Study Of Polymorphs And Different Amorphous Forms Of M-nisoldipine

M-nisoldipine, a new dihydropyridine calcium channel antagonists, ismainly used in the treatment of hypertension and heart disease. Twocrystalline froms with different colors were observed in the synthesis process.In present study, various spectral characteristics, stability, solubility andthermodynamic parametes of transformation of the two polymorphs wereinvestigated. Furthermore, two amorphous froms were prepared using twocrystalline. The physicochemical properties of the two amorphous forms,including glass transition temperature(Tg), solubility, dissolution rate, andtransformation rule from amorphous form to crystalline form, wereinvestigated. The results can provide a guide to screen the advantage solidform of m-Nisoldipine and to control the quality of production.Part one The study of m-nisoldipine polymorphsObjective: To Investigate the physicochemical properties ofm-nisodipine and identify the crystal phase of m-nisoldipine polymorphs. Thesolubility of the two polymorphs under different conditions was also examined.The curves of solubility-temperature were obtained, which were used tocalculate the thermodynamic parameters of transform reaction, and theθ A,BΔG,θA,BΔH andθA,BΔS of crystal phase transition. The crystal phase transition underdifferent condition and the thermal stability of polymorphs A and B wereinvestigated.Methods: Identifications of m-inisoldipine polymorphs A and B wereperformed using Differential scanning calorimetry(DSC), infraredspectroscopy(IR), Raman, Terahertz spectroscopy(THz) and x-ray diffraction(XRD). The concentration of m-inisoldipine was determined by ultravioletspectrophotometry. In order to investigate the thermal stability of polymorphsA and B, the two polymorphs were subject to DSC determination at differentscanning speed. The crystal phase transition of polymorphs was analyzed useXRD at solid grind condition.Results: The melting points of polymorphs A and B were 136℃, 128℃,respectively. Theθ A,BΔG,θA,BΔH andθA,BΔS of crystal phase transition at 47℃in water medium were-2.45 k J·mol-1,-35.74 k J·mol-1 and-111.7J·mol-1·K-1,respectively, while those at 48.8℃ in 20% ethanol medium were0.008 k J·mol-1, 16.43 k J·mol-1 and 51.03J·mol-1·K-1. The solubility of the twocrystalline had no difference in 40% ethanol and 60% ethanol(P > 0.05).Polymorph A had higher solubility than that of B in anhydrous ehanol(P<0.05). The active energies of de-compound of polymorphs A and B at hightemperature were 109.0k J·mol-1 and 58.82 k J·mol-1, respectively. The patternsof XRD of polymorphs A and B did not change after grinding and hightemperature.Conclusion: There were some differences in diffraction peaks in XRDpatterns and vibration peaks in IR, Raman, THz spectra between polymorphsA and B. The results showed that the activation energies of de-compound ofpolymorphs A was higher than polymorphs B. Furthermore, the crystal phasetransition of polymorphs was not found under solid grinding condition andhigh temperature. The thermodynamic stability of polymorphs A and B weredifferent in different solvent.Part two The study of different amorphous forms of m-nisoldipineObjective: To prepare two amorphous forms, amorphous A and B, ofm-nisodipine from polymorphs A and B by melt quenching method. Toinvestigate the physicochemical properties of the amorphous forms and toevaluate the differences between crystalline and amorphous form, andbetween amorphous A and B. The solubility of the amorphous and crystallineforms at different temperature were determined; the values were used tocalculate the thermodynamic parameters and to explore the transform rule oftransform process. The physicochemical properties including glass transitiontemperature, solubility, dissolution rate and hygroscopic were investigated.Methods: Amorphous A and amorphous B were prepared by meltquenching method from the crystalline forms A and B. Infrared spectroscopy(FTIR), Raman spectroscopy(Raman), x-ray powder diffraction(XRD),terahertz(THz) technology were used to characterize the crystalline andamorphous state and to evaluate the conversion process of amorphous forms tocrystalline forms. The glass transition temperature(Tg) of the amorphousforms were determined using differential scanning calorimetry(DSC). Theconcentration of m-nisoldipine was determined by ultravioletspectrophotometry; the curves of solubility-temperature were drawn andused to calculate the thermodynamic parameters. The hygroscopic curves ofamorphous and crystalline forms were drawn by the USP method.Results: There is no difference in variety of patterns between amorphousA and amorphous B. However, amorphous forms had different spectracharacter with crystaline forms. The differences in the IR spectra betweenamorphous and crystaline forms indicated the increasing of molecular freedomand the strength of intramolecular hydrogen. Amorphous forms had a highersolubility and dissolution than that of the crystaline forms in 20% ethal and thedisssolution medium. The Tg of the amorphous forms is 23.15℃. AmorphousA and amorphous B had different solubility in 20% ethal and the disssolutionmedium(P<0.05); amorphous A had higher solubility than that of amorphousB. The transition temperatures from amorphous A to crystalline A andamorphous B to crystalline B were-1.7 ℃ and-46.4 ℃, respectively. Thetransformation of the two amorphous forms occures at 32.3℃. In solid state,the two amorphous forms transformed to the crystalline A. Crystaline A and Bof m-nisoldipine were nonhygroscopic, undergoing a weight gain of less than0.09%, however amorphous forms were hygroscopic, undergoing a weightgain about 0.6% in 20℃、75% humidity.Conclusion: Amorphous forms can be formed by melt quenched. TheXRD pattern can be used to characterize the formation of amorphous.Compared with the crystalline forms, amorphous forms had higher solubility,dissolution and hygroscopic. Amorphous A and amorphous B had differentsolubility and dissolution rate. Furthermore, the freshly prepared amorphous(Amorphous A0) and the amorphous form placed for 24h(Amorphous A24)had difference in dissolution rate and hygroscopic. Amorphous forms were notstable forms and transformed into stable crystalline A.