comprising administering to a patient in need thereof one or more of the crystalline forms of the ozantinode addition salt of any of claims 1 to 51, or the pharmaceutical composition of claim 54 or 55, in an amount effective for the treatment and/or prevention of the disease.